Handbook of Ionic Liquids: Fundamentals, Applications and Sustainability 9783527350667

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Handbook of Ionic Liquids

Handbook of Ionic Liquids Fundamentals, Applications, and Sustainability

Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma

Editors Dr. Sanchayita Rajkhowa

Department of Chemistry Haflong Govt. College Dima Hasao, Assam India

All books published by WILEY-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Dr. Pardeep Singh

Department of environmental studies PGDAV College University of Delhi New Delhi India

Library of Congress Card No.: applied for

Dr. Anik Sen

Bibliographic information published by the Deutsche Nationalbibliothek

Department of Chemistry GITAM (Deemed to be University) Visakhapatnam, Andhra Pradesh India Dr. Jyotirmoy Sarma

Department of Chemistry GITAM (Deemed to be University) Visakhapatnam, Andhra Pradesh India Cover: © qimono/Pixabay

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The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2024 WILEY-VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-35066-7 ePDF ISBN: 978-3-527-83950-6 ePub ISBN: 978-3-527-83951-3 oBook ISBN: 978-3-527-83952-0 Typesetting

Straive, Chennai, India

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Contents Preface xvii 1 1.1 1.2 1.3 1.4 1.5 1.5.1 1.5.2 1.5.3 1.6 1.6.1 1.6.2 1.6.3 1.6.4 1.6.5 1.6.6 1.6.7 1.6.8 1.6.9 1.6.10 1.6.11 1.6.12 1.6.13 1.7 1.8 1.9

History and Development of Ionic Liquids 1 Sumana Brahma and Ramesh L. Gardas Introduction 1 Constituents of ILs 2 The Brief History 3 Ionic Liquid-Like Systems 6 The Generation of ILs 6 First-Generation ILs 7 Second-Generation ILs 7 Third-Generation ILs 8 Structural Development of ILs 9 Task-Specific ILs (TSILs) 9 Chiral ILs 10 Switchable Polarity Solvent ILs 11 Bio-ILs 11 Poly-ILs 12 Energetic ILs 13 Metallic ILs 14 PILs 15 Acidic ILs 15 Basic ILs 15 Neutral ILs 16 Supported ILs 16 Magnetic ILs 16 Scope of ILs 17 Commercialization of ILs 18 Conclusions 20 Acknowledgments 21 References 21

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2 2.1 2.1.1 2.1.2 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.3 2.3.1 2.3.1.1 2.3.1.2 2.3.1.3 2.3.2 2.3.2.1 2.3.2.2 2.3.2.3 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.4

3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.2.7 3.2.8 3.2.9 3.2.10 3.2.11

Growth of Ionic Liquids and their Applications 29 Sudakhina Saikia, Himadri Borah, Pangkita Deka, and Rekha R. Dutta Introduction 29 Cations 30 Anions 30 Growth of Ionic Liquids 30 Quaternization 30 Anion Exchange 32 Acid–Base Neutralization 32 Direct Combination 33 Microwave-Assisted Synthesis 33 Ultrasound-Assisted Synthesis 33 Applications of Ionic Liquids 33 Electrochemistry 33 Electrodeposition 34 Electrosynthesis 34 Electrocatalysis 34 Solvents and Catalysis 35 Ionic Liquids as Solvents for Organic Synthesis 35 Ionic Liquids as Solvents for Inorganic Synthesis 37 Ionic Liquids as Catalysts for Organic Reactions 38 Separation 41 Heat Transport and Storage 41 Analytics 42 Engineering 42 Performance Additives 43 Biotechnology 43 Conclusion and Future Prospects 44 References 44 Study of Physicochemical Properties of Ionic Liquids 51 Tridib Mondal and Palas Samanta Introduction 51 Physicochemical Properties of Ionic Liquids 52 Density 52 Melting Point 53 Thermal Stability and Decomposition 56 Conductivity 56 Solubility 58 Surface Tension 58 Viscosity 59 Polarity 60 Diffusion 60 Vapor Pressure 61 Miscibility 61

Contents

3.3

Conclusion and Perspectives 62 Acknowledgments 62 References 62

4

Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable? 69 Helen Treasa Mathew, Kumar Abhisek, Shashikant Shivaji Vhatkar, Arvind Kumar, and Ramesh Oraon Introduction 69 Toxicity and Biodegradability of Ionic Liquids 71 Toxicological Effects and Toxicity Mechanisms of ILs 71 Scope of Biodegradable and Nontoxic ILs 76 Applications of Ionic Liquids as Green Solvents 78 Ionic Liquids as Green Solvents in Biomass Utilization and Extraction 78 Ionic Liquids as Green Solvents in Energy Applications 80 Ionic Liquids as Green Solvents in Biomedical Applications 81 IoNanofluids 82 Properties of INFs 82 Applications of INFs 85 Are IoNanofluids Nontoxic and Biodegradable? 86 Conclusion 88 References 88

4.1 4.2 4.2.1 4.2.2 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.4.2 4.4.3 4.5

5

5.1 5.2 5.2.1 5.2.1.1 5.2.1.2 5.2.1.3 5.2.1.4 5.2.1.5 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6 5.2.7 5.3 5.3.1 5.3.2 5.3.3

Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations 97 Sudeshna Kalita and Anup Singhania Introduction 97 Carbon—Carbon Bond Formation Reactions 98 C—C Cross-Coupling Reactions 98 Heck Coupling 98 Suzuki Coupling 103 Sonogashira Coupling 106 Stille Coupling 109 Hiyama Coupling 109 Aldol Condensation 111 Claisen–Schmidt Condensation Reaction 113 Friedel–Crafts Alkylation 114 Diel–Alder Reaction 114 Henry Reactions 115 Other C—C Bond Formation Reaction 116 Carbon—Nitrogen Bond Formation Reaction 117 Biginelli Reaction 117 N-Allylation Reactions 120 Mannich Reaction 121

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5.3.4 5.4

Other C—N Bond Formation Reactions 123 Conclusion 131 References 131

6

Ionic Liquids in Separation Techniques 141 Hailu Demissie, Fidelis O. Ajibade, Eden Mulu, Jean J.R. Kinhoun, Temitope F. Ajibade, Kayode H. Lasisi, Nathaniel A. Nwogwu, and Daniel A. Ayejoto Introduction 141 General Characteristics of ILs 143 The Use of ILs in Separation Technology 145 IL-Based Solid–Liquid Extractions 145 Simple SLEs 146 Microwave-Assisted Extractions 147 Ultrasound-Assisted Extractions 147 Liquid–Liquid Extraction 148 ILs as Mobile Phase Additives in Liquid Chromatography 149 ILs Used as Surface-Bonded Stationary Phases 151 Conclusions and Future Perspectives 153 References 153

6.1 6.2 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 6.3.6 6.3.7 6.4

7

7.1 7.2 7.3 7.4 7.5

8

8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.3 8.3.1 8.3.2 8.3.3

Polymers and Ionic Liquids 161 Hailu Demissie, Fidelis O. Ajibade, Jean J. R. Kinhoun, Eden Mulu, Temitope F. Ajibade, Ehiaghe A. Elimian, Bashir Adelodun, Pankaj Kumar, and Oluwaseyi A. Ajala Introduction 161 Properties of ILs 163 Synthesis of PILs 166 Types and Application of Common PILs 167 Conclusion 167 References 172 Effect of Ionic Liquids on Electrochemical Biosensors and Other Bioelectrochemical Devices 179 Himadri Borah, Upakul Dutta, and Rekha R. Dutta Introduction 179 The Importance of Ionic Liquids in Electrochemistry 181 Larger Electrochemical Window 181 Ionic Conductivity 182 Hydrophobicity 183 Viscosity 183 Catalytic Performance 184 Fabrication of IL-Based Sensing Layers 184 Direct Mixing 184 Physical Adsorption 185 Casting and Rubbing 185

Contents

8.3.4 8.3.5 8.3.6 8.3.7 8.4 8.4.1 8.4.1.1 8.4.1.2 8.4.1.3 8.4.1.4 8.4.1.5 8.5 8.6

9

9.1 9.2 9.3 9.4 9.5 9.6

10 10.1 10.2 10.3 10.4 10.5

11

11.1 11.2 11.3 11.3.1 11.3.2 11.3.3

Electrodeposition 185 Sol–Gel Encapsulation 185 Layer-by-Layer (LbL) Method 186 Sandwich-Type Immunoassay 186 IL-Based Electrochemical Biosensors 186 Application of RTILs in Construction of Electrochemical Biosensors 187 CNMs-ILs-Based Electrochemical Biosensor as Cancer Biomarker CNMs-ILs-Based Electrochemical Biosensor for Cardiac Diseases CNMs-ILs-Based Electrochemical Biosensor for Immunoglobulins CNMs-ILs-Based Electrochemical Biosensor for Neurotransmitters CNMs-ILs-Based Electrochemical Glucose Biosensors 191 Application of Ionic Liquids in Bioelectrochemical Devices 191 Conclusions and Future Prospects 191 References 192

189 190 190 190

Nanopharmaceuticals With Ionic Liquids: A Novel Approach 195 Bharadwaj Ittishree, Lipeeka Rout, Vinod Kashyap, and Rahul Sharma Introduction 195 Applications of Ionic Liquids in Various Fields 196 Nanotechnology and Ionic Liquids 197 Use of Ionic Liquids in Nanocarrier Development (Reported Work) 198 Ionic Liquid-Assisted Metal Nanoparticles 198 Conclusion 201 References 201 Anticancer Activity of Ionic Liquids 203 Atrayee Banaspati and Nirupamjit Sarmah Introduction 203 Classification of Ionic Liquids 205 Toxicity of Ionic Liquids 207 Anticancer Potential of Ionic Liquids 209 Conclusions and Future Scope 213 References 214 Importance of Ionic Liquids in Plant Defense: A Novel Approach 221 Mamun Mandal and Abhijit Sarkar Introduction 221 Generation of ILs and Their Application 222 Role of ILs in Plant Defense Mechanisms 224 ILs as Antibacterial Agents 224 ILs as Antifungal Agents 225 ILs as an Herbicide and Plant Growth Promoters 226

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11.3.4 11.3.5 11.3.6 11.4 11.5

12

12.1 12.2 12.2.1 12.2.2 12.3 12.4 12.4.1 12.4.2 12.5 12.5.1 12.5.2 12.5.3 12.6 12.7

13

13.1 13.2 13.3 13.3.1 13.3.2 13.4 13.4.1

14

14.1 14.2

Effects of ILs as Deterrents 227 Application of ILs as Bioactive Formulations 228 Role of ILs in SAR Induction Mechanism 228 IL Products in Future Management of Agri Industries: An Innovative Approach 229 Conclusions 230 References 230 Theoretical Description of Ionic Liquids 235 Daniel A. Ayetoro, Nathaniel A. Nwogwu, Kelechi E. Igwe, Ehiaghe A. Elimian, Hailu Demissie, Temitope F. Ajibade, Abdulhamid Yusuf, Kayode H. Lasisi, Pankaj Kumar, Bashir Adelodun, and Fidelis O. Ajibade Introduction 235 Ionic Liquid Dynamics 237 Self-Diffusion 237 Viscosity 238 Theoretical Advances in Force Fields and Electronic Structures 239 Mixtures in Ionic Liquids 241 Ionic Liquids and Interfaces 241 Ionic Liquids and Water 243 Applications of Ionic Liquids in Chemical Processes 245 Preamble 245 Separation and Purification 245 Reaction Media in Chemical and Biochemical Catalysis 245 Future Developments 247 Conclusion 248 References 248 Theoretical Understanding of Ionic Liquid Advancements in the Field of Medicine 255 Mrinal K. Si Introduction 255 A Brief History of Ionic Liquids and Deep Eutectic Solvents 257 Biomedical Applications 257 Solubilization of Drugs 257 Protein Stabilization 258 Summary and Future Aspects 260 Developing a Microscopic Understanding to Enable Task-Specific Design 260 References 260 Recent Developments in Ionic Liquid Research from Environmental Perspectives 265 Prarthana Bora and Swapnali Hazarika Introduction 265 Applications of Ionic Liquids 267

Contents

14.2.1 14.2.2 14.2.3 14.2.3.1 14.2.3.2 14.2.3.3 14.2.3.4 14.2.4 14.2.5 14.2.6 14.2.7 14.2.8 14.2.9 14.2.10 14.3 14.4

Ionic Liquids as Solvents and Catalysts 267 Ionic Liquids in Analytical Chemistry 268 Ionic Liquids in Electrochemical Applications 270 In Electrodeposition 270 Energy Management 270 Bioscience 271 Biomechanics 271 Ionic Liquids in Industrial Applications 272 Ionic Liquid as Lubricants 273 Ionic Liquids as a Corrosion Resistant Material 274 Ionic Liquids as Additives in Drilling Fluid 275 Ionic Liquids as Absorbents in Gas Capturing 276 Ionic Liquid Crystals 277 Ionic Liquids in Biomedical Applications 278 Limitations of Ionic Liquids 278 Conclusion 279 References 280

15

Ionic Liquids for Sustainable Biomass Conversion in Biorefinery 283 Rakesh Dutta and Khemnath Patir Introduction 283 Biomass as a Source of Organic Compounds and Fuels 284 Biomass Conversion Process 285 Thermochemical Process 285 Lignin Extraction Processes 285 Enzymatic Processes 286 Value-Added Organic Compounds from Biomass in Ionic Liquids 286 Production of Biodiesel with Ionic Liquids 291 Toxicity and Ecotoxicity of ILs for Biorefinery 292 Toxicity of ILs Used in Biorefinery 293 Biodegradation of ILs Used in Biorefinery 293 Conclusion Regarding Toxicity and Biodegradation of ILs 294 Conclusions 295 References 295

15.1 15.2 15.3 15.3.1 15.3.2 15.3.3 15.4 15.5 15.6 15.6.1 15.6.2 15.6.3 15.7

16

16.1 16.2 16.2.1 16.2.2 16.2.3

Ionic Liquids for Atmospheric CO2 Capture: A Techno-Economic Assessment 301 Kumar Abhisek, Helen T. Mathew, Shashikant S. Vhatkar, Dipti S. Srivastava, Rahul Minz, and Ramesh Oraon Introduction 301 Different Processes of CO2 Capture 303 Membrane Separation 304 Cryogenic Separation 305 Absorption 306

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16.2.3.1 16.2.3.2 16.2.3.3 16.2.4 16.2.5 16.3

Chemical Absorption 306 Physical Absorption 311 Ionic Liquids for Physical Absorption of CO2 313 Adsorption 314 Ionic Liquids as a Catalyst for Chemical Fixation of CO2 Conclusion 316 References 317

17

Recovery of Biobutanol Using Ionic Liquids 333 Kalyani Motghare, Diwakar Shende, Dharam Pal, and Kailas L. Wasewar Introduction 333 Biofuel 333 Classification of Biofuels 333 First Generation 333 Second Generation 334 Third Generation 334 Fourth Generation 334 Biobutanol: First-Generation Biofuels 335 Butanol Production 335 Butanol Production via Biochemical Conversion 335 Butanol Production via Petrochemical Conversion 336 Butanol Recovery 337 Butanol Recovery Techniques 337 Distillation 337 Liquid–Liquid Extraction 337 Pervaporation 338 Gas Stripping 338 Perstraction 338 Adsorption 339 Ionic Liquids 339 Ionic Liquids: A Brief History 339 Production of Ionic Liquids 341 Applications of Ionic Liquids 341 Recovery of Biobutanol Using Ionic Liquids 343 World Butanol Demand 344 Conclusion 345 Acknowledgments 346 References 346

17.1 17.1.1 17.1.2 17.1.2.1 17.1.2.2 17.1.2.3 17.1.2.4 17.2 17.3 17.3.1 17.3.2 17.4 17.4.1 17.4.1.1 17.4.1.2 17.4.1.3 17.4.1.4 17.4.1.5 17.4.1.6 17.5 17.5.1 17.5.2 17.5.3 17.6 17.7 17.8

18 18.1 18.1.1

Bio-Carboxylic Acid Separation by Ionic Liquids 353 Anuj Kumar, F.M. Antony, D.Z. Shende, and K.L. Wasewar Introduction 353 Applications of Bio-Carboxylic Acids 353

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Contents

18.1.2 18.1.3 18.2 18.3 18.4 18.4.1 18.4.2 18.4.3 18.4.4 18.4.5 18.5 18.6

19

19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9

20

20.1 20.1.1 20.1.2 20.1.3 20.2 20.2.1 20.2.2 20.2.3

Market of Bio-Carboxylic Acids 354 Production of Bio-Carboxylic Acids 354 Ionic Liquids 355 Challenges in the Separation of Bio-Carboxylic Acids 357 Methods for Separating Bio-Carboxylic Acids 357 Distillation 357 Evaporation 359 Adsorption 359 Membrane Extraction 359 Solvent Extraction 360 Separation of Bio-Carboxylic Acids by the Reactive Extraction Process 360 Conclusion and Perspectives 364 References 364 Current Trends in QSAR and Machine Learning Models of Ionic Liquids: Efficient Tools for Designing Environmentally Safe Solvents for the Future 369 Supratik Kar and Jerzy Leszczynski Ionic Liquids and Their Structural Characteristics 369 Properties of ILs 372 Application of ILs 372 Do ILs Follow Green Chemistry Principles and Are Hazard Free for Environment? 375 Regulatory Proposals for Toxicity Assessment of ILs 376 Why In Silico Modeling Is Needed for ILs 377 Predictive Toxicity Models for ILs 378 Databases of Ionic Liquid 380 Overview and Future Avenues 388 Declaration of Competing Interest 389 Acknowledgments 389 References 389 Advances in Simulation Research on Ionic Liquid Electrolytes 395 Huo Feng and Yue Bowen Simulation Method of Ionic Liquid Electrolytes 396 Density Functional Theory 396 Ab Initio Molecular Dynamics Simulation 399 Molecular Dynamics Simulation 402 Advances in Simulation of Ionic Liquid Electrolytes in Batteries 403 Ionic Liquids Are Used as Solvents in Electrolytes 403 Ionic Liquids Are Used as Salts in Electrolytes 407 Ionic Liquids Are Used as Additives in Electrolytes 407

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20.3 20.3.1 20.3.2 20.4

21 21.1 21.2 21.3

22 22.1 22.2 22.3 22.4 22.5

23

23.1 23.2 23.2.1 23.2.2 23.2.3 23.2.4 23.2.5 23.3 23.4 23.5 23.5.1 23.5.2 23.6

Advances in Simulation of Ionic Liquid Electrolytes in Capacitors 408 Simulation of Ionic Liquid Electrolytes in Flat-Electrode Capacitor 409 Simulation of Ionic Liquid Electrolytes in Porous Electrode Capacitor 410 Conclusion 413 References 414 Applications of Ionic Liquids in Heterocyclic Chemistry 419 Suresh Rajamanickam and Binoyargha Dam Introduction 419 Application of Ionic Liquids in the Syntheses of Various Heterocycles 421 Conclusion and Future Prospective 440 References 440 Application of Ionic Liquids in Drug Development 443 Partha Dutta, Charu Arora, and Sanju Soni Introduction 443 Classification of Ionic Liquids 444 General Synthetic Methodologies 444 An Overview of Applications in Diverse Fields 445 Specific Applications in the Field of Pharmaceutical Development 447 References 451 Application of Ionic Liquids in Biocatalysis and Biotechnology 459 Ehiaghe Agbovhimen Elimian, Fidelis Odedishemi Ajibade, Temitope Fausat Ajibade, Hailu Demissie, Nathaniel Azubuike Nwogwu, Kayode Hassan Lasisi, Daniel A. Ayetoro, and Ehizonomhen Solomon Okonofua Introduction 460 Properties of Ionic Liquids 460 Hydrophobicity 461 Polarity 461 Purity 461 Miscibility of Ionic Liquids 462 Viscosity 462 Whole-Cell Biotransformations 464 Ionic Liquids as Solvents for Enzyme Catalysis 467 Enzyme Selectivity in Ionic Liquids 469 Enantioselectivity 469 Regioselectivity 470 Ionic Liquid Stability of Enzymes 470

Contents

23.7 23.8 23.9

Application of Ionic Liquids in Bioethanol Production 471 Ionic Liquids Applied in the Synthesis of Biodiesel 475 Conclusion 479 References 479 Index 489

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Preface Almost every “new” discovery was preceded not only by earlier work upon which you based your research but also by developments you wish you had been aware of before you got started. The roots of ionic liquids (ILs) go back to alchemists’ studies on molten nitrates and ammonium salts, although they are in unorganized fashion over a century ago. It was followed by the systematic study, which began with Humphry Davy’s pioneering work on the electrolytic decomposition of simple molten salts under the influence of an applied DC electric field, to produce the elements that initially had been chemically combined in the salt form. Davy was the first person to work with high-melting simple salts for scientific research. Later, it is known that the Nobel Prize–winning physicist Sir William Ramsay worked with ILs at an ambient temperature called “syrupy ionic liquids” that he prepared by combining acids with picoline. Nevertheless, the independent work on molten salts can be rooted back to 1914 when Paul Walden discovered ethylammonium nitrate, [EtNH3 ][NO3 ] that has a melting point of 12 ∘ C. Almost 40 years later, Hurley and Weir (1951) made a solution by mixing alkylpyridinium halides with “true inorganic salts” from which the metals could be electroplated. The electrodeposition of metals is still a burning topic in the field of IL research. With the discovery of room temperature ILs (RTILs), it gained a wider attention from researchers with different academic backgrounds by the late twentieth century. Another fact for ILs being so popular and studied lies with its environmentally benign nature, although some groups deny this fact for several ILs. Whatever one’s stance in this debate, there is no doubt about the application of ILs to “clean” and/or “green” technologies, particularly the growing green chemistry movement in so much so that at one point the RSC journal Green Chemistry was forced to limit the papers about ILs that it would accept. As this field has grown extensively over the years, it is often noticed that researchers are more focused on one or two applications of ILs along with their physical properties in present times. The idea of publishing a book on ILs was conceived a couple of years back as I was going through one of my old pieces of work and looking for its future aspects. During that time, I realized that this field has enormous potential mainly due to its peculiar properties, such as the absence of flammability and good ability to dissolve organic, organometallic, and even some inorganic compounds. ILs offer numerous advantages over conventional organic solvents for carrying out organic

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Preface

reactions, such as easier product recovery, recyclable catalysts, and reusable ILs. In addition, ILs exhibit distinct thermodynamic and kinetic behaviors. Rates of reaction are often enhanced, and selectivity is frequently better. I discussed this topic with Dr. Jyotirmoy Sarma and Dr. Pardeep Singh to have their views on the relevance of the topic with current research trends. Dr. Sarma remarked on the chemical applications of ILs, while Dr. Singh offered some insights on the environmental sustainability and green chemistry aspects of the same. Dr. Anik Sen, with his profound theoretical and experimental knowledge, has suggested including recent theoretical studies on this field in order to provide readers with a substantial understanding of ILs. This is how our journey in framing the Handbook of Ionic Liquids: Fundamentals, Applications and Sustainability began. This book emphasizes on the basic concepts of ILs, their properties and applications, their recent advancements in various fields, and their theoretical understanding. Dr. Sanchayita Rajkhowa

1

1 History and Development of Ionic Liquids Sumana Brahma and Ramesh L. Gardas Indian Institute of Technology Madras, Department of Chemistry, IIT P.O., Chennai 600036, India

1.1 Introduction For the past two decades, the term ionic liquid (IL) has been familiar to a very small number of research groups. However, ILs have attracted significant attention as innovative fluids in a wide range of research fields during this period [8, 60]. Generally, ILs are liquids that exist only in ionic form [79]. ILs can be defined as liquids consisting of ions with a melting point ≤100 ∘ C. In another way, ILs, which exist as liquids at or near room temperature, are frequently termed room temperature ionic liquids (RTILs) [54]. In 1914, Paul Walden reported ethylammonium nitrate as the first IL [13]. According to Walden, the liquid, i.e. ethylammonium nitrate, composed of cations and anions and a minimal amount of molecular species, is an IL. Since the nineteenth century, several synonyms and abbreviations have been given to ILs by different research groups. Among the scientific community, the most frequent synonyms of ILs are molten salt, molten organic salt, low-melting salt, fused organic salt, ambient temperature ILs, neoteric solvent, and many more [40]. ILs are associated with unique features such as high ionic conductivity, high viscosity, low volatility, nonflammability, negligible vapor pressure, tunable solubility, and a wide electrochemical potential window [82]. All the mentioned IL properties can be altered by tuning the combination of the cations and anions of the ILs. Hence, ILs can also be termed “designer solvents” [55]. Due to their unique properties, ILs are used in various research applications. A multidisciplinary research on ILs is developing, including materials science, biotechnology, chemical engineering, chemistry, energy field, and atmospheric chemistry. Due to the low-volatile, nonflammable nature of ILs, they are highly preferred over any conventional organic volatile solvents or catalysts in various physical and chemical processes [73]. Furthermore, recently, green technology has been the greatest challenge for researchers concerning environmental hazards. The linkage between ILs and green chemistry is associated with the solvent properties of ILs [17]. ILs are also entitled to green solvents as they possess negligible vapor pressure and high thermal stability, resulting in advantages such as product recovery, desulfurization of liquid fuel, ease Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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1 History and Development of Ionic Liquids

of containment, and recycling capability [42, 51]. ILs never possess the explorer risk compared with volatile organic solvents. In terms of volatility, molecular solvents could not (except molten polymers) reach even near the ILs. ILs can exhibit high polarity. Based on the normalized polarity scale, the polarities of tetramethylsilane and water are 0.0 and 1.0, respectively, whereas the polarity of ILs is usually in the range of 0.6–0.7 [85]. Due to their high polarity, ILs are used as catalysts in various chemical and biochemical reactions. ILs easily dissolve in different solvents, including organic, inorganic, polar and nonpolar, and polymeric compounds. From the chemical engineering perspective, the most critical disadvantage, i.e. gas/liquid–solid mass transfer limitations during catalytic reactions, is resolved using efficient IL catalysts, as reported in detail by Tan et al. [75]. In view of the growing field of renewable energy, it is necessary to replace the conventional volatile electrolytes with green electrolytes in energy storage devices such as batteries, supercapacitors, fuel cells, and dye-sensitized solar cells. [44, 84]. ILs are appropriate in energy storage devices because of their high conductivity, low volatility, nonflammability, and high electrochemical and thermal stability. Imidazole- and pyrrolidinium-based electrolytes have exhibited promising outcomes as electrolytes in lithium-ion batteries and capacitors [14]. However, the investigation and deep learning of ILs as electrolytes for new devices such as hybrid batteries and Al oxygen/ion batteries and for CO2 reduction are in the early stages [53]. Millions of ILs can be synthesized by tuning the combination of cations and anions with desired properties and applications. Based on their properties and applications, ILs can be classified as task-specific ILs, energetic ILs, magnetic ILs, polyionic liquids, and supported ILs. [52]. For a specific process, screening for appropriate ILs is a prerequisite. To identify the structure–performance relationships, it is required to determine the nature of the interactions between cations–cations, anions–anions, and cations–anions of IL species [12]. Therefore, experimental, theoretical, and computational methods are needed to summarize the proper nature of ILs. More profound knowledge of IL nature at the microscopic scale will support the interpretation of macroscopic fluid phenomena and therefore endorse the application of ILs in industry. The multiscale features of ILs extending from the molecular level to the industrial level have been described by Dong and his coworkers [38]. Because of a wide range of applications and prospects of the ILs in the industry, ILs were exclusively named as "solvents of the future" in industrial processes [65]. However, the toxicity of ILs is identified as an emerging limitation for practical applications of ILs. ILs containing high alkyl chain lengths or fluorine anions are more toxic [97]. The toxicity can be affected by changing the structure of ILs . Hence, a detailed toxicity analysis is recommended before real-life applications of ILs. The brief history, development, and future scope are further summarized in the next section.

1.2 Constituents of ILs ILs are usually made up of organic cations and inorganic anions. Generally, nitrogen- (imidazolium, pyrrolidinium, pyridinium, ammonium, choline, etc.) or

1.3 The Brief History

Figure 1.1 Widely studied cations and anions of ionic liquids. R

N

N

N

R R2

R R

R

F B

R3

O O

S

F

R

O

F

F Cl

R4

R

O

Br

N

N

N R

F

R1

F

F P F

O F F

phosphorus-containing cation moieties with linear or branched alkyl chains are used to prepare ILs. The most commonly used anions are halides (Cl− , Br− , I− ), nitrate [NO3 − ], chloroaluminates [AlCl4 − , Al2 Cl7 − ], hexafluorophosphates [PF6 − ], tetrafluoroborate [BF4 − ], alkyl carboxylate [RCOO− ], acetate [CH3 COO− ], trifluoromethylsulfonate [CF3SO3 − ], triflate [OTf− ], and bistriflamide [NTf2 − ]. Recently, amino acids are also used as anions. The most studied cations and anions are shown in Figure 1.1.

1.3 The Brief History There are numerous inceptions to the story of ILs in which they were recognized independently. The reporter’s opinion will essentially influence the history of ILs [88]. The background of the ILs started with the finding of molten liquid salt. In the early 1990s, Paul Walden was searching for liquid molten salt at a particular temperature at which he could have accomplished his experiment. In 1914, Walden discovered ethyl ammonium nitrate [EtNH3 ][NO3 ] with a melting point of 12 ∘ C and termed it the first protic ionic liquid (PIL) [47]. Further, Walden and his coworkers formulated the “Walden rule”, which correlates the equivalent conductivity (𝜆) as well as viscosity (𝜂) of the liquid (aqueous solution). 𝜆𝜂 = Const Later on, the Walden rule could not interpret the properties of low-melting silver salt. Further, the Walden rule was modified to the fractional Walden rule by a group of molten salt chemists from a German school [5]. The fractional Walden rule is as follows: 𝜆𝜂 𝛾 = Const

3

4

1 History and Development of Ionic Liquids

where 𝛾 is a constant 0 < 𝛾 < 1. But after that, there was no potential progress for molten salt studies for a prolonged time. According to the partial Walden rule, the Arrhenius activation energy for conductivity was lower than that for viscosity in the case of a low-melting silver iodide salt. Therefore, the silver iodide salt is a good conductor even in its crystalline state near its melting point temperature. The Walden rule was unable to predict the “superionic” behavior of molten salt, which made Walden rule very useful for the classification of ILs. Furthermore, in the mid-nineteenth century, chemists H observed the so-called “red oil” during Friedel–Crafts reactions. Al2Cl7 The “red oil” was the first documented observation of ILs R [88]. Using nuclear magnetic resonance (NMR) technique, H chemists were able to identify the structure of “red oil,” which Figure 1.2 was the stable intermediate in Friedel–Crafts reactions termed Structure of sigma complex, which was basically heptachlorodialuminate heptachlorodialusalt (Figure 1.2). Prof. Jerry Atwood from the University of minate salt. Missouri termed the structure early IL. Afterwards, ILs started to be used as either catalysts or solvent systems for organic reactions. Their effects on the reaction rates and their antimicrobial activity and toxicity were further premediated. Numerous literature surveys suggested that chloroaluminate molten salts attracted significant attention in the mid-nineteenth century. The research based on chloroaluminate molten salts was mainly conducted by the US Air Force Academy in Colorado Springs. Since the early 1960s, the Air Force Academy has endorsed their research in molten salts/IL systems. The chloroaluminate molten salts were used in various research fields, especially electrochemistry. Hurley and Weir were the first to study the potential benefits of molten salts [40]. They mixed aryl and N-substituted alkyl pyridinium halides with several metal halides and nitrates to achieve low liquids for electrochemical extractions. At room temperature, they discovered the formation of liquid 1-ethylpyridinium bromide-aluminum chloride ([C2 py]BrAlCl3 ). First, they presented a phase diagram for the system, including two eutectics at 1 : 2 at 45 ∘ C and 2 : 1 at −40 ∘ C molar ratios. Bromochloroaluminate was developed at the 1 : 1 M ratio (88 ∘ C). In 1975, Bob Osteryoung and his group further studied [C2 py]BrAlCl3 (2 : 1 M ratio mixture) species for the electrochemical study of ferrocene, ferrous(II) diimine complexes, and hexamethyl benzene [98]. The first paper based on the [C2 py]BrAlCl3 system was published by the Osteryoung group, and the patent was granted by the Air Force Academy. In 1979, Robinson and Osteryoung used 1-butylpyridinium chloride-aluminum chloride ([C4 py]-AlCl3 ) for electrochemistry and Raman spectroscopy [64]. George Parshall and his group synthesized [Et4 N][GeCl3 ] (melting point of 68 ∘ C) and [Et4 N][SnCl3 ] (melting point of 78 ∘ C) and used them as solvents for hydrogenation reactions [21]. Further, he also worked on [Et3 NH][CuCl2 ] to explore different ammonium and phosphonium chlorocuprate systems. Warren Ford worked on alkyl ammonium alkyl borides and found that triethylhexylammonium triethylhexylboride IL is less viscous among all. In 1983, Chuck Hussey and his groups published a review

1.3 The Brief History

article on “Room Temperature Molten Salt Systems”. This review includes the development, properties, and application of chloroaluminate systems [16]. Moreover, in the 1980s, research on ILs was carried out by new researchers like Ken Seddon and Tom Welton. In 1981, Evans et al. [26] started the study on [EtNH3 ][NO3 ]. They investigated the thermodynamic properties of its solutions of krypton, ethane, methane, and n-butane. They mainly studied the “hydrophobic bonding” present in the system [11]. They illustrated that [EtNH3 ][NO3 ] as a nonaqueous solvent could be used in biochemical systems. Colin Poole and his coworkers used [EtNH3 ][NO3 ] as a stationary phase in gas–liquid chromatography [61]. Early in the 1980s, John Wilkes and his coworkers discovered the 1-alkyl-3methylimidazolium chloride-aluminum chloride ([Cn C1 im]Cl-AlCl3 ) IL system and examined the transport properties of the systems. Later on, the introduction of 1-alkyl-3-methylimidazolium cations promoted an argument on the role of hydrogen bonding in the structure of ILs. However, all the controversies were fixed by identifying the imidazolium ring protons, which can act as hydrogen bond donors in the presence of hydrogen bond acceptors. Afterwards, researchers focused on removing chloroaluminate species from IL-chloroaluminate systems. Abdul-Sada and his group worked on that [3]. In the 1990s, extensive research was performed on ILs by many groups worldwide. In 1992, Wilkes et al. first synthesized water- and air-stable 1-ethyl-3methylimidazolium-based ILs [89]. Over the period, several moisture-stable ILs have been synthesized. In 1996, Bonhote et al. synthesized a new class of ILs by introducing [NTf2 ]− anions [9]. This class of ILs is significantly less viscous and highly conductive. Fraser and MacFarlane’s group also introduced a new subclass of ILs based on phosphonium cation [27]. In 1998, ILs became very popular in the scientific community when the journalist Michael Freemantle wrote the first report in Chemical & Engineering News [91]. Based on the application in different research areas, millions of ILs were synthesized by tuning the combination of cations and anions. Therefore, ILs are termed as “designer solvent.” Ken Seddon had carried forward the extensive research on ILs in the Queen’s University Ionic Liquids Laboratory (QUILL). Later, he initiated the collaboration between the academy and industry to explore the industrial applications of ILs. Further, ILs are used as a green solvent in green technologies. In 2000, Robin Rogers led a NATO Advanced Research Workshop on “Green Industrial Applications of Ionic Liquids” in Heraklion [81]. During this time, Jim Davis termed ILs as task-specific ILs. In 1999, Joan Brennecke discovered the first biphasic system combining ILs with supercritical CO2 . Numerous studies were published on CO2 and other gas solubilities in different ILs. Due to negligible vapor pressure and the nonvolatile nature of ILs, researchers have focused on using ILs as lubricants. In 2001, Ye et al. reported the promising performance of ILs as a lubricant for the first time [92]. In 2004, Phillips and Zabinski used ILs as additives for conventional lubricants [59]. The most significant breakthrough in the application of ILs was the utilization of ILs in energy storage devices. ILs can exhibit a wide electrochemical potential window and high conductivity. Therefore, to maximize the energy density of the

5

6

1 History and Development of Ionic Liquids

devices such as lithium-ion batteries, supercapacitors, fuel cells, and dye-sensitized solar cells, ILs are used as electrolytes. Furthermore, ILs are used in separations in analytical chemistry and nuclear chemistry. The first application of ILs at the commercial level was BASF’s BASIL (biphasic acid scavenging utilizing ionic liquids) process. ILs are also a promising candidate for pharmaceutical applications. In 1998, Davis discovered the first IL derivative from the pharmaceutical constituent (API).

1.4 Ionic Liquid-Like Systems During the last century, there was a massive argument on the properties and the characteristic features of molten salt vs. ILs. There was a bit of confusion over which materials should be counted in the IL family and which should be left out. The term IL solely defines a liquid comprised of ions. The restriction is that ILs should be liquid below 100 ∘ C temperature. Tom Welton said, “Room-temperature ionic liquid, non-aqueous ionic liquid, molten salt, liquid organic salt, and fused salt have all been used to describe salts in the liquid phase. With the increase in electronic databases, the use of keywords as search tools is becoming ever more important. While authors are free to choose any name that they wish for their systems, I would suggest that they at least include the term ionic liquid in keyword lists” [86]. However, the system consisting of molecular constituents can also often be termed an IL system. For example, the deep eutectic solvents (DESs) are IL-like systems. The first DESs were discovered by Abbott et al., where choline chloride was mixed with urea (1 : 2 M ratio). Here the formation of ions occurs due to the strong H- bond between the donor molecules and the chloride ion. Therefore, the cation–anion interactions are suppressed, resulting in a low melting point and the system performing like the IL system. Later, based on deep learning, it was found that different types of H-bonds were present in the system. The urea was responsible for creating a H-bonded complexed cation [urea(choline)]+ additional to [Cl(urea)2 ]− ion. In the first paper of Andy Abbott, he termed the system as the DES but not the IL system. Later, another group of materials was included in the IL family, i.e. lithium-glyme-solvated IL system [2]. Here, glyme was added to Li salt to make complex cations [Li(glyme)]+ . Due to the large size of the complex cations, the interactions between the cations and anions are lowered, causing the low melting point of the system. Watanabe et al. first discovered the system and used it in the application of lithium-ion batteries. When 5 M lithium perchlorate-diethyl ether was utilized for organic reaction, it was designated as “fused salt” comprising both [Li(ether)]+ and [Li(ether)2 ]+ ions.

1.5 The Generation of ILs To achieve green technology, it is necessary to replace volatile organic solvents. Hence, instead of volatile organic solvents, researchers have focused on the

1.5 The Generation of ILs

production of IL media for various applications, especially in biocatalytic processes. ILs can resolve the disadvantages of organic solvents, such as high volatility, high flammability, and low thermal and chemical stability. Therefore, ILs have recently been used as solvents in various applications, from biology to electrochemistry. But still, ILs are associated with certain drawbacks in terms of their toxicity and biodegradability [77]. Several recent reports stated that the ILs, including alkylmethylimidazolium cations, primarily used in biocatalysis, are ecotoxic, and the ecotoxicity escalates with the alkyl chain length of the cations. Hence, those ILs cannot be termed “green solvents.” Concerning environmental hazards and health and safety issues, it is essential to synthesize less toxic, biodegradable ILs. Presently, three different generations of ILs can be classified, as illustrated below and represented in Figure 1.3. ILs can be categorized into three distinct generations based on their toxicity [99].

1.5.1

First-Generation ILs

As stated before, the first known IL was ethylammonium nitrate, as reported by Walden. Afterwards, several ILs were synthesized with different combinations of cations and anions. In the 1980s, Wilkes et al. started the vast research on first-generation ILs [100]. These ILs are associated with cations such as alkylpyridinium, alkylimidazolium, and dialkylimidazolium. In the case of anions, chloroaluminate and metal halides are mainly used. But those anions are highly reactive with water and air. Those ILs are not appropriate for biotransformations. Due to their high hygroscopic nature, the first-generation ILs are always carefully handled under an inert atmosphere. Due to this drawback, the application of the first-generation ILs is very inadequate. Therefore, researchers have further focused on the synthesis of moisture-insensitive ILs.

1.5.2

Second-Generation ILs

The second-generation ILs appeared after a decade. In this category, the chloroaluminate anions are replaced by the anions that are less reactive with air and water, such as Cl− , Br− , I, PF6 − , BF4 − , and C6 H5 COO− . In the case of the selection of cations, ammonium- and phosphonium-based cations are included along with alkylpyridinium, alkylimidazolium, and dialkylimidazolium. The second-generation ILs possess certain properties such as a low melting point, low viscosity, and high solubility. Hence, they hugely succeeded in attracting research interest in several applications in the early 1990s [77]. The maximum number of literature published is in biocatalysis applications. In the early 2000s, the first literature on biocatalysis with ILs media was published. However, second-generation ILs are also toxic, similar to first-generation ILs. Further, the second-generation ILs are very costly. Gorke et al. stated that the high costs were associated with starting materials and final product purification [32]. Therefore, researchers have further focused on synthesizing less toxic, low-cost ILs.

7

8

1 History and Development of Ionic Liquids

Evolution of ionic liquids Cation

Anion New, functionalized ionic liquid material Cation

Anion

Generation 1: ILs with unique tunable physical properties

Physical property

O

+

R1

R1

R4 N R2

R4 P R2

R3

R3

+

- Melting point - Density - Viscosity - Thermal stability - Conductivity - Hydrophobicity - Refractive index

+

+

N

N

+N

R OH

+

N

N

Lower melting point/hydrophobicity

C6H13 +

C6H14 P C14H29 NC C6H14

N –

CN

- Melting point - Density F 3C - Viscosity - Thermal stability NC - Conductivity - Hydrophobicity - Refractive index

O

O

+

N

N

N

CN

N –

S O

High thermal stability/hydrophilicity

FeCl4– O

–

BF4

O O

O

– Cl

N

– Cl

S N S CF3 – O O

Hydrophobicity/lower viscosity +

N

Physical property

O

F3C S N S CF3 – O O

HO S O

–

O

–

O – PF6

O S O– O

– O

Generation 2: ILs with targeted chemical properties combined with chosen physical properties

Chemical property + N

N

OEt

N +

+ N

N

+

N

- Chemical reactivity - High energy density - Electrochemical window - Flammability - Coordination - Solvation - Chiral induction

O

+

N

N N

N

+

N

n

N

SO3H

CN

N

+

NO2

N N

N

Energy density/oxygen balance +

N

N

– Cl

Lower density/solvation

- High energy density - Electrochemical window - Flammability - Oxygen balance - UV blocker - Chiral induction - Solvation

O O O F3C S N S CF3 – OEt O O

+

N

N

N

Chemical property

N

O 2N

N

N

O2N – Cl

OH

N N NC N

N

N–

N

– COO H

CN

–

I – CO Rh I CO

CN

– COO

NO2

N N –

Chiral induction/hydrophobicity

Generation 3: ILs with targeted biological properties combined with chosen physical and chemical properties +

n

N+ n = 14

N+

NH

n

+N

Biological property

n

– COO

N+

n

n=7

O O

Local anesthetic/emollient

O +

+N

O

O

- Antibacterial - Local anesthetic - Anticholinergic - Antifungal

n = 5-15

n

– O3S NH

O

NH

Biological property

n=5-15

Anti-bacterial/UV blocker

NH

n

O O Ph HO Ph

- Emollient - Anti-acne H2N - Antibiotic - Non-steroidal Anti-inflammatory drug (NSAID) - Vitamin

+N

– COO

n=7 n

Lower melting, antibacterial/NSAID

O O O

– COO

O

– COO O

O –O3S

O – S N O

Ph

O NH H S N O

– COO

Figure 1.3 The evolution of the scientific focus on ILs from unique physical through unique chemical and now biological property sets. Source: Hough et al. [99]/Royal Society of Chemistry.

1.5.3

Third-Generation ILs

The third-generation ILs is mainly associated with cations such as choline. Generally, amino acids, alkylphosphates, alkylsulfates, bis(trifluoromethanesulfonyl) amide (TFSI) [(CF3 SO2 )2 N− ], and sugars are used as hydrophobic anions [99]. The choice of cations and anions is based on their being less biodegradable, less toxic, and low cost. The third-generation ILs is also termed as advanced ILs. These ILs

1.6 Structural Development of ILs

are mainly characterized by their biological activity, such as being bacteriostatic, fungicidal, and herbicidal. Their biological activity is generally related to the anion, where the cations are premeditated to enhance their potentiality in various applications. This generation also includes a new class of solvent systems, termed “deep eutectic solvents” [80]. DES are highly water-soluble and more hydrophilic than the second-generation ILs. DESs are not liquids at room temperature. They are basically mixtures of salts such as choline chloride, alcohols, amides, amines, urea, and carboxylic acids. As this generation is new to the research field, very few reports have been published. But due to their low toxicity and low cost, the third-generation ILs will reach the commercial level soon [39].

1.6 Structural Development of ILs Based on the applications, altering the properties of ILs is a prerequisite. The properties of the ILs can be changed by tuning their structures with different combinations of cations and anions. On the basis of cation and anion combinations and their properties, ILs are classified into several categories.

1.6.1

Task-Specific ILs (TSILs)

Theoretically, millions of ILs can be synthesized by switching the combinations of different cations and anions. Davis et al. first established the perception of designing IL, which can interact with a solute in a specific fashion [19]. For the benzoin condensation reaction, Davis et al. showed that thiazolium-based IL could perform as both solvent and catalyst. Further, he introduced the term “task-specific ionic liquids” (TSILs) and described the concept of TSIL in a brief review [18]. He explained how the properties and reactivity of the ILs could be changed by incorporating functional groups into the IL moieties. The TSILs can be defined as ILs with functional groups incorporated covalently into the cations or anions of the ILs. TSILs are also coined as functionalized ILs. Over the last few decades, TSILs have received remarkable consideration owing to their precise properties that can be altered according to the user’s needs by tuning the combination of cations and anions [15]. In the last 15 years, several types of TSILs have been intended to perform specific tasks such as organic synthesis (Michael addition, Heck reaction, Knoevenagel condensation, etc.), nanoparticle synthesis, simulation of chirality, CO2 adsorption, and electrochemical applications. [30, 67]. The first synthesized TSIL is 3-sulfopropyl triphenyl phosphonium p-toluene sulfonate, as shown in Figure 1.4. Lee and his coworkers have reviewed the developments in functionalized imidazolium TSILs [46]. Further, Giernoth et al. have shown the potential of TSILs as a gas reservoir, new magnetic materials in chromatography, and other industrial applications. For example, the imidazolium-cation-based IL, including amine functionality, can form carbamate upon the addition of CO2 [30]. In this chemisorption approach, the maximum uptake of CO2 is 0.5 mol per mole of IL (Scheme 1.1).

9

10

1 History and Development of Ionic Liquids SO3H

Figure 1.4 Structures of 3-sulfopropyl triphenyl phosphonium p-toluene sulfonate. SO3

P

BF4

BF4 NH3

N

N

+ CO2

N

H N

O

N O

Scheme 1.1

Chemisorption of CO2 by a task-specific IL.

However, the synthesis of TSILs is a bit difficult and time-consuming process. The active functional groups present in TSILs are highly reactive toward the wide range of reactants.

1.6.2

Chiral ILs

So far, the RTILs have been used as an alternative to conventional organic solvents for several organic reactions due to their low volatility. The enormous majority of studies associated with RTILs include achiral syntheses [22]. However, there is a rapid growth in literature indicating that chiral ILs have wide applications in the areas of synthesis of chiral compounds, liquid chiral chromatography, liquid crystals, stereoselective polymerization, and NMR chiral discrimination. [71]. In 1996, Herrmann et al. described the synthesis of N-heterocyclic carbenes of the corresponding imidazole moieties and validated their utilization in an asymmetric homogeneous catalysis reaction [7]. However, there was no consequent attention in the case of the solid precursor (the chiral imidazolium chloride salt). In 1997, Howard and his coworkers synthesized homochiral dialkylimidazolium bromide salt as a Lewis acid catalyst for the Diels–Alder reaction. In 1997, Seddon and his coworkers studied 1-butyl-3-methylimidazolium ([BMIM]) lactate as the first chiral IL [25]. This chiral IL was synthesized from [BMIM][Cl] and sodium (S)-2-hydroxypropionate via anion exchange (Scheme 1.2) [7]. The chiral ILs are associated with a chiral center either at the cations or the anions or both within the ILs. These ILs are promoted as catalysts or solvents for the asymmetric synthesis of chiral compounds. The additional benefit of this synthetic

N

N

Cl

H

HO + H3C

C

C

ONa

Acetone

O

Scheme 1.2

Synthesis of [BMIM][lactate].

N

N

H

HO H3C

C

C O

O

1.6 Structural Development of ILs

HO

HO N

HO N

Me2SO4

[CH3SO4]

CH2Cl2

Scheme 1.3

N

Li[(CF3SO2)2N]

[(CF3SO2)2N]

H2O

Chiral ILs derived from the “chiral pool.”

approach is the high yield. The synthesis of chiral ILs is challenging because of their chiral nature. In 2002, Wasserscheid and group described the development of numerous new chiral ILs synthesized directly from the “chiralpool” [83]. For example, chiral hydroxyl ammonium salts were prepared by Scheme 1.3. In 2002, Saigo et al. reported the synthesis method and structure of a novel imidazolium-based IL with planar chirality [43]. In 2003, Bao et al. defined the synthesis of chiral imidazolium ILs from chiral amines (D-a-phenylethylamine) and amino acids (L-alanine, L-valine, and L-leucine) with 30–33% yields [6]. In 2004, Vo Thanh et al. premeditated an effectual procedure for preparing chiral ephedrinium ILs using solvent-free conditions and microwave irradiation [78]. The chiral ILs are used in many organic reactions, such as asymmetric Michael addition, enantioselective hydrogenation reactions, enantioselective photodimerization, Heck reaction, and asymmetric dihydroxylation.

1.6.3

Switchable Polarity Solvent ILs

Switchable ILs are generally derived from alcohols and organic bases [62]. However, their precise solvent structure is still under investigation. They are used in various applications such as gas capture, separations, and nanomaterial synthesis. Predominantly, switchable ILs are green, nonaqueous absorbents for CO2 capture [50]. The improvement of viscosity and regeneration efficiency of switchable ILs is still required. An activator is applied during the synthesis of switchable ILs, which promotes them to equilibrate between very low polarities and high polarities for both anions and cations. Secondary amines are typically used to get switchable ILs by applying CO2 as an activating agent to form the carbamate salt reaction in Eq. (1.1) [57]. +NHR2

+CO2

−−−−−−−− ⇀ −−−−−−−− ⇀ NHR2 + − ↽ −R2 NCOOH− ↽ −[R2 NH2 ][R2 NCOO2 ] Carbmic acid

(1.1)

Carbamate salt

The switchable ILs with high polarity were obtained with 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) and alcohol which switched from lower to higher polarity while activated with CO2 .

1.6.4

Bio-ILs

Imidazolium- and benzimidazolium-based ILs with long alkyl chain lengths are generally toxic, less biodegradable, and also related to other disadvantages.

11

12

1 History and Development of Ionic Liquids

NH(3–n)

NH(4–n)

RCOOH

HO

HO n

RCOO

n n = 1,2,3; R=CH3CH(OH)-

Scheme 1.4

Synthesis of (2-hydroxyethyl)-ammonium lactate-based ILs.

Researchers have started to discover a new class of ILs derived from sustainable bioprecursors to overcome those limitations. Bio-ILs are comparatively less toxic, biodegradable, and biocompatible [31]. As choline is a precursor of the phospholipids that include biological cell membranes, choline is used as a cation to synthesize ILs. The choline-containing ILs are more promising and biocompatible than the other bio-ILs. Apart from choline, 2-hydroxyalkyl-ammonium cation is also used to synthesize bio-ILs (Scheme 1.4). Usually, amino acids and acetic acid are used as counteranions. Scheme 1.4 represents the synthesis. The European Standards methods are used to scrutinize the toxicity and biodegradability of ILs. For example, according to the European Standards, (2-hydroxyethyl)-ammonium lactate was noted to have the highest biodegradable (95%) levels. Choline-based bio-ILs are used for drug delivery, solvents for biopolymers, sensors, and actuators [69].

1.6.5

Poly-ILs

When ILs are incorporated into the polymer chains, they introduce a new class of polymeric materials. Polymerized ILs, termed poly-ILs, are formed by repeating units of each monomer and associated through a polymeric backbone to develop a macromolecular structure [63]. Poly-ILs can be dimers, trimers, or oligomers. Based on the application of poly-ILs, several numbers of poly-ILs can be synthesized by tuning the monomeric unit of ILs with some unique properties [94]. Poly-ILs are usually synthesized by the direct radical polymerization of IL monomers. In the 1970s, Salamone et al. first synthesized poly-ILs with vinyl imidazolium-based ILs [66]. However, the synthesized poly-ILs were not able to attract significant attention at the time. In the late 1990s, Ohno et al. discovered several poly-ILs for the application of solid ion conductor materials [56]. Recently, numerous task-specific poly-ILs have been developed based on their applications. The foremost design efforts toward synthesizing novel poly-ILs are based on vinylimidazolium. Further, poly-ILs with phosphorous-containing cations (PILs) have attracted attention in catalysis and gene delivery applications. Döbbelin and his group discovered new poly(diallyldimethylammonium TFSI) poly-ILs with high ionic conductivities [23]. Apart from the linear poly-ILs, researchers have focused on nonlinear or branched poly-ILs due to their high thermal stability. Poly-ILs are also used as photoresists, corrosion inhibitors, dispersants, and stabilizers. These branched or hyperbranched poly-ILs are used in phase transfer systems. Tang et al. have reported several new

1.6 Structural Development of ILs

Cationic PILs N

N

N

N

N X

X

O

N

N

N X

O X

O P O O

O P HO OH

N

X

N

N

O S HO O

HO

O O O

R= R

N

N N N

X

O

O

N

X

O

O

O O

O O

R=

X N

S

R P 2 X R3 R1 n = alkyl chains

HO

O

9

N H

O

R

Anionic PILs O

O Y CF3 S N S O O OO

Figure 1.5 Elsevier.

O

O

O

Y

Y S N CN O O

O

O

CN S C CN O

Recently reported poly-IL chemical structures. Source: Yuan et al. [95] /

imidazolium- and tetraalkylammonium-based poly-ILs with unique dielectric properties, mainly used as microwave-absorbing materials [76]. Poly-ILs exhibit unique properties such as wide electrochemical potential windows, low glass transition temperatures, and high thermal stability. Hence, poly-ILs have attracted significant attention due to their wide range of applications in various research fields such as electrochemistry, materials science, catalysis, separation studies, and analytical chemistry. In electrochemistry, poly-ILs are used as polyelectrolytes or polyelectrolyte membranes in fuel cells, supercapacitors, lithium-ion batteries, dye-sensitized solar cells, polyelectrolyte membranes, and organic transistor devices. [68]. However, the major drawback of poly-ILs is that the ionic conductivity of poly-ILs is lowered by at least two magnitudes compared to the corresponding IL monomer unit. Figure 1.5 shows the structure of recently reported poly-ILs.

1.6.6

Energetic ILs

In the arena of materials science, energetic ILs are one of the most useful materials. Commonly, energetic materials are compounds that can store large amounts of chemical energy and are able to release the energy under certain conditions such as shock, heat, and friction. Due to global concerns and safety issues, researchers have focused on synthesizing environmentally friendly, green energetic ILs. Hence, a new class of nitrogen-enriched ILs has received significant attention [96]. Energetic

13

14

1 History and Development of Ionic Liquids O

NH N

NO2

O2N

NO2

N

N

N

N N

NO2

NC

Et

C N

NO2

Figure 1.6

Structures of energetic ILs.

ILs, including nitrogen-rich heterocycles such as pyrazole-, triazole-, tetrazole-, and guanidinium-based materials, possess high density, high thermal stability, low vapor pressure, and high heat of formation [58]. In general, bulky anions containing energetic groups (−NO2 , −N3 , −CN, etc.) are used to synthesize energetic ILs. In the earlier 1890s, quaternary ammonium nitrate salts, i.e. hydroxyethylammonium nitrate and ethylammonium nitrate, had been synthesized and defined as energetic ILs. However, for almost 80 years, no further development for energetic ILs was reported. In 1996, Klapötke and his coworkers analyzed the physical and structural properties of hydrazinium azides [45]. In 2001, Drake and his co-workers reported “energetic hydrazinium salts” in a US patent. They have also discovered the potential applications of hydrazinium salts as propellant fuels [24]. Drake and his co-workers further defined some heterocyclic-based salts with NO3 , ClO4 , and N(NO2 ) anions in 2003. The first approach of using dicyanamide-based ILs in propellant formulations was recommended in 2008. Afterwards, a wide range of lanthanide-based energetic ILs such as 4-amino-1-ethyltriazolium, 1,5-diamino-4-methyl tetrazolium, 4-aminotriazolium, guanidinium, and 4-amino-1-butyltriazolium have been synthesized with lanthanide (La, Ce) nitrate ([Ln(NO3 )6 ]3 ) anion [96]. Lanthanide-containing energetic ILs can exhibit good photochemical stability and luminescence properties. The structures of energetic ILs are shown in Figure 1.6.

1.6.7

Metallic ILs

In 1948, Hurley et al. synthesized the first metal-containing IL, or metallic IL, from [EMIM]Cl-AlCl3 system for the application of Al electroplating [41]. Further, in 1972, Parshall et al. used the tetraalkylammonium chlorostannate IL/PtCl2 system as a catalyst in catalytic olefins reactions [101]. In 1986, an acidic [EMIM]Cl-AlCl3 system was used as a catalyst for the Friedel–Crafts reaction [10]. Later, in 1990s, Seddon, Welton, Dupont, and their groups gave significant attention to the ILs and their derivatives, comprising main group metals as well as transition metals. Hence, researchers have focused on synthesizing metal-containing ILs with ammonium, pyrrolidinium, imidazolium, choline, and pyridinium moieties and simple inorganic or halometallate anions for several applications [48]. Shreeve et al. have reported the preparation of ferrocene (Fc)-containing RTIL (Scheme 1.5) [29]. N(Me)3 Fc

I

Imidazole Fc

N

NH

MeI/LiNTf2 Fc

N

N Me NTf2 H

Scheme 1.5

Formation of metal-containing ILs containing ferrocenium.

1.6 Structural Development of ILs

1.6.8

PILs

PILs are a subclass of ILs, in which proton transfer takes place between acids and bases, resulting in the formation of the H-bond between proton donors and an acceptor site. The PILs are closely related to Brønsted acidic ILs. Hence, PILs are used as either solvents/catalysts or both for various organic reactions such as hydrolysis and dehydration. Further, PILs are significantly less viscous and highly conductive, due to which they can also be used as electrolytes in energy storage devices [74]. The ionic conductivities of the PILs increase with decreasing molecular mass. The synthesis of PILs occurs via two steps: the first step includes the formation of zwitterions, and the second step includes the neutralization or synthesis of ILs. PILs are also used in various drug delivery applications.

1.6.9

Acidic ILs

RTILs are also categorized into acidic, basic, and neutral ILs. The acidic ILs are composed of the protic ammonium, pyrrolidinium, and imidazolium cations. The acidic ILs are mainly of two types, i.e. Lewis acidic ILs and Brønsted acidic ILs. The Lewis acidic ILs are synthesized by using ZnCl2 , AlCl3 , pyrrolidinium, pyridinium, and imidazolium salts [4]. Lewis acidic ILs exhibited higher melting points than the analogous chloroaluminate salts; however, they still remain fluids at room temperature. The structures of Lewis acidic ILs are shown in Figure 1.7. The first Brønsted IL (ethanolammonium nitrate) was discovered by Gabriel in 1888 [28]. This Brønsted IL is synthesized by the reaction of equimolar Brønsted acids and Brønsted bases (Scheme 1.6). These Brønsted acidic ILs are used as solvents or catalysts for various organic reactions such as Knoevenagel condensation, alcohol dehydrodimerization, and pinacol rearrangement. [35].

1.6.10 Basic ILs Basic ILs can be formed using basic anions, mainly inorganic bases. For example, acetate, lactate, formate, cyanide, and dicyanamide anion are commonly used basic anions. Subsequently, these basic anions are able to deliver some advantages, such R4

R1 N

R3

N R2 AlCl4

N

N R1

R2 AlCl4

R1

N R2

R2 FeCl 4

R1

FeCl4

R1, R2, R3, R4 = alkyl, allyl, vinyl

Figure 1.7

Structures of Lewis acidic ILs. H

C2H5-NH2 + HNO3

C2H5

N

H NO 3

H

Scheme 1.6 Synthesis of Brønsted acidic ILs with acidic hydrogens on cations by proton transfer from Brønsted acids to Brønsted bases.

15

16

1 History and Development of Ionic Liquids R1

R1 N

N N

R2

N

O

R2

N

O R1

O

N

O R1, R2 = alkyl, allyl, vinyl

Figure 1.8

Structures of basic ILs.

as low viscosity, catalytic properties, and different solubilizing properties [34]. The structures of basic ILs are shown in Figure 1.8. The basic ILs can replace the usual inorganic bases as they are noncorrosive, nonvolatile, and highly soluble with many organic solvents. For instance, basic ILs are used in organic reactions such as aldol condensation, Markovnikov addition, and aza-Michael reactions [90]. Instead of using basic anions, an alternative way to design basic ILs is to incorporate a basic site into the cations. Those ILs are generally more thermally stable ILs than those with basic anions.

1.6.11 Neutral ILs Neutral ILs exhibit weak electrostatic interactions between the cations and anions. Therefore, these ILs are less viscous, possess low melting points, and have high thermal stability. Hence, these neutral ILs are used as inert solvents in a wide range of thermal windows [36]. Generally, the anions such as hexafluorophosphate (PF6 ), TFSI, tetrafluoroborate (BF4 ), methanesulfonate (mesylate), thiocyanate (SCN− ), and p-toluenesulfonate (tosylate) are used to synthesize neutral ILs.

1.6.12 Supported ILs Supported ILs signify a class of materials with typical characteristics and considerable potential concerning their promising applications in various research fields. Supported IL systems are mainly used in catalytic reactions such as hydrogenation, Friedel–Crafts reactions, Heck reactions, and hydroformylations (Rh-catalyzed). The first supported Lewis acidic IL catalysts were discovered in the 1990s.

1.6.13 Magnetic ILs Nowadays, magnetic ILs have attracted extensive attention due to their several applications. The RTILs, which can exhibit paramagnetic properties by themselves without adding any magnetic particles, are defined as magnetic ILs [102]. The paramagnetic properties of magnetic ILs are induced by either cations, anions, or both. Figure 1.9 represents the common cations used to prepare the magnetic ILs. The cations generally used to synthesize magnetic ILs are 1-ethyl-3-methylimidazolium and 1-butyl-3-methylimidazolium. Apart from these imidazole cations with longer alkyl chain lengths, trihexyl(tetradecyl)phosphonium cations are also used to

1.7 Scope of ILs

N

(CH2)5CH3

N N

N

N

(a)

N

H3C(H2C)5

HO

P

(CH2)13CH3

(CH2)5CH3

(b)

(c)

(d)

(e)

Figure 1.9 Common cations in magnetic ILs: (a) [Emim], (b) [Bmim], (c) [P6,6,6,14 ], (d) [choline], and (e) [Aliquat 336].

Cl

Fe

Cl

Cl

Cl Cl

Cl

Mn

Cl

Cl

Co

Cl

Cl

Cl

(a)

(b)

(c)

Figure 1.10 (d) [GdCl6 ].

Cl

Cl Cl

Cl

Gd Cl

Cl Cl

(d)

Common anions in magnetic ILs: (a) [FeCl4 ], (b) [MnCl4 ], (c) [CoCl4 ], and

prepare magnetic ILs [103]. Transition metals or lanthanide complexes are usually utilized as anions to synthesize magnetic ILs. Del Sesto and his coworkers have studied the magnetic ILs with Fe(III), Co(II), Mn(II), and Gd(III) comprising anions [20]. In 2004, 1-butyl-3-methylimidazolium tetrachloroferrate, [Bmim][FeCl4 ], was known as the first magnetic IL, which was synthesized by Hayashi and Hamaguchi [72]. Further, Yoshida and coworkers described the magnetic properties of FeCl4 and FeBr4 , anion-based magnetic ILs [93] (Figure 1.10). The metal-containing magnetic ILs can exhibit the common properties of RTILs, including photophysical properties and potential responses to the external magnetic field. The emissions of magnetic ILs are toxic with respect to human health and environmental hazards. However, their negligible vapor pressure and low flammability decrease air emissions risk. According to literature reviews, the anions containing [FeCl4 ] and [GdCl6 ] are less toxic, whereas [CoCl4 ] and [MnCl4 ] are highly toxic. Magnetic ILs are used in different research areas such as fluid–fluid separations, polymer chemistry, electrochemical and medical devices, and magnetic fluids.

1.7 Scope of ILs Since the last century, the extensive and continuous research on ILs has accelerated the improvement of green and sustainable chemistry. ILs are considered green solvents due to their specific and unique properties. Especially “air- and

17

1 History and Development of Ionic Liquids

Number of publications/patents

18

Patents 9000

Publications

6000

3000

0

2005

2010

2015

2020

Year

Figure 1.11 The number of publications and patents each year from 2001 to 2021. Source: SciFinder - Chemical Abstracts Service (CAS), a division of the American Chemical Society (ACS), Columbus, Ohio, USA; https://scifinder.cas.org (accessed 22 April 2022).

moisture-stable” ILs can replace conventional volatile organic solvents. Furthermore, ILs demonstrate numerous promising approaches in various research fields such as synthesis, biological science, materials science, physical chemistry, nuclear physics, sustainable energy science, heredity, and medicinal chemistry. The application of ILs is enhanced both at the academy and industry levels. According to Welton, the 1990s marked the birth of a new field of ILs [86]. Afterwards, the fundamental and applied research on ILs was exponentially enhanced by the birth of the new area of ILs. More than 90 000 publications have been reported by the scientific community since 1990 [33]. The total number of publications in each year from 2001 to 2021 is presented in Figure 1.11. The interest in industrial applications of ILs further expands the number of patents shown in Figure 1.11. Morton and Hamer from the intellectual property firm Mathys & Squire LLP have reported a remarkable article on the application of ILs. They acknowledged that imidazolium or pyridinium ILs are primarily used in recent patents with different applications. Hence, there is a vast scope to explore the synthesis and properties of new ILs to apply in various research fields.

1.8 Commercialization of ILs The thought that ILs could replace conventional solvents generated a lot of curiosity in academic as well as industrial societies. This replacement is initiated by the EU REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) regulations intended to minimize the environmental hazards and ensure safety. They have listed the hazardous chemicals and started to substitute them with green substances. ILs have been used as alternative solvents, catalysts, or electrolytes in various applications, as shown in Figure 1.12. In the past few years, numerous

1.8 Commercialization of ILs

Catalysis

Solvents

Isomerization

Acid scavenging

Alkylation

Dissolution

Dimerization

Catalyst recovery

Hydroformylation

Separation

Hydrogenation

Thermal fluids

Electrochemistry

Additives Antistatic Dispersing agents Hydraulic fluids Lubricants

Metal plating Batteries Sensors Dye-sensitized solar cell

Analysis

Absorption chillers

Chemistry

GC column stationary phase

Gas capture and storage

SEM visualization

Mercury capture Recycling Materials

Figure 1.12

Design of some well-known applications of ILs.

IL products have been industrialized. In 2008, Plechkova and Seddon published the first review article on the commercial visions of ILs [60]. The latest published book, Commercial Applications of Ionic Liquids, including 57 applications of ILs, has provided a comprehensive perception of various industrial processes [70]. The first reported commercial IL technology was developed by the Texas Eastman Division of Eastman Chemical Company in 1996. A Lewis base IL (tetraalkylphosphonium iodide) was used for the isomerization of 3,4-epoxybut-1-ene to 2,5-dihydrofuran. They manufactured 1400 tonnes of product per year until 2004 and further continued the process in association with Cytec Industries, a major IL manufacturer [33]. Professor Daniel Armstrong, University of Texas at Arlington, has developed moisture dicationic and polycationic ILs for gas chromatography (GC) columns. A range of capillary GC columns is currently available with IL technology. The technique is also utilized to detect water using a thermal conductivity detector (TCD). The columns are now commercially available from Sigma Aldrich. The IL technology is further utilized in several metal processing applications for electrochemical applications, such as Scionix’s chromium electroplating process. DES system with choline chloride and chromium(III) chloride is used for this electroplating process. The use of ILs helped to enhance the current efficiencies (>90%) and minimize corrosion [33]. Further, NOHMs Technologies used ILs as an alternative electrolyte (NanoLyte) in lithium-ion batteries, resulting in 400% additional

19

20

1 History and Development of Ionic Liquids

cycle lifetime [33]. NantEnergy has used ILs in Zn-air batteries. ILs are also commercially used in dye-sensitized solar cells (DSSCs) [33]. For large-scale utilization of ILs, QUILL has collaborated with a Malaysian oil and gas company. They have developed a novel technique to remove mercury from natural gas [1]. For this process, a chlorocuprate(II) IL impregnated on a high surface area support or SILP (supported IL phase) has been used [87]. Furthermore, in 1999, QUILL collaborated with Chevron and started using ILs as alkylation catalysts and established a demonstration unit with ISOALKYTM technology (2010–2015) to optimize reaction conditions. In 2016, Chevron developed a new chloroaluminate IL alkylation catalyst. The China University of Petroleum-Beijing has also commercialized an IL-based alkylation process [37, 49]. The US Department of Defense has started using IL in the “natural fiber welding” process. The method includes ILs, such as [C2 mim][AcO], for processing natural fibers (cellulose, hemicellulose, silk, etc.) to develop a gelatinous network that preserves the inherent polymer structure. The ILs are also used in operating fluids in which ILs act as heat transfer materials or lubricants. Mettop GmbH, in collaboration with Proionic, established a new cooling technology (ILTEC) to permit direct water substitution with an equivalent viscosity IL (IL-B2001), which could offer a higher operating temperature. Further, ILs are also used as additives in a broad range of applications. IoLiTec, a renowned manufacturing company, carried forward their research and further found out the IL performance as additives in different applications such as dispersing agents (commercial), cleaning additives (commercial), and alcohol synthesis (pilot). Furthermore, Institut Français du Pétrole (IFP) developed a homogeneous IL-based catalyst for the dimerization of light alkenes. Therefore, there has been a start-up in utilizing ILs at the commercial level since the last century due to their unique properties. However, ILs have not been commercialized solely because they possess limitations such as high cost, recyclability, and toxicity. ILs are still not “inherently green,” but they can expand the green metrics by constructing more sustainable processes, both economically and environmentally.

1.9 Conclusions This chapter includes a brief history of ILs starting from the first discovery of the IL reported. Over the past 30 years, enormous research has been conducted in this field. To date, plenty of ILs have been synthesized, characterized, and analyzed, and their properties are acknowledged in an acceptable way. The development of ILs on their structure and applications are discussed in this chapter. Further, the growing challenge of the commercialization of ILs is also briefly illustrated. However, many limitations still persist that need to be overcome. ILs should not only be appreciated as a new class of materials, but they should also be elucidated as a perception to consider diversity in chemistry. There is a lot of hope that ILs will become a promising green material for different research fields by resolving certain limitations in their properties.

References

Acknowledgments The authors acknowledge IIT Madras for the financial support through grant number CY/20-21/069/RFIR/008452. The authors thank Prof. Kothandaraman Ramanujam, Department of Chemistry, IIT Madras, for scientific discussions. SB would like to acknowledge IIT Madras for the doctoral fellowship.

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68 Shaplov, A.S., Marcilla, R., and Mecerreyes, D. (2015). Recent advances in innovative polymer electrolytes based on poly(ionic liquid)s. Electrochimica Acta 175: 18–34. https://doi.org/10.1016/j.electacta.2015.03.038. 69 Sharma, M., Mondal, D., Sequeira, R.A. et al. (2021). Syntheses and characterization of few bio-ionic liquids comprising of cholinium cation and plant derived carboxylic acids as anions. Journal of the Indian Chemical Society 98 (11): 100205. https://doi.org/10.1016/j.jics.2021.100205. 70 Shiflett, M.B. (2020). Commercial Applications of Ionic Liquids. Cham: Springer https://doi.org/10.1007/978-3-030-35245-5. 71 Singh, A., Kaur, N., and Kumar Chopra, H. (2019). Chiral recognition methods in analytical chemistry: role of the chiral ionic liquids. Critical Reviews in Analytical Chemistry’, Taylor & Francis 49 (6): 553–569. https://doi.org/10.1080/ 10408347.2019.1565985. 72 Hayashi, S. and Hamaguchi, H.-o. (2004). Discovery of a magnetic ionic liquid [bmim]FeCl4 . Chemistry Letters 33 (12): 1590–1591. https://doi.org/10.1246/cl .2004.1590. 73 Smiglak, M., Reichert, W.M., Holbrey, J.D. et al. (2006). Combustible ionic liquids by design: is laboratory safety another ionic liquid myth? Chemical Communications 24: 2554–2556. https://doi.org/10.1039/b602086k. 74 Stettner, T. and Balducci, A. (2021). Protic ionic liquids in energy storage devices: past, present and future perspective. Energy Storage Materials 40: 402–414. https://doi.org/10.1016/j.ensm.2021.04.036. 75 Tan, J., Ji, Y., Deng, W., and Su, Y. (2021). Process intensification in gas/liquid/solid reaction in trickle bed reactors: a review. Petroleum Science 18 (4): 1203–1218. https://doi.org/10.1016/j.petsci.2021.07.007. 76 Tang, J., Radosz, M., and Shen, Y. (2008). Poly(ionic liquid)s as optically transparent microwave-absorbing materials. Macromolecules 41 (2): 493–496. https:// doi.org/10.1021/ma071762i. 77 Tavares, A.P.M., Rodríguez, O., and Macedo, E.A. (2012). New generations of ionic liquids applied to enzymatic biocatalysis. In: Ionic Liquids—New Aspects for the Future, 537–556. London: IntechOpen https://doi.org/10.5772/51897. 78 Thanh, G.V., Pegot, B., and Loupy, A. (2004). Solvent-free microwave-assisted preparation of chiral ionic liquids from (−)-N-methylephedrine. European Journal of Organic Chemistry 5: 1112–1116. https://doi.org/10.1002/ejoc.200300601. 79 Thuy Pham, T.P., Cho, C.W., and Yun, Y.S. (2010). Environmental fate and toxicity of ionic liquids: a review. Water Research 44 (2): 352–372. https://doi.org/10 .1016/j.watres.2009.09.030. 80 Turguła, A., Ste˛sik, K., Materna, K. et al. (2020). Third-generation ionic liquids with: N-alkylated 1,4-diazabicyclo[2.2.2]octane cations and pelargonate anions. RSC Advances 10 (15): 8653–8663. https://doi.org/10.1039/d0ra00766h. 81 Vishwakarma, S. (2014). Ionic liquids-designer solvents for green chemistry. International Journal of Basic Sciences and Applied Computing (IJBSAC) 1 (1). 82 Wang, X., Chi, Y., and Mu, T. (2014). A review on the transport properties of ionic liquids. Journal of Molecular Liquids. 193: 262–266. https://doi.org/10 .1016/j.molliq.2014.03.011.

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83 Wasserscheid, P., Bösmann, A., and Bolm, C. (2002). Synthesis and properties of ionic liquids derived from the “chiral pool”. Chemical Communications 2 (3): 200–201. https://doi.org/10.1039/b109493a. 84 Watanabe, M., Thomas, M.L., Zhang, S. et al. (2017). Application of ionic liquids to energy storage and conversion materials and devices. Chemical Reviews 117 (10): 7190–7239. https://doi.org/10.1021/acs.chemrev.6b00504. 85 Weiß, N., Gabi Thielemann, G., Nagel, K. et al. (2021). The influence of the cation structure on the basicity-related polarity of ionic liquids. Physical Chemistry Chemical Physics 23 (47): 26750–26760. https://doi.org/10.1039/d1cp03986e. 86 Welton, T. (2018). Ionic liquids: a brief history. Biophysical Reviews. Biophysical Reviews 10 (3): 691–706. https://doi.org/10.1007/s12551-018-0419-2. 87 Werner, S., Szesni, N., Kaiser, M. et al. (2012). A scalable preparation method for silp and scill ionic liquid thin-film materials. Chemical Engineering and Technology 35 (11): 1962–1967. https://doi.org/10.1002/ceat.201200210. 88 Wilkes, J.S. (2002). A short history of ionic liquids—from molten salts to neoteric solvents. Green Chemistry 4 (2): 73–80. https://doi.org/10.1039/b110838g. 89 Wilkes, J.S. and Zaworotko, M.J. (1992). Air and water stable 1-ethyl-3-methylimidazolium based ionic liquids. Journal of the Chemical Society, Chemical Communications 13: 965–967. https://doi.org/10.1039/ C39920000965. 90 Xu, J., Liu, B., Wu, W. et al. (2006). Basic ionic liquid as catalysis and reaction medium: a novel and green protocol for the markovnikov addition of N-heterocycles to vinyl esters, using a task-specific ionic liquid, [bmIm]OH. Journal of Organic Chemistry 7 (10): 3991–3993. 91 Yang, Z. and Pan, W. (2005). Ionic liquids: green solvents for nonaqueous biocatalysis. Enzyme and Microbial Technology 37 (1): 19–28. https://doi.org/10 .1016/j.enzmictec.2005.02.014. 92 Ye, C., Liu, W., Chen, Y., and Yu, L. (2001). Room-temperature ionic liquids: a novel versatile lubricant. Chemical Communications 21: 2244–2245. https://doi .org/10.1039/b106935g. 93 Yoshida, Y. and Gunzi Saito, G. (2006). Influence of structural variations in 1-alkyl-3-methylimidazolium cation and tetrahalogenoferrate(III) anion on the physical properties of the paramagnetic ionic liquids. Journal of Material Chemistry 16: 1254–1262. https://doi.org/10.1039/B515391C. 94 Yuan, J. and Antonietti, M. (2011). Poly(ionic liquid)s: polymers expanding classical property profiles. Polymer 52 (7): 1469–1482. https://doi.org/10.1016/j .polymer.2011.01.043. 95 Yuan, J., Mecerreyes, D., and Antonietti, M. (2013). Poly(ionic liquid)s: an update. Progress in Polymer Science 38 (7): 1009–1036. https://doi.org/10.1016/j .progpolymsci.2013.04.002. 96 Zhang, Q. and Shreeve, J.M. (2014). Energetic ionic liquids as explosives and propellant fuels: a new journey of ionic liquid chemistry. Chemical Reviews 114 (20): 10527–10574. https://doi.org/10.1021/cr500364t. 97 Zhao, D., Liao, Y., and Zhang, Z.D. (2007). Toxicity of ionic liquids. Clean—Soil, Air, Water 35 (1): 42–48. https://doi.org/10.1002/clen.200600015.

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98 Chum, H.L., Koch, V.R., Miller, L.L., and Osteryoung, R.A. (1975). An electrochemical scrutiny of organometallic iron complexes and hexamethylbenzene in a room temperature molten salt. Journal of American Chemical Society 97: 3264–3265. https://doi.org/10.1021/ja00844a081. 99 Hough, L.W., Smiglak, M., Rodr𝚤guez, H. et al. (2007). The third evolution of ionic liquids: active pharmaceutical ingredients. New Journal of Chemistry 31: 1429–1436. https://doi.org/10.1039/B706677P. 100 Wilkes, J.S., Levisky, J.A., Wilson, R.A., and Hussey, C.L. (1982). Dialkylimidazolium chloroaluminate melts: a new class of room-temperature ionic liquids for electrochemistry, spectroscopy and synthesis. Inorganic Chemistry 21 (3): 1263–1264. https://doi.org/10.1021/ic00133a078. 101 Parshall, G.W. (1972). Catalysis in molten salt media. Journal of American Chemical Society 94: 8716–8719. https://doi.org/10.1021/ja00780a013. 102 Santos, E., Albo, J., and Irabien, A. (2014). Magnetic ionic liquids: synthesis, properties and applications. RSC Advance 4: 40008–40018. https://doi.org/10 .1039/C4RA05156D. 103 Hice, S.A., Clark, K.D., Anderson, J.L., and Brehm-Stecher, B.F. (2019). Capture, concentration, and detection of salmonella in Foods using magnetic ionic liquids and recombinase polymerase amplification. Analytical Chemistry 91: 1113–1120. https://doi.org/10.1021/acs.analchem.8b04751.

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2 Growth of Ionic Liquids and their Applications Sudakhina Saikia 1 , Himadri Borah 2 , Pangkita Deka 3 , and Rekha R. Dutta 4 1

Tezpur University, Department of Chemical Sciences, Napaam, Tezpur 784028, India North Gauhati College, Department of Chemistry, College Nagar, Guwahati 781031, India 3 Jorhat Engineering College, Department of Chemistry, Garmur, Jorhat 785007, India 4 The Assam Kaziranga University, Department of Chemistry, Koraikhowa, Jorhat 785006, India 2

2.1 Introduction As already introduced in Chapter 1, ionic liquids (ILs) are defined as a class of compounds, composed of organic cations and organic/inorganic anions, which are liquid at temperatures below 100 ∘ C. Although the first report of IL dates back to 1914, research in the field of ILs has only been increasing exponentially since the discovery of water-stable ILs by Wilkes and Zaworotko in 1992 [1, 2]. The unique properties of ILs, such as negligible vapor pressure, high thermal stability, nonflammability, a wide electrochemical window, and recyclability, merit their application in various fields, which will be discussed later in this chapter [3]. These physicochemical properties of ILs can be fine-tuned to requirements by altering the combination of cations (nature, length, and symmetry) and anions (structure and charge delocalization) during their synthesis process [4]. For instance, air and water stability is associated with different anions in the IL structure, while thermal stability is linked to the strength of heteroatom-carbon (and its hydrogen bonds) in the cationic component [5]. Nowadays, numerous ILs covering a wide range of properties are commercially available [3]. Moreover, ILThermo (v2.0), a free-access web database of ILs, allows researchers worldwide to access up-to-date data collected from publications on experimental studies of thermodynamic and transport properties of ILs [6]. Recently, Acar et al. employed a deep-learning model to predict the melting point of various ILs with reasonably high accuracy [7]. In 2008, Plechkova and Seddon estimated that there may be 1012 possible ILs with binary combinations of known IL cations and anions and may reach up to 1018 if ternary systems are investigated [8]. This chapter provides an overview of the growth of ILs using different synthetic routes and methods. A brief summary of the types of cations and anions used in the growth of ILs is also presented prior to describing the synthesis methods of ILs available in the literature. In the later part of the chapter, the diverse applications of Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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2 Growth of Ionic Liquids and their Applications

ILs in various areas like electrochemistry, solvents and catalysis, physical chemistry, analytics, engineering, and heat transfer and storage have been discussed.

2.1.1

Cations

Typically, the cation of IL has a bulk organic structure with low symmetry, which gives these compounds low melting points. Figure 2.1 displays the structures of some cations based on imidazolium, pyrrolidinium, piperidinium, phosphonium, pyridinium, ammonium, sulfonium, thiazolium, cholinium, and guanidium ions. Based on the properties exhibited by a series of imidazolium-cation-based ILs, it has been found that with increasing size and asymmetry of the cation, the melting point of the IL decreases. On the other hand, an increase in the melting point is observed with an increase in branching on the alkyl chain (denoted by R in Figure 2.1) [5].

2.1.2

Anions

Typical anions of ILs include halides, tetrachloroaluminate, tetrafluoroborate, hexafluorophosphate, and many more, as shown in Figure 2.1. The anions greatly affect the ability of ILs to form bonds with substrates as well as their tendency for chemical reactions such as hydrolysis [9]. The hydrophobicity, density, viscosity, and solvation properties of ILs may be altered by changing the anion. On the basis of anion, ILs are classified into four groups: (i) ILs based on AlCl3 and organic salts such as [bmim]Cl; (ii) systems based on anions such as BF4 − , PF6 − , and SbF6 − ; (iii) ILs based on anions such as [CF3 SO3 ]− , [(CF3 SO2 )2 N]− , [Tf2 N]− , and similar; and (iv) ILs based on anions such as alkylsulfates and alkylsulfonates [10–12]. The first group represents the ILs whose Lewis acidity can be optimized by varying the relative amounts of organic salt/AlCl3 . However, this group of ILs is extremely hygroscopic in nature. The second group of ILs is relatively neutral and air stable, although they react exothermically with strong Lewis acids such as AlCl3 [13]. The third group of ILs is much more stable toward such reactions and usually possesses low melting points and viscosities, high conductivities, a wide electrochemical window, and air stability. ILs based on anions mentioned in (iv) are relatively cheap and do not contain fluorine atoms. They can be prepared by reacting organic bases with dialkyl sulfates or alkyl sulfonate esters under ambient conditions.

2.2 Growth of Ionic Liquids 2.2.1

Quaternization

The formation of cations via protonation with a free acid or quarternization of suitable starting materials such as amine and phospine is the simplest method for the formation of ILs (e.g. 1-butyl-3-methylimidazolium chloride and ethyl-ammonium nitrate) [14, 15]. The protonation reaction used for the synthesis of [C2 H5 NH3 ]NO3 requires the addition of HNO3 to cooled aqueous ethylamine solution. The excess

Cations

Anions +

R N +

N

N

Cl−

R

Br− F−

1-Alkyl-3 methylimidazolium [Cnmin]+

1-Alkyl-1-methylpyrrolidinium [Cnmpyrr]+

+

R

1-Alkyl-1-methylpiperidinium [Cnmpip]+

R +

N R R R

N R

Tetraalkylammonium [Nn,n,n,n]+

Alkylpyridinium [Cnpyr]+

Trialkylsulfonium [Sn,n,n]+

Figure 2.1

HO

+

− O O N S S F 3C CF3 O O

Bis(flurosulfonyl)imide [fsi]− or [N(SO2F)2]−

Bis(trifluromethanesulfonyl)imide [NTf2]− or [N(SO2CF3)2]−

H2N Cholinium [Ch]+

C

NH2

Guanidinium [Gdm]+

F F P F F

Hexafluorophosphate [PF6]− CN −

B CN NC CN

O−

F3C

− O O N S S F F O O

P

F

O O−

Acetate [AcO]−

O

F

Tetrafluoroborate [BF4]−

O

OH

NH2

N

Tetrachloroaluminate [AlCl4]−

Trifluoromethanesulfonate or triflate [OTf]− or [CF3SO3]−

+ +

S R R R

F B F F F

Cl Al Cl Cl

O

Tetraalkylphosphonium [Pn,n,n,n]+

+

Halides

O F3C S O−

R P R R R

+

N

Cl

Trifluoroacetate [tfa]−

Tetracyanoborate [B(CN)4]−

F −

C2H5

N N

N

Dicyanamide [N(CN)2]− or [dca]−

F

P

F C2H5

Fluoroalkylphosphates [fap]−

O O−

HO

S

O−

OH

O

Dihydrogenphosphate [H2PO4]− or [dhp]−

Hydrogen sulfate [HSO4]−

Overview of some commonly used cations and anions as constituents of ILs.

C2H5

SO3−

p-Toluenesulfonate or tosylate [Tos]−

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2 Growth of Ionic Liquids and their Applications

amine can be removed along with water by heating to 60 ∘ C in vacuo [13]. The same procedure may be followed to synthesize ILs of this type. However, contamination by residual amines may be observed if amines of higher molecular weights are employed. Apart from HNO3 , haloalkanes are also utilized for the quaternization of amines and phosphines under mild reaction conditions. The temperature and time of the reaction vary according to the nature of the alkylating agent.

2.2.2

Anion Exchange

In most cases, the counteranion that is generated in the quaternization reaction is not the desired one. Therefore, an anion exchange reaction is carried out by any of the following methods: (i) direct reaction of the halide salt with Lewis acids and (ii) anion metathesis [13]. The former method results in the formation of the respective Lewis acidic IL via the simple mixing of a Lewis acid with the halide salt [NR3 R′ ]+ [X]− (Scheme 2.1). Depending on the ratio of halide salt to Lewis acid (MXy ), more than one anionic species with different acidities may be observed. On the other hand, to obtain air- and water-stable ILs, the anion metathesis method may be followed. Lewis acid MXy

NR3

R′X

[NR3R′]+[MXy+1]−

[NR3R′]+[X]−

(1) +Metal salt [M]+[A]− − MX (precipitation)

[NR3R′]+[A]−

(2) +Bronsted acid H+[A]− − HX (evaporation) (3) Ion exchange resin

Scheme 2.1

Typical synthesis paths for ionic liquids.

The metathesis involves the reaction of the halide salt with a group 1 metal or any other desired anion (Scheme 2.1). For instance, the metathesis of [Emim]I with Ag[BF4 ] in methanol results in the formation of [Emim][BF4 ]. This method of synthesis of IL is the most widely used method due to its simplicity.

2.2.3

Acid–Base Neutralization

Acid–base neutralization reaction also results in the formation of ILs, similar to the preparation of monoalkylammonium nitrate that results from the neutralization of the aqueous solution of amine with HNO3 [4]. Similarly, tetraalkylammonium sulfonates are synthesized by mixing equimolar amounts of sulfonic acid and tetraalkylammonium hydroxide, producing water as the only byproduct [16]. Therefore, the ILs are kept under vacuum for 48 hours to remove the excess water. Some washes with organic solvents are also done to remove any undesirable contaminants [4].

2.3 Applications of Ionic Liquids

2.2.4

Direct Combination

This method involves the direct combination of a halide salt with a metal halide. Examples of ILs synthesized by the direct combination method are halogenoaluminate and chlorocuprate ILs [17, 18].

2.2.5

Microwave-Assisted Synthesis

Besides the abovementioned conventional methods, ILs can also be synthesized using a microwave-assisted technique. Microwave irradiation shows several advantages compared to conventional synthesis procedures due to its fast, selective, and environmentally benign behavior [14]. In 2001, Verma and Namboodiri developed a microwave irradiation method to synthesize 1-alkyl-3-methylimidazolium halides and dialkyl-3-methylimidazolium dihalides ILs in solvent-free conditions, furnishing >70% yields in less than two minutes [19]. Chiral and amino-acid-based ILs were synthesized by using the microwave-assisted approach and used for various applications [20, 21].

2.2.6

Ultrasound-Assisted Synthesis

Ultrasound, an environmentally benign synthesis methodology, has been used to synthesize ILs under solvent-free conditions, achieving high yields of product. The ultrasound process works most effectively at the interfacial layers of two immiscible liquids and improves the reaction rate and enhances material transformation. Banrath’s and Verma’s group synthesized ILs based on 1-alkyl-3methylimidazolium cation and a set of anions (Cl− , Br− , I− , BF4 − , PF6 − , CH3 SO3 − , and BPh4 − ] using ultrasound-assisted technology [22, 23]. Ameta et al. synthesized N-methyl-2-pyrrolidinium hydrogen sulfate-based IL with considerable yields using the ultrasound-assisted method in solvent-free conditions [24].

2.3 Applications of Ionic Liquids 2.3.1

Electrochemistry

ILs have been widely employed in electrochemistry owing to their unique properties, such as good ionic conductivity (up to 0.1 S cm−1 ), a wide electrochemical window, high thermal stability, high viscosity, a wide liquid range, and tunable solvent properties [25]. The electrochemical reactions are basically processes at the IL/electrode interface involving the diffusion of electroactive species and electron transfer processes that determine the performance of IL in electrochemical applications. The electrochemical properties of ILs are highly dependent on the charge, polarization, size, and intermolecular interactions at the electrode interface. Some of the electrochemical applications of ILs in the fields of electrodeposition, electrosynthesis, and electrocatalysis have been discussed here.

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2.3.1.1 Electrodeposition

ILs have found application in the field of electrodeposition due to their good ionic conductivities and wide electrochemical windows. The deposition of metals found in aqueous solutions could be carried out at room temperature in ILs unlike high-temperature molten salts [25]. The deposition of Li in chloroaluminate ILs was first reported by Lipsztajn and Osteryoung in 1985 [26]. They observed that LiCl dissolved in slightly acidic ILs with a certain excess of AlCl3 , which was otherwise insoluble in neutral ILs. They added an equivalent amount of LiCl into the solution, from which the lithium ions got reduced on tungsten, glassy carbon, and aluminum electrodes. Al was also deposited initially from neutral chloroaluminate ILs. However, the hygroscopic and corrosive nature of chloroaluminate IL prompted the use of air- and water-stable ILs for Al deposition [16]. It should be noted that electrodeposition in ILs avoids hydrogen embitterment, thereby resulting in good metal quality. Many other metals, such as Ga, In, Sn, Sb, Te, Co, Cu, and Zn, have also been successfully electrodeposited in ILs [25]. 2.3.1.2 Electrosynthesis

ILs are promising media for electro-organic synthesis due to their distinct electrochemical advantages. Unlike chemical synthesis, electrosynthesis uses fewer reagents, produces less byproducts, and proceeds under mild conditions. The rate, selectivity, and degree of completion can also be controlled in this method by adjusting the nature of the electrolyte, the electrode material, or the applied potential. The electrosynthesis of cyclic carbonates has been carried through the cycloaddition of CO2 to epoxides in ILs [27, 28]. The Henry reaction has also been electrochemically induced under mild conditions in ILs, affording high yields of nitroalcohols [29]. Moreover, conducting polymers are produced by electrooxidative polymerization of suitable monomers [30]. Other conducting polymers, such as polyaniline [31, 32], polypyrrole [33–36] and polythiophenes [37], are synthesized by electrochemical polymerization in ILs. 2.3.1.3 Electrocatalysis

The remarkable properties of ILs have led to their application as catalysts or electrocatalytic activators in electroanalytical fields. The introduction of ILs in electrocatalytic reactions as reaction media, binders, and catalyst surface modifiers alters the selectivity, activity, and stability of the reactions. For example, the use of IL [C4 mim][BF4 ] as electrolyte for hydrogen oxidation reaction (HOR) on transition metals such as Mo, increases the exchange current density three times than that of HOR on Pt [38]. Again, benzyl alcohol could be selectively electrooxidized to benzaldehyde on a Pt electrode using [C4 min][BF4 ] and [C4 mim][PF6 ] as the reaction media [39]. Similarly, phenol and 4-tert-butylphenol could be efficiently converted to phenyl triflate molecule in [C2 mim][NTf2 ] and [C4 mpyrr][NTf2 ] [40]. Protic ILs have been used as electrolytes in fuel cells for better stability and performance compared to conventional inorganic acid electrolytes [41–44]. Owing to their high conductivity and suitably viscous nature, ILs have found way as binders by replacing conventional nonconductive organic ones in fabrication of

2.3 Applications of Ionic Liquids

carbon paste electrodes (CPEs) [45]. For instance, Wang et al. fabricated an IL-CPE using pyridinium-based IL and observed that the electrochemical performance of the electrode was enhanced remarkably. The use of [(C4 H9 )2 -bim]3 [La(NO3 )6 ] in CPE showed good electrocatalytic activity toward the reduction of hydrogen peroxide, bromate, nitrite, and trichloroacetic acid [46]. Surface modification of carbon materials using ILs introduces more binding sites for anchoring metal nanoparticles, thereby improving compatibility and stability of the materials. Wang et al. synthesized Au/CNT-IL nanohybrids and observed that the nanohybrids showed good electrocatalytic performance toward the oxygen reduction reaction [47]. Again, Chen and coworkers developed a PtRu/CNTs-IL (or Pt/CNTs-IL) electrocatalyst based on IL-functionalized CNTs [48]. The electrocatalyst showed better performance toward direct electrooxidation of methanol compared to PtRu/CNTs (Pt/CNTs) which could be attributed to the smaller particle size, better dispersion, and higher active surface area of Pt and PtRu nanoparticles in the IL-modified electrocatalyst.

2.3.2

Solvents and Catalysis

ILs have been widely used as green alternatives to conventional organic solvents for volatile organic compounds (VOCs) due to their negligible vapor pressure [49]. The major differences in properties between organic solvents and ILs have been reported by Greer et al. [50]. Unlike conventional solvents, ILs can be fine-tuned to specific applications, which earned them the term “designer solvents” [51]. However, the compatibility of an IL must be monitored with respect to the operational units of a process prior to substituting any organic solvent. The solvation properties of ILs are greatly determined by the ability of the ions to act as hydrogen bond acceptors and/or donors and the degree of localization of the anionic charge [52]. Further, the noncoordinating, yet highly polar nature of ILs has shown to improve the reaction rates, yields, and selectivity of various reactions [53, 54]. Moreover, the ILs can be recycled and reused for several times, which makes them an environmentally friendly choice in many cases. In recent years, several reports on the use of ILs as green solvents have been available, especially for organic and inorganic synthesis [49, 55–58]. 2.3.2.1 Ionic Liquids as Solvents for Organic Synthesis

A significant number of organic reactions have been explored using ILs as solvents and the products formed and yields obtained coincide with those of polar solvents. Despite their similar effects as polar solvents, some unique “IL effects” have also been observed. The ability of ILs to interact with ionic compounds differs from conventional solvents due to their ionic nature [57]. This effect of ILs has determined the outcome of two notable reactions: nucleophilic substitution of a chloride anion with a sulfonium cation (Scheme 2.2) and dediazoniation of a benzenediazonium cation (Scheme 2.3) [59, 60]. In the former case, different reaction orders have been observed in ILs compared to polar and nonpolar solvents. A bimolecular dependence by dimethyl-4-nitrophenylsulfonium ion and chloride

35

36

2 Growth of Ionic Liquids and their Applications

CH3 S+ CH3

O2N

Scheme 2.2

Cl− S

O2N

+ CH3Cl CH3

Nucleophilic substitution of a chloride anion with a sulfonium cation.

anion is detected with the use of ILs. On the other hand, positive partial kinetic orders are observed with polar solvents, and nonpolar solvents result in negative dependence [57]. These observations could be substantiated by the presence of ion-pairing mechanism in molecular solvents [60]. Polar solvents produce partially dissociated ions, whereas nonpolar solvents lead to insoluble sulfonium chloride. However, ILs furnish completely dissociated ions in the reaction medium [57].

+

O

N

N

N(SO2CF3)2

O

S

NSO2CF3 CF3

[bmim][Br] + [bmim][NTf2]

Scheme 2.3 Dediazoniation of benzenediazonium in [bmim][Br]–[bmim][NTf2 ] to form [NTf2 ]− adduct.

In Scheme 2.3, the non-nucleophilic [NTf2 ]− competes with Br− and reacts preferentially with the arene. This observation could be attributed to the deactivation of Br− ions owing to hydrogen bonding and clustering around [bmim]+ ions. Therefore, the use of ILs as reaction media for specific substrates dramatically influences the outcome of a reaction. Another application of ILs as solvents for organic synthesis is in the Diels–Alder cycloaddition reaction. The first study of the effect of ILs as solvents in the Diels–Alder reaction was performed by Jaeger and Tucker in 1989 [61]. They examined the reaction of cyclopentadiene with methylacrylate and methyl vinyl ketone in ethylammonium nitrate (EAN) IL and found that the reaction shows endo selectivity enhancement with respect to exo products in a ratio of 7 : 1. Again, Rosa et al. studied two types of thermal Diels–Alder reactions using ILs as reaction media. They observed that the presence of IL improves the yields of reactions compared to molecular solvents, and the time of reaction decreases significantly [62]. Santos and coworkers conducted the Baylis–Hillman reaction in imidazoliumbased ILs and reported that the reaction proceeded 33 times faster in [C4 mim][PF6 ] than in acetonitrile, but afforded moderate yields [63]. Aggarwal et al. provided a detailed 1 H NMR analysis showing that the slightly acidic C2 position of the imidazolium ion is easily deprotonated in the presence of bases like 1,4-diazabicyclo[2.2.2]-octane (DABCO) in this reaction and leads to the formation of carbenes [64]. These carbenes react with the reactant aldehyde in the Baylis–Hillman reaction, generating undesirable side products. Therefore, highly inert ILs, such as N-ethylpyridinium tetrafluoroborate [C2 py][BF4 ] and

2.3 Applications of Ionic Liquids

1,3-dialkyl-1,2,3-triazolium-based ILs, have been later reported to improve the yields of the Baylis–Hillman reaction [65, 66]. Other organic reactions, such as Sonogashira coupling with tetraalkylphosphonium ILs by Central Glass Company, where the IL acts as a polar solvent to accelerate the reaction and demethylation of aryl ethers using [Hpy][Cl] by Eli Lilly and Co, where the chloride anion acts as a nucleophile, have been pursued industrially [57]. Therefore, commercialization of organic reactions using ILs as solvents is currently in progress, where ILs are more effective solvents for reaction compared to molecular solvents.

2.3.2.2 Ionic Liquids as Solvents for Inorganic Synthesis

ILs have been actively employed for the synthesis of a variety of inorganic materials such as metal nanoparticles, metal oxides, and framework materials, such as zeolites, mesoporous silicas, and metal organic frameworks, due to their unique ability to act as structural templates, precursors to materials, and coordination abilities [5, 67, 68]. ILs, being ionic in nature, exhibit strong electrostatic interactions with charged surfaces. They stabilize metal nanoparticles that have polar surfaces through electrostatic stabilization [69]. Other interactions between ILs and nanoparticles that result in the formation of stable dispersions involve hydrogen bonding and van der Waals interactions [16]. The strong stabilizing power of ILs, along with comparatively low interfacial energy and high viscosity, allows rapid nucleation and restricted growth of particles [57]. This phenomenon is necessary for achieving a narrow size distribution and avoiding agglomeration in nanoparticles. Therefore, ILs can be regarded as excellent solvents for the synthesis of metal nanoparticles. Moreover, the use of ILs in inorganic synthesis eliminates the requirement of adding capping agents to the reaction medium for stabilizing the synthesized nanoparticles. The size and morphology of nanoparticles can be controlled by tuning the size of polar domains in ILs. For instance, longer alkyl chains on imidazolium ions of ILs increase the size and change the morphology of iridium nanoparticles based on the charge of the precursor used [70]. Functionalized ILs with coordinating groups such as thiols have also been explored to synthesize nanoparticles with different sizes, morphologies, and improved stability compared to long alkyl chain based ILs [68]. The capability to stabilize charged surfaces by ILs as discussed earlier has also been exploited for the synthesis of metal oxides with exposed high-energy surfaces. The use of ILs stabilizes the growth of high-energy surfaces in metal oxides, thereby leading to their slow growth and the presence of higher active sites in the final synthesized material [57]. This results in unusual morphologies of ZnO particles, as, for instance, shown in Figure 2.2 [71]. Zeolites are usually synthesized using hydrothermal methods by heating precursors in water under high autogenous pressure in the presence of structure-directing agents (SDAs). Intriguingly, ILs have been used both as solvents and SDAs for the synthesis of zeolites by a method termed ionothermal synthesis [72]. This method is safer than the conventional hydrothermal method, as the lack of volatility in ILs reduces the risk of high-temperature depressurization [57]. In addition, the

37

2 Growth of Ionic Liquids and their Applications

c

O2− Zn2+

58°

30

(0001)

40

50

(103)

60

(200) (112) (201)

58°

(110)

{1011}

(102)

64°

(101)

(b)

(100) (002)

(a)

Intensity (a.u.)

38

70

2-Theta (degree) (c)

(d) 64°

400 nm

58° 5 μm

58° 200 nm

Figure 2.2 (a) Schematic model of a hexagonal ZnO micropyramid synthesized in an IL, (b) X-ray diffraction pattern (XRD) of synthesized ZnO, (c) scanning electron microscope (SEM) image of synthesized ZnO and an enlarged SEM image (inset), (d) SEM image of an individual hexagonal ZnO micropyramid as investigated by Zhou et al. Source: Zhou et al. [71]/Reproduced with permission from Royal Society of Chemistry.

use of ILs as solvents and SDAs eliminates competition between the two, thereby simplifying the protocol [73].

2.3.2.3 Ionic Liquids as Catalysts for Organic Reactions

Due to their unique physicochemical properties, ILs play a significant role as catalysts in organic reactions. They can be classified as acidic or basic depending upon the type of functional groups attached to the cationic and/or anionic components of the ILs [74]. The acidic (Brønsted as well as Lewis) nature of ILs has found tremendous application in various organic transformations such as Beckmann rearrangement, asymmetric aldol condensation, aza-Michael reaction, Pechmann reaction, Koch carbonylation, Hantzsch reaction, Mannich reaction, synthesis of chalcones, furfural, biodiesel, oxidation reactions, and Prin’s reaction [74]. It has been observed that ILs often perform better compared to conventional solvents and catalysts [49]. Wang and Wang explored the Friedel–Crafts reaction of PCl3 and benzene with the IL [trEHAm]Cl-XAlCl3 for the synthesis of dichlorophenylphosphine

2.3 Applications of Ionic Liquids

PCl3

+

[trEHAm]Cl-XAlCl3

Ph-H

Scheme 2.4

PhPCl2

IL-catalyzed Friedel–Crafts reaction of PCl3 and benzene.

(DCPP) (Scheme 2.4) [75]. They observed that this protocol exhibits easy isolation of products and consumes a lesser amount of reusable catalyst. Wasserscheid and coworkers reported a highly selective alkylation of phenol and anisole using Brønsted acidic ILs [MIMBS][OTf] as catalysts in a biphasic medium (Scheme 2.5) [15]. The higher selectivity could be attributed to biphasic operation with differential solubility effects as well as the specific acidity bestowed by the IL environment. OTf− OR

N

+ N OR

HO3S [MIMBS][OTf]

+

+

Isomerization alkylation

Scheme 2.5

OC6H13

C6H13

+ R

Multialkyated products

IL-catalyzed alkylation of phenol.

Esterification of alcohols by carboxylic acids has also been carried out in halogen-free Brønsted acidic IL, N-methyl-2-pyrrolidinium methyl sulfonate ([NMP]+ CH3 SO3−) at room temperature (Scheme 2.6) [76]. This methodology exhibits good conversion rates with high selectivities and easy isolation of products, along with catalyst reusability. O +

N H RCOOH

+

Scheme 2.6

R′OH

CH3SO3−

[NMP]+CH3SO3−

RCOOR′

IL-catalyzed esterification of alcohol.

A solvent- and metal-free protocol with mild reaction conditions and easy product isolation has been reported by Taheri et al. for the synthesis of 3-vinyl ketones from indoles and ketones using sulfonyl containing ILs [77]. They observed that the presence of sulfonyl and sulfonic acid groups simultaneously in the same IL results in increased catalytic activity. Moreover, challenging substrates such as bulky ketones afforded products with satisfactory yields (Scheme 2.7). Basic functionalized ILs have also attracted considerable interest owing to their easy recyclability and high catalytic activity compared to inorganic bases [78]. They have been employed to catalyze various reactions such as Henry reaction, Michael addition reaction, aldol condensation, Knoevenagel condensation, quinoline

39

40

2 Growth of Ionic Liquids and their Applications

O

O S +

O

SO3H

N

O

−

+

CF3SO3

N H

Solvent-free, 60 °C

Scheme 2.7

N H

IL-catalyzed synthesis of 3-vinyl ketones.

synthesis, condensation reactions of carbonyl compounds with hydroxylamine, and many more [74]. The Henry reaction between carbonyl compounds and nitroalkyl has been carried out in the presence of ILs yielding 82% of product in 16 hours. The same reaction without IL afforded only 20% yield in 46 hours (Scheme 2.8) [79]. O +

H

CH3NO2

HO

ILs

NO2

Ph

Ph

Cl− ILs =

N +

Scheme 2.8

N

N

Cl−

+

IL-catalyzed Henry reaction.

Li and coworkers reported the synthesis and application of ethanolaminefunctionalized quaternary ammonium salt-based IL for Pd catalyzed Heck reaction (Scheme 2.9) [80]. The IL in this protocol plays multifunctional roles of base, ligand, and reaction medium, as well as exhibiting high activity and recyclability. OH

N

+

X

(n-C4H9)3N + R

Scheme 2.9

Br−

OH R

(PdOAc)2, 100 °C

IL-catalyzed Heck reaction.

Xu et al. developed a green protocol for Michael addition of amines to α,β-unsaturated carbonyl compounds under mild conditions using basic IL [bmim]OH as a reusable catalyst and reaction medium (Scheme 2.10) [81]. The products of the reaction could be distilled directly from the IL in large-scale reactions, thereby avoiding the use of other organic solvents.

2.3 Applications of Ionic Liquids

R

1

R

NH

+

R′

EWG

[bmim]OH r.t., 10–20 min

R′

R1 N R2

R EWG

R2 EWG = CN, COCH3, COOCH3

Scheme 2.10

2.3.3

IL-catalyzed Michael addition reaction.

Separation

The unique properties of ILs, such as good stability, negligible vapor pressure, a wide liquid range, low flammability, and adjustable polarity, make them attractive alternative media in liquid–liquid extractions for the separation of metal ions [5]. One such example is the separation of Sr2+ from aqueous solutions into a series of dialkylimidazolium-based room temperature ILs as solvents in the presence of dicyclo-hexyl-18-crown-6 (DCH18C6) as an extractant [82]. The extraction of alkali metal salts such as nitrates of Na+ , Cs+ , and Sr2+ from aqueous solutions of 18-crown-6 (18C6), DCH18C6, and 4,4′ (5′ )-di-(tert-butylcyclohexanol)-18-crown-6 (Dtb18C6) in imidazolium-based room temperature ILs was reported by Rogers and coworkers [83]. The best extraction could be observed with Dtb18C6, and the selectivity pattern followed Sr2+ > Cs+ > Na+ . The separation of actinides such as Am3+ , Pu4+ , Th4+ , and (UO2 )2+ into similar ILs has been performed using extractants like CMPO (octyl[phenyl]-N,N-diisobutylcarbamoylmethylphosphine oxide) [84]. Usually, a metal ion-ligating functional group is included in the IL structure to improve the solubility of the metal ion in the IL [5]. The extraction of heavy metal ions like Hg2+ and Cd2+ has been carried out using thiourea, urea, and thioether derivatives of ILs, as reported by Visser et al. [85, 86]. The works reported so far in the field of ion separation with ILs have been reviewed by Zhao et al. [87] and Chen and Li [88].

2.3.4

Heat Transport and Storage

The emerging heat transfer demand of modern technologies has instigated the search for more effective heat transfer fluids (HTFs). In this regard, the tunable structural composition and thermophysical properties, such as density, viscosity, thermal stability, thermal conductivity, specific heat capacity, and melting point, of ILs make them excellent alternatives as HTFs [4]. The desirable specifications of thermal fluids for application in solar parabolic trough systems are thermal stability >430 ∘ C, freezing point 803∘ C), but ILs normally have a MP lower than 100∘ C, and several ILs are liquid at RT. This lower MP is basically due to decreased lattice energy during the replacement of inorganic ions by IL’s delocalized ions [31], and this lattice energy could be described by the following formula: ) N MZ + Z − e2 ( 1 (3.1) 1− E=− A 4𝜋𝜀0 r0 n where N A indicates the Avogadro number, M indicates the Madelung constant, Z + and Z − are the change of cation and anion, respectively, E represents the ion’s elementary charge, 𝜀0 indicates the open space’s permittivity, r 0 represents the closest ion’s distance, and n indicates the Born exponent. ILs consist of relatively large polarized cations (mostly organic cations) and anions, resulting in relatively feeble ion–ion coupling in comparison to molten salt like NaCl. On the other hand, electrostatic attraction of totally ionized components of ILs exhibits a much greater liquid phase range than common molecular solvents like water, ethanol, benzene, and so on. Preiss et al. [25] using quantum chemical program code in combination with COSMO-RS (dielectric constant adjusted to ∞ employing optimal radii) predicted MP of 67 ILs, considering volume-based thermodynamics principles (with ionic quantities as the dominant driver), location of

53

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3 Study of Physicochemical Properties of Ionic Liquids

symmetrical nature, and quantity of ionic torsion angles (𝜏). The experimental and calculated MPs are linearly correlated with an average error of 24.5∘ C. QSPRs-based model is a very popular approach to predict the MP, viscosity, ST, and density of ILs. ILs that make up the ions under investigation are expressed using a range of molecular descriptions (MDs), and ions’ geometry is optimized. Królikowska and Kumar’s group using QSPRs models determined the MP of a group of ILs [27, 28]. Another method that is widely used nowadays to forecast IL’s MP is GCM [29, 30]. The following equation is widely adopted to calculate/predict the IL MP or associated relationship: Tm =

ΔHm ΔSm

(3.2)

where T m indicates MP, ΔH m indicates the melting heat enthalpy, and ΔSm represents the MP entropy at standard condition. According to Valderrama and Cardona [30], MP enthalpy is determined by couplings among molecular fragments of anion and cation and this coupling is linearly combined or contributed by each group or fragments. The contribution of groups or fragments is different when they are attached to cation and anion. Accordingly, in suggested GCM approach, the following equation is applied for ΔH m : ∑ ∑ ΔHm = ΔHmo + [nic ΔHm,ic ] + [nia ΔHm,ia ] (3.3) where H mo represents all IL’s constant quantity, nic indicates frequency number of each cation group “i,” and ΔH m,ic denotes the contribution of each cation group “i” to MP enthalpy. Similar like cation, nia indicates the frequency number of each anion group “i” and ΔH m,ia represents the contribution of each anion group “i” to MP enthalpy. The entropy of melting depends on the structural characteristics as proposed by several authors [32–34]. It may depend on rotational and conformational freedom of IL. Valderrama and Cardona [30] have used IL’s structural variable, separately contributed to the overall entropy according to their mass of cation and anion. The entropy of melting (ΔSm ) is represented by, ΔSm = 𝛼 + 𝛽Mc + 𝛾Ma

(3.4)

where 𝛼, 𝛽, and 𝛾 represent IL’s constant values. M c and M a indicate the cationic and anionic mass, respectively. According to this model, the MP of an IL is given by Eq. (3.3.5). ∑ ∑ ΔHmo + [nic ΔHm,ic ] + [nia ΔHm,ia ] Tm = (3.5) 𝛼 + 𝛽Mc + 𝛾Ma It gives a quick estimation of MP without extensive computational calculation. Using this method, Valderrama and Cardona [30] calculated the MP and melting heat for a group of ILs. The comparisons between experimental and calculated MPs are nicely correlated with ±15% of relative deviation. Despite the fact that the MPs correlation results were pretty good, they conclude that with the current information and limited understanding, more precise and generalized models must be constructed [30].

3.2 Physicochemical Properties of Ionic Liquids

GCM2 800

700

700

600

600

Calculated Tm(K)

Calculated Tm(K)

GCM1 800

500 400 300

500 400 300

200

200

100 100 200 300 400 500 600 700 800

100 100 200 300 400 500 600 700 800

(a)

Figure 3.1

Experimental Tm(K)

(b)

Experimental Tm(K)

Illustration of experimental vs. calculated MP plot for (a) GCM1 and (b) GCM2.

Mital et al. [29] using GCMs estimated the MPs of 933 ILs and compared them with the experimental MP data. Two different dataset (GCM1 and GCM2) models were used to estimate MPs. In the GCM1 model, the cation was expected to have a core group (e.g. pyridinium and imidazolium) and a subgroup and/or a functional group attached to it. The GCM2 model was more complex and breaks down the functional group used in GCM1 to more number functional group. They reported that the association between experimental and calculated MPs is much better correlated in GCM2 than the GCM1 model based on the statistical absolute average relative deviation (AARD) (Figure 3.1). The MP of ILs depends not only on the charge and size of cation–anion, but also on the cation–anion symmetry, alkyl chain length and branching, specific substitution in organic ions, hydrogen bonding, and π–π stacking interaction. Holbrey and Seddon [35] studied phase transition temperature variation of 1-(Cn H2n + 1 )-3-methyl imidazolium tetrafluoroborate as alkyl chain length function at position 1. It was noticed that, when n ≤ 5, the MP decreases but increases as the number of carbon atoms n > 5. It was explained that alkylation of position 1 affects the crystal packing efficiency of cation up to n ≤ 5 and after n > 5, the alkyl chain becomes the key structural component in the cation that leads to higher glass/MPs [23]. Similarly, it was observed that C-alkylation in anionic portion may lead to significant lowering of MPs [23]. Increasing symmetry in the ions of ILs leads to efficient crystal packing, higher lattice energy, and higher MP. Gordon et al. [36], using [NR4 ]X salt (where total alkyl substituent contains 20 carbons and X is a different anion), showed that MP varies depending on the symmetry of the cation (some cases with poor symmetry the salt is liquid at RTIL). For example, when X = Br− , [N5555 ]Br, [N6644 ]Br have MP 101.3 and 83.0 ∘ C, respectively. Salts with low symmetry of cations, such as [N8543 ]Br, [N8663 ]Br, [N7757 ]Br, [N9551 ]Br, and [N9641 ]Br, are liquid at RT.

55

56

3 Study of Physicochemical Properties of Ionic Liquids

The MP of ILs is also affected by the branching of alkyl groups in organic cations. Carda-Broch et al. [37] showed that MP of three isomers of 1-butyl-3methylimidazolium hexafluorophosphate [BMIM][PF6 ] depends on branching types. The MPs of ILs are 64, 83.3, and 159.7 ∘ C when the isomers are n-butyl, sec-butyl, and tert-butyl. The degree of chain branching restricts the free rotation, changes the crystal packing, and as a result the volume decreases and atomic density increases. Ring substitutions by functional group or alkyl group may have significant impact on MP. Substitution at any position in imidazolium ring containing ILs affects the crystal packing and MPs. The MP generally increases at second carbon position substitution. This position is very diverse and influence the crystal packing, H-bonding, aromatic stacking interaction, and many more. Similar like the cation, the structure of the anion contributes to the thermal properties of ILs [38, 39]. Imidazolium cation containing Cl− , Br− , and NO3 − has relatively high value of MP. In contrast, bis{(trifluroethyl)sulfonyl}(NTf2 − ) and bis{(pentafluoroethyl)sulfonyl}(NPf2− ) containing anion have lower MP [39]. The lower MP may be attributed to electron delocalization. The delocalization resonance easily explain why [C2 mim][NO3 ] has 17 ∘ C lower MP than [C2 mim][NO2 ] [38]. Further, many ILs does not have clear MPs, exhibits as super cooled liquids [40] or glass transition temperature [41]. The MP and glass transition temperature are significantly influenced by impurities like water, halides ion, organic solvents, metal cation, and so on [42].

3.2.3

Thermal Stability and Decomposition

Thermal stability is another important property of ILs. The majority of ILs have stability above 400 ∘ C. This thermal decomposition is generally regulated by anionic nature rather than cation, more specifically, IL’s heteroatom–hydrogen or heteroatom–carbon bonds (weakly coordinated with cation–anion). The thermal decomposition temperature can vary from 100 ∘ C to above 400 ∘ C [43, 44]. For instance, almost all quaternary ammonium chloride salts are stable up to 150 ∘ C, [EMIM][BF4 ] have stability until 300 ∘ C, while [EMIM][(CF3 SO2 )2 N] (MP −3 ∘ C) remains stable beyond 400 ∘ C [45]. PILs (protic ILs) containing TFSI with imidazolium cation, alkylammonium cation, and a diversity of heterocyclically cationic species are considered as highly durable ILs, with breakdown temperature exceeding 200 ∘ C [43, 44]. Additionally, it has been demonstrated that IL’s thermal decomposition reduces with the enhancement of anion’s hydrophilicity [46]. Thermogravimetry analysis (TGA) is the most common thermal analysis technique for determining IL’s decomposition temperature that looks at a sample’s mass loss as a function of temperature under controlled environment [43].

3.2.4

Conductivity

Conductivity is one of the prime properties that regulates interaction mechanism and its application. The ionic conductivity changes with the ion size and molecular weight and is dependent on available carrying charges and their mobility (which

3.2 Physicochemical Properties of Ionic Liquids

is dependent on viscosity). ILs’ conductivity is usually restricted by their ionic mobility, originated from their aggregation [43]. As a result, lower interaction and more delocalized charge result in increased conductivity; thus, higher conductivity values are expected for stronger Brønsted bases and acids [47]. ILs having longer alkyl chains possess lower conductivity as ion conductivity diminishes with the increase in cation size (reduced mobility) [43]. Accordingly, the lower conductivity of 1-benzyl-2 methyl imidazolium IL over 1-methyl-2-methyl imidazolium IL and 1-benzyl-2 methyl imidazolium-based PILs, as well as the lower conductivity value for butyl ammonium formate compared to methyl formate, should be owing to lower cation size [48]. Additionally, when cationic structure becomes less symmetrical and the molecular weight falls, the conductivity of heterocyclic ILs is elevated [43]. But there is no obvious trend in case of anions. For instance, when compared with butrate, formate, lactate, and acetate in ethyl ammonium ILs, nitrate displayed maximum conductivity, but nitrate displayed minimal conductivity when compared to similar anions in ethanol ammonium ILs [48]. Further, the ILs’ ionicity can be illustrated efficiently by Walden plot (equivalent conductivity vs. log fluidity [inverse viscosity], using Walden rule Λ𝜂 = constant), where Λ represents the molar conductivity and 𝜂 represents the viscosity (Figure 3.2). Negative deviations from solid straight line indicates IL aggregation or absence of proton transport [43]. The solid straight ideal line represents a diluted KCl solution (aqueous) that is known to be completely dissociated with equivalent mobile molecules. Vertical divergence from WL shows the presence of parental alkali/acid ions. The link between IL’s conductance and fluidity suggested that ILs have a perfect quasi-lattice structure. It has now been discovered that IL’s conductivity is affected not only by their viscosity but also by other factors. Ionic pairs and ion size are also crucial factors in determining the IL’s conductivity. 4

Log (Λ (S cm2/mol))

3 2 1

Good Ils

0 −1 −2 −3 −4

Poor Ils −4

−2

Non-ILs

0

2

Log(η−1(Pa−1.s−1))

Figure 3.2

Graphical representation of Walden plot.

4

57

58

3 Study of Physicochemical Properties of Ionic Liquids

3.2.5

Solubility

Solubility is another important attribute of ILs with regard to catalytic processes or chemical synthesis, and finally its application in diverse fields. More specifically, solvation ability of ILs determine their applicability during separation/extraction. IL’s solvation is regulated by a variety of forces hydrogen bond, dipole–dipole interactions, van der Waals interactions, and so on [49]. Neutral (specifically nonpolar) substances are more easily dissolved in ILs than ionized substances [50]. ILs form homogenous systems during solvation of organic polar substances, while ILs form biphasic systems during solvation with low-polar organic substances or water [51]. Advanced ILs have recently gained popularity for dissolving a diverse variety of inorganic/organic/polymeric substances [50].

3.2.6

Surface Tension

ST is one of the most significant property of liquids, as it measures the cohesive energy at the liquid vapor interface. The value of ST for most ILs is lower than water (∼72 × 10−3 N m−1 at 298 K) but generally higher than common organic solvents. Structural reforms in ionic species and subsequent ST value change indicate both the ions present in the surface and influence the ST. In most of the ILs series, ST decreases and became plateaus with increasing chain length in both ions. For example, Shirota et al. [52] showed that in imidazolium-based mono-cationic and di-cationic ILs with anions bis(pentafluoroethysulfonyl)amide [NPf2 ]− , bis(thiofluoromethylsulfonyl)amide [NTf2 ]− , tetrafluoroborate [BF4 ]− , and nitrate [NO3 ]− , the ST decreases as the carbon chain of an alkyl substitution inside a cation gets longer. Similarly, the ST falls when the n value in alkyl chain (n = 2, 4, 5) increased in case of IL N-alkylpyridinium bis(trifluoromethylsufonyl)imide ([Cn Py][NTf2 ]) [53]. Greaves and coworkers examined a series of protic ILs with diverse structural variation in both ions and proposed that branching in alkyl chain decreases ST but addition of hydroxyl group in alkyl chain specially at the terminal significantly increases the ST [54]. Recently, GCMs was postulated to calculate ST of ILs from their molecular structure [55]. In this method, the IL’s molecular makeup including all ionic species are encoded by the number of occurrences of preset functional groups. The breaks are assigned in such a way that it covers the entire cation and anions without any overlapping. Then a stepwise multiple linear regression was performed to identify the most significant groups and outliers’ data points that were excluded later. The regression was performed to reduce dimensionality of the data base and ST value predicted at a reference temperature and variation with temperature. ̂ 𝛾 (T; n) = ̂ 𝛾0 (n)̂f (T; n)

(3.6)

where 𝛾 0 represents ST at 298.15 ∘ C. The f indicates the temperature variation from T 0 to T. ST of ILs highly depends on impurities and temperature. Eötvös suggested that the ST of liquids bears a linear relationship to temperature T and vanished at critical

3.2 Physicochemical Properties of Ionic Liquids

temperature (T c ). The proposed relationship is 2∕ 𝛾 ⋅ Vm 3 = K(TC − T)

(3.7)

where 𝛾 denotes ST, V m represents the liquid’s molar quantity, T c indicates the critical constant, and K denotes the empirical factor. For most ILs, the variations of ST with temperatures follow the Eötvös equation.

3.2.7

Viscosity

IL’s viscosity is a significant feature for extraction, distillation, chemical reaction, and various chemical industries. At RT, ILs have a wide spectrum of viscosities, ranging from 10 to 1000 cP, and this is significantly higher than conventional solvents. Thus, relatively IL’s higher viscosity is a limitation for general usage, may be lowered by structural modification and increasing temperature. Viscosity largely depends on temperature, purification, protocol and impurities [56]. Vogel–Tammann–Fulcher (VTF) model forecast/simulate IL’s viscosity as temperature function at atmospheric pressure, Bn (3.8) ln 𝜂 = An + T − Ton An =

k ∑

ni ai,n

(3.9)

ni bi,n

(3.10)

i=1 k

Bn =

∑ i=1

𝜂 = aebVm

(3.11)

where T denotes the absolute temperature; An , Bn , and T on indicate the adjustable coefficients; ni denotes the group type number; i and k represent the molecule’s total number of diverse units; ai,n and bi,n indicate the empirical coefficients; Bn /T on denotes the Angell strength parameter; and T on represents all ILs’ constant value. The calculated viscosity of ILs according to VTF model is very close to the experimental viscosity [57, 58]. The size of ions in ILs also regulates the viscosity: higher the size of ions, greater is the viscosity. Accordingly, introduction of alkyl chain or functional group may lead to an increase in H-bonding, van der Waals force, or dipole–dipole (coulombic) interaction, and therefore, viscosity increases. It was observed that ILs having alkyl substitution imidazole cation, viscosity progressively increases with increasing alkyl chain’s carbon number [59]. Actually, the change of viscosity is nonmonotonic when a new functional group is added to cation; the viscosity may increase or decrease depending on van der Waals force strength and hydrogen bonding. Further, branching in alkyl substitution reduces chain rotational motion; as a result, the liquid becomes more viscous [60]. It has also been demonstrated that for a given cation [C4 mim]+ and varied anions, the IL’s viscosity increases in the following series [61]: “[AlCl4 ]− < [C(CN)3 ]− < [N(CN)2 ]− < [FeCl4 ]− < [SCN]− < [FeBr4 ]− , [NTf2 ]− < [CF3 CO2 ]− < [OTf]− < [NPf2 ]− < [O2 CMe]− < [NO3 ]− < [BF4 ]− , [O3 SOC1]− < [ONf]− , [O3 SOC2 ]− < [PF6 ]− < [O3 SOC8 ]− ”.

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The above series clearly indicates that viscosity not only depends on the anion size, but the strength of H-bonding. In addition to this, synthesis difficulty can render the application of best suitable IL which can be viable using IL mixture [62]. If the mixture is close to ideal, combining/integrating could either lead to formulating properties that are beyond the limits described by ideal components, or it could permit for precise tweaking of attributes within the limits [63]. The ILs behaving like ideal mixture generally follow the Katti and Chaudhri equation: log 𝜂Vm = 𝜒 log 𝜂1 Vm,1 + (1 − 𝜒) log 𝜂2 Vm,2

(3.12)

where 𝜂, 𝜂 1 , and 𝜂 2 denote the viscosity of mixed solution, pure IL1 and IL2, respectively; V m , V m,1 , and V m,2 are the volume of mixed solution, IL1, and IL2, respectively; and 𝜒 indicates the solution’s mole fraction. However, in very few cases, specially binary IL mixtures series [C4 C1 im][NTf2 ] [Me2 PO4 ] shows a noticeable deviation from ideal behavior. It explained that size differences between ions, packing efficiency, and breakdown of ionic H-bonding inside this mixture lead to divergence from optimal behavior.

3.2.8

Polarity

Polarity is an important IL physical feature that regulated ILs application. Actually, the ability of ILs to dissolve solutes is determined by their polarity. Structural architecture could play a crucial role to dissolve a variety of nonpolar molecules in addition to polar or charged solutes [64–66]. Additionally, it also indicates specific/nonspecific combined strength of solvent–solute interactions, i.e. solvent strength. The specific solvent–solute interactions are very simple to understand and are observed in ordinary molecular solvents, while nonspecific interactions are very complex to understand as well as unpredictable [50]. As a result, empirical solvents polarization study was conducted. To assess the IL’s solvent concentration, fluorescent probes are routinely employed. For instance, three different fluorescence markers (e.g. pyrene, bromonaphthalene, and pyrenecarboxaldehyde) were used to measure the 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide IL properties [45]. In addition to this, recently, microwave/EPR spectroscopy, 2-nitrocyclohexanone tautomerism approach, FT-IR probe (Fe[CO]5 ), and combined density functional calculations (DFT)-mounted FT-IR were adapted to assess ILs polarity [64, 67].

3.2.9

Diffusion

Diffusion (intradiffusion and interdiffusion) is another prime physical property that regulates ILs interaction mechanism, their transit across environmental compartments, and finally their application. Fick’s law of diffusion and Nernst–Einstein and Stokes–Einstein equations are generally employed to define diffusivity of IL [46]. According to Fick’s law of diffusion, diffusivity is defined as follows [68]: 𝜕c J = −DAB 𝜕x where J represents the flow of substance amount over small area under a short time period; DAB represents the diffusivity or diffusion coefficient; C indicates the

3.2 Physicochemical Properties of Ionic Liquids

substance concentration; and x denotes the substance’s length. D is determined by fluid viscosity, temperature, particle size, and solvent–particle interaction. Intradiffusion coefficients are important indicators of solvation, as well as solution’s dynamics and structure. Self-diffusion of ILs is studied more than interdiffusion to explore reaction rate and liquid–liquid extractions rates. The counterion employed to make an IL has a strong relationship with its diffusivity. In addition to this, IL’s diffusion coefficients are strongly regulated by ion aggregates and ion pairs [68]. Taylor dispersion technique is often employed to measure IL’s diffusion coefficients. The IL’s diffusion coefficients in water at infinite dilution elevated with temperature, generally ranging from 0.9 to 1.5 × 10−9 m2 s−1 at 303 K. Further, IL’s diffusion coefficients are directly proportional to their molar mass, which can be easily measured by Wilke–Chang model. Wilke–Chang model is defined as follows [68]: DAB = 7.4 × 10−12

(𝛹 MA )0.5 T 𝜂A VB0.6

where 𝜓 represents the solvent’s association parameter (water = 2.26104 ), M A represents the solvent’s molar mass, V B represents the solute’s molar volume.

3.2.10 Vapor Pressure Vapor pressure is another important physical property that regulates IL applications. ILs have emerged as novel alternatives to volatile organic compounds (VOCs), which have historically been used as industrial solvents. More specifically, ILs have been widely utilized in green chemistry for developing environmentally benign clean technology as ILs do not produce observable vapor pressure. Accordingly, azeotrope generation during distillation process between the products and solvents does not happen. On the other hand, water-sensitive chloroaluminate-based RTILs generate a lot of HCl when exposed to air, which necessitates restriction toward oxide contaminants and moisture. Consequently, ILs based on chloroaluminates have been restricted to a small number of organic materials, like Friedel–Crafts materials [45]. Accordingly, more water- and air-stable ILs have been developed recently like hexafluorophosphates or tetrafluoroborates or other freshly created ILs to improve their potential applications in diverse applications.

3.2.11 Miscibility Miscibility is another important physical property. IL solubility/miscibility can be fine-tuned with respect to anionic/cationic structural alteration, despite the fact that ILs have outstanding solvents properties for a variety of substances. Cationic modification regulates the IL’s miscibility by two pathways: (i) exhibiting similar IL polarity with other fluids and (ii) producing free spaces between ions by large side strands (actually chain). For instance, when alkyl group contains < 6 carbon atoms, ([RMIM][BF4 ]) ions are water miscible at 25 ∘ C, but in the presence of 6 or above C atoms produce a second phase with water [45]. As a result, ([RMIM][BF4 ]) displayed lower solubility in polar solvents like water as longer alkyl chain possess greater hydrophobicity and lower polarity. The analysis of 1-octene dissolution

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in four distinct tri-n-alkylmethylammonium-tosylate at 80 ∘ C is another example of cationic influence on miscibility. The 1-octene solubility increases with the elevation carbon atoms, and this is probably due to 1-octene’s low polarity and wider free space. Newly generated 3-alkoxymethyl-1-alkyl-based ILs do not really combine with water due to their anti-electrostatic properties; however, they are miscible in chloroform, DMF, acetone, and ethyl acetate [45]. The anionic modification displayed, on the other hand, greater impact on IL’s miscibility property. ILs having anions like Br− , Cl− , I− , [CF3 COO]− , [Al2 Cl7 ]− , [CH3 COO]− , [NO3 ]− , and [AlCl4 ]− , for example, are miscible in aqueous solution, whereas ILs having anions like[(CF3 SO2 )2 N]− , [PF6 ]− , [BR1 R2 R3 R4 ]− , for example, create biphasic mixed water. On the other hand, the solubility of [CF3 SO2 ]− and [BF4 ]− are totally dependent on cation’s characteristics [45]. According to Bonhote [45], if the IL’s dielectric constants are greater than a particular threshold (anion–cation pair combinations), they may be totally miscible with organic solvents. In this example, the anion has a far greater impact on miscibility than the alkyl chain change.

3.3 Conclusion and Perspectives ILs have exhibited superior activity in a number of applications, including isolation, catalysis, organic synthesis, and material preparation, resulting in a quick transformation into a global science and research hotspots. This resulted in a massive rise in the amount of physicochemical characteristics data, laying the ground work for IL screening and designing. Accordingly, in this chapter, an attempt have been made to accumulate all the physicochemical features of IL. Although a substantial advancement on ILs have been achieved, the following IL properties or issues should be addressed in the future to improve further knowledge on ILs such as (i) certain ILs are simple to distil or distillate, (ii) certain ILs have a lower polarity, (iii) certain ILs have been shown to be poisonous and detrimental to the environment, (iv) generally, ILs coordinate, and (v) molecular layout could be used to manage the stability of ILs. Finally, hope these accumulated IL properties will help the researcher to improve their knowledge and to develop new and tunable ILs for the sake of humankind.

Acknowledgments The authors thank the principal of Sukanta Mahavidyalaya for his continuous support and encouragement during the COVID-19 pandemic.

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4 Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable? Helen Treasa Mathew 1 , Kumar Abhisek 1 , Shashikant Shivaji Vhatkar 1 , Arvind Kumar 1 , and Ramesh Oraon 2 1 Department of Metallurgical and Materials Engineering, Central university of Jharkhand, Ranchi, 835205, India 2 Department of Chemistry, Central University of Jharkhand, Cheri-Manatu, Ranchi, 835222, India

4.1 Introduction The global science community is vowed to the advantageous principles and techniques put forward by green chemistry to foster benign, nontoxic, and readily degradable products in the chemical sector. The current scenario reveals that manufacturing processes that depend on highly reactive reagents and solvents can be consequential and toxic with their exposure or release. In addition to that, when the qualitative analysis of the products is taken into account, it unintentionally neglects the heap of environmental and/or health hazards. The nurturing of a sustainable scientific civilization requires the assimilation of the principles of green engineering and the concepts for better yield and performance to evaluate the products, reagents, and methods of manufacturing prior to processing. However, to transmute the whole method, substitutes for the conventionally used solvents and introduction of newer methods of degradation will necessitate the integration of scientific explorations and culture blended with novel techniques that should start at the molecular level. Hence, the functionality of the resultant products should be governed, considering the multitude of adverse effects when released into the environment. The choice of ionic liquids (ILs), proclaimed as “green solvents,” as a major solvent in different chemical processes has been a prolific alternative to the volatile organic compounds (VOCs) and keeps the manufacturing sector more environmentally friendly and nonhazardous. ILs are organic compounds that are fully composed of ions and are fluidic in nature at a temperature of less than 100 ∘ C [1]. ILs, being solvents, owing to their electrostatic characteristics between the ions, persist as a nonflammable, non-inhalable solvent with negligible vapor pressure, high material miscibility, and high thermal, chemical, and electrochemical stability [2]. They are safe for exposure to a certain level. ILs possess organic cations, such as imidazolium, pyridinium, aliphatic ammonium, alkylated phosphonium, and Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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sulfonium ions. However, anions can be both inorganic and organic ions [3]. ILs with their exceptional properties act as “designer solvents,” as they can be tuned by combining selected cations and anions, creating the possibility of designing ideal electrolytes for batteries, supercapacitors, actuators, dye-sensitized solar cells, and thermo-electrochemical cells [4]. With the increase in the demand for energy storage mechanisms, the vitality of high-performance, environmentally friendly batteries and supercapacitors is increasing day by day. In this scenario, ILs can be viewed as green electrolytes that promise enhanced electrochemical efficiency and can be used for energy conversions. Room-temperature ILs (RTILs) have been endorsed as the most suitable ionic solvents referring to their characteristic properties, for instance, temperate ionic conductivity of nearly 0.01 S cm−1 , enhanced thermal stability within a temperature range of 400 to 500 ∘ C, and exceptional electrochemical stability ranging from about 4.0 to 6.0 V [5]. They also possess inherent properties like nonflammability, nonvolatility, marginal vapor pressure, and reasonable plasticization potential, and can easily be merged with organic solvents [6]. ILs with their exclusive properties are being used in various other applications like catalytic synthesis [7, 8], biocatalysis [9], coordination chemistry [10], and analytical chemistry [11]. The ILs are self-organized solvents that inculcate high polarity and can synthesize crystalline nanoparticles at ambient temperatures by carrying out highly polar reactions within them, provided without or with a controlled amount of water. This noticeable organization of the solvent acts as a tool for the synthesis of self-aggregated, well-organized hybrid nanostructures with unsurpassed quality [12, 13]. They not only provide an amiable chemical environment, but also acts as templating and stabilizing agents in nanoparticles’ fabrication. According to David et al., ILs can be deployed for capturing carbon dioxide chemically [14]. However, utmost care should be taken when proposing any IL for CO2 capture, as they have to be engineered contemplating its potential toxicological effects when released in considerable amounts. If the CO2 capture system itself remains a threat to the external environment, then there would be an unintentionally produced excess pollution, and the replacement with VOCs would have been futile. In this chapter, the applications of the ILs as green solvents in various chemical sectors for different processes have been discussed. The key point to be focused on is the fact that although not every IL is nontoxic, they can be tuned to receive the required properties. There are a multitude of ion combinations that upshot the emergence of an IL exhibiting a unique set of features, asserting the concept of making the ILs green, even though they are not intrinsically green, taking the principles of green chemistry into consideration. The chapter also traverses through the toxicity assessment of the ILs when released in considerable amounts into the environment. The toxicity of the precursor ions can also be retained in the newly engineered ILs. However, the measurements of toxicity should be done with respect to certain standards, which are to be discussed further in the journey. The chapter also deals with the biodegradable and the biorenewable ILs. Also, we feature IoNanofluids, their properties, applications, and whether they can be degraded biologically, as well as evaluate the behavior of ILs when integrated with nanoparticles.

4.2 Toxicity and Biodegradability of Ionic Liquids

4.2 Toxicity and Biodegradability of Ionic Liquids The chemical sector has discerned the fact that ILs can thrash conventionally used solvents as they are well recognized for their green nature. However, there is no assurance granted that they cannot impart any harmful effects when released into the external environment. Although their effects are minimum in air, the degree of contamination of water bodies and soil resulting from unintentional release or improper treatment methods for wastewater, straining of landfill sites, or through effluents is very high. Hence, their existence in air, water, and soil can account for biodegradation, penetration into groundwater, and bioaccumulation in aquatic as well as terrestrial organisms, and ecotoxicity is crucial as we focus on a cleaner environment. Suitable choice of anionic and cationic combinations can forbid the chances of hazardous effects to some extent. An obvious fact is that, normal ILs are composed of large organic cations, such as imidazolium and pyridinium, with alkyl chain substituents, whereas the anions can be hexafluorophosphate (PF6 − ), tetrafluoroborate (BF4 − ), bis(trifluoromethylsulfonyl)imide (Tf2 N− ), dicyanamide (N(CN)2 − ), halides, and nitrates [15]. The important fact prevalent is that the precursors used in making these liquids are marked with recognized hazard symbols, for instance, 1-methylimidazole as corrosive, sodium dicyanamide as harmful, and Li [Tf2 N] as toxic. As these ILs are easily tunable to attain required features, they are readily employed in applications such as separation of liquids, in fuel cells, extraction, and the synthesis of elemental materials like gels and membranes, deprioritizing their toxicological effects [4, 16–18]. In addition to that, the ILs can be functionalized with organic compounds, such as acids, alcohols, amines, urea and thiourea, glycidyl chains, phosphonyl, and ferrocenyl groups, thereby perplexing the study of toxic nature of ILs [19–23]. There was a tremendous increase in research toward the toxicity assessment of ILs concerning the disputes among the different chemical sectors. The assessment was done by the scientists to check the toxicity of certain ILs on various organisms of aquatic and terrestrial ecosystems and potential exposure to ILs was found to be hazardous to them, eventually dilapidating the green visage of ILs. The degree of consequences is influenced by the structure of the ILs, the parameters or standards of the experiment, and the nature of the organism on which they are being tested. Hence, the generalized perception of all ILs as green solvents was thrashed, and an increased concern for nontoxic ILs was entrenched. Let us trench into the depths of the studies perpetuated by the researchers on the toxicity assessment of ILs. Figure 4.1 shows the toxicity grading of different cations and anions and their structural effects.

4.2.1

Toxicological Effects and Toxicity Mechanisms of ILs

Various studies were conducted to estimate the harmful effects of ILs on the organisms of the biosphere. Wells et al. evaluated the toxicological and ecotoxicological effects of a few ILs on freshwater algae and Daphnia magna, a freshwater invertebrate, following Organisation for Economic Cooperation and Development (OECD) standard methods, thereby exposing the toxicity levels [25]. Ecotoxicity

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4 Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable?

Cations

Anions Less toxic Guanidium, morpholinium, cholinium, dicationic moiety, sulfonium, protic moiety, with few substitutes or small alkyl chains, hydrophobic functionalization with ester or hydroxyl groups

Less toxic Halides, anions with small molecular volume, hydrophilicity, high Brønsted acidity or functionalized with amino acids

Highly toxic Highly toxic Imidazolium, phosphonium, ammonium, pyridinium, quinolinium, cations with hydrophobic compunds (e.g. aryl), long alkyl chain, many substitutes or with herbicide-, menthol-, ampicillin-, theophylline-based bioactive molecules

Cations, hydrophobic structures, metalcontaining molecules (e.g. GdCl4, MnCl4, and CoCl4), Unstable in aquatic environment (e.g. BF4, PF6, and SbF6), bioactive molecules

Figure 4.1 The comprehension of the toxicity assessment of the cations and anions. Source: Adapted from Cho et al. [24].

was approximately 104 –106 times higher than methanol and showed an increased degree of toxicity toward the bioremediating microorganisms prevailing in the biosphere that may slow down the nitrification process. Even though ILs by virtue of their nonvolatile nature reduce the risk of air pollution, they can create significant water contamination when released into aquatic environments. Their study thus highlighted the fact that the choice-suitable ILs play a special role in keeping a benign chemical environment when used as potential solvents and when released into aquatic ecosystems. The presence of certain head groups can add to the toxicity of ILs in the aquatic environment [26, 27]. Ranke et al. studied these effects on a marine bacterium (Vibrio fischeri), a limnic green alga (Scenedesmus vacuolatus), and a freshwater plant (Lemna minor) to engineer a novel molecular design of ILs that pave the way toward a biodegradable IL with demeaned hazard potential. The toxicity values showed a reduction in the test organisms with the introduction of short functionalized side chains replacing the nonpolar alkyl chains. Additionally, the indication that the membrane system of the test organisms is the target location for the toxic action, displayed by the strong interactions of hydrophobic IL cations with two common biological lipid bilayers, proclaims that the choice of a suitable structure can also result in the declination of hazardous effects of ILs. In 2018, Xu et al. investigated the toxic effects of ILs to wheat (Triticum aestivum L.) using three imidazolium-based ILs with various other anions, namely 1-octyl-3-methylimidazolium tetrafluoroborate ([C8 mim]BF4 ), 1-octyl-3-methylimidazolium chloride ([C8 mim]Cl), and 1-octyl-3-methylimidazolium bromide ([C8 mim]Br) [28]. The experimental results revealed the inhibitory effects on the saplings of wheat due to all three ILs and generated reactive oxygen species, inducing reactive oxygen stress, owing to the inflation in MDA and/or H2 O2 contents. In 2020, Xu and his coworkers studied the

4.2 Toxicity and Biodegradability of Ionic Liquids

effect of these three anion-based ILs on Vicia faba, which also triggered reactive oxygen species formation, thereby causing oxidative damage, lipid peroxidation, protein disruption, and DNA damage, promoting an increase in antioxidant content and enzyme activity [29]. In both the studies the inference could be that the oxidative damage is the initial underlying mechanism of IL toxicity in these plants. Zhu et al. found in their study of growth performance and antioxidative response of microalgae (Anabaena cylindrica, Chlorella pyrenoidosa, and Dunaliella salina) to certain ILs ([BMIM]Br, [BMIM]Cl, [EMIM]Cl, and [EMIM]EtOSO3 ) that these ILs are capable of demeaning the chlorophyll content in microalgae, enhancing ROS levels, activities of superoxide dismutase, and malondialdehyde contents in the majority of the cases, when fed at higher concentrations (Table 4.1) [30, 31]. Figure 4.2a,b illustrates the effects of the ILs with long alkyl chains on rat C6 glioma cells and V. fischeri, respectively [32]. Zhao et al. in 2007 pondered in a review of ILs and their toxicological effects on the aquatic environments, microorganisms, cyto-systems, and animals and came up with the idea of biodegradable ILs for future applications [33]. Ruokonen et al. studied the impact of 11 ILs based on amidinium, imidazolium, and phosphonium on the zebrafish (Danio rerio) and Chinese hamster ovary cells (CHO). Though long-chain ILs were more toxic for the organism, the long-term investigations suggested that there are no considerable effects on the behavior, breeding, or histology of zebrafish when used within the moderate concentration range [34]. Another Table 4.1 The log10 EC50 values of some test systems of ILs and few commonly used solvents; V. fischeri and IPC-81 Leukemia cells.

S.⋅No

Chemical compound

IPC-81 Leukemia cells log10 (EC50 /[𝛍M])

V. fischeri log10 (EC50 /[𝛍M])

1

C4 MIM BF4

3.14 ± 0.02

3.55 ± 0.04

2

C4 MIM pTS

3.19 ± 0.2

3.52 ± 0.07

3

C5 MIM Cl

3.16 ± 0.06

—

4

C5 MIM BF4

3.09 ± 0.05

3.14 ± 0.02

5

C6 MIM BF4

2.95 ± 0.08

3.18 ± 0.03

6

C6 EIM BF4

2.26 ± 0.05

2.15 ± 0.05

7

C7 MIM BF4

2.58 ± 0.07

2.44 ± 0.06

8

C8 MIM BF4

1.74 ± 0.06

1.41 ± 0.07

9

C9 MIM BF4

1.65 ± 0.05

0.718 ± 0.04

10

C10 MIM Cl

1.34 ± 0.04

0.498 ± 0.07

11

C10 MIM BF4

0.77 ± 0.08

−0.182 ± 0.06

12

Methanol

6.2

7.00

13

Acetone

>6.8

5.47

14

MTBE

>5.6

3.89

15

Acetonitrile

6.5

5.77

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4 Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable?

1.5

C3MlM BF4 C4MlM BF4 C5MlM BF4 C6MlM BF4 C7MlM BF4 C8MlM BF4 C9MlM BF4 C910MlM BF4

100

Inhibition in %

80 1.0 Viabilities

74

C3MlM PF6 C4MlM PF6 C5MlM PF6 C6MlM PF6 C7MlM PF6 C8MlM PF6 C9MlM PF6 C10MlM PF6

0.5

0.0 –1

(a)

0

1

60 40 20 0

2

3

4

Decadic logarithm of the concentration in ∝M

–4

(b)

–2

0

2

4

Decadic logarithm of the concentration in ∝M

Figure 4.2 The toxicity effect of ILs with long alkyl chains on (a) rat C6 glioma cells where the concentration ranges within 1000 μM (n = 12). (b) Luminescence suppression of V. fischeri (n = 2–6).

analysis conducted on the topic concentrated on the toxicity, bioaccumulation, biodegradation, and mobility of ILs with respect to PBT (persistence, bioaccumulation, and toxicity) and PMT (persistence, mobility, and toxicity) assessment [35]. The study revealed that the sorption coefficient of ILs increases with an increase in the length of the alkyl side chain and is easily quenched by soils rich in organic matter. Although ILs are not spontaneously disintegrated, they are potentially able for bioaccumulation according to the initial reports on their interactions with lipids and proteins. Some studies established the fact that different types of soils and sea sediments can adsorb the hydrophobic long-chain ILs, imidazolium and pyridinium cations, relatively more firmly than the short alkyl side chains and functionalized derivatives that contain hydroxyl groups [36]. The latter ILs restrict the smooth transport of substances through the crust layer as they are lightly held back by the adsorption within the non-interlayer clay systems, which could result in the deterioration of the ground and surface water reserves. This is an indication that the hydrophobic nature of the ILs directly influences their existence and transport in the environment. The endurance of the hydrophobic ILs as permanent pollutants in the nature is because the sand/soil could imbibe them within the crust, whereas the mobile hydrophilic ILs could more easily linger in the aquatic ecosystems. Hence, different types of soils may possess different IL sorption rates as they have dissimilar size distributions for sediments, organic matter present, ionic interactions, pH values, and cation exchange capacities [37]. Over many years, various studies were conducted on the toxic influence of ILs on the biological systems such as cells, plants, enzymes, bacteria, vertebrates, and invertebrates. The cell membrane of Escherichia coli was disturbed when exposed to a set of choline and geranate (CAGE)-based ILs [38]. In 2016, Dickinson et al. studied the toxicity of imidazolium-based ILs as they intervene into the mitochondrial membrane of Saccharomyces cerevisiae on prompting hyperpolarization of this membrane [39, 40]. At the end, there was reactive oxygen generated as a byproduct, subsequently leading to the cell death of the organism under study.

4.2 Toxicity and Biodegradability of Ionic Liquids

Kumar et al. examined the effect on the structural properties of increasing chain lengths in [CnMIM]+ of lipid bilayers and opined that the long chains in cations disrupted the plasma membrane and the permeability rate, and hence cytotoxicity has to be taken seriously into account [41]. Dolzonek et al. studied the ability of ILs for bioaccumulation along with the toxicity analysis. The bioconcentration factor (BCF) was found by considering experimental membrane partitioning of the cationic (imidazolium, pyridinium, pyrrolidinium, and phosphonium) and anionic ([C(CN)3 ]− , [B(CN)4 ]− , [FSO2 )2 N]− , [(C2 F5 )3 PF3 ]− , and [(CF3 SO2 )2 N]− ) combinations or individually [42]. Strong affinity toward phosphatidylcholine bilayers was shown by both cations and anions, which eventually led to the high membrane–water partition coefficient that corresponds to BCFs with recognizable bioaccumulation potential and falls under the classification of Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). In 2018, Ruokonen et al. studied the viability of ILs on mammalian and bacterial cells using different analytical methods and cytotoxicity assays [43]. Hemolysis was conducted with human red blood cells in such a way as [P444-14] [1COO] incited RBC disruption when the concentration of the IL overpassed its effective concentration, or EC50 value. The results can be used to categorize the ILs into three groups with respect to their cytotoxicity mechanisms. The first group of ILs disrupts the cell wall; the second group induces toxicity by penetration as well as by metabolic alteration; and the third group influences only the metabolism in cells. Various histopathological studies revealed that ammonium-based ILs displayed morphological alterations, deteriorating the cell structures in the cell wall and special organs like gills. A study conducted to determine the biocidal effects of imidazolium-based ILs on living breast metastatic cancer cells (MDA-MB-231) manifested that ILs are capable of revamping the total rigidity and morphology of the cells [44]. Diego et al. monitored the influence of various bromide-based ILs, with phosphonium and ammonium cations, on D. magna, Aliivibrio fischeri, and Raphidocelis subcapitata. Results revealed the dependence of toxicity on the type of biomodel chosen. A. fischeri exhibits least sensitivity, whereas D. magna seemed to be adversely affected when exposed to the ILs under examination. The toxicological effects of phosphonium moieties are comparatively less severe as compared to ammonium ILs. Additionally, a remarkable forecast regarding the oral toxicity and carcinogenic effects of ILs under study is also made. Their structural properties suggest that they might be predominantly toxic but are not potentially able to trigger any genotoxic or nongenotoxic carcinogenicity [45]. There are various methods to determine the toxicity of different solvents. As we look at the toxicity analysis of ILs, it is crucial to get to know the exact component of the ILs that affects the bioactivity of the testing organisms and the response that they express toward IL toxicity. Practically, the experimentally detected and estimated toxicity values of ILs based on toxicity monitoring systems (TMS) and quantitative structure activity relationship (QSAR) models, respectively, are confusing as there are factors like experimental conditions, deployed software, and statistical analytical methods that affect the value. Even the identical ILs may exhibit dissimilar toxicity values on the basis of the TMS type used in the experiments. These elements

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add to the difficulties to determine the exact toxicity values for the ILs. In order to resolve that issue, the baseline toxicity was found and also its association with each IL toxicity dataset. In 2022, Kang et al. instigated a predictive model using the atom surface fragment contribution (ASFC) method for measuring the toxicity of ILs. They segregated a toxicity dataset of 140 ILs toward leukemia rat cell line (ICP-81) and utilized it to train and validate models [46]. Protic ILs (PILs) are generally considered to be green and nontoxic and are widely used as solvents in industries such as noncorrosive lubricants. However, the evaluation of the toxicity of PILs, 2-hydroxyethylammonium oleate, N-methyl-2-hydroxyethylammonium oleate, and bis-2-hydroxyethylammonium oleate, on the biological models E. coli and zebrafish embryos, which adapt within an aquatic habitat and human body, revealed that there was no E. coli bacterial growth inhibition, whereas it led to the death of human skin cells. The zebra fish embryos are also being influenced with sublethal consequences at lower concentrations, for instance, hatching retardation, low heart rate, and the absence of free swimming [47]. In 2021, another notable investigation was conducted on a library of 24 L-phenylalanine-derived surface-active ILs (SAILs) that possess cationic head groups (pyridinium, imidazolium, and cholinium) and alkyl ester chains (C2 to C16 ) and their contribution toward ecotoxicity, with R. subcapitata and aquatic crustaceans Thamnocephalus platyurus. The results proclaimed that only PyC2 and CholC2 SAILs were ranked as less toxic owing to their EC values (EC50 > 100 mg/L). The fate of the algae is more lethal than that of the crustaceans under study [48]. On reviewing these toxicity assessments, one can conclude that the most commonly used ILs are nonbiodegradable and can be structurally flexed to obtain desired biodegradable and biorenewable properties.

4.2.2

Scope of Biodegradable and Nontoxic ILs

The ILs are not intrinsically benign solvents that expose a high degree of toxicity and can cause bioaccumulation upon reviewing their structural components. They also generate issues like waste production during synthesis and separation processes. Predictive QSAR models contribute a prudent chance to research the structural nature of ILs toward different physicochemical and toxicological destinations subsequently resulting in the design of solvents that are nontoxic and degradable, with enhanced process selectivity [49]. The scope of the biorenewable and biodegradable ILs is also evaluated in various studies. The stability characteristics of ILs have to be taken into account while talking about their environmentally degradable nature when used in operational quantities [50]. As observed in the previous section, the structural and functional properties and their association with toxicity mechanisms should also be studied prior to designing novel eco-friendly green ILs. These factors include the length of alkyl side chains of cations, presence of positively charged atoms in anions, nitrogen in cationic aromatic rings, polar head groups, molecular size, and branching of side chains which impart toxicological effects on the organism under study [51]. Scammells and his coworkers designed, prepared, and critically studied the biodegradable nature of the amide/ester comprising ILs within their alkyl side chains. The study revealed that new biodegradable ILs can be successfully prepared by incorporating

4.2 Toxicity and Biodegradability of Ionic Liquids

the factors improving the biodegradation of surfactants into them. Besides, the integration of groups that are feasible toward enzymatic hydrolysis highly enhances the biodegradation when compared with the conventionally utilized dialkylimidazolium ILs like bmimBF4 and bmimPF6 . The highest rate of biodeterioration was seen in 3-methyl-1-(alkyloxycarbonylmethyl)imidazolium bromide series, when the alkyl group was butyl, pentyl, hexyl, and octyl, whereas the amide-containing group was found to be the least biodegradable. They again worked toward more readily biodegradable ILs and concluded that the octyl sulfate anion is relatively more biodegradable than the other anions, and the introduction of an ester group in the side chain of the 1,3-dialkylimidazolium cation leads to biodegradation values very close to the pass level of the closed bottle test. The closed bottle test along with CO2 headspace test proved that the integration of these groups contributes to predominant enhancements in biodegradability of the ILs [52]. On reviewing the structural influence on the toxicity mechanism, one could find that the long alkyl chains are more toxic, whereas the less toxic short alkyl chains reveal a risk of persistence and sorption to organic matter and clay minerals, which are blocked as they do not possess appreciable biodegradability and have reduced mobility. As a result, new methods and suitable pristine precursors such as organic acids, amino acids, sugars, choline, or urea have to be introduced to fulfill all the criteria demanded to design a completely benign solvent. Davis et al. put forward the usage of nontoxic precursors of saccharin and acesulfame in the preparation of new ILs. These alkali-metal salts are introduced into IL as anions, and they present characteristic features more similar to those of certain fluorous anions than those of common carboxylates that are more environmentally friendly [53]. Kau et al. describe the engineering of a class of nontoxic ILs by employing amino acids and their derivatives as cations and some biodegradable materials as anions, and the resulting ILs possess the features of imidazolium ILs with the same chirality as natural amino acids [54]. All the properties of these new versions of ILs were similar to those of the conventional ILs and were more environmentally biodegradable with negligible toxicity effects. Efforts were made to design fully green ILs and hence they were further modified using degradable inorganic or organic anions like saccharides and NO3 − , which thereby gave rise to a new generation of fully green ILs. It is an important fact that ILs can be utilized as a catalyst as well as a solvent. Hou et al. investigated the toxicity and biodegradability of cholinium amino acid ILs toward enzymes and bacteria, and they were found to be less toxic and readily biodegradable as they obtained to 62–87% of mineralization [55]. Hence, the low-lethal and high-biodegradable [Ch][AA] can be regarded as a promising candidate for use as an environmentally amiable solvent in large-scale industrial and chemical applications. In 2014, Bubalo et al. briefed the elements of risk in using the ILs in various applications and also suggested the formation of biodegradable ILs that can inherently be nontoxic [56]. Low toxicity is observed while incorporating alkyl sulfates, linear alkyl sulphonates, linear alkyl benzene sulfonates, and organic acid salts as anions, which are highly endorsed in the applications owing to their biodegradable nature and thereby minimizing the usage of fluorinated anions. Docherty et al. carried out an analysis on the biodegradability of six ILs with the help of activated sludge microorganisms gathered from the South Bend Wastewater Treatment Plant, Indiana, prior to their release into the environment.

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The examination was conducted on 1-butyl, 1-hexyl, and 1-octyl derivatives of 3-methyl-imidazolium and 3-methyl-pyridinium bromide compounds, considering the standard OECD dissolved organic carbon die-away test, and found that there is complete mineralization of the hexyl and octyl substituted pyridinium-based ILs, whereas the imidazolium-based ILs exhibited partial mineralization [57]. Harjani et al. also studied to the biodegradability factor of pyridinium-based ILs with an ester side chain moiety using the CO2 headspace test (ISO 14593). These ILs were synthesized from either pyridine or nicotinic acid and portrayed exceptionally increased levels of biodegradation under aerobic conditions and were considered to be “spontaneously biodegradable ILs” [58]. Another study was on the bacterial toxicity, environmental biotransformability, corrosive nature, and miscibility of PILs in various types of lubrication oils. The result shown was that PILs are poor to moderately biodegradable and less toxic solvents whose environmental properties are more feasible than zinc dialkyldithiophosphate (ZDDP), which is utilized as the reference lubricant additive in industries. Among them, five PILs were noncorrosive toward steel [59]. It was thus established that PILs are much favorable than the classical substituted imidazolium and pyridinium chloride talking in terms of toxicity as well as biodegradability. In 2021, Morandeira et al. designed ILs using biocompatible and biodegradable choline cation and oligopeptide-based anion so as to utilize them as green solvents in biotechnological industrial sectors, in particular for microalgae biorefineries [60]. In 2022, tetrabutylammonium-based ILs were designed to inhibit the amyloid aggregation of superoxide dismutase 1 (SOD1) and were found to be degradable and less toxic [61]. A design of magnetic ILs with the introduction of magnetic moieties into the structure of ILs was established and exploited the catalytic property of ILs [62]. The major advantage is the recyclability of these catalysts with the aid of an external magnetic source. Hence, magnetic (poly) ILs can be synthesized further to obtain sustainable green catalysts.

4.3 Applications of Ionic Liquids as Green Solvents We have so far traversed through various aspects of the toxicity and biodegradability of different kinds of ILs. As a result, it is inferred that green ILs are the ones that we can create or redesign by considering the principles of green chemistry, requirements for the solvents in particular applications, recyclability, ecotoxicity, and biodegradability of the ILs. It may vary from one application to another. Here in this section, we are traveling across various domains where ILs are employed as green solvents tuning their ionic configuration in order to accomplish biocompatibility to a certain extent (Figure 4.3).

4.3.1 Ionic Liquids as Green Solvents in Biomass Utilization and Extraction The structural complexity of the biomass can be overviewed as a factor that makes biomass dissolution and utilization a sinuous area. It is observed that ILs can

4.3 Applications of Ionic Liquids as Green Solvents

Electrochemistry

* Batteries * Solar panels Pharmaceutical industry

* Fuel cells Chemistry

* Drug delivery

* Catalysis

* Active ingredients

* Polymerization

* Synthesis

Ionic liquids Others * Nanomaterials

Coating * Surfactants

* Liquid crystals * CO2 capture * Protein purification

* Lubrication Chemical engineering

* Metal deposition

* Separation * Extraction * Liquid membrane

Figure 4.3 et al. [63].

Applications of ILs in various sectors. Source: Adapted from Thuy Pham

effectively and selectively solvate the plant cell walls and/or remove hemicellulose and lignin within mild reaction conditions in many biomass-related applications. Recently, the reduction of rice husk into sugars was done by utilizing ILs. Rice husk is a lignocellulose-rich residue obtained from the agricultural sector which can be used in the production of second-generation ethanol with the necessary treatment. The structural sugars are released on biomass pretreatment as there are recalcitrance-related properties of lignin and silicon. The use of a long-chain imidazolium IL, [C16 MIM] [Br− ] resulted in a larger concentration of reducing sugars relative to untreated biomass. This study thus proved that the solid ILs along with water could be employed as effective alternative solvents for lignocellulosic biomass pretreatment [64]. Another lignocellulosic biomass degradation of wheat straw was conducted using ILs as they are bio-based salts that are renewable, recoverable, and difficult to oxidize. The chemical pretreatment results in the attenuation of cellulose up to 59% and lignin up to 69%, and the biodegradability is extremely high with 88.3% [65]. A comparative study on the extraction of polysaccharides from a large number of biomass resources, including lignocellulosic materials and food residues, done with the help of ILs and deep eutectic solvents (DESs) is conducted. Both solvents under examination are potentially able to solvate and extract the most profuse polysaccharides, particularly cellulose, chitin, starch, hemicelluloses, and pectins, which are from natural resources [66]. Another study was conducted by He et al. on levulinic acid-based PILs as potential solvents for the dissolution

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4 Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable?

pretreatment of cellulose toward enhanced enzymatic hydrolysis. The researchers were looking forward for economically viable and sustainable methods. This solvent system was found to be appreciable for the sugar production through dissolution pretreatment of corn stover-based lignocellulosic biomass, besides the requirement for higher temperature and longer duration. Recyclability and reusability can be identified as the most highlighting feature of this approach [67]. The investigation on the usage of PILs specifically triethylammonium hydrogen sulfate (TEAHSO4 ), 1-butylimidazolium hydrogen sulfate (HBIMHSO4 ), and 4-methylmorpholinium hydrogen sulfate (HMMorpHSO4 ), for the endorsement of biomass at economically feasible conditions were done to evaluate their performance. PILs, used for the pretreatment of the hardwood species, hornbeam (Carpinus betulus L.) put forward the fact that HBIMHSO4 can be used for larger-scale pretreatment of biomass–PIL interactions [68]. More effective, selective, and nonlethal methods have to be introduced to green synthesis of the biomass, its conversion, dissolution, and characterization.

4.3.2

Ionic Liquids as Green Solvents in Energy Applications

The increased energy demands and intermittent renewable energy sources have paved the way toward intensive research in the fields of energy storage and production. ILs can be viewed as a family that provides the necessary and salient structural features so that they can be flexed according to the mode of application they are employed in the energy storage and production sectors. They are used as electrolytes in metal-ion batteries, fuel cells and supercapacitors, in dye-sensitized solar cells, in hydrogen generation by water splitting and thermal storage applications. Kar et al. assessed a novel family of closo-boron-cluster based RTILs for energy storage application, owing to their very low glass transition temperatures, exceptional cathodic and anodic stabilities, and compatibility with metals like Li and Mg, which encourage them as brilliant electrolytic agents for rechargeable batteries and other hybrid devices [69]. The ILs play a significant role as electrolytes and structure-navigating compounds in proton exchange membrane (PEM) fuel cells (PEMFCs). In these cells, the ILs are integrated with polymers like Nafion, poly (vinylidene fluoride), polybenzimidazole, sulfonated poly(ether ether ketone), and sulfonated polyimide and their application as PEM. The results revealed that the presence of certain ILs can enhance the conductivity of the PEM and boost the performance of PEMFCs [70]. The ILs are readily used as electrolytes for electrochemical energy storage devices such as supercapacitors and metal-ion batteries. Mixtures of glyme and aprotic–protic ILs are used as electrolytes for energy storage devices [71]. Amino acid PILs rich in C, N, O, and S elements make them an efficient precursor of N/S codoped carbon materials for high-performance supercapacitors. The Lys-K2 CO3 prepared in this way, possessed a very high specific capacitance of 350 F g−1 at 1 A g−1 . It also exhibited a 100% specific capacitance retention after 5000 cycles at 5 A g−1 in 6 M KOH electrolyte for a three-electrode system [72]. It can also be used in various other domains, owing to its large surface area, outstanding electrical conductivity, environmental amiability, and the potential for the replacement of

4.3 Applications of Ionic Liquids as Green Solvents

flammable solvents. However, the ILs employed should be designed so as to meet the performance rate as well as the biotoxicity.

4.3.3

Ionic Liquids as Green Solvents in Biomedical Applications

According to studies, certain ILs can be employed as antibacterial agents owing to their toxicity factor. Even though the toxicity of the common ILs based on imidazolium or pyridinium cation should be considered, they are specifically used in certain processes that cannot be substituted by any other designed fluid. This may lead to the thought of taking intensive care to handle and dispose of them. Although they possess toxic nature and are forbidden from the courtyard of green chemistry, tunability of these compounds may be used beneficially in the development of antimicrobials and other pharmaceuticals. However, in a study, most of the imidazolium salts were found to be nontoxic (IC95 > 2 mM) to the 12 fungi strains and 8 bacteria strains proclaiming that they are suitable agents for “green chemistry” applications. The Biodegradation ISO 14593 “CO2 Headspace Test” conducted to test the ecotoxicity of two bromide ILs containing L-phenylalanine residues manifest that these ILs go beyond the expectations (>60% in 28 days) and can be classed as readily biodegradable [73]. Although they may act as antimicrobial agents, one should ensure maximum effectiveness with negligible toxicity, preventing the spontaneous ability for the target organisms to become potentially resistant to their application. Ibsen et al. studied the biocidal action of CAGE ILs on the Gram-negative cell wall of E. coli and using molecular dynamics (MD) simulations, it was found that there is a high affinity for choline toward the negatively charged cell membrane, subsequently introducing geranic acid into the lipid bilayer and thereby breaking the cell membrane [38]. The latter was substantiated with propidium iodide staining via flow cytometry and SEM techniques. Further, the treated cells are analyzed with the aid of Fourier transform IR spectroscopy to confirm the breaking down of the lipid bilayer. Another important observation of the study that opens a window toward the pharmaceutical efficacy of CAGE ILs is that, even though E. coli cells were continuously exposed to CAGE, they did not develop any resistance to it. From the toxicity assessment, the biocompatibility of cholinium-based ILs was evident. Palanisamy et al. studied the role of ILs on the structural disruption of main protease (Mpro) of ARS-CoV-2 using the Universal Natural Product Database (UNPD) and they encouraged the research toward antiviral application and Mpro inhibition using these cholinium-based ILs. This can be vital to forbid the spreading of COVID-19 pandemic [74]. The important step for the extraction of human hair is its efficient dissolution in the solvent. In his work, Qin assessed 143 types of ILs and three model compounds to assume the solvation capability of ILs for human hair, employing COSMO-RS, and the structure of regenerated keratin at the end is similar to the human hair [75]. More and more versatile, greener approaches toward various other sectors of the biotechnological industries have to be developed in the upcoming days. ILs have widespread usage as solvents and as catalysts, and their incorporation with other compounds like polymers can extend their applications to vast dimensions. However, we have focused on the very recent studies conducted

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4 Ionic Liquids as Green Solvents: Are Ionic Liquids Nontoxic and Biodegradable?

on energy applications, biomass dissolution and extraction, and biomedical applications.

4.4 IoNanofluids ILs can be identified as the organic salts that are molten and having a very low melting point that is lower than 100 ∘ C [76]. IoNanofluids (IFNs) are an innovative class of fluids characterized as nanoparticle dispersion/suspensions in ILs, and it is a hot topic of research. Due to the recent advancements of RTILs, there has been a huge inquisitiveness among researchers and industries, enabling them to employ and utilize them for a wide range of applications as they possess low melting temperatures (99% yield

Scheme 5.1

Heck coupling in the presence of TBHP and TBAB.

Other disadvantages of the traditional Heck reaction involve catalyst recyclability and the requirement of catalyst greater than 1 mol% for the activation of aryl halides, especially for less reactive substrates like chloroarenes. But by using ILs as

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

solvents, mainly tetra-n-butylammonium bromide [NBu4 ]Br, even less reactive palladium catalysts like PdCl2 and Pd(PPh3 )4 showed excellent activity in the coupling of chloroarenes, but no general conclusion regarding the effect of ILs on these catalysts could be derived. There was no increase in the overall cost of the reaction, and the most important advantage was that the catalyst, as well as the rather expensive solvent, could be recycled efficiently [26]. Molten salts of [NBu4 ]Br were also employed for synthesizing β-arylated carbonyl compounds [27] through the Heck reaction of aryl halides and allylic alcohols using PdCl2 as the catalyst and NaHCO3 as the base at a temperature range of 80–120 ∘ C (Scheme 5.2). R2 R1

R3

PdCl2 NaHCO3 + PhX

n-BU4NBr 80–120 °C

OH

Scheme 5.2

R2 R1

R3 Ph

O

Heck coupling by PdCl2 /[NBu4 ]Br.

The reaction has also been carried out using tributylammonium bromide (TBAB) and various 1-butyl-3-methyl-imidazoline salts, especially [bmim]PF6 in the presence of a Pd catalyst, and Et3 N or NaHCO3 as base [28, 29] (Scheme 5.3). It was observed that separation of the byproducts from the product into a nonpolar solvent became easier. The catalyst and IL could also be recycled and reused. O O

X +

OEt OEt

R

Pd(OAc)2 [bmim][PF6] Base

R= H, –OMe, –NO2, –CHO, –Cl X = Br, I

Scheme 5.3

[bmim][PF6 ]-mediated Heck coupling.

Imidazolium-based ILs are frequently used in organic synthesis as a consequence of their low melting points, favorable viscosities, and their stability in high temperatures. Reactions carried out using imidazolium-based ILs have proved to exhibit much higher catalytic activities than those carried out using pyridinium-based ILs. One of the reasons behind this improved activity is ascribed to the Pd N-heterocyclic carbene complexes formed by the reaction of imidazolium ILs with Pd(OAc)2 [30]. As compared to 27% conversion of the halides to trans-stilbene with 92% selectivity in the reactions carried out [bmim][BF4 ], the Heck reactions performed using [bmim][Br], gave a 100% conversion with 99% selectivity as a consequence of the stable Pd carbene complex forming quite easily in the later. The agglomeration and aggregation of Pd-NPs negatively affect the catalytic behavior of the catalyst. Therefore, ILs have found applications in the in situ generation of NPs as they prevent their aggregation and formation of Pd black. One of the

5.2 Carbon—Carbon Bond Formation Reactions

vital steps in this regard is to graft ILs on solid surfaces to generate a non-leachable, retrievable, and reusable heterogeneous catalyst. Using a mesoporous cage-like material SBA-16, and grafting it with Pd-NHC and imidazolium-based ILs [31], a heterogeneous catalyst system was prepared, which showed better efficiency even after being recycled 10 times. Even by loading 0.01 mol% of the catalyst, a 100% conversion of the inactivated aryl halides was achieved (Scheme 5.4). Being heterogeneous, the catalyst system had further advantages in terms of catalyst separation, easy handling, and product purification. Br + R

Z

0.01 mol% Pd Z

NHC–Pd/SBA–16–IL R

R= H, 4–COMe, 4–CHO, 4–CN, 4–NO2, 4–Me, 4–COMe, 2–CN, 4–NO2 Z = Ph, CO2Me

Scheme 5.4

Heck coupling in the presence of Pd-NHC and imidazolium-based IL.

Chiral ILs (CILs) are used to bring about asymmetry in organic synthesis reactions, and as such, these CILs have been applied in the Mizoroki–Heck reaction to induce chirality in the synthesized product through the formation of a chiral Pd complex. Several reactions were explored using CILs as the reaction media [32, 33] and it was found that the yield and stereoselectivity of the coupling products were greatly influenced by the non-chiral cations found in the CILs. 2,3-Dihydrofuran (DHF) reacts with iodobenzene in the presence of Pd(OAc)2 as catalyst, K2 CO3 as base and [DDA][L-PRO] (DDA = didodecyldimethylammonium cation, L-PRO = (L)-prolinate), [BA][L-PRO] (BA = cation containing C12 H25 and C14 H29 groups), [Bu4 N][L-PRO], and [Bu4 N][L-Lact] (L-Lact = L-lactate anion), resulting in enantioselective products. Especially, when [Bu4 N][L-PRO] and the catalyst were used in the ratio of 2 : 1, excellent results (>99% ee) were obtained pertaining to the influence of the cation on the Pd(0) NPs formed in situ in the reaction, possibly stabilized by the non-chiral cations through electrostatic interactions [34]. The proposed reaction scheme of the coupling that proceeds under the influence of [Bu4 N][L-PRO] is demonstrated in Scheme 5.5.

O + PhI

Scheme 5.5

Pd(OAc)2 [Bu4N][L-PRO] 70 °C, 6 h

O

Ph

H N

OH

N(C4H9)4 O [Bu4N][L-PRO]

> 99% ee

[Bu4 N][L-PRO]-mediated Heck coupling with 2,3-dihydrofuran.

First described in 2009 [35], imidazolium-based tunable aryl alkyl ILs (TAAILs) are a group of ILs that combine the effects of sp3 alkyl groups and sp2 aryl groups

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

at both the N atoms contained in the imidazole ring. This group of ILs can be electronically fine-tuned to have different properties by deliberately changing the substituents on the rings. For example, these tailored ILs were used as media in the Heck reaction of styrene with bromobenzene to produce trans-stilbene (Scheme 5.6). Products with isolated yields up to 97% were obtained, a value higher than those obtained with commercially available imidazolium and phosphonium ILs. The products formed were also confined to the formation of the E-isomer only [36].

R2

Br

[Pd(II)] salt

+ R1

Scheme 5.6

R2

Base, TAAIL 140 °C, 4 h

R1

TAAIL= N

R NTf2

N CnH2n+1

Heck coupling with TAAIL.

In most Heck reactions that employ imidazolium-based ILs as the solvent and ligand-free palladium(II) precursors as catalysts, the actual catalytic activity is shown by soluble heterogeneous Pd molecules resulting from the zero-valent Pd-NPs. These Pd(0) NPs are resulted by the reduction of Pd(II) assisted by a base. ILs as reaction media along with Pd nanoparticles (Pd-NPs) have been observed to show activity in the Heck reaction as ILs prevent the aggregation of Pd-NPs. These soluble Pd-NPs, which are formed in situ in carbon—carbon cross-coupling reactions, behave like a reservoir of active molecular palladium catalysts. Pd-NPs can be synthesized through various methods under thermal decomposition conditions using Pd(dba)2 , Pd(OAc)2 , or Pd-NHC complexes, by reductive elimination with hydrides or molecular hydrogen gas, or by reaction of palladacycles with dienes [37]. Pd-NPs dispersed on the surface of chitosan can be electro-synthesized using a three-electrode cell and used for C—C bond formations [38]. Such fixing of the palladium source to solid supports converts the homogenous catalytic system to heterogenous to avail the benefits of the latter, involving the prevention of leaching of the Pd metal and recovery of the catalyst system [39]. For instance, the Heck coupling reaction between iodobenzenes and unsaturated aliphatic hydrocarbons was significantly accelerated when [1,3-di-n-butylimidazolium bromide (BBI⋅Br) and 1,3-di-n-butylimidazolium tetrafluoroborate (BBI⋅BF4 )] were used as solvents in the presence of Na2 CO3 at 30 ∘ C under ultrasound irradiation (Scheme 5.7). The yield of the trans product was obtained up to 87% and this was attributed to the catalytic activity of the soluble Pd species generated from the Pd(0) particles. Analysis of the reaction through transmission electron microscopy (TEM) and nuclear magnetic resonance (NMR) showed that a Pd-carbene complex is formed first from the palladium acetate catalyst, which then gets converted to the Pd-NPs [40]. Another example is the synthesis of tetramethyl salvianolic acid F by one-pot chemoselective Heck reaction, employing Pd-NPs in IL as catalyst resulting in the highest yield (= 66%) of the salvianolic drug achieved so far [41].

5.2 Carbon—Carbon Bond Formation Reactions

R1

I IL

R1

+

R

R

30 °C ))))))) I +

IL 30 °C )))))))

R

R IL = [(bbim)+Br –], [(bbim)+BF4 –]

R = H, 4–OMe, 4–Cl R1 = COOMe, COOEt, Ph

Scheme 5.7

Formation of C—C bond using alkyne and alkene substituents.

5.2.1.2 Suzuki Coupling

The coupling of air- and moisture-stable boronic acids with aryl halide, vinyl halide, or triflate accompanied by Pd catalysts to yield a cross-coupled biaryl as product is called the Suzuki reaction. Although the mechanistic pathway is quite similar to that of the Heck reaction, the presence of a base (NaOH/NaOMe/Na2 CO3 /K3 PO4 ) is an important requirement in the Suzuki coupling due to the low nucleophilic nature of the boranes. Various reactions have been carried out using ILs as the solvent system instead of the generally used organic solvents like THF, dioxane, or DMF, accounting for green organic synthesis. In keeping with the Heck reaction, implementation of tetrabutylammonium salts as a green solvent in the Suzuki coupling has also been explored, and when used with Pd-NPs supported on chitosan [38], exceptional yields and selectivity of the desired product were obtained. Through hydroxyl functionalization, the hydrophilic nature of ILs can be increased, thereby resulting in increased polarity and dielectric constants of the ILs [42]. Such hydroxyl-functionalized TSILs display remarkable results in Suzuki– Miyaura cross-coupling reactions, addressing limitations like catalyst recyclability and the use of environmentally demeriting catalyst system. This is illustrated by the water-mediated coupling of boronic acids with aryl halides utilizing 1-(2-hydroxyethyl)-1-methylpyrrolidinium prolinate [HEMPy][Pro] as the catalytic system (Scheme 5.8). Higher catalytic activity, ease in product recovery, and the recyclability of the catalyst up to seven cycles were achieved. This dualfunctionalized TSIL showed quite good coupling results even with inactivated substrates like aryl chlorides. The cationic part incorporated with the hydroxyl group influenced the increased reaction rate in aqueous solvent, along with its acting as the reducing agent. The anionic part having the prolinate ion, on the other HO X + R'

Scheme 5.8

R"

B

OH Pd(OAc)2, base, IL H2O, 80 °C

R'' IL= R'

Suzuki coupling in the presence of [HEMPy][Pro] TSIL.

N

OOC OH

H N

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

hand, stabilized the in situ formed Pd-NPs that behaved as the storehouse of Pd(0) molecular species [43]. Polymeric IL, poly(3-(4-vinylbenzyl)-1-methylimidazolium bis(trifluoromethylsulfonyl)imide) poly[vbim][Tf2 N], obtained from an imidazolium salt cross-linked with styrene worked as the catalyst in the Suzuki reaction (Scheme 5.9) under mild reaction conditions although no activity for aryl chlorides was observed [44].

X

B(OH)2

+ R

n Pd, base, IL 35 °C

R= H, CN, NO2, OMe, COOH X= Br, I

Scheme 5.9

IL = N + N

R

Tf2N-

Yield >99%

Suzuki coupling in the presence of polymeric IL, poly[vbim][Tf2 N].

The same IL but with the anionic part changed to chloride to form poly[vbim]Cl, the hydrophobic nature changes to hydrophilic and it becomes capable of stabilizing transition-metal NPs [45]. By attaching one more vinyl group to the imidazolium species, a polymer of 1,3-bis(4-vinylbenzyl)imidazolium chloride [bvbim]Cl, termed as poly[bvbim]Cl is obtained [46]. This system was used to stabilize Pd-NPs in the Suzuki coupling between aryl iodides/bromides/chlorides and phenylboronic acid at a temperature of 100 ∘ C by utilizing as the base (Scheme 5.10). Using water as the reaction medium, a reasonable yield of the products was obtained with all the halides and sterically hindered substrates at a catalyst loading of just 1.7 mol%. When the reusability of this Pd-NP-polymeric IL (PIL) in water was tested using two different aryl iodides, it was found that the PIL can be reused for five catalytic cycles with greater than 90% of its catalytic activity preserved. X

R

(HO)2B

Pd-NP-PIL

R

K2CO3, H2O X=I, Br, Cl R= Me, OMe, CN, NO2,...

Scheme 5.10

12 examples up to 98%

Suzuki coupling in the presence of Pd-NP-PIL.

ILs, specifically tetraalkylammonium salts, have been observed to form biphasic systems in water. This biphasic system, when tested in the Suzuki reaction of p-tolylboronic acid and aryl halides in a ligand-free palladium catalytic system (PdCl2 ), achieved conversions equal to those obtained with toxic palladium systems like (dppf)PdCl2 or (Ph3 P)2 PdCl2 . The catalytic activity, in this case, was also attributed to the Pd-NPs stabilized by the IL [47]. Another Suzuki reaction in a similar biphasic medium comprising an ammonium IL and an aqueous medium of hydroxide ions with free monodispersed Pd-NPs was also performed under mild conditions. Through this reaction, the function played by the cationic part of

5.2 Carbon—Carbon Bond Formation Reactions

the IL on the catalysis could be evaluated. When tetraheptylammonium bromide (THeptAB) having an alkyl chain longer than TBAB was employed, much better catalyst activity was achieved owing to the better stabilization of the Pd-NPs through the protection of the metal core and inhibiting its access by steric hindrance [48]. The use of IL stabilized transition-metal NPs in the Suzuki reaction has been demonstrated in the examples above. However, as compared to the unimetallic NPs, bimetallic mixed NPs outperformed the competition in terms of catalytic activity. Use of Au—Pd-NPs grafted on rice husk ash silica synthesized by immobilizing imidazolium chloride IL as the catalytic system, enhancement in physicochemical properties, higher catalytic efficiency, and easy recovery of the catalytic system with no negative impact on its catalytic behavior were observed [49]. Immobilization of ILs in mesoporous silica (SBA-16) to be used as support for palladium catalysts has been seen accordingly in the Heck reaction. A similar grafting of the imidazolium IL 1-methyl-3-(3-trimethoxysilylpropyl)-imidazolium chloride in a mesoporous cage, SBA-15, was done and used as solid support for the Pd ion. The resulting catalyst, Pd-NPs(2.4 nm)_me-Im@SBA-15, was tested in the Suzuki reaction (Scheme 5.11) and found active as well as reusable for the coupling of aryl halides and phenylboronic acid in aqueous solution [50].

X

B(OH)2 +

R

Base IL rt, 2–6 h, air

R Yield >99%

R= H, Me, OH, OMe X= Br, I, Cl

Scheme 5.11

IL= PdNPs(2.4 nm)_me-Im@SBA-15

Suzuki coupling using IL-supported Pd-NP.

Phosphonium-based ILs are one class of ILs having phosphonium ion as the cation counterpart of the IL that have found applications in carbon—carbon bond formation reactions. This category of ILs compared to those having nitrogen atom is advantageous owing to their better thermal stability up to 400 ∘ C [51], defiance to get decomposed under basic reaction conditions [52], and increased acidity leading to ease in carbene formation along with the unchallenging isolation of the product. So, the PILs found applications in the majority of cross-coupling reactions, including the Suzuki coupling as mentioned in the following examples. Tri-tert-butyl(n-alkyl)phosphonium ILs, having an odd number of methylene units in the alkyl substituents, were designed to form a hybrid catalytic system with Pd-NPs. The PILs having large sterically hindered alkyl groups (C11–17 H23–35 ) provided more stability to the zero-valent Pd-NPs formed by the reduction of palladium acetate in ethanol, through steric factors. On the other hand, those PILs with short CH3 and C3 H7 alkyl chains stabilized the Pd-NPs through electrostatic attractions and showed a reduction in catalytic activity as compared to those PILs providing steric stabilization. However, PILs containing medium-length alkyl group C9 H19

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stabilized the Pd(0) species through electrosteric interactions, i.e., by combined effects of steric and electrostatic factors, and hence depicted slightly higher activity than the others [53]. Some other phosphonium ILs used in catalysis of the Suzuki reaction are tri-tertbutyl(decyl)phosphonium bromide and tri-tert-butyl(decyl)phosphonium tetrafluoroborate. In the phosphonium-cation-based ILs, along with the nature of the cation, their ratio to the palladium source was also observed to have a dependence on the catalytic behavior of the NPs. With just small amounts of the PIL, maximum conversion of 1,3,5-tribromobenzene to 1,3,5-triphenylbenzene was achieved (Scheme 5.12). Using similar structured PILs, a higher yield was obtained in each case for very small ratio of the Pd:PIL systems [54]. Br

Br

B(OH)2 +

0.36 mol% [Pd] PIL

Ph

Ph

30 °C, 16 h Br

Ph

Scheme 5.12

Synthesis of 1,3,5-triphenylbenzene using PIL.

5.2.1.3 Sonogashira Coupling

The coupling of aryl or vinyl halides to terminal alkynes to give disubstituted alkynes in presence of a palladium catalyst, a co-catalyst of copper(I), and a base, typically amines, in stoichiometric amount is known as the Sonogashira reaction. The use of Cu(I) co-catalyst in assistance of a base in the Sonogashira coupling yields an undesired outcome of homo-coupled products involving the acetylene substrates formed in situ. This calls for the maintenance of a completely inert environment while the reaction is performed. Hence, reactions discarding the use of copper have been extensively studied in recent decades, and such reactions have also been studied using ILs. One such example is the use of biodegradable molten salt 3-(alkoxycarbonyl)-1-methylpyridinium bis(trifluoromethanesulfonyl)imide for catalyzing the Cu-free coupling reaction between iodoarenes and phenylacetylene at ambient temperature irradiated by ultrasonic waves (Scheme 5.13) [55]. O

H Y + I

Scheme 5.13

PdCl2/Et3N

O

IL=

Ultrasound, IL Y

N

N(SO2CF3)2

Ultrasound-assisted Sonogashira coupling using IL.

A study related to the mechanism of the coupling of 4-iodotoluene with phenylacetylene in Cu-free conditions depicted that the equivalent of base (generally amines) used should be higher [56]. However, employing basic ILs, the need for a greater amount of base can be minimized while also fulfilling the requirement of a green organic solvent. Cu, as well as external base-free Sonogashira reactions, are

5.2 Carbon—Carbon Bond Formation Reactions

found to be extremely tolerant to moisture and air [57], and hence the reactions need not be performed under inert conditions. This has been possible by the use of choline hydroxide (ChOH), a basic room temperature IL (RTIL) that is hydrophilic in nature. The dual characteristic shown by ChOH acting both as a green reaction medium and a base resulted in moderate to excellent results in the Sonogashira coupling reaction between arylacetylenes and aryl halides (Scheme 5.14) depending on the substrate combination [58]. The mechanistic study of the reaction revealed that ChOH played the principal role in formation of the actual catalyst Pd(0) by reduction of the Pd(II) precursor along with its function of eliminating the hydrogen halide. H OH

Y Pd(PPh ) Cl 3 2 2 + X X= I, Br

Scheme 5.14

ChOH 40 °C

ChOH =

N

OH

Y

Up to 98%

Choline hydroxide and Pd-catalyst-mediated Sonogashira coupling.

The basic TSIL, piperidine-appended dimethyl-imidazolium-NTf2 , also performed dual activities as an environmentally benign solvent as well as a base for synthesizing a variety of diaryl- and aryl-alkyl-acetylene products in a Cu-free or Cassar–Heck coupling reaction. The IL proved to be advantageous in terms of easy isolation of the products, reusability, and recyclability of the IL [59]. One more example is the use of tetrabutylphosphonium 4-ethoxyvalerate ([TBP][4EtOV]), an IL-based on γ-valerolactone (GVL). This biomass-derived IL was also examined under similar Cu and external base-free conditions in the Sonogashira reaction [57]. Reactions between different iodoaromatic compounds and phenylacetylene while using PdCl2 (PPh3 )2 as catalyst resulted in quite good yields of the desired cross-coupled products (Scheme 5.15). When comparing the outcome of the Sonogashira reaction in imidazole-based ILs and GVL-based IL such as [TBP][4EtOV] (tetrabutylphosphonium 4-ethoxyvalerate), it was found that the valerate-originated IL could successfully result in >99% formation of the desired products in the absence of both the toxic triethylamine (TEA) base and the Cu(1) co-catalyst while in imidazole-based ILs the reaction did not proceed in absence of the two. OC2H5 [P( C4H9)4]

Pd(PPh3)2Cl2 H

+ R I

[TBP][4EtOV] 55 °C R= Aryl groups

Scheme 5.15

R

COO

[TBP][4EtOV]

Using IL [TBP][4EtOV] to form C—C bond.

As mentioned previously, using ILs as support for metal NPs accounted for the recovery of the catalyst and prevention of metal leaching. Along with silica and polymers, magnetic nanoparticles (MNP)-based ILs can serve as solid support

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and can show good conversion in the cross-coupling reactions. For instance, Co-NHC@MC, a cobalt N-heterocyclic complex attached to magnetic chitosan (MC) NPs were immobilized on the N-methyl imidazole-based IL [mim]Cl and employed as an alternative to other solid support catalytic systems used in the Cu-free Sonogashira coupling reaction between aryl chlorides with substituted phenylacetylenes in the presence of a base (Scheme 5.16). R1

Cl R1

+

Co-NHC@MC R2

R2

Base, 70 °C

R1= NO2, CH3, OCH3, COCH3, CN, NH2 R2= CH3, OCH3

Scheme 5.16 Reaction of aryl halides derivatives with phenylacetylenes in the presence of IL.

The MC NPs, having a large surface area in relation to their volume, have the added advantage of being isolated without performing workup and with no noticeable loss of catalytic activity after seven cycles [39]. The imidazolium IL works as the stabilizing agent for the NPs possessing a magnetic core covered by an organic shell. The preparation of the catalyst was performed in the following four steps: (i) the reaction of n-methyl imidazole with epichlorohydrin to form [mim]Cl; (ii) shielding of the magnetic NPs synthesized chitosan particles to produce MC through a procedure reported in the literature; (iii) immobilization of the MC on [mim]Cl to produce me-Im@MC; (iv) finally, the reaction of the me-Im@MC with Co(OAc)2 afforded the desired MC-supported Cobalt-NHC catalyst (Co-NHC@MC) (Scheme 5.17). CH3 N

HCl, EtOH

N

Epichlorohydrin

(i)

OH H3 C N

N

CH2Cl

Cl [mim]Cl (ii) FeSO4·7H2O + FeCl3·6H2O (iii) [mim]Cl + MC

Scheme 5.17

Magnetic nanoparticles (MNPs) me-Im@MC

Co(OAc)2

Chitosan

MC

Co-NHC@MC

Synthesis of MC-supported cobalt-NHC catalyst.

Limited studies on the impact of ILs on other cross-coupling reactions like Stille, Hiyama, and Negishi have been carried out. Of the reports available, only a few have been discussed.

5.2 Carbon—Carbon Bond Formation Reactions

5.2.1.4 Stille Coupling

Just as ILs are used to address the different limitations of the previously mentioned cross-coupling reactions, similarly, their use has also been exploited in the Stille reaction to overcome the difficulty of product separation and its key disadvantage in the formation of toxic tin wastes. By grafting tin reagents on TSILs synthesized from 1-methylimidazole and haloalkanes [60], an efficient Stille coupling at low temperature was achieved with a high yield of the cross-coupled products (Scheme 5.18). X Pd(II) catalyst IL

n

X= Br, I

Scheme 5.18

Sn(n-Bu)2Ph

Yield up to 98%

Stille reactions catalyzed by tin reagents supported by ionic liquids.

A further benefit of recycling the tin compounds and reusing it in subsequent reactions was obtained. The recycling of the tin compounds is expected to follow the pathway shown in Scheme 5.19.

IL

Sn(n-Bu)2Ph

n

PhI

Stille cross-coupling

PhLi THF

IL

Scheme 5.19

n

Sn(n-Bu)2X

Ph-Ph

Recycling of IL-tin reagent.

The immobilization of organostananes on TSILs also resulted in the decreased and controlled formation of tin-polluted byproducts under solvent-free conditions. Examples include the Stille coupling of aryl bromides and arylstannanes using 5 mol% [Pd(OAc)2 ] as catalyst at 100 ∘ C for 15 hours (Scheme 5.20) and reactions between anisole- and fluorine-containing tin reagents with heteroaryl or aryl bromides carried out using a similar protocol (Scheme 5.20) [61, 62]. 5.2.1.5 Hiyama Coupling

Discovered by Hiyama et al. in 1988, the Hiyama coupling is employed in organic chemistry for constructing biaryl structures in general through the coupling of aryl halides and organosilanes. The Hiyama coupling is quite comparable to the Suzuki– Miyaura reaction and requires a fluoride ion or a base as an activator for the transmetallation step as a consequence of the low reactivity of the organosilanes. This C—C bond formation reaction has greater benefits in comparison to the other

109

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

OH

Pd(II) catalyst IL

6

Sn(Bu)2 +

Br

R

R

130 °C

R= H, COMe, CO2Et

OH

R1 Pd(II) catalyst IL

6

Sn(Bu)2

+

R Br

R

100 °C

R= Py, PhCOMe, PhCHO R1 R1= OMe, F

Scheme 5.20

TSIL immobilized with organostananes employed in Stille coupling.

coupling reactions owing to its economic feasibility, easy availability, lower toxic effects, and high stability of the organosilanes; greater stereochemistry and high regioselectivity in product generation; as well as the fact that the silicon byproducts generated can be incinerated to innocuous SiO2 . In spite of these advantages, the modifications of this reaction are carried out to replace the utilization of toxic chemicals such as tetrahydrofuran, dioxane, N,N-dimethylformamide, toluene, and 1,2-dichloroethane with environmentally benign ILs. Moreover, efforts have also been made to reduce the quantity of catalyst loading as the reaction demands large concentrations of catalyst to be employed. From the previous examples of cross-coupling reactions, we have seen the use of Pd-NPs for catalyzing the formation of carbon—carbon bonds. Although the NPs due to their thermodynamic and kinetic instability require stabilizing by supports such as polymers, dendrimers, and surfactants. the grafting of transition-metal NPs in ILs do not call for extra stabilizers. This is because ILs provide stabilizing effect to the NPs through electrosteric effects. As such, the applicability of Pd-NPs grafted in IL has been tested in the Hiyama coupling, to make the reaction greener. Much higher formation of biaryl compounds was observed while coupling of aromatic and heterocyclic halides with various silane derivatives when the coupling reaction progressed in [CN-bmim]PF6 [63], an imidazolium-based IL functionalized with a nitrile group. By using [bmim]F as the activator, only 4 mol% loading of the recyclable catalyst was sufficient to obtain products with 76–98% yield (Scheme 5.21). X R +

Si(OMe)3

Pd(OAc)2 [bmim]F [CN-bmim]PF6 60–70 °C

R

R= CH3, OCH3, NO2, CN, COMe X= I, Br, Cl

Scheme 5.21

{[CN-bmim]PF6 } used in synthesis of C—C bond.

5.2 Carbon—Carbon Bond Formation Reactions

Fluorides as activators for the formation of silicon intermediate is a requisite for the reaction and the use of IL fluoride, [bmim]F, proved to be superior in terms of being easy to handle, easy to store, and easier to remove through workup. The Hiyama reaction was found to proceed successfully under mild conditions to produce allyl–aryl coupling products when 1-pentyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([C5MPyrr][Tf2 N]) was used as a reaction media. Moreover, the use of heterogeneous and reusable catalyst system NHC-Pd/ SBA-15/IL, prepared by supporting NHC-Pd and IL mixture on mesoporous silica SBA-15, was also found to exhibit chemoselectivity toward Hiyama cross-coupled products of phenyltrimethoxysilane with a variety of haloarenes [64]. The control over the environmental impact of the reaction can also be established by the use of biomass-derived ILs such as tetrabutylphosphonium 4-ethoxyvalerate ([TBP][4EtOV]), whose application was also studied in the Sonogashira reaction as mentioned above. The upper hand these valerate-based ILs have over other ILs lies in their synthesis. ILs like [bmim]BF4 and [bmim]Otf require over 30 synthetic steps [65] for their preparation, whereas valerate ion-based ILs can be synthesized directly from the platform molecule, GVL. This chiral molecule, on the other hand, can be synthesized by the one-pot conversion of levulinic acid (LA) to optically active 4-hydroxyvaleric acid (4-HVA) and subsequently to chiral GVL (Scheme 5.22) [66]. OH

O

–H2O

+ H2 COOH Levulinic acid

Scheme 5.22

Chiral catalyst

O O

COOH

(R or S)–GVL

(R or S)-4HVA

Synthesis of γ-valerolactone.

The utility of [TBP][4EtOV] as an unconventional reaction medium in the Hiyama coupling [67] of aryl iodides and triethoxyphenylsilane for 24 hours at 130 ∘ C resulted in products in their purest (>98%) forms and with moderate to good yields (Scheme 5.23).

I

(EtO)3Si +

Pd(II) F- source [TBP][4EtOV]

R

R

R= H, CH3, tBu, OCH3, Ph, Cl, OCF3, F, COPh, CF3

Scheme 5.23

5.2.2

Hiyama coupling in the presence of IL.

Aldol Condensation

The aldol reaction is considered among the most powerful methods of constructing carbon—carbon bonds in organic chemistry, where an enantioselective β-hydroxy-

111

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

aldehyde or ketone is obtained as the product through the combination of two carbonyl compounds. A subclass of stereoselective reactions, asymmetric synthesis, involves selectively synthesizing one enantiomeric form over another of a desired optically active molecule. In the last few decades, this synthetic procedure has captured much attention and sparked the interest of synthetic organic chemists. Asymmetric direct aldol reactions result in straightforward access to the optically active beta-hydroxy carbonyl group found in a large number of natural product drugs, and hence they have attracted quite a deal of attention in organic synthetic chemistry. Increasing selectivity for the desired product in aldol condensation is also an important need as the product formed is accompanied by aldol, acid, and alcohol wastes. Utilization of metal-free small organic molecules (SMOs) like L-proline and its derivatives to catalyze asymmetric aldol condensation reactions has also gained much attraction to overcome the various limitations of the conventional nonrecyclable metal oxide NP catalysts. However, the insolubility of these SMOs in most organic solvents has raised the need for novel metal-free molecules that can catalyze these asymmetric reactions along with the added benefits of catalyst reusability and recyclability. This reaction was thus executed in ILs such as (bmim)PF6 and (bmim)BF4 ., where these ILs function as solvents, base alternatives, and catalysts. Immobilizing the proline catalyst in the IL showed enhanced selectivity in the desired products in contrast to that obtained in conventional solvents like acetone. Although the values of isolated yields and the enantiomeric excess (ee) obtained were quite moderate, no elimination product was formed and excellent enantioselectivity in the desired addition products was achieved [68]. By immobilizing the catalyst in an IL, the catalytic system displayed reusable characteristics in subsequent reactions and simple product separation was possible. ILs synthesized from renewable and nontoxic substances like choline chloride and L(−)-proline have also found utility in the aldol reaction. The IL named, [Choline][Pro], results in a good yield of the desired products within a short amount of time without the formation of byproducts [69]. It is well known that Brønsted acid additives are extremely crucial in activating the aldol acceptor in asymmetric aldol reactions based on enamines. So, an asymmetric aldol reaction catalyzed by prolinamide catalyst derived from a source of cinchonine utilized Brønsted acidic ILs, where the ILs acted both as recoverable solvent systems and Brønsted acid additives [70]. These ILs were shown to play a positive role in improving catalytic performance and stability. The application of a multifunctional IL, [TAIm]OH [71], having high basicity and anion stabilizing property, allowed for the reaction to be carried out in the absence of externally added reagent, co-catalyst, or solvent, thus complying with the laws of environment preservation(Scheme 5.24). Chiral RTILs containing a chiral imidazolium cation as well as a chiral L-prolinate anion were also employed as organocatalysts in the aldol reaction [72] between aldehydes and cyclohexanone at ambient temperature for a duration of 24 hours, as shown in Scheme 5.25. The structural features of the salts result in complex supramolecular interactions whereby few of the intermediates and transition states get stabilized selectively.

5.2 Carbon—Carbon Bond Formation Reactions

OH– O

O

N

N

O

N

[TAIm]OH =

[TAIm]OH

R

N

N

OH–

N N

Ar

N OH–

Up to 96%

Scheme 5.24

N

Aldol condensation using [TAIm]OH. OH

H O

O Chiral RTIL

+

24 h

R1

R1

O

Chiral RTIL = (R,R)–trans–Cy6–OAc–Im–Bu–L-Pro or (S,S)–trans–Cy6–OH–Im–Bu–L–Pro

Scheme 5.25

Aldol condensation using chiral RTIL.

Hence, the use of chiral RTILs improves the activity, selectivity, and principally the enantioselectivity of the reaction in addition to the reaction efficiently progressing in solvent less media. This scenario defines the catalyst used as a enzymatic catalyst because of its similarity to that observed in the active centers of enzymes.

5.2.3

Claisen–Schmidt Condensation Reaction

The application of ILs as solvents in Claisen–Schmidt condensation reaction for the formation of the C—C bond following the green reaction protocols has also been explored. As such Brønsted acidic t TSILs, having combined properties of solid as well as mineral acids, have been used to replace the conventional mineral acids like H2 SO4 and HCL employed in these reactions [73]. Reversible IL, n-BuTMG ethylene glycol (TMG = 1,1,3,3-tetramethyl-2-i-propylguanidine), was also used as solvent and catalyst systems in the Claisen–Schmidt reaction of 16-formyl steroids and aromatic ketones to achieve good selectivity of products (Scheme 5.26). The catalyst was also successfully recovered and recycled [74]. Cl O

O + R

H

H

H

60 °C, 4 h

R H

O

N

O R=

Cl

nBu-TMG ethylene glycol

,

Scheme 5.26

Fe ,

N

Claisen–Schmidt condensation using n-BuTMG ethylene glycol.

113

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5 Promising Uses of Ionic Liquids on Carbon—Carbon and Carbon—Nitrogen Bond Formations

It was also observed that the basicity and shape of metal oxide NPs used as catalysts in the Claisen–Schmidt reaction can be fine-tuned with the help of ILs and MW irradiations, and as the basicity and surface area of the metal oxide NPs increased, higher activity of the nanostructured catalysts was achieved in the IL-assisted reaction [75].

5.2.4

Friedel–Crafts Alkylation

Friedel–Crafts alkylation of 2,4-dichlorofluorobenzene and CCl4 catalyzed by the Lewis acid IL, EmimCl—AlCl3 gave the desired product 1,5-dichloro-2-fluoro-4(trichloromethyl)benzene in greater yield (70%) than that obtained using AlCl3 as the catalyst [76]. The IL favored fast reaction rate along with good selectivity (>80%). The use of ILs as solvent and Lewis’s acid catalyst for this reaction is beneficial because their electrostatic attractions and high polar nature create a much more stable intermediate, which therefore prefers the main reaction and eliminates the formation of byproducts. Excellent product selectivity (>99%) and product yields (99%

Puerarin

[C4mim]Br

IL + K2 HPO4

>99%

Gallic acid, vanillic acid, eugenol, nicotine, and caffeine

[C4mim]Cl, [C4mpyr]Cl, [C4mpip]Cl, [N4444]Cl, and [P4444]Cl

PEG + C6 H5 K3 O7 / C6 H8 O7 + IL as adjuvant

—

Capsaicin

[Ch]Cl, [Ch][Bit], and [Ch][DHC]

IL + acetonitrile

90.57%

Anthocyanins

[C2mim][Ac]

IL + K2 CO3

31.90%

Phenolic acids, ferulic acid, and p-coumaric acid

[Ch][DHC]

IL + Tween 20

97% of total phenols, 89% of ferulic acid, and 93% of p-coumaric acid

Polyphenols and saponins

[Ch]Cl

IL + K3 PO4

35–70%

Gallic acid

[Cnmim][CF3 SO3 ], [C4 mim]Br, [C4mim][CH3 SO4 ], [C4mim][C2 H5 SO4 ], [C4mim][OctylSO4], [Cnmim]Cl, and [C4mim][N(CN)2 ]

IL + K3 PO4 , IL + K2 HPO4 / KH2 PO4 , and IL + Na2 SO4

Up to 98.80%

Source: Adapted from Refs. [1, 17].

6.3 The Use of ILs in Separation Technology

Table 6.2 The most commonly exhibited physical properties of ionic liquids while applied in separation technology. Melting Viscosity point Molecular at 25 ∘ C (∘ C) at Density weight (cP) 25 ∘ C (g mL−1 )

Cation

Anion

Abbreviation

C6 H12 N2 −

[PF6]−

[EMIM][PF6]−

−

−

C8 H16 N2

−

256.13

450

58–62

1.373

[BF4 ]

[EMIM][BF4]

197.8

66

6

1.248

[PF6]−

[EMIM][PF6]−

284.18

400

10

1.1373

[Br]

−

[EMIM][Br]

218.9

Solid

60

1.134

[Cl]−

[EMIM][Cl]−

146.5

Solid

89

1.120

260

90

16

1.290

52

−4

1.420

−

−

[CF3 SO3 ]

−

[EMIM][CF3 SO3 ]

[(CF3 SO2 )2 N]− [EMIM][(CF3 SO2 )2 N]− 487.9 −

−

[NTfO2 ]

[EMIM][NTfO2 ]

433

48

−8

1.404

[BF4 ]−

[AMIM][BF4 ]−

240

321

−88

1.231

C10 H20 N2 − [BF4 ]−

[HMIM][BF4 ]−

254.08

211

−82

1.075

[HMIM]

312

800

−61

1.304

C9 H18 N2 −

[PF6 ]− C12 H24 N2 C5 H8 N1

−

−

C2 H8 N1− C9 H20 N1

−

−

−

[BF4 ]

[OMIM] [BF4 ]

281.8

440

−79

1.11

[Cl]−

[OMIM][Cl]−

230.5

16,000

0

1.0000

−

−

[NTfO2 ]

[MPPyr][NTfO2 ]

416

39

0

1.44

[HCOO]−

BAF[HCOO]−

91

11.5

−10

0.99

412

71

−50

1.4

−

[NTfO2 ]

−

[BMPyrrol][NTfO2 ]

Source: Adapted from Refs. [1, 20].

common are different extraction techniques and capillary electrophoretic and liquid chromatographic modifiers for the stationary and mobile phases. However, while choosing ILs as a solvent for extraction or chromatographic methods, considering their solvation characteristics and physicochemical properties should be the first step (Table 6.2).

6.3 The Use of ILs in Separation Technology 6.3.1

IL-Based Solid–Liquid Extractions

Solid–liquid extraction (SLE) is basically employed in the biorefinery process where solvents are added to the solid biomass to achieve an extraction rich in enhanced compounds under a set of operating conditions [21]. Du et al. [22] introduced a pioneering effort on the application of IL-SLE as an alternative approach for the extraction of trans-resveratrol from a Chinese medicinal herb. After this evidence, a large number of works exist on SLE-based separation and extraction of natural compounds, commonly lignans, saponins, alkaloids, terpenoids, phenolics, flavonoids,

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6 Ionic Liquids in Separation Techniques

etc., using either pure ILs, ILs’ aqueous solutions, and or their ethanol/methanol mixtures [23]. Besides the simpler SLE, SLE techniques are often integrated with ultrasonicassisted extraction (UAE) and microwave-assisted extraction (MAE) to augment the extraction effectiveness while endeavoring to decrease the time of extraction and the used solvent amount. Therefore, simple IL-based SLE, IL-based UAE, and IL-based MAE are the most extensively reported IL-based extraction processes where controlling the optimum extraction conditions (pH, extraction time, and temperature), as well as the selection of solid−liquid ratio, appropriate IL, and its concentration, have been known to be equally important.

6.3.2

Simple SLEs

The use of IL aqueous solutions on the SLE of alkaloids (e.g. caffeine from Paullinia cupana (guaraná seeds), piperine from Piper nigrum, and glaucine from Glaucium flavum have been published for decades [23–25]). ILs with various lengths of alkyl side chains formed by joining various anions to cations for the extraction of glaucine from G. flavum had been screened by Bogdanov and Svinyarov [26]. Accordingly, the time of extraction, the ILs’ aqueous concentration effect, and the solvent–biomass ratio were improved. With the aqueous solutions of [Cn C1 im][Ace] (n = 4, 6, and 8), there was an increase in the extraction yield of glaucine (85%) compared with methanol at 80 ∘ C for 1 h, where the glaucine’s extraction yield was improved with the aqueous IL concentration, attaining a 99% extraction efficiency at 2 M IL concentration. The aromatic π-cloud in the imidazolium cation plays an important role in improving the extraction process, due to the strong reaction of the π-cloud with polarizable and aromatic solutes, without interrupting the effect of the anion on the whole IL structure [26]. Similarly, caffeine extraction from guaraná seeds and the extraction of galantamine, ungiminorine, and narwedine employing aqueous ammonium-, pyrrolidinium-, and imidazolium-based ILs were investigated by Claudio et al. [24] and Svinyarov et al. [27]. In both studies, [C4 C1 im]Cl was discovered to be the appropriate IL at the respective optimal conditions. In another effort, surface-active ILs ([Cn C1 im]+ (n = 10, 12, and 14), combine of anions ([N(CN)2 ]− , [C1CO2 ]− , [CF3 SO3 ]− , Br− , and Cl− ) were employed for the SLE-based extraction of piperine from black pepper; ILs of betaine-derivative and a long-chain biodegradable ILs, [N111 [2O(O)12 ]]Cl) were also applied for the SLE [26]. However, the performance of these surface-active ILs depends on their critical micellar concentration (CMC), and the aqueous self-aggregation behavior was found to be the key favorable feature for the improved extraction yields. As such, while 10−4 S cm−1 ), rapid ion mobility during redox reactions (>10−14 m2 V−1 s), wide electrochemical potential windows (>1 V), and low volatility. Interestingly, RTILs exhibit many of these important properties and characteristics [11]. In general, ionic conductivities of aqueous electrolytes are very high. However, their electrochemical stability window is confined to a very narrow range; for example, the thermodynamic stability of water at room temperature is found to be 1.23 V, and therefore they are not suitable to use at a broad temperature range or on a very small scale (due to the 100 ∘ C boiling point of water) and are often highly corrosive. Moreover, nonaqueous common electrolytes (e.g. tetraethyl ammonium or triethylmethylammonium tetrafluoroborate salts in acetonitrile) also exhibit very narrow potential windows mainly due to the decomposition of the used solvent, for example, the potential window of commercially available devices based on acetonitrile is 2.7 V. To overcome the above potential differences and limitations, ILs might act as a useful alternative as solvent-free electrolytes. It is observed that, RTILs often showcase greater electrochemical stability windows as compared to common nonaqueous electrolytes, associated with nonflammability, high thermal stability, and in certain cases high conductivity. Simple electrochemical methods, such as cyclic voltammetry and potentiometry, can be used to study the electrochemical potential window of ILs and usually they are found to possess a similar or slightly larger potential window than that found for conventional organic solvents. However, results are much larger than those of aqueous electrolytes. Compared to phosphonium ones, imidazolium-based ILs display shorter electrochemical windows, indicating a higher electrochemical activity of the latter [12]. The unique characteristics of ILs relevant to electrochemistry are centrally based on the following befitting properties: conductivity, viscosity, electrochemical potential windows, and excellent catalytic performance [13].

8.2.1

Larger Electrochemical Window

One of the most prominent characteristics of ILs is their extensive electrochemical potential window, which is a measure of their electrochemical stability against oxidation and reduction processes [11]. It is a key criterion to be considered when any medium is used in electrochemical measurements, which is a highly desirable property for applying the ILs as electrochemical solvents. A usual feature of ILs is their inherent redox robustness, because of the robustness of cations and anions

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8 Effect of Ionic Liquids on Electrochemical Biosensors and Other Bioelectrochemical Devices

employed for their preparation [14]. In other words, the electrochemical potential window can be defined as the voltage range within which the electrolyte is not oxidized or reduced. This value, in fact, characterizes the electrochemical stability of ILs, that is, the limits of the window correspond to the beginning and the end of the electrochemical decomposition of the involved ions. On the other hand, the range of potentials available for the electrochemical processes is governed by the width of the electrochemical window without affecting the solvent. It has been observed that the electrochemical potential window is sensitive to impurities. Halides are oxidized much more easily than organic anions because in organic anions, the negative charge is delocalized over greater volume. Thus, contamination with halides leads to lower electrochemical stability [11].

8.2.2

Ionic Conductivity

In order to exhibit optimum performance, an electrolyte should possess high ionic conductivity to minimize ohmic losses [12]. Mobility of ions especially cations determines the ionic conductivity of an IL because in general the diffusion coefficients of cations of ILs are higher than those of anions. Reported data show that ILs based on imidazolium and pyridinium cations have the highest ionic conductivity (∼1 and 10−1 S m−1 , respectively). Typical RTILs have conductivities of >10−2 S cm−1 which are often not useful as electrolytes. This can be troublesome because ions of IL electrolyte also migrate along the potential gradient. However, ILs possessing a zwitterionic structure in which the cation and anion are not supposed to migrate with the potential gradient is considered useful in construction of electrochemical cells. They exhibit much lower ionic conductivities in the range of 10−5 –10−7 S cm−1 . The electrochemically most stable materials having comparable small conductivities are N-butyl-N-methylpyrrolidinium, bis(trifluoromethylsulfonyl)imide, triethylsulfoniumbis(trifluoromethylsulfonyl)imide, and N-methyl-N-trioctylammonium bis(trifluoromethylsulfonyl)imide. These materials show useful applications as electrolytes for developing batteries, fuel cells, metal deposition, and electrochemical synthesis of nanoparticles. The ILs showing the highest conductivities, for example, 1-ethyl-3-methylimidazolium thiocyanate ([EMIM][SCN]) and dicyanamide ([EMIM][DCA]), however, exhibit the lowest electrochemical stabilities. Nevertheless, these materials are excellent candidates to employ in any application where a high conductivity combined with thermal stability and nonvolatility is required. When conductivity along with electrochemical stability are both essential requirements in an application, for example, in super capacitors, sensors, and biosensors, imidazolium-based ILs with stable anions, for example, tetrafluoroborate or trifluoromethylsulfonate, are the appropriate choice for this purpose [11]. Table 8.1 provides the knowledge about the conductivity, viscosity, and electrochemical window values for the ILs mentioned in this chapter. It is observed that 1-ethyl-3-methylimidazolium thiocyanate ([EMIM][SCN]) and dicyanamide ([EMIM][DCA]) are showing highest value of conductivity with low electrical stability. Likewise, [BMIM][PF6 ] shows the highest value of viscosity with low conductivity.

8.2 The Importance of Ionic Liquids in Electrochemistry

Table 8.1

Conductivity, viscosity, and electrochemical values of some mentioned ILs. Conductivity (mS/cm)

Ionic liquids

Viscosity (in cP)

Electrochemical window (in V)

[BMIM][PF6 ]

1.46–1.0

308

—

[EMIM][PF6 ]

5.2

—

—

+

−

[[BMIM BF4 ]

3.5

154

—

[EMIM][BF4 ]

12.0

33.8

4.3

[EMIM][SCN]

27.0

24.7

2.9

[EMIM][DCA]

21.0

14.6

2.3

[Pyr14][Tf2 N]

2.1

0.002

6.6

8.2.3

Reference

[15]

Hydrophobicity

Miscibility of ILs with water is often explained by their hydrophobicity. Hydrophobicity of ILs mainly depends on their composition. From the perspective of hydrophobicity (solubility in water), ILs can be classified into two groups. Water-immiscible or hydrophobic IL like1-decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([DMIM][Tf2 N]) and 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6 ]) and water-miscible or hydrophilic ILs such as [BMIM] [BF4 ]. The first category is unstable in aqueous solutions due to their immiscibility with water and is not suitable for use in devices that are in contact with water. The second category is a good candidate for use in the construction of electrochemical sensors and biosensors because these electrochemical devices contact water for a long period of operation. The miscibility of ILs in water is strongly dependent on their anions. Cl− , Br− , I− , NO3 − , CH3 COO− , and CF3 COO− are anions that make the ILs miscible with water. ILs composed of anions such as hexafluorophosphate [PF6 ]− and bis(trifluoromethanesulfonyl)imide ([Tf2 N]− ) are immiscible with water. Miscibility of water of ILs based on anions such as BF4 − and CF3 SO3 − is dependent on the structure of the cations, even though they in general are miscible with water. The miscibility will decrease with the increase in the cation chain length which is due to the increased surface activity of the longer chain cations [11].

8.2.4

Viscosity

Viscosity affects the diffusion coefficient of species. ILs show much higher viscosities than normal electrochemical supporting electrolytes. Studies show that viscosity and charge have considerable effects on the transport of diffusing species in IL solutions [11]. Usually, ILs are way more viscous fluids compared to conventional organic solvents and water, and the viscosity values of most ILs are 2–3 orders of magnitude greater than those of organic solvents [16]. It is obvious that low viscosity is a major requirement for electrochemical applications, as this factor greatly influences the ionic conductivity, mass transfer of solutes, dispersion, mixing, and diffusion of

183

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8 Effect of Ionic Liquids on Electrochemical Biosensors and Other Bioelectrochemical Devices

the redox couple [17]. Thus, in order to obtain optimum device performance, it is necessary to prepare low-viscous ILs, and the beauty of these liquids is that it is possible to design low-viscous ILs by making some structural changes [18].

8.2.5

Catalytic Performance

Designing an efficient biosensor requires effective enzyme immobilization with higher surface area and a faster charge transfer rate in order to achieve better catalytic activity. These major key factors are to be considered while selecting the electrode material. ILs, which act as solvents or additives, have been widely used in enzymatic catalysis and present enzymes with excellent activity and long-term stability because of their environmentally friendly nature and are endowed with desirable features like a larger surface area and better redox activity in the electrode material [19, 20]. ILs are specifically found to be advantageous in improving some restraints in enzymatic reactions in terms of sensitivity and response time. ILs are well efficient to provide a microenvironment favorable to biomolecular stability and functionality [21].

8.3 Fabrication of IL-Based Sensing Layers IL-modified electrodes, wherein the IL usually serves as both binder and conductor, are by far the most highly explored avenue of IL-based electrochemical sensors. Incorporation of ILs into electrodes garnered some acceleration in common qualities such as enhanced conductivity, better selectivity and sensitivity, higher catalytic ability, and long-term stability. Different electrochemical sensors have been developed using ILs [14]. Various strategies have been employed to fabricate IL-based modified electrodes. Among these approaches, the most widely used techniques include direct mixing, physical adsorption, electrodeposition, casting and rubbing, layer by layer, sol–gel encapsulation, and sandwich-type immunoassays. A brief explanation of each of these methods is summarized below.

8.3.1

Direct Mixing

In the majority of instances, electrodes modified with IL droplets or films are produced by direct deposition of IL on the surface of the electrode [22]. Since the first report on preparation of “bucky gel” materials by Fukushima et al. in 2003, which was done by grinding suspension of a high-purity single-wall carbon nanotube (CNT) in imidazolium cation-based ILs, this practice has been continued and used extensively for preparing carbon ionic liquid electrodes (CILEs). These electrodes can be prepared by directly mixing a specific amount of graphite powder with corresponding ILs together in an agate mortar and the resulted mixture can be used as substrate for the electrodeposition, followed by the immobilization of protein/ enzymes to fabricate the corresponding biosensor. Direct mixing of IL, CNT, and glucose oxidase (GOx) was also used to fabricate glucose biosensors [23, 24].

8.3 Fabrication of IL-Based Sensing Layers

8.3.2

Physical Adsorption

Physical adsorption method of preparing the IL sensing layer on solid support is perhaps the simplest and most often used method. In this method, an IL is physically coated over the electrode surface. This method is based on nonspecific physical adsorption, and the binding forces include ionic and hydrophobic interactions, hydrogen bonds, and van der Waals forces. The main purpose of binding ILs is to enhance the conductivity of electrodes as well as the effective immobilization of protein molecules [25, 26].

8.3.3

Casting and Rubbing

This is the most empirical method for fabricating protein-based biosensors. In the casting process, liquid materials are usually poured into a mold. Many reports put forward stabilization of biomolecules onto CNT/IL-nanocomposite-modified films using this method. In another method called rubbing, a designated amount of premixed biomolecule/CNTs with an IL is ground in an agate mortar for a certain time to form a black gel, which can be coated on the smooth glass surface of a pretreated glassy carbon electrode (GCE), which is rubbed to mechanically attach the gel to the surface [23, 24].

8.3.4

Electrodeposition

It is a technique of IL film deposition on the electrode surface based on the principle of electrolysis, which uses electrical current for the reduction of ions of a desired material from an electrolyte and then coating those materials as a thin film onto a conductive electrode surface. This is done in order to obtain favorable electrical and corrosion resistances, reduced wear and friction, and improved heat tolerance. Owing to their properties, such as negligible vapor pressure, nonflammability, and heat resistance, ILs are superior media for electrodeposition of metals and semiconductors. The use of ILs as a superior medium paves the way for successful electrodeposition of metals that have previously been difficult to reduce in aqueous solutions. For example, researchers have developed biosensors by electrodeposition of gold nanoparticles (AuNPs) on to IL/CNT to fabricate AuNP/IL/CNT nanocomposite biosensors. The IL employed on the CNT and AuNP accelerates the electron transfer between the protein molecule and the electrode, and this results in improved sensing performance of the biosensor [23]. Besides, ILs have proved themselves as superior media for the electrodeposition of metals and semiconductors and have an unparalleled ability to revolutionize electroplating [27].

8.3.5

Sol–Gel Encapsulation

The sol–gel encapsulation or entrapment method of fabrication of IL-based biosensor consists of synthesis of an IL silica sol, which is then mixed with biomolecules like enzymes or proteins to obtain a sensing layer. This method is basically practiced

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to retain biomolecules in a semi-permeable host membrane or in a network matrix like hydrogels and other polymeric materials through noncovalent interactions. Biomolecules entrapped via this technique in IL-silica sol were found to exhibit improved stability, storage, and operational activities. Since, encapsulation occurs under mild conditions, the three-dimensional (3D) structure and biological function of the biomolecules remain intact. Moreover, the penetration matrices allow the transport of low-molecular-weight compounds without leaking the entrapped enzymes [23, 24].

8.3.6

Layer-by-Layer (LbL) Method

This method applies sequential deposition of multiple layers to bind final enzyme or protein layers onto the electrode surface via hydrogen bonding, electrostatic or van der Waals forces, and charge-transfer interactions. The LBL method is a cost-effective technique to form layered structures with the required thicknesses and layer sequences using an ample variety of compounds. In LbL films, the packing density of the constituents is not high, and this factor is favorable for material transport across and along the layers. Besides, these features are attractive for the design of biological, nanosized devices. For example, reports suggest glucose biosensors fabricated by the LbL method on a GC electrode. The outcome of using IL showed a significant effect on electron transfer efficiencies of the modified electrode toward the oxidation of glucose [23, 24].

8.3.7

Sandwich-Type Immunoassay

Electrochemical immunoassays based on antigen–antibody interaction have fascinated researchers owing to their high sensitivity, cost effectiveness, simple instrumentation, fast response, and low detection limit. Furthermore, sandwich-type electrochemical immunosensors have attracted much recognition because of their high specificity as well as sensitivity. This method involves the immobilization of the target antigen between two antibodies labeled as primary and secondary antibodies. A particular amount of primary antibody specific for the antigens is initially coated on the sensor surface. For the development of sandwich-type electrochemical immunoassays, attaining signal amplification and ultrasensitive detection is the key point. In order to achieve these remarkable properties, ILs were successfully used. The crucial role that these ILs play is to elevate the sensitivity of the immunosensor when used in fabrication of some carbon-based electrodes [23, 28].

8.4 IL-Based Electrochemical Biosensors IL-based electrochemical biosensors are analytical appliances utilized to detect various molecules [29]. The electrochemical biosensor is an analytical device used for the detection of a variety of molecules. In general, a biosensor system contains three parts. One is the analyte recognition constructed by the sensitive biological

8.4 IL-Based Electrochemical Biosensors

elements such as microorganisms, enzymes, antibodies, nucleic acids, and cell receptors. The second part is the signal transducer, which transmutes the interaction signals among the identified analyte and biological substances reoriented upon the electrode into the electrical signal. The final part of the electrochemical biosensor device is the electronic reader [9]. In the last few decades, these biosensing devices have received significant recognition in connection with the detection of numerous analytes including glucose, nucleic acids, proteins, hydrogen peroxide, and environmental pollutants. The high sensitivity of such devices, coupled with their compatibility with modern microfabrication technologies, portability, low-cost (disposability), minimal power requirements, make them excellent candidates as testing devices for biological and environmental significance [24]. As a model material, ILs are utilized in electrochemical biosensors, and they have shown good compatibility with biomolecules and enzymes and even whole cells are active in various ILs [14]. As an ideal material used in the electrochemical biosensors, ILs have broad application prospects [9]. As stated earlier, ILs exhibit stability in a wide range of electrochemical window, enhanced sensitivity, and more ionic conductivity and activity, all of which contribute to the rising applications of ILs in electrochemical biosensors. ILs-based electrochemical biosensors are used to detect a wide range of analyte molecules, for example, sodium nitrite, dopamine (DA), cholesterol, choline, adenine, antigen, pesticides, catechol, and glucose. ILs have adapted many electrode systems for electrochemical biosensing and can also be used as electrolytes [29].

8.4.1 Application of RTILs in Construction of Electrochemical Biosensors RTILs are a class of IL solvents generally found in a liquid state at ambient conditions. They consist of a mixture of large, asymmetric organic cations with high electropositivity and inorganic or organic anions with high electronegativity. They consist of ions of equal and opposite polarities, making them electrically neutral in nature. They were previously preferred to be called as “room-temperature molten salts” by electrochemists until Earl and Seddon coined the term “room-temperature ionic liquid (RTIL).” They marked these solvents as ILs with a melting point less than 100 ∘ C. In general, RTILs possess virtually no vapor pressure and are found to be denser than water. Because of these features RTILs can ace within the deck of solvents of choice. If either on the cationic or anionic side, they contain bulky groups, in that case they cannot form a conventional ionic bond; however, they tend to adhere to strong ionic as well as noncovalent interactions that make them electrically neutral and chemically stable. Most commonly used RTILs for extraction and synthesis involve cations bearing imidazolium or pyridinium ring with one or more alkyl groups attached to the carbon or nitrogen atoms. Besides these, quaternary ammonium salts are also used extensively for electrochemical synthesis. Among anions, halide ions, tetrafluoroborate (BF4 − ), tetrachloroaluminate (AlCl4 − ), hexafluorophosphate (PF6 − ), bistriflate imide

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(Tf2 N− ), and bis(perfluoromethyl-sulfonyl)imide anion (CF3 SO2 )2 N− are the most widely used [30]. One of the significant attributes arising from the chemical structures of RTILs is that alteration in either their cation or anion can bring a change in properties such as viscosity, density, melting point, and water miscibility according to one’s requirements. Therefore, it is not at all surprising that RTILs can manifest tremendous applications in a number of chemical processes [31]. These salient features open the door to exploring them for protein extraction, purification, stability, and many other related biochemical applications based on enzymes, amino acids, and peptides. Due to scientifically intriguing physical and electrochemical properties, RTILs are gaining popularity in biomedical applications [32]. ILs are well matched with many biomaterials and enzymes. The stability and activity of biomolecules and enzymes are higher in ILs as compared to conventional organic solvents. ILs also act as a stabilizer for some protein molecules at high temperatures. Considering all the facts, ILs are considered as potential candidates for electrochemical biosensing and other bioelectrochemical applications. In recent advances, utilization of [BMIM+ BF4 − ] (1-decyl-3-methylimmidazolium tetrafloroborate) RTIL for the immobilization of horseradish peroxidase (HRP) enzyme in sol–gel matrix has been optimized. This system showed much higher efficiency than the sol–gel matrix without RTIL [33]. The first application of RTILs as electrolyte carriers in a biosensing system was in 2008 [34]. The other successful applications comprise the development of a novel and effective carbon paste electrode (CPE) incorporated with RTIL N-butylpyridinium hexafluorophosphate ([BPPF6 ]), graphite15-incorporated CPE as a biosensor probe for the determination of alpha-fetoprotein (AFP), a well-known tumor marker [35], the development of chitosan-integrated 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIMPF6 ]) composite material as a novel immobilization matrix for protein entrapment and applied in electrochemical sensing of hemoglobin (Hb) on glassy carbon electrode (GCE), the development of IL-CPE electrode for hemoglobin investigation, the use of 1-ethyl-3-methylimidazolium tetrafluoroborate modified IL-CPE for metol detection, the synthesis of GO (graphene-oxide)-IL hybrid nanocomposite for acid catalysis reactions, and the synthesis of RGO (reduced grapheme oxide)-IL nanocomposite for supercapacitor preparation. [14]. Utilization of RTILs for the enhancement of stability of biomolecules like proteins, enzymes, and antibodies, and integration of these stable products with functional nanomaterials toward the designing of electrochemical biosensors in the field of health science has also emerged [36]. In the current scenario, an enormous number of electrochemical sensors and biosensors are developed using carbon nanomaterials (CNMs) owing to their stability, sensitivity, and reproducibility with advanced physiochemical properties of the biosensors. Alternatively, on integration with ILs, the resulting electrochemical biosensor can display high performance with superior properties. Fabrication of an electrochemical biosensor layer using CNMs and IL composite materials opens the door to a new research field. This process has numerous advantages in aspects of intrinsic thermal, mechanical, and electrical properties of CNMs along with better solvent and conductivity of RTILs [14].

8.4 IL-Based Electrochemical Biosensors

Properties of ILs

* High thermal stability * Low vapor pressure * Wide potential window * High conductivity * Nonflammable * Moderate viscosity + N H3C F F –B F F F

F F – F F F F

H

CH3

Applications of CNMs-ILs composite

i qu i ds w i t h c ic l aterials arbo n n Io nom na

Glucose

Gluconic acid

e– Enzymatic sensor

* Electrochemical * Immunosensor * Enzymatic sensors * Biosensors

* Surface functionality * Act as stabilizer * Green solvent media * Improve conductivity Immunosensor

Advantages of ILs

Figure 8.2

Properties, advantages, and applications of CNMs-ILs.

Figure 8.2 explains the properties, advantages and applications of CNMs-ILs composite materials. A numerous number of methods are proposed for the synthesis of CNMs-IL composite materials. Ultra-assessed hydrothermal, microwave irradiation, and direct mixing are some advantageous and environmentally friendly methods for the synthesis of IL-functionalized hybrid CNMs. The applications of several CNMs-ILs-based electrochemical sensors are detailed in the following sections. 8.4.1.1 CNMs-ILs-Based Electrochemical Biosensor as Cancer Biomarker

In recent years, biomarkers for the early determination of cancer have been developed. In this regard, carcinoembryonic antigen (CEA) determination is vital. Graphene quantum dots GQD-ILs-Nafion film and IL-RGO composite are two recently developed voltammetric biosensors for the detection of CEA with an effective detection limit in femtogram concentration. Another study includes the development of a sandwich-type voltammetric biosensor using amine-terminated IL (NH2 -IL) on graphene oxide for the diagnosis of AFP and CEA with a limit of detection (LOD) in nanogram concentration and the construction of a multiwalled CNT screen-printed biosensor using fourth-generation eco-friendly RTILs for CEA

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determination [37]. In recent research, utilization of reduced graphene (GR)-ILs and platinum nanoparticles (GR-ILsPtNPs) based nanocomposites of sandwich electrochemiluminescence (ECL) assay for the ratiometric determination of CEA in serum samples and utilization of ECL assay for CEA biomarkers of various cancer determination are two examples of successful development [15]. 8.4.1.2 CNMs-ILs-Based Electrochemical Biosensor for Cardiac Diseases

In this context, biomarkers such as cardiac troponin I (cTnI), troponin T (cTnT), troponin C (cTnC), myoglobin, C-reactive protein (CRP), and creatine kinase (CK) are used to for the diagnosis of cardiac diseases. For the successful prediction of the diseases, early diagnosis is necessary. IL-based nanocomposites may play a vital role in this purpose. Works like construction of IL-integrated helical CNT composite material for the electrochemical diagnosis of cardiac troponin I (cTnI) and utilization of helical CNT with aldehyde-functionalized IL nanocomposite for the construction of a label-free voltammetric biosensor for the diagnosis of (cTnI) are important. All reported biosensors can show a great stability, reproducibility, sensitivity with a significant LOD [15]. 8.4.1.3 CNMs-ILs-Based Electrochemical Biosensor for Immunoglobulins

The immune system of our body regularly generates the immunoglobulins called antibodies to give the protection against antigen, the harmful foreign substances. The important immunoglobulins are immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), and immunoglobulin D (IgD). The quantitative determination of the immunoglobins is the crucial point to determine immune response, diagnostics, and health condition of the body against the antigens. Thus, for the purpose of diagnosis, plentiful immunosensors are reported to date. Examples include the construction of amine-terminated CNT integrated with aldehyde-functionalized ILHO nanocomposite-based voltammetric biosensors for the IgG detection through an LOD of 0.02 ng ml−1 and 0.1–15 ng ml−1 linear range. Development of another electrochemical sandwich immunoassay using similar matrix with selected modifications was reported for the diagnosis of IgG in clinical samples. Development of level-free electrochemical immunosensors for CRP detection in serum sample is being completed using ZnO-porous carbon and ILs. The developed sensor showed a significant LOD of 5 pg ml−1 with good stability and reproducibility [15]. 8.4.1.4 CNMs-ILs-Based Electrochemical Biosensor for Neurotransmitters

A well-known neurotransmitter DA helps in physical functions of our body to transmit the nerve signal in the whole nervous system. Deficiency as well as the elevated level of DA indicates toward serious diseases like schizophrenia and Parkinson. So early detection of DA to control these diseases is the key concern. In this context, electrochemical voltammetric sensors play a significant role to detect DA concentration at a low level. Manufacture of Graphene oxide (GO)-IL-AuNPs composite-based voltammetric sensor, GQD-IL-based sensor, single-walled CNT (SWCNT)-IL-based voltammetric sensors are few examples of recently developed work for DA detection in serum samples [15].

8.6 Conclusions and Future Prospects

8.4.1.5 CNMs-ILs-Based Electrochemical Glucose Biosensors

In the proper functionalization of metabolic system, the oxidation of monosaccharide viz. glucose is very important, as it release an enormous amount of energy and gluconic acid. The high level of glucose in blood and less catalytic activity indicates serious health issues like diabetes and failure of organs like liver kidney and lungs. In this concern, several enzymatic or nonenzymatic electrochemical biosensors are reported to detect glucose level. For enzymatic sensor, glucose oxidase enzyme is used for the catalysis and detection of glucose level and in nonenzymatic sensor, an appropriate material is fabricated on the sensor’s surface for the catalytic action. Development of nonenzymatic Ni—Pd nanoparticles modified with IL-RGO biosensor for glucose detection, CuO-IL-RGO nanocomposite based electrochemical biosensor for glucose detection in urine sample, imidazolium based IL-HRP (horse radish peroxidase) immobilized on GO-MWCNs electrochemical sensor for glucose detection are some recently reported successful work. All the reported works show excellent sensitivity and LODs [15].

8.5 Application of Ionic Liquids in Bioelectrochemical Devices Owing to the exceptional thermal and chemical stability, electrical conductivity ILs can act as a device matrix for the construction of many bioelectrochemical devices. In recent development, biopolymer and ILs composite electrolytes for electro devices have been considered emerging applicants. Biopolymers like gelatin and DNA, and polysaccharides like agarose, cellulose, chitosan, and cellulose can be incorporated with ILs for this purpose. This biopolymer-IL-integrated biocomposite can provide high flexibility, high mechanical strength, and high ionic conductivity to the devices. Electrodevices like actuators, solar cells, and lithium-ion batteries are being developed by utilizing these biodegradable and novel polymer electrolytes. Construction of [C4mim]Cl-cellulose-MWCNTs polymer composite-based supercapacitor was one of the best examples. The prepared capacitor can provide a power density of 1.5 kW kg−1 , which is comparable with commercially available ones and is applicable to a wide range of temperatures. There is another interest of using DNA and ILs as novel functionalized materials for nanowire construction, as well as the application of ionic liquidized DNA composites in ionic conductive materials. Last but not least, the use of cellulose-triacetate-encapsulated IL composite for lithium-ion conduction is an important application that has been reported recently [38].

8.6 Conclusions and Future Prospects In this chapter, we have summarized some intrinsic chemical and physical properties exhibited by ILs and their respective applications in the domains of electrochemical biosensors and other biosensing devices. Herein, we have discussed

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the different methods and methodologies for the construction of IL-based electrochemical biosensors. ILs are considered suitable substituents in biosensor assembly owing to their unique properties such as a high boiling point, low vapor pressure, and high stability at elevated temperatures. ILs also possess dual characteristics in prosperities of immobilizing matrix as well as direct electron transfer promoter between the transducers and biomolecules to provide efficient biocatalytic behavior toward biosensor construction. The application of IL-based electrochemical biosensors in different domains of research is also discussed. Particularly, the aspects and application of CNMs and ILs integrated composite materials for the construction of various types of electrochemical biosensors for various diseases such as cancer and cardiac diseases, and immunology and some other types of biomarkers are highlighted. The use of ILs in other types of bioelectronic devices is also summarized. It is believed that the use of ILs in the construction of electrochemical biosensors and other electrochemical devices is an exciting and hopeful domain of research, and further investigations are definitely required. Integration of ILs with electrochemical sensors and biosensors has a great potential to widen or even modernize the range of analytical methods to a great extent.

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9 Nanopharmaceuticals With Ionic Liquids: A Novel Approach Bharadwaj Ittishree 1,2 , Lipeeka Rout 3 , Vinod Kashyap 3 , and Rahul Sharma 4 1 Pt. B. D. Sharma University of Health Sciences, Hindu College of Pharmacy, Gohana Road, Sonipat, Haryana 131001, India 2 Institute of Pharmaceutical Research, GLA, Mathura, Uttar Pradesh 281406, India 3 National Institute of Technology, Department of Chemistry, Tiruchirappalli, Tamil Nadu 620015, India 4 Dr. K.S. Krishnan Marg, CSIR National Physical Laboratory, New Delhi 110012, India

9.1 Introduction In drug research and development, it is believed that 40% of marketed medications and 90% of understudied compounds have insufficient pharmacological characteristics, significantly limiting their therapeutic usefulness. As a result, there is a considerable need for techniques to improve medication delivery [1]. Ionic liquids (ILs) are a new type of solvent made up of organic salt mixtures that may be used alone or in conjunction with drug delivery methods [1]. Because of their important physicochemical features, ILs have been extensively investigated in various applications. Previously, the use of ILs was thoroughly studied in the pharmaceutical field by various researchers, notably as functional excipients to increase the efficacy of drug delivery systems, as a result of their extensive applications [2]. Also, ILs were being used as solvents, excipients in many formulations, solubility and permeability promoters, and surface-active ILs, and to help in the improvement of biomolecules such as enzymes and proteins, among other things. Further, because of their reduced toxicity (in comparison to other ILs), some of them have been dubbed “green solvents,” making them important materials in medication delivery techniques. As a result, ILs have a lot of promise and are becoming more important in the growth of novel drug delivery systems [3]. Nanoparticles (NPs) have also been explored as a strategy to raise drug delivery efficiency. The fundamental reason for their popularity in nanosystems is the substantial advantages they may provide, notably in terms of medication safety and efficiency. The synergetic effects emerging from the mixing of NPs and ILs have aroused curiosity as a result of the desirable qualities that both NPs and ILs exhibit. This method might be crucial in the development of more reliable and high-performing systems. However, ecologically acceptable processes for the synthesis of these IL-based NP systems must be established, and the toxicity generated Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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Figure 9.1 Pharmaceutical applications of ILs.

Ionic liquid drugs

Synthesis of drugs

Ioliomics

Drug delivery

Biomedical analytics

by the systems must also be carefully examined [2]. ILs have been extensively in use in sample preparation for different liquid phase microextractions. High enrichment factor of the ILs can be achieved by deciding the volume of the IL used for liquid phase microextraction, which is typically less than 25 μL. A vigorous stirring operation and relatively long extraction time are necessary to finely mix the IL with the liquid phase. However, due to the adhesion and dissolution in water on the vial wall, it is difficult to extract a small amount of the IL properly from the aqueous phase [4]. Nano-based systems are also sought-after materials for preventing drug degradation, improving drug transport and distribution, and extending drug release. In order to achieve synergistic effects, complexes incorporating ILs and NPs have been designed [5] (Figure 9.1).

9.2 Applications of Ionic Liquids in Various Fields 1. Biological applications First, the extreme bioavailability property of ILs was considered for various applications. Although the biological activity of ILs changes from one creature to the other, usually water is present in all of them. All life systems rely on it. As a result, solubility and one of the influencing aspects, interactions with water, influence the environmental and biological activities of ILs [6]. 2. ILs for active pharmaceutical ingredients Traditional pharmaceutical problems with solubility, thermal stability, and bioavailability have been reduced by converting drug molecules into ILs, which are also referred to as active pharmaceutical ingredient-ionic liquids (API-ILs) [7]. The reasoning underlying API-ILs is that the profile of drugs can be preserved while the solvent class and counterion as a whole are imbued with desirable qualities. The first generation of API-ILs concentrated primarily on the production of novel salts in liquid form with established pharmacophores [7].

9.3 Nanotechnology and Ionic Liquids

3. Drug delivery The next challenge is delivering the drug after a good drug formulation has been prepared [8]. Recently, various ILs have been used to produce nano- and microemulsions in particular [9]. In comparison to first-generation ILs, secondand third-generation ILs were found to have cations and anions with higher biocompatibility, and they are also less toxic in nature. In order to enhance the biological activity, pharmacodynamics, and pharmacokinetics of drugs, various ILs with good biocompatibility have been developed [10]. 4. As solvents Compared to organic solvents, various physical and chemical properties of ILs, including low vapor pressure, higher ionic conductivity, and enhanced chemical and thermal stability, make them better solvents for a wide range of applications [11]. Previously, ILs have been employed as a solvent for synthesizing nanocrystalline films of various metals, alloys, and semiconductors, using electrodeposition techniques [12]. Also, various porous composites with uniform size distributions have been synthesized using ILs as solvents.

9.3 Nanotechnology and Ionic Liquids Nanotechnology, identified as the particles on an atomic, molecular, and supramolecular level, is a game-changing technology that will enable massive changes in today’s sectors of business, as well as the creation of whole new sectors ranging from sensors to catalysis. ILs coupled with nanotechnology offer more appealing and efficient options for future industrial scale nanomaterials [13]. The synthesis of hundreds of unique nanostructures and various approaches such as adsorption, entanglement, self-assembled monolayers, and covalent combining for the effective manufacturing of industrial goods or services, such as sensors, electrocatalysts, and membranes, demonstrate the tremendous growth and development in nanotechnology [14]. Ultrasound, iontophoresis, jet injectors, microneedles, and permeation enhancers are just a few of the ways that have been developed to improve skin permeability to pharmaceuticals. ILs and deep eutectic solvents have recently demonstrated significant promise for drug delivery [15]. Schematic of various types of ILs is shown in Figure 9.2. The unique features of ILs make them ideal media for NP production and stabilization. The following are their most notable characteristics for NP synthesis: 1. Highly structured liquids are ILs that may form long H-bonded chains, they have a major effect on the morphology of the produced NPs. 2. Their anionic and cationic components help to form an electrostatic shield that helps to reduce the agglomeration of nanomaterials. Electronic and steric stability of NPs and limiting particle growth were enhanced by the use of ILs. Furthermore, due to the presence of ionic or covalent interactions between cations and anions, stability of NPs increases in the solution. 3. Because of their low surface tension and significant nucleation rates, ILs can aid in the synthesis of nano-sized particles.

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Metal salt ILs Protic ILs

Supported ILs

Polarizable ILs

Ionic liquids (ILS)

Task-specific ILs

Chiral ILs

Amphiphilic ILs Bio ILs

Figure 9.2

Types of ionic liquids.

9.4 Use of Ionic Liquids in Nanocarrier Development (Reported Work) 1. Han et al. have studied the use of cotton cellulose (CC) in [bmim+ ] [Cl] IL for cellulose-based NP synthesis [16]. 2. Gericke et al. have synthesized NPs with a hydrodynamic radius of c. 160 nm using modified xylan with phenyl carbonate groups [17]. 3. Starch-based NPs with a size range of 64–255 nm in a water/ionic liquid emulsion (W/IL) have been synthesized by Zhou et al. by a cross-linked technique [18].

9.5 Ionic Liquid-Assisted Metal Nanoparticles ILs are termed as the mixture of organic cations and anions in their molten state. In recent literature, they were referred to as molten salts with a lower melting point and were often specified as room-temperature ionic liquids. Paul Walden discovered the first IL in 1914, which is named ethyl ammonium nitrate and has a melting point of 12 ∘ C [19]. In the 1990s, there were more discoveries of ILs that are stable at room temperature, such as hexafluorophosphate, tetra fluoroborate, and sulfate and acetate salts. [20]. Some cations and anions which are commonly being used ILs are shown in Figure 9.3. In general, ILs share some resemblance with water. Previously, it was seen that water exists as a mixture of H-bonded water molecule clusters and free water molecules. Similarly, ILs are considered hydrogen-bonded ionic supramolecular

9.5 Ionic Liquid-Assisted Metal Nanoparticles

Commonly used cations CH3 H3C

N

N+

R1

N+

+

R2 N

R3

R1 N-alkyl-pyridinium

1,2-dialkyl pyrazolium

N+

+

R1

R4

R2

N-alkyl-N-Alkyl pyrrolidinium

Tetraalkylammonium

Commonly used anions O F F

S

N−

O

O O F

F [NTf2]−

Figure 9.3

O F

S

F

CH3

O

S

O O

[EtSO4]−

Commonly used anions and cations in ILs (R represents the alkyl group).

structures and free ion mixtures. The presence of both weak directional interactions and strong Columbic interactions, which include van der Waals, H-bonding interactions, and dispersion interactions, may results in the formation of IL–solvent or IL–solute mixtures and nanoscale structures in ILs [21]. ILs are considered as one of the alternative solvents for a wide range of applications in various fields. The unique properties of ILs, such as negligible vapor pressure, high conductivity, high polarity, nonflammability, and good electrochemical stability and dielectric constant, made them suitable media for synthesizing nanomaterials without using any stabilizing agents [22]. ILs can be categorized as alternative electrolytes for electrochemical devices as well as media for preparing conducting polymers due to their efficient electrochemical stability and ionic conductivity [23, 24]. Furthermore, they can also be utilized as efficient media for dispersion of NPs as well as for functionalization of surface morphology. The distinctive properties of ILs are also utilized in various other applications, including lithium batteries, solvents for drug delivery, dye-sensitized solar cells, and biomass processing [7, 25, 26]. In recent years, metal NPs have attracted great deal of attention in various applications due to their exceptional chemical and physical properties [27, 28]. The properties of NPs are much different from their bulk counterparts, including their high surface area, unique chemical reactivity, interatomic distance, and electronic, magnetic, and optical properties, which make them unique materials for various applications such as medicine, spectroscopy, catalysis, and optics. Synthesis of NPs of noble metals, such as Au, Ag, Pd, and Cu, for various applications is a recent trend in the research field. To achieve the unique properties of NPs, controlled synthesis with narrow size and well-defined morphologies is quite essential. Furthermore, the catalytic activity of NPs depends on the smaller size, surface area, and surface atomic energy. In recent decade, it has been studied that the synthesis of NPs with ILs provides better morphology to the NPs. ILs help to form a protective layer around the NPs, as the NPs are electron-deficient, the negatively charged anions of ILs form a double layer with oppositely charged cations which further prevent

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9 Nanopharmaceuticals With Ionic Liquids: A Novel Approach

Ionic liquid

Electrostatic interaction H Aromaticity H (π-stacking) [A]− N+ R H-bond acceptor N Possible delocalization charge n Lewis acid H H

Figure 9.4 Mechanism of the solubility of LASSBio-294 drug in ILs. Source: Refs. [32–34].

Cardiovascular drug LASSBio-294

H-bond acceptor S

O O O

N

N

H

H

Hydrophobic domain

H-bond donor

H-bond acceptor

200

Hydrophobic domain

the NPS from agglomeration. Additionally, the longer alkyl chain of ILs when interacting with the NPs results in the formation of coulomb force and hydrogen bonds between the ions which avert the NPs from aggregation without altering their structure [29]. The abovementioned exceptional chemical tunability of ILs allows the stability of the NPs for various applications. Recently, Kumar et al. have studied IL-assisted gold NPs for antimicrobial activity and thermal stability of enzymes. In the article, they have used 1-ethyl-3-methylimidazolium methylsulfate IL [EMIM] for the modification of Au NP [30]. In 2011, Kolekar and coworkers prepared Ag NP using 1-(dodecyl) 2 amino-pyridinium bromide IL and studied its biocidal activity [31]. In addition to that, NPs were also found to be potential candidates for drug delivery applications. The main drawback of IL-assisted NPs is their scaling up and wide size distribution. Though, as nanoplatforms, they observed great possibility of allowing the release of targeted drugs to specific tissues or cells. In 2017, Monti et al. showed that the enhanced incorporation is an essential factor related to the chemical and physical properties of ILs [35]. The first vesicle based on API-IL was reported by Zhang and others in 2013. Further research showed that ILs with NPs can be used as potential materials for drug delivery applications [36]. In 2021, Jadhav et al. described the formulation, therapeutic updates, and drug delivery applications of ILs [34]. In the article, they have investigated both molecular dynamics simulation and experimental studies of the solubility interaction between imidazolium based IL and a cardiovascular drug (Figure 9.4), LASSBio [32, 33]. They showed that the presence of H-bonding between ILs and the drug, the π – π interaction present in between the cation of IL and the aromatic ring of drug and the presence of van der Waals interaction are responsible for the enhanced solubility of the drug with ILs [32]. Further, the above information suggests that ILs can be used solvents for many pharmaceutical applications.

References

9.6 Conclusion Due to poor bioavailability, solubility, stability, and polymorphic conversion, pharmaceutical companies face a number of hurdles in delivering many recently created therapeutic compounds. Because of their unique and tunable bioactive components, ILs are considered a novel class of mixtures of salts that are also considered environmentally friendly solvents. In recent years, many researchers have explored various properties of ILs and utilized them as potential solvents for various pharmaceutical applications and API formulations. As the ILs are prepared by combining various anions and cations and their nature to act as green solvents due to their nonflammability, nonvolatility, and recyclability, they are excellent options to contribute to the formation of various NPs and different nano-sized pharmaceuticals for a wide range of applications.

References 1 Amaral, M., Pereiro, A., Gaspar, M. et al. (2020). Nanomedicine 16: 63–80. 2 Almeida, T., Caparica, R., Júlio, A., and Reis, C. (2021). Nanopharmaceuticals 1: 181–204. 3 Júlio, A., Costa, J.G., Pereira-Leite, C., and Santos de Almeida, T. (2022). Nanomaterials 12: 7. 4 Kokorin, A. (ed.) (2011). Ionic Liquids: Applications and Perspectives. London, United Kingdom: IntechOpen https://www.intechopen.com/books/1373. https:// doi.org/10.5772/1782. 5 Davies, K.P. (2015). Future Science 1. 6 Egorova, K.S., Gordeev, E.G., and Ananikov, V.P. (2017). Chemical Reviews 117: 7132–7189. 7 Hough, W.L., Smiglak, M., Rodriguez, H. et al. (2007). New Journal of Chemistry 31: 1429. 8 Zhang, Y., Chen, X., Lan, J. et al. (2009). Chemical Biology & Drug Design 74: 282. 9 Sanchez-Fernandez, A., Hammond, O.S., Jackson, A.J. et al. (2017). Langmuir 33: 14304. 10 Moshikur, R.M., Chowdhury, M.R., Moniruzzaman, M., and Goto, M. (2020). Biocompatible ionic liquids and their applications in pharmaceutics. Green Chemistry 22 (23): 8116–8139. https://doi.org/10.1039/D0GC02387F. 11 Hagiwara, R., Hirashige, T., Tsuda, T., and Ito, Y.J. (2002). Electrochemical Society 149: D1. 12 Yong, Z. (2005). Current Nanoscience 1: 35–42. 13 Arumugam, V., Redhi, G., and Gengan, R.M. (2018). Micro and Nano Technologies 371–400. 14 Huo, D., Li, Q., Zhang, Y. et al. (2014). Sensors and Actuators B: Chemical 199: 410–417.

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15 Tanner, E.E., Curreri, A.M., Balkaran, J.P. et al. (2019). Design principles of ionic liquids for transdermal drug delivery. Advanced Materials 31 (27): 1901103. https://doi.org/10.1002/adma.201901103. 16 Han, J., Zhou, C., French, A.D. et al. (2013). Polymers 94: 773–781. 17 Gericke, M., Gabriel, L., Geitel, K. et al. (2018). Polymers 193: 45–53. 18 Zhou, G., Luo, Z., and Fu, X. (2014). Preparation and characterization of starch nanoparticles in ionic liquid-in-oil microemulsions system. Industrial Crops and Products 52: 105–110. https://doi.org/10.1016/j.indcrop.2013.10.019. 19 Walden, P. (1914). Bulletin de l’Académie Impériale des Sciences de Saint-Petersbourg 405–422. 20 Dupont, J. (2011). Accounts of Chemical Research 44: 1223–1231. 21 Ueki, T. and Watanabe, M. (2008). Macromolecules 41: 3739–3749. 22 Correa, C.M., Faez, R., Bizeto, M.A., and Camilo, F.F. (2012). RSC Advances 2: 3088–3093. 23 Bazito, F.F.C., Silveira, L.T., Torresi, R.M., and de Torresi, S.I.C. (2008). Physical Chemistry Chemical Physics 10: 1457. 24 Fernicola, A., Scrosati, B., and Ohno, H. (2006). Ionics 12: 95. 25 Armand, M., Endres, F., MacFarlane, D.R. et al. (2009). Nature Materials 8: 621–629. 26 Zakeeruddin, S.M. and Gratzel, M. (2009). Advanced Functional Materials 19: 2187–2202. 27 Liu, L. and Corma, A. (2018). Chemical Review 118: 4981–5079. Sharapa, D.I., Doronkin, D.E., Studt, F., Grunwaldt, J.D., Behrens, S., Adv. Mater. 31 (2019) e1807381. 28 Liao, H.G., Jiang, Y.X., Zhou, Z.Y. et al. (2008). Angewandte Chemie (International Ed. in English) 47: 9100–9103. 29 He, Z. and Alexandridis, P. (2015). Physical Chemistry Chemical Physics 17: 18238–18261. 30 Kumar, S., Sindhu, A., and Venkatesu, P. (2021). ACS Applied Nano Materials 4: 3185–3196. 31 Patil, R.S., Kokate, M.R., Salvi, P.P., and Kolekar, S.S. (2011). Comptes Rendus Chimie 14: 1122–1127. 32 Dasari, S. and Mallik, B.S. (2020). Journal of Molecular Liquids 301: 112449. 33 de Azevedo, J.R., Letourneau, J.-J., Espitalier, F., and Ré, M.I. (2014). Journal of Chemical & Engineering Data 59: 1766–1773. 34 Jadhav, N.R., Bhosale, S.P., Bhosale, S.S. et al. (2021). Journal of Drug Delivery Science and Technology 65: 102694. 35 Monti, D., Egiziano, E., Burgalassi, S. et al. (2017). International Journal of Pharmaceutics (Amsterdam, Netherlands) 516: 45–51. 36 Zhang, L., Liu, J., Tian, T. et al. (2013). ChemPhysChem 14: 3454–3461.

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10 Anticancer Activity of Ionic Liquids Atrayee Banaspati 1 and Nirupamjit Sarmah 1,2 1 2

Gauhati University, Department of Chemistry, Guwahati, Assam 781014, India The Assam Royal Global University, Department of Chemistry, Guwahati, Assam 781035, India

10.1 Introduction Cancer is a group of diseases characterized by abnormal cell growth with the potential to penetrate adjacent tissues or spread throughout the body [1–5]. Cancer is among the leading causes of death worldwide, apart from infectious diseases, malnutrition, and cardiac diseases [6]. Although different therapeutics have been developed to treat cancer, there is still scope available for the development of newer therapeutics with lesser side effects and greater efficacy [2, 6, 7], among which ionic liquids (ILs) have attracted the attention of researchers as potential anticancer therapeutics as they are found to possess significant biological activity against various cell lines [8]. It was challenging for medicinal researchers to find new and potent drugs and their subsequent application in therapies. The majority of active pharmaceutical ingredients (APIs) are obtainable in solid form, a form whose bioavailability is often hampered by reasons such as polymorphic conversion and low solubility. Different medicinal salts of sodium or potassium have been developed to boost the aqueous stability [9]. ILs are salts consisting of ions that are liquid at room temperature or typically liquid at or below 100 ∘ C [8, 10]. Since the last few decades, researchers are interested in ILs owing to their low vapor pressure, high thermal stability, chemical stability, recyclable nature, nonvolatility, and noncombustibility. [11, 12]. An important characteristic of ILs is their unique salvation properties, which facilitate the dissolution of both polar and nonpolar compounds [13]. They pose a significant difficulty in medicinal chemistry, especially when creating new therapeutic drugs, and have been a subject of discussion in a number of domains due to their potential pharmacological qualities [7]. ILs affect life at all scales, from simple proteins to multicellular organisms. There are various reports using ILs as therapeutic agents, such as antitumor cytotoxic agents [2, 14–17]. Generally, ILs consist of organic cations including imidazolium, pyridinium, ammonium, phosphonium, and guanidinium (Figure 10.1), and a wide variety of

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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10 Anticancer Activity of Ionic Liquids Imidazolium 2

R

N

Quinolinium

Quaternary ammonium

1

+

R

N

Pyrrolidinium

1

4

R

R

+

+

R2

R3

N

R1

N

N

CH3

R1 R1 = −C2H5, −C4H9, −C6H13, −C8H17, R1 = −C4H9, −C8H17, −C10H21, R1–4 = −CH3, −C4H9, −C2H4OC(O)CH3, R1 = −C4H9 −C10H21, −C12H25, −C14H29, −C16H33, −C12H25, −C14H29, −C16H33, −CH2OC9H19,−CH2OC10H21, −CH2OC11H23, −C3H6OH, −CH2OC2H5, −C2H4OCH3, −C18H37 −CH2OC12H25, −CH2OC14H29, −C3H6OCH3, −CH2CN 2 R = −CH3

Morpholinium

Piperidinium

1

+

R

R

+

CH3

R1 = −C4H9

Bromide Br−

Bis(trifluoromethylsulfonyl)imide

R1–4 = −C4H9, −C6H13, −C14H

CF3 − N S O H [(CF3SO2)2N]−

Hexafluorophosphate

F3C

F

−

Acesulfamate H3C

F

O

P

F

F

F

Methyl sulfate

−

Octyl sulfate

−

O

C8H17

C

−

N H

C

N

[(CN)2N]−

Trifluoromethanesulfonate O

O O

N

O

O

O S

CF3

Dicyanamide

O S N

F [PF6]−

−

N

[(CF3)2N]−

F

F

O

Bis(trifluoromethyl)imide

O

F3C O S

B

H3C

R1 R2

R3

R1 = −C4H9

O

Tetrafluoroborate

F

+

P

Structures of cations commonly used in ionic liquids.

Cl−

−

R4

CH3

R1 = −C4H9

Chloride

F

Quaternary ammonium

1

N

CH3

Figure 10.1

R

+

N

N

O

Pyridinium

1

O

S

O −

O

−

O

O

S

CF3

[(CF3SO3]−

Figure 10.2

Structures of anions commonly used in ionic liquids.

anions such as halides, hexafluorophosphate, tetrafluoroborate, trifluoroacetate, bis-(trifluoromethylsulfonyl) amide, and dicyanamide (DCA) (Figure 10.2). ILs are prominent for their tunable nature, by virtue of which their properties can be tuned by modifying counteranions and alkyl side chain length, which is not possible for molecular compounds. ILs are now a novel and expansive field of scientific study thanks to the deft exploration of this property and its intriguing applications in a variety of domains [7, 12, 18], including antiviral, antibacterial, antifungal, anti-inflammatory, and anticancer actions [19, 20]. The antitumor activity and cytotoxicity of ILs are significantly influenced by the length of the N-alkyl side chain [15]. On increasing the N-alkyl side chain length and variation in the counteranions, the activity of ILs was found to increase [12, 15, 21].

10.2 Classification of Ionic Liquids

During the preceding years, various studies have been done on ILs by the researchers, resulting in several publications on ILs. However, regarding both the toxicity and safety of ILs, only limited studies were available [22]. The toxic API counterion in ILs is the primary cause of the delayed introduction of ILs into the biosciences sector [23, 24]. The full spectrum of biocidal potencies, from mildly inactive molecular solvents to high concentrations in aqueous solutions for medicinal uses [25–27], as well as feasible in vitro anticancer treatments, are toxic against microbes and eukaryotic cell cultures [18, 28]. As a result, it is questionable whether these chemicals should be used in biological applications, particularly as medicines and therapeutic agents. Contrarily, the legendary Swiss physician Paracelsus, who is credited with saying “The poison is in the dose,” suggested that toxicity may also be a valuable attribute, as seen by the numerous toxins that were once used as poisons but were later discovered to be significant medically. As toxins are biodynamic substances that alter how the victim’s body functions, they may one day play a significant role in the development of new medications. In the field of drug research and development, it presents a significant obstacle. Hence, the primary focus in the field of drug discovery is on the design and development of anticancer medicines that lower the toxicity associated with current chemotherapeutics and are intended to stop tumor resistance mechanisms [18]. Bioavailability of a compound becomes an important challenge if it is found to have drug-like property. As a result, one method frequently employed to address the issues of solubility and stability of APIs is the salt production of APIs. There are numerous instances where pharmaceutically active cations and anions combine to produce salt, demonstrating the medicinal effects of both constituents [29]. Researchers have discovered that many of these ionic salts’ properties are akin to those of ILs. ILs can therefore be created as possible anticancer agents and used in other therapies due to their tunable properties and toxicities [18].

10.2 Classification of Ionic Liquids ILs may be broadly classified into three generations based on the advancements being made in the discipline of ILs and their applications [30]. (i) First-generation ILs: The first generation of ILs was made using physical properties such as density, viscosity, thermal stability, conductivity, and hydrophobicity [23, 31]. This generation contains ILs, which frequently have distinguishing physical properties like low vapor pressure and excellent thermal stability [6, 32]. (ii) Second-generation ILs: In terms of their anticancer activity, secondgeneration ILs have received the most attention to date [2]. This generation of ILs consists of non-haloaluminate ILs with alkyl substituted imidazolium, pyridinium, piperidinium, morpholinium, quaternary ammonium, and phosphonium cations and halides, as well as hexafluorophosphate, tetrafluoroborate, trifluoroacetate, and bis-(trifluoromethylsulfonyl) amide anions [2]. A number of reports are available on the cytotoxic effects of different compounds representative of this second-generation ILs. The IC50 (half-maximum

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10 Anticancer Activity of Ionic Liquids

Doxorubicin O

Mitoxantrone

OH

O

OH

O

HN

OH

O

HN

H N

OH

OH OH

O

O

OH

O

O

OH

N H

OH NH2

Ampicillin

Methotrexate O

NH2

O

H N

O

H

N

N

N O

Figure 10.3

NH2

S

OH

H2N

N

COOH M H

N

COOH

N

Some third generation ionic liquids having anticancer properties.

inhibitory concentration) values reported for these ILs on various cell lines vary from micromolar to millimolar range depending on the structure of ILs and the cell used. Among the many cell lines used, it is observed that hepatocarcinoma, breast cancer, melanoma, cervical and ovarian cancers, as well as colon cancer, are the most researched [30, 33]. (iii) Third-generation ILs: Third-generation ILs include those organic salts containing natural, biodegradable, or API to produce formulations that have biological activities (Figure 10.3) [2]. ILs are thought to have one of the most promising uses when combined with APIs to create API-ILs [23, 25, 27, 31]. There are studies on the creation of API-ILs using buffer-controlled techniques using the well-known antibiotic ampicillin, which contains ammonium, imidazolium, phosphonium, and pyridinium cations [18, 34, 35]. These types of API-ILs can improve a drug’s water solubility, permeability, and bioavailability as well as provide an innovative solution to the polymorphic behavior of some medications [9]. Due to their low cost, simplicity in production, excellent cellular permeability, and capacity to regulate pharmacodynamic parameters and therapeutic agent polymorphism, these third-generation ILs have drawn increased interest in oncology [36, 37]. In some cases, it was found that they had stronger anticancer characteristics than their parent molecules; for example, ampicillin tetraethylammonium salt was extremely toxic to osteosarcoma and breast cancer cells and had very low IC50 values. According to a study by Ferraz et al., the analogue of 1-ethyl3-methylimidazolium is more lethal to colon cancer cells than ampicillin sodium salt [9]. Moshikur and his group reported the conversion of methotrexate, a class IV medication for chemotherapy, to ILs made of cholinium, tetramethylammonium,

10.3 Toxicity of Ionic Liquids

1-ethyl-3-methylimidazolium, tetrabutylphosphonium, or amino acid ester cations. When compared to methotrexate sodium salts, the lethal effects of methotrexate tributylphosphonium, 1-ethyl-3-methylimidazolium, and phenylalanine ester salts on cervical cancer cells were shown to be greater. The hydrophobic property of the cation and the cell membrane interact strongly (Π-Π interactions), causing cell death, which is attributed to this [38]. IL 1-(doxorubicin-10-carboxydecyl)-3 methylimidazolium bromide, IL based on doxorubicin, a common DNA-interacting anticancer drug, has been examined by Egorova et al. Doxorubicin and 1-(doxorubicin- 10-carboxydecyl)-3 methylimidazolium bromide were hazardous to colon cancer cells, with an IC50 value of roughly 6–9 mM [2]. ILs made from mitoxantrone and 3-(10-carboxydecyl)-1 methylimidazolium bromide have been reported by Kucherov et al. to be cytotoxic to human colon cancer and human colorectal adenocarcinoma cells [39].

10.3 Toxicity of Ionic Liquids The toxicities of ILs depend on: (i) the length of a cation side chain, (ii) the existence of a functionalized cation side chain or the level of functionalization, (iii) the type of the cation, and (iv) nature of the anion [24]. (i) Length of a cation side chain: Numerous studies have suggested that the cation’s alkyl side chain contributes to the toxic properties of ILs. Various headgroups, viz., ammonium, imidazolium, pyridinium, and phosphonium, possessing alkyl side chains of C-1 to C-18 and diverse anions, have the aptness to become more poisonous with an increase in the length of the alkyl side chain, which in turn reduces the viability of cells [40, 41]. The anticancer potential and cytotoxicity of ammonium and phosphonium-based ILs were assessed against 60 human tumor cell lines, and was observed that the chain length of the alkyl substituents has a significant impact on the antitumor activity and cytotoxicity of ILs [18]. For 1-butyl-3-methylimidazolium and 1-octyl-3-methylimidazolium, independent of the substituent anion BF4 or PF6 , 1-octyl-3-methylimidazolium decreased cell viability more than 1-butyl-3-methylimidazolium did against the HT-29 cell line. Similar to this, the cytotoxicity of the C-2 to C-5 methylimidazolium cations increases with an increase in the length of the alkyl side chain [42]. According to a different study, it was found that ILs based on phosphonium and ammonium are cytotoxic and have anticancer properties. However, it was observed that phosphorium-based ILs are more bioactive than ammonium-based ILs [18], and the antitumor activity increases noticeably with an increase in alkyl side chain length [35, 43]. (ii) Presence of a functionalized cation side chain or degree of functionalization: The best mechanism of biological activity for ILs differs depending on the organism. Water, however, seems to be quite important for the majority of the mechanisms in biological systems. The solubility of the ILs in water and their interactions with it serve as the primary determinants of their biological,

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10 Anticancer Activity of Ionic Liquids

pharmacological, and environmental activity. It has been demonstrated that the hydrophilicity, hydration state, or hydration number of ILs affects their biological activity [44–46]. Contrary to the assumption that more polarity meant less toxicity, it was found that the ILs with polar groups exhibited decreased cytotoxicity [16]. However, along with elongated alkyl chain, cation side chain or degree of functionalization also play a pivotal role in toxicities of ILs. The biological effects of side chains having functional groups were also investigated by numerous groups [41]. ILs with polar functional groups, such as hydroxyl, ether, and nitrile, exhibit less cytotoxicity than their structural analogues with nonpolar alkyl side chains, as was anticipated and later demonstrated. These polar groups reduce lipophilicity-based interactions with the cell membrane by impeding cellular absorption by membrane diffusion [24, 47]. The presence of polar groups in (1-(2-hydroxyethyl)-3-methylimidazolium) and (1-(2-(2-methoxyethoxy)ethyl)-3-methylimidazolium) increases cell viability against the cell line HT-29, so it can be said that the toxicity decreases in the presence of functional polar groups and contributes to nontoxic ILs. Ferraz and his co-workers reported that ILs with hydroxyl functionalized cations ([C2 OHC1 im]+ ) show more toxicity against HepG2 cells in comparison to ILs with nonfunctionalized cations ([C2 C1 im]+ ) [9]. Jovanovic-Santa et al. have also reported cytotoxicity data for some ILs against HeLa and A549 cell lines, which are found to be consistent with this rule [16]. (iii) Nature of the cation: In comparison to ILs containing hydrophilic and nonaromatic cations, ILs with hydrophobic and aromatic rings are more toxic. The predominant component in cation toxicity is determined to be the chain length of the alkyl substituents in the cation. According to some reports, for ILs possessing the same anion, toxicity of the cation increases with the chain length of the substituent [35]. In comparison to imidazolium or pyridinium, guanidine is more hazardous to malignant cells when the cations have the same substituents. Long-alkyl-chain substituent-containing guanidinium ionic liquids are more toxic toward hepatocarcinoma, melanoma, and cervical cancer cells. It was discovered that the dodecyl substituent molecule was 10 times more cytotoxic than the commonly used chemotherapy mitomycin C [2]. Wang et al. investigated the effect of various cations, viz., ammonium, choline, imidazolium, phosphonium, and pyridinium, on the viability of HeLa cells [48]. It was observed from their studies, that the pyridinium and imidazolium cations containing hydrophobic and aromatic rings are more polar in comparison to the highly polar choline compounds and ammonium derivatives [48]. On the other hand, Kumar et al. reported that aromatic headgroups like imidazolium and pyridinium are more toxic to cancer cells than nonaromatic and hydrophilic compounds like pyrrolidinium and piperidinium [49]. (iv) Nature of the anion: In contrast to all the abovementioned factors, the nature of the anion had a different effect on the anticancer activity of ILs. On the basis of various research studies, researchers have claimed that the toxicity effect of anions on cancer cells is limited. Stepnowski et al. reported that hexafluorophosphates are 450 times more toxic than chlorides and greater than 20 times

10.4 Anticancer Potential of Ionic Liquids

more toxic than tetrafluoroborates for a series of 1,3-dialkylimmidazolium salts that were tested against cervical cancer cells [2]. Frade and his co-workers investigated the effect of ILs containing 1-methyl-3-octyl-imidazolium or alkyl modified-choline [chol-Cn] cation and a magnetic anion such as [FeCl4 ], [GdCl6 ], [MnCl4 ], or [CoCl4 ] on colorectal cancer CaCo-2 cell lines [50]. They found that the ILs containing the 1-methyl-3-octyl-imidazolium cation follow the descending order of toxicity for anions: MnCl4 > CoCl4 > CdCl6 > FeCl4 , and this investigation demonstrated that [CoCl4 ] and [MnCl4 ] are more likely to produce cytotoxicity effect. Kumar et al. have studied the difference in toxicities of ILs of several anions which are in combination with different cation headgroups using human breast cancer cell line (MCF-7). In general, they established that for identical cations, hydrophilic and small anions like tetrafluoroborate and hexafluoroarsenate have higher EC50 values than significantly fluorinated, hydrophobic and bulky Tf2 N, TfO, or NfO [30]. Frade et al. proved that the toxicity effects against HT-29 and CaCo2 cell lines are lower when BF4 − , PF6 − , or dicyanoamide anions were replaced by [(CF3 SO2 )2 N]− anion [41, 42]. From the investigations of Wang et al. [48] and Chen et al. [51], it is evident that anions significantly affect the EC50 values for HeLa and A549 cells. However, ILs with tetrafluoroborate, [BF4 ]− anion are found to exhibit less toxicity than ILs with bis-(trifluoromethylsulfonyl)imide ([NTf2 ]− ) anion [52]. In spite of all the factors mentioned above, the toxicity of ILs also depends on the cell type used [40]. Depending on the characteristics and various properties of the cells used, the viability of different cell lines varies with exposure to the same ILs. Kaushik et al. investigated the anticancer activity of a few ammonium and imidazolium ILs in T98G brain cancer cell lines and compared the findings with those with human embryonic kidney (HEK) nonmalignant cells. It was discovered that the substance 1-butyl-3-methylimidazolium chloride was less active and toxic toward nonmalignant HEK cells than T98G brain cancer cells [53].

10.4 Anticancer Potential of Ionic Liquids Despite the fact that there have been numerous studies on the physical and chemical characteristics of ILs, their biological activities and toxicity have recently been regarded as two of the most extensively studied topics in this field [6]. Biologically active ions have been employed in the creation of new ILs. The use of low toxicity ions to produce ILs with the appropriate properties has been the main focus of research [6]. ILs are used as raw materials and as solvents and cosolvents in a variety of applications [54–56]. Moreover, ILs are also used in diverse fields, for example, in pharmaceutics (drug delivery and formulation), biotechnology (biocatalysis, biomolecule purification, and biofuel generation), and as antimicrobial agents [57]. The technological efficacy of pharmaceutically active compounds (APIs) can be

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increased by making use of ILs rather than pharmaceutically accepted organic solvents or in water [58]. ILs have been regarded as attractive prospects or beneficial components for innovative formulations in the pharmaceutical industry because of their effectiveness in dissolving a wide variety of chemicals, complex molecules, and biologically active compounds like proteins, amino acids, and so on. [6]. The studies of the potential of ILs as antitumor agents ushered a new direction for the applicability of these compounds. There are numerous reports available on antitumor activity and toxicity of ILs on human cancer cell lines [7, 15, 18, 35, 48, 49, 59–62]. Studies were carried out for human colorectal adenocarcinoma (CaCo-2) cells, cervical cancer (HeLa) cells, human immortal keratinocyte cells, human pancreatic cancer cells, human hepatocellular carcinoma cells, human breast cancer cells (MCF-7), human renal cancer tumor cells, and human skin cells [63]. The bulk of these studies express the toxicities of the ILs in terms of IC50 values, or inhibitory concentrations (IC) that inhibit biological or biochemical systems’ activity by 50%. In some other studies, toxicity is expressed as the EC50 value, or effective concentration, which results in a 50% reduction in the number of dead cells, while in others, it is given as the LD50 value, or median lethal dose, that is, the quantity of material that kills 50% of the population [24]. Earlier reports suggest that 1-methyl-3-octyimidazolium chloride ([C8 MIM][Cl]) induces oxidative stress in human hepatocarcinoma (QGY-7701) cells by increasing intracellular reactive oxygen species (ROS) generation and by lowering antioxidant enzyme activities [30]. The IL ([C8 MIM][Cl]) induced apoptosis through altered intracellular Ca2+ levels, mitochondrial dysfunction, and cellular ATP exhaustion. Therefore, these data revealed that a major mechanism behind the cytotoxicity of ILs may be due to ROS-mediated oxidative stress and mitochondrial malfunction. Whereas certain other report suggest that 1-methyl-3-octyimidazolium bromide ([C8 MIM][Br]) exerts cytotoxicity against human hepatocellular carcinoma (HepG2) cell lines via apoptotic mechanism of the cells. The ROS are believed to be the primary early signal of the [C8 MIM]Br-induced apoptotic process through the intrinsic (mitochondrial) pathway [62]. Bansode et al. produced a series of ferrocene-tethered ILs by quaternizing 1-N-(ferrocenylmethyl)benzimidazole, 1-N-(ferrocenylmethyl)imidazole, and 1-N-(ferrocenylmethyl)-1,2,4-triazole along with long-chain alkyl bromides like ocytl, decyl, and dodecyl. The anticancer activities of the IL so produced were evaluated using human breast cancer cell line (MCF-7), and it was discovered that they exhibited extraordinary anticancer potential. In comparison to the standard medication doxorubicin, they exhibit moderate to good selectivity against human breast cancer cells MCF-7 over normal Vero cells [13]. To evaluate the selectivity, the SRB assay method was used to screen the ferrocene-tethered ILs against normal Vero cells. The selectivity test was done in view of the fact that some anticancer drugs have been found to interfere with the growth of normal cells, which is currently considered to be the most significant concern for anticancer drug development. It was discovered that majority of the ferrocene-tethered ILs exhibit moderate to good selectivity against the human breast cancer cell line MCF-7 over normal Vero cells. The outcome also disclosed the safety profile of the ferrocene-tethered ILs [13].

10.4 Anticancer Potential of Ionic Liquids

Recent work published by Musial et al. provided a thorough analysis of the cytotoxicity of imidazolium cations, cyano-based (thiocyanate [SCN], dicyanoamide [N(CN)2 ], tricyanomethanide [C(CN)3]), and bis-(trifluoromethylsulfonyl)imide ([NTf2 ]) anion-based ILs toward two types of human cells, namely normal (kidney and lung) and cancer (lung, liver, and cervix) cell lines [52]. They investigated a series of six nonidentical cell lines, including the normal Vero kidney cells of Cercopithecus aethiops, the LLC-MK2 normal kidney cells of Macaca mulatta, the MRC-5 normal fibroblasts of the human lung, the A549 normal lung carcinoma cells, the HepG2 normal hepatocellular carcinoma cells, and the adenocarcinoma cells of the human cervix (HeLa). The IL with the longest alkyl chain linked to the cation, 1-methyl-3-octylimidazolium bis(trifluoromethylsulfonyl)imide ([C8 C1 im][NTf2 ]), displayed the highest level of biological activity, whereas 1-ethyl-3-methylimidazolium thiocyanate was found at the receding end of toxicity. Among the ILs having identical numbers of –CH2 – (methylene) groups substituted to cations, [C2 C1 im][N(CN)2 ] and [C2 C1 im][SCN], respectively, displayed the highest and lowest cytotoxicity toward normal human cells (Vero and LLC-MK2 cell lines). In comparison to other [C2 C1 im]-based ILs, Musial et al. found [C2 C1 im][N(CN)2 ] to be the most toxic IL against nontumor cell lines. However, toxicity toward the A549 cell is lower in comparison to the toxicity obtained for [C2 C1 im][SCN] and [C2 C1 im][C(CN)3 ], but higher than that for [C2 C1 im][NTf2 ]. Since [C2 C1 im][N(CN)2 ] is significantly active against nontumor cells, it cannot be considered a potent anticancer agent [52]. The physicochemical characteristics of ILs are well recognized and beneficial in a variety of applications. In contrast, ILs have a hostile effect on the environment. Santa et al. have investigated a variety of imidazolium- and salicylate-based ILs with minimal overall toxicity while considering their medicinal potentials. They demonstrated the anticancer potential of these salicylate- and imidazolium-based ILs against human cancer cell lines using a cell viability MTT assay. Anticancer activity of salicylate- and imidazolium-based ILs was evaluated against six human cancer cell lines: two types of human breast adenocarcinoma MCF-7 and MDA-MB-231 cell lines, prostate cancer cell line PC-3, cervix adenocarcinoma cell line HeLa, colon cancer cell line HT-29, and lung cancer cell line A549, together with regular fetal lung fibroblast cell line MRC-5. However, there are only a few reports available regarding the toxic effect of salicylate-based ILs against human cell lines in comparison to reports available for the imidazolium-based ILs [50, 64–66]). Santa and his coworkers discovered that ILs containing 1-butyl-3 methylimidazolium or imidazolium cation had the lowest dipole moment and maximum lipophilicity, which led to increased toxicity in colon and lung cancer cell lines while exhibiting good selectivity in normal cells. The nonpolar IL with the anion 1-butyl-3-methylimidazolium displayed the strongest anticancer properties and increased toxicity against normal cells, in spite of the fact that its cytotoxicity was lower in comparison to the cytotoxicity of commercially used chemotherapeutic agents [16]. The most cytotoxic IL was found to be [2-(4-Hydroxyethoxy)ethyl]-3-methylimidazolium salicylate with an IC50 value of 9.26 μM against the studied cancer cell line. This compound consists of a polar substituent in the N-1 position and has both

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hydroxyl and ether functional groups. Imidazolium salicylate, that is, salicylate with a nonsubstituted imidazolium moiety with an IC50 value of 39.94 μM exhibited moderate toxicity against HT-29 cell lines. The most nonpolar group in 1-butyl-3-methylimidazolium salicylate, n-butyl, also exhibited effects similar to those of the compound [2-(4-Hydroxyethoxy)ethyl]-3-methylimidazolium salicylate, even though 1-butyl-3-methylimidazolium salicylate show cytotoxicity against normal human lung fibroblasts (MRC-5) cell line. Left alone colon carcinoma cell line, the other ILs they studied were toxic to lung adenocarcinoma cell line A549, exhibiting moderate cytotoxicity [16]. Rezki and his coworkers reported the formation of novel imidazolium IL halides by quaternizing 1-methylimidazole and 1,2-dimethylimidazole with an appropriate quantity of 2-chloro-N-(fluorinated phenyl)-acetamides [7]. These novel halides have various fluorinated phenylacetamide side chains attached to them and were converted into their corresponding ILs using fluorinated counteranions. They have investigated the ILs’ ability to bind DNA and their anticancer capabilities. The measured DNA binding constants suggest that they have a strong affinity for the biomolecule DNA. The report suggests that the anticancer activity of the ILs ranges from 48 to 59 using the H-1229 cell line. Simulation studies were carried out to determine the anticancer mechanism. They have excellent anticancer potential, making them an excellent anticancer candidate for the treatment of human cancer. Ferraz et al. have demonstrated the antiproliferative effects of ionic solutions based on ampicillin salt against a variety of tumor cell lines. Anionic ampicillin was combined with the appropriate ammonium, imidazolium, phosphonium, and pyridinium cations to create active pharmaceutical ingredient ionic liquids (API-ILs). These liquids have potential antiproliferative properties against a variety of human cancer cell lines, viz., the breast cancer cell line (T47D), the prostate cancer cell line (PC3), the liver cancer cell line (HepG2), the osteosarcoma cell line (MG63), and the colon cancer cell line (RKO). However, the API-ILs’ minimal cytotoxicity against the primary cell lines of gingival fibroblasts and skin (SF) suggests that the majority of them are not toxic to healthy human cells. Among the tested compounds, 3-(2-hydroxyethyl)-1-methylimidazolium-ampicillin salt ([C2 OHMIM][Amp]) was found to be the most promising API-IL against the five cancer cell lines studied and also have greater selectivity, having a combination of antitumor activity and low cytotoxicity toward healthy cells [9]. A standard antibiotic ampicillin sodium salt ([Na][Amp]), exhibits toxicity against only PC3 and RKO cell lines. However, it showed very low activity toward the cell lines studied, barring the liver cancer cell line (HepG2). Remarkably contrasting results have been noticed when ampicillin is combined with distinct organic cations. For example, while ammonium-based IL [TEA][Amp] was extremely cytotoxic against osteosarcoma cell line (MG63) and breast cancer cell line (T47D) cell lines, whereas ammonium-based IL [Cholin][Amp] was especially selective for the colon cancer cell line (RKO) [23]. In MG63 cell lines, this API-IL shows strong antiproliferative action. The high cytotoxicity of [Cholin][Amp] toward MG63 cancer cells and its high selectivity away from noncancerous cells can be partially attributed to its high water solubility

10.5 Conclusions and Future Scope

and partition coefficient, which make it easier for ampicillin to enter the cytosol of cancer cells when compared to other bulky cations [23]. From the investigations conducted by Ferraz et al. it can be said that the aforementioned API-ILs are promising for upcoming in vivo studies. Due to the stronger and more stable cation–anion interactions than the sodium equivalent, choosing the right counterions can explain these antitumor activities. As a result, the formation of effective ion pairs by suitable organic cations can increase the pharmaceutical salts’ water solubility, permeability, and bioavailability, as well as serve as lipophilic drug carriers [9]. Choline salts with the carbon chain lengths of acetate, propanoate, butanoate, hexanoate, and pivalate showed increased cytotoxicity against the MCF-7 cancer cell line [65]. Other ILs that include quaternary ammonium cations typically do not show cytotoxicity when applied to cancer cell lines [18]. According to Malhotra et al., ILs based on methylimidazolium demonstrate cytotoxicity when the alkyl side chain has more than 11 methylene units [35]. ILs are found to be similar to cationic surfactants and can easily cross biological membranes, according to the results of the numerous investigations conducted by the researchers. In the world of medicine, this discovery is noteworthy. As was previously mentioned, the type of alkyl chains connected to the cations of the ILs determines the toxicity and anticancer activity of the ILs. However, there are other ways to get the desired IL characteristics. Doxorubicin-loaded ionic liquid polydopamine (IL-PDA-DOX), which was investigated by Tang and his colleagues, is used in microwave thermal therapy and biocompatible delivery nanoplatforms for chemotherapy [67]. By packing the IL into polydopamine nanoparticles, the method of combinatorial therapy can be applied, which becomes a nanocarrier for chemotherapeutic drugs. IL-PDA-DOX, which exhibited antitumor characteristics, performed well in tests combining chemotherapy and microwave thermal therapy. This discovery opens up new therapeutic options for the treatment of cancer [6].

10.5 Conclusions and Future Scope ILs having a wide range of physicochemical characteristics are nowadays in focus and have received attention due to their application in the medicinal field. Hence, it is not shocking that ILs have received attention of biomedical researchers as suitable catalytic media for the synthesis of drugs and as potential components of drug formulations. A large number of ILs have been synthesized, and few of them have been tested for their anticancer potential. It is clear from the preceding discussions that all the described studies and discoveries are crucial to the new understanding of anticancer therapy, but other fresh discoveries and studies will still be required in the future. For potential toxic interferences that ILs might use in human cancer cell lines, Arning and Matzke developed a general assessment of the significant basal cellular and subcellular targets [40]. This could help determine where and how ILs can act on the cell. The majority of research on ILs is restricted to in vitro testing of the ILs’ cytotoxic effects on various cell types. A few reports are also available on in vivo cytotoxicity

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of ILs against various cell lines. According to some assumptions made on the mechanism of cytotoxicity of ILs, the cytotoxic effect is because of the interactions between ILs and the lipid membrane, resulting in the destruction of cell membrane. The design of novel compounds with desirable anticancer activity and greater selectivity could benefit from a complete understanding of the mechanism of cytotoxicity of ILs [2]. In addition to the older diseases that have been eradicated or effectively controlled by various medications and other therapeutic procedures, the number of new diseases is continually rising. As a result, there is an increasing need to carry out more research to develop new treatments. The latter are required to replace medications that are no longer effective as a result of the target bacteria’s or other disease-causing agents’ strengthening of immunity. Additionally, there is a pressing need to replace pharmaceuticals that have a variety of adverse effects, some of which are so terrible that even patients cease using them [6]. Growing interest requires the development of new chemicals with low or no toxicity and anticancer properties. Exploring advanced treatment options and personalized medicines is one of the major focus areas of the pharmaceutical industry. ILs and the advantages associated with them may play a crucial role in this field in the future. ILs may present an amazing prospect and a potential substitute for medication design when compared to other conventional medicines, according to the studies that are currently accessible. The tunable properties of ILs by the choice of right anion or cation and adjusting the cationic part with different substituents could manage their biological activity, cytotoxicity, and drug solubility. This characteristic may be crucial in the therapeutic use of ILs, such as in the treatment of cancer [18, 30, 35]. To comprehend their harmful effects, future toxicity studies should also incorporate the investigation of metabolic pathways. In the future, it may be possible to compare the outcomes in terms of IC50 or LD50 to those obtained with other anticancer drugs available on the market or with a reference medicine in each cancer cell line. In addition, because there are so many possible combinations of cations and anions, future research will need to invest in cutting-edge methods based on structure–activity relationship data to handle the large number of potential structures [30].

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11 Importance of Ionic Liquids in Plant Defense: A Novel Approach Mamun Mandal and Abhijit Sarkar Laboratory of Applied Stress Biology, Department of Botany, University of Gour Banga, Malda - 732 103, West Bengal, India

11.1 Introduction Ionic liquids (ILs) are generally organic salts with melting point temperatures lesser than decomposition temperatures, especially under 100 ∘ C and also at room temperature, i.e. RTILs (room-temperature ILs; [1]). Their ionic structures govern a variety of qualities, including moderate to high viscosity, extraordinarily low volatility, incombustibility under normal temperatures, the capacity to dissolve various components, and great thermal stability, especially in the natural polymers [2]. Based on their cation dependency, ILs are classified as ammonium, imidazolium, pyridinium, piperidinium, phosphonium, sulfonium, morpholinium, and, more recently, pyrylium [3]. These physical features have made it easier to use ILs as “green” liquids or multifunctional liquids, as has been well documented in many scientific literatures [4, 5]. ILs are used in various biological applications such as antimicrobials, fungicidal herbicides, antibacterial adhesives, dual-function plant resistance, and growth promoters, which are simple to make and use [6]. ILs have a variety of environmental, biological, medicinal, and pharmaceutical applications, including those listed above, as well as many more [6]. Naturally derived materials in ILs appear to be particularly attractive, owing to the introduction of green [7, 8], and economic elements [9], as well as high availability in some cases [10]. Strong biologically active abilities of natural source stimulants are the important medium of biological abilities that are being used to introduce and strengthen bioapplications, so all of these are possible to adapt in ionic salt forms [11]. Phenolics, alkaloids, and terpenoids are three primary families of plant secondary metabolites of these multifunctional activities [3, 12]. Terpenoids, on the other hand, are the most varied natural chemical class on the planet, with over 80,000 recognized distinct types of structures. A wide range of biologically important functions arise from this wide diversity of structures. From the standpoints of both bioapplication and environmental issues, such isoprene byproducts are suitable natural recyclable ingredients for IL synthesis and/or designing [13]. Interestingly, Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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asymmetrical catalysis, wherein optical activity-based salts are incorporated as chiral-reaction products or/and catalysts is the most common use of terpene-based ILs, as well as other usages of these kinds of chiral ILs are mostly responsible for the appearance of optically active site [14]. Surprisingly, terpene-based IL segments with high biological activity are rarely used. These salts have significant antibacterial capabilities, can be used as wood preservatives, can activate and stabilize enzymes, and can even be used for scent targeted delivery [15, 16]. Feder-Kubis et al. [6] looked at how terpene-based ILs may help plants perform better in their natural settings by modifying the anion and cation groups of the IL structures. They have acquired plant resistance-inducing salts and antibacterial from natural sources in particular. Systemic acquired resistance (SAR) is a naturally occurring plant defense system that protects plants from bacteria, viruses, and fungi. This mechanism, which evolved during evolution, can be caused biologically by pathogenic assaults or artificially by chemicals that mimic plant–pathogen interactions. SAR is active within a few hours after infection, and signaling molecules known as elicitors are delivered to every region of the plant [17]. SAR inducers are used in the same way as traditional pathogen prevention strategies. As a result, SAR is a very proficient strategy for plant protection in the future due to its high effectiveness and wide range of functional activity against the phytopathogens. Aside from infections, several chemicals can mimic plant–pathogen interactions when applied to plants. Naturally produced signaling chemicals, such as SA, are constituents of physiological induction, and can induce systemic protection when administered externally [18]. Other chemicals that induce immunity include succinic, aminobutyric, azelaic, pipecolic, S-methylbenzo[1.2.3]-thiadiazole-7-carbothioate (BTH), 2,6-dichloroisonicotinic acids, and their derivative components. It is worth noting that chemically altered BTH substances employed at extraordinarily low dosages (20 mg/L) were completely effective in inducing SAR in plants [6]. In this method, a previously neutral active molecule with one biological activity obtained other properties following transforming into an ILs form, such as quasi-selective contact with a pest’s outermost layer. This newly obtained characteristic created the new product work as a biological agent, comparable to commonly used drug delivery vectors, with the exception to, in this situation, the ILs are the pharmaceutical and the vector concurrently. In this chapter, we have detailed instances of scenarios in which ILs were developed especially for a specified plant defense and agriculture-related use.

11.2 Generation of ILs and Their Application ILs have a lengthy history of discovery, yet they are still a growing subject of study. ILs have quietly developed in the last several years from simple salts with a lower melting temperature and remarkable inherent physical characteristics that were primarily used as solvents for extensive tunable materials with distinctive chemical, physical, and perhaps even biological capabilities [19]. A recent study

11.2 Generation of ILs and Their Application

indicates that an IL’s adaptation to a certain application can be so precise that it might be referred to as a customized tool built for a specific purpose rather than a basic chemical molecule. To give an example, ILs have been used as naturally producing green solvents [20, 21], drug delivery systems [22], catalysts [23], electrochemical sensors [24], liquid membranes [25], conducting medium in power storage, and conversion devices (like solar cells, batteries, supercapacitors; [26]). The key reasons for ILs’ ever-increasing popularity as extensively used chemicals are their distinguishing features. For all of them is their customizability, which is defined as the capacity to create and regulate the features of the acquired salt within a specified range to tailor it to a certain activity. Researchers have classified ILs under three generations since the publication of Hough et al. [27]. This section is considered as a new mode of thinking as well as a growing branch of research known as “ILs.” ILs were originally utilized as solvents [28] because they have an exceptional type of physical feature, for example, thermal stability, non- or low volatility, and vast liquid ranges [29]. Because of the increased interest in these ILs, the second generation of ILs was developed, which are materials with adjustable chemical and physical characteristics that may be used as energetic materials [30] and lubricants [31]. As a result, it became widely accepted that diverse characteristics of ILs might be given to the molecule by both types of the component ions, and the name “task-specific ILs” was the coin [32]. The discovery of the third generation (3rd-Gen) of ILs – ILs with potent biological activity began with using ILs as bioactive pharmaceutical ingredients (BPIs), but subsequent advances have broadened the issue to include ILs for bio-related applications, the antifungal and antimicrobial properties of ILs. A significant illustration of the 3rd-Gen of ILs was published in 2011, where Pernak et al. [3] explained the first time about herbicidal ILs with their dual functional activity. The fundamental idea was to synthesize ionic derivatives of widely existing herbicides. To decrease the water solubility and so lessen the detrimental impact on environment while keeping the herbicide’s fundamental bioactive action, ionic compounds were formed from neutral main constituents. Because of their potential biological activities and adaptability, ILs have found applications in other aspects of life, agriculture with its issues and challenges, including dangerous viruses, darnel, fungi, and bacteria, as well as invertebrates, insects, and rodent pests [32] (Figure 11.1). Davis Jr et al. [33] reported the earliest literature studies on physiologically active ILs in 1998, and they involved ILs made up of alkylated derivatives of an available commercial antifungal medication in the form of cations mixed with inorganic anions. Consequently, this discovery had a significant impact on people’s perceptions of ILs, which were previously viewed as either a type of green solvent or substances that were potentially dangerous to human health and the environment. The breakthrough in IL research began in 2009, demonstrating that, in addition to being designer solvents, ILs can also incorporate physiologically bioactive constituents. The original method for bioactive ILs (including one or both bioactive ions) was designed to demonstrate that freshly produced ILs retained their physiological activity against a variety of microorganisms, and in certain cases, an improved antibacterial action was even seen [32].

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Resistance Ionic liquids

Systemic signal

224

Growth regulators

Systemic acquired resistance

Fungicides

Plant resistance inducer

Ionic liquids

Formulations

Bactericides

Herbicides

Figure 11.1 Different types of functional activity of ionic liquids in plant defense mechanisms.

11.3 Role of ILs in Plant Defense Mechanisms 11.3.1 ILs as Antibacterial Agents All organic resources in the consumer economy are susceptible to harmful microbes, such as detrimental bacteria. Attempts to protect resources and nutrition against these unseen foes have been made since the start of time, and they have developed into increasingly complex forms. The employment of chemicals (biocides) is one of the most advanced, with a group of ILs functioning as antimicrobial agents emerging especially pervasive. Pernak’s team began looking into the link between the cations of specific ILs and antibacterial properties of the salt that resulted [34]. The findings demonstrated a link between the size of such cationic alkyl chains and the bioactivities of the compounds studied, comparable to what has been shown with most quaternary ammonium compounds as well as other long-chain surfactants. Antibacterial activities of ILs were first investigated as a side project while studying the physicochemical features of simple, common pyridinium or imidazolium cation-based ILs [35]. Zajac et al. [32] described a set of ILs based on antibacterial cations and anions in their review study. The second category of dual-functional ILs contains molecules in which each role is provided by a distinct ion, according to the researchers. Due to the nearly limitless number of property alteration options,

11.3 Role of ILs in Plant Defense Mechanisms

this has been the most convenient circumstance. Also, it permits the combination of bactericidal activity in one ion with biological property in another, making these ILs promisingly valuable as agricultural agents. Another important study in this field focused on the combination of ILs’ antibacterial and resistance-inducing action in plants. The fact that these experiments were centered on plant bacteria, pests, and viruses (rather than human/animal pathogens) is remarkable, since it represents an altogether new approach to this issue in the research. This one was especially significant given the growth of antiviral plant defense, which is unsolvable by conventional pesticides. Smiglak and his coworkers projected combining antimicrobial activities with so-called SAR inducers, wherein their antiviral activity is exhibited throughout the plant’s resistance development and allows the plant to combat infection independently after activation [36]. The researchers produced a number of BTH-based ILs, wherein the constituent has previously been shown to be a strong SAR activator inside its standard state, but also has extremely poor water solubility, posing application challenges [36]. The approach of using its ionic state and adding functionality was expected to have a variety of advantages, including improved solubility in water and increased functionality. And also, the study discovered that the cationic and anionic BTH forms had high levels of SAR activity (in certain scenarios, greater than the neutral precursor) against the latent olives (OLV-1) and tobacco mosaic viruses (TMV), and counterions, for example, lauryl sulfate, anionic docusate, cationic tetraalkylammonium, or N-morpholinethanesulfonate-substituted imidazolium, benzethonium, and pyridinium cations, were bringing a preferred subsequent functional activity (biological or physical) toward the salt constitution [5, 30, 36, 37]. As a result, the explanations introduced above can be considered one of the most admirable among many of the dual purposeful ILs mentioned throughout aspects of their functionality in agricultural production due to their higher capability (plant antiviral and antimicrobials activities) and concurrent plant resistance induction characteristics with remarkably low deleterious impacts on the surrounding environment (i.e. substantial effectiveness at a lower dose).

11.3.2 ILs as Antifungal Agents Bacterial infections are not always the most significant hazard in the plant kingdom, unlike in the animal kingdom. In the case of plants, fungal pathogens are primarily responsible for this function. As a result, developing effective fungicides is critical for healthy and ecologically friendly agriculture. Bica et al. [38] produced ILs as a cationic derivative of fungicides (imazalil and thiabendazole) now used against potato tuber diseases and were the first to offer the notion of employing fungicidal ILs for prospective application in the agricultural field. Only two fungicides have been licensed for use in agricultural fields at this time [32]. Phytophthora erythroseptica (pink rot), Fusarium spp. (root rot disease), and Phoma spp. are the most common causes of potato tuber diseases (gangrene). In vitro tests were performed on two synthetic ILs such as imazalilium docusate and thiabendazolium docusate against 10 phytopathogenic funguses. The antifungal effectiveness of

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acquired ILs against the broad spectrum of potato tuber infections was not only maintained, but substantially improved, when compared to traditionally available precursors. These first findings demonstrate that the use of ILs in agricultural productivity has huge promise [32]. Khungar provided another example in which ILs with antagonistic activity against phytopathogenic fungi were identified [39]. Pernak et al. [3] made a significant contribution to the hunt for novel ILs that are effective pesticides. Theophylline, a natural substance, was combined with ammonium- and piperidinium-based cations to produce nonhazardous, pesticidal ILs in this idea. Theophylline is a naturally occurring chemical contained in brewed tea and coffee beans that is pharmacologically and structurally similar to caffeine and is frequently utilized in the treatment of respiratory illnesses. The scientists postulated that theophylline-based ILs may be viewed as possibly effective in plant defense based on the knowledge that even higher concentrations of caffeine in younger tea leaves defend the plant against insects and viruses. Such ILs were found to have antifungal efficacy against many fungal pathogens like Sclerotinia sclerotiorum, Fusarium culmorum, Botrytis cinerea, and Microdochium nivale [40, 41]. The experiments revealed that an equal antifungal impact was obtained compared to the commercial antifungal agent Tebu EW (tebuconazole), but only at the higher concentrations of theophylline-type ILs. The evaluated ILs fungicidal characteristics, and therefore their unneutral influence on environmental components, necessitated concurrent biological/physiological investigations for a more accurate assessment of their toxicity in the environment. Lethal dosage (LD) values and biodegradability were studied, followed by mechanistic investigations [41, 42], examining the mechanism of action of different IL groups on fungi. Furthermore, the findings of these fungicidal investigations showed a novel application possibility.

11.3.3 ILs as an Herbicide and Plant Growth Promoters Herbicides are another agro-related use for which ILs have been studied. Herbicidal ionic liquids (HILs) are more effective herbicides than commercially available herbicides. These molecules, like classic ILs, are formed up of ions, one of which has been proven to have herbicidal characteristics, like 4-chloro-2methylphenoxyacetic acid (MCPA), 2,4-dichlorophenoxyacetic acid (2,4-D), 4-(4chloro-2-methylphenoxy)butanoic acid (MCPB), 3-(4-chloro-2-methylphenoxy) propanoic acid (MCPP), 3,6-dichloro-2-methoxybenzoic acid (dicamba), clopyraid, and glyphosate. Researchers are focusing their attention on the synthesis of HILs from naturally occurring compounds, for example, rapeseed oil, Pelargonium roseum, D-glucose, and choline, according to the newest trends in HILs synthesis. Bio-HILs (bioherbicide ionic liquids) are the resultant chemicals [43, 44]. HILs of the third-generation phytopharmaceuticals were recently reported [3, 45] (Table 11.1). Chlormequat chloride 2-chloroethyltrimethylammonium chloride (CCC) is used as a plant growth regulator. In addition, CCC is used to promote flowering in some ornamental plants and lateral branching, as well as fruit set in pears, vines, tomatoes, and olives. On the other hand, (2,4-dichlorophenoxy)acetic acid (2,4-D) is a systemic herbicide used to suppress broadleaf weeds as well as a synthetic auxin widely used in laboratories for plant research purposes [3]. The use of 2,4-D and

11.3 Role of ILs in Plant Defense Mechanisms

Table 11.1

Application of ionic liquids in plant protection from the stressors.

Ionic liquids

Category of ion

Functional activity

References

2,4-Dichlorophenoxy

Acetate anion

Plant resistance inducer, antimicrobial agent, herbicide, and plant growth regulator

[3]

(−)-Menthol (derived from Mentha piperita) + benzothiadiazole (synthetic)

Pairing of anions with cations

Antimicrobial activity and plant resistance inducer (SAR induction)

[6]

Chloromethyl(1R,2S,5R)-(−)menthyl ether (derived from natural-origin material (1R,2S,5R)-(−)-menthol)

Cations (chiral ionic liquids)

Induce the antioxidant enzyme activity in plants

[46]

3-Ethyl-1-[(1R,2S,5R)-(−)menthoxymethyl]-imidazolium chloride (derived from natural-origin material (1R,2S,5R)-(−)-menthol)

Cations (chiral ionic liquids)

Induce the antioxidant enzyme activity in plants

[46]

CCC is frequently condemned because to their toxicity and adverse effects. These, particularly 2,4-D, are, nonetheless, inexpensive and frequently utilized, and they seem to have an ionic nature as well. They are used as substrates in the synthesis of third-generation ILs by Pernak et al. [3]. The goal of our research was to create novel salts and investigate their potential as plant growth regulators and herbicides.

11.3.4 Effects of ILs as Deterrents As previously said, the products of our farming, which are critical for the existence of our species, are easily damaged by microorganisms; therefore, we are continuously looking for ways to regulate them. But our concerns about this subject are far from over. Also, there are larger foes, such as insects, that regard our crops and food as a plentiful larder. Of course, we could eradicate them using different techniques, but this strategy would have two undeniable drawbacks: tremendous disruption of the ecosystems, in which they play an essential role, and the higher amount of toxicity of the chemicals used there, which might hurt other beneficial creatures [47]. It would be fairer to utilize biocompatible chemicals that have a repellent effect on these pests. In reality, these substances are known as “insect antifeedants” and have already been used by nature to deter insects. Insect antifeedants (also known as feeding inhibitors or feeding deterrents) are a class of chemicals that interrupt the mating and reproductive part development of insects without destroying them [47]. Major types of plant secondary metabolites frequently demonstrate this function; in fact, they are the most well-known natural deterrents [3]. However, because their concentration on plants is often lower and the expense of obtaining them is considerable, these chemicals have yet to be widely used. ILs can be utilized to protect harvested grains and plants from insects by functioning as effective feeding deterrents, in addition to

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being employed for many applications linked to plant and crop protection against microorganisms. Azadirachtin is one of the most potent natural antifeedants produced by Azadirachta indica [48]. This substance has activity against a wide range of pests, making it one of the most popular effective bioactive feeding deterrents, allowing for the production of goods with lower toxicity than synthetic pesticides.

11.3.5 Application of ILs as Bioactive Formulations Pesticides have severely damaged the groundwater, land, and atmosphere, posing a major hazard to human health. As a result, it is vital to increase efficiency while reducing the amount of insecticides utilized. It is also critical that formulations stay stable at room temperature after application. Furthermore, because most pesticides are only marginally soluble in water, substantial volumes of hazardous organic solvents are used in liquid formulations [49]. For example, acetochlor, metolachlor, prochloraz (fungicide), thiamethoxam (insecticide), and clethodim (herbicide) are not totally soluble in water, and these pesticides are extensively used in agriculture field. Various molecules might be dissolved with ILs, different combinations of ILs or IL-based solution system that meets the need for employing soluble form compounds while reducing the amount of hazardous organic solvents [2]. One of the most basic applications for ILs as “agro-active” agents is as additions in pesticide formulations to enhance the active chemicals’ solubility [50]. It is widely acknowledged that current plant protection agents (pesticides) should be effective, selective, nonaccumulative, and function in the manner indicated by the maker. This implies that sometimes the impact must be one-time but rapid, and other times the active substance must persist on the seeds and plants for a length of time to ensure adequate defense [51]. Pesticides must also be easy to store, have minimal side effects on beneficial creatures and people, and, most critically, show effectiveness at low doses. Pesticide formulations with aqueous suspensions are now the most popular. The issue is that active compounds are often water insoluble. As a result, increasing their solubility and effectiveness is a critical feature. Adjuvants are commonly used to increase the solubility of active substances in the final reaction mixture. A simple change in pesticide composition can result in a 20%–25% reduction in the number of insecticides needed [52]. Two research articles were published in 2013 that described compositions that included oil and ILs as active components, with the ILs acting as an adjuvant for traditional pesticide formulations. The authors stated that using ILs enhanced the active component’s solubility in the oil. As a result, the plant protection agents’ amount used per 1 ha of cultivar was lowered without a reduction in pesticide effectiveness [50, 53].

11.3.6 Role of ILs in SAR Induction Mechanism The SAR phenomenon has several advantages. SAR works against a wide range of pathogens, most commonly bacteria, viruses, and fungi, all at the same time [54, 55]. SAR inducers, on the other hand, are environmentally safe since they do not disrupt the natural balance and do not directly interact with the microbiota. Phytopathogens do not produce immunization activity against SAR inducers because they do not directly interact with the pathogens and the mechanisms are also too complicated.

11.4 IL Products in Future Management of Agri Industries: An Innovative Approach

SAR is a long-term process that may be handed on down the generations. SAR induction components can be utilized in conjunction with another crop protection agent to minimize the dose [56] or instead of genetically engineered plants. These inducers are also used in the same way as traditional pathogen prevention strategies. As a result, it is a very potential approach for future crop protection due to its high effectiveness and broad range of activity against pathogens [57]. Feder-Kubis et al. [6] studied the feasibility of creating dual functions of ILs by combining SAR inducer anions with bactericidal terpene-based cations. The mixture of such structural properties is obtained by combining (1R,2S,5R)-(−)-menthol, which occurs in natural way, is inexpensive, and is widely used in a variety of fields, with BTH that would be essential for plant resistant stimulation. They designed and synthesized five novel salts and thoroughly examined their physicochemical and biological features, particularly their phytotoxic and SAR-inducing effects on plants.

11.4 IL Products in Future Management of Agri Industries: An Innovative Approach Despite all of ILs’ advantages, further study is needed to assess their potential negative qualities, such as high toxicity and occasionally low biodegradability, and hence ecological incompatibility. Further study should take into account that investigating a particular biological characteristic, such as antibacterial activity, is insufficient because this property, although having an optimistic connotation in its desired effect, may be poisonous to all other creatures, especially plants themselves. The development of a consistent theoretically and experimentally supported method for predicting ILs toxicity, bioactive properties, and biodegradability would be a huge footstep forward in this area, for the reason that well-designed agro-effective and eco-friendly ILs can form the foundation of advanced agriculture for plant defense and food security (Figure 11.2).

Biotic and abiotic stressors

Ionic liquid

Ionic liquid application

Development of disease and senescence

SAR induction

Increasing day by day (disease and senescence)

Development of resistance activity against stressors

Unhealthy plant

Healthy plant Lack of different stress effects

Figure 11.2 Diagrammatic illustration of plants’ resistance against biotic and abiotic stressors’ effects without and with prior application of the ionic liquids.

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11.5 Conclusions With this assessment, we hope to demonstrate why there is so much interest in employing ILs as a platform for food security, crop production, plant protection from phytopathogens, and as a deterrent for agricultural use. And the related topics should not be neglected, with a particular emphasis on the development and examination of novel physiologically active ILs with significantly higher efficiency and lower toxic effects. ILs may eventually be used to replace traditional plant protection agents and pesticides. When all of the advantages and disadvantages of using traditional chemicals versus ILs are considered, the option appears to be clear. ILs are superior in many aspects, including functionality, dosage, environmental impact, selectivity, and bioavailability. All of these properties permit us to think of ILs as exceedingly selective, multipurpose, and safe-hands tools for the cultivation and plant protection, as well as their ongoing development. As a result of increased efficiency and the removal of negative effects, ILs can open a door to sophisticated, contemporary, but controlled agriculture and the conservation of its products. We might even say that the use of ILs in the agricultural field is a logical progression and the way of the future for this industry. In the next few years, we should expect greater employment and profits.

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24 Wei, D. and Ivaska, A. (2008). Applications of ionic liquids in electrochemical sensors. Analytica Chimica Acta 607 (2): 126–135. 25 Matsumoto, M., Inomoto, Y., and Kondo, K. (2005). Selective separation of aromatic hydrocarbons through supported liquid membranes based on ionic liquids. Journal of Membrane Science 246 (1): 77–81. 26 Watanabe, M., Thomas, M.L., Zhang, S. et al. (2017). Application of ionic liquids to energy storage and conversion materials and devices. Chemical Reviews 117 (10): 7190–7239. 27 Hough, W.L., Smiglak, M., Rodríguez, H. et al. (2007). The third evolution of ionic liquids: active pharmaceutical ingredients. New Journal of Chemistry 31 (8): 1429–1436. 28 Wasserscheid, P. and Welton, T. (ed.) (2008). Ionic Liquids in Synthesis, vol. vol. 1, 145. Weinheim: Wiley-Vch. 29 Deetlefs, M., Seddon, K.R., and Shara, M. (2006). Predicting physical properties of ionic liquids. Physical Chemistry Chemical Physics 8 (5): 642–649. 30 Smiglak, M., Metlen, A., and Rogers, R.D. (2007). The second evolution of ionic liquids: from solvents and separations to advanced materials-energetic examples from the ionic liquid cookbook. Accounts of Chemical Research 40 (11): 1182–1192. 31 Bermúdez, M.D., Jiménez, A.E., Sanes, J., and Carrión, F.J. (2009). Ionic liquids as advanced lubricant fluids. Molecules 14 (8): 2888–2908. 32 Zajac, A., Kukawka, R., Pawlowska-Zygarowicz, A. et al. (2018). Ionic liquids as bioactive chemical tools for use in agriculture and the preservation of agricultural products. Green Chemistry 20 (21): 4764–4789. 33 Davis, J.H. Jr., Forrester, K.J., and Merrigan, T. (1998). Novel organic ionic liquids (OILs) incorporating cations derived from the antifungal drug miconazole. Tetrahedron Letters 39 (49): 8955–8958. 34 Pernak, J., Sobaszkiewicz, K., and Mirska, I. (2003). Anti-microbial activities of ionic liquids. Green Chemistry 5 (1): 52–56. 35 Pendleton, J.N. and Gilmore, B.F. (2015). The antimicrobial potential of ionic liquids: a source of chemical diversity for infection and biofilm control. International Journal of Antimicrobial Agents 46 (2): 131–139. 36 Smiglak, M., Lewandowski, P., Kukawka, R. et al. (2017). Dual functional salts of benzo[1, 2, 3]thiadiazole-7-carboxylates as a highly efficient weapon against viral plant diseases. ACS Sustainable Chemistry & Engineering 5 (5): 4197–4204. 37 Smiglak, M., Kukawka, R., Lewandowski, P. et al. (2016). New dual functional salts based on cationic derivative of plant resistance inducer benzo[1, 2, 3] thiadiazole-7-carbothioic acid, S-methyl ester. ACS Sustainable Chemistry & Engineering 4 (6): 3344–3351. 38 Bica, K., Cooke, L.R., Nugent, P. et al. (2011). Toxic on purpose: ionic liquid fungicides as combinatorial crop protecting agents. Green Chemistry 13 (9): 2344–2346. 39 Khungar, B., Rao, M.S., Pericherla, K. et al. (2012). Synthesis, characterization and microbiocidal studies of novel ionic liquid tagged Schiff bases. Comptes Rendus Chimie 15 (8): 669–674.

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40 Mandal, M., Chatterjee, S., and Majumdar, S. (2022). Outside the cell surface: encoding the role of exopolysaccharide producing rhizobacteria to boost the drought tolerance in plants. In: Plant Stress: Challenges and Management in the New Decade, 295–310. Cham: Springer. 41 Suchodolski, J., Feder-Kubis, J., and Krasowska, A. (2017). Antifungal activity of ionic liquids based on (−)-menthol: a mechanism study. Microbiological Research 197: 56–64. ˇ ´ Z.D., Comi ´ L., Stefanovic, ´ O. et al. (2012). Antimicrobial activity of 42 Petrovic, c, the ionic liquids triethanolamine acetate and diethanolamine chloride, and their corresponding Pd (II) complexes. Journal of Molecular Liquids 170: 61–65. 43 Piotrowska, A., Syguda, A., Wyrwas, B. et al. (2018). Effects of ammonium-based ionic liquids and 2,4-dichlorophenol on the phospholipid fatty acid composition of zebrafish embryos. PLoS One 13 (1): e0190779. 44 Syguda, A., Gielnik, A., Borkowski, A. et al. (2018). Esterquat herbicidal ionic liquids (HILs) with two different herbicides: evaluation of activity and phytotoxicity. New Journal of Chemistry 42 (12): 9819–9827. 45 Pernak, J., Niemczak, M., Materna, K. et al. (2013). Ionic liquids as herbicides and plant growth regulators. Tetrahedron 69 (23): 4665–4669. ´ 46 Pawłowska, B., Feder-Kubis, J., Telesinski, A., and Biczak, R. (2019). Biochemical responses of wheat seedlings on the introduction of selected chiral ionic liquids to the soils. Journal of Agricultural and Food Chemistry 67 (11): 3086–3095. 47 Łe˛gosz, B., Biedziak, A., Klejdysz, T., and Pernak, J. (2016). Quaternary ammonium nonanoate-based ionic liquids as chemicals for crop protection. European Journal of Chemistry 7 (2): 217–224. 48 Pernak, J., Łe˛gosz, B., Walkiewicz, F. et al. (2015). Ammonium ionic liquids with anions of natural origin. RSC Advances 5 (80): 65471–65480. 49 Moniruzzaman, M., Kamiya, N., and Goto, M. (2010). Ionic liquid based microemulsion with pharmaceutically accepted components: formulation and potential applications. Journal of colloid and Interface Science 352 (1): 136–142. 50 Marguerre, A.K., Geyer, K., Mertoglu, M. et al. (2014). Aqueous agrochemical composition comprising a pesticide in suspended form, a dispersant, and an ionic liquid. WO 2014128009A1, 28. 51 Zhao, X., Zhu, Y., Zhang, C. et al. (2017). Positive charge pesticide nanoemulsions prepared by the phase inversion composition method with ionic liquids. RSC Advances 7 (77): 48586–48596. 52 Kurkal-Siebert, V., Marguerre, A.K., Badine, D.M., Troppmann, U., Schäfer, A., Koltzenburg, S., Geyer, K., Cetinkaya, M., Schreiner, E., Nestle, N. and Hopf, A., 2018. Composition comprising active ingredient, oil and ionic liquid. U.S. Patent 9,949,475. 53 Chen, C., Liu, F., Fan, T. et al. (2017). Solubilization of seven hydrophobic pesticides in quaternary ammonium based eco-friendly ionic liquid aqueous systems. New Journal of Chemistry 41 (19): 10598–10606. 54 Lewandowski, P., Kukawka, R., Pospieszny, H., and Smiglak, M. (2014). Bifunctional quaternary ammonium salts based on benzo[1, 2, 3]thiadiazole-7-

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carboxylate as plant systemic acquired resistance inducers. New Journal of Chemistry 38 (4): 1372–1375. 55 Smiglak, M., Kukawka, R., Lewandowski, P., and Pospieszny, H. (2014). Cationic derivatives of the plant resistance inducer benzo[1, 2, 3]thiadiazole-7-carbothioic acid S-methyl ester (BTH) as bifunctional ionic liquids. Tetrahedron Letters 55 (25): 3565–3568. 56 Luna, E., Bruce, T.J., Roberts, M.R. et al. (2012). Next-generation systemic acquired resistance. Plant Physiology 158 (2): 844–853. 57 Thakur, M. and Sohal, B.S., 2013. Role of Elicitors in Inducing Resistance in Plants Against Pathogen Infection: A Review. International Scholarly Research Notices.

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comprehending completely. Fascinating discoveries about the physical features of ILs continue to appear in recent reviews [1–4]. Furthermore, some ILs can develop vastly complicated H-bond structures, adding another layer of complexity to the issue. The major competitive advantage for advanced materials is their ability to tune their material characteristics with varying chemical frameworks of their component ions and the fact that they can be used as greener alternatives to more hazardous organic solvents. It is worth noting that ILs do not simply match the traditional definition of molecular fluids, and explaining many of their unique qualities has necessitated a microscopic examination of their physical constitution. ILs are substances entirely made up of ions [5–7] and have a melting point of less than 100 ∘ C, making them liquid in normal conditions. However, defining the liquid phase – particularly complex liquids like ILs – remains difficult [8]. While quantum chemistry (QC) methods may be used to obtain features of such materials in the gaseous state, single-molecule methods of this sort do not sufficiently capture most aspects of the liquid state, primarily because they disregard temperature and surroundings as well as dynamics. ILs present a unique set of problems for theoretical chemistry. Due to their elevated viscosity, ILs must be considered over a wide simulation timeframe. Additionally, the analysis must include a dependable electrical structure to acquire accurate results, owing to the significant significance of intermolecular interaction [9]. Regrettably, the theoretical methods necessary are only practical for medium-sized structures. These methods have the required electrical and structural flexibility for an effective ab initio description of intermolecular interactions. Additionally, dispersion forces complicate selecting a suitable strategy for ILs. Nonetheless, well-chosen theoretical approaches can provide forecasts for ILs and validate and explore numerous experimental discoveries [10]. Simple models based on continuum theories can often produce superior results, although molecular dynamics (MD) simulations are still the preferred method for condensed-matter research [11, 12]. Large samples may be catered for, including a model-inherent dynamical description. Scientists can address several molecules with this technology, which uses periodic boundary settings to simulate signals around the center cell, overcoming issues caused by surface impacts. Despite the reality that MD is gradually approaching the capabilities of modern supercomputers, it is still not a feasible option for studying dynamical characteristics. The reason for this limitation is twofold: the significant computational expense involved and the exceedingly high viscosity of most ILs. These necessitating simulation timeframes are still impractical for evaluating dynamical features like self-diffusion ratios. For the theoretical conclusions to be reliable, the classical force field must be chosen carefully [13–15]. Even though the force fields have been tested against a variety of experimental parameters, their flexibility with other systems that were not actually linked in the verification phase can be problematic [16, 17]. Due to the plethora of molecular variations conceivable with ILs, the use of any force field must be empirically confirmed, even though it has been successfully utilized previously. We are confident that this chapter will not only provide information on how to use an interpretation tool to forecast experimental amounts of IL but will also offer additional information on recent experimental quantities and allow us to observe

12.2 Ionic Liquid Dynamics

numerous factors that IL experiments cannot. As a result, in this chapter, we will outline and discuss current advances in theoretical simulations of ILs and potential future prospects. We will go through some of the challenges with theoretical simulations of ILs in particular. We will also go over general theoretical methodologies and the nuances of applying them to ILs.

12.2 Ionic Liquid Dynamics With improved modeling tools and force fields, atomistic MD simulations have become valuable for gaining molecular scale knowledge of structure-property correlations and the virtual development of advanced materials [18]. MD simulations have uncovered numerous details regarding the dynamic characteristics of ILs, such as viscosity, self-diffusivity, electrical conductivity, and thermal conductivity. ILs have evolved from simple liquids, catalysts, isolation media, or electrolytes to task-specific, programmable molecular machines with specialized features. A comprehensive understanding of these features and structure-property correlations is required to adequately harness their capabilities, explore future paths in IL-based research, and appropriately deploy suitable implementations. In this section, we present and discuss the existing data on a wide range of IL systems’ physicochemical properties (self-diffusion and viscosity).

12.2.1 Self-Diffusion Self-diffusion is a basic molecular feature that provides quantifiable data on ion mobility in a liquid and may be readily estimated over a sufficiently lengthy simulation period. An equation for diffusion coefficient can be formulated in terms of the Stokes–Einstein equation [17] for a special instance of Brownian particle diffusion in a viscous fluid: k×T Ds = (12.1) 6 × π × 𝜂 × RH where k denotes the viscosity and RH denotes the particle’s hydrodynamic radius. This equation has been effectively used to explain glycoprotein diffusion in diluting liquids. Equation (12.1) can be adjusted in some circumstances where the molecule form is clearly quasi by inserting an experimental actor (c) accountable for the divergence of the particle’s self-diffusion action, as stated by Eq. (12.2): Ds =

k×T c × π × 𝜂 × RH

(12.2)

The type of an IL’s cation and anion and parameters, such as temperature and pressure, impact its diffusion properties. To explore the dynamics of [C4 mim][PF6 ], Hu and Margulis [18] employed MD simulations for 3 ns at 400 and 500 K and for 9 ns at 300 K. The non-Gaussian parameter 𝛼(t) led to the highest at roughly 2.5 ns at 300 K, and slightly over 100 ps at 400 K, in keeping with Del Popolo and Voth’s results that these liquids have continuous variability. They also discovered that, whereas most ions have slow movements, a tiny proportion of ions move rapidly; these fast-moving ions travel 200 times faster than less mobile ions. The behavior of

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aromatic hydrocarbons at the liquid–liquid interface and the alkylation efficiency of IL/benzene have been investigated using MD simulations and experimental research. The acid–hydrocarbon interfacial layer was shown to be the richest in benzene due to the larger interfacial area. The vertical self-diffusion of isobutane was calculated using the survival rate. It was discovered that benzene’s interface properties improved isobutane diffusion in the interfacial layer. The accumulation of benzene molecules in the acid–hydrocarbon interfacial layer, which buffered the acid content of anions in that location, was the fundamental reason for the improved butane alkylation efficiency [19]. MD simulations were utilized by Blanco-Diaz et al. to examine the effects of different chain lengths on the density, self-diffusion coefficient, and viscosity of [Cn mim][TF2 N] ILs. With increasing chain length, density and self-diffusion rates were reduced [20]. Using nuclear magnetic resonance (NMR) fast-field-cycling (FFC) relaxometry, Overbeck et al. calculated the self-diffusion ratios and rotational correlation durations of the anions and cations in triethylammonium-based PILs. At room temperature, the diffusion coefficients of the cations were found to be in the order of 6 × 10−11 m2 s1 and nearly 50% greater than those of the anions [21]. The diffusion ratios of both ions in PILs contrasted with those found in pulsed-field gradient (PFG) NMR investigations and those calculated using a unified dispersal power law. The Stokes–Einstein and Stokes–Einstein–Debye relationships were employed to link the diffusion coefficients and correlation durations with the high viscosity [21]. ILs/graphene oxide (GO) membranes have recently been suggested as a potential replacement for CO2 capture. Nevertheless, no apparent link exists between ILs/GO microstructure and CO2 separation efficiency [22]. MD simulation was used to investigate the dynamic characteristics and relationships for CO2 /CH4 in three imidazole compounds ([Bmim][PF6 ], ([Bmim][BF4 ], and ([Bmim][TF2 N]) contained between two GO plates with varying layer distances. The increased solubility and diffusion selectivity of CO2 /CH4 in the ILs/GO membrane can be attributed to the stronger affinity of CO2 ions and the faster mobility of CO2 compared to CH4 . Furthermore, it was discovered that lowering layer distance increased solubility selectivity while decreasing diffusion selectivity. However, because solubility specificity was found to be the most important factor, the ideal layer spacing was determined to be 2 nm. Low-viscosity ILs were also advantageous in improving diffusion selectivity [22].

12.2.2 Viscosity Shear viscosity is a second property allowing reliable MD simulation confirmation. To calculate the viscosity, the off-diagonal variables of the stress tensor can be auto-correlated and averaged ∞

𝜂=

V ⟨Pxz (0)Pxz (t)⟩ dt kB T ∫0

(12.3)

where Pxz represents the stress tensor’s off-diagonal component. While Eq. (12.3) is technically valid, the integral’s infinite-time limit indicates that the simulation is lengthy enough to sample all important motions. In addition, the integral’s signal-to-noise ratio must be adequate throughout this duration. The dynamics of

12.3 Theoretical Advances in Force Fields and Electronic Structures

ILs are clearly more complicated than those of “simple” liquids, as they include numerous timeframes and various forms of mobility. Because of the intricate dynamical behavior, simple notions of the relationship with diffusion rate, viscosity, and conductance may not be relevant in several cases. Increasing the duration of molecular simulations was investigated using the time-temperature superposition (TTS) approach [23]. The IL exhibited a Newtonian plateau in shear viscosity at low flow rates, followed by shear-thinning behavior at high flow rates. The IL displayed characteristics of a viscous liquid at high and low frequencies, whereas at high frequencies and low temperatures, it exhibited viscoelastic properties akin to those of an elastic substance. This work highlights TTS’s intriguing capacity to bridge the enormous temporal gap between simulations and experiments, allowing molecular simulations to reliably forecast rheological property values at a frequency of practical importance [23]. Ntum and Silpizi investigated the out-of-equilibrium characteristics of [BMIM][BF4 ] enclosed between metal surfaces using MD simulations. They were particularly interested in learning how the shear flow affects the interfacial characteristics. They discovered the system does not act like the ideal linear Couette flow. The section of fluid closest to the shearing slabs was discovered to behave as a chaotic, thick wall that stretched to a few nanometers under the examined conditions [24]. The observed viscosity of the ILs 1-ethyl-3-methyl-imidazolium tetrafluoroborate ([EMIM][BF4 ]) and 1-butyl-3-methyl-imidazolium tetrafluoroborate ([BMIM][BF4 ]) as a factor of the shear rate was determined using non-equilibrium molecular dynamics (NEMD) simulations at pressures of 0.101, 507, and 1013 MPa [25]. A comparable investigation was also carried out for benzene as a comparative. It was found that the IL’s zero shear viscosity and relaxation time were strongly influenced by pressure. At high pressure, shear thinning commenced at lower shear rates, coinciding with the thinning of the initial coordination shell of anions surrounding cations. At high shear rates, both the imidazolium ring and benzene selectively retain a lateral flow direction, and this impact is amplified at increased pressure [25]. A burgeoning amount of research is being conducted to investigate the self-diffusivities and viscosities of various ILs. Furthermore, additional macroscopic mobility characteristics, such as electrical and thermal conductivities, have also been investigated, albeit far less commonly. Although it is hard to assess all previous work thoroughly, a fair sample of latest projects will indicate the reliability that can be achieved along with some of the difficulties that these calculations can present. With respect to transport properties, imidazolium-based ILs are still the most widely investigated based on molecular simulations.

12.3 Theoretical Advances in Force Fields and Electronic Structures The task of selecting, developing, or modifying force fields for MD computations is complex and necessitates meticulous verification of the results against current experimental measurements. To construct a force field, one can pick from a variety

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of frameworks: the “atomistic” scale and the electrostatic method are two popular options. There are two primary possibilities for electrostatic interactions (which are obviously critical for the depiction of ILs): fixed partial charges and polarizable formulations [17]. Partial charges must be known properly to do accurate MD simulations of these ionic systems [26–28]. Their quantities can greatly impact the structural and dynamical features of ILs that are computed [29, 30]. The impact of thermostat selection and fundamental variables like Drude particle masses and force constants on ILs’ stationary and nonstationary features was investigated [31]. The enormous computational effort required for polarizable MD simulations of ILs was reduced by employing a graphics processing unit (GPU)-enhanced CHARMM algorithm to speed up the calculations. This study demonstrated how to speedily and effectively apply polarizable MD simulation for complex and viscous processes, such as the simulation of ILs. The influence of hydrogen bonding on the structural features of the IL [C4 C1im ][Br] was investigated using MD simulations with various model charge systems. These findings correspond to experimental observations [30]. Based on the extent of the modification, the hydrogen bonding capability, indicated by differing molecular partial charges on the most acidic hydrogen atom and its connected carbon atom, affects the morphology and kinetics significantly [30]. New OPLS force field parameters were established for imidazolium-based ILs, yielding precise dynamic behavior, thermoelectric characteristics, and valid intermolecular interactions between cations and anions. The OPLS-VSIL offers an empirically based collection of partial charges for [RMIM] with a unique configuration that integrates a virtual site particle dividing the nitrogen atoms to unload negative electrical charge to the ring’s interior plane [31]. The following equation [32] can express nonpolarizable OPLS force fields: )2 ∑ ( )2 ∑ ( kij rij − rij0 + aijk 𝜃ij − 𝜃ij0 Vnonpolar = Vbonded + Vnonbonded = ij

ijk

( )6 ( ) 3 ⎡ 𝜎 12 ∑∑ ∑ qi qj 𝜎ij ⎤ ij 1 ⎢ ⎥+ + 4𝜀ij − (12.4) Vn cos(n∅ijkl ) + ⎢ ⎥ 2 r rij 4𝜋𝜀0 rij ij ijkl n=1 ⎣ ij ⎦ The first term represents the linked sets’ periodic vibrational energy, and the second represents the bending energy. The third term is associated with 1–4 torsion connections, while the final two terms represent the Lennard-Jones (LJ) short-range term and the electrostatic binding energies. The last two terms are referred to as nonbonded connections. A structure-based coarse-grained force field (CGFF) has been designed to simulate imidazolium-based ILs with acceptable transferability across varied chain lengths. The structure and pressure produced from coarse-grained (CG) models match with all-atom MD simulations at different thermodynamic conditions for varying alkyl chain lengths. It was also discovered that the CG model’s dynamical features, such as diffusion, maintain the heavy cation’s quicker dynamics compared to the anion. The methods for reproducing thermodynamic properties and treating lengthy Coulombic connections presented here can be applied to other soft-matter systems [33].

12.4 Mixtures in Ionic Liquids

The nonpolarizable force field of ILs can be modified through the use of a self-consistent methodology combining MD simulation and first-principles computation based on the order-N density functional theory (DFT). In imidazolium, pyrrolidinium, and ammonium-rich ILs, the efficiency of nonpolarizable force fields computed with the MD-DFT method was examined [34]. The efficient DFT charge was found to increase the flow of ILs, electrical properties, and kinematic precision. This is due to decreased ion couplings, and the overly slow movements detected with a fitted model have been well adjusted through MD and DFT repetition. The collection of nonpolarizable force fields produced using the MD-DFT self-consistent system was more accurate in describing the flow behavior of ILs. The accuracy of ab initio MD simulations has also been studied. These electronic structural techniques use Kohn-Sham density functional theory (KS-DFT) [35, 36]. In the literature, substantial variations between B3 LYP estimates and experimental data have been observed [29]. One inaccuracy could be due to the failure of standard density functionals to describe dispersion forces [37]. Due to interactions, such as the agglomeration of alkyl chains leading to nanoscale partition [38] or the grouping of imidazolium cations [39], they are thus inaccurately portrayed. As a result, the KS-reliability DFT in these IL systems has been evaluated for both standard density functionals and recently developed dispersal-adjusted approaches [40]. It has been demonstrated that omitting dispersion forces in ab initio MD simulations results in unrealistically quicker anions than cations diffusion, which contradicts experimental evidence [41]. Nonetheless, given the importance of inductive forces [42, 43], the issue emerges as to whether the possible system scale of ab initio MD simulations is adequate for the agreement of electronic characteristics. It has been demonstrated in collaboration with the Holm, Berger, and Delle Site teams that when eight ion sets are considered under regular boundary conditions, electronic parameters such as the dipole moment agree [44, 45]. As a result, dispersion-adjusted KS-DFT methods, particularly ab initio MD approaches, are a good fit for IL systems. Szabadi and colleagues examined three polarizable MD force fields with an ab initio path for a 1-butyl-3-methylimidazolium tetrafluoroborate and chloride IL system, assessing their ability to describe both steady-state and transient phenomena. [46]. Radial distribution patterns accord qualitatively in most circumstances; nevertheless, the high polarization of chloride in MD directions leads to inherently unknowable findings. The good accordance between dipolar dispersion indicates the importance of explicit polarizability in MD simulations. The agreement between experimental and theoretical infrared spectra also highlights the similarities between classical and ab initio dynamics in the low-wavenumber region.

12.4 Mixtures in Ionic Liquids 12.4.1 Ionic Liquids and Interfaces Many essential macroscopic features, such as solubility, liquid crystallization degree, oxygen content, and so on, are influenced by interfacial structure. Furthermore, the properties and shape of the liquid–vapor interface influence many critical aspects of

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liquids, particularly chemical processes that are mediated primarily by species near the surface. Understanding the nature and structure of IL interfaces is also crucial to determining chemical species’ movement across them [47]. Whenever an interface develops, particles at the interface have fewer interactions, and changes in molecular alignment, volume, or concentration can sometimes decrease the energy state of a surface. Two well-known instances are surface deposition in liquids and the coordination of water droplets along the gas–liquid surface, where the dipole moments are located [48]. IL interfaces exhibit a significant impact on local composition, which may be proven using simulations and investigated using a variety of experimental methods. Many research studies have employed simulation to study the interface morphology of ILs with various inorganic anions [49, 50]. MD simulations utilizing bis(trifluoromethylsulfonyl)imide (NTf2 ) as the anion have been used to investigate the effect of imidazolium cation alkyl chain uniformity on the morphology and characteristics of the IL–vapor interface [51]. The electric potential gap between the gas and liquid states was found to be positive and significantly reduced as the alkyl group length increased. In interfacial studies and electrochemistry, ILs have theoretical and practical applications. Unfortunately, analyzing their behavior near a surface is difficult due to strong Coulomb contacts and huge and uneven ionic sizes, which influence both their morphology and kinetics. Voegtle et al. reported a mixed experimental and theoretical investigation that used a vibrational sensor particle, 4-mercaptobenzonitrile, placed at the interface between a metal and a range of ILs, to identify the situation better. They also used MD simulations of these surfaces to learn more about the ionic structures that created the observed forces. They discovered that partial complexation of smaller anions into the probe layer caused a stiffer packing of ionic levels near the surface, which caused the connection. The total lateral ion packing density at the surface was decreased by greater anions, which lowered the net charge per unit area and explained the lower measured fields [52]. Gomez-Gonzalez and colleagues ran MD simulations of mixes of a model protic IL, ethylammonium nitrate, with lithium or magnesium nitrate (LiNO3 /Mg[NO3 ]2 ) contained in two graphene layers. They used ab initio DFT to study the morphology of the mixture with Li salt interlayer, and the performance was compared to that obtained from classical MD simulations. They discovered that the charge of the salt cation in these combinations seemed to be primarily influenced by its location near the interface. With a lower ion charge density, the cation was able to traverse fewer miles to the sheets, both in aprotic and protic solutions [53]. The immediate environment near IL ions is isotropic, as shown by simulations [54–56]. Because the ions’ electron concentrations are deformed during their contact, they may not be properly represented as solid bodies in such a system. It is essential to characterize these contacts using a completely electrically polarizable force field [47]. CL&Pol polarizable force field was developed recently by Goloviznina et al. as a comprehensive yet expandable and transportable model that can describe solutions, mixes, and material interfaces and is not too hard to apply to other systems [47]. The polarizable model reflects the modification of the charged particle of the ion in a more practically precise way once the electric field is turned on through

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chain size of the cation rises. The findings also revealed that raising the surface charge of the anion boosts the anion’s interface with the water molecules [60]. [C6 mim][PF6 ] and water combinations were simulated using MD [61]. Water was observed to be strongly connected with the anions, and their availability improved both the translational and rotational dynamics of the ILs. The rapid mobility generated by contact with water was inferred to be the source of the experimentally measured reduction in viscosity [61]. It was also discovered that the spectral analysis of Coumarin-153 is red-shifted, which is attributed to the prevalence of water, which is consistent with the findings. Using MD simulations, Zhou et al. investigated two types of ILs: ([Bmim][PF6 ]) and ([Bmim][NTf2 ]) [62]. They looked into how water molecules could distribute into the IL after being absorbed from the vapor phase. Agglomeration was detected as the water content increased. Despite the fact that the amount of absorbed water grew noticeably, the level of available water and small clusters in the ILs did not alter much and remained constant. Because of their hydrophobic nature, [Bmim][PF6 ] was found to have more available water and tiny clusters than [Bmim][NTf2 ]. Zhou and colleagues utilized MD simulations to explore the impact of impurities on the viscosities of three different ILs, namely [Bmim][BF4 ], [Bmim][Tf2 N]], and [Bmim][Ac], and investigated the dependence of their viscosities on temperature and water content. The study was motivated by the observation that even small amounts of impurities can significantly affect the viscosity of ILs. The viscosities were investigated using NEMD simulation, and it was discovered that viscosities changed in distinct ways. For example, viscosities for [Bmim][BF4 ] and [Bmim][Tf2 N] fall rapidly during the first phase, then steadily decline with additional water addition. The viscosities of [Bmim][Ac] nevertheless rise in the first phase and thereafter drop [63]. It has been proven that the viscosity of ILs can be considerably altered by adding water. The excess chemical potentials 𝜇A of a series of molecules dissolved in the IL [C1 mim][Cl ] were computed to highlight the effect of water on viscosity further [16]: 𝜇A − 𝜇Aideal + 𝜇AXS

(12.6)

where 𝜇Aideal denotes substance A’s ideal gas chemical potential with the same number density as in a solution. The chemical potential could be calculated using the thermodynamic integration method: ) 1( 𝜕H(𝜆) d𝜆 (12.7) 𝜇 A − 𝜇B = ∫0 𝜕(𝜆) 𝜆 where H(𝜆) is the solvent interaction energy of a hybrid molecule similar to molecule A at 𝜆 = 0 and molecule B at 𝜆 = 1. The MD simulation was recently used to explore the mechanism of water molecule adsorption by a carbon-based substrate in the presence of NaCl impurities [64]. The findings revealed that as the defects in atomic structures increase, the rate of water molecule adsorption by the porous carbon matrix drops, disrupting the process. The adsorption process of disrupting atoms by the porous carbon matrix also increased when aberrations in atomic structures increased. Finally, by running this simulation

12.5 Applications of Ionic Liquids in Chemical Processes

and examining the influence of contaminants on water absorption by porous carbon structures, it was discovered that an efficient water treatment procedure might be devised, one of humanity’s most pressing concerns [64].

12.5 Applications of Ionic Liquids in Chemical Processes 12.5.1 Preamble ILs have attracted significant attention in chemical processes due to their unique properties, such as nonvolatility, high thermal stability, and tunable physicochemical properties [65]. These properties make ILs a promising alternative to traditional organic solvents and offer many opportunities for their use in various chemical processes [66]. ILs can be used as reaction media, catalysts, separation agents, and electrolytes in chemical reactions, including organic synthesis, catalysis, extraction, and electrochemistry [67]. This subsection will cover recent applications of ILs in chemical processes, emphasizing their benefits compared to traditional solvents and their potential role in sustainable and eco-friendly chemistry.

12.5.2 Separation and Purification ILs have shown great potential as separation and purification agents due to their ability to dissolve and extract a wide range of compounds, including polar and nonpolar species. Moreover, the unique physicochemical properties of ILs, such as their high thermal stability, low volatility, and tunable solubility, make them attractive alternatives to traditional solvents in separation and purification processes. This subsection will discuss some recent applications of ILs in separation and purification processes, highlighting their advantages and limitations. One of the most promising applications of ILs in separation and purification is extracting natural products, such as essential oils, alkaloids, and flavonoids. ILs effectively extract these compounds from plant material, offering advantages over traditional organic solvents regarding selectivity, efficiency, and environmental impact [68]. IL-based extraction processes have also been applied to recover value-added compounds from waste streams, such as phenolic compounds from lignocellulosic biomass [69]. ILs have also been used to separate a wide range of chemicals, including organic acids, aromatics, and carbohydrates, from complex mixtures. The selectivity and efficiency of ILs in these separations depend on the choice of IL, their physicochemical properties, and the operating conditions (e.g. temperature, pressure, and extraction time). ILs have also been applied in separating rare earth elements, offering advantages over traditional solvent extraction methods in terms of selectivity, efficiency, and environmental impact [70].

12.5.3 Reaction Media in Chemical and Biochemical Catalysis Due to their environmentally friendly physicochemical characteristics, such as their near-zero relative volatility, high electrical conductivity, high polarity and thermal

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Poor solvating medium

Figure 12.1 Effect ionic liquids on the reactivity of a chemical reaction.

R+ X−

ΔG≠′ Molar free energy

ΔG≠

Better solvating medium

R−X Reaction coordinate

stability, and many other properties, which have been treated in different sections of this chapter, ILs are becoming more significant and have proven to be extremely useful as a suitable media for some chemical processes, thereby substituting some previously known solvents and catalysts. Some examples of reaction media for bioconversions are water, organic solvents, supercritical fluids, two-phase systems, and emulsions. However, some of the challenges observed in over 85 million organic and inorganic conventional substances registered by CAS are their low volatility, poor miscibility, and other non-friendly properties, which pose complications during chemical reactions. Particularly in organic reactions, water is not a suitable solvent due to its high boiling point. Other conventional solvents are highly volatile in biocatalysis reactions and might threaten the environment. But in contrast, ILs are widely used for organic and inorganic processes, including new processes for pollution reduction. This makes them preferred and highly sought after since other conventional substances pollute the environment and eventually pose major health risks. Due to this fact alone, ILs are quickly being adopted as new technologies for extracting, separating, transforming, and eliminating chemicals [71]. ILs have been commonly used as extraction media in gas–liquid or liquid–liquid equilibria and as reaction media in other non-equilibrium chemical reactions. This is major because of the impact they have on the reactions. For example, Figure 12.1 is a schematic diagram by [71] explaining briefly how ILs may influence chemical reactivity when used as solvents in a chemical reaction. Generally, when reaction rates approach diffusion control, the selectivity of a process decreases as the reactivity increases [71]. And it can be seen from the illustration that ILs tend to actively reduce the free energy of both the initial state (IS) and intermediate stage (TS). In the process, energy is generated, whose magnitude depends on the differential stabilization of IS and TS. The role of ILs as extraction media has already been discussed in other chapters of this book, but they also have broad applications as reaction media in many different

12.6 Future Developments

processes. For example, they are more cost-effective when used as enzymes in the enzymatic transesterification process. According to Nawshad et al. [72], although the enzymatic transesterification method has several advantages over chemical methods, such as its mild reaction conditions, flexibility in enzyme selection for different substrates, reusability of enzymes, and reduced water requirements resulting in lower waste treatment, the process faces challenges due to the limitations of conventional enzymes. For example, the poor miscibility of solvents like methanol with fats and oils when performing the transesterification reaction forces the process to be conducted in heterogeneous systems involving complicated liquid–liquid interfaces. This produces more waste and also increases costs. The use of IL as a catalyst in the separation of biodiesel was also referenced in the study. The unique ability of ILs to selectively dissolve various organic, inorganic, and organometallic materials due to their high polarity proved useful in the separation process. While several processes utilizing ionic liquids have yet to be implemented commercially due to ongoing research into their properties, it has been demonstrated that ionic liquids substantially benefit various chemical processes. For instance, in the production of alkoxyphenolphospines, their inclusion significantly diminishes the required amount of reactants, resulting in a considerable enhancement of production capacity [72]. Other applications of ILs are in enzymatic esterification in microreactor devices and special esterification in ionic liquid in integrated systems.

12.6 Future Developments It is obvious from the preceding discussion that molecular simulations are becoming more important in aiding the development of theoretical knowledge of ILs. In addition to predicting IL properties, MD simulations are often used to help explicate the framework of ILs, such as structure and polarity. Despite all of the tremendous development, a number of issues persist. For a considerably greater spectrum of materials, reliable force fields must be constructed and confirmed. Many force fields, particularly for imidazolium-based ILs, have been published. Force-field characteristics are still unavailable for several cation and anion types, and many proposed force fields have not undergone thorough validation. In addition to validating established force fields, the development of new force fields for various cation and anion categories is necessary. Developing new force fields is arduous and tedious, yet it is necessary if molecular simulations are to be employed to drive the creation of novel ILs. The use of molecular simulations will dwindle until new force fields are developed that allow for the investigation of a wide variety of probable ILs. The methods used to run simulations are another key area where improvements can be made. As previously stated, one of the most challenging parts of modeling ILs is that their dynamics are typically slow, making conformational sampling problematic. The difficulty is particularly challenging in MD simulations with predictable trajectories. There is a need to find a method that allows for rapid

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53 Gómez-González, V., Docampo-Álvarez, B., Otero-Mato, J.M. et al. (2018). Molecular dynamics simulations of the structure of mixtures of protic ionic liquids and monovalent and divalent salts at the electrochemical interface. Physical Chemistry Chemical Physics 20 (18): 12767–12776. 54 Georgi, N., Kornyshev, A.A., and Fedorov, M.V. (2010). The anatomy of the double layer and capacitance in ionic liquids with anisotropic ions: electrostriction vs. lattice saturation. Journal of Electroanalytical Chemistry 649 (1–2): 261–267. 55 Konar, S., Sharma, A., Banerjee, S. et al. (2019). Water-mediated weakening of inter-ionic interactions in aqueous mixtures of ionic liquid: an investigation combining quantum chemical calculations and molecular dynamics simulations. Chemical Physics 524: 31–39. 56 George, N.C., Pell, A.J., Dantelle, G. et al. (2013). Local environments of dilute activator ions in the solid-state lighting phosphor Y3–x Cex Al5 O12 . Chemistry of Materials 25 (20): 3979–3995. 57 Jia, H., Wang, S., Xu, Y. et al. (2022). Systematic investigation on the abnormal surface and interfacial activity of fatty acid ionic liquids. Colloids and Surfaces A: Physicochemical and Engineering Aspects 634: 127902. 58 Arai, N., Koishi, T., and Ebisuzaki, T. (2021). Nanotube active water pump driven by alternating hydrophobicity. ACS Nano 15 (2): 2481–2489. 59 Zhang, H., Zhu, M., Zhao, W. et al. (2018). Molecular dynamics study of room temperature ionic liquids with water at mica surface. Green Energy & Environment 3 (2): 120–128. https://doi.org/10.1016/j.gee.2017.11.002. 60 Shokri, S., Sadeghi, R., and Ebrahimi, S. (2021). A theoretical study for isopiestic equilibrium mixtures of ionic liquid 1+ ionic liquid 2+ water systems. Journal of Molecular Liquids 328: 115280. 61 Huo, F., Ding, J., Tong, J., and He, H. (2021). Ionic liquid-air interface probed by sum frequency generation spectroscopy and molecular dynamics simulation: influence of alkyl chain length and anion volume. Molecular Simulation 1–11. 62 Zhou, G., Jiang, K., Wang, Z., and Liu, X. (2021). Insight into the behavior at the hygroscopicity and interface of the hydrophobic imidazolium-based ionic liquids. Chinese Journal of Chemical Engineering 31: 42–55. 63 Bernardino, K. and Ribeiro, M.C. (2022). Role of density and electrostatic interactions in the viscosity and non-Newtonian behavior of ionic liquids – a molecular dynamics study. Physical Chemistry Chemical Physics . 64 Moghadam, R.A., Sajadi, S.M., Abu-Hamdeh, N.H. et al. (2022). Water molecules adsorption by a porous carbon matrix in the presence of NaCl impurities using molecular dynamic simulation. Journal of Molecular Liquids 347: 117998. 65 Plechkova, N.V. and Seddon, K.R. (2008). Applications of ionic liquids in the chemical industry. Chemical Society Reviews 37 (1): 123–150. 66 Mallakpour, S. and Dinari, M. (2012). Ionic liquids as green solvents: progress and prospects. In: Green Solvents II: Properties and Applications of Ionic Liquids, 1–32. 67 Wasserscheid, P. and Keim, W. (2000). Ionic liquids – new “solutions” for transition metal catalysis. Angewandte Chemie International Edition 39 (21): 3772–3789.

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13 Theoretical Understanding of Ionic Liquid Advancements in the Field of Medicine Mrinal K. Si Sardar Patel University, Department of Chemistry, Balaghat, Madhya Pradesh 481001, India

13.1 Introduction Ionic liquid (IL) solvents consist of bulky and asymmetric organic anions and cations that behave generally as liquids below 100 ∘ C. Deep eutectic solvents (DESs) experience a depression in the melting point predominantly due to the formation of hydrogen bonds [1], which consist of nonbinary mixtures of anions and cations, whereas ILs are classically formed through 1 : 1 combination, which is dominated by nondirectional ionic interactions [2]. There are various applications of ILs and DES in the biomedical field. The physicochemical properties and biological outcomes of ILs depend on the selection of ions. Generally, cations and anions are important to create ILs (Figure 13.1). The ILs are used in the field of biomedicine as they are soluble in both polar and nonpolar solvents. ILs show a number of fundamental chemical details that allow for their unique miscibility. Melting temperature is often used as a descriptor of ILs, which is less than 100 ∘ C [4]. ILs have a lower melting point than that of ionic compounds as ionic compounds form well-defined crystal structures [5]. Three major factors are important for the low melting points of ILs. These are intermolecular forces between the ions involved in the solvent, ion symmetry, and ion conformational degrees of freedom [6]. The tightness of packing decreases due to weak intermolecular ionic and hydrogen bonding interactions [7]. Asymmetrical compounds also have a low melting point as they cannot pack easily into repeating lattice structures [8]. Conformational degrees of freedom can prevent crystal lattice symmetry and formation of consistent intermolecular interactions [9]. The melting point of ILs has been controlled by utilizing ions that allow for delocalization of charges, those that are asymmetrical in nature, and those that have long substituents with many rotational degrees of freedom [6]. Low-melting ILs (i.e. room-temperature ILs) are basically used for biomolecular applications as they need to be used in liquid form at physiologically relevant temperatures (≈37 ∘ C) [1, 2, 4]. At this relevant temperature, the ILs show their inherent conductivity. Many ILs are in the molten state at body temperature, and they conduct electricity without dissolving in other solvents. Because ions are free to move , First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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13 Theoretical Understanding of Ionic Liquid Advancements in the Field of Medicine R N

N n

R

OH

N

n

R

Imidazolium

OH

Figure 13.1 Common cations and anions used to create ionic liquids [3].

Ammonium R R

N

P R

OH

Pyrrolidinium

OH

Phosphonium

Cations O S F3C

N

O S

O O

Cl

CF3

Halogens

Bis(trifluoromethylsulfonyl)imide O NC

N

CN

HO

n

Dicyanamide

Carboxylic acid

F

O

F

B

F O Acetate

F Tetrafluoroborate

Anions

in the liquid state, they easily allow for the transfer of electrons through the bulk compound. The conductivity of ILs can be controlled by manipulating ion size and charge, and it increases with the use of smaller cations and anions, allowing for easier ion mobility. The conductivity of ILs becomes lower in the presence of highly charged molecules due to the occurrence of more ion–ion interactions [10]. This impact of charge mobility on conductivity appears to apply more to cations than anions [11]. These intermolecular interactions that can prevent ion mobility give rise to another relevant property, viscosity. Unsurprisingly, like other fluids, the viscosity of ILs is mostly mediated by intermolecular forces [12]. These can range in strength from ion–ion interactions down to dispersion forces, with hydrogen bonding playing a key role in biocompatible ILs. Strong intermolecular forces, like ion–ion and dipole–dipole, prevent IL layers from being able to easily shear past each other, but even dispersion forces can drive viscosity. This causes many RTILs to possess viscosities in the hundreds to thousands of centipoise [13, 14]. Viscosity can be controlled by the selective use of molecules having greater intermolecular forces. For example, utilizing ammonium-based anions with longer alkyl chains can allow for stronger dispersion forces and increase viscosity [15]. Another important property of ILs is their miscibility, especially with water, which is very important in the application of chemistry. However, the solubility of ILs in water is entirely dependent on the solvation energy and whether it is sufficient

13.3 Biomedical Applications

to overcome the ion cohesive forces. The IL will be miscible if the free energy is lower in the dissolved state than in the biphasic state. The miscibility, conductivity, and viscosity of ILs depend on the normal room temperature lab conditions to physiological temperatures [16, 17]. Miscibility, and in turn amphiphilicity, of ILs can be affected by incorporating long hydrocarbon chains or aromatic rings for poorer water solubility, or carboxyl, alcohol groups, and nitrogen atoms to increase hydrophilicity through hydrogen bonding. All of the above properties are important for extensive use of ILs in biomedicine. ILs show inherent conductivity, which allows for easy charge transfer in biosensors. Now, ILs play a vital role in the fields of protein stabilization, active pharmaceutical ingredient development, drug delivery of macromolecules, antimicrobial agents, modification of nanocarriers, and biosensing [18]. This chapter focuses on the theoretical understanding of ILs and recent developments of ILs in these fields, which are used in the field of biocompatible IL research, and discusses what the future of ILs for biomedical use might look like.

13.2 A Brief History of Ionic Liquids and Deep Eutectic Solvents The IL, ethylammonium nitrate was reported first by the research group of Taul Walden in 1914 [19]. However, the first IL was not used in various applications because it was more sensitive to the air and moisture and was difficult to handle. This changed in 1992, when the first set of air- and moisture-stable ILs were prepared by Wilkes and Zaworotko using imidazolium cations [20]. Since this report, ILs have been broadly used across chemistry, engineering, and materials science owing to a slew of favorable properties, which are low volatility, high thermal and electrochemical stability, recyclability, and, most importantly, tunability. The properties of ILs, such as viscosity, conductivity, and miscibility, are different from those of other solvents, including water, due to the presence of atomistic components in ILs. In 2001, DES were first reported. These eutectic ILs became more popular because of their ease of synthesis, and the fact that they were largely composed of inexpensive and often biocompatible materials. The application of ILs in biomedical field was started in the late 1990s and early 2000s, and researchers started to use ILs to enhance thermostability of both enzymes [21] and model proteins [22] as well as augment enzymatic catalytic efficiency [23]. Additionally, ILs were used as antimicrobial agents [24] and for anticancer drug synthesis from the 2000s [25]. Nowadays, ILs are widely used in the field of biomedical applications like controlled release systems [26] and as formulation excipients [27] for poorly water-soluble compounds.

13.3 Biomedical Applications 13.3.1 Solubilization of Drugs There are many important bioactive molecules that are less effective and have less therapeutic utility due to their poor solubility in water and biological media. Three

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major factors play the role in solubilization: the interactions within the solute lattice, the formation of “holes” in the solvent, and the interaction and integration of the solute into the “hole” formed in the solvent [28]. This solubility problem is solved using ILs because the poorly soluble compounds can be solubilized in ILs as the compounds interact with the solute and, if present, co-solvent molecules, disrupting the existing interactions and promoting integration of the solute. Reports on drug solubilization in ILs suggest that the small-molecule drugs can be dissolved through the formation of neat and aqueous ILs [29]. These early studies particularly reveals that the imidazolium and quaternary ammonium ILs can dissolve the small molecules [30]. Supramolecular structure of the IL-drug formulations [31], solubility parameters [32], and broadening the scope by including phosphonium and pyrrolidinium cations have been studied by researchers before 2010 [32]. In the mid of 2010, the studies on ILs were based on the development of a number of specifically tuned ILs [33] and in vitro assessments of retention of drug efficacy [34]. However, recently, the solubility of an antiviral, acyclovir, in neat ILs, has been studied using a conductor-like screening model and experimentally validated choline-acetate systems as providing the highest solubility [35]. The solubility of acyclovir has been improved using cholinium amino acid ILs but also allowed for transdermal delivery of the drug [3, 36]. ILs with a higher degree of substitution to solubilize anesthetics lidocaine hydrochloride and procaine hydrochloride have been reported by Pal and Yadav [37], which shows strong interactions between the drug molecules and the IL components. The stability studies of complexes with curcumin have been reported with choline oleic acid IL [38]. The same choline oleic IL has been used to form microemulsions, which reveal that the solubility of celecoxib, acyclovir, methotrexate, and dantrolene sodium increases by greater than 20 times in water [39]. Mirheydari et al. [40] reported that the stability of anticonvulsant lamotrigine increases while using an imidazolium bromide IL. The interactions between LASSBio-294, a cardiovascular drug, and ILs have been studied using molecular dynamics simulations whose results corroborate the experiments [41].

13.3.2 Protein Stabilization Research on IL–protein interactions plays an important role in the prevention of aggregation [42, 43], reversal of aggregation [44], and refolding [45], with a significant focus on long-term stability [46]. The designing of ILs for stabilization of native proteins depends on the investigations involved in these systems [47–50]. Recent studies reveal that ammonium-based ILs interact with proteins [51–53], including enzymes [54–57] (Figure 13.2) due to their low toxicity and thermal and conformational stability [58–60]. The experimental and theoretical approaches have been used to understand interactions between proteins and other biological materials and ILs [61–65]. The amphiphilicity of biocompatible ILs shows the unique properties when formulated with hydrophilic molecules like proteins. The longer protein shelf lives can be achieved using ILs, which overcome some of the formulation hurdles faced by the traditional aqueous buffered solutions. For example, the

13.3 Biomedical Applications

SAIL : IL : Ethylene glycol :

Lysozyme (LYZ) 120 °C SAIL LYZ extraction IL

Enzymically active LYZ LYZ in EG

Interfacial adsoption of LYZ in ME

Figure 13.2 Schematic representation of lysozyme (LYZ) stabilization in surface-active IL formulation. Source: Adapted from Kaur et al. [54].

stabilization of insulin amyloids, which play important role for protein aggregates, has strong implications in therapeutic insulin treatment. Aqueous formulations with 20% mol/mol of 1-butyl-3-methylimidazolium hexafluorophosphate-based ILs ([Bmim][SCN], [Bmim][NO3] are used to find the ways to prevent fibril formation and facilitate refolding of amyloids into monomers, which applies to the field of medicine [51]. This is used for stable storage of insulin amyloids and 80% of insulin secondary structure is recovered after IL removal. The restriction of the microstates of various Xaa-Pro (any amino acid followed by a proline) dipeptides was performed using IL 1-butyl-1-methylpyrrolidinium bis(trifluoromethysulfonyl)imide ([C4 mpy][Tf2N]), which allowed for energetically unfavorable conformations to form that cannot be observed in water or octanol [52, 53]. Testing various proteins has given insight into how the size and type of proteins can affect IL interactions. Dilational rheology studies of [C12 mim][Br] with bovine serum albumin (BSA) reveal that increasing IL concentration drastically affected the BSA secondary structure [53]. One of most recent studies has reported on protein stability in the presence of various ILs, where thermal stability of BSA has subsequently been improved by 16 ∘ C using polyethylene glycol and choline chloride urea [66]. This study also suggests that β-lactoglobulin experiences structural changes when exposed to choline iodide. However, those effects can be canceled using choline dihydrogen phosphate [67]. The thermal stability of lysozyme (LYZ) has been examined by the adsorption at the nanointerfaces of IL-based microemulsions (MEs) [54]. In this study, they have prepared and characterized MEs composed of dialkyl imidazolium-based surface-active ILs (SAILs) as surfactants, ILs as the nonpolar phase, and ethylene glycol (EG) as the polar phase, without any cosurfactants [54].

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13.4 Summary and Future Aspects In recent years, use of ILs and DES has played a vital role in biomedical applications due to their unique properties and inherent tenability. In this chapter, we have discussed about ILs and deep eutectics and their advancement in the field of medicine, like solubilization of drugs, creation of active pharmaceutical ingredients, and stabilization of proteins and nucleic acids. Recently, many computational techniques and theoretical methods have been used to study ILs such as molecular dynamics simulations, which are based on an empirical force field and have been carried out to investigate the properties of a zwitterionic phospholipid (POPC) bilayer in contact with a water solution of various ILs at various concentrations. In this chapter, theoretical and computational methods have been discussed to understand on the IL advancement in the field of medicines.

13.4.1 Developing a Microscopic Understanding to Enable Task-Specific Design The application of ILs in the field of biomedicine reveals that various interactions are observed in complexes of biomolecules and ILs. However, the screening of ILs is performed by brute force without an understanding of the microscopic interactions both within the solvent and between the solvent and any biological material, and without knowledge of the possible broader implications of altering the ionic components. Very few reports on the above topic show that there can be very interesting, unexpected structures that form when ILs are mixed with other solvents or drugs. The structural behavior of ILs must be understood for the interaction of ILs with the local tissues after injection, topical application, or oral administration. These insights are important to the study of action for antimicrobial applications and protein stabilization. Some of these studies have been achieved with two-dimensional nuclear magnetic resonance spectroscopy (2D NMR) and dynamic light scattering. However, more detailed studies and research are required to establish a clearer understanding of the microscopic-level interactions, especially within the human body. One of the recent reports on mechanistic and microscopic research on ILs reveals that ILs can cause an increase in the cell migration rate through a localized area by affecting the cell membrane elasticity, which provides fundamental knowledge for IL design [68]. Similar types of above studies must be performed and a large library of ILs will provide a great service to all biomedical IL research.

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, 1. Amsterdam: Elsevier. McDaniel, J.G. and Verma, A. (2019). 123: 5343. Shaheen, A., Arif, R., Mir, A.W., and Rehman, S. (2019). 33: 100204. Egorova, K.S., Gordeev, E.G., and Ananikov, V.P. (2017). 117: 7132. Hong, M. and Luo, Z.-Q. (2012). 8: 405. Wilkes, J.S. and Zaworotko, M.J. (1992). 13: 965. Garlitz, J.A., Summers, C.A., Flowers, R.A., and Borgstahl, G.E.O. (1999). 55: 2037. Baker, S.N., McCleskey, T.M., Pandey, S., and Baker, G.A. (2004). 8: 940. Erbeldinger, M., Mesiano, A.J., and Russell, A.J. (2000). 16: 1129. 5: 52. Pernak, J., Sobaszkiewicz, K., and Mirska, I. (2003). Yen, Y.-H. and Chu, Y.-H. (2004). 45: 8137. Jaitely, V., Karatas, A., and Florence, A.T. (2008). 354: 168. Moniruzzaman, M., Tahara, Y., Tamura, M. et al. (2010). 46: 1452. Bergström, C.A.S. and Larsson, P. (2018). 540: 185.

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29 Kumar, V., Parmar, V.S., and Malhotra, S.V. (2007). 48: 809. 30 Mizuuchi, H., Jaitely, V., Murdan, S., and Florence, A.T. (2008). 33: 326. 31 Moniruzzaman, M., Kamiya, N., and Goto, M. (2010). 352: 136. 32 Manic, M.S. and Najdanovic-Visak, V. (2012). 44: 102. 33 McCrary, P.D., Beasley, P.A., Gurau, G. et al. (2013). 37: 2196. 34 Azevedo, A.M.O., Ribeiro, D.M.G., Pinto, P.C.A.G. et al. (2013). 443: 273. 35 Moniruzzaman, M., Tamura, M., Tahara, Y. et al. (2010). 400: 243. 36 Islam, M.R., Chowdhury, M.R., Wakabayashi, R. et al. (2020). 582: 119335. 37 Pal, A. and Yadav, A. (2018). 251: 167. 38 Chowdhury, M.R., Moshikur, R.M., Wakabayashi, R. et al. (2019). 55: 7737. 39 Ali, M.K., Moshikur, R.M., Wakabayashi, R. et al. (2020). 8: 6263. 40 Mirheydari, S.N., Barzegar-Jalali, M., Shekaari, H. et al. (2019). 135: 75. 41 Dasari, S. and Mallik, B.S. (2020). 301: 112449. 42 Fujita, K., MacFarlane, D.R., and Forsyth, M. (2005). 38: 4804. 43 Dreyer, S. and Kragl, U. (2008). 99: 1416. 44 Constatinescu, D., Herrmann, C., and Weingärtner, H. (2010). 12: 1756. 45 Attri, P., Venkatesu, P., and Kumar, A. (2011). 13: 2788. 46 Byrne, N., Wang, L.-M., Belieres, J.-P., and Angell, C.A. (2007). 2714. 47 Geng, F., Zheng, L., Yu, L. et al. (2010). 45: 306. 48 Naushad, M., Alothman, Z.A., Khan, A.B., and Ali, M. (2012). 51: 555. 49 Attri, P. and Venkatesu, P. (2011). 13: 6566. 50 Weingärtner, H., Cabrele, C., and Herrmann, C. (2012). 14: 415. 51 Ishikawa, Y., Takekiyo, T., and Yoshimura, Y. (2018). 272: 1019. 52 Heyert, A.J., Knox, S.L., Lindberg, G.E., and Baker, J.L. (2017). 227: 66. 53 Cao, C., Zhou, Z.-L., Zheng, L. et al. (2017). 233: 344. 54 Kaur, M., Singh, G., Kaur, A. et al. (2019). 35: 4085.

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55 Zhao, J., Frauenkron-Machedjou, V.J., Fulton, A. et al. (2018). 20: 9600. 56 Satish, L., Millan, S., and Sahoo, H. (2019). 329. 57 Suo, H., Xu, L., Xu, C. et al. (2018). 119: 624. 58 Sequeira, R.A., Singh, N., Pereira, M.M. et al. (2018). 120: 378. 59 Guncheva, M., Ossowicz, P., Janus, E. et al. (2019). 283: 257. 60 Mamashli, F., Badraghi, J., Delavari, B. et al. (2018). 272: 597. 61 Benedetto, A. and Ballone, P. (2018). 551: 227. 62 Harada, L., Pereira, J., Campos, W. et al. (1983). 2018: 29. 63 Arumugam, V., Rajamanikandan, R., Ilanchelian, M. et al. (2019). 273: 634. 64 Arumugam, V., Rajamanikandan, R., Ilanchelian, M. et al. (2019). 210: 299. 65 Janati-Fard, F., Housaindokht, M.R., Monhemi, H. et al. (2018). 114: 656. 66 Bhakuni, K., Yadav, N., and Venkatesu, P. (2020). 22: 24410. 67 Sindhu, A., Kumar, S., Mondal, D. et al. (2020). 22: 14811. 68 Kumari, P., Pillai, V.V.S., Rodriguez, B.J. et al. (2020). 11: 7327.

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14 Recent Developments in Ionic Liquid Research from Environmental Perspectives Prarthana Bora 1,2 and Swapnali Hazarika* 1,2 1 CSIR-North East Institute of Science and Technology, Chemical Engineering Group, Centre for Petroleum Research, Jorhat, Assam 785006, India 2 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India

14.1 Introduction Among all the greener approaches made in recent years, ionic liquids (ILs) have gained large popularity having diverse potential applications. After the discovery of ionic liquids in the late 1990s, they gradually proved their importance in different fields of science, which made them one of the most efficient presently available solvent, electrolyte, catalyst, as well as lubricant. Ionic liquids can be defined in various ways: the mostly used definition is that ILs are assembly of ionic species having one cationic counterpart (organic) and one anionic moiety (organic or inorganic), which exist in liquid state at a low temperature ( linear) are responsible for high viscosity of ILs. ILs are preferred as a high-temperature lubricant as they show high thermal stability. Thermal stability of ILs depend on the alkyl chain length and vary inversely. Dicationic ILs possess higher thermal stability than the monocationic one. Keeping cationic part constant if we study the impact of different anions on thermal stability, the increasing order can be demonstrated as follows: I− , Br− , Cl− < N(CN)2 − < BF4 − < CF3 SO3 − < C(CF3 SO2 )3 − < NTf2 − . The halides are observed to show lower thermal resistance than other anions, which can be explained on the basis of their comparatively high nucleophilic basic character. Another parameter is thermo-oxidative stability, which is an important lubricant property [11]. When ILs are tested for thermo-oxidative stability, with same cation NTf2 − anions show high stability in comparison to BF4 − . With increase in carbon number in the alkyl group, there is a decrease in the stability of alkylimidazolium ILs. The properties of a lubricant should include good lubricity, desirable viscosity, high thermos-oxidative stability, nonflammability, nontoxicity, and chemical stability. Based on these properties, around 400 different ILs have been tested to date as a lubricating substrate for varied sliding pairs, and many more newer works are expected to be undergoing for achieving better lubricating performance.

14.2.6 Ionic Liquids as a Corrosion Resistant Material Magnesium (Mg) and its alloys are important engineering materials in aerospace, infrastructure, and automotive fields, where the priority is to minimize the weight. The high value of the ratio between strength and weight of Mg and its alloy made them applicable in the above fields [12]. But they are very prone to corrosion, which limits their growing demands to some extent. Mg and its alloys upon exposing into the atmosphere easily undergo oxidation to form oxide–carbonate–hydroxide types of films on the surface. Thus prevention of such metal surface corrosion needs to be studied preferentially. The best solution for this prevention can be surface treatment of Mg and alloys before their applications. Surface treatment includes coating, electrochemical plating, or anodizing. IL with bis(trifluoromethanesulfonyl)amide [NTf2 ]− anion is reported to be coated onto the metal surface, and when subjected to atmospheric exposure, it shows an improved corrosion resistivity (Figure 14.5). The anticorrosive property of ILs lies in their advantageous intrinsic properties. The use of ILs in corrosion protection minimizes the need of pretreatment. In lithium-ion battery research, the formation of solid-layered electrolyte interphase was reported on

14.2 Applications of Ionic Liquids

Figure 14.5 Surface film on reactive metal on treatment with ionic liquids. Source: Adapted from Zamir et al. [13].

{MX + IL} layer (X = oxide/hydroxide)

Metal (M)

the lithium electrodes where the outer layer consists of NTf2 − reduction product and the inner part has LiF. This surface film obtained as Li is immerged into pyrrolidinium IL. The formation of the surface film can lead to an improvement in electrochemical behavior in addition to recyclability and efficiency. Thus, it can be summarized that the pretreatment with IL is able to form a surface protective layer, which could offer electrochemical stability followed by corrosion resistance. Early works on corrosion prevention through IL treatment were mainly based on trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)amide ([P6,6,6,14 ][NTf2 ]) IL since this IL is commercially available and possesses superior electrochemical properties. The use of phosphate conversion coating can be done in place of chromate conversion coating in environmental concern. Phosphate group containing ILs are best proved in the literature in terms of corrosion resisting performance. Thus, to acquire better performances, numerous numbers of ILs are developed until now, making it very important to find out the most efficient one in order to mitigate the corrosion of metal substrates. The metal surface is covered with inorganic oxide/hydroxide in ambient atmosphere. The plausible interactions between the IL and metal oxide or hydroxide are the absorption of the IL anion onto the Mg(OH)2 and SiO2 , leading to the exposure of the IL cation on the outer portion of the surface film, while minimal interaction is possible in case of other inorganic oxide/hydroxides, such as Al2 O3 , ZnO, MgO, and ZrO2 [12]. This different behavior of interactions can be explained with the hydroxyl groups present on the surface. Which made it easier for solid-state NMR to give quick insight into the surface layer obtained as a result of interaction with IL.

14.2.7 Ionic Liquids as Additives in Drilling Fluid For a successful drilling operation, the must needed factor is the proper designing of the drilling fluid or mud. The fluid can be of two types: one is oil based and the another one is water based [13]. There are reports where air-based fluid is used in drilling although it is very rare. The rheology of the drilling mud and filtrate control can be improved with additive incorporation. Few additives that are reported to be used in the literature are starch, low-solids, water-soluble polymers, and xanthan gum. But the main problem related to these polymer-based additives is that, they undergo degradation at elevated temperatures. In comparison to this polymer-based drilling mud, the oil-based muds are beneficial with high thermal stability and outstanding cutting carrier capability. The synthesis of oil-based muds is very costly and their dumping is not environmentally friendly. Thus, in order to overcome these problems, water based-muds are more preferred and they offer the tuning of

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mud properties through introduction of different additives [13]. The main functions of drilling muds are (i) hydraulic pressure for ending fluid influx formation, (ii) suspension, (iii) removal, and (iv) transportation of cutting. Now, the design of a drilling mud should be done in such a way that the mechanical properties in the formation become less. The rheology of different muds vary with different additives. In the calculations of drilling hydraulics, the knowledge on plastic viscosity and point are very important since their role is unavoidable in transportation of cuttings. The resistance of the fluid in flowing can be calculated and it is termed as yield point. While the plastic viscosity can be defined as the measurement of solid content available in the drilling mud. The design of drilling fluid should be done by minimizing plastic viscosity to the least. ILs possessing electrostatic behavior and versatile nature are suitable for using in drilling fluid as additives and are being used lately in various drilling industries. The impact of ILs on rheology of mud and its filtration properties are undeniable. The length of the alkyl chain in the IL moiety can alter the properties of a drilling mud if added as additive. A high yield stress value of the mud is required for holding and effective transporting of the cuttings. Simultaneously, high yield stress can lead to excessive pressure drop with an increase in the circulation density [13]. ILs can show effective impact on plastic viscosity as well as yield point of drilling mud. Again the filtration properties of ILs also varied with the length of the alkyl chain; the longer is the alkyl chain, the better is the filtration property.

14.2.8 Ionic Liquids as Absorbents in Gas Capturing Out of many hazardous gaseous substances, carbon dioxide is one of the major pollutant, whose elevated emissions needed to be taken care of immediately in concern for the environment. Carbon capture and storage includes separation, transportation, capturing, and storage of CO2 . If we consider cost-effectiveness, the capture and separation of CO2 are more efficient [14]. In natural gas, with hydrocarbons CO2 is also present in small quantity, which makes the natural gases sour. Sour gas sweetening process has always been demanding and needs to be done preferentially before transportation of natural gases [15]. Otherwise, the corrosive nature of CO2 can affect the transportation pipelines and the equipment. These made the removal of CO2 an important matter of concern. There are different methods available for CO2 capturing, which are chemical and physical absorption, physical adsorption, cryogenic and membrane separation. Between chemical and physical absorption, the chemical one is favored over physical absorption. The use of ILs as a solvent for CO2 absorption have been studied in the last few decades as ILs can offer high liquid range, thermal stability, negligible volatility, structure tenability, and high solubility for gases. In ILs with [BF4 ]− and [PF6 ]− anions, there is an interaction possibility through acid–base mechanism with CO2 . Another mechanism involved is the IL free volume that exists due to the presence of alkyl chain and high fluorine-containing anionic moiety. The more is the fluorine-containing anion and long alkyl-containing cation, the more is the free volume, and the more will be the CO2 solubility [16]. In addition to this, comparatively weaker interactions like halogen and hydrogen bonding are present, and

14.2 Applications of Ionic Liquids

CO2 solubility depends on these types of interactions to some extent. The nonvolatility and wide solubility range of ILs also make them useful as solvents in selective separation of azeotropic gas mixtures such as olefin/paraffin [15].

14.2.9 Ionic Liquid Crystals A new term named liquid crystalline (LC) phase was introduced, which acquires orientational, translational, or positional order of both crystals as well as liquids. Molecules that contain rigid and flexible parts in their structure are more likely to show these types of resembling phases and are called thermotropic LCs, and their behavior mainly depends on temperature and pressure. Another type of LC called lyotropic LCs is generally observed in colloidal solutions, and its formation depends mainly on solvent medium as well as concentration [17]. A new class of LCs having ionic characteristics in its structure has been developed, which has been named as ionic liquid crystals (ILCs). The first ILCs were reported in 1938, and were not studied in wide scale. Lately, a full scale study on this hybrid LC material has been started. ILs and liquid crystals both blends themselves to generate these new ILCs. ILCs are composed of cations and anions, which are covalently bound to each other, and show characteristics of both ILs and liquid crystals, such as dynamic nature and ionic character of ILs, and fluidity, anisotropy, and self-assembling nature of LC’s. Having these properties, ILCs can be considered as ILs and LCs simultaneously. For designing of ILCs, cations and anions used are the same as that used in ILs with long carbon chains [17]. Important properties that ILCs have are (i) orientability, (ii) miscibility, (iii) phase stability, (iv) packing tunability, and (v) polar nanochannels. With these properties, ILCs are proved as a potential candidate in material chemistry applications. Cations of aliphatic organic salts with anions of small size and anions of aliphatic organic salts with cations of small sizes – both these combinations can lead to the formation of ILC. Correlation diagram of ILC properties with different applications are shown in Figure 14.6. With the properties of phase stability, wide range of miscibility, tunability at nanolevels, forming capability of polar nanochannels, ILCs have been utilized in applications in various fields, such as host frameworks, media for reactions, Characteristics of ILCs 1) Orientability

Applications of ILCs 1) Host framework for guestbinding

2) Miscibility 2) Separation membrane 3) Phase stability 4) Packing tenability

3) Ion/proton-conduction medium 4) Reaction medium

5) Polar nanochannels 5) Optoelectronic material

Figure 14.6

Correlation diagram of ILC properties with applications [17].

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materials in optoelectronics, and separation-based as well as conducting membranes. A lot of newer cationic cores are developed in the synthesis of ILCs such as morpholinium, pyrrolidinium, pyridinium, imidazolium, and piperazinium, which are composed of quaternized nitrogen-based heterocyclic rings. In comparison between pyrrolidinium and imidazolium cations, the former is superior in terms of electrochemical stability [9]. And also, there are no hydrogen bonding possibilities in the case of pyrrolidinium due to the absence of an acidic H atom. Another term “mesophase” is used to define the LC state since this state of matter show their existence as borderline of isotropic liquid and solid phases. Mesophase is also sometimes referred as the fourth state of matter. When there is an extension of chain length in the alkyl chain attached to the cationic or anionic moiety, there is an increase in clearing and melting temperatures. Anions can impart more effect on the stability factor of mesophase. With an increase in anion’s size, there is a decrease in mesophase stability [18].

14.2.10 Ionic Liquids in Biomedical Applications Out of numerous uses, ILs have also been used in biomedical fields as sensor materials and actuators [19]. ILs provide newer medical and pharmaceutic strategies, which made them a center of attraction for many researchers in the corresponding field. When we talk about the application of ILs in biomedical fields, their biological activity is the main reason. ILs can show cytotoxicity against cancer-causing cells and also antimicrobial activity. ILs can also be used in drug delivery. Concerning the environmental aspects, research nowadays is mainly focused on the synthesis of ILs with protein-derived amino acids as a precursor. Amino acids are biocompatible, biodegradable, naturally available, and nontoxic organic moieties, which can be a good choice as a precursor material for IL synthesis. Few studies on amino-acid-based IL synthesis have been successfully conducted [20]. Biological buffers having nontoxicity, chemical inertness, UV–vis inactivity, no interference in metal–protein binding, high water solubility and organic insolubility, temperature resistance, and low cost can be used as anions for developing biocompatible ILs. ILs in combination with a lot of different biopolymers have evolved recently. In biomaterial preparation, ILs have played different roles, such as dissolution or regeneration of polymers. ILs can also be used as reaction media. Different biomedical applications of biopolymer/IL combinations have been demonstrated in Figure 14.7. The tuning property of ILs offers a wide range of possible IL synthesis for use in various fields. There are available reports of incorporation of ILs into different polymer-based matrices to prepare membranes and other advanced materials. Choline-ILs are the mostly used ILs in biomedical applications compared to others because of their better biocompatibility as well as nontoxicity [20].

14.3 Limitations of Ionic Liquids ILs have been predominantly used in different fields of chemistry for decades due to their superior properties. However, some limitations are present as well.

14.4 Conclusion

Ionic liquids

e os llul e s ote C id ins ac c i cle Nu

Pr

Dissolution Processability Chemical modification Material components

Drug delivery

Pharmaceutical candidates

Gene delivery

Figure 14.7 Ionic liquids/biopolymers for different biomedical applications. Source: Adapted from Zhanga et al. [20].

The halogen-containing typical ILs in their anionic part somehow proved to be inferior in terms of “greenness” [4]. The halogen atom has the probability to cause significant concern when the anion possesses poor hydrolysis stability or the IL is desired to undergo thermal treatment. These aforementioned processes lead to the liberation of HF or HCl into the environment, which are labeled as toxic as well as corrosive; thus, to avoid their liberation, they need extra effort. These consequences trigger the researchers to look for newer, greener noble ILs. It is already proved that the presence of impurities in ILs can have a significant impact on the physicochemical properties of a material [4]. Some of the potential sources of impurities labeled for the IL “[bmim][n-C8 H17 OSO3 ]” are volatile organics, halides, water, and other ionic impurities. Thus, in order to eliminate the presence of impurities in ILs, one must take utmost care during their synthesis. For ILs to be used for industrial purposes, their technical availabilities as well as detailed toxicology are essentially needed to be studied [4]. Halide-containing ILs are compared with polychlorinated biphenyls (PCBs) due to their similar properties. PCBs, when emitted in a high scale, can produce devastating environmental impacts as a result of widespread use and lack in disposal management. This implicates the need of further understanding of biodegradability of ILs [5]. Again, the poor biodegradability and long-term toxicity of ILs do not favor their widespread use. ILs are derived basically from petroleum-derived products, for example, imidazolium and pyridinium, which under decomposition can lead to the release of toxic and hazardous products [20]. Thus, the term green for IL is always questionable. To mitigate the biocompatibility-based doubts about ILs, one must find a way to synthesize ILs with more and more bio-friendly and cost-effective precursors and synthetic routes.

14.4 Conclusion As ILs have high chemical stability as well as low volatility, there is a very low probability of emission. Owing to their numerous advantages, ILs are superior to other conventional materials. Due to these properties, ILs made their footprint in various application-based fields. Based on their wide range of applications, ILs can be termed

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as green, but sometimes they could not stand with this greener tag because ILs can be a stable and persistent pollutant in the environment. A thorough study on the toxicity, biodegradability, and biocompatibility of ILs is needed so that one can take the utmost advantage of them without any environmental concern. In the near future, ILs will hold tremendous scopes as a membrane material since their applicability in gas separating liquid membranes is already established [21]. With evolution of newer ILs with superior functionalities, they can be applied as a potential candidate for varied applications [21].

References 1 Shamsuri, A.A., Abdan, K., and Md. Jamil, S.N.A. (2021). Properties and applications of cellulose regenerated from cellulose/imidazolium-based ionic liquid/co-solvent solutions: a short review. e-Polymers 21: 869–880. 2 Boona, Y.H., Raoova, M., Zaina, N.N.M. et al. (2017). Combination of cyclodextrin and ionic liquid in analytical chemistry: current and future perspectives. Critical Reviews in Analytical Chemistry 47 (5): 454–467. 3 Wanga, L.Y., Guoa, Q.J., and Lee, M.S. (2019). Recent advances in metal extraction improvement: mixture systems consisting of ionic liquid and molecular extractant. Separation and Purification Technology 210: 292–303. 4 Swapnil, S. (2012). A ionic liquids (a review): the green solvents for petroleum and hydrocarbon industries. Research Journal of Chemical Sciences 2 (8): 80–85. 5 Clarke, C.J., Tu, W.C., Levers, O. et al. (2018). Green and sustainable solvents in chemical processes. Chemical Reviews 118 (2): 747–800. 6 Marinkovic, J.M., Riisager, A., Franke, R. et al. (2019). Fifteen years of supported ionic liquid phase-catalyzed hydroformylation: material and process developments. Industrial and Engineering Chemistry Research 58: 2409–2420. 7 Pino, V. and Afonso, A.M. (2012). Surface-bonded ionic liquid stationary phases in high-performance liquid chromatography—a review. Analytica Chimica Acta 714: 20–37. 8 Armand, M., Endres, F., MacFarlane, D.R. et al. (2009). Ionic-liquid materials for the electrochemical challenges of the future. Nature Materials 8 (8): 621–629. 9 Kuhlmann, E., Haumann, M., Jess, A. et al. (2009). Ionic liquids in refinery desulfurization: comparison between biphasic and supported ionic liquid phase suspension processes. ChemSusChem 2: 969–977. 10 Zhou, F., Liang, Y., and Liu, W. (2009). Ionic liquid lubricants: designed chemistry for engineering applications. Chemical Society Reviews 38: 2590–2599. 11 Cai, M., Yu, Q., Liu, W., and Zhou, F. (2020). Ionic liquid lubricants: when chemistry meets tribology. Chemical Society Reviews 49: 7753. 12 Huanga, P., Lathama, J.A., MacFarlane, D.R. et al. (2013). A review of ionic liquid surface film formation on Mg and its alloys for improved corrosion performance. Electrochimica Acta 110: 501–510.

References

13 Zamir, A., Elraies, K.A., Rasool, M.H. et al. (2021). Influence of alkyl chain length in ionic liquid based drilling mud for rheology modification: a review. Journal of Petroleum Exploration and Production Technology 1–8. 14 Babamohammadi, S., Shamiri, A., and Aroua, M.K. (2015). A review of CO2 capture by absorption in ionic liquid-based solvents. Reviews in Chemical Engineering 31 (4): 383–412. 15 Fallanza, M., Ortiz, A., Gorri, D., and Ortiz, I. (2012). Experimental study of the separation of propane/propylene mixtures by supported ionic liquid membranes containing Ag+ –RTILs as carrier. Separation and Purification Technology 97: 83–89. 16 Shukla, S.K., Khokarale, S.G., Bui, T.Q., and Mikkola, J.P.T. (2019). Ionic liquids: potential materials for carbon dioxide capture and utilization. Frontiers in Materials 6: 42. 17 Salikolimi, K., Sudhakar, A.A., and Ishida, Y. (2020). Functional ionic liquid crystals. Langmuir 36: 11702–11731. 18 Goossens, K., Lava, K., Bielawski, C.W., and Binnemans, K. (2016). Ionic liquid crystals: versatile materials. Chemical Reviews 116: 4643–4807. 19 Correia, D.M., Fernandes, L.C., Fernandes, M.M. et al. (2021). Ionic liquid-based materials for biomedical applications. Nanomaterials 11: 2401. 20 Zhanga, J., Dua, Y., Zhanga, Q. et al. (2013). Investigation of the synergistic effect with amino acid-derived chiral ionic liquids as additives for enantiomeric separation in capillary electrophoresis. Journal of Chromatography 1316: 119–126. 21 Gogoi, G., Hazarika, S., (2015). Role of Ionic Liquid in Membrane Technology. Chapter 5, Lignocellulose, Nova Science.

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15 Ionic Liquids for Sustainable Biomass Conversion in Biorefinery Rakesh Dutta 1 and Khemnath Patir 2 1 Pandit Deendayal Upadhyaya Adarsha Mahavidyalaya, Behali, Department of Chemistry, Biswanath, Assam 784184, India 2 Assam University, Department of Applied Science and Humanities, Silchar, Assam 788011, India

15.1 Introduction Currently, fossil fuels are the primary sources of energy for humanity. Fossil-based sources are decreasing at a very rapid rate. Hence, it is necessary to explore other sources of chemicals and energy that are sustainable in nature. Globally, about 1011 tons of biomass is produced annually. In recent years, biomass has been able to substitute fossil fuels as the main source of fuels and biodiesel [1]. High demand for biomass utilization for organic compounds and fuel production has led to the development of biorefinery concept similar to petroleum refineries processing fossil fuel sources. Ionic liquids (ILs) are a type of salts that remains as liquids below 100 ∘ C. They mainly consist of organic cations and organic/inorganic anions (Figure 15.1) [2, 3]. A biorefinery is a facility in which biomass is transformed to organic compounds, fuels, and power (Figure 15.2) [4]. Industrial biorefineries are one of the most potential sources for the development of new domestic biobased industry. For the development of an efficient biorefinery, different conditions are required, which include effective processing technology, catalytic conversion system, and separation process [5]. Application of ILs in biomass treatment has been emerging as one of the most environmentally friendly and homogenous methodologies for biorefinery industries [6, 7]. ILs are used as solvents and catalysts to transform biomass to organic compounds and biofuels. This involves materials synthesis, catalytic transformation of cellulose to monomeric constituents, organic compounds, and biodiesel [8]. In this chapter, the extraction, composition, and characterization of biomass, along with its conversion using ILs, are discussed in detail. In addition, the application of sustainable biomass components for the production of various organic compounds, fuels, and energy is also discussed in the prospective of biorefinery.

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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R1

+

R2

N

+

R3

R4

P

Cations R4

R3

R2 +

N R

Anions

Figure 15.1

Biomass

−

BF4−

CH3CO2−

CF3CO2−

PF6

−

N(CN)

Ionic liquids consist of cations and anions.

Ionic liquids

Figure 15.2

NO3−

Cellulose

Fuels

Hemicellulose

Chemicals

Lignin

Materials

The concept of ionic liquid-based biorefinery.

15.2 Biomass as a Source of Organic Compounds and Fuels Lignocellulosic biomass is derived from plant-based materials, such as wood chips, rice straw, grass, wheat straw, corn stover, and bagasse. These are abundant, renewable, and economically feasible resources if efficient technologies are developed for the extraction and separation of valuable components. Rapid declines of petroleum reserves and global warming induced by burning of fossil fuels have led to the use of biomass as an alternative resource for fuels and organic compounds [4, 9–11]. Biomass may come from different sources, but all lignocellulose materials are composed of cellulose, hemicellulose, and lignin [12]. The cheapest source of these biopolymers are bagasse, corn stover, and wheat straw. However, the separation and transformation of lignocellulose biomass by cost-effective methods is a major challenge [4]. Multiple organic compounds such as methanol, ethanol, cellulose, lignin, lactic acid, furfural, vanillin, and xylitol can be produced from biomass, making them highly economic. Application of biomass as a feedstock for chemical production requires separation of the useable components, which maximizes availability in different chemical industries [4, 11]. Cellulose is a biopolymer consisting of glucose units connected by 1,4-glycosidic bonds that is crystalline in nature [13]. Hydrolysis of cellulose results in the formation of glucose, which is a substrate for various organic compounds such as ethanol, malic acid, fumaric acid, lactic acid, succinic acid, citric acid, glycerol, furfural, levulinic acid, gluconic acid, and riboflavin [14–16]. Hemicellulose is an amorphous polysaccharide found within plant cell walls [17]. A product of the hydrolysis of hemicellulose, xylose is applied for producing xylitol, furfural, levulinic acid, hydroxyl-xylal esters,

15.3 Biomass Conversion Process

and pyrazole [16]. Lignin is a biopolymer with three building blocks, namely guaiacylpropane, syringylpropane, and hydroxyphenylpropane. Its primary source is plant kingdom [18, 19]. The presence of lignin in lignocellulose prevents enzymatic hydrolysis of cellulose by cellulases, and it also forms phenolic compounds, which in turn hinder the fermentation process [20–24]. Due to its heterogeneity in structure, its applications are dependent on the extraction process [11]. Kraft lignin and lignosulfonates are produced by the sulfite process and therefore contain sulfur as an impurity. The various applications of Kraft lignin are energy production, phenolic thermoplastics, and epoxy and polyurethane resins [23]. On the other hand, lignosulfonates found applications as dispersants, emulsifiers, and surfactants [25].

15.3 Biomass Conversion Process 15.3.1 Thermochemical Process The direct combustion of biomass to create energy is the oldest method that has been used for thousands of years. Thermochemical methods such as gasification, liquefaction, acid hydrolysis, and pyrolysis are applied for the transformation of biomass to organic compounds, which involves depolymerization at specific temperatures and pressures. In gasification process, carbon-containing substrates such as biomass or municipal waste are heated at 100–500 ∘ C, 1–10 bar, under controlled oxygen atmosphere, resulting in the formation of mixture of CO and H2 with smaller fractions of CO2 , CH4 , and N2 , which may be in turn converted into hydrocarbons, methanol, or hydrogen by Fischer–Tropsch process [26]. In gasification process, lignin components can also be converted, which was not possible in the hydrolysis of cellulose and hemicellulose to fermentable sugars. Bio-oils having mixtures of large number of compounds, such as alcohols, acids, esters, aldehydes, ketones, and aromatic organic molecules, can be produced by the pyrolysis and liquefaction of biomass [27]. Pyrolysis is carried out at 375–525 ∘ C and 1–5 bar in the absence of oxygen, while the liquefaction is carried out at 250–325 ∘ C and 50–200 bar. Since 1930, commercial plants have been operating for the transformation of cellulose to glucose via acid hydrolysis. This is further used for fermentation to produce different organic compounds [28]. In Biofine process, lignocellulose is converted to different useful organic compounds, such as furfural, levulinic acid, and formic acid, using dilute sulfuric acid as a catalyst [29].

15.3.2 Lignin Extraction Processes One of the most traditional methods of extracting lignin from lignocellulose is used in paper and fiber industries. These methods used kraft, sulfite, soda, and organosolv processes. All these processes require high pressure and therefore high investment capital. The kraft process involves treating the woods and lignocellulosic materials with sodium hydroxide and sodium sulfite at a temperature and pressure of around 165 ∘ C and 0.7 MPa, respectively [30]. However, the kraft process has many demerits,

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such as high water use, pollution, odor, and economic issues [31]. To overcome these demerits, a few organic compounds such as acetic acid, formic acid, and phosphoric acid are used for fractionating biomass under milder conditions. But the major drawback of these organic compounds is their corrosiveness. Hence, this process is not fully explored in terms of energy usage and solvent recovery [32, 33].

15.3.3 Enzymatic Processes Enzymes are a type of protein found in living organisms, which behave as catalysts under specific conditions; hence, they are called biocatalysts. They are useful for the breakdown of polymers or synthesizing organic compounds [34]. The research on biomass conversion using cellulases has improved to a significant extent during the last 20 years [35]. Higher yield of glucose is obtained by the depolymerization of cellulose using cellulases enzymes as compared to acid hydrolysis. But the rate of cellulase-catalyzed reaction is relatively less due its crystallinity and the presence of hemicellulose, lignin, as impurity [36]. The most common and effective reaction of cellulases is the production of ethanol. It involves the saccharification and fermentation of sugars by yeast, which hinders the sugars from inhibiting the end products [37]. Industrial-scale production cannot be materialized due to the high cost of the cellulases [38].

15.4 Value-Added Organic Compounds from Biomass in Ionic Liquids Currently, fossil fuels are the primary sources of energy for humanity. Fossil-based sources are decreasing at a very rapid rate, and the price of petroleum-based fuels is increasing. Hence, it is necessary to explore other sources of organic compounds and energy that are sustainable and cost-effective in nature. Biomass is a suitable alternative that can act as a feedstock for fuel and chemical industries [39]. In petrochemical industries, crude oil is fractionated and refined into different liquid fuels or organic compounds. Here, the biorefinery concept is the utilization of biomass to produce energy, fuels, and useful organic compounds. Some of the important issues that need to be taken care of for the successful conversion of biomass to organic compounds and fuels are to depolymerize the biopolymers, reduce oxygen content, and generate high-molecular-weight products [38]. ILs have the ability to dissolve biomass. Due to these merits, valuable feedstock has been produced from biomass by hydrolysis, dehydration, and hydrogenolysis processes. Fuels and many organic compounds such as monosugars, 5-hydroxymethyl furfural, levulinic acid, and long-chain alkyl glycosides have been synthesized by these processes [39]. Hydrolysis of cellulose results in fermentable sugars which is an important step of biofuel and organic compounds production. Currently, two methods that are widely used for cellulosic biomass hydrolysis are acid hydrolysis and enzymatic hydrolysis. Pretreatment is essential to overcome the lignocellulose recalcitrance. The purpose of pretreatment is to change the physical properties and chemical

15.4 Value-Added Organic Compounds from Biomass in Ionic Liquids

composition to make them easily digestible by acids and enzymes [40]. ILs have been used as a catalyst to produce fermentable sugars. The enzymatic hydrolysis of cellulosic materials from ILs is regenerated by addition of antisolvent. Cellulose is enzymatically hydrolyzed in biocompatible ILs. In addition to these, acid catalysts are also used to hydrolyze the soluble carbohydrates in ILs [41]. Many researchers have investigated the ILs as suitable solvents for catalysis [42]. Enzymatic hydrolysis of cellulose using ILs eliminate the requirement of an antisolvent to extract the biomass [42]. Kamiya et al. applied the IL, 1-ethyl-3-methylimidazolium diethyl phosphate [Emim] [DEP], for dissolving cellulose. This IL-cellulose is mixed with different volumes of citrate buffer (10 mM, pH-5) and cellulase is added by directly heating at 40 ∘ C. The volumetric ratio of ILs significantly affects the activity of the cellulase. A 70% sugar yield was obtained after 24 h reaction when the ILs to water ratio was 1 : 4 [43]. The ILs, [Emim] [OAc], were applied under same conditions, and then the cellulase activity is decreased to half value, suggesting that structure plays a key role in enzyme compatibility. A mixture of cellulases and beta-glucosidase such as Celluclast 1.5L-Trichoderma reesei and Novozyme 188-Aspergillus niger respectively, was found to retain 77% and 65% of its original activity when pre-incubated in 15% and 20% (w/v) IL solutions, at 50 ∘ C for a time period of 3 h. Avicel is produced by 15% [Emim] [OAc], which have an efficiency of 91% [43]. Bose group investigated the activity and stability of cellulase samples in eight ILs by applying optical and calorimetric methods [44]. Out of the eight ILs, only 1-hydrogen-3-methylimidazolium chloride and tris-(2-hydroxyethyl) methyl ammonium methyl ammonium methylsulfate were efficient in cellulose hydrolysis. Detailed investigations have revealed that enzymatic activity, thermal stability, and rate of hydrolysis are directly related to viscosity of the ILs and enzyme stability (Table 15.1). Catalysis of cellulose with acid produces monosaccharides which are carried out under heterogeneous and harsh conditions. Various solid and mineral acids are used for hydrolyzing cellulose in ILs (Table 15.2). Zhao group was the first to study the hydrolysis behavior of cellulose in ILs in the presence of mineral acids under homogenous conditions [7]. They found that a specific amount of acid was suitable for the hydrolysis reaction. A 1 : 4 mass ratio of acid/cellulose yield 64% of total reducing sugar and 36% of glucose at 100 ∘ C after a reaction time of 42 min. Kinetic study shows that the cellulose hydrolysis by [B4 mim] [Cl] in presence of sulfuric acid followed a first-order reaction. This reaction system can be extended to different lignocellulosic materials [7, 46]. Cellobiose in the presence of 1-ethyl-3-methylimidazolium chloride [E2mim] [Cl] display two types of competitive reactions: polysaccharide hydrolysis and sugar degradation under varied acid strengths [65]. The complete dissolution of cellulose in ILs renders the glycosidic oxygen accessible to external acid catalysts, favoring a fast hydrolysis reaction. Rinaldi et al. used a solid acid (Amberlyst 15 DRY) catalyst for the hydrolysis of cellulose and lignocellulose in ILs media, where the depolymerized cellulose is extracted by mixing water [53]. Gel-permeation chromatography was applied for estimating the degree of polymerization and size of the cellulose fibers extracted, which became successively smaller with time. Shimizu and coworkers synthesized

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Table 15.1

Catalytic hydrolysis of lignocellulose into monosugars in ILs. TRS

Glucose

Materials

Acid

Ionic liquids

Regeneration solvent

Avicel

H2 SO4

[Bmim] Cl

Water

73

32

[45]

α-Cellulose

H2 SO4

[Bmim] Cl

Water

63

39

[45]

Corn stalk

HCl

[Bmim] Cl

Water

66

—

[7]

Rice straw

HCl

[Bmim] Cl

Water

74

—

[7]

Pine wood

HCl

[Bmim] Cl

Water

81

—

[7]

Bagasse

HCl

[Bmim] Cl

Water

66

—

[7]

Eucalyptus grandis

HCl

[Amim] Cl

Water

74

—

[7]

or methanol or ethanol

95

—

[46]

Water

—

89

[47]

Water

32

—

[48]

Cellulose

HCl

Lignocellulose H3 PW12 O40

—

[Emim] Cl

Yield Yield (%) (%)

References

Cellulose

Nafion NR50

[Bmim] Cl

Water

35

—

[49]

σ-Cellulose

HY Zeolite

[Bmim] Cl

Water

42.4

32.5

[50]

β-Cellulose

HY Zeolite

[Bmim] Cl

Water

—

12.5

[51]

Wood

Trifluoric acid [Bmim] Cl

Water

79

—

[52]

Corn stover

Boronic acids

42.4

32.5

[53]

[Emim] [OAc] Water

H3 PW12 O40 and applied it for hydrolysis of lignocellulose, which is found to be effective for better production of TRS in comparison to sulfuric acid in water [48]. Nafion NR50 and sulfonated silica/carbon nanocomposites have been applied for the hydrolysis of cellulose in ILs. In addition, this catalyst is used for hydrolysis of hemicellulose solid into sugars by enzymes that are separated by adding antisolvents [49]. Binder et al. investigated the fermentation potential of sugars produced from cellulose in ILs after separation by ion-exclusion chromatography. The results showed that increasing the water amount to a chloride ILs-containing catalytic HCl led to a 90% yield of glucose from cellulose and an 80% yield of sugars from untreated corn stover [47]. Brennan and coworkers demonstrated that the sugars can be recovered from ILs by extraction based on the chemical affinity of sugars to boronates such as phenyl boronic acid and naphthalene-2-boronic acid [52]. About 90% of mono- and disaccharides were found to be extracted from IL solutions using boronate complexes, IL systems, or hydrolysates of corn stover containing ILs. Lignin is the second most abundant component of biopolymers in biomass. Recently, its conversion into aromatic compounds in ILs has started as it has beta-O-4 linkage as primary units. Joseph and coworkers studied the reactions of lignin model compounds in 1-ethyl-3-methyl-imidazolium triflate [Emim] [OTf]

15.4 Value-Added Organic Compounds from Biomass in Ionic Liquids

Table 15.2

Biodiesel production in ILs. Biodiesel

Materials

Catalyst

Ionic liquids

Conditions

Yield (%) References

Soybean oil Candida antarctica

[Emim][TfO]

50 ∘ C, 12 h

80

[54]

Soybean oil Acid/base

[Bmim][NTf2 ]

98

[55]

Fatty acid

Brønsted acid

[NMP][CH3 SO3 ]

H2 SO4 /K2 CO3 70 ∘ C, 8 h

95.3

[56]

Rapeseed oil

Brønsted acid

[Bmim][BF4 ]

72 h

60

[57]

Triolein

Novozym 435

[Bmim][PF6 ]

48 ∘ C 50 ∘ C, 96 h

72

[58]

98

[59]

93.3

[60]

Miglyol 812 Novozym 435

[Me(OEt)3 -Et3 N] [OAc]

Olive

Novozym 435

[C16 mim][NTf2 ]

Sunflower

Novozym 435

[C16 mim][NTf2 ]

60 ∘ C, 24 h 60 ∘ C, 24 h

92.78

[60]

Cooking waste

Novozym 435

[C16 mim][NTf2 ]

60 ∘ C, 24 h

96.91

[60]

Palm oil

KOH

[Bmim][HSO4]

98.4

[61]

Soybean

[HBSSB][HSO4] [HBSSB][HSO4]

1% KOH, 50 min 60 ∘ C, 5 h

91.9

[62]

Sunflower

[HBSSB][HSO4] [HBSSB][HSO4]

60 ∘ C, 5 h

93.3

[63]

Corn oil

Penicillium [Bmim][PF6 ] expansum lipase

40 ∘ C, 20 h

86

[64]

using Brønsted acid catalysts at temperatures below 200 ∘ C, which resulted in the formation of an 11.6% molar yield of the dealkylation product 2-methoxyphenol from 2-methoxy-4-(2-propenyl) phenol and cleaved 2-phenylethyl phenyl ether from lignin ethers [66]. Lignin model compound guaiacylglycerol-beta-guaiacyl ether was investigated in a series of organic bases of various basicity and structures to determine the cleavage of the beta-O-4 bond using 1-butyl-2,3-dimethylimidazolium chloride as a solvent. The results showed that out of all the tested nitrogenous bases, 1,5,7-triazabicyclo[4.4.0]dec-5-ene was the most active compound, having 40% of O-4 ether bond cleavage, which may be due to the higher accessibility of the N atoms [67]. Two lignin model compounds, guaiacylglycerol-beta-guaiacyl ether, and veratrylglycerol-beta-guaiacyl ether are degraded by different ILs, such as 1-methylimidazolium cation with chloride, bromide, hydrogensulfate, and tetrafluoroborate counterions along with 1-butyl-3-methylimidazolium hydrogensulfate. The reactivity of the model compounds in ILs is related to acidity as well as nature of the ions and their interactions [67]. Guaiacylglycerol-guaiacyl ether (GG) with interunit linkage of lignin can be converted to glycerol type enol-ether (EE), 3-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-2-propenol under heat treatment at 120 ∘ C in ILs medium. Nuclear magnetic resonance (NMR) results showed that GG conversion process progresses stereospecifically and Z-isomer

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is formed as predominant product [53]. Recently, the catalytic conversion of lignin in ILs and its structural modification by oxidation catalyzed with metal salts in ILs have been investigated [53]. Alcell and soda lignin were dissolved in 1-ethyl-3-methylimidazolium diethylphosphate [Emim][DEP], and it was oxidized using several transition-metal catalysts and molecular oxygen in mild conditions. CoCl2 in [Emim] [DEP] is highly effective for the oxidation of benzyl and other alcohol functionalities in lignin. However, phenols and phenylcoumaran is left out as evident from attenuated total reflection with infrared (ATR-IR) spectroscopy [68]. ILs are found to be highly useful solvents for biomass dissolution and catalytic conversion [69]. Different valuable organic compounds can be synthesized using various catalysts in ILs medium. Various valuable organic compounds such as furfural derivatives, levulinic acid, esters, sugars, alcohols, and long-chain alkyl glycosides are studied. Ignatyev and coworkers found that a combination of the heterogeneous catalysts Rh/C and Pt/C in Lewis acid BF3 ⋅ Et2 O at 20 ∘ C under 2 MPa hydrogen gas is efficient for the hydrogenation of 1, 1-diethoxycyclohexane to ethoxycyclohexane [70]. A 43% sorbitol yield was obtained from cellulose by replacing the heterogeneous catalysts with homogeneous catalyst precursor [HRuCl (CO) (PPh3 )3 ] under optimized conditions. Zhu et al. reported that ILs with boronic acid functionality are capable of reversibly binding cellulose and stabilizing transition-metal nanoparticles which help in the breakdown of crystalline cellulose [71]. Hence, it improved the solubility and catalytic activity. A 15% conversion of cellulose hydrogenation to hexitols was achieved using Ru nanocluster catalyst in [Bmim][Cl]. Its yield can be increased up to 93% in specifically designed ILs. A 95% glucose yield was obtained from cellulose in ILs at 80 ∘ C under a time period of 5 h with catalytic activity remaining efficient up to five cycles. Long-chain alkyl glycoside compounds possess excellent surfactant properties, low toxicity, and good biodegradability, which make them useful in cosmetics, detergents, food emulsifiers, and pharmaceutical dispersing agents [72]. Cellulose could be converted to various alcohols such as butanol, hexanol, and octanol by varied surfactant concentrations in acid resin catalyst. Removal of water from the system reduced the reaction pressure and the glycosidation formation. Levulinic acid and levulinic-acid esters are two important bioderived organic compounds that can act as precursor for the production of biodiesel [73]. Saravanamurugan and coworkers reported different sulfonic acid functionalized IL (SO3 H-ILs) catalysts transform fructose, glucose, and sucrose to ethyl levulinate in the presence of ethanol as solvent and reactant [74]. Different catalysts such as acidic resins, Y-type zeolites, Fe-pillared montmorillonite suffer from various demerits such as low yields, low selectivity, and low thermal stability. On the other hand, the acidic ILs have high thermal stability, catalytic activity, and good reusability. For all these reactions, fructose is converted to ethyl levulinate with yields of 68%, 70%, and 74%, using the ILs, 1-methyl-3-(4-sulfobutyl)imidazolium hydrogensulfate ([Bmim-SO3 H][HSO4 ]), 1-(4-sulfobutyl)pyridinium hydrogensulfate ([BPyr-SO3 H][HSO4 ]), and N,N,N-triethyl-4-sulfobutan-ammonium hydrogensulfate ([NEt3 BSO3 H][HSO4 ]) respectively. Higher yield of ethyl levulinate (77%) is obtained with ILs based on the [NTf2 ] anion in comparison to other ILs indicating that reaction progression is directly related to the acid strength of the ILs [74].

15.5 Production of Biodiesel with Ionic Liquids

15.5 Production of Biodiesel with Ionic Liquids Biodiesels are basically monoalkyl esters of long-chain fatty acids derived from renewable feedstocks such as vegetable oils and animal fats. The biodiesel is produced by the chemical and biological reactions of oil or fat with monohydric alcohol in the presence of an acid or base catalysts and lipases, as shown in Figure 15.3 [75]. ILs possess different special properties such as tunability and nondetectable vapor point which makes them better than traditional organic solvents. Their properties can be tuned for specific reactions by adding cation, anion, or both acids based on its purpose to be used in biodiesel synthesis [76]. The most common use of ILs for biodiesel synthesis is to carry out transesterification reactions under multiphase acidic and basic conditions, such as K2 CO3 , NaOH, hydroxide salts of ammonium cations, sodium methoxide, lithium diisopropylamide, and H2 SO4 in ILs [55]. After the end of the reaction, ILs can be extracted from the biodiesel system and recycled for further use. The miscible ILs in biodiesel and glycerol can also be extracted while purifying the biodiesel by the traditional process [77]. However, the chemical stability of ILs needs to be considered for this purpose under the drastic acidic or basic condition. For example, the tetrafluroborate and hexaflurorophosphate-based ILs should not be used during the decomposition of cellulose due to the formation of HF during the reaction [54]. The modified ILs can be synthesized by surface functionalization of acidic functional groups of either the cation or anion, or adding a Lewis-acid catalyst in ILs. The ILs behave as solvents or catalysts and provides a simple and effective pathway for the biodiesel synthesis with high yields and purities depending on catalysts used (Table 15.2). ILs can also act as good solvents for catalytic conversion of biomass to biodiesel. In comparison to acids/bases catalytic processes, the enzyme-catalyzed process is highly safer and low corrosive in nature [56]. Different lipase-based ILs have been widely used for biodiesel synthesis [55, 57, 78, 79]. For example, Pseudomonas cepacia lipase and Candida antarctica lipase were successfully immobilized in different structural ILs for the methanolysis of soybean oil. From this work, it is evident that O

H 2C

O

O R1

C

HC

O

C

H2C

O

O

R2

RO

+ 3ROH Alcohol

R1

O

+ RO

C

+

R3

C

C

+

Catalysts

OH

HC

OH

H2C

OH

R2

O

Glycerol

O RO

Triglyceride

Figure 15.3

H2C

C

R3

Ester

Transesterification of triglycerides to biodiesel in the presence of catalysts.

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use of ILs can resolve the problems of low stability of enzymes and decreased enzyme activity, which are observed in the case of traditional organic solvents. In addition, biodiesel production reaction can be carried out at room temperature as well as IL-enzyme catalytic system can be extracted and used four times without losing the catalytic activity. Zhao group synthesized a new type of ether-functionalized ILs with anion of acetate or formate, which was found to be capable of dissolving oils at 50 ∘ C with methanol concentration of 50%v/v) [59]. On carrying out the catalytic reaction in presence of alkylammonium ILs, Miglyol oil yield was found to be very high in mixtures of ILs and methanol (70/30, v/v). The transesterification reaction of soybean oil in ILs/methanol mixtures confirms the oil-dissolving and lipase-stabilizing ILs for efficient production of biodiesels.

15.6 Toxicity and Ecotoxicity of ILs for Biorefinery There are some toxicity and ecotoxicity of ILs that were used for production of biodiesel. The discussion is based on some existing toxicity data. During modeling of the ILs, the toxicity data will help to avoid poor selection while choosing an IL for study. The research on nontoxic ILs and the biodegradable ILs are different. However, it is an intrinsically linked problem to the researchers. To determine nontoxic ILs, it is impossible to test nontoxicity to organism in the planet. One can only test the low or the high toxicity to the organism. A particular compound could have high toxicity to a particular type of organism. But we could not estimate the toxicity without knowing the experimental data. In this situation, we can take the help of modeling and extrapolation from a known data to estimate the best result about the toxicity of a particular compound. The biodegradation partially solves the problems of toxicity to the ILs. If an IL trends toward rapid biodegradation, then the issue of toxicity gets lifted. Regarding designing or modeling any biodegradable ILs, researchers have to overcome two challenges. First, the compound should rapidly breakdown to the environment. Second, the compound should fit to the purpose in biorefinery for production of biodiesel. But, these two principles are not mutually exclusive. In this regard, the researchers have to focus on the effects of metabolites. It is followed by the bioaccumulation process. The shortfall in screening the toxicity results due to the reporting of the tested values of toxicity in simplified form. A compound can be tested less toxic or highly toxic to a particular organism. A particular IL or organic compound affect different organisms with different levels of toxicity. However, the compound under study could convert to a toxic compound undergoing some chemical or biochemical changes. So, it is impossible to test toxicity of every compound with every organism under consideration. To make it possible, we need to analyze and identify the complex mixture of compounds for every test of toxicity. But, it is not possible. However, with the help of green chemistry it will be possible to reduce the toxicity limit of a desired compound. Moreover, ILs are best described as green solvent due to their lower vapor pressure than the conventional medium of reaction [80]. As green solvents, ILs should satisfy the requirements of

15.6 Toxicity and Ecotoxicity of ILs for Biorefinery

being neither persisting in the environment nor releasing toxic materials into the environment. In the absence of this study on toxicity and biodegradation of ILs, there is no parameter to estimate the effect on the environment. It is also quite possible that ILs leach to the groundwater from the surface. To estimate this effect, we need computer modeling and experimental data. ILs are considered as lower risk to the environment than the other volatile organic compounds (VOCs). Nowadays, the researchers have also undertaken the role or the effect of ILs on the aquatic life as well as on the terrestrial life. A detailed study of toxicity and hazardous nature of ILs was conducted by Jastorff and coworkers in 2002 [81]. After that, the research increased in the field of ILs in large-scale industrial applications. Since then, the attention of the researchers has been shifted to the potential risk of contamination of environment by the ILs through effluent release or accidental spills. Alkyl-methylimidazolium, ammonium, and pyridinium are commonly used cations that have been studied in various systems on the basis of different levels of biological parameters to estimate the environmental risk of ILs [82]. Phosphonium cation-based ILs have also been studied by the researchers, which show little biodegradability [83].

15.6.1 Toxicity of ILs Used in Biorefinery In spite of having many researches in the field of ILs in biorefinery, a few numbers of toxicity data are available. Some researchers have studied 25 types of ILs from a paper of R. D. Roger and published a review article [84–86]. But out of 25 ILs, only 11 have toxicity data. Majority of the ILs do not have the toxicity or ecotoxicity data. One needs to study a wide range of parameters to assess the toxicity of an IL. It includes toxicity to different levels of biological systems such as enzymes, bacteria, algae, rat cells, human cells, and invertebrates. From the above discussions it became clear that there is a lack of toxicity data for ILs that have been used for the biorefinery purpose. However, studies are underway to estimate the toxicity or ecotoxicity of a IL.

15.6.2 Biodegradation of ILs Used in Biorefinery In the case of biodegradable ILs, the abovementioned 25 numbers of ILs are reviewed by two researchers and reported the biodegradability of 5 ILs. Out of which four ILs are not biodegradable and one IL is biodegradable inherently [87, 88]. The remaining 20 ILs have no reported data regarding biodegradability. Here, we have seen that biodegradability limit is very low among the studied ILs. But, what we have seen is not the real problem. The real problem is the limited research that is going on regarding the biodegradability of ILs. In biodegradation tests, we should remember that when one compound shows a positive test result, it means that it is biodegradable compound. However, for a particular compound, a single negative test result does not signify it as a nonbiodegradable compound. It signifies more and detailed study needed to that compound in case of biodegradability to the environment. After a detailed study, one should come to conclusions regarding biodegradability of a particular compound. After successful

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completion of the biodegradability test, if a compound or an IL passes the test, then the IL should be promoted as the potential candidate for the purpose of biodiesel production in a biorefinery. Bioaccumulation process is also the parameter of toxicity and ecotoxicity studies of ILs. Introduction of safer and greener ILs leads to the development of green chemistry. According to the green chemistry, the cost of ILs should be low and it should be of low toxicity and biodegradable. If the desired IL along with the required solvent could be made from renewable raw materials in a sustainable manner, then it can improve the entire process which includes nontoxic and biodegradable ILs [84].

15.6.3 Conclusion Regarding Toxicity and Biodegradation of ILs A wide range of researches have been carried out to analyze the toxicity impact of ILs in the environment. The study reveals that the structure of ILs play an important role in the environmental impact. The cationic parts of IL are more responsible for toxicity compared with the anionic parts. The alkyl chain attached to the IL is also very much responsible for the environmental toxicity in comparison to the shorter part. The introduction of polar group to the side chain reduces toxicity of ILs significantly. The study regarding the toxicity of ILs progress significantly. However, the exact reason behind toxicity is not defined clearly. There are some common industrial chemicals such as cationic surfactants that are toxic to the environment. The main reason behind the toxicity is due to the lipophilic alkyl chain. The integration of this lipophilic alkyl chain to the cellular membrane leads to the disruption of the cell membrane [89, 90]. The structure of the cationic surfactant is similar to the structure of ILs. Hence, the lipophilic long alkyl chain integrates into the cell membrane, leading to toxicity [91, 92]. The study shows that the anionic part of IL could also be toxic to the environment. However, this effect is insignificant with respect to the alkyl side chain present on the ILs [93]. The best findings for the researcher are to develop or design IL structure with no toxicity along with biodegradable properties. There are some ILs that are closer to the above condition. Some of the examples are choline and betaine as cation and tartrate, citrate, malate, and saccharinate as the anionic parts. From the study, it is revealed that the acidity or the basicity of such ILs restricts their wide application due to their hydrophilic character. This problem can be overcome by the development of imidazolium and its pyridinium analogues. It can be the potential candidate for ILs in the near future. The researchers have studied the toxicological effect of ILs such as imidazolium and pyridinium on a range of aquatic organisms and some higher plants and animals. However, enough studies have been published regarding the toxicity of ILs, but the toxicity data of ILs toward humans are not so much validated. Until the toxicity data of ILs are validated regarding human exposure, it is difficult to take the risk to expose humans to the ILs [94]. So, it is the responsibility of the researchers in the field of environmental science or chemical science to reduce the toxicity and enhance the sustainability and biodegradability of different synthesized compounds or ILs for the utilization of human welfare.

References

15.7 Conclusions Biorenewable resources are recognized as the suitable source for production of different sustainable organic compounds, which can be further transformed to green fuels or biofuels. There is a structural difference between biomass and petroleum-based materials, which leads to different issues such as hydrolysis, dehydration, and hydrogenation reaction of carbohydrates. In this regard, these need to be addressed properly to produce sustainable organic compounds from biomass. The ability of ILs to dissolve biomass is an advantage for converting them to suitable materials that can be used for biodiesel production. Different organic compounds have been produced from biomass, including cellulose composite, cellulose fiber for textile industry, levulinic acid, HMF, levulinic acid esters from carbohydrates, and biodiesel in the presence of ILs. However, there is not enough significant progress in the desired area to fulfill the current demand for biodiesel. In this chapter, we have discussed the overview of ILs in conversion of biomass to various suitable and sustainable organic compounds in the perspective of biorefinery or biofuels. In addition, the toxicity and ecotoxicity of ILs have been discussed broadly, along with biodegradation-related issues. Here, the toxicity or the biodegradation issues are discussed on the basis of the literature, which carried out the research with the help of different organic compounds. It is the major challenge for the researchers in this field to minimize the toxicity and to enhance the biodegradability factor of the organic compounds or ILs, for better utilization for the development of human welfare.

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16 Ionic Liquids for Atmospheric CO2 Capture: A Techno-Economic Assessment Kumar Abhisek 1 , Helen T. Mathew 1 , Shashikant S. Vhatkar 1 , Dipti S. Srivastava 1 , Rahul Minz 1 , and Ramesh Oraon 1,2 1 Central University of Jharkhand, Department of Metallurgical and Materials Engineering, Brambe, Ranchi, Jharkhand 835205, India 2 Department of Chemistry, Central University of Jharkhand, Cheri-Manatu, Ranchi, Jharkhand, 835222, India

16.1 Introduction Carbon dioxide (CO2 ) is one of the major factors in the evolution of life on earth. As a greenhouse gas, it adsorbs heat radiated from the earth’s surface, which in turn helps in maintaining the optimum temperature for the existence of life on our planet [1]. According to recent data, the average concentration of CO2 in the atmosphere has reached 417 ppm globally [2]. Photosynthetic organisms utilize CO2 from the surroundings in the dark cycle of photosynthesis and produce sucrose, starch, and amino acids as the end products of the reaction [3–5]. Since, CO2 is an inflammable gas, it is also used in fire extinguishers [6]. As an abundant and benign material, it can potentially replace toxic chemicals that are used as refrigerants as well as precursors for needful chemicals such as urea, methanol, and methane, along with some pharmaceutical chemicals [7–9]. Although CO2 plays an important role in our lives, according to the National Institute for Occupational Safety and Health (NIOSH) guide for hazardous chemicals, only 5000 ppm of CO2 is the maximum tolerable exposure limit for humans [10]. The overall CO2 fixation mechanism in plant leaves is well described by Zeeman et al. [11]. pH of the blood is mainly regulated by the CO2 -biocarbonate buffer solution, which is controlled by the partial pressure of CO2 in the air [12, 13]. Deviation from the optimum concentration may cause severe chronic diseases and may lead to the death of the individual [14]. The excess CO2 level in the atmosphere also causes harmful impacts on the environment, for instance, global climatic change and ocean acidification. According to the World Meteorological Organization (WMO) report, it has been estimated that there will be at least a 3–5 ∘ C increase in the global temperature by 2100, and it has also declared that 2019 was the second warmest year on record [15]. Looking upon to these concerns, it has been added to the Sustainable Development Goals (SDG) under “climatic action” [16]. Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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There has been a rapid growth in the human population in the last few decades, which ultimately increases the demand for land, food, and energy [17, 18]. To fulfill this growing energy demand, carbon and its derivatives are mainly used as energy sources in the form of fossil fuels. However, the combustion of these substances results in the generation of CO2 [19, 20]. According to the report of “Global Carbon budget 2021,” it has been estimated that at the end of 2021, around 36.4 gigaton of CO2 will be released into the atmosphere due to the burning of fossil fuels [16]. Except for power industries, some other anthropogenic sources like cement industries, automobiles, burning of solid waste, and biological materials are also contributing to CO2 emissions [21, 22]. According to the National Energy Technology Laboratory, volcanic eruption, respiration, forest fire, and decomposition of organic matter serve as natural sources of CO2 emissions [23]. Mainly forests and oceans act as natural sinks of CO2 [24]. On an average, 25% of the total CO2 emission is found to be captured by oceans [25]. Moreover, forests alone sink 1.5 times more CO2 than that released by the United States, which is about 7.6 billion metric tons of CO2 per year [26, 27]. Furthermore, ornamental plant species like Epipremnum aureum, Spathiphyllum wallisii, and Dieffenbachia sp. accumulate CO2 and help in improve the indoor air quality [28, 29]. Apart from forest fires, agricultural expansion, colonialism, industrialism, and population growth are some of the natural and anthropogenic causes responsible for deforestation, causing the climatic change to worsen [30]. The environmental impacts of CO2 emissions can be mitigated by limiting the energy utilization, promoting the use of renewable energy sources, afforestation, or by CO2 capturing [21, 31–34]. Solar, tide, wind, geothermal energy, and biodiesel are some emerging sources of renewable energy that are an alternative source of energy to fossil fuels [35]. However, heavy initial investment, weather dependency for energy production, and requirement of huge land areas for installation are some of the obstacles in the way of energy production from the renewable sources [36, 37]. So, CO2 capture (CC) can be an emerging alternative to achieve net carbon zero emissions [38]. There are several methods, such as membrane separation/permeation, cryogenic distillation, absorption, and adsorption, that are being extensively used or have been reported [39]. These methods are usually used to separate and CO2 from the flue gases [40]. Cost-effectiveness of adsorption-based methods makes them a preferable choice for commercial purposes of CC [41]. Several materials have been developed and are being studied for CC based on the phenomenon adsorption. One of such adsorbents is aqueous solution of amines. Researchers from the University of Kentucky Center for Applied Energy Research studied post-combustion CC using monoethanolamine (MEA) as a baseline solvent. They have also found that the presence of metals like iron and copper affects the efficiency of adsorption [42, 43]. Among several adsorption-based materials, ionic liquids (ILs) become the first choice over other materials, as they have high thermal stability, nonvolatility, noncorrosiveness, nonflammability, and high selectivity toward the adsorption of CO2 at high temperatures as well as at room temperature [44, 45]. Due to the abovementioned benefits, ILs are being considered as green solvent for this purpose. Basically, ILs are liquids of fused salts containing only ions [46]. It has been found that, under a wide range of temperature and pressure, the solubility of CO2 in ILs is

16.2 Different Processes of CO2 Capture

comparatively higher than that of other organic solvents [47]. In ILs, due to the lack of symmetry among the ions, they behave as polar solvents, which enhances their CC ability [48]. ILs not only capture CO2 , but also help in the conversion of it into some useful chemicals like methanoic acid (HCOOH) [49, 50]. Solubility as well as the adsorption capacity of CO2 in ILs also depends on the nature of the anionic groups in them. ILs containing fluorinated alkyl groups provide better solubility, while ILs having an acetate anion provide better adsorption capacity than others [51, 52]. At different stages of combustion, the amount of CO2 released is found to be different, so based on the structural configuration, a suitable IL needs to be chosen. For example, in post-combustion process, the CO2 released has a low partial pressure, so the solubility of CO2 is found to be reduced even with the best conventional ILs [53]. So, task-specific ILs have been developed to mitigate these limitations via structural modifications [54]. From the above context, it is clear that the design of the ILs plays a major role in developing an efficient CC system. So, herein, a comparative study among different materials used for CC and ILs is presented, along with the recent trends in the development of ILs and CC, and their mechanisms of action will be discussed in detail.

16.2 Different Processes of CO2 Capture CC techniques are being employed mainly in three processes. They are pre-combustion, post-combustion, and oxyfuel combustion, and each of them involves different techniques for the capturing purpose [40]. In the pre-combustion process, carbon monoxide (CO) and hydrogen gas are produced as a result of the combustion of the gasified coal. The CO so formed is then converted to CO2 using water shift conversion. In the end, CO2 is separated from hydrogen and captured. In the post-combustion process, CO2 is separated from the fuel gas that resulted from the combustion of the fuel using air as an oxidant. In the oxyfuel combustion process, the fuel gas is produced as a result of combustion of the fuel using oxygen as an oxidant. The fuel gas formed by this method mostly contains steam and CO2 . We are also utilizing natural gas as a fuel in many fields. Although it is considered one of the cleanest fuels, still it contains CO2 or H2 S as a contaminant. The contaminant’s level is relatively higher in the case of gases like sour gas, which decreases its fuel value. So, Bates and coworkers developed an IL that has the ability to selectively sequester and transport 0.5 mol of CO2 per mole of IL [55] . The predicted mechanism is as follows: 2

N

N

– NH2 BF4 + CO2

Δ O

O N

N

H3N NH

N

N

2BF4–

As industries persist as the major contributors of CO2 pollution, researchers are mainly focusing on the CC at various stages. These include pre-combustion stage,

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post-combustion stage, and oxycombustion stage. The overall approach of CC is the same in every stage but has some technological differences depending on the form of carbon. In the precombustion process, first CO, which is formed from the combustion of fuels, is converted to CO2 and then captured by various of methods. These methods are mainly involved in membrane separation, cryogenic separation, adsorption, and absorption.

16.2.1 Membrane Separation In membrane separation method, a membrane made up of metal organic framework (MOF) or polymer, or ILs, is used for the separation and capture of CO2 from the sifted syngas, produced by gasification of fuels. The sifted syngas may contain CO2 and H2 . When it is allowed to pass through the membrane, a steam of pure hydrogen gas is produced by the decarbonization of syngas. The H2 gas so produced can be utilized for power generation. The Pt and Pd alloy-based high-temperature metallic membranes show excellent sensitivity to the adsorption of all gases. Which brings about 99.99% purity of in the case of H2 . But Chiesa et al. found that for power plants, the membrane efficiency drops by 4–6% [56]. This process also has some limitations, like poor mechanical and chemical stability. As precious metals are involved in this process, this method is not cost-effective. Microporous ceramic membranes are one of the promising alternatives for this application, as they show high chemical resistance as well as low cost. Franz et al. studied their application in plants and found that the efficiency decreased by 9% [57]. Nowadays, polymeric membranes are gaining interest of the scientific communities. Polybenzimidazole (PBI)-based polymeric membranes are mostly investigated nowadays due to their excellent mechanical, physical, and chemical stability. It has been found that PBI can show its best performance up to 600–630 ∘ C and also have a glass transition at around 450 ∘ C [58, 59]. Low permeability and brittleness of the membrane are major disadvantages of this membrane [60]. Javier et al. synthesized an asymmetric defect-free PBI membrane, which was able to capture 20.3 GPU of H2 and showed H2 /CO2 selectivity of 35.6 GPU even under harsh conditions, i.e. at 250 ∘ C temperature and 6 bar pressure [61]. Indira and coworkers have developed a PBI hollow fiber membranes ,which is selectively able to capture 90% of CO2 and recovered approximately 99% of H2 from the syngas. They have also found that the efficiency of the membrane increases with increase in the temperature of the system. But, under offset conditions, the CC drops to 7% [62]. Wu et al. developed a highly efficient polymer membrane with a tunable supramolecular cavity that was able to capture CO2 in the precombustion stage. They have synthesized a nanocomposite membrane using soluble organic macrocyclic cavitands with a tunable cavity size, which provides excellent processibility to the polymer [63]. Chung et al. developed a supramolecular polymer network membrane by immersing prefabricated PBI in a methanolic solution of 4-sulfocalixarane, which increases the permeability as well as selectivity toward H2 and CO2 separation [64]. Shan et al. developed a porous organic framework membrane using PBI supported over porous α-Al2 O3 and β-Al2 O3 . They have found

16.2 Different Processes of CO2 Capture

that at 1 bar transmembrane pressure difference, the membrane shows selectivity to H2 /CO2 around 40 GPU and H2 permeance of 24 GPU [65]. Having, unique properties of excellent physical, chemical, and thermal stability, ILs have potentially being utilized in the membrane separation methods. Various simulation-based models are being proposed, which help in optimization of the designing and ultimately targeting to optimize the operational cost [66]. Based on CO2 material balance and resistance in the series model, Usman et al. have developed a one-dimensional mathematical model. This model was developed for predicting mass transfer of CO2 and CO2 adsorption by a tubular membrane contractor made up of IL 1-butyl-3-methylimidazolium tricyanomethanide. They have found that the concentration of CO2 in the syngas as well as the pressure of the feed gas are the important factors that affect the CC rather than the operational temperature, i.e. with an increase in the concentration of CO2 as well as the feed gas pressure, the concentration gradient at the membrane interface increases, which in turn increases the efficiency of the membrane for CC. They have also predicted that with an increase in flow rate of the gas, CC increases due to a decrease in the thickness of the gas–liquid boundary layer [67]. Some of the studies focus on the CC ability of the IL coupled with hollow fiber membrane contractors. Zhongde and coworkers conducted a comparative study on the effects of ILs, i.e. 1-butyl-3-methylimidazolium tricyanomethanide as the absorbent on six different polymeric membranes on CC. They found Teflon-PP composite membrane as a suitable material for CC [68]. Sohaib et al. developed a membrane by coupling hollow fiber membrane contactors with IL 1-ethyl-3-methylimidazolium ethylsulfate for CC using 2D modeling. They have predicted that with an increase in the porosity and length of the module membrane, the CC will increase. While, a decrease in the separation efficiency can be observed by increasing the glass flow rate, tortuosity, and inner diameter of the membrane [69]. Despite having a number of advantages like membrane compactness, excellent selectivity, and superior flexibility for gas/liquid flow velocity [70], membrane separation techniques lag with some operational issues like fouling of the membrane and low flux production. The framework of the membranes also provides some resistance to the CC [71].

16.2.2 Cryogenic Separation Membrane separation methods are unable to capture CO2 from the flue gas completely. The retentate in general comprises random gases, ranging up to 10%. These random gases include H2 O, H2 , CH4 , and CO. [72]. This can be overcome by the cryogenic separation. The cryogenic separation refers to the low-temperature CC techniques in which 99.99% of CO2 is separated from the flue gas using various desublimation and condensation techniques [73]. Atsonios and coworkers developed a model with the help of AspenplusTM , which can help in cryogenic separation of CO2 in the pre-combustion stage. It also helps in predicting the factors that are influencing the CC. They studied the model based on two cryogenic systems, i.e. Fast separation with internal cooling, which is able to generate electricity along with

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high separation efficiency, whereas in the second process the highly pure CO2 stream is produced at the cost of high power consumption [74]. Aizad and coworkers also developed a simulation-based plant design using Aspen HYSYS software version 8.8, which targets cryogenic CC along with the production of methanol using captured CO2 in the pre-combustion stage. According to their model, around 50 000 tons of methanol can be produced per year by hydrogenation of CO2 . This target can be achieved when the air flow is maintained at 3 × 109 tons per year [75]. Apart from these types of modeling-based techniques, there are several other methods through which cryogenic CC can be done. These include cryogenic bed [76], external cooling loop cryogenic CC [77], antisublimation [70], cryogenic distillation [78], control freezing zone [79], cryocell process [80], and Stirling cooling system [81]. The role of ILs in cryogenic separation is found to be negligible.

16.2.3 Absorption According to IUPAC, absorption refers to a physical or a chemical process by which one substance (absorbent) is retained (absorbed) on another substance (absorbent) [82]. In this process, generally solvents like alkanolamine, aqua ammonia, potassium carbonate, and ILs are used, which capture CO2 within them. The absorption of CO2 can be done through two methods: (i) physical absorption and (ii) chemical absorption. The methods of absorption mainly depend on the condition of the emitted gas [83]. 16.2.3.1 Chemical Absorption

In chemical absorption methods, a chemical reaction occurs between the solvent and CO2 , which results in the formation of a carbonate salt and helps in CC. Amine-based solvents like MEA, diethanolamine (DEA), methyldiethanolamine (MDEA), and piperazine (PZ), and potassium carbonate (K2 CO3 ), sulfolane, and ILs are some of the widely investigated solvents of CC. Since 1950s, amine-based solvents have been extensively used for the CC and are considered as one of most developed technologies for H2 S and CO2 removal [84]. Aqueous amine-based solvents form a carbonate salt of amine during CC. Among several amine-based solvents, MEA is one of the preferred solvents used in CC as it provides faster rate of reaction as compared to others [85]. Hamid and coworkers did the simulation as well as experimental modeling to study the CC ability of MEA. The simulation was run to study the effect of various operating variables, such as temperature and pressure, on the partial pressure and gas loading on the capturing of CO2 in a gas capturing dynamic pilot plant. Whereas the experimental setup utilizes a packed column contactor containing MEA that absorbs CO2 that comes through a countercurrent process. Less than 0.5 mol% of CO2 has been reported in the product gas [86]. Similarly, some researchers developed another model based on a generalized Patel–Teja–Valderrama equation to study the effect of the density of MEA on the CC. They have found that at 25% weight of aqueous amine solution density, the system shows better result, and the Patel–Teja–Valderrama equation is found to show minimum deviation as compared

16.2 Different Processes of CO2 Capture

to other models [87]. After adsorption, desorption of CO2 is an important step for reusability of materials, but it is found to be challenging for an amine-based solvent. To address this, many catalysts like V2 O5 , MoO3 , WO3 , TiO2 , and Cr2 O3 were developed but they do not provide much efficiency [88]. Gao and coworkers developed a composite catalyst for the first time based on SO4 2− /ZrO2 /SBA-15, which increases the desorption factor 100–200% and drops the energy consumption by 20–25% [89]. Even though MEA is a preferable choice it is still dealing with some difficulties, like not meeting its theoretical CC capacity. i.e. 1 mol of CO2 per mole of MEA. It was always preferred to operate under 0.5 mol of CO2 per mole of MEA, at higher concentration of MEA. This prevents the system from corrosion [90, 91]. Han and coworkers tried to resolve this using 2-amino-2-methyl-1-propanol as a solvent for the same purpose. They have found that the used solvent provides an enhanced CC as compared to the MEA [85]. Despite having many advantages, it is dealing with operational difficulties such as corrosion of the equipment, low energy efficiency, and solvent degradation [92]. The solvent degradation generally occurs in three ways: carbamate polymerization, thermal degradation, and oxidative degradation. Carbamate polymerization occurs when MEA reacts with CO2 at elevated temperatures. Thermal degradation of MEA has been observed at elevated temperatures, i.e. >250 ∘ C, whereas oxidative degradation occurs when MEA reacts with O2 , which is present in the flue gas, and forms NH3 and some organic compounds like carboxylic acid [93]. The MEA degradation mechanisms are given in Figures 16.1 and 16.2. Potassium carbonate is also one of the absorbents that has gained the attention of the scientific community for CC through chemical absorption. Mainly industries like power plants, crude hydrogen, and natural gas treatment have been reported to use K2 CO3 as a chemical absorbent for CC [84]. The advantages like high CO2 solubility, a cheaper price, low toxicity, and high stability to degradation make it a preferable choice for CC [95–97]. In these processes, the natural gas stream containing CO2 is allowed to pass from the top of the absorption column containing the K2 CO3 solvent [95, 98]. As the CO2 content in the stream is low, the system is made to operate under high pressure, i.e. 3000–6000 kPa, for effective transfer of CO2 from the natural gas stream to the absorbent solution [99–101]. High pressure not only favors the absorption of CO2 by maintaining the required partial pressure but also helps in the desorption of CO2 by marinating high temperature for desorption without the loss of excess solvents [102]. High temperatures also increase the solubility of CO2 in K2 CO3 as well as prevent the condensation of hydrocarbons [103]. The chemical reactions involved in this process are described below, as given by [98, 104, 105]. CO2 + H2 O + K2 CO3 ⇌ 2KHCO3 (non-ionic form) − CO2 + H2 O + CO2− 3 ⇌ 2HCO3 (ionic form)

At pH >8 2H2 O ⇌ HO+3 + OH− CO2 + OH− ⇌ HCO−3 HCO−3 + OH− ⇌ CO2− 3 + H2 O

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Vinyl alcohol

MEA

Methanamine

Acetaldehyde

Formic acid

2-Aminoacetaldehyde

Acetic acid

Glycine

Glycolic acid

Glyoxalic acid Oxalic acid

Figure 16.1 Oxidative degradation mechanism of MEA, as proposed by Rooney et al. [94]. Source: Rooney et al. [94] / CHERIC.

At pH 8, it has been found that CO2 reacts with the hydroxide ion rather than with water to produce carbonate. But the major drawback of this process is the slow rate of the reaction. This can be overturned by using promoters like MEA, tetraethylenepentamine, and boric acid. [106]. Feng and coworkers used cyclohexane as a promoter, which increases the absorption of CO2 from 26% to 56% [107]. Sulfolane is another widely and extensively investigated solvent used for CC. According to NIH, “Sulfolane are the colourless industrial solvent miscible in aqueous or hydrocarbon medium and are belongs the class of tetrahydrothiophenes in which the sulphur group is oxidised to Sulfolane” [108]. Wagaarachchige and coworkers prepared a solvent by mixing an amine-based solvent, sulfolane, and methanol in the ratio of 1 : 0.3 : 1.1 for CC [109]. They have also synthesized a low-viscosity solvent by blending amine, methanol, and sulfolane. The CC occurs through this solution via the formation of monomethyl carbonate and carbamate

16.2 Different Processes of CO2 Capture

N-(2-Hydroxyethyl)formamide

Formic acid

N-(2-Hydroxyethyl)acetamide

Acetic acid

2-Hydroxy-N-(2-hydroxyethyl)acetamide

Glyceric acid

MEA

Oxalic acid 2-((2-Hydroxyethyl)amino)-2-oxoacetic acid

Propanoic acid

N1, N2-bis(2Hydroxyethyl)oxalamide

N-(2-Hydroxyethyl)propionamide

Butyric acid N-(2-Hydroxyethyl)butyramide

Lactic acid

Malonic acid

2-Hydroxy-N-(2-hydroxyethyl)propanamide

1,5-Bis((2hydroxyethyl)amino)pentane-2,4dione

Bis(2-hydroxyethyl)glycine 2-(Bis(2-hydroxyethyl)amino)-N-(2-hydroxyethyl)acetamide

Figure 16.2 Reaction between MEA and its acidic degradation product, as proposed by Ling et al. [92]. Source: Ling et al. [94] / with Permission of Elsevier.

anion. An advantage with the monomethyl carbamate is its low viscosity, which helps in thermal decomposition of blending solution at low temperatures, which makes the CO2 desorption process easier [110]. Nozaeim and coworkers performed a comparative study on aqueous solutions of N,N-diethylethanolamine (DEEA), N-methyl-diethanolamine (MDEA), and a mixture of both with sulfolane (hybrid solution). The have found that the hybrid solution containing DEEA shows higher absorption rate and better solubility than those of its aqueous solution. It also found that the rate of desorption of hybrid solution is comparatively higher than that of the aqueous solution [111]. Sulfolane is found to contaminate domestic wells, and ground and surface water [112]. Moreover, they are found to be toxic

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as well as carcinogenic when they exceed the exposure limit, and they also have a corrosive nature [113, 114]. Among several solvents that are used for chemical absorption, ILs are found to be the most suitable choice. The CC is found to be enhanced especially when functionalized ILs are being used [115–117]. The properties of the ILs such as and enthalpy of reaction during CC can be enhanced either by structural modification or by reducing the solvent viscosity after CO2 absorption. This in turns increases the CC through chemical adsorption [118]. Imidazolium ILs with carboxylate moieties are thought to be the settlers and most extensively studied materials for CC, and especially [Bmim][Ac] has drawn the attention of the scientific community the most [119–122]. The results from both experimental as well as computational works indicate that CO2 undergoes chemical adsorption with ILs in the 1 : 2 stoichiometry. In the process of chemical adsorption, the CO2 reacts with the cationic part of the ILs, resulting in the CO2 capture [121, 123]. Low heat formation, low thermal stability, high solvent viscosity are some of the disadvantages of this solvent [124–127]. Moreover, one of the major disadvantages of [Bmim][Ac] is solvent regeneration, which makes its reaction with CO2 irreversible [123, 128]. To resolve this, nowadays ILs are encapsulated with various polymeric materials [129, 130] or supported with some materials, which helps in improvement of the reaction kinetics of the system [131–133]. Nowadays, co-solvents like TGM and dimethyl ether of propylene glycol are used along with the ILs, which enhances the reactivity of the conventional ILs [134, 135]. Nowadays, researchers are focused on the sustainable development of ILs form the amino the amino acids. In this aspect, Davarpanah and coworkers developed four task-specific biobased ILs with choline moiety and studied their CC process. They have found that these biobased ILs are cost-effective, cause no harm to the environment, have high regenerability, and possess an excellent ability to separate CO2 from the flue gas. They have also found that the issue of high viscosity and production cost can be resolved by using DMSO as the solvent for ILs [136]. Its structure and reaction mechanisms are represented in Figure 16.3. Based on density functional theory (DFT) calculation, researchers have predicted the mechanism of

[Cho][Ala] CO2

Carbamate

[Cho][Ser]

[Cho][Pro]

[Cho][Gly]

Ammonium

CO2

Carbamic acid

Figure 16.3 Structure of choline-based ILs and their CO2 absorption mechanism developed by Davarpanah et al. [136]. Source: Davarpanah et al. [136] / John Wiley & Sons.

16.2 Different Processes of CO2 Capture

CO2 [P1111][Gly]

Pre-complex

[P1111][GCO]

Figure 16.4 CO2 absorption mechanism of [P1111 ][Gly] by Shaikh et al. [137]. Source: Shaikh et al. [137] / with Permission of Elsevier.

CC by the amino acid-based ILs, tetramethylphosphonium glycinate ([P1111 ][Gly]) and tetrabutylphosphonium glycinate [P4444 ][Gly]. The results indicate that CO2 reacts with the glycinate to form a zwitterionic intermediate which undergoes intermolecular hydrogen transfer to from the final product. From the molecular dynamic study it has been found that the presence of water leads to an increase in the density of ILs and also decreases the rate of reaction by affecting the cation–anion interaction [137]. The predicted mechanism is represented in Figure 16.4. Zhai and Rubin studied the post-combustion CC by trihexyl-(tetradecyl)phosphonium 2-cyanopyrrolide ([P66614 ][2-CNpyr]) and found that the reaction between CO2 and the ILs is reversible and requires 3.6 GJ∕tCO2 of energy for the regeneration of the ILs [138]. To identify the factors influencing the chemical absorption of CO2 by ILs Benito and coworkers performed a simulation study using six different ILs in three different CC process, i.e. pre-combustion, post-combustion, and biogas upgradation. They identified that viscosity, enthalpy of reaction, and solubility of CO2 in the ILs are the main factors that affect the CC. Moreover, they have also found that moderate viscosity, high solubility, and heat of reaction of [P2228 ][CNPyr] with CO2 make it a promising material over other ILs [139]. To improve the CC, researchers are also focusing on the tailoring of the amino acid-based ILs. This will enhance the intermolecular hydrogen bonding, which will decrease the viscosity during CC [140]. Some researchers developed [bmim][Tf2 N] which not only separates H2 S and CO2 from the syngas but also helps in CC and reduces the cost by limiting the energy consumption [141]. Metal-based ILs have also drawn significant attention from the scientific community due to their low viscosity and high CO2 absorption ability [142, 143]. Li et al. studied the CO2 absorption by four different metal-based ILs, namely [ZnCl4 ]2− , [CuCl4 ]2− , [CrCl4 ]− , and [FeCl4 ]− , and found that the smaller the size of the anion, the higher is the CC tendency, so [FeCl4 ]− has the highest CC capability [144]. High solvent viscosity, high production cost, and high power consumption are some of the drawbacks of the chemical absorption process for CC [145]. 16.2.3.2 Physical Absorption

Physical absorption is one of the CC techniques that draws significant attention of the scientific community. Unlike chemical absorption, here the CO2 vapors are impregnated into the solvent through weak intermolecular interactions [146]. The extent of absorption depends on the solubility of the CO2 in the sorbent and is governed by Henry’s law which states that at a particular temperature the amount of gas dissolved per unit volume of the solvent varies directly with the change in

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partial pressure of the gas which is in equilibrium with the solvent [145]. This can be expressed as P 𝛼 X (at constant temperature) P = KH X PCO2 = KH XCO2 where P = partial pressure of the solute; PCO2 = partial pressure of CO2 ; X = amount of solute dissolved per unit volume of the solvent; XCO2 = amount of CO2 dissolved per unit volume of the solvent; and K H = Henry’s constant From Henry’s law, it is clear that pressure plays a role in the solubility of CO2 in a given solvent, so physical absorption process works efficiently in the IGCC plants, where the pressure of CO2 in the syngas is relatively high [147, 148]. Low temperatures and high pressures favor the solubility of CO2 in the physical absorption process. While solvent regeneration can be achieved either by lowering the pressure or by increasing the temperature [145], low operational cost, high selectivity, and use of nondegradable solvents and non-corrosive solvents are a few operational advantages that make physical absorption a preferable choice over other CC techniques [149–151]. Especially, physical solvents are found to be suitable for use in the IGCC power plants where the CO2 is released from the plant with high pressure in the precombustion CC [152]. Various solvents, like Selexol, Rectisol, Fluor, Purisol, and Sulfinol, including ILs, are extensively used for the CC through physical absorption methods [153]. Selexol is a physical solvent that is made up of dimethyl ether of polyethylene glycol and is used during the Selexol process [154]. This solvent was first developed by Union Carbide [155]. This solvent was found to work efficiently under high pressures, low temperatures, and high acidic gas conditions, and is used for the selective absorption of gases like CO2 , H2 S, and mercaptans from both natural as well as synthetic gas streams [153]. Various simulation-based studies are carried out to determine the best operating conditions for Selexol process for CC. It has been found that by changing the operational conditions, the CC efficiency can vary from 75% to 90% [156]. With an increase in the power generation of the IGCC plant, the CC is found to be decreasing [157, 158]. Using the dual-stage Selexol process, the CC efficiency can be enhanced to 95% [159]. The cost estimation for the Selexol process was predicted on the basis of the Billet and Schultes correlation, the Hanley and Chen correlation, and Bravo’s model. According to Bravo’s model, it has been estimated that with a decrease in the absorber height, the flow rate of the lean solvent increases in order to achieve the CO2 recovery rate. Based on the Billet and Schultes correlation, it has been estimated that the lowest cost for CO2 absorption is about 26.66$2018 /t of CO2 when the packing height of the absorber is 7 m. Using the Hanley and Chen correlation, it has been found that when the mass transfer was much

16.2 Different Processes of CO2 Capture

H2S

Purified gas

CO2

T1

T2

T4

T5

Feed gas

H2O

T1-Absorption tower: T2-Desorption tower: T4-Heat regeneration tower: T5-Methanol–water separation tower

Figure 16.5 et al. [161].

Flow diagram of the Rectisol wash process. Source: Adapted from Sun

lower, to maintain the flow rate, the height of the absorber needed to be increased, and the lowest cost was found to be 30.84$2018 when the absorber height was 22 m. And it has been found that 89% of the operational cost is used to maintain the CO2 at high pressure [160]. The Rectisol process is a physical-solvent-based CC technique used for the removal of acidic gases such as CO2 , H2 S, and COS. In this process, methanol is being used as the solvent for the removal of acidic gases because at low temperatures acidic gases are highly soluble in methanol [161]. The Rectisol process is highly efficient compared to other physical absorption-based processes such as Selexol and Purisol, as it provides high selectivity and utilizes low-cost solvents [162–164]. Yang et al. developed a CC model that is able to capture 96.8% of the CO2 and also avoid the dilution of the CO2 in the tailing gas. Another major advantage of this model is that it is highly energy efficient than others [165]. Results from the quantitative evaluation of Park’s two-stage pre-combustion CC techniques indicate that the Rectisol process is found to be more economically viable than the Selexol and Purisol processes due to low solvent loss and small plant dimensions [166]. But very high refrigeration cost and chances of amalgam formation at low temperatures are a few operational difficulties of this process [153]. A flow diagram of the Rectisol wash process is represented in Figure 16.5. 16.2.3.3 Ionic Liquids for Physical Absorption of CO2

ILs are best known for their physicochemical properties, such as high thermal stability, low volatility, and easily tunable properties [167]. As conventional ILs are

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not efficient in the physical absorption of CO2 , various functional modifications have been adopted to achieve the target [167]. Hazifi and coworkers developed a tricationic IL and studied its CC ability at low temperatures. They have found that the total CO2 intake increases with increases in the concentration of the aqueous solution of the synthesized ILs due to an increase in the number of CO2 capturing functional groups per molecule [167]. Akbari et al. developed an amine-functionalized novel ILs that can uptake CO2 even at low pressures [168]. A comparative simulation-based study among various physical solvents will help in deciding the best solvent for CO2 removal through physical absorption processes. Taheri and coworkers conducted a comparative study between Rectisol and two ] [ newly developed ILs ([EMIM] [Tf2 N] and [EMIM] BF−4 ). This was the first time practically developed ILs were subjected to a simulation study. The results from this study indicate that the use of ILs reduces the energy consumption as compares to the conventional solvents. But the cost of the solvent is 4.4 times that of the Rectisol. In addition to this, IL systems require a large vacuum compressor for solvent regeneration. Which further increases the energy consumption as well as the cost of the operation [169]. Kinetic and the thermodynamics are the key factors responsible for CC by ILs. To optimize the efficiency of ILs, various simulation-based studies are being carried out. So, a multiscale simulation-based study was conducted by Palomer et al. to demonstrate the key role of kinetics over thermodynamics in the selection of ILs for CC through physical absorption. They have considered 50 ILs among which 10 ILs are selected as representative ILs based on their favorable transfer properties and solubility of CO2 in them. The results indicate that the physical absorption of CC is a kinetically controlled process rather than a thermodynamically controlled process. And also, due to the favorable mass transfer and low molecular weight of these ILs, the operational costs, such as solvent cost, energy requirements, and equipment cost, can be minimized [170]. Although CC by the ILs through physical absorption provides enhanced solubility and excellent selectivity toward CO2 , issues like maintaining the high-pressure conditions for absorption and the high-cost solvent limit their application at the pilot or industrial scale [167, 169].

16.2.4 Adsorption Adsorption is the process through which components of the mixture are segregated with the help of a solid surface. Unlike absorption, this process is a surface phenomenon [171]. If the interaction of the surface with the adsorbed materials occurs through weak van der Waal’s force of attraction, it is termed physical adsorption, while if the interaction occurs through the formation of chemical bonds, it is called chemical adsorption [172]. Various materials, such as metal oxides, carbon nanotubes, MOFs, organic calixarene, zeolites, silica materials, and ILs, are being studied for CC through adsorption mechanism [172–174]. Over these ILs, and their composite-based materials have gained the attention of the scientific community due to their unique properties. Due to high solubility of CO2 in amino-acid-functionalized ILs, researchers are developing such types of

16.2 Different Processes of CO2 Capture

materials [175]. Shahrom et al. developed 8 amino-acid-based poly (ionic liquids), among which ILs with the maximum number of amino groups show highest tendency for CC [174]. Functionalized ILs or supported ILs have shown enhanced CC ability, so different composite materials have been adopted for them. When ILs are supported over silica materials derived from rice husks, the CC efficiency of the material decreases, but the desorption efficiency is found to be enhanced. This provides a low-cost method for the enhancement of desorption properties of ILs [176]. Composite materials of ILs with an imidazolate framework (ZIF-8) provide excellent selectivity toward CO2 capture. Presence of certain fluorinated hydrophobic groups, such as [BF4 ]− , [PF6 ]− , and [Tf2 N]− , in the composite material also provides them with a better CC tendency [177]. The study reveals that although the CC tendency of the composite material decreases as compared to pristine ZIF-8, but the selectivity was increased up to 2.2 and 4 times for CO2 /CH4 and CO2 /N2 , respectively [178]. Monto Carlo and molecular dynamic simulation study reveals that the presence of ILs like [EMIM]+ [SCN]− incorporation with MOF increases the selective adsorption of CO2 to the MOF [179].

16.2.5 Ionic Liquids as a Catalyst for Chemical Fixation of CO2 In the late eighteenth century and early nineteenth century, researchers were fascinated by studies on the catalytic activity of metals and oxides [180]. Due to their efficiency, metals and their compounds are extensively used as catalysts in various chemical reactions, including chemical fixation of CO2 [181, 182]. But the drawbacks, like high material costs and incomplete recovery of catalytic materials from the final product, urged researchers to find novel ways to develop metal-free catalysts [183]. ILs are one such novel innovation that are being investigated as a catalyst as well as a co-catalyst to convert CO2 into various useful chemicals. Dia and coworkers developed microporous polymer-grafted TBD-based ILs for the catalytic addition of CO2 into epoxide through cycloaddition process. Among various developed catalysts, the catalysts with carboxyl-functionalized ILs have the highest efficiency over others due to the formation of H-bond between —COOH and the epoxide group, which facilitate the nucleophilic attack by halides for facile ring opening of the epoxide [184]. The catalytic cycle of the functionalized ILs is represented in Figure 16.6. Similarly, Hernández et al. demonstrated that CO2 can be volarized to propylene carbonate using IL as a catalyst [185]. Quinazoline-2,4(1H,3H)-diones, a highly bioactive compound [186], can be easily synthesized from CO2 and 2-aminobenzonitrile under ambient temperature condition with the help of an IL, [BMIM][Ac]. The researchers also found that up to five catalytic cycles, there was a significant loss in the catalytic activity of [BMIM][Ac] [187]. Qiu and coworkers found that chemical fixation of CO2 to α-alkylidene cyclic carbonate using DBU-based ILs. Especially, maximum yield was obtained with [DBUH][MIm] and the cationic and anionic groups present in the ILs play key roles in this CO2 fixation process [183]. Similarly, other useful chemicals such as methanol and acetic acid can be synthesized from CO2 with the help of ILs [188–191].

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(I) (III)

(II)

Figure 16.6 Possible mechanism for the cycloaddition of CO2 with epoxides catalyzed by PS–[CETBD]Br. Source: Adapted from Dai et al. [184].

Rudnev et al. studied factors affecting catalytic properties of ILs using three different ILs through electroreduction process using different electrode materials. They have found that the nature of the cationic group in ILs and electrode materials are the two key factors responsible for CO2 redox reaction [192]. ILs are found to be an emerging material to catalyze various reactions without compromising the yield. They are also being used as solvents as well as catalysts without significant loss in catalytic activity. This helps in minimizing the reaction cost, and provides a sustainable route for the chemical fixation of CO2 .

16.3 Conclusion CO2 plays an important role in the exitance of life on our planet. But some natural and anthropogenic sources are responsible for the increase in CO2 content in the atmosphere, leading to harmful effects like global warming, ocean acidification, and glacier melting. So, CO2 capture can be an alternative to minimize the abovementioned consequences caused by increased CO2 levels in the atmosphere. Among various materials for CC, ILs are one of the emerging materials. This chapter has focused on a comparative study among various materials used for CC and the ILs in different CC processes. We have also included an economical assessment of a few materials with ILs. In the case of the membrane-based processes, PBI, metals and alloys, MOFs, and ILs are being used for CC. High-temperature metal- and alloy-based membranes

References

provide excellent selectivity toward CO2 capture, but are not cost-effective due to the use of metals like Pt and Pd. PBI membranes are also being used for this purpose due to their high physical and chemical strength, but low permeability is a disadvantage of this process. Similarly, the use of microporous ceramic membranes for CC is found to be cost-effective, but when it is used in large-scale plants, membrane efficiency is found to be decreased. IL-based membrane are found to be effective materials for CC when used alone or with composite materials. But membrane fouling and clouting of the membrane are the disadvantages of this process. Cryochemical method is one of the well-developed processes for CC. But it is not cost-effective, and ILs were found to have no role in this. CC through absorption process is a well-established technology. The CC is done through two mechanisms: either chemical absorption or physical absorption. IL shows high efficiency (around 90%) and high selectivity toward CO2 by absorption. Chemical absorption of CO2 is more effective than physical absorption. But a huge amount of energy is used during the solvent regeneration process for chemical absorption. Compared to the chemical absorption, the physical absorption process is cost-effective. But on comparing ILs with different solvents, which are being used for this process, the cost of ILs is found to be around 4.4 times higher than that of other solvents like methanol. According to an estimation, for ILs, it requires US$ 222 MM of direct capital, whereas for Rectisol only US$ 50 MM of the direct capital is required. Similar cases were observed for physical absorption [169]. Chemical fixation of CO2 to useful chemicals using ILs as a catalyst has also opened an innovative approach toward sustainably handling the carbon footprint. The biggest advantages of the ILs are their tunable properties and their physicochemical nature, which make them an emerging material for the better future. But due to the lack of large-scale production, the material cost is not economically viable, which is the biggest obstacle to their industrial- or pilot-scale application. The conventional ILs do not fit good in all the different processes for CC. So, with the help of retrosynthetic analysis, if desired ILs can be synthesized using cost-effective chemicals, then the issue of industrial-level applications can be resolved.

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17 Recovery of Biobutanol Using Ionic Liquids Kalyani Motghare 1 , Diwakar Shende 1 , Dharam Pal 2 , and Kailas L. Wasewar 1 1 Visvesvaraya National Institute of Technology (VNIT), Advance Separation and Analytical Laboratory (ASAL), Department of Chemical Engineering, South Ambazari Road, Nagpur, MS 440010, India 2 National Institute of Technology, Department of Chemical Engineering, Great Eastern Road, Raipur, India

17.1 Introduction 17.1.1 Biofuel A biofuel is a sustainable alternative to petroleum-based fuels in today’s rapidly degrading environment because of its adaptability to existing transportation technology and, more importantly, its sustainability, and in order to reduce the effects of greenhouse gas emissions. The low price of fossil fuels slowed the development of biofuels until the 1950s, when they were considered an alternative fuel for transportation. A revival of interest in the commercial production of biofuels for transportation took place in the mid-1970s. The increased production of biofuels worldwide followed over the last decade, with impressive government policies encouraging it. Currently, biofuels supply about 3% of the total fuel required for road transportation globally, with much higher percentages in certain countries [1].

17.1.2 Classification of Biofuels The use of biofuels in transportation is a source of renewable energy that can be obtained by either using them directly as fuel or blending them with conventional fossil fuels. Biofuels can be classified on the basis of feedstock and production process. Classification of biofuels based on feedstock is given in Figure 17.1. 17.1.2.1 First Generation

A conventional, well-established process produces biofuels in this category. Most of these products are made from sugars, grains, or seeds, utilizing only a specific portion (often edible) of the plant’s aboveground biomass. Many of these are produced using relatively simple processes [2]. One of the most well-known first-generation biofuels is ethanol, which is created by fermenting sugars extracted from starch-containing crops such as sugarcane, sugar beet, and corn. The process of making butanol is similar, using a different microbe for fermentation. Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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1st Generation Biodiesel Vegetable oil Bioethanol

4th Generation

2nd Generation

Bio-butanol

Dimethyl Ether

Biofuels

Bio-hydrogen Bio-methane

Fischer-tropsch Diesel Cellulosic Ethanol

3rd Generation Algae based biofuels Butanol, Propanol, Ethanol

Figure 17.1

17.1.2.2

Classification of biofuels based on feedstock.

Second Generation

Typically, lignocellulosic biomass is used to make biofuels in this category. This category is defined by the [2] as either nonedible residues of food crop production (e.g. corn stalks or rice husks) or nonedible whole plant biomass (e.g. grasses and trees grown specifically for energy). Biofuels can be manufactured from feedstock grown on marginal arable lands and/or from nonfood crops and residues [3]. Among these products, ethanol is the most common, but its production is not yet competitive [4]. As of today, academia and industry tend to focus on these two generations of biofuels. There are inherent limitations to first- and second-generation biofuels, making them unsuitable for long-term use as an alternative to petroleum. There are many reasons for this, including the use of food-based materials, the scarcity of cropland and fresh water, fertilizer use, seasonality, and the rise in population [5]. Furthermore, these fuels cannot be used in quantities greater than small blends of fuels without modification of engines, and they have no application in Jet fuel (another large transportation fuel segment) [5, 6]. To fill this gap, researchers are investigating advanced biofuels. 17.1.2.3

Third Generation

Utilizing nonarable land, integrated technologies generate a feedstock (such as vegetables) and a fuel (or fuel precursor, such as pure vegetable oil). The second-generation fuels are similar to these, but they use a lot fewer resources to generate the feedstock [7]. It is being extensively researched to reduce production costs and improve the metabolic production of fuels [6]. 17.1.2.4

Fourth Generation

A biofuel made from nonarable land is included in this category. In order to produce these fuels, biomass does not have to be destroyed. To directly convert solar energy into fuel, it uses cheap, abundant, and inexhaustible resources. Solar fuels made by

17.3 Butanol Production

photobiology and electro fuels are considered the most advanced biofuels currently being investigated by [6].

17.2 Biobutanol: First-Generation Biofuels A four-carbon alcohol produced through the fermentation of biomass is biobutanol. Due to its long hydrocarbon chain, it is nonpolar. It is possible to produce biobutanol in ethanol production facilities, but in an anaerobic environment. Internal combustion engines use biobutanol as a fuel due to its similar properties like gasoline. Compared to gasoline, biobutanol is capable of reducing carbon emissions by 85%, thus making it a viable alternative fuel to gasoline and gasoline–ethanol blends.

17.3 Butanol Production Butanol (butyl alcohol) can be produced by biochemical and petrochemical pathways. In the petrochemical sector, two of the methods are oxy-synthesis and aldol condensation [8]. Propylene is chemically reacted with carbon monoxide and hydrogen to form n-butanol. It is necessary to hydrogenate a mixture of n-butyraldehyde and iso-butyraldehyde to produce n-butanol and isobutyl alcohols. According to Park et al. [9], Jones developed a bacterial fermentation process to produce butanol in 1913 [10]. Butanol is traditionally produced by anaerobic fermentation, the anaerobic conversion of carbohydrates using Clostridium strains to acetone, butanol, and ethanol, which is a biochemical route to produce biobutanol [11]. However, since butanol produced by Acetone-Butanol-Ethanol process could not compete on a commercial scale with the butanol produced synthetically, due to problems associated with low yields and slow fermentations, almost all ABE production ceased as the petrochemical industry grew. 1-Butanol (or just butanol) is a straight-chain, 4-carbon alcohol that has the chemical formula C4 H9 OH. It is a highly useful industrial chemical, which can be used to dissolve paints, dyes, varnishes, and coatings. It is also used as a precursor or intermediate in the chemical synthesis of plastics and chemicals, including hydraulic fluids and safety glass [12]. Additionally, butanol has desirable fuel properties [13]. Table 17.1 summarizes the properties of butanol over other fuels.

17.3.1 Butanol Production via Biochemical Conversion Butanol production via biochemical conversion occurs through acetone–butanol– ethanol process. It is characterized by two phases in the anaerobic fermentation of Clostridium acetobutylicum [17–20] or Clostridium beijerinckii. It involves two phases, such as acidogenic and solventogenic phases. Phase I begins with sugars being converted into acetic and butyric acids, causing the pH level of the culture to decrease. Acidogenic fermentation is the first phase of fermentation. During the second phase, known as the “solventogenic phase,” sugars and some acids are converted

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17 Recovery of Biobutanol Using Ionic Liquids

Table 17.1

Comparison of butanol with other fuels [13–16].

Fuels

Chemical structure

Carbon Density ratio (%) (g l−1 )

Energy content (lower heating value, MJ kg−1 )

RON

MON

Gasoline

C8 H18

86.3

744.7

32.4

91–99

81–89

Biobutanol CH2 CH2 CH2 CH2 OH

64.69

809.7

27.8

96

78

Bioethanol CH2 CH2 OH

52.2

789.3

21.3

129

102

Fatty acid methyl (or 77.6 ethyl) esters (FAMEs)

887.9

33.3

—

—

Biodiesel

Glucose

Lactate

Pyruvate

is

H2

nes

is

to g e

nes

2CO2

Ethanol

Acetyl-CoAa

S o lv

e n to

to g e

Acetate

Ac e

336

Butyryl-CoA

Acetoacetyl -CoA

Acetone CO2

Butyrate

Figure 17.2

Butanol

Butanol production via biochemical conversion.

to solvents, such as acetone, butanol, and ethanol, accompanied by an increase in pH. Sometimes, an excess of acids is produced before the microbes are able to switch to the solventogenic phase. This is known as an “acid crash.” The acetic and butyric acids produced in higher quantities during ABE fermentation are the result of an acid crash during this fermentation process [21]. The ABE fermentation process uses Clostridium bacteria that produce acetone–butanol–ethanol in a ratio of 3 : 6 : 1 for the production of biobutanol [22–24]. Butanol production via biochemical conversion is shown in Figure 17.2.

17.3.2

Butanol Production via Petrochemical Conversion

Petrochemical routes include oxy-synthesis [8] and aldol condensation. The process involves the chemical reaction between propylene and carbon monoxide. Various catalysts may be used such as rhodium or cobalt. Hydrogenation would then be used to create n-butanol and isobutyl alcohols from the mixture of n-butyraldehyde and isobutyraldehyde. The first bacterial fermentation for the production of butanol was developed by Jones in 1913 [25]. Butanol production via petrochemical conversion is shown in Figure 17.3.

17.4 Butanol Recovery

Figure 17.3 Butanol production via petrochemical conversion.

CH3

H C H

C

CH3-CH = CH2

H

Propylene H2 + CO

Rh or Co catalyst

N-Butanol H2

Ni catalyst

n-Butanol

17.4 Butanol Recovery Unlike conventional distillation, which is energy-intensive for biofuel recovery and purification due to the thin composition of fermentation broths, conventional distillation yields bioethanol with a boiling point of 78.39 ∘ C, water with a boiling point of 100.0 ∘ C, and n-butanol with a boiling point of 117.73 ∘ C. However, and as an additional consideration, both ethanol and butanol are azeotropic with water at 78.2 ∘ C and a concentration of 95.6 wt% and 92.7 ∘ C and a concentration of 57.5 wt%, respectively [26, 27]. According to Huang et al. [28], distillation is the best separation technique for ethanol concentrations between 10 and 85 wt%. Distillation is, however, very expensive close to the azeotrope. Therefore, ethanol dehydration is usually carried out in two steps: first, the ethanol is sprayed into a vacuum, followed by a heat treatment that dehydrates the ethanol. There are several butanol recovery methods, including distillation, gas stripping, adsorption, liquid–liquid extraction, perstraction, and pervaporation.

17.4.1 Butanol Recovery Techniques 17.4.1.1 Distillation

The recovery of this green biofuel from the fermentation broth can be enhanced using different separation techniques. However, the concentration of biobutanol (normally >10 g/L) [29] obtained in the fermentation broth is what will inhibit the biobutanol production. There are several different separation techniques for biobutanol separation, such as liquid–liquid extraction, adsorption, membrane solvent, gas stripping, and pervaporation, which are economically and environmentally suitable [30–33] for the separation of butanol from the fermentation broth [34]. 17.4.1.2 Liquid–Liquid Extraction

An extraction solvent, usually a water-insoluble organic extractant, is mixed with the fermentation broth in a liquid–liquid extraction process in order to remove solvents (acetone, butanol, and ethanol) from the fermentation broth. Butanol selectivity concentrates in the organic extraction phase due to its greater solubility in the organic extraction phase than in the fermentation broth. An extraction solvent,

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17 Recovery of Biobutanol Using Ionic Liquids

Feed

Retantate

Membrane

Condenser

Vacuum pump Permeate

(a)

Feed

Membrane

Retantate

Carrier gas

Permeate Condenser

(b)

Figure 17.4 Pervaporation process. (a) Pervaporation vacuum operation. (b) Carrier gas pervaporation.

usually a water-insoluble organic extractant, is added to the fermentation broth. Due to its hydrophobic character, biobutanol selectively extracts into a solvent in liquid–liquid extraction [35]. However, there are a few challenges inherent in this method of extraction [36, 37]. 17.4.1.3

Pervaporation

This method of butanol separation involves partial vaporization using a nonporous or porous membrane to separate mixtures of components from the fermentation broth. Pervaporation is also called pervaporative separation [38]. Pervaporation process using vacuum operation and a carrier gas is shown in Figure 17.4. According to Evans and Wang [39], by feeding the fed-batch fermentation process with C. acetobutylicum, butanol concentrations increased from 24.2/l to 32.8/l and 0.34/l to 0.5/l. Liu et al. [40] used a polydimethylsiloxane/ceramic composite membrane to separate butanol aqueous solution. 17.4.1.4

Gas Stripping

Butanol can be recovered using gas stripping during the fermentation of ABE. A sparger transfers CO2 and H2 from the fermentation process into a bioreactor, creating bubbles. By bubbling the gas through the fermentor, the solvents can be captured, cooled in the condenser, and then collected in the receiver. This process continues until the culture uses all the sugar in the fermentor. Various fermentation modes can be used with gas stripping, including batch, fed-batch, fluidized bed, and continuous reactors. 17.4.1.5

Perstraction

This is a method of extracting liquids from liquids and membranes from membranes, which is also known as perstraction. A liquid–liquid extraction might be improved

17.5 Ionic Liquids

Figure 17.5

Perstraction.

Phenolic solution

Agitation propeller

Membrane

Stripping solution

Stirrer

by mitigating solvent toxicity and emulsion formation after batch-fed fermentations, a problem in batch-fed fermentations. By using a membrane, this system provides dispersion-free extraction as the solvent and broth are separated by a membrane [41]. In order to calculate the overall mass transfer, we need to consider the individual mass transfer coefficients on the aqueous (fermentation broth) and extractant sides, as well as the mass transfer through the membrane [42]. An important parameter is the mass transfer across the membrane [41, 42]. Moreover, the broth and extractant flow rates may be independently controlled with the technique [42]. Figure 17.5 shows the perstraction process. 17.4.1.6 Adsorption

Adsorption is a simple technique that can be used to remove desired components from fermentation broths. Desired components are first adsorbed by the adsorbents and then desorbed by a proper method. A variety of materials can be used for butanol recovery, but hydrophobic materials are desired because of the high water concentration and low butanol and butyric acid concentrations. Silicalite and zeolite are used more often. Advantages and disadvantages of biobutanol recovery techniques are summarized in Figure 17.6.

17.5 Ionic Liquids 17.5.1 Ionic Liquids: A Brief History Ionic liquids (ILs) are the salts that were reported as early as 2500 BCE Paul von Walden investigated these in 1914, and his findings were: it was developed in the 1970s and 1980s that ILs containing alkyl-substituted imidazolium and pyridinium cations, with tetra halogenoaluminate anions, could be used to make batteries [43, 44]. Ethanol ammonium nitrate (C2 H7 NO) compound (mp: 52–55 ∘ C) was first reported in 1888 by S. Gabriel and J. Weiner.

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17 Recovery of Biobutanol Using Ionic Liquids

Cost-effective and easy to use Costliest, possible membrane fouling

Toxicity of solvent for the cells

Adsorption Cost-effective

Perstraction Membrane solvent extraction

Simple in operation, nontoxic to the microorganism

Gas stripping Low selectivity foam formation

Biobutanol recovery techniques

Pervaporati on

Rx outside fermenter, possible membrane fouling

Figure 17.6

Adsorption site competition

Liquid-liquid extraction High capacity, selectivity solvents based

Solvent toxicity to the cells, emulsion

Advantages and disadvantages of biobutanol recovery techniques.

The room-temperature organic salts known as ILs that are liquid below 100 ∘ C have garnered considerable attention as potential substitutes for volatile organic solvents. Since they are nonflammable, nonvolatile, and recyclable, they qualify as green solvents. They are considered suitable medium candidates for chemical synthesis because of their outstanding properties, such as outstanding solvating capacity [45], thermal stability [46] and their tunable properties [47]. The term “ionic liquids” usually refers to salts of ionic ions with melting points below 100 ∘ C. There are many interesting systems whose melting point is near or below room temperature. Several key scientists have discussed the history of ILs elsewhere, but it is worth recalling briefly here. Walden described in 1914 the physical properties of ethyl ammonium nitrate (mp: 12–14 ∘ C) produced by the reaction of ethylamine with concentrated nitric acid. A comparison between ILs and traditional salts is given in Figure 17.7. Based on their cationic segment, ILs can be classified into four types: 1. 2. 3. 4.

alkylammonium, dialkylimidazolium, phosphonium, and N-alkylpyridinium-based ILs.

17.5 Ionic Liquids

NaCl: m. p. 803 °C

...Imidazolium “Cl: m.p.80 °C

Traditional salts like sodium chloride pack efficiently to form a crystal lattice

Ionic liquid cations are asymmetrically substituted with different Bulky groups to weaken this ionic interactions Prevents packing of the cations/anions into a crystal lattic

Figure 17.7

Comparison between ionic liquids and traditional salts.

17.5.2 Production of Ionic Liquids In the last three decades, ILs have become more common on an industrial scale. These improvements enhance the ability to conduct IL-assisted process investigations and facilitate them on a broad scale. In addition to providing ILs as part of their existing chemical portfolio, many companies now market them as complementary products, such as Acros Organics, BASF (BasionicsTM ), Cytec Industries (part of the Solvay Group), TCI, SACHEM, and DuPont, as well as manufacturers specializing in ILs, such as IoLiTec, Proionic, Scionix, and Solvionic. In addition to their research and development efforts, many of these companies engage in their own research and development, such as IoLiTec, as detailed in the previous section. Currently, there are 500 industrial liquids available commercially on the 1 g to 10 kg scale, dozens of industrial liquids on the 10–1000 kg scale, and 10 industrial liquids in quantities greater than 1 t [48–51]. Commercial-scale industries producing ILs are shown in Figure 17.8.

17.5.3 Applications of Ionic Liquids ILs are widely used for a variety of chemical research projects because of their unique properties. Applications of ILs are summarized in Figure 17.9. There are many types of reactions that are performed using ILs as reaction solvents. ILs can be widely used in the areas of: (a) (b) (c) (d) (e) (f)

synthesis, biotechnology, separation technology, analytical applications, energy, and others.

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17 Recovery of Biobutanol Using Ionic Liquids

Figure 17.8 Commercial-scale industries producing ionic liquids. IoLiTec

Proionic

Companies producing ILs on a commercial scale

Scionix

Solvionic

Synthesis Organic synthesis, catalysis, metal organic chemistry

Biotechnology Biocatalysis, synthesis, protein purification, dissolution of biopolymers

Separation technology Membranes extractions, chromatography, extractive distillation

Applications of ionic liquids

Analytical applications Column coatings, solvents, eluents

Energy Battery electrolytes, solar and fuel cells, heat storage, nuclear fuel processing, Propellants

Others Lubricants, embalming, and tissue preservation, surfactants, metal deposition, sol–gel templates

Figure 17.9

Applications of ionic liquids.

17.6 Recovery of Biobutanol Using Ionic Liquids

17.6 Recovery of Biobutanol Using Ionic Liquids Aside from their great reactivity, ILs possess interesting chemical and physical characteristics that make them useful for separation and purification processes. Many separations and purifications are now performed using ILs. A fermentation broth can be extracted from butanol using ILs. Chemists in China studied solid–solid separations using ILs, according to Deng and Roux [52]. BMIM-PF6 has been used as a leaching agent to isolate taurine from sodium sulfate solid mixture. The IL recovery rate is 97%, making it a suitable option for a variety of applications. Study of the binary liquid–liquid equilibrium of butanol was carried out by Wu et al. [53]. According to Sahandzhieva and coworkers, liquid–liquid equilibrium was established between [bmim][PF6] and three alkanols, ethanol, 1-propanol, and 1-butanol, over a range of temperatures. Combinations of ILs and alkanol form two phases as a function of concentrations as well as the length of the chain on the alkanol [54–57]. It has been shown that by combining butanol and water at very low concentrations of butanol (5% by weight), Fadeev and Meagher have determined the solubility of 1-butyl-3-methylimidazolium ([bmim][PF6]) and 1-octyl-3-methylimidazolium hexafluorophosphate ([omim][PF6]) [58]. The ternary liquid–liquid equilibrium of 1-(2-hydroxyethyl)-3-methylimidazolium tetrafluoroborate ([C2OHmim][BF4]) and 1-(2-hydroxythyl)-2,3-dimethylimidazolium ([C2OHdmim][BF4]) with butanol and water was investigated by Hu et al. [59]. Room-temperature ionic liquids (RTILs) based on ammonium and phosphonium cations were used to investigate the partitioning of butanol. Solvents and their blends are also tested for butanol separation to study butanol extractability and toxicity of ILs [60]. Separation of butanol from aqueous streams was studied with a five-component two-phase system composed of 1-hexyl-3-methylimidazolium hexafluorophosphate ([HMIM][PF6]) and 1-butyl-3-methylimidazolium bis (tri-fluoro-methylsulfonyl) imide ([Bmim][TF2N]) [61]. For liquid–liquid extraction processes, Garcia-Chavez et al. analyzed various parameters, including distribution coefficients and selectivities, for nonfluorinated ILs for the extraction of butanol from aqueous phases [62]. The separation of butanol using a binary liquid–liquid equilibrium system with imidazolium-based IL [Bmim][PF6] has been studied [57]. Stoffers et al. found that TCB ILs can recover butanol through a continuous multistage extraction method, requiring a non-random two liquid (NRTL) model. There has been widespread exploration of ILs based on phosphonium and other forms in order to separate ILs. In addition, imidazolium-based ILs were investigated for using as extractants for the separation of methanol-n-hexane, benzene-methanol, and heptane-butanol mixtures. In addition, ILs have very interesting physical and chemical properties, making them suitable for separation and purification technologies. ILs are now being used in a number of separations and purifications. It is possible to extract butanol from the fermentation broth using ILs. Supercritical CO2 dissolved in an IL can extract the nonvolatile organic compounds. The IL recovery rate is 97%, making it an excellent option for many applications.

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Compared to other liquids, ILs have very low volatility (often greater than 200 ∘ C) [63, 64], which may facilitate easy regeneration (via low-pressure distillation) and recirculation. In addition, no toxic fumes are released. Researchers from the University of Houston used bifluoromethylsulfonyl imide ([Bmim][Tf2N]) to remove butanol in a study published in 2013. Using butanol and a variety of IL molecules, Wu et al. [53] examined binary liquid–liquid equilibrium. Also in accordance with previous studies, Bendova and Wagner [57] studied the binary equilibrium of [Bmim][PF6] and 1-butanol. The use of ILs at room temperature for liquid–liquid extraction has become increasingly popular over the last decade. In this study, hydrophobic ILs were evaluated as liquid extraction agents. Recently, ILs at room temperature have become very popular for liquid–liquid extraction. ILs with a hydrophobic nature were evaluated as liquid extraction agents in this study. The use of ILs at room temperature for liquid–liquid extraction has become increasingly popular over the last decade. The distribution ratios and selectivities of ILs differ widely depending on their properties toward butanol. Since different cations and anions have different structures, the separation performance can differ greatly [29, 62, 65–70]. The high price of ILs makes them inaccessible for extraction processes. It is most efficient to distill the mixture of extracted substances during ABE fermentation to reclaim the used-up solvent. According to Ezeji et al., acetone is the most common component of ABE, and ethanol, in its total amount, is usually no more than 10% [30, 71]. Up to 80% of the substance comprises butanol, according to Ezeji et al. [30], Qureshi and Blaschek [72]. A commercial extraction process design must consider how the thermodynamic equilibrium is affected by the composition of the feed solution and the extractant at the outset, as well as by physical parameters such as temperature or pressure. Future extraction processes could integrate extraction and distillation. A mathematical model of equilibrium may be approximated in the future using this knowledge, allowing for the integration of extraction and distillation in multistage extraction. NRTL and UNIQUAC (based on the so-called “local composition” concept) are the most common equations used to approximate liquid–liquid equilibrium (they provide estimated activity coefficients of the individual components in each liquid phase). It is often the case that NRTL equations yield more accurate results. In addition, they can also be used to model water and organic compounds, such as ILs [65, 73–80]. The separation of butanol from the aqueous phase was also performed using phosphonium-based ILs and imidazolium-based ILs [81, 82]. When the binary parameters of NRTL equations are defined in relation to the interactions among their constituents, they can only be applied.

17.7 World Butanol Demand In the biofuels application, butanol can overcome two of the problems present for ethanol, according to Informa. The refinery would no longer need to purchase

17.8 Conclusion

World butanol demand

4%

13%

Solvents

15% 6%

Plasticizers Acrylates

Total 1.3 Billion gallons

Acetate Glycol ethers

24%

All other

38%

Figure 17.10 World butanol demand (bn gallons). Source: Adapted from greenchemicalsblog.

renewable identification numbers (RINs) from independent blenders – whose prices have recently been much higher than those in previous years – as biobutanol and ethanol are blended at refineries and transported through existing pipeline systems (unlike ethanol, which is typically blended downstream at terminals). A breakthrough is the 10% ethanol (E10) blend wall, and ending the need for refiners to purchase RINs from independent blenders at inflated prices. In addition to the benefits of biobutanol as a fuel, the prospectus published by Informa Economics has listed other benefits. In terms of chemicals, biobutanol is expected to be initially used in high-value chemicals. With lower production costs, the market expands to other chemical derivatives. Globally, there are 1.3 billion gallons of biobutanol at a value of $6 billion. Figure 17.10 shows the world butanol demand in billion gallons.

17.8 Conclusion A next-generation alternative biofuel that is similar to petroleum fuel, biobutanol can be used as a replacement for conventional petroleum fuel. As the concentration of butanol in the fermentation process is toxic to microbes, an aerobic fermentation approach provides biobutanol production with few challenges. Numerous techniques are discovered for separation, including gas stripping, membrane-based adsorption separation, and improved distillation. As an alternative to volatile, toxic solvents, ILs can serve as a novel form of extractant. Due to its excellent blending properties with fewer emissions, biobutanol might be recovered by ILs in combustion systems powered by gasoline. In light of this, ILs, which have recently received some notable recognition in science and industry, may prove to be really useful for the recovery of biobutanol.

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Acknowledgments Authors acknowledge the Department of Biotechnology, Government of India, India, for the financial support under the project titled “Design and synthesis of ionic liquids for separation of biobutanol from fermentation broth to enhance.”

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30 Ezeji, T.C., Qureshi, N., and Blaschek, H.P. (2004). Acetone butanol ethanol (ABE) production from concentrated substrate: reduction in substrate inhibition by fed-batch technique and product inhibition by gas stripping. Applied Microbiology and Biotechnology 63 (6): 653–658. 31 Oudshoorn, A., van der Wielen, L.A.M., and Straathof, A.J.J. (2009). Assessment of options for selective 1-butanol recovery from aqueous solution. Industrial and Engineering Chemistry Research 48: 7325–7336. 32 Abdehagh, N., Tezel, F.H., and Thibault, J. (2014). Separation techniques in butanol production: challenges and developments. Biomass and Bioenergy 60: 222–246. 33 Kujawska, A., Kujawski, J., Bryjak, M., and Kujawski, W. (2015). ABE fermentation products recovery methods – a review. Renewable and Sustainable Energy Reviews 48: 648–661. 34 Philips, J.A. and Humphrey, A.E. (1985). Microbial production of energy: liquid fuels. In: Biotechnology and Bioprocess Engineering (ed. T.K. Ghose), 157–186. New Delhi: United India Press. 35 Qureshi, N. and Blaschek, H.P. (1999). Butanol recovery from model solution/fermentation broth by pervaporation: evaluation of membrane performance. Biomass and Bioenergy 17 (2): 175–184. 36 Ezeji, T.C., Qureshi, N., and Blaschek, H.P. (2007). Bio-production of butanol from biomass: from genes to bioreactors. Current Opinion in Biotechnology 18: 220–227. 37 Tanaka, S., Tashiro, Y., Kobayashi, G. et al. (2012). Membrane-assisted extractive butanol fermentation by Clostridium saccharoperbutylacetonicum N1-4 with 1-dodecanol as the extractant. Bioresource Technology 116: 448–452. 38 Strathmann, H. (2001). Membrane separation processes: current relevance and future opportunities. AICHE Journal 47 (5): 1077. 39 Evans, P.J. and Wang, H.Y. (1988). Enhancement of butanol formation by Clostridium acetobutylicum in the presence of decanol-oleyl alcohol mixed extractants. Applied and Environmental Microbiology 54: 1662. 40 Liu, H., Wang, G., and Zhang, J. (2013). The Promising Fuel-Biobutanol, 175–198. Gaseous and Solid Biofuels-Conversion Techniques: Liquid. 41 Groot, W.J. and Luyben, K.C.A. (1986). In situ product recovery by adsorption in the butanol/isopropanol batch fermentation. Applied Microbiology and Biotechnology 25 (1): 29–31. 42 Ranjan, A. and Moholkar, V.S. (2012). Biobutanol: science, engineering, and economics. International Journal of Energy Research 36 (3): 277–323. 43 Chum, H.L., Koch, V.R., Miller, L.L., and Osteryoung, R.A. (1975). Electrochemical scrutiny of organometallic iron complexes and hexamethylbenzene in a room temperature molten salt. Journal of the American Chemical Society 97 (11): 3264–3265. https://doi.org/10.1021/ja00844a081. 44 Wilkes, J.S., Levisky, J.A., Wilson, R.A., and Hussey, C.L. (1982). Dialkylimidazolium chloroaluminate melts: a new class of room-temperature ionic liquids for electrochemistry, spectroscopy and synthesis. Inorganic Chemistry 21 (3): 1263–1264. https://doi.org/10.1021/ic00133a078.

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59 Hu, X.S., Yu, J., and Liu, H.Z. (2006). Liquid-liquid equilibria of the system 1-(2-hydroxyethyl)-3-methylimidozolium tetrafluoroborate or 1-(2-hydroxyethyl)2,3-dimethylimidozolium tetrafluoroborate plus water plus 1-butanol at 293.15 K. Journal of Chemical and Engineering Data 51 (2): 691–695. 60 Cascon, H.R., Choudhari, S.K., Nisola, G.M. et al. (2011). Partitioning of butanol and other fermentation broth components in phosphonium and ammonium-based ionic liquids and their toxicity to solventogenic clostridia. Separation and Purification Technology 78 (2): 164–174. ´ 61 Kubiczek, A. and Kaminski, W. (2013). Ionic liquids for the extraction of n-butanol from aqueous solutions. Ecological Chemistry and Engineering A 20 (1): 77–87. 62 Garcia-Chavez, L.Y., Garsia, C.M., Schuur, B., and de Haan, A.B. (2012). Biobutanol recovery using nonfluorinated task-specific ionic liquids. Industrial & Engineering Chemistry Research 51B (24): 8293–8301. 63 Fredlake, C.P., Crosthwaite, J.M., Hert, D.G. et al. (2004). Thermophysical properties of imidazolium-based ionic liquids. Journal of Chemical & Engineering Data 49 (4): 954–964. 64 Johnson, R.B., Onwuegbuzie, A.J., and Turner, L.A. (2007). Toward a definition of mixed methods research. Journal of Mixed Methods Research 1 (2): 112–133. 65 Rabari, D. and Banerjee, T. (2013). Biobutanol and n-propanol recovery using a low density phosphonium based ionic liquid at T = 298.15 K and p = 1 atm. Fluid Phase Equilibria 355: 26–33. 66 Stoffers, M. and Górak, A. (2013). Continuous multi-stage extraction of n-butanol from aqueous solutions with 1-hexyl-3-methylimidazolium tetracyanoborate. Separation and Purification Technology 120: 415–422. ´ 67 Domanska, U. and Królikowski, M. (2012). Extraction of butan-1-ol from water with ionic liquids at T = 308.15 K. The Journal of Chemical Thermodynamics 53: 108–113. https://doi.org/10.1016/j.jct.2012.04.017. 68 Huang, H.J., Ramaswamy, S., and Liu, Y. (2014). Separation and purification of biobutanol during bioconversion of biomass. Separation and Purification Technology 132: 513–540. https://doi.org/10.1016/j.seppur.2014.06.013. 69 Simoni, L.D., Chapeaux, A., Brennecke, J.F., and Stadtherr, M.A. (2010). Extraction of biofuels and biofeedstocks from aqueous solutions using ionic liquids. Computers and Chemical Engineering 34: 1406–1412. https://doi.org/10.1016/j .compchemeng.2010.02.020. 70 Marciniak, A., Wlazło, M., and Gawkowska, J. (2016). Ternary (liquid + liquid) equilibria of {bis(trifluoromethylsulfonyl)-amide based ionic liquids + butan-1-ol + water}. The Journal of Chemical Thermodynamics 94: 96–100. https://doi.org/10 .1016/j.jct.2015.11.002. 71 Green, E.M. (2011). Fermentative production of butanol – the industrial perspective. Current Opinion in Biotechnology 22: 337–343. https://doi.org/10.1016/j .copbio.2011.02.004. 72 Qureshi, N. and Blaschek, H.P. (2006). Butanol production from agricultural biomass. In: Food Biotechnology (ed. K. Shetty, A. Pometto, G. Paliyath, and R.E. Levin), 525–551. Boca Raton: CRC Press.

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18 Bio-Carboxylic Acid Separation by Ionic Liquids Anuj Kumar, Fiona Mary Antony, Diwakar Z. Shende, and Kailas L. Wasewar Visvesvaraya National Institute of Technology (VNIT), Department of Chemical Engineering, Ambazari Road, Nagpur, India

18.1 Introduction Bio-carboxylic acids are small-chain acids, having mono aliphatic, ketonic, and dicarboxylic acid groups. These are the essential acids due to their application in various sectors like pharmaceuticals, food, agriculture, plastic, solvents, and textile. Consumption of food, medical supplies, and other necessities has risen in recent years as the world’s population and economic interdependence grow. As a result, bio-carboxylic acids are an essential component of daily living in today’s society. Various bio-carboxylic acids are lactic, levulinic, itaconic, succinic, glutaric, malic and acids, which are present in fruits, leaves, and vegetables. These acids can be produced by agricultural biomass waste, plants, fruit peels, and flowers. According to the Energy Department of the United States, bio-carboxylic acids, viz., itaconic, levulinic, and lactic acids, are listed in top 12th bio-based building block chemicals [1, 2].

18.1.1 Applications of Bio-Carboxylic Acids Many bio-carboxylic acids like itaconic, aspartic, glutaric, levulinic, and succinic acid are produced by biomass and are used in food, chemical, pharmaceutical, agricultural, and fuel industries for the production of valuable products (Figure 18.1). The various industries bio-carboxylic acids are used are as following: Pharmaceutical industries: Bio-carboxylic acids are used as raw materials to make pills, injections, capsules, antidotes, toothpaste, and vitamin A and are also used in drug delivery. Chemical industries: To prepare chemical solvents, paints, and valuable derivatives. Food industries: To make a different types of flavors and are used in cakes and pastries. They are also used as a bread-softening agent and are used in food preservation.

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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B I O C A R B O X L I C A C I D S

Figure 18.1

Succinic acid

Pharmaceutical industry

Itaconic acid

Food industry

Levulinic acid

Chemical industry

Aspartic acid

Agriculture industry

Lactic acid

Cosmetic industry

Glutaric acid

Fuel industry

Applications of bio-carboxylic acids in various sectors.

Agricultural industries: To make pesticides and fertilizers. Fuel industries: Replacing petrol/diesel and increasing the efficiency and life of an engine.

18.1.2 Market of Bio-Carboxylic Acids With the higher consumption of bio-carboxylic acids in industries, their demand increases daily. The production of bio-carboxylic acids also increases, as lactic, itaconic, aspartic, and succinic acids are produced 270 000, 41 000, 30 000, 16 000 tons per year [3–6]. The global market for levulinic acid was indicating a 4.9% compound annual growth rate during 2019–2024 [7–9]. Data Bridge Market Research shows that glutaric acid market will be grow at a 4.40% annual rate between 2021 and 2028 [1].

18.1.3 Production of Bio-Carboxylic Acids Most bio-carboxylic acids are directly produced from biomass using fermentation and chemical synthesis process at laboratory and industrial scales. The various biomass like wheat straw, rice straw, rice husk, coconut husk, and algae are used as raw materials to produce bio-carboxylic acids. Biomass has a high quantity of glucose, xylose, cellulose, lignocellulose, and hemicellulose. Bio-carboxylic acids can be made by both fermentation and chemical synthesis processes. But some challenges are there, like the char produced by synthesis process, wastewater in

18.2 Ionic Liquids

downstream waste, and generation of fermentation broth during the fermentation process of making bio-carboxylic acids. This challenge increases the price of production of bio-carboxylic acids. The chemical synthesis process is more costly and non-environmentally friendly than the fermentation process, as it need more energy and produced waste in downstream. The biological fermentation process is cheap and environmentally friendly than the synthesis process to produce bio-carboxylic acids [9]. The separation of bio-carboxylic acids from the fermentation broth is expensive and challenging due to the requirement of pretreatment process. Various separation processes have been used to recover bio-carboxylic acids from water and fermentation broth, including adsorption, chromatography [10], extraction [11–14], nanofiltration [15, 16], ion exchange [17–19], electrodialysis [20–23], crystallization [24], and adsorption [25, 26]. These processes are costly, time-consuming, and generate waste. The reactive extraction process is inexpensive, simple, ecological, and environmentally friendly due to negligible wastes in downstream. Acid molecules formed compounds with organic molecules in the organic phase during this process, and separate acid from aqueous phase. This chapter discusses the reactive extraction process using ionic liquids to separate bio-carboxylic acids. The toxicity of ionic liquids can be reduced and provide a sustainable path for the recovery of valuable acids.

18.2 Ionic Liquids The term “ionic liquid” refers to a liquid made entirely of ions, which is a solution of salt in a molecular solvent [27]. Ionic liquids are fluids composed completely of ions, which have a melting point less than 100 ∘ C. In 1914, Paul Walden published the first ionic liquid (ethyl ammonium nitrate). Still, he had no idea that ionic liquids would become a significant scientific field over a century later [28]. They represent a wide diversity of industrial applications, several physicochemical properties, and sustainable profiles. They are usually referred to as “green solvents”; nevertheless, the issues regarding their toxicity to the environment and humans are still scarce. Ionic liquids have been divided into different types based on their properties (Figure 18.2). Ionic liquids replaced the conventional solvents and were used as green solvent to separate bio-carboxylic acids. Ionic liquids have been utilized as green solvents in separation procedures to reduce the environmental impact of volatile organic compounds during the extraction process. Ionic liquids have less viscosity and higher molecular weight, which transfer more higher molecular mass from the aqueous phase to the solvent phase and provide higher bio-carboxylic acid separation efficiency. They have been utilized to separate bio-carboxylic acids with success. Therefore, ionic liquids are considered future solvents to recover valuable biochemicals from industrial and fermentation broths. Ionic liquids are used in different sectors like separation, analytics, materials, heat storage, electrolytes, solvents, tribology, and additives. Their application has made a special liquid solvent that can decrease the toxicity and environmental issues during

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Task-specific ILs Amphiphile ILs

Bio ILs

Supported ILs

Chiral ILs

Ionic liquids Deep eutectic solvent

Metal salt ILs

Switchable polarity solvents

Polarizable ILs Protic ILs

Figure 18.2

Types of ionic liquids [29] / with permission of Elsevier.

Membranes

Gas separations

Distillations

Extractions Thermal fluids

Fuel additives Heat storage

Microwave Polymerization chemistry

Separation Tribology

Lubricants Protein crystallization

Synthesis

Nanoparticle synthesis Biphasic Catalysis

Ionic liquids

Solvents

Mass spectrometry

Analytics

Gas and liquid chromatography

Supercaps Sensors

Flue cells Corrosion inhibitors

Materials

Electrolytes

Batteries Coating Solubilizes Metal finishing Dispersing agents

Figure 18.3

Thermodynamic fluids

Additives Plasticizers Liquid crystals

Compatibilizers

Applications of ionic liquids in various sectors.

18.4 Methods for Separating Bio-Carboxylic Acids

the separation of bio-carboxylic acids. The ionic liquids can be used for extraction, protein crystallization, liquid crystal, batteries, thermal fluids, and dispersing agents. (Figure 18.3). The maximum application of ionic liquids is in electrolytes (synthesis, polymerization, microwave chemistry, nanoparticle synthesis, biphasic, and catalysis) and solvents sector (batteries, coating, metal finishing, corrosion inhibitors, fuel cells, supercars, and sensors).

18.3 Challenges in the Separation of Bio-Carboxylic Acids The separation of bio-carboxylic acids from the waste stream and fermentation broth is challenging during the production of bio-carboxylic acids using various toxic catalysts like H2 SO4 , HCl, and HNO3 . As poisonous spurs are present in industrial and fermentation downstream materials, and the pretreatment of fermentation broth and industrial downstream is expensive. Industries use calcium hydroxide for separating bio-carboxylic acids by precipitation with calcium hydroxide, which is unfriendly to the environment because it requires large amounts of sulfuric acid and produces solid waste in the form of calcium sulfate. For the separation of bio-carboxylic acids, many methods, such as membrane adsorption and chromatography, are available, but these methods have some advantages and disadvantages (Table 18.1). Compared to all other processes, reactive extraction is a simple, easy, and intensification method for separating bio-carboxylic acids. But in the case of reactive extraction, many toxic solvents are used to recover acids, which is dangerous for the microorganisms in the fermentation broth. Some researchers have used nontoxic solvents, such as mustard, sunflower, rice bran, sesame, and canola oils, to reduce the toxicity [7, 8, 31, 32]. But they did not find sufficient extraction efficiency for the recovery of bio-carboxylic acids. Therefore, the separation of bio-carboxylic acids from fermentation broth is challenging.

18.4 Methods for Separating Bio-Carboxylic Acids Various methods are present for the separation of bio-carboxylic acids from industrial waste, fermentation broth, and water stream. They are used in chemical industries for the recovery of acids.

18.4.1 Distillation The distillation process is the most commonly used process in the chemical industries to separate mixtures of chemicals. It is based on the difference in the boiling point of the substances to be separated. It covers about 80% of chemical industries. The main advantages of this process are a simple flow sheet, low capital investment, and low risk. If the chemicals to be separated, have relatively, volatility 1.2 or high and are thermally stable, then distillation is the first choice for separation.

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Table 18.1

Available separation methods for the separation of bio-carboxylic acids [30].

Method

Advantages

Disadvantages

Evaporation

– Low capital investment, – Low-risk operation

– High energy demand

Ion-exchange adsorption

– No waste generation during production – Easy to handle and does not need costly instruments for operation – High selectivity and stability of process – Take less time to recover the product – Low running costs and energy – consumption – Good for microorganisms – Possibility of integration into a heterogeneous system – Recycled and reused of regin

– Higher waste liquor – Not suitable for long-term production at high-temperature processes – Problem with co-extraction of other compounds

Solvent extraction

– Downstream material is negligible – There is little possibility of heat degradation. – Selectivity is high – End-product inhibition is low

– Low separation of products due to stepwise evaporation and pre-extraction step – Consumption expensive solvents – Product purity is low – Possibility for intoxication in the process – Risk of co-adsorption

Membrane extraction

– The recovery processes are highly adaptable and selective – High product purity – High degree of adaptability because it is simple to scale up – Impurities are effectively removed

– Membranes prices are high – Polarization issues – Fouling problems in membrane

Distillation

– Solvents are not required – Higher efficiency and high product purity are provided

– Complex process – Complicated to scale up – Process needed specific pressure and temperature conditions with operation – Optimal process conditions have a mismatch problem – Volatility restrictions are causing issues

18.4 Methods for Separating Bio-Carboxylic Acids

The component should be thermally stable at their boiling point; this is one of the disadvantages. Significant energy saving could be done by replacing distillation with the low-intensity operation. Bio-carboxylic acids like glutaric and lactic acids were separated using the reactive distillation process. The reactive distillation column with top-bottom external recycling (RDC-TBER) was used to separate glutaric acid from two-stage cascade reacting mixtures [33]. Kim et al. [34] used two distillation columns to study lactic acid separation and discovered that 85.6% of the acid was recovered. Reactive batch distillation with two Oldershaw columns was used in this investigation to extract high-purity lactic acid.

18.4.2 Evaporation The central concept of this process is based on the nonvolatile nature of some components in the mixture and boils away the volatile part. The nonvolatile element must be thermally stable. Low capital investment, low-risk operation, and simplicity are the main advantages. It is a natural method but still has scope regarding energy saving.

18.4.3 Adsorption The accumulation of a component on a solid or liquid surface is known as adsorption. The adsorbent component is thermally or chemically recovered in a subsequent operation, and the adsorbent is reused. The adsorption method can create high-quality goods with pollutant concentrations as low as a few parts per million. They can successfully remove both low- and high-molecular-weight organics at several hundred gallons per minute flow rates. The fundamental disadvantage of fixed-bed procedures is that the concentrations of components to be removed are restricted to a few hundred parts per million. Levulinic acid was separated by the adsorption method using multi-walled carbon nanotubes (MWCNTs) as an adsorbent. Liu et al. [35] also used granular activated carbon to separate levulinic acid from formic acid.

18.4.4 Membrane Extraction A membrane separates the influent into two effluents: permeate and retentate, or concentrate. Permeate stream is the one that is separated by passing through the membrane, whereas the composition that is not passed through the membrane is called retentate or concentrate. There is no phase change that occurs in this process except pervaporation. A membrane has a thin layer (artificial or natural) that controls the selective mass movement of solvents and solutes over a border for physical separation or enrichment. Due to its selectivity and adaptability, this method could result in high-purity target products. Nanofiltration, electrodialysis microfiltration, ultrafiltration, pervaporation, and reverse osmosis are examples of membrane filtrations used for separation.

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18.4.5 Solvent Extraction This process involved two immiscible liquid phases. In this process, the solvent is introduced to remove one of the components from the mixture solution. The components are separated based on their relative solubility in the solvent. This process offers energy savings. The solvent extraction process is carried out at low to moderate temperatures near atmospheric pressure. The main disadvantage of this process is the required solvent recovery process, which is typically energy-intensive. This process is mainly used to separate the azeotropic mixtures. Reactive extraction occurs when extractants react with the solute molecules being extracted, resulting in the production of an association complex or a chemical compound. In the organic phase, the molecule is further solubilized [36]. The procedure transforms the product into other molecules, like esters, allowing it to be extracted. The various types of solvents, like phosphorus solvents, aliphatic amines, and hydrocarbon solvents, were utilized for the separation of bio-carboxylic acids from the fermentation broth. To decrease the toxicity of extractants, some authors have used conventional solvents for the separation of bio-carboxylic acids. Lactic, levulinic, aspartic, succinic, itaconic, and glutaric acids are also extracted by conventional solvents like mustard, rice bran, sunflower, and sesame oils [8, 37]. This research advocates separating bio-carboxylic acids using nontoxic solvents, critical for environmental considerations. However, when compared to chemical solvent efficiency, nontoxic solvents were less effective. As a result, the experimental data can be employed in a series of mixer-settlers to improve lactic acid separation efficiency. Meanwhile, Ionic liquid extraction is a separation method that employs chemically stable, nonvolatile, nonflammable organic salts with a lower viscosity and higher density (ionic liquid) like quaternary phosphate [38], imidazolium [39], and quaternary ammonium salts [40]. Ionic liquids based on imidazolium and phosphonium [39] are two examples of ionic liquids that work well as lactic acid extractants [38]. Polyethene glycol (PEG) and dextran are examples of two-polymer aqueous solutions; other examples include a polymer and salt (e.g. sulfate, phosphate, or citrate). The aqueous two-phase system (ATPS) has unique properties [41, 42]. The application of alcohol/salt ATPS for lactic acid extraction was reported by Aydo˘gan et al. [43]. The purification process was adjusted using a response surface approach to assess ethanol/dipotassium hydrogen phosphate consumption for the separation of lactic acid. In this investigation, more than 80% recovery of lactic acid was observed [43].

18.5 Separation of Bio-Carboxylic Acids by the Reactive Extraction Process Reactive extraction was used to remove bio-carboxylic acids from industrial waste and fermentation broths. The term “reactive extraction” refers to the

18.5 Separation of Bio-Carboxylic Acids by the Reactive Extraction Process

simultaneous solvent extraction and chemical complexation reaction. Using suitable systems (extractant and solvent) enhances separation efficiency and distribution coefficient and involves using smaller equipment. In the reactive extraction method, aliphatic amines, such as tributylamine (TBA) and trioctylamine (TOA), and phosphorus-containing compounds (organophosphorus compounds), viz., trioctylphosphine oxide (TOPO), and tributyl phosphate (TBP), are frequently used as good extractants. Some researchers used ionic solvents instead of chemical solvents to increase the extraction efficiency of bio-carboxylic acids (Table 18.2). To separate levulinic acid, six different ionic liquids were used. There are no significant differences between imidazolium, pyridinium, or sulfonium cations for levulinic acid extraction from water. Moreover, the obtained results also indicate there is no powerful impact by alkyl chain length on the extraction capability of these ionic liquids, while selectivity increases when one substituent of the cation is removed in pyridinium-based ionic liquids [44]. Pratiwi et al. [45] used several ionic liquids to extract acids, viz., L-lactic, succinic, and L-malic acids. They discovered that phosphonium-based ionic liquids are more effective than ordinary organic solvents for separating short-chain bio-carboxylic acids from aqueous streams. The maximum extraction efficiency of 89.6% was observed while separating succinic acid using phosphonium-based tetradecyltrihexylphosphonium bis (2,4,4-trimethylpentyl) phosphinate ionic liquid. The ability of ionic liquids to remove carboxylic acids was investigated by Pandey et al. [47]. The software COSMO-RS was used to screen ionic liquids and forecast their properties. They discovered that imidazolium cation-based ionic liquids have the highest selectivity. For capacity, octyl sulfate and butyl sulfate are favored, whereas bis-trifluoromethanesulfonimide is chosen for selectivity, according to the findings. COSMO-RS program calculates the extraction efficiency and distribution coefficient from the liquid–liquid equilibrium data. Sun et al. [46] used salting-out and sugaring-out extraction procedures using ionic liquid techniques to recover succinic acid from the fermentation broth. The succinic acid extractability in the ionic liquids/salts system was 45–85%, and the succinic acid (SA) concentration was a crucial component that controlled the extraction efficiency. According to the authors, their findings suggest the use of ionic liquid-based sugaring-out extraction as a good foundation for environment. These cost-effective techniques significantly reduce environmental impacts and economic concerns. According to the literature, ionic liquid solvents provide a green method for separating bio-carboxylic acids from downstream materials. Chemical solvents in the solvent process can be replaced by ionic liquids. Many researchers have been using ionic liquids as green solvents to separate various bio-carboxylic acids, viz., levulinic, glutaric, succinic, and lactic acids, and found sufficient extraction efficiency for separation.

361

Table 18.2

Separation of bio-carboxylic acids with ionic liquids through reactive extraction process.

Bio-carboxylic acids

Ionic liquids

Distribution coefficient

Extraction efficiency

References

Levulinic acid

1-Butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl) imide 1-Ethyl-2,3-dimethylimidazolium bis (trifluoromethylsulfonyl)imide 1-Ethyl-3-methylpyridinium bis(trifluoromethylsulfonyl)imide 1-Hexyl-3-methylpyridinium bis(trifluoromethylsulfonyl)imide 1-Ethylpyridinium bis(trifluoromethylsulfonyl)imide Triethylsulfonium bis(trifluoromethylsulfonyl)imide

— — — — — —

— — — — — —

[44]

Succinic acid

1-Butyl-3-methylimidazolium bromide 1-Hexy-3-methylimidazolium bromide 1-Octyl-3-methylimidazolium bromide

2.91 1.92 2.86

48.1 33.4 42.7

[45]

Tetradecyltrihexylphosphonium chloride Tetradecyltrihexylphosphonium decanoate Tetradecyltrihexylphosphonium bis(2,4,4-trimethylpentyl) phosphinate

— — —

89.5 80.8 89.6

[38]

1-Ethyl-3-methylimidazolium tetrafluoroborate 1-Butyl-3-methylimidazolium tetrafluoroborate 1-Hexy-3-methylimidazoliumbromide 1-Butyl-3-methylimidazoliumbromide 1-Butyl-3-methylimidazolium triflate

— — — — —

— — — — —

[46]

Tetradecyltrihexylphosphonium chloride Tetradecyltrihexylphosphonium decanoate Tetradecyltrihexylphosphonium bis(2,4,4-trimethylpentyl) phosphinate

— — —

61.8 65.7 83.3

[38]

1-Butyl-4-methylimidazolium bis (trifluoromethanesulfonyl) imide

0.67

76.92

[47]

Lactic acid

Glutaric acid

1-Butyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imide 1-Butyl-3-methylimidazolium hexafluorophosphate 1-Hexyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imide 1-Hexyl-3-methylimidazolium hexafluorophosphate

2.31 3.13 3.33 3.33

69.77 75.81 76.90 76.92

[48]

Itaconic acid Glycolic acid Tartaric acid Oxalic acid Propionic acid Acetic acid Acrylic acid Glyoxylic acid Nicotinic acid

1-Butyl-4-methylimidazolium bis (trifluoromethanesulfonyl) imide

1.35 0.05 0.05 0.03 1.50 1.22 2.33 1.22 2.51

87.11 20.82 20.82 11.27 88.24 85.94 92.11 85.94 92.63

[47]

L-Malic

Tetradecyltrihexyl phosphonium chloride Tetradecyltrihexyl phosphonium decanoate Tetradecyltrihexyl phosphonium bis(2,4,4-trimethylpentyl) phosphinate

_ _ _

83.8 80.0 81.5

[38]

acid

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18 Bio-Carboxylic Acid Separation by Ionic Liquids

18.6 Conclusion and Perspectives The fermentation process is the primary source of bio-carboxylic acids, producing waste products like fermentation broth. Therefore, the separation of bio-carboxylic acids from industrial waste and fermentation broth are most important due to acids’ higher demand in industries. Many processes are present to separate bio-carboxylic acids from aqueous streams, like distillation, adsorption, absorption, membrane processes, and solvent extraction. Due to higher costs and complex handling, these methods did not provide the best way for separating bio-carboxylic acids. The solvent extraction method is inexpensive, straightforward, and sustainable as it helps decrease the toxicity from downstream and separate valuable bio-carboxylic acids. But it is used with various toxic chemical solvents and extractants in the separation process. Therefore, poisonous solvents are harmful to fermentation bacteria and do not provide entirely environmentally friendly methods. Ionic liquids are the best extractants in the solvent extraction process to decrease toxicity and increase the extraction efficiency of bio-carboxylic acids. Many kinds of literatures are available to separate bio-carboxylic acids using ionic liquids from fermentation broth. According to the literature, phosphonium-based ionic liquids provided a higher distribution coefficient and separation efficiency than other ionic liquids for separating the bio-carboxylic acids from fermentation broth. Therefore, it can be used for separating valuable acids. Ionic liquids are very important in separating bio-carboxylic acids because they are considered green solvents. They have created an environmentally friendly path for separating bio-carboxylic acids from industrial waste and fermentation broth.

References 1 Kumar, A., Shende, D.Z., and Wasewar, K.L. (2021). Experimental investigation of reactive extraction of levulinic acid from aqueous solutions. Chemical and Biochemical Engineering Quarterly 35 (4): 381–390. 2 Kumar, A., Mohadikar, P., Anthony, F.M. et al. (2021). Optimization and experimental design by response surface method for reactive extraction of glutaric acid. International Journal of Chemical Reactor Engineering. 3 Alexandri, M., Schneider, R., Mehlmann, K., and Venus, J. (2019). Recent advances in D-lactic acid production from renewable resources: case studies on agro-industrial waste streams. Food Technology and Biotechnology 57 (3): 293–304. 4 Du, G., Liu, L., and Chen, J. (2015). White biotechnology for organic acids. In: Industrial Biorefineries & White Biotechnology, 409–444. Elsevier. 5 Eggeling, L. and Sahm, H. (2011). Amino Acid Production. 6 Trivedi, J., Bhonsle, A.K., and Atray, N. (2020). Processing food waste for the production of platform chemicals. In: Refining Biomass Residues for Sustainable Energy and Bioproducts, 427–448. Academic Press.

References

7 Kumar, A., Shende, D.Z., and Wasewar, K.L. (2020). Separation of levulinic acid by reaction with tri-n-butylphosphate diluted in nontoxic solvents. Journal of Chemical & Engineering Data 65 (6): 3002–3007. 8 Kumar, A., Shende, D.Z., and Wasewar, K.L. (2020). Extractive separation of levulinic acid using natural and chemical solvents. Chemical Data Collections 28: 100417. 9 Kumar, A., Shende, D.Z., and Wasewar, K.L. (2020). Production of levulinic acid: a promising building block material for pharmaceutical and food industry. Materials Today: Proceedings 29: 790–793. 10 Thang, V.H. and Novalin, S. (2008). Green biorefinery: separation of lactic acid from grass silage juice by chromatography using neutral polymeric resin. Bioresource Technology 99 (10): 4368–4379. 11 Brouwer, T., Blahusiak, M., Babic, K., and Schuur, B. (2017). Reactive extraction and recovery of levulinic acid, formic acid and furfural from aqueous solutions containing sulphuric acid. Separation and Purification Technology 185: 186–195. 12 Hano, T., Matsumoto, M., Uenoyama, S. et al. (1992). Separation of lactic acid from fermented broth by solvent extraction. Bioseparation 3: 321–321. 13 Lin, S.H., Chen, C.N., and Juang, R.S. (2006). Extraction equilibria and separation of phenylalanine and aspartic acid from water with di (2-ethylhexyl) phosphoric acid. Journal of Chemical Technology & Biotechnology: International Research in Process, Environmental & Clean Technology 81 (3): 406–412. 14 Pehlivano˘glu, N., Uslu, H., and Kirba¸slar, S.I. (2010). Extractive separation of glutaric acid by Aliquat 336 in different solvents. Journal of Chemical & Engineering Data 55 (9): 2970–2973. 15 Antczak, J., Szczygiełda, M., and Prochaska, K. (2019). Nanofiltration separation of succinic acid from post-fermentation broth: impact of process conditions and fouling analysis. Journal of Industrial and Engineering Chemistry 77: 253–261. 16 Dey, P., Linnanen, L., and Pal, P. (2012). Separation of lactic acid from fermentation broth by cross flow nanofiltration: membrane characterization and transport modelling. Desalination 288: 47–57. 17 Ataei, S.A. and Vasheghani-Farahani, E. (2008). In situ separation of lactic acid from fermentation broth using ion exchange resins. Journal of Industrial Microbiology and Biotechnology 35 (11): 1229. 18 Li, Q., Xing, J., Li, W. et al. (2009). Separation of succinic acid from fermentation broth using weak alkaline anion exchange adsorbents. Industrial & Engineering Chemistry Research 48 (7): 3595–3599. 19 Magalhães, A.I. Jr., de Carvalho, J.C., Ramírez, E.N.M. et al. (2016). Separation of itaconic acid from aqueous solution onto ion-exchange resins. Journal of Chemical & Engineering Data 61 (1): 430–437. 20 Kim, J.H., Na, J.G., Yang, J.W., and Chang, Y.K. (2013). Separation of galactose, 5-hydroxymethylfurfural and levulinic acid in acid hydrolysate of agarose by nanofiltration and electrodialysis. Bioresource Technology 140: 64–72. 21 Komáromy, P., Rózsenberszki, T., Bakonyi, P. et al. (2020). Statistical analysis on the variables affecting itaconic acid separation by bipolar membrane electrodialysis. Desalination and Water Treatment 192: 408–414.

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22 Szczygiełda, M., Antczak, J., and Prochaska, K. (2017). Separation and concentration of succinic acid from post-fermentation broth by bipolar membrane electrodialysis (EDBM). Separation and Purification Technology 181: 53–59. 23 Thang, V.H., Koschuh, W., Kulbe, K.D., and Novalin, S. (2005). Detailed investigation of an electrodialytic process during the separation of lactic acid from a complex mixture. Journal of Membrane Science 249 (1–2, 182): 173. 24 Li, Q., Wang, D., Wu, Y. et al. (2010). One step recovery of succinic acid from fermentation broths by crystallization. Separation and Purification Technology 72 (3): 294–300. 25 Datta, D. and Uslu, H. (2017). Adsorption of levulinic acid from aqueous solution by Amberlite XAD-4. Journal of Molecular Liquids 234: 330–334. 26 Sheng, Z., Tingting, B., Xuanying, C. et al. (2016). Separation of succinic acid from aqueous solution by macroporous resin adsorption. Journal of Chemical & Engineering Data 61 (2): 856–864. 27 Stark, A. and Seddon, K.R. (2000). Ionic liquids. In: Kirk-Othmer Encyclopedia of Chemical Technology. 28 Lei, Z., Chen, B., Koo, Y.M., and MacFarlane, D.R. (2017). Introduction: ionic liquids. Chemical Reviews 117 (10): 6633–6635. 29 Vekariya, R.L. (2017). A review of ionic liquids: applications towards catalytic organic transformations. Journal of Molecular Liquids 227: 44–60. 30 Din, N.A.S., Lim, S.J., Maskat, M.Y. et al. (2021). Lactic acid separation and recovery from fermentation broth by ion-exchange resin: a review. Bioresources and Bioprocessing 8 (1): 1–23. 31 Deshmukh, S.K., Punjarwar, S., and Mote, S.R. (2015). Reactive extraction of itaconic acid using natural nontoxic solvent. International Journal of Researches in Biosciences, Agriculture & Technology. 32 Harington, T. and Hossain, M.M. (2008). Extraction of lactic acid into sunflower oil and its recovery into an aqueous solution. Desalination 218 (1–3): 287–296. 33 Yao, X., Huang, K., Chen, H., and Li, S. (2013). Employing top-bottom recycled reactive distillation to the separations of adipic acid and glutaric acid esterifications. Industrial & Engineering Chemistry Research 52 (47): 16870–16879. 34 Kim, J.Y., Kim, Y.J., Hong, W.H., and Wozny, G. (2000). Recovery process of lactic acid using two distillation columns. Biotechnology and Bioprocess Engineering 5 (3): 196–201. 35 Liu, B.J., Liu, S.W., Liu, T.B., and Mao, J.W. (2012). A novel granular activated carbon adsorption method for separation of levulinic acid from formic acid. In: Advanced Materials Research, vol. 550, 1691–1695. Trans Tech Publications Ltd. 36 Antony, F.M. and Wasewar, K. (2020). Reactive extraction: a promising approach to separate protocatechuic acid. Environmental Science and Pollution Research 27 (22): 27345–27357. 37 Beg, D., Kumar, A., Shende, D., and Wasewar, K. (2022). Liquid-liquid extraction of lactic acid using nontoxic solvents. Chemical Data Collections 100823. 38 Oliveira, F.S., Araújo, J.M., Ferreira, R. et al. (2012). Extraction of L-lactic, L-malic, and succinic acids using phosphonium-based ionic liquids. Separation and Purification Technology 85: 137–146.

References

39 Lateef, H., Gooding, A., and Grimes, S. (2012). Use of 1-hexyl-3-methylimidazolium bromide ionic liquid in the recovery of lactic acid from wine. Journal of Chemical Technology & Biotechnology 87 (8): 1066–1073. 40 Kulkarni, P.S., Branco, L.C., Crespo, J.G. et al. (2007). Comparison of physicochemical properties of new ionic liquids based on imidazolium, quaternary ammonium, and guanidinium cations. Chemistry–A. European Journal 13 (30): 8478–8488. 41 Iqbal, M., Tao, Y., Xie, S. et al. (2016). Aqueous two-phase system (ATPS): an overview and advances in its applications. Biological Procedures Online 18 (1): 1–18. 42 Goja, A.M., Yang, H., Cui, M., and Li, C. (2013). Aqueous two-phase extraction advances for bioseparation. Journal of Bioprocessing & Biotechnology 4 (1): 1–8. 43 Aydo˘gan, Ö., Bayraktar, E., and Mehmeto˘glu, Ü. (2011). Aqueous two-phase extraction of lactic acid: optimization by response surface methodology. Separation Science and Technology 46 (7): 1164–1171. 44 Villar, L., González, B., Díaz, I. et al. (2020). Role of the cation on the liquid extraction of levulinic acid from water using NTf2-based ionic liquids: experimental data and computational analysis. Journal of Molecular Liquids 302: 112561. 45 Pratiwi, A.I., Yokouchi, T., Matsumoto, M., and Kondo, K. (2015). Extraction of succinic acid by aqueous two-phase system using alcohols/salts and ionic liquids/salts. Separation and Purification Technology 155: 127–132. 46 Sun, Y., Zhang, S., Zhang, X. et al. (2018). Ionic liquid-based sugaring-out and salting-out extraction of succinic acid. Separation and Purification Technology 204: 133–140. 47 Pandey, S., Chomal, N., Kamsonlian, S., and Kumar, S. (2018). Theoretical and experimental studies on extraction of carboxylic acids from aqueous solution using ionic liquids. International Journal of Chemical Engineering 9: 20–25. 48 Baylan, N. (2020). Ionic liquids as green solvents for reactive separation of glutaric acid from water. Water, Air, & Soil Pollution 231 (4): 1–10.

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids: Efficient Tools for Designing Environmentally Safe Solvents for the Future Supratik Kar 1 and Jerzy Leszczynski 2 1 Chemometrics and Molecular Modeling Laboratory, Kean University, Department of Chemistry, 1000 Morris Avenue, Union, NJ 07083, USA 2 Interdisciplinary Center for Nanotoxicity, Jackson State University, Department of Chemistry, Physics and Atmospheric Sciences, Jackson MS-39217, USA

19.1 Ionic Liquids and Their Structural Characteristics With the evaluation of the future of green chemistry and green synthesis of chemicals and pharmaceuticals, a promising substitute for volatile organic liquids as solvent and/or catalyst is evolved: ionic liquids (ILs) [1]. As organic liquids are the major source of concerns for environmental pollution, thus, as an alternative, ILs provide a source of new, promising chemicals, allowing a multitude of industrial applications. Additionally, easy modification of their chemical structures allows fine-tuning of their behavioral manifestation [2, 3]. Although ILs possess multiple beneficial features, ILs are not always devoid of hazardous outcomes, instead, many of them are toxic in nature. Interestingly, to diminish the toxicity profile of toxic ILs, the major features responsible for toxicity can be modified and designed to be environmentally friendly. This is a promising way of safe utilization of those novel solvents. ILs are the chemical salts depicted by the coexistence of two oppositely charged ions (anions and cations) held by the ionic force. These chemicals are physically liquids with a melting point less than the boiling point of water [4]. Some of the ILs remain liquid at room temperature and are called room-temperature ionic liquids (RTILs). Ammonium, imidazolium, pyrrolidinium, pyridinium, and phosphonium are the frequently used cations. Anions could be inorganic species like Br− , Cl− , [PF6]− , and [BF4]− , or organic such as acetate, glycolate, propionate, alkylsulfate, bis(trifluoromethyl)sulfonylimide, thioglycolate, trifluoromethylsulfonate, and others. Permutations of diverse cations and anions offer a million binary ILs with distinctive properties [5]. ILs are also frequently defined with different names, including “low-temperature molten salt,” “room-temperature molten salt,” “ambient temperature molten salt,” “liquid organic salt,” and “ionic fluid”. [6]. However, throughout the chapter, we will Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

use the term “ionic liquids” (ILs) to represent those species being liquid at room temperature only. Although the rising interest in ILs in academia and industry has been observed only recently, the true journey started at the beginning of the 1900s. The synthesis of ethylammonium nitrate ([EtNH3 ][NO3 ]), melting point in the range of 13–14 ∘ C, using ethylamine and concentrated nitric acid was reported in 1914. But owing to the limited application of this chemical, the number of studies was limited. It was not until 1992 that the first air- and water-stable ionic liquid containing 1-ethyl-3-methylimidazolium cation was reported [6]. The pioneering discoveries paving the path of ionic liquids toward modern research can be found in the literature [3, 7–12]. The “neoteric” nature elicited by ILs is completely due to discrete chemistry shown by this group of chemicals. Two oppositely charged ionic species, viz., cation and anion, remaining together produce an intriguingly new chemistry compared to the conventional organic volatile solvents. Figures 19.1 and 19.2 illustrate the chemical structures of the most frequently used cations and anions. The geometry and charge distribution of the ions are the foremost elements of the ILs. Their

+

R2

R3

R3

R3 R2

S R1

Trialkylsulfonium

+

N

R4

+

R2

P

OH

R1

Tetraalkylammonium

Tetraalkylphosphonium +

NH NH+

R2

N R1

R2

R3

+

N

R1

R2

N

N

R1

R1 1-alkyl-2,3tetramethylene imidazolium Trialkylpyridinium

+

+

Trialkylimidazolium

+

N

N N

N

N

CN

R1

Dialkylimidazolium

N

R1

N

N

+

N

Dialkypyrazolium

+

R2

R3

N R1

1,1,3,3Dialkylpyrrolidinium Tetramethylguanidium R2

+

S N-Alkylthiazolium

Choline

N

N

+

R

N

N

R1

N

+

+

R4

Cyanoalkyl alkylimidazolium

R1

n

n

Alkoxyalkyl alkylimidazolium

1-alkyl-2,3-trimethyleneimidazolium

R1 N

+

NH2

O

+

N R1

O n

R2 N

Alkoxyalkyl alkylpyrrolidinium

p-Dimethylamino pyridinium

+

+

N

N

R1 R2

R1 R2

Piperidinium

Morpholinium

N

N

+

H 3N

N Melamine

Figure 19.1 Chemical structures of selective IL cations. R, R1 , R2 , and R3 are alkyl substituents and “n” denotes the number of –CH2 – groups.

NH2

19.1 Ionic Liquids and Their Structural Characteristics

Cl

−

Br

−

I

Bromide

Chloride

B

O

Iodide

S

Cl

CN

O

−

NC

B

−

Cl

CN

−

S

Fe Cl

C

N

−

Thiocyanate Cl CN Slufamate Tetracyanidoborate Tetrachloroferrate (III) O

O

Cl Cl

NH2

−

HO

−

F

Cl

N F

Cl

O

Tetrafluoroborate

−

O

N

F

OH

N −

Dicyanamide

Trifluoroacetate

O Salicylate

HO

O O

−

−

O Acetate

Glycolate

O O

−

O

−

O

−

O O

H O

O

R1

O

Formate

Propionate

Isobutyrate

O

R2 O

P

O

−

R

S

OH

N

O S

O

Dialkylphosphate

−

O

O

Alkylsulfate

1,1-Dioxo-1,2-dihydrobenzo[d]isothiazole-3-onate F

O S

O

−

p-Toluenesulfonate

F

F O

F

−

F

P

C

F

O

F

O

O

−

F

O

F

Trifluromethanesulfonate

S

N

O

O

−

S

O

F

O O F

F

F

Bis(trifluoromethanesulfonyl)imide

−

F F

F

Bis(pentafluroethyl) phosphinate

−

F

P F

O F

F

Hexaflurophophate

−

B O

O

O

O

Bis[oxalato(2-)]borate O

O HS

B O

O

O

F F

C

O S

F

O

F

F

O

Bis[1,2-benzenediolato(2-)]borate

O

−

Thioglycolate

Figure 19.2 Chemical structures of selective IL anions. R, R1 , R2 , and R3 are alkyl substituents.

behavioral expression is monitored by the net Coulombic charge between the component cation and anion. A directional feature is observed since Coulombic force decreases with increased molecular size and asymmetric charge distribution. The cations are usually large-sized quaternary organic species, while the anions are small and can be inorganic as well as organic [5]. The lowered melting point of this group of chemicals can be attributed to the unsymmetrical structural arrangement of the actions that undergo loose packing with the corresponding anions in the solid state. Hence, cations having low structural symmetry with delocalized charge and/or long alkyl group(s) render them low melting salt. The crucial viewpoint is that the developer can utilize numerous combinations of prevailing cations and anions and alter the ions’ structure to create a new analogue, meeting certain constraints. The presence of hexafluorphosphate (PF6 − ), bis-(trifluoromethanesulfonyl)imide ((CF3 SO2 )2 N− ) anions impart hydrophobic property to ILs because of their lipophilic nature [13], and occurrence of CH3 CH2 OSO3 − and CH3 COO− provides stabilization of the ILs even at low

371

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

temperatures [14]. Anions like BF4 − , (CF3 SO2 )2 N− , and (FSO2 )2 N− introduce a wide electrochemical window [15]. The delocalization of the 3-center-4-electron configuration of 1-alkyl-3-methylimidazolium salts is responsible for their uniqueness involving the generation of acidic H-atom [16]. Additional experiments also revealed the formation of a charged matrix of cationic and anionic head groups, bearing entrenched nonpolar alkyl chains [17]. Thus, the structural configuration of ILs presents a broad prospect of designing by alteration of cationic and anionic cores or the substituents present therein. Therefore, it is feasible to fine-tune the physical and chemical attributes of ILs just by producing changes in cationic or anionic fragment. QSAR and machine learning studies can play a crucial role in the predictive properties and toxicology concept by presenting appropriate assistance toward the hazard identification as well as prioritization of ILs before initiating synthetic or any experimental evaluation. Such studies accompany the 3Rs concept (replacement, refinement, and reduction of animals in research), minimizing animal testing [18, 19]. However, such studies often suffer from the burden of complex computational operations. Hence, it will be very useful to develop chemometric models involving simple and straightforward formalism without compromising the quality of predictions [20]. Therefore, the present chapter exclusively discusses the available in silico approaches to model toxicity profiling of frequently used ILs against the Organisation for Economic Co-operation and Development (OECD)-approved organisms.

19.2 Properties of ILs ILs are characterized by a series of attractive behavioral attributes [21, 22]. Proper utilization of the features makes them effective in a multitude chemical operations. The major characteristics and chemical features of the ILs are reviewed in Table 19.1. ILs have become a topic of discussion in academia and industry with the abovementioned easily tunable chemical properties. This group of chemicals legitimately offers a good substitute option to revolutionize new chemical methodologies by switching the conventional toxic solvents. It might be fascinating to mention that by employing simple one million systems, it is feasible to generate one billion (1012) binary systems and one trillion (1018) ternary systems of ILs [22].

19.3 Application of ILs ILs can be perfect contenders for a plethora of several applications, such as catalysts, reaction solvents, electrolytes, lubricants, drug delivery systems, and extraction media. [11, 12]. The possibility of ILs’ application is endless if the researcher can tune the properties of anions and cations of ILs as per their required usage. The most common applications are discussed by dividing major research area-wise in Figure 19.3.

19.3 Application of ILs

Table 19.1 Characteristics and essential properties of ILs, which make them different from other chemicals. Property

Description

Solvating property

ILs show solvating characteristics for a wide range of organic, inorganic, polymeric, compounds, and various gases, e.g. H2 , CO, O2 as well. ILs do not usually form coordination with metal complexes. In addition to that, immiscibility of ILs with many solvents make them useful as two-phase nonaqueous systems

Low vapor pressure

ILs are characterized by extremely low vapor pressure, allowing their minimal discharge into the environment

Wide electrochemical window

The electrochemical window of the ILs is sufficiently large with the minimum value being more than 2 V, while in some cases it is even 4.5 V

Nonflammability

Most of the ILs are nonflammable and hence reduce operational hazards

Liquidity over a wide temperature range

ILs remain liquid over a temperature range of around 300 ∘ C (from –96 to 200 ∘ C), allowing broader kinetic control over the operations

Acidic property

The features of Brønsted, Franklin, Lewis, and “super” acidity are shown by some ILs

High thermal stability

Thermal stability of ILs is usually high. Examples include [EMIM][BF4] and [EMIM][(CF3SO2)2N], which are stable at respective temperatures of 300 and 400 ∘ C

High ionic conductivity

The ionic conductivity of ILs is very high, allowing suitable electrochemical applications

High viscosity

Compared to the conventional organic solvents, ILs are characterized by high viscosity. The values are usually less than 100 cP but may be very high in systems like [NHH,(C2OH)2][OAc] with a viscosity value of 5647 cP. The viscosity of imidazolium cation containing ILs can be easily tuned by modifying branchedness

Rate of chemical reaction modification

ILs accelerate the rate of chemical reactions even under conditions of Microwave (MW) irradiation

Stereoselectivity

ILs are extremely useful in controlling stereoselectivity

In recent times, visible advancements have happened related to the application of ILs in pharmaceutical and health industries. ILs have been examined to play a substantial role in the pharmaceutical industry, which can be grouped into the following features. (a) Synthesis of drugs: ILs have no vapor pressure and are thermally robust with liquid ranges of, e.g. 300 ∘ C, compared to 100 ∘ C for water. Hydrophilicity/hydrophobicity and polarity can be tuned by an opposite combination of cation and anion. Additionally, specific physiochemical properties in room

373

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

Electrochemistry: Electrochemical biosensing, fuel cells, battery electrolyte, electro synthesis and catalysis, ion-propulsion, metal plating, solar panels, supercaps

Analytical chemistry: Gas chromatography columns, HPLC stationary phase, MALDI-TOF matrix, mass spectrometric matrix, refractive index, protein crystallization, mobile phase modifier

Polymerization reactions: Charge transfer polymerization, acid-catalyzed polymerization, ionic polymerization, oxidative polymerization, radical polymerization, microemulsion polymerization, living radical polymerization

Enzymatic reactions: Ammonolysis, alcoholysis, esterification of carbohydrates, Nacetyllactosamine synthesis, resolution of amino acid ester, synthesis of polyesters, transesterification

Separation and extraction chemistry: Gas separation, binary and ternary system, extractive distillation, liquid–liquid extraction, liquid-phase microextraction, metal extraction

Biological and engineering application: Biocides, biomass processing, coatings, artificial muscle, compatibilizers, dispersant, drug delivery, dry cleaning, embalming fluid, nuclear waste recycling, robotics, tribochemical application, embalming fluid

Figure 19.3

Application of ILs in different fields of research and day-to-day life.

temperature make them attractive media or designer solvents. Multiple green reaction schemes considered ILs as green solvents and alternative reaction media, which can be found elsewhere. The room-temperature ionic liquids (RTILs) are emerging green solvent options to the volatile organic solvents due to their ease of reuse, thermal stability, nonvolatility, and capability to dissolve a range of organic and organometallic compounds. Therefore, ILs can be emerging green and alternative solvents [1]. (b) Extraction of active pharmaceutical ingredients (API): ILs are exemplified by their exceptional extraction capability involving liquid–liquid systems. The presence of API in the river, drinking water, and wastewater effluents poses a severe hazard to the ecosystems. The reported occurrence of APIs in aquatic systems is even in the ng/L level [23]. ILs can be tactfully applied in the analytical approaches, especially in ion-exchange chromatography, to remove trace quantities of drugs from the wastewater prior to their release in the environment. (c) Drug delivery system: There is a report of solubility enhancement of albendazole and danazole using butylmethylimidazolium hexafluorophosphate IL for drug delivery [24]. A mixture of ILs can also be used as drug reservoirs. Zhang et al. [25] reported the implication of imidazolium ILs to improve skin permeation in a transdermal drug delivery system. Azevedo et al. [8] illustrated the application of ILs as cosolvent for controlling the pharmacokinetic and pharmacodynamic (PK/PD) parameters of nimesulide.

19.4 Do ILs Follow Green Chemistry Principles and Are Hazard Free for Environment?

(d) Pharmaceutical salts-ionic liquids: To overcome the drawbacks of diverse physicochemical properties and/or toxicity, a suitable salt can be formed with neutral API which has the ability to modify the physicochemical property like crystallinity, melting point, dissolution rate, and hygroscopicity. Florindo et al. [26] reported efficient bactericidal action when amipicillin API is merged with ILs like cetylpyridinium and cholinium 1-ethyl-3-methylimidazolium, 1-ethanol-3-methylimidazolium, tetraethylammonium, and trihexyltetradecylphosphonium as cationic counter parts of ampicillin.

19.4 Do ILs Follow Green Chemistry Principles and Are Hazard Free for Environment? Due to the enormous possibility of ILs’ wide implication, there is a necessity to have a complete toxicity profile of ILs to the ecosystem. The appropriateness of the ILs in improving the process productivity of chemical processes is very high, contemplating good economic return. A notion of green chemistry was enforced on the ILs that can be primarily assigned due to their straightforward changeable structures and characteristics like nonflammability posing negligible process hazards and decreased volatility leading to minimum environmental discharge [27]. However, the question is what will happen in case of accidental release of ILs into the environment. Due to ionic nature, ILs are highly soluble in aqueous medium and has the capability to pollute the aquatic biosystem. Therefore, only structural modifications and beneficial attributes impacting the industrial operational variables are not adequate to decide or label a class of chemicals as safe [28]. Literatures also reported that ILs are not naturally safe chemicals. Rather, several properties of ILs like nonflammability were also questioned [29]. The release of IL vapors and their disintegrated products at higher temperatures should be studied instead of measurement at standard conditions [29]. To test toxicity covering diverse compartments of the environment requires OECD-approved organisms. The most common aquatic organisms for toxicity testing of ILs are fungi and bacteria, vertebrates and invertebrates, in vitro cell line toxicity, and enzyme inhibitory effects. Preliminary evaluation of chemical hazards and toxicity of ILs toward diverse organisms is critical for the safety assessment. Table 19.2 illustrates a comprehensive list of organisms for toxicity screening of ILs. Kulacki and Lamberti [10] reported toxicity of imidazolium ILs to freshwater algae Chlamydomonas reinhardtii and Scenedesmus quadricauda. Ma et al. [30] also demonstrated toxicity of imidazolium ILs to the green algae Chlorella ellipsoidea and Scenedesmus obliquus. ILs have also been reported to elicit toxicity to other invertebrates like Folsomia candida [31], Dreissena polymorpha [32], Physa acuta [33], and Caenorhabditis elegans [34]. 1-Butyl-3-methylimidazolium chloride showed increased teratogenic potential against CD-1 mice [35] and developmental toxicity to Rana nigromaculata was observed for the IL 1-methyl-3-octylimidazolium bromide [36].

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

Table 19.2

List of organisms used for toxicological screening of ILs.

Organism type

Name

Algae

Chlorella ellipsoidea, Cyclotella meneghiniana, Geitlerinema amphibium, Chlorella vulgaris, Oocystis submarina, Pseudokirchneriella subcapitata, Scenedesmus obliquus, Ulva lactuca, Scenedesmus vacuolatus

Bacteria and fungi

Clostridium sporogenes, Bacillus subtilis, Pseudomonas fluorescens, Bacillus cereus, Vibrio fischeri, Staphylococcus aureus, Candida albicans, Klebsiella pneumonia, Escherichia coli, Lactobacillus fructivorans, Photobacterium phosphoreum, Proteus vulgaris, Pseudomonas aeruginosa, Saccharomyces cerevisiae, Pichia pastoris

Invertebrates

Dreissena polymorpha, Daphnia magna, Folsomia candida, Caenorhabditis elegans, Physa acuta

Vertebrates

Danio rerio, Xenopus laevis, Rana nigromaculata,

Plants

Hordeum vulgare, Lepidium sativum, Lemna minor, Raphanus sativus, Triticum aestivum

Sponge (marine organism)

Amphimedon viridis

Rat

IPC-81 leukemia rat cell line

19.5 Regulatory Proposals for Toxicity Assessment of ILs To establish ILs as green solvents for the future, toxicity profiling and environmental safety data are inevitable. In the background of proper application and implication of ILs on Green Chemistry perspective, a Research Workshop was organized by the North Atlantic Treaty Organization (NATO) in 2000 under the title of “Green Industrial Applications of Ionic Liquids”. In that meeting NATO proposed a series of measures to develop and more reasonable uses of ILs [37]. The measures are the following: (a) ILs are fundamentally valuable to study for the advancement of science regarding ionic solvents and molecular solvents with the anticipation that somewhat beneficial may be obtained from their study. (b) Toxicity profile, biodegradation, bioaccumulation in diverse environmental compartment, safety, health, and environment (SHE) influence data are required for the approval of ILs. (c) Amalgamated with green chemistry, a new concept in thinking about synthesis in general, ILs provide an opportunity for science, engineering, and business. (d) Regulatory complexities need to be tackled to implement ILs in the chemical and pharmaceutical industries. (e) Before approval of market usage, the IL should be well characterized, readily available, and free of intellectual property.

19.6 Why In Silico Modeling Is Needed for ILs

(f) An open access, web-based database of thermodynamic and physicochemical data is needed and identifying the best methods to achieve it. (g) International collaboration, communication, and proper education regarding the results are required.

19.6 Why In Silico Modeling Is Needed for ILs Designing and synthesis of thousands of ILs followed by checking their hazard and toxicity profile for ecosystem and human is an uphill task. Thus, implication of in silico models using the existing experimental data of ILs for different endpoints is critical for the future design of efficient and harmless green ILs. Development of predictive QSAR models, read-across models, machine learning, and artificial intelligence help to understand how the property/toxicity of ILs differs from their structural composition [38]. Most used in silico techniques for modeling the property and toxicity of ILs are illustrated in Figure 19.4. Thus, analogs with “task-specificity” can be created using mechanistic interpretation from the in silico models of ionic liquids. A similar idea may be employed to model toxicity by offering design guidelines for less or no-toxic ILs. The basic objectives of in silico modeling of ILs are the following: (a) Prediction of toxicity endpoints for different species to have the toxicity profile of new ILs even before synthesis.

Artificial intelligence Machine learning Supervised learning Support vector machine

Artificial neural network

Figure 19.4

Decision tree Random forrest Deep neural learning

Deep learning

Unsupervised learning

Statistical modeling: QSAR

Clustering: K-Means, Hierarchical, Kmedoid

RASAR

Dimensionality Reduction: Principal Component Analysis (PCA),

Similarity search: read-across

Major in silico approaches used for toxicity and property modeling.

377

378

19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids O R2 O− R O P O O S O − R1 O O O R3 + R + + N R2 P R4 N R1 OH S O−

Data for modeling

Figure 19.5

Chemical structure of ILs

RF/DT SVM ANN QSAR RASAR AI PCA

In silico model

R2, Q2, R2pred RMSE, AUROC, accuracy, precision, recall, F-measure

Model validation

Workflow of in silico modeling approaches.

(b) Fill the toxicity data gaps for ILs. (c) Environmental risk assessment of ILs in different environmental compartments followed by risk management. (d) Regulatory decision-making and approval for marketing of newly designed and synthesized ILs. (e) Reduce the use of experimental animals, complying 3R’s rule of replacement, reduction, and refinement of animals. (f) Interpretation of mechanism of toxicity of diverse ILs for specific species. (g) Classification and structural clustering of different ILs for grouping. Several studies reported risk hazard assessment and toxicity modeling of ILs to different organisms, especially to Vibrio fischeri [39–42], Daphnia magna [43, 44], Scenedesmus vacuolatus [18, 19, 45], Staphylococcus aureus [46–48], and rat cell line IPC-81 [49, 50] which are the most studied ones. Along with the toxicity and risk assessment, vital property like critical micellar concentration (CMC) [9, 51] and enzyme activity of ILs are also modeled by the computational researchers [52–54]. The most common workflow of any in silico model is reported in Figure 19.5, where most of the steps are the same and only vary with the model development algorithm.

19.7 Predictive Toxicity Models for ILs De Melo [55] developed a QSAR model to study the toxicity of 100 ILs against leukemia rat cell line (IPC-81) employing Ferreira-Kiralj hydrophobicity parameter is a constitutional descriptor and computed as a number fraction of hydrophobic carbon atoms in an IL. The developed model showed good statistical quality with a squared correlation value of 0.809. Gupta et al. [56] examined the chemical features of structurally diverse ILs to their cytotoxicity in leukemia rat cell line IPC-81 by developing multiple nonlinear QSAR models. The models were developed using algorithm like probabilistic neural network (PNN), the cascade correlation network (CCN), and generalized regression neural networks (GRNNs) to establish the discrimination of ILs into four categories of cytotoxicity. The classification and regression model reported the accuracy of >86% and correlation (R2 ) of >0.90 in test data, respectively. Roy and Das [57] have employed linear discriminant analysis (LDA), regression study, and molecular docking to study ILs toward the inhibition of the

19.7 Predictive Toxicity Models for ILs

acetyl cholinesterase enzyme of Electrophorus electricus. The classification model discovered the existence of charged quaternary N atom as contributing to the toxicity, which is also confirmed by the docking study due to the formation of a π–cationic interaction. While the regression and classification-based models revealed the inverse effect of H-bond acceptor and donor features to the toxicity. A positive impact to the toxicity was reported by predictors defining molecular shape, lipophilicity, and branchedness. A further positive effects of resonating lone electron pair was detected in the regression model, supported by the π–cationic interaction established by the dimethylamino amino N atom as found in the docking study. Cvjetko Bubalo et al. [58] illustrated cytotoxicity modeling of ILs to the channel catfish ovary (CCO) cell line, where toxicity was computed by reducing the WST-1 dye after 72 hours exposure resultant in dose- and structure-dependent toxicities. Authors developed regression and classification-based QSAR models to identify the effects of shape and hydrophobicity parameters of cations have significant contributions to the toxicity. Additionally, critical impact of the quantum topological molecular similarity (QTMS) feature ellipticity (𝜀) of the imine bond was also observed. Das et al. [40] developed interspecies toxicity models employing toxicity data of ILs for three aquatic organisms, D. magna, V. fischeri, and S. vacuolatus. The simple interspecies model employing only experimental toxicity showed acceptable values of R2 suggesting a comparable mechanism of the toxicity of ILs for these species. Additionally, authors reported that their analysis suggested that V. fischeri may be used as an appropriate surrogate species to D. magna and S. vacuolatus in the context of toxicity. Later, models with computed chemical descriptors reported better predictive quality. The computed lipophilicity parameter for the cations, i.e. logk0 (cation) demonstrated the significance of bio-membrane partition in modeling ecotoxicity of ILs. The electron richness, molecular bulk of the cations and anions, presence of heteroatoms in cations, and hydrogen bonding propensity were also prominent in creating the models. Authors also predicted toxicity toward S. vacuolatus and D. magna for a true test set to fill the data gaps and aid future studies on the hazard of ILs. The developed model permits an extrapolation of data when ecotoxicity data to one of the organism is absent. Ahmadi et al. [7] developed a cytotoxicity QSAR models for natural deep eutectic solvents (NADESs) against HEK-293 human embryonic kidney cells (using MTT assay). Authors developed a three-parameter linear model. The identified attributes are rotatable bond number (RBN), the interaction of second power carbon numbers with the molar ratio of HBA to HBD in each NADES (C2 Ratio), and mean atomic van der Waals volume (Mv). The statistical model showed R2 and Q2 value of 76.4% and 69.8%, respectively. Das et al. [40] have attempted to mechanistically interpret chemical structure of ILs for their cytotoxicity to IPC-81. The developed classification- and regression-based QSAR model investigates the accountable attributes of both the anions and cations. The study concludes that the cytotoxicity of ILs could be reduced by making appropriate structural variations containing reduced cationic surfactant behavior by the usage of short length side chains and reduced cationic lipophilicity, evading dialkylamino substituent at 4-position of the pyridinium

379

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

nucleus, addition of nonaromatic cations whenever possible. The built models can be applied to predict the cytotoxicity potential to IPC-81 of new ILs and the existing ones falling within the applicability domain (AD) of the models. Barycki et al. [59] developed quantitative toxicity-toxicity relationship (QTTR) models covering diverse ILs against human HeLa (dataset 1) and MCF-7 cancer cell lines (dataset 2). The datasets 1 and 2 consist of 40 and 26 ILs, respectively. To develop models, authors used a multiobjective genetic algorithm (MOGA) to select the best set of explanatory features for multiple dependent variables at a go. Authors considered DRAGON 7 descriptors for modeling purpose. Both models showed high squared correlation value of 0.8. Das and Roy [3] found ETA indices are very fruitful in generating predictive in silico models correlating toxicity of ILs to D. magna in combination with other thermodynamic parameters. Interestingly, authors also checked the quality of the models using non-ETA parameters and thermodynamic features for comparison purposes. Authors concluded that they found models developed employing thermodynamic and ETA descriptors were either better or comparable to the models generated employing non-ETA and thermodynamic descriptors in terms of statistical quality. The mechanistic interpretation from the regression and linear discriminant analyses identifies important features correlated with the toxicity: electronegativity, lipophilicity, presence of long cationic side chains, the volume of heteroatoms, branching pattern at terminal atoms, terminal branches, and C atom nearer to heteroatomic substitution. In Table 19.3, we have reported a comprehensive discussion of the number of ILs in the datasets, tested organisms, toxicity endpoints, modeling quality and details, and the model’s availability information.

19.8 Databases of Ionic Liquid The development of any in silico predictive model is mainly reliant on the quality and quantity of data. Thus, computational modelers are heavily dependent on the available experimental literature and open-access databases to develop mathematical models. The selection of databases for the preparation of in silico model relies on the following characteristics: 1. The number of data points should be more than 50 for the statistically acceptable model. 2. As per OECD guidelines, the toxicity or property endpoint of IL should be defined for all the ILs. One cannot combine diverse data points for specific data for modeling purposes. 3. The data are preferably collected from the same experimental protocols under the same laboratory conditions. 4. The experimental protocols should be defined, and any error in the experimental data directly leads to an error in the in silico model.

Table 19.3 Study

Comprehensive details of different predictive toxicity in silico models for ILs. Species

Endpoint

Number of ILs

Model details 2

Reference 2

1

V. fischeri, D. magna

IC50 , LC50

24 bromide ILs

The R and Q values for V. fischeri and D. magna are 0.954 and 0.895, and 0.942 and 0.876, respectively. Models were prepared employing Energy of the Lowest Unoccupied Molecular Orbital (ELUMO ), total energy, the electron affinities dipole moment, volume of ILs cation, and molecular volume

[42]

2

S. aureus

EC50

25 imidazolium ILs

Linear QSAR models showed R2 and Q2 values with a range of 0.963–0.972 and 0.97–0.98, respectively, using the charge density distribution (σ-profiles) as molecular descriptors with accuracies as high as 95%

[46]

3

V. fischeri, D. magna

EC50 , LC50

40 and 33 ILs

Authors used QTMS descriptors along with computed lipophilicity and ETA indices to make models with R2 and Q2 values ranges of 0.843–0.910 and 0.832–0.952, respectively, for both datasets

[40]

4

V. fischeri

EC50

43 ILs

Group contributions from cations, anions, and substitutions are used as descriptors to build the model with a R2 value of 0.925

[41]

5.

V. fischeri

EC50

75 ILs consists of 9 cations and 17 anions

Group contributions from cations, anions, and substitutions are used as descriptors to build the model with a R2 value of 0.924

[60]

6

IPC-81

EC50

227 ILs consists of 227 cations and 25 anions

Kier symmetry index, topological charge index of order 8, and heavy atom count were employed to build a model with a quality of 0.92 (R2 )

[61]

7

S. aureus, E. coli, C. albicans

MIC, MBC

76, 49, 70, 48, 54, and 29 ILs for 6 models

Six QSAR models were developed using linear free energy relationship (LFER) employing descriptors calculated by density functional theory (DFT) and conductor screening model. The range of R2 for all 6 models is 0.803–0.947

[62]

(Continued)

Table 19.3

(Continued)

Study

Species

Endpoint

Number of ILs

Model details

Reference

8

V. fischeri

EC50

51 ILs, where cations consist of a halide anion (Cl or Br)

DFT-B3LYP was used to calculate partial atomic charges

[39]

as applied in Gaussian along with CODESSA program to calculate 2D and 3D descriptors. Best models obtained following features WPSA-1, minimum net atomic charge for a C atom, TMSA, PPSA1, LUMO+1 energy and maximum atomic orbital electronic population and with R2 value of 0.903–0.912

9

V. fischeri

EC50

69 ILs

QSAR models were developed using least squares support vector machine (LSSVM) and genetic function approximation (GFA) algorithm. The linear GFA model was developed employing five descriptors named MW, DisPm, HATSv, Mor16u, and C08AL from Dragon software. R2 and Q2 values for the GFA and LSSVM are 0.903 and 0.933, and 0.847 and 0.897, respectively

10

V. fischeri

EC50

157 ILs consist of 74 cations and 22 anions

Topological index (TI) used based on categorization of atom and atom positions in the hydrogen-suppressed molecular structure as descriptors to build the QSAR model. The developed model obtained following results: R2 is 0.908 and the average absolute error (AAE) is 0.278 σ-Profile descriptors by COSMO-RS were used to build linear and nonlinear QSAR models. The multiple linear regression (MLR) model showed R2 value of 0.906. While, nonlinear multilayer perceptron (MLP) model illustrated following results: T r = 0.978, T v = 0.961, and T e = 0.979

11

V. fischeri

EC50

110 ILs with 29 anions and 49 cations

12

V. fischeri, IPC-81, S. vacuolatus

EC50

97 ILs

In silico models were prepared using LFE descriptors computed by COSMO calculations. The features are following hydrogen-bonding basicity, excess molar refraction, hydrogen-bonding acidity, McGowan volume and dipolarity/polarizability. Prediction models for cytotoxicity of ILs toward the V. fischeri (R2 of 0.762), IPC-81 (R2 of 0.778), and S. vacuolatus (R2 of 0.776)

[63]

pp. 410–415

[64]

[65]

13

S. aureus

MIC, MBC

169 and 101 ILs with MICs and MBCs, respectively

Two models reliably calculated 0.919 (R2 ) and 0.341 standard error of estimate (SE) for pMIC; 0.913 (R2 ) and 0.282 SE for pMBC. The modeled features are following atom weight, molecular weight, atom charge, number of atoms, matrix norm index, electronegativity, atomic radius, and branching degree

[66]

14

IPC-81

EC50

281 ILs with 15 cationic head groups, 20 cationic side chains, and 31 anions

The in silico model prepared with Molecular ACCess System (MACCS) structural keys had accuracy of 80%

[49]

15

S. aureus

MIC

131 ILs

QSAR approaches used Random Forests (WEKA-RF) and Associative Neural Networks (ANN) methods employing ALogPS, E-State indices, Dragon 7.0, ADRIANA.Code, Chemaxon, Fragmentor descriptors, Inductive descriptors, and GSFrag. Model reliability calculated with R2 value of 0.83–0.88. The cross-validated coefficients Q2 = 0.82–0.87 for regression models and overall prediction accuracies of 80%–82.1% for classification models were observed

[47]

16

IPC-81

EC50

100 ILs

Four parameters (Min partial charge for a N atom, TMSA, relative number of O atoms and number of C atoms) based QSAR models were developed using MLR and support vector machine (SVM). The R2 and the root mean square error (RMSE) of training sets for MLR and SVM models are 0.918 and 0.959, 0.258, and 0.179, respectively. While the prediction R2 and RMSE of the test sets are 0.892 and 0.329, and 0.958 and 0.234, respectively

[50]

17

S. aureus

MIC

242 ILs

QSAR model was developed using E-State indices, Chemaxon, GSFrag, ALogPS, and ToxAlerts (Structural Alerts). The models obtained acceptable validation metrics with R2 and Q2 values 0.85 and 0.82

[48]

(Continued)

Table 19.3

(Continued)

Study

Species

Endpoint

Number of ILs

Model details

Reference

18

IPC-81

EC50

253 ILs

Nonlinear QSAR models were prepared using the CCN, GRNN and PNN employing simple descriptors like XLogP, TPSA, NAtoms, InertiaZ, Polariz, Span, and Dipole. The classification models depicted the R2 value of >0.9 and accuracy of >86%

[56]

19

IPC-81

EC50

119 ILs with 57 cations and 21 anions

The electrostatic potential surface area (SEP) and charge distribution area (Sσ-profile) descriptors were employed to build extreme learning machine (ELM), MLR, and SVM models. The ELM model emerged as the best model among three. The R2 and Q2 values of MLR, SVM and ELM models are 0.92, 0.941, 0.969 and 0.849, 0.874, 0.940, respectively

[67]

20

IPC-81

EC50

289 ILs

QTMS indices and 2D descriptors calculated from Dragon software were employed to develop classification and regression based QSAR models. The regression-based QSAR model has developed using partial least squares (PLS) algorithm with R2 and Q2 values of 0.869 and 0.856, respectively

[68]

21

IPC-81

EC50

269 ILs with 9 cationic cores and 44 types of anions

Alignment free GRid-INdependent Descriptors (GRINDs), derived from molecular interaction fields (MIFs), were correlated to the cytotoxicity values by PLS and support vector regression SVR. The PLS model showed R2 and R2 pred values of 0.86 and 0.92 with five latent variables. While SVR model showed R2 and R2 pred values of 0.89 and 0.91.

[69]

22

S. vacuolatus

EC50

60 ILs

The QSAR models were developed employing extended topochemical atom (ETA) indices along with topological non-ETA parameters and atom-type fragment descriptors. The best model reported R2 and Q2 values of 0.883 and 0.829, respectively.

[45]

23

D. magna

EC50

64 ILs

Group contributions from cations, anions, and substitutions are used as descriptors to build the model with an R2 value of 0.974

[43]—

24

S. vacuolatus

EC50

41 ILs

Final QSAR models were prepared using ETA indices and QTMS indices. The statistical quality of the models was 0.904–0.914 (R2 ) and 0.851–0.864 (Q2 ). Authors also developed interspecies QSAR model with D. magna and S. vacuolatus

[53, 54]

25

D. magna

LC50

62 ILs

Partial least squares (PLS) based model is developed employing lipophilicity, atom-type fragment, QTMS, and ETA Descriptors with R2 of 0.955, Q2 of 0.917, and R2 pred of 0.848. The best model evidently reveals the significance of aromaticity indicating that more lipophilic ILs with less toxicity may be designed by sidestepping aromaticity, N atoms, and increasing branching in the cationic structure

[44]

26

B. subtilis, P. aeruginosa

MIC

83 and 47 ILs, respectively

Authors developed regression-based QSAR model using ANN and k-nearest-neighbor (kNN) algorithms employing E-State indices, ADRIANA.Code, ALogPS, Chemaxon, Dragon V6.0, and Inductive descriptors. The classification QSAR models were built using random forest in WEKA-RF. The predictability of the models was tested by cross-validation (fivefold) [Q2 = 0.77–0.92] for regression models and accuracy of 83%–88% for classification models.

[70, 71]

27

IPC-81, fungi and bacteria

Aquatic toxicity scores

ILs with 48 anions and 128 cations

VolSurf+ in silico physicochemical descriptors for both cation and anion counterparts were used to build up QSAR model with Q2 value ranges from 0.57–0.62

[53, 54]

28

S. aureus, E. coli, A. hydrophila, L. monocytogenes

EC50

52 ILs with 11 anions and 4 cations

MLR-based QSAR models were developed using functional group contribution in structural elements of ILs. The R2 and Q2 values for the MLR models are 0.904–0.927 and 0.907–0.933, respectively

[72]

(Continued)

Table 19.3

(Continued)

Study

Species

Endpoint

Number of ILs

Model details

Reference

29

B. subtilis, P. aeruginosa

MIC

83 ILs

E-State indices, ALogPS, ADRIANA.Code, Dragon V6.0, Chemaxon, Inductive descriptors were used to develop QSAR model with R2 , Q2 and accuracy ranges from 0.75–0.87, 0.73–0.87 and 80% ± 5

[53, 54]

30

S. aureus, E. coli, A. hydrophila

EC50

25 room-temperature ionic liquids (RTILs)

Linear QSAR models were developed employing the charge density distribution (𝜎-Profile) as molecular descriptors which showed accuracy of 95%. The obtained R2 and Q2 values range from 0.963–0.972 and 0.97–0.98, respectively

[46]

Vibrio fischeri: V. fischeri; Daphnia magna: D. magna; Staphylococcus aureus: S. aureus; Scenedesmus vacuolatus: S. vacuolatus; Pseudomonas aeruginosa: P. aeruginosa; Bacillus subtilis: B. subtilis; Leukemia rat cell line: IPC-81; Minimum inhibitory concentration: MIC; Minimum bactericidal concentration: MBC; Escherichia coli: E. coli; Aeromonas hydrophila: A. hydrophila; Listeria monocytogenes: L. monocytogenes.

Table 19.4

Databases of ILs for modeling purposes.

Database

Description

Link

Beilstein database

A comprehensive database in the field of organic chemistry that includes ILs. The database is maintained by the North Carolina State University, Raleigh, United States

https://www.lib.ncsu.edu/databases

COSMO baseIL database

The database consists of 32 anions and 71 cations, anticipating the computation of properties of solutes in IL mixtures

https://www.3ds.com/products-services/biovia/ products/molecular-modeling-simulation/ solvation-chemistry/

delphIL

A constantly updated physicochemical data provider that includes synthetic procedural data, analytical data, and simulated/predicted data of existing and unknown ILs even from other databases

http://www.delphil.net/web/html/

ILThermo

A free comprehensive database containing experimental thermodynamic and transport properties of ILs including binary and tertiary mixtures. The website is maintained by the National Institute of Standards and Technology (NIST). The present version contains pure ionic liquids, binary mixture systems containing ionic liquids, ternary mixture systems containing ionic liquids, thermodynamic properties, thermochemical properties, and transport properties of ILs

https://www.nist.gov/mml/acmd/trc/ionicliquids-database;

The UFT/Merck ionic liquids biological effects database

It is known as Bremen Toxicity Database too. The UFT consisted of more than 300 ILs and their precursors in screening toxicity assays. Multiple ILs have been categorized in terms of ecotoxicity covering different levels of biological complexity – from enzymes, cells, microorganisms up to organisms and multi-species-systems. Additionally, numerous biodegradation tests were executed to ascertain the biodegradability of ILs

UFT Merck Ionic Liquids Biological Effects Database, (n.d.). http://www.il-eco.uft .unibremen. de/login.php?page=home&view=ionicliquids& lang=en (accessed October 9, 2018)

DDBST (Dortmund Data Bank)

The Dortmund Data Bank (DDB) was started in 1973 at the University of Dortmund with the compilation of VLE-data for normal boiling mostly organic compounds. It was later extended to cover also pure component properties, liquid–liquid equilibrium data, ILs, excess enthalpies, and activity coefficients at infinite dilution

http://www.ddbst.com/ionic-liquids.html

https://ilthermo.boulder.nist.gov/

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19 Current Trends in QSAR and Machine Learning Models of Ionic Liquids

Once the modeler collects the data following the abovementioned rules, the resulting input is ready for modeling. Along with the experimental collaborators and literature data, there exist few databases that combined majorly accessed ILs in their webservers for modeling purposes. Few major databases are reported in Table 19.4.

19.9 Overview and Future Avenues The impact of diverse chemicals in the ecosystem regarding risk hazards and assessment is a concerning issue. World regulatory agencies have recognized the paramount effort need for sustainable chemical development, and the philosophy of “green chemistry” is a research area to consider. Thus, the development and usage of alternate, safe chemicals is necessary. ILs are one of the prominent alternatives possessing novel chemical attributes, making them valuable in numerous industrial applications. The present chapter investigates the physicochemical and structural features associated with ILs and their toxicity potential using predictive in silico modeling techniques. Statistically acceptable and predictive mathematical models can identify the examined compounds’ chemical and physicochemical features. This permits the prediction of the chemical hazards and toxicity of untested/new ILs even before their synthesis. The chemical information revealed from in silico studies can conclude the following outcomes: ● ●

●

●

●

Statistical reliability owing to the implementation of multiple validation strategies The chemical information derived using the reported models can be used as suitable structural alerts for the screening and designing of ILs to make them environmentally benevolent “green chemicals” in the true sense. Easy screening and identification of potential analogs using discriminant analysis and regression analysis-based models. Accepted mechanistic information that can be further utilized to enrich the chemical and biological knowledge of ILs. Interspecies models allowing the filling of data gaps within surrogate indicator organisms.

A detailed understanding of cation and anion chemistry from the predictive models can help modify the major physicochemical properties to decrease the hazardous properties of ILs to the environment. The QSAR models can successfully help in modifying the existing cations and anions and their combinations. Thus, in silico models offer immense prospects for designing and synthesizing new and efficient ILs with minimum toxicity to the ecosystem. The future research should concentrate on using large number of databases to increase the reliability of models, including diverse toxicity endpoints and multiple species. Multi-endpoint models and interspecies models are fundamental to develop and fill the major toxicity data gaps spanning different compartments of ecosystems. The role of machine learning and artificial intelligence cannot be ignored, and those techniques are key tools for solving major complex issues in designing green ILs and assessing their vital toxicity issues.

References

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this chapter.

Acknowledgments SK thanks the administration of Dorothy and George Hennings College of Science, Mathematics and Technology (HCSMT) of Kean University for providing research opportunities through research release time and resources.

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20 Advances in Simulation Research on Ionic Liquid Electrolytes Huo Feng 1 and Yue Bowen 2 1 Beijing Key Laboratory of Ionic Liquids Clean Process, Institute of Process Engineering, China Academy of Sciences, Beijing, China 2 College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, Hebei, China

With the rapid development of new energy electric vehicles, personal portable equipment, aerospace industry, and basic medical equipment, electrochemical energy storage systems with high energy density, high cycle stability, and high power density are facing major opportunities and challenges. As typical electrochemical energy storage devices, batteries and supercapacitors have attracted much attention in the field of energy storage on account of their fast charge and discharge rate, long service life, and high energy density [1, 2]. As a key component of the energy storage system, electrolytes not only have the function of conducting ions and transporting energy, but also the interaction between the electrolyte and electrons/ions at the electrode interface is one of the vital factors affecting the battery capacity and cycle performance. An excellent electrolyte should have the following characteristics: (i) strong electrochemical stability; (ii) outstanding compatibility with positive and negative components in the battery; (iii) wide working window and high conductivity; (iV) high security; and (v) materials are environmentally friendly, nontoxic and low-cost. At present, organic electrolytes are widely used in industries, which cannot take into account the above-mentioned at the same time. Therefore, the optimization and design of electrolytes has become the necessary way to promote the rapid development of energy storage devices. Ionic liquids (ILs), as a new type of green soft functional materials, are liquid at room temperature. They are generally composed of asymmetric organic cations and organic/inorganic anions with weak coordination [3, 4]. Due to their high thermal stability, low vapor pressure, low flammability, high conductivity, wide electrochemical window, flexible and adjustable hydrophobicity, solubility, and density, they are being widely researched as the electrolyte in a variety of energy storage equipment, such as lithium-ion batteries and supercapacitors [5]. Compared with ordinary solvents, ILs exhibit complex and changeable structures under the synergistic action of hydrogen bond, electrostatic interaction, and van der Waals interaction. Therefore, it is difficult to systematically analyze the complex Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

20 Advances in Simulation Research on Ionic Liquid Electrolytes

interactions in IL electrolytes only by experimental measures. Second, because the arrangement of electrons/ions at the electrolyte and electrode interface plays a decisive role in the safety and energy storage characteristics of the energy storage device, it is difficult to obtain an in-depth cognition of its structure, interface formation, and mechanism of action at the nano- and micro-levels by relying entirely on the experimental operation. As a mature research tool, computer analog technology has become an indispensable research means in the field of energy storage in recent years because it can effectively explore the multiscale microstructure of the system, observe the dynamic variation rule of ions, and clarify the interface structure–activity relationship.

20.1 Simulation Method of Ionic Liquid Electrolytes As shown in Figure 20.1, the simulation methods commonly used for IL electrolytes can be divided into three categories according to the space scale and time scale: density functional theory (DFT), molecular dynamics simulation (MD), and ab initio molecular dynamics simulation (AIMD).

20.1.1 Density Functional Theory Density functional theory (DFT) is widely used in the study of IL electrolytes. By calculating the ion–ion interaction energy and the total energy of the system, we can Length scale 0.1 nm

1 nm

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Larger scales – applications

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ab initio MD DFT Smaller scales – physics and chemistry

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396

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102

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Infinity

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Figure 20.1

Multiscale simulation method for ionic liquids in electrolytes [6–13].

20.1 Simulation Method of Ionic Liquid Electrolytes

determine the charge distribution of each atom in the system, predict the molecular structure and molecular reaction behavior, analyze the interaction between active substances, and further explore the relaxation structure, lithium intercalation potential, migration path, activation energy and energy band of electrode materials, and clarify the battery voltage and charge discharge characteristics. At present, many teams at home and abroad have used DFT to explore the relevant mechanism of batteries and capacitor materials and have made major breakthroughs [14]. The electronic structure of electrolytes and the chemical environment of atoms are the key factors affecting the stability of battery materials, electron transfer, and atomic bonding. Because the DFT calculation is based on charge density, the electronic structure information including molecular orbital, energy band, density of states (DOS), and charge distribution can be effectively obtained in the calculation process. At present, there are a large number of literature reports on the calculation of the electronic structure of electrolytes. For example, Dubnikova and Zeiri [12] simulated the charge distribution of complexes composed of Li+ and TFSI- through DFT. As shown in Figure 20.2a, the electron charge in TFSI- is mainly distributed around four electronegative oxygen atoms, and showed that the high stability of Li − (TFSI)2 is caused by the strong Coulomb interaction between Li+ and oxygen atoms in TFSI- . Similarly, Sodeyama et al. [13] studied the influence mechanism of lithium salt concentration on the stability of LiTFSA/AN electrolyte through DFT. The results show that TFSI− can spontaneously decompose into CF3 fragment and (SO2 )2 CF3 NCF3 fragment after accepting electrons. At the same time, through the further analysis of the DOS curve before and after TFSI- decomposition (Figure 20.2b), it is clarified that CF3 fragment can form a special chain structure after dissociation, resulting in the electron affinity migration of anions, so as to improve the electrochemical stability of the electrolyte. As we all know, the stability of the electrode/electrolyte interface is closely related to the electrochemical window of the electrolyte. If the electrochemical window of the electrolyte component at the interface is greater than the working voltage of the battery, there will be no electrochemical decomposition in the process of battery charge and discharge, and the electrode/electrolyte interface can achieve real stability. As shown in Figure 20.2c, Ceder et al. [15] used DFT method to calculate the electrochemical window of six IL electrolytes composed of two cations Bmim+ and P13 + and three anions PF6 − , BF4 − , and TFSI− . And the cathode limit of P13 -based IL is significantly lower than that of [Bmim]-based IL, which indicates that aliphatic cations are usually more stable than aromatic cations. The calculated electrochemical windows of [Bmim][PF6 ], [Bmim][BF4 ], and [Bmim][TFSI] are 4.9, 5.1, and 5.5 respectively, and all [Bmim]-based ILs have similar cathode limits, because the redox of [Bmim] is unstable. In addition, the spectral verification of the electrolyte system by DFT to characterize its structural characteristics is also very common in the calculation of energy storage materials. Johansson and coworkers [16] conducted a detailed Raman spectroscopic study on two IL-based electrolytes, [Bmim][TFSI] and [Emim][TFSI], to analyze the sodium ion solvation process. The results show that the energy band shift of [Bmim][TFSI] is slightly higher with the increase of sodium salt concentration, which is due to the effective dynamic cross-linking between high

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

(a) C_TFSA N_TFSA O_TFSA S_TFSA F_TFSA N_ANsolvated C_ANsolvated_Me N_ANfree C_ANfree_Me

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Figure 20.2 Application of DFT in electrolytes. (a) Charge distribution in Li–TFSI (left), [Li2 –TFSI]+ (middle), and [Li–(TFSI)2 ]− (right) complexes. Source: Dubnikova et al. [12]/American Chemical Society; (b) DOS of TFSA− before and after the decomposition. Source: Sodeyama et al. [13]/American Chemical Society; (c) electrochemical windows of ILs. Source: Ong et al. [15]/American Chemical Society.

salt concentration Na+ and TFSI- , which changes the local structure of the material and affects the stability of the electrolyte. The binding energy between the two ions is calculated by DFT to verify this conclusion. Similarly, Spencer et al. [17] combined infrared spectroscopy with DFT calculation to analyze the influence mechanism of local structure change of [NNBH2 ]- and [(TMEDA)BH2 ]-based ILs, and gain insight into the influence of ion interactions in electrolyte on lithium-ion coordination environment. After adding lithium salt, the increase of coordination number between anions and the boron ion can explain the displacement shift of BH2 bond and the vibration mode of CH bond. In addition, the stretching and deformation of BH2 bond indicate that there is a role of charged hydrogen atoms in Li+ and BH2 .

20.1 Simulation Method of Ionic Liquid Electrolytes

To sum up, DFT simulation is mainly based on the analysis of the properties of ILs in the electronic layer. In the simulation process, it is usually combined with other simulation methods for comprehensive analysis.

20.1.2 Ab Initio Molecular Dynamics Simulation Due to the high charge concentration and highly correlated aggregation structure in ILs, the model based on dilute electrolyte theory is not applicable. For example, due to the influence of long-range force, DFT calculation cannot fully describe anions. However, the classical force field used in classical molecular MD cannot deal with the problem of partial charge transfer between cations and anions in ILs well, and the calculation accuracy is low, so it is still challenging to make quantitative prediction. AIMD is a method based on quantum chemistry, which can provide an accurate image of ion–ion interaction of liquid structure changing with time. It is the only means to predict the intermolecular structure and vibration dynamics of ILs under specific thermodynamic conditions through the first principle. It is also an important tool of “first principle” to evaluate the volume characteristics and dynamics of ILs [18, 19]. Ceder et al. [20] applied AIMD simulation to the study of ion diffusion in Li conductor materials, such as Li10 GeP2 S12 (LGPS), which confirmed the existence of rapid diffusion of Li in one-dimensional channels. Figure 20.3a–c shows the diffusion trajectory of Li atom during AIMD simulation. In Figure 20.3a, it can be observed that Li is easy to diffuse in the one-dimensional diffusion channel along the c direction. Figure 20.4b shows a new diffusion path, connecting the two LiS4 tetrahedrons in the diagonal direction of the ab plane. Figure 20.3c connects the Li atom at the center of the LiS6 octahedron with the c-axis diffusion channel. Anta et al. [21] verified the force field of MD through AIMD and focused on adding different concentrations of NaTFSI to [Pyr14 ][TFSI]. The radial distribution function curve (RDF) shown in Figure 20.3d shows that AIMD is in good agreement with MD. It can be seen from Figure 20.3e that the ionic conductivity decreases with the increase of concentration, which is largely due to the formation of large ion clusters. Mo et al. [26] found that the rapid diffusion phenomenon in the superionic conductor is not formed by the typical jump of isolated ions in the solid, but the cooperative migration mechanism of multiple ions plays a unique role. He et al. [22] studied the sodium mechanism of transition metal oxide NiO. Through AIMD simulation, it was found that due to the layer-by-layer reaction in the process of Na+ insertion, as shown in Figure 20.3f and g, the mechanism difference between sodium and lithium in metal oxide conversion materials was revealed. Thomas et al. [27] calculated the vibration spectrum of 1-ethyl-3-methylimidazolium acetate IL based on AIMD for the first time, and studied the physical absorption and solvation of carbon dioxide in ILs. The simulated infrared spectrum showed that the formation of carboxylate (NHC–CO2 ) was the main way of carbon dioxide absorption, and the calculated results were consistent with the experimental data. To sum up, AIMD is a simulation method for studying atomic dynamics with complex chemical changes, which has the accuracy that MD simulation cannot achieve.

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(d)

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MD [Na]+ AIMD [Na]+ MD [Li]+ AIMD [Li]+

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r (Å) (f)

0.0 M [Na]+[Tf2N]− 0.2 M [Na]+[Tf2N]− 0.5 M [Na]+[Tf2N]− 1.0 M [Na]+[Tf2N]−

0.9 0.6 0.3 0.0 290 300 310 320 330 340 350 360

(g) NiO

Na2O

Na+

Na+ NiO Ni Li2O

NiO Li

Li+

+

Ni

NiO

Figure 20.3 Application of AIMD in electrolytes. (a–c) Diffusion trajectories of Li atoms in AIMD. Source: Mo et al. [20]/American Chemical Society; (d) radial distribution function between Na+ /Li+ and [Tf2 N]− , from AIMD and MD. Source: Vicent-Luna et al. [21]/John Wiley & Sons; (e) conductivity of ionic liquid electrolyte containing Na+ [Tf2 N]− and Li+ [Tf2 N]− . Source: Vicent-Luna et al. [21]/John Wiley & Sons; (f) snapshots of sodiated and lithiated NiO surfaces. Source: He et al. [22]/American Chemical Society; and (g) schematic cartoons showing different reaction modes between sodiation and lithiation. Source: He et al. [22]/American Chemical Society.

However, due to the limitation of system scale and simulation time, AIMD can only simulate a system of hundreds of atoms, and the total running time is limited to the order of picoseconds. Because of these characteristics, AIMD is more suitable to study the electrochemical stability, local interaction, material diffusion mechanism, reaction process, and vibration frequency of ILs in small-scale systems, which provides a new idea for the description of first-principle molecular dynamics based on ILs in theoretical chemistry.

20.1 Simulation Method of Ionic Liquid Electrolytes

100% ILs

100% Salt Ionic liquids in salt

Salt in ionic liquids 0.3 mol/l

0.5 mol/l

1.5 mol/l

[Li[FSI]3]2−

Low concentration

(a) 1.70

1.50 [C2mim][TFSI] [C2mim][FSI] [C4mim][TFSI] [C4mim][FSI]

1.45 1.40 1.35 0.3

0.6

0.9

1.2

7

1.5

1.8

Viscosity (kg/ms)

0.8 0.6

Solvent

DMC

DEC

σtot (S/m)

2.191

1.572

[C2mim][TFSI] [C2mim][FSI] [C4mim][TFSI] [C4mim][FSI]

6 5 4 3 2 1 0

0.3 0.6 0.9 1.2 1.5 1.8 2.1

0.4

Concentration of LiTFSI (mol/l)

0.2 0.0

2.1

0.3

Concentration of lithium salt (mol/l)

4 Conductivity (S/m)

Viscosity (kg/ms)

1.55

1.0

0.6

0.9

1.2

1.5

1.8

2.1

Concentration of LiTFSI (mol/l)

[C2mim][BF4] [C2mim][TFSI] [C4mim][BF4] [C4mim][TFSI]

4.265

2.748

5.593

12

298 K DEC DMC

2

0

5.075

298 K [C2mim][BF4] [C2mim][TFSI] [C4mim][BF4] [C4mim][TFSI]

8

Conductivity (S/m)

Density (g/cm3)

1.60

(b)

High concentration

1.2

1.65

2.0 mol/l

4 0 −4

σ(δcat)

(c)

σ(dcat)

σ(δcat)

d σ(dan) σ( cat, an)

8

P13OTf-Li2S8 + − Li -OTf RDF + 2− Li -S8 RDF + − Li -OTf CN + 2− Li -S8 CN

σ(dcat)

σ(dan) σ(dcat, an)

10 8 4

6 4

8

P13TFSI-Li2S8 Li+-TFSI− RDF Li+-S82− RDF Li+-TFSI− CN Li+-S82− CN

6 CN

8

12

g(r)

10

σ(δan)

Conductivity type

Conductivity type 12

g(r)

σ(δan)

6 4

6 4

2 2

2 2

0 0

(d)

CN

−2

4.84

0 5

10 r(Å)

15

0 0

4.34 5.69

5

10

0 15

r(Å)

Figure 20.4 Application of MD in electrolytes. (a) Snapshots of different lithium concentrations from MD; (b) density and viscosity vs. concentration of LiTFSI for all ionic liquid electrolytes ([Cn mim][TFSI] and [Cn mim][FSI], n = 2,4, 26]. Source: Tong et al. [23]/Frontiers Media S.A / CC BY 4.0.; (c) conductivity of the organic solvent electrolyte and the ionic liquid electrolyte. Source: Tong et al. [24]/Royal Society of Chemistry; and (d) the center-of-mass RDFs and coordination number curves of Li+ -S8 2+ and Li+ -anions for [P13][OTf]-Li2 S8 and [P13][TFSI]-Li2 S8 systems. Source: Hu et al. [25]/John Wiley & Sons.

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

20.1.3 Molecular Dynamics Simulation With the improvement of large-scale computing power, the development of mature force field, and advanced modeling technology, molecular MD, as a calculation method based on Newtonian mechanics to simulate the motion of the system and obtain atomic scale information including atomic position and motion speed, is widely used in electrolyte calculation [3, 28]. MD simulation is the evolution process of the system over time in a long enough time to produce enough phase space configurations to meet our needs, and then ensemble average these configurations, which can effectively obtain the macro properties of the system, such as microstructure, dynamics, thermodynamics, and so on. For example, our team [23] used MD simulation method to explore the viscosity, density, lithium-ion migration number, self-diffusion coefficient, and other properties of four IL electrolytes (LiTFSI-[Cn mim][TFSI] and [Cn mim][FSI], (n = 2, 4)) under different lithium salt concentrations (Figure 20.4a and b). The results show that the density and viscosity of all IL electrolytes increase with the increase in lithium concentration, and the simulation results are highly consistent with the experimental values. At the same time, we found that the increase in lithium salt concentration can make the coordination structure between lithium ion and IL anion closer, so as to form cluster structure and promote the migration of lithium ion. Subsequently, the team compared the solvation structures of traditional organic solvent electrolytes (LiTFSI-DMC-DEC) and IL electrolytes (LiTFSI-[Cn mim][TFSI][Cn mim][BF4 ](n = 2, 4)) at high concentrations through MD calculation [24]. As shown in Figure 20.4c, the organic solvent greatly limits the free movement of ions under high lithium salt concentration, resulting in a reduction of the conductivity of the system. In addition, because MD calculation can obtain the real-time motion trajectories of all atoms, the diffusion coefficient of ions can be obtained directly through analysis. It is often used to study the ion diffusion behavior and diffusion mechanism of electrolytes. Therefore, Hu [25] explored the micromechanism and transport behavior of Li2 S8 in ILs and IL-based electrolytes through MD simulation. Figure 20.4d shows that [OTF]− has higher coordination strength with Li+ than [TFSI]− . And [OTF]− can accelerate the Li+ exchange rate in the electrolyte and make the Li+ solvation layer easier to decompose. Similarly, Kirchner and coworkers [29] further concluded that the mobility and transport of Li+ are positively correlated with the interaction of IL and inversely proportional to the dissolution rate of Li+ by comparing the four IL electrolytes. In conclusion, MD simulation can be carried out on a large system containing hundreds or even thousands of IL pairs, and the time scale is nanoseconds or even microseconds. Because of this characteristic, MD simulation is widely used in the simulation of IL electrolytes to study the static microstructure, dynamic behavior, and transmission characteristics of electrolytes. It is not only a common tool to study the structural characteristics and dynamic mechanism of electrolytes, but also a key means to screen and design new electrolytes and improve their performance.

20.2 Advances in Simulation of Ionic Liquid Electrolytes in Batteries

20.2 Advances in Simulation of Ionic Liquid Electrolytes in Batteries The research on ILs in batteries can be divided into three categories according to the role of ILs in electrolytes: IL, as the solvent in electrolyte, plays the role of transporting electrons. As a salt in electrolyte, it acts as an electroactive substance. As an additive in electrolyte, it can effectively alleviate the defect of high viscosity of ILs.

20.2.1 Ionic Liquids Are Used as Solvents in Electrolytes ILs are commonly used as electrolytes in batteries to realize energy storage because of their excellent properties, such as fire resistance, nonvolatility, and wide electrochemical window. Through experiments and simulations, the strategy of using ILs as solvent in electrolytes is a new choice, which is expected to improve the safety performance and energy storage capacity of the battery. Due to the complex liquid structure and ion association in ILs, understanding the molecular mechanisms that control electrolyte behavior is critical. Focusing on this problem, the interaction law and mechanism between structure and performance of IL electrolytes are studied using simulation calculation. As early as 2006, Borodin et al. [30] first reported the MD simulation of IL electrolytes doped with lithium salt, and observed that there was obvious lithium aggregation in the system, especially when the temperature is low, the formed clusters can remain stable in tens of nanoseconds. The liquid density, ion self-diffusion coefficient and conductivity predicted by MD are in good agreement with the experimental data. Bedrov et al. [31] used the MD method to simulate the mixing of N-methyl-N-propylpyrrolidinium (Pyr13 ) bis (trifluoromethaanesulfonyl)-imide (TFSI) IL [Pyr13 ][TFSI] and LiTFSI salts with different concentrations (x = 0–0.33). It was found that compared with low concentrations (x ≤ 0.2), when the salt concentration was higher than 0.2, the first coordination shell of Li+ changed, as shown in Figure 20.5a. On account of the increase of anion number at high salt concentration, the corresponding bidentate coordination around each Li+ decreases and the monodentate coordination increases. It is also found that the contribution of Li+ to ionic conductivity does not increase with the increase in Li+ concentration, but reaches stabilized platform at a certain concentration level, as shown in Figure 20.5b. Lesch et al. [33] showed that the solvation structure of Li+ has no association with the cation of IL basically, and the interaction between cation and anion will significantly affect the dynamics of metal ions. Maginn et al. [34] analyzed the structure and transport characteristics of two kinds of ILs [Bmim][TFSI] and [Bmpyr][Pyl] doped with Li+ , and studied the effect of ionic structure on Li+ mobility in IL/Li+ mixture. The results showed that [Bmpyr][Pyl] with “plane to plane” structure showed good electrochemical performance when used as an electrolyte. The addition of lithium salt disturbed the charge sequence between ions in the IL, and the mobility of Li+ decreased due to the strong interaction between Li+ and anions. The MD simulation using polarizable force field reported by Borodin et al. [35] in 2018, studied the properties of electrolyte doped with different metal salts (Li+ , Na+ , Mg+ ,

403

20 Advances in Simulation Research on Ionic Liquid Electrolytes 1.6 1.4 0.197 0.216 0.190

0.194 0.216 0.188

0.193

λLi(mS/cm)

0.187

1.2

423 K 363 K 298 K

1.0 0.8 0.6 0.4

(a)

0.2 Mm+–[Tf2N]3–(3–m)

Mm+–[Tf2N]4–(4–m)

0.0

0

5

10

15

20

25

30

35

X (mol%)

(b) 0

Li

Na

Ni

Metal Zn Co

Cd

Al

–200

Mm+–[Tf2N]5–(5–m)

Mm+–[Tf2N]6–(6–m)

Binding energies (KJ/mol)

404

–400 –600 –800 –1000 –1200 –1400 –1600 –1800 –2000

1 2 3 4 5 6

–2200

(c)

(d)

Figure 20.5 (a) Diagrammatic drawing of two Li+ cation solvation structures and (b) Li+ contribution to the ionic conductivity of ionic liquid electrolytes ([Pyr13 ][TFSI]/LiTFSI). Source: Li et al. [31]/American Chemical Society; (c) representative ion clusters from the small MD simulations; and (d) binding energies of the ion clusters. Source: Vicent-Luna et al. [32]/John Wiley & Sons.

and Zn2+ ) in [Pyr14 ][TFSI] IL. By calculating the residence time of metal cations in the electrolyte and the average moving distance within a residence time, as shown in Figure 20.6a and b, they observed that divalent cations have longer residence time than monovalent cations. In other words, it has slower dissolution kinetics. Ant et al. [32] reported the effects of different metal cations on the behavior of [Pyr14 ][TFSI] IL-based electrolyte, captured representative cluster forms in the system, and calculated the binding energy between them to estimate the most stable form of existence, as shown in Figure 20.5c and d. They also discovery that there is a “sub diffusion” state in the system, as shown in Figure 20.6c. This is due to the slow dynamics of the system and the “cage effect” of ions in a short time before reaching the normal diffusion behavior. Compared with pure ILs, the “cage effect” is more obvious when adding salt. The higher the valence state of metal cations, the lower the diffusion coefficient, and the slower the movement of ions in the electrolyte, as shown in Figure 20.6d. Ionic conductivity is an important parameter to determine the rapid charge and discharge capacity of a battery. Improving the ionic conductivity of electrolyte materials and designing new electrolyte with the excellent ion transport performance has become an important direction of many simulation and experimental studies.

20.2 Advances in Simulation of Ionic Liquid Electrolytes in Batteries

100

Li Na Mg Zn

103

Zn

Displacement (Å)

Residence time (ns)

104

102 101

Mg Li

100 2.0

2.2

2.6

1000/T

(a)

2.8

3.0

(K–1)

2.4

2.6

1000/T

2.8

3.0

3.2

(K–1)

104 103 102

pure IL Li Na Ni Zn Co Cd Al

101 100 10–1 10–2 10–5 10–4 10–3 10–2 10–1 100 101 102

Simulation Experimental

10–11

10–12

pure IL Li

Na

Zn Co Cd

Ni

Al

(d) diag. Me

diag. EMIM

off-d, c-c

diag. TFSI

2

1.5

1.5

1

1

σ (S/m)

2

0.5 0

–1

off-d, a-a

off-d, Me-TFSI

off-d, EMIM-TFSI

0.5 0 –0.5

–0.5

(e)

Na 2.2

(b)

(c)

σ (S/m)

10 2.0

3.2

Diffusion coefficient (m2/s)

Mean squared displacement (Å2)

2.4

Li

–1 0

0.1

x

0.2

0.3

Na 0

(f)

0.1

x

0.2

0.3

Figure 20.6 (a) Metal cation residence time and (b) displacement of the metal cations during residence time of [Pyr14 ][TFSI]/MeTFSI (Me = Li+ , Na+ , Mg+ , Zn2+ ). Source: Borodin et al. [35]/American Chemical Society; (c) logarithmic representation of the mean squared; (d) self-diffusion coefficients for [pyr14 ] of the [Pyr13 ][TFSI]/MeTFSI (Me = Li+ , Ni2+ ). Source: Vicent-Luna et al. [32]/John Wiley & Sons; and (e, f) contributions to the conductivity of the [Emim][TFSI]/MeTFSI (Me = Li+ , Na+ ) electrolytes. Source: Kubisiak et al. [36]/American Chemical Society.

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

The transport characteristics of electrolyte depend on the structure of liquid, the interaction between dissolved ions and the interaction between ions and solvents. Therefore, in terms of simulation, scholars propose to decompose the conductivity according to two ways: ion self-diffusion and ion interaction, which can directly analyze the interaction between ions. Eilmes et al. [36] simulated the effect of salt addition on conductivity in an electrolyte composed of Li(Na)TFSI/[Emim][TFSI], as shown in Figure 20.6e and f. Due to the strong interaction between metal cations and IL anions, the movement between them is positively correlated and has a destructive impact on the conductivity. It is proposed that Na+ and Li+ have similar properties because they belong to alkali metal group. Some scholars also use other theories and definition methods about conductivity to study the interaction and transport properties in electrolytes. Matubayasi et al. [37] from the Osaka Institute of Technology deduced the Green-Kubo ionic conductivity equation based on the linear response theory, which is applicable to homogeneous electrolyte and heterogeneous electrolyte solutions. Schroeder et al. [38] of the University of Vienna calculated the translational dipole moment according to the Einstein–Helfand conductivity formalism, which is derived from the mean squared displacement. They also analyzed the interaction rule between the collective rotating dipole moment and the current frequency according to this equation. Wohde et al. [39] combined the Onsager relation with linear response theory to deduce the theoretical expression of all relevant Li+ migration numbers in the movement of positive and negative ions. In an IL electrolyte, a special solvated IL is used, which not only has the general characteristics of ILs, but also has many conductive electrolyte properties, including high ionic property, high lithium ion migration number, and high oxidation stability. It can be used as a thermally stable electrolyte for lithium batteries. Molten [Li(G3 or G4 )][TFSA] is considered to be a typical representative of this kind of solubilized ILs. Watanabe team has conducted a series of relevant studies on this new solvent IL, mainly focusing on its ionic[40, 41], oxidation stability, and thermal stability [42–44]. In 2012, through the study of dynamic ion correlation [41], the team revealed the difference of ionic conduction mechanism in some liquid lithium salt electrolytes and its correlation with the number of lithium ion migration. The experimental results show that the oxidation stability of G5 increases by 0.5 eV after adding Na+ to the solvated IL, which clearly shows that the stability increases with the increase of Na+ concentration [43]. Subsequently, the effect of electric field induced by alkali metal cations on the oxidation stability of glyme complexes was further studied [42]. The results showed that due to the influence of the size and charge density of alkali metal cations, the electric field effect was correlated with electrostatic interaction, and the solvent containing NaTFSA salt had higher stability. In the same year, with the help of quantum chemical calculations [44], it was proved that [Mg(G4 )][TFSA]2 had superior thermal and electrochemical stability than [Li(G4 )][TFSA] and [Na(G4 )][TFSA]. This is due to the strong interaction between G4 and Mg2+ induced by the strong electric field of divalent Mg2+ . There are many interaction sites in the IL, which can directly participate in any reaction and have a strong impact on the transport properties of the electrolyte. It is necessary to make appropriate theoretical calculations to analyze it. The dissolution

20.2 Advances in Simulation of Ionic Liquid Electrolytes in Batteries

of metal salts in the IL will increase the viscosity and reduce the conductivity of the electrolyte, which requires us to reasonably design and optimize the dosage of each component in the electrolyte. In addition, a special solvated IL is expected to further improve the ionic conduction and stability of the battery because of its unique conductivity.

20.2.2 Ionic Liquids Are Used as Salts in Electrolytes The ultrahigh concentration lithium bis(trifluoromethanesulfonyl)imide–water mixture developed by Suo [45] has far more electrochemical window stability than the typical water electrolyte, and has the characteristics of higher safety than the traditional organic electrolyte, so it has become a new promising electrolysis solution. In a high-concentration electrolyte, when the concentration of ordinary inorganic salt is too high, it is often limited by salt solubility, resulting in high viscosity and low ionic conduction. Atsuo et al. [46] used an asymmetric imine anion lithium salt and found that it has high solubility in water, salt/water molar ratio reached 1.0, and the concentration was as high as 55.6 mol/kg, providing a wide potential window of about 5 V. However, its viscosity increased significantly, up to 8555 MPa s, accompanied by a decrease in ionic conductivity (0.1 ms/cm), which indicates that if the lithium salt concentration is increased alone, it is at the cost of reducing the conductivity of the battery. ILs are not only the transport medium of electroactive substances, but also electroactive substances. Researchers add ILs as an ionic salt to improve the conductivity of electrons and ions. Hu et al. [11] added IL with inert tetraethylammonium (TEA+ ) as the cation. This strategy avoided the problem of co-embedding of mixed cations in the circulation process, inhibited the dissolution of transition metals in the cathode, and formed 9 mol kg–1 NaOTF + 22 mol kg–1 [TEA][OTF] sodium-ion battery, showing superior cycle stability. Borodin et al. [47] introduced asymmetric ammonium salt ([Me3 EtN][TFSI]) to increase the solubility of lithium salt (LiTFSI) by two times, and the salt/water molar ratio increased from 0.37 to 1.13. When the 42 m LiTFSI + 21 m [Me3 EtN][TFSI] ultrahigh concentration electrolyte is used in the lithium-ion battery with LiMn2 O4 as the anode and Li4 Ti5 O12 as the cathode, the coulomb efficiency is as high as 95% and the cycle stability of the battery is greatly improved. Compared with conventional inorganic salts, the application of IL ionic salts in the development of ultrahigh concentration electrolyte in energy storage system is a new field. However, its theoretical cognition is still in its infancy, and theoretical research will continue to promote progress in this regard.

20.2.3 Ionic Liquids Are Used as Additives in Electrolytes Adding a small amount of IL as salt to the electrolyte can improve the cycle stability of the battery and broaden the electrochemical window. However, due to the defect of high viscosity of IL, adding too much will seriously reduce the conductivity of the battery. Therefore, researchers have reduced the content of ILs as electrolyte additives to improve battery energy storage and other characteristics. When the IL

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

[Emim][TFSI] was introduced into the electrolyte as a cosolvent [48], due to the small quantity of IL added, the water/salt/IL electrolyte formed realized the full storage of Li+ . The interaction between water and other molecules and the solvation structure of Li+ were analyzed by MD and DFT simulations, which showed that the reduction of water molecules led to an increase in the electron density of surrounding Li+ and the widening of electrochemical window. Kühnel et al. [49] added two kinds of ILs [EMIM][TFSI] and [EMIM][OTF] to the electrolyte to form the ternary mixture of “LiTFSI/ionic liquid/water”. The results show that, due to the decomposition of IL in water, anions surround the Li+ solvation layer, which boosts the solubility of LiTFSI. It is the nonvolatility of the IL that improves the safety of the electrolyte and reduces the viscosity of high-concentration LiTFSI-aqueous solution. The electrolyte formed by [EMIM][TFSI] has better stability than that formed by [EMIM][OTF]. Sawangphruk et al. [50] studied the effect of ILs with three different cation types (imidazole, pyrrolidine, and piperidine) as additives on the solid electrolyte interface (SEI) in metal batteries through experiments and a variety of simulation methods. The simulation results show that the stable existence of cations in the electrolyte forms a positive protective layer and inhibits the growth of lithium dendrites. The SEI layer of ILs with a saturated ring structure is thinner than that with an aromatic ring structure, which is more conducive to the rapid diffusion of Li+ in the electrolyte interface layer. In conclusion, ILs as additives in electrolytes have the following advantages: (i) the water consumption is greatly reduced, which not only retains the advantage of high conductivity of aqueous electrolyte, but also overcomes the short plate with narrow electrochemical window; (ii) abundant anions in ILs are distributed near the Li + solvation layer, which can effectively alleviate the problem of limited salt solubility; and (iii) avoiding using organic solvents can effectively improve the safety performance of the battery.

20.3 Advances in Simulation of Ionic Liquid Electrolytes in Capacitors Electric double-layer capacitor (EDLC), also known as a supercapacitor, stores energy through the separation of electrode material and electrolyte interface charge. Due to the advantages of lower energy density and higher power density, hundreds of thousands of charge and discharge cycles can be carried out to realize rapid charging without any electrochemical reaction. Not only the molecular/ionic structure and dynamics at the electrode–electrolyte interface play an important role in the performance of the capacitor, but also the electrochemical working window of the electrolyte directly affects the maximum working potential of the capacitor, which has a significant impact on the energy density and power density. Using ILs with wide electrochemical window and low volatility, electric double-layer capacitors work can work in extremely harsh conditions. According to the structural characteristics of electrode materials, this chapter mainly introduces

20.3 Advances in Simulation of Ionic Liquid Electrolytes in Capacitors

the simulation research on IL electrolytes in flat-electrode capacitor and porous electrode capacitor.

20.3.1 Simulation of Ionic Liquid Electrolytes in Flat-Electrode Capacitor Graphene material has the characteristics of efficient adsorption of electrolyte and its structure is similar to a flat plate. The adsorption behavior of ILs on the charged surface of the electrode and the functional relationship between ionic chemical structure and electrical bilayer structure are very important. Therefore, the combination of ILs and graphene electrode material is the focus of early research. As shown in Figure 20.7a, Bedrov et al. [51] proved that the C–V curve of IL ([Cn mim][TFSI], n = 2, 4, 6, 8) near the basal (flat) and prismatic edge face (rough) graphene electrode is camel-shaped. The potential mechanism between differential capacitance and the structure of the IL electrolyte deserves further study, and the type of IL may be one of the influencing factors. Subsequently, Bedrov Research Group [53] compared [Bmim][BF4 ] and [Bmim][PF6 ] ILs and found that asymmetry would increase the gap between maximum and minimum capacitance. For the purpose of more accurately describing the spatial and chemical structure of graphene-based electrodes, Jung et al. [52] explored the influence of the oxidation degree of graphene in parallel-plate capacitors on the capacitance in 2014. By understanding the response of IL charge recombination to electrode charging, we can comprehend how the hydroxyl oxidation of the electrode affects the screening of electrode charge by IL, as shown in Figure 20.7b. With the increase in oxidation rate, the ion density recombination decreases with the oxidation of the electrode. When the oxidation rate reaches 70%, the steric hindrance produced by the oxygen atom in the hydroxyl group begins to increase the electric double-layer gap. As a result, the decrease in charge recombination ability of ILs and the expansion of bilayer gap lead to a negative correlation between capacitance and graphene oxidation. By directly considering the charging process and analyzing the ionic layer structure, Jung et al. [54] studied the charging mechanism of 1-ethyl-3-methylimidazolium thiocyanate [Emim][SCN] IL and graphene electric double-layer capacitor. The results show that the electrode charge and the ions in the electrolyte interact and restrict each other. In addition, they found that the capacitance of supercapacitor in the charging process is affected by the heterogeneity of IL dynamics, so it is impossible to fit the unsteady electrode charge density through a single exponential relationship, and then it is impossible to quantitatively analyze the charging dynamics. It is proved that ions play a nonnegligible role in the electrical performance of capacitors. Two-dimensional layered transition metal carbides and nitrides (MXenes) can contract freely due to their flexibility, which ensures the rapid transport of ions in the layer. This dynamic charge storage mechanism has been the focus of research in recent years. Simon et al. [55] studied the capacitor composed of Ti3 C2 Tx MXene electrode and [EMIM][TFSI] IL using the MD simulation method of electrode free movement under conditions of constant charge and discharge, described the charge–discharge mechanism of the positive electrode and the negative electrode,

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

7

Differential capacitance

6

5

4 –2

–1

0

1

(a)

ρcharged

ρdischarged

Anions 40 Q = 0

Cations

25

Q=0

0 –40 40 +5e

0%

–10 25

–5e

10% 25%

0

40%

–40 40

–10

70%

10

100%

0

0

–10 –40 2.7 –3.1 –2.9 –2.7

(b)

2

Electrode potential

Δρ

410

z (nm)

2.9

3.1

z (nm)

Figure 20.7 Simulation of ionic liquid electrolytes in plate-electrode capacitor. (a) C–V curves of ionic liquids near flat and rough graphene electrode surfaces. Source: Adapted from Vatamanu et al. [51]; and (b) anion charge and cation charge density near the electrode. Source: DeYoung et al. [52]/American Chemical Society.

and fitted the changes of electrode volume measured by the experiment. The positive electrode mainly realizes charge storage through ion exchange process, while the negative electrode mainly realizes charge storage through counterion intercalation process. In order to understand the microdynamics and electrochemical performance of ions, Gogotsi et al. [56] studied the effect of water adsorption on ion mobility through MD simulation. Although MXene/[EMIM][TFSI] absorbed a large amount of water, most water molecules were attached to the surface of MXene, only a few water molecules entered the internal IL, so humidity had little effect on ion diffusivity.

20.3.2 Simulation of Ionic Liquid Electrolytes in Porous Electrode Capacitor Ion adsorption on the surface of porous electrode and ion diffusion in the hole are two important factors affecting the performance of supercapacitors. In recent years, research in this area has focused on porous carbon electrodes and IL electrolytes

20.3 Advances in Simulation of Ionic Liquid Electrolytes in Capacitors

(pure IL or mixed with organic solvents) to improve the energy and power density of supercapacitors. Van Aken et al. [57] explored the effect of cations on the electrochemical performance of onion-like carbon (OLCs) supercapacitors and established the relationship between cation mobility and electrochemical performance. In this chapter, the sizes of three cations are [Emim] < [Hmim] < [Bmih]. The results show that ILs with smaller-size cations have a larger diffusion coefficient and higher capacitance at a faster charge discharge rate. In addition, it is also found that the performance of IL electrolyte is related to the increase of temperature, which limits the voltage stability window, and a solid electrolyte interface phase is formed on the surface of the carbon electrode. Feng et al. [58] used MD simulation method to compare the capacitance behavior of OLC and carbon nanotube (CNT) carbon-based supercapacitors. As shown in Figure 20.8a, the size and curvature of spherical/cylindrical electrode will affect the size of capacitance and its dependence on temperature. In order to reveal the difference between IL electrolytes and organic electrolytes, Jiang et al. [59] predicted the microbehavior of electrode–electrolyte interface of IL and organic electrolyte double-layer capacitors (EDLCs) and the dependence of capacitance on pore size through classical density functional theory (CDFT), as shown in Figure 20.8b. Feng et al. [60] studied the molecular scale properties of [Bmim][TFSI] in nano carbon pores. Due to the relative size of micropores and the strong attraction of ions to the surface, the structure of IL is destroyed and the density of ILs in the pores is increased, as shown in Figure 20.8c. When ILs are used in porous media, the interaction between ILs and electrode surface plays a key role in the charge and discharge processes of supercapacitors. Wu et al. [62] found that the capacitance of slit nanopore double-layer capacitor filled with room-temperature ILs shows a U-shaped trend, and the ionic solvation structure and pore size are the crucial factors to control the capacitance. The size, chemical properties, pore geometry, and pore size of ILs are closely related to the performance of supercapacitors. However, there are few reports on the interface structure of IL electrolytes in supercapacitors, such as the interaction mechanism between surface charge density, electrode potential, and charging dynamics. Hung et al. [8, 9] confined [Emim][TFSI] to slit graphite nanopores. The surface charge density affects the structure and dynamics of ILs, especially depending on the distance between ions and the wall. As ions approach the pore wall, their kinetic speed slows down, and the relaxation time increases significantly. Our team [61] studied how the hydrophobic ion electrode affects the charging mechanism of the supercapacitor. In the distribution diagram of ions in the hole on different electrodes in Figure 20.8d, the ionophilic pores can be easily wetted by ILs, and the number density of in-pore cation/anion characters shows a nearly linear change as U elec increases. The in-pore population of counterions in the ionophobic pore also increases with U elec , whose dependence is similar to that in the ionophilic pore. However, the in-pore population of co-ions with ionophobic pores will increase first and then decrease, which shows that the ionophilic pores show faster charging dynamics than the counterions. Then the equivalent circuit model is used to predict the resistance of the supercapacitor. The low resistance

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

0.07

12

Rs = 0.71 nm Rs = 1.22 nm Rc = 0.54 nm Rc = 0.68 nm R=∞

11

(b) Model TEA-BF4 in ACN

10 Capacitance (μF/m2)

Capacitance (F/m2)

0.06

0.05

9 8 7

(a) Model ionic liquid

6 5

(a)

4

(b)

3 2

0.04

1

–3

–2

–1

(a)

0 1 Potential (V)

0 0.0

3

2

0.5

1.0

1.5 2.0 2.5 Pore size (nm)

(b)

3.0

3.5

4.0

Mesopore

PN (number/nm3)

412

fmeso = 1.0

12

Micropores

fmeso = 0.42

Anion Cation

8

12

Anion Cation

8

10

4

6

0

0

0.4 0.6 0.8 1.0 1.2

30

Anion Cation

20

0

0.4 0.6 0.8 1.0 1.2

micropore

12

4

(c)

0.4 0.6 0.8 1.0 1.2

Anion Cation

0

0.35

0.40

0.45

Distance from electrode (nm) In-pore [BF4]– population (#/nm3)

In-pore [EMIM]+ population (#/nm3) 7

2

Ionophobic

ηion

1

6

0.3 0.4 0.5 0.6

5

–4

–2

ηion

2 6

0.7 1.0 1.2 1.5

3

3

2

2

3 0

Uelec (V)

2

1

3

Co-ion

1

5 4

1

3

7

Ionophobic

4

Counterion

(d)

fmeso = 0.16 18

3 Counterion

Co-ion 4

–4

–2

0

2

4

Uelec (V)

Figure 20.8 (a) Influence of electrode curvature on the differential capacitance. Source: Feng et al. [58]/American Chemical Society; (b) the dependence of the integral capacitance of an EDLC on the pore size for the ionic liquid and the organic electrolyte. Source: Adapted from Jiang et al. [59]; (c) structural model showing the mesopore and micropore components, simulation snapshots and ion density distributions of [Bmim] and [TFSI]. Source: Bañuelos et al. [60]/American Chemical Society; and (d) in-pore cation and anion population at electrodes. Source: Gan et al. [61]/Royal Society of Chemistry.

shows that the hydrophobic electrode promotes the charging dynamics. Simon et al. [63] studied the response of a supercapacitor when the potential difference was suddenly applied in the model composed of a nanoporous carbon electrode and IL [Bmim][PF6 ], and found that the charge gradually penetrated into the electrolyte from the electrode interface, and the charge dynamics on the nanoscale showed heterogeneity.

20.4 Conclusion

20.4 Conclusion With the improvement of various theoretical methods and the development of computer software and hardware, simulation calculation has become one of the most important methods in scientific research. Compared with experimental research, the application of the multiscale simulation method has greatly improved our understanding and exploration of the multilevel relationship of energy storage materials from atom/molecule to macro, and provided a new way for the design and development of materials. Based on the emerging material in the field of energy storage, IL electrolytes, this chapter summarizes its simulation research work in batteries and capacitors in recent years and highlights the differences and advantages between IL electrolytes and traditional organic electrolytes in performance and microstructure. However, the development of IL electrolytes still faces many challenges: (1) Due to the limitations of the simulation scale, the simulation method cannot match the experimental research completely. The existing simulation methods have a certain gap with the real system in both time scale and space scale, and there is a certain error between the simulation results and the experimental values. Therefore, for the first principle, on the basis of ensuring the accuracy, we should focus on the development of large-scale DFT calculation software. For molecular dynamics, although there is a certain expansion in the simulation scale, the calculation accuracy of this method depends on the selection of force field. Most of the existing simulation studies use universal nonpolarizable force field and polarizable force field developed for organic solvents. So far, there is no polarizable force field model suitable for IL electrolyte. In the future, with the advent of high-precision IL polarizable force field, it is expected to achieve a high correlation between simulation and experimental research. (2) Due to the special structure of ILs, the ionic conduction and electrochemical stability of the electrolyte cannot be matched together. ILs themselves have excellent electrochemical characteristics. Compared with traditional organic electrolytes, ILs have the characteristics of thermal stability, chemical stability, and high conductivity. However, the internal structure of IL electrolytes is complex and changeable under the synergistic action of hydrogen bonds, electrostatic forces, and van der Waals forces. At the same time, after years of research, our team found that there are a large number of heterogeneous cluster structures in ILs. The cluster structures between the system and ions/molecules will hinder the free movement of ions and cause mass transfer problems. Therefore, it is necessary to deeply understand the nanostructure of the IL electrolytic liquid phase and the electrode surface, the dynamic structural changes during charge and discharge, and the storage mechanism of ion de-intercalation. (3) Although IL electrolytes can effectively improve the performance of lithium-ion batteries and capacitors, there are still many challenges for ILs to truly realize their industrial application. Therefore, the development and design of new electrolyte materials is an important direction for the development of IL electrolytes

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20 Advances in Simulation Research on Ionic Liquid Electrolytes

in the future. With the help of the existing structure in the IL database, setting reasonable restrictions according to industrial applications, and combined with high-throughput material genome technology, it is expected to screen and design the next generation of high-performance industrial IL electrolytes. In short, electrolyte, as an ion transport medium, is very important in energy storage devices. In the future, with the in-depth understanding and exploration of the structure–activity relationship, transport mechanism, interaction mechanism on the electrode surface, and storage mechanism of the IL electrolyte, the models and theoretical methods suitable for the IL electrolyte will continue to be improved, providing a theoretical basis for the electrochemical application of the IL medium.

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27 Thomas, M., Brehm, M., Holloczki, O. et al. (2014). Simulating the vibrational spectra of ionic liquid systems: 1-ethyl-3-methylimidazolium acetate and its mixtures. The Journal of Chemical Physics 141 (2): 024510. 28 Bedrov, D., Piquemal, J.P., Borodin, O. et al. (2019). Molecular dynamics simulations of ionic liquids and electrolytes using polarizable force fields. Chemical Reviews 119 (13): 7940–7995. 29 Ray, P., Balducci, A., and Kirchner, B. (2018). Molecular dynamics simulations of lithium-doped ionic-liquid electrolytes. The Journal of Physical Chemistry. B 122 (46): 10535–10547. 30 Borodin, O., Smith, G.D., and Henderson, W. (2006). Li+ cation environment, transport, and mechanical properties of the LiTFSI doped N-methyl-N-alkylpyrrolidinium+TFSI- ionic liquids. The Journal of Physical Chemistry. B 110 (34): 16879–16886. 31 Li, Z., Smith, G.D., and Bedrov, D. (2012). Li+ solvation and transport properties in ionic liquid/lithium salt mixtures: a molecular dynamics simulation study. The Journal of Physical Chemistry. B 116 (42): 12801–12809. 32 Vicent-Luna, J.M., Azaceta, E., Hamad, S. et al. (2018). Molecular dynamics analysis of charge transport in ionic-liquid electrolytes containing added salt with mono, di, and trivalent metal cations. Chemphyschem 19 (13): 1665–1673. 33 Lesch, V., Li, Z., Bedrov, D. et al. (2016). The influence of cations on lithium ion coordination and transport in ionic liquid electrolytes: a MD simulation study. Physical Chemistry Chemical Physics 18 (1): 382–392. 34 Liu, H. and Maginn, E. (2013). Effect of ion structure on conductivity in lithium-doped ionic liquid electrolytes: a molecular dynamics study. The Journal of Chemical Physics 139 (11): 114508. 35 Borodin, O., Giffin, G.A., Moretti, A. et al. (2018). Insights into the structure and transport of the lithium, sodium, magnesium, and zinc bis(trifluoromethansulfonyl)imide salts in ionic liquids. Journal of Physical Chemistry C 122 (35): 20108–20121. 36 Kubisiak, P., Wrobel, P., and Eilmes, A. (2020). Molecular dynamics investigation of correlations in ion transport in MeTFSI/EMIM-TFSI (Me = Li, Na) electrolytes. The Journal of Physical Chemistry. B 124 (2): 413–421. 37 Tu, K.M., Ishizuka, R., and Matubayasi, N. (2014). Spatial-decomposition analysis of electrical conductivity in concentrated electrolyte solution. The Journal of Chemical Physics 141 (4): 044126. 38 Schroder, C., Haberler, M., and Steinhauser, O. (2008). On the computation and contribution of conductivity in molecular ionic liquids. The Journal of Chemical Physics 128 (13): 134501. 39 Wohde, F., Balabajew, M., and Roling, B. (2016). Li+ transference numbers in liquid electrolytes obtained by very-low-frequency impedance spectroscopy at variable electrode distances. Journal of the Electrochemical Society 163 (5): A714–A721. 40 Shigenobu, K., Dokko, K., Watanabe, M., and Ueno, K. (2020). Solvent effects on Li ion transference number and dynamic ion correlations in glyme- and

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21 Applications of Ionic Liquids in Heterocyclic Chemistry Suresh Rajamanickam 1,2 and Binoyargha Dam 3,4 1 Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bioorganic Chemistry Laboratory, New Chemistry Unit, Rachenahalli Lake Road, Bengaluru, Karnataka 560064, India 2 Indian Institute of Science, Materials Research Centre, Bengaluru, Karnataka 560012, India 3 Indian Institute of Technology Guwahati, Department of Chemistry, Guwahati 781039, India 4 The Assam Royal Global University, Department of Chemistry, Guwahati 781035, India

21.1 Introduction Synthesis of heterocycles forms the largest division of organic chemistry. The majority of pharmaceuticals that mimic natural products are heterocycles. In addition to that diverse range of alkaloids, antibiotics, and pesticides are heterocyclic natural products, which are significant to animal and human health. Heterocycles also possess other practical utilities, like acting as modifiers and additives in diverse fields like in cosmetics, information storage, vulcanization accelerators, reprography, and solvents. A diverse range of compounds having different chemical, physical, and biological characteristics can be developed by combining a huge number of permutations of carbon, heteroatoms, and hydrogen [1a–e]. It is therefore understandable why both the strategic exploitation of recognized methods and the development of newer methodologies for synthesizing heterocyclic moieties continue to persuade the field of synthetic organic chemistry. Ionic liquids (ILs) are basically compounds that are completely composed of ions with a melting point less than 100 ∘ C. Paul Walden reported the first IL in 1914 [1f]. In 1982, Wilkes and research group reported the first-generation ILs, which are based on 1-alkyl-3-methylimidazolium salts [2]. Later in 1992, the moisture-sensitive anion was replaced with tetrafluoroborate ions and were designated as the second-generation IL [3]. These air- and moisture-stable ILs have found tremendous applications in organic synthesis as reaction media. Later in 2004, Davis reported task-specific ionic liquids (TSILs) that represent the third-generation ILs [4]. Figure 21.1 represents the structures of three generations of IL. Although at first, because of their unique thermal stability, nonvolatility, and nonflammability characteristics, ILs were introduced as an alternative green reaction medium, but in recent years, because of the characteristics mentioned below, ILs

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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21 Applications of Ionic Liquids in Heterocyclic Chemistry First generation

H3C

N

Second generation

CH3

N

H3 C

AlCl4

Chloroaluminate ILs (1980s)

Figure 21.1

N

Third generation

CH3

N BF4

Air- and moisture-stable ILs (1990s)

S H3C

N

CH3

N PF6

Task-specific ILs (2000s)

Three generations of ionic liquids.

have marched beyond the boundaries of their initial expectations and showed noteworthy roles in controlling the reaction as a solvent or catalyst. (a) Their physical properties like viscosity, melting points, density, and solubility can be tuned by modifying the structures of ILs by simply altering either the anionic or cationic components (designer solvents). (b) Desired product can be separated more conveniently from ILs as compared to other conventional solvents. (c) Their significant property of being reused many times makes them a successful candidate from green chemistry point of view. Figure 21.2 shows a pictorial representation of various tunable properties of ILs because of which they have emerged as a standout applicant (as catalyst and solvent) in the field of heterocyclic chemistry. Even though, till now, the working mechanism of ILs as catalyst/solvent in organic syntheses is not clear, but their ability to solubilize both organic and inorganic reactants enhances the rate of reaction. ILs are capable of many interactions like hydrogen-bonding, π–π, n–π interactions, and dipolar interactions [5]. Since ILs are composite systems proficient of undergoing several interactions,

Atom economy Multifunctional

Eco-friendly

Ionic liquids

Recyclable

Nonflammable

Negligible vapor pressure

Economic

Figure 21.2 Few properties of ionic liquids taht help them in attaining the role of catalysts and solvents in heterocycle synthesis.

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

exemplifying them with a single polarity term fails to cover the broad range of types and the enormity of individual interactions that make each IL unique. ILs can also be beneficial if anion or cation of IL can play a role as catalysts, cocatalysts, or catalyst activators. Advancements in computational chemistry field have facilitated the explanation of the above-mentioned interactions with quantum mechanical calculations [6]. Functionalized ILs were prepared, particularly with [SeO3 Me]− , an anionic selenium species containing imidazolium salts. This acts as catalyst for oxidative carbonylation of anilines [7] On the other hand, ILs containing acid counteranions like [H2 PO4 ]− and [HSO4 ]− found their application as recyclable media in esterification reactions [8]. SO3 H functionalized ILs were also used in oligomerization of diverse alkenes to produce branched alkene derivatives [9]. Results obtained were quite promising. Cations like pyridinium, tetraalkyl ammonium, imidazolium, and tetraalkyl phosphonium, and anions like tetrafluoro borate and trifluoro methane sulfonate, have been found in several ILs [10]. Further, confinement of ILs on metal–organic frame works (MOFs) and on metal nanoparticles have enabled the interactions between pore walls and ILs leading to their diverse applications in organic synthesis [11]. Thus, syntheses of biologically relevant heterocycles using ILs have received tremendous interest in academics as well as in industries. Therefore, in this chapter, we will be discussing about many such applications of ILs for the synthesis of various heterocyles, which possess many biological and medicinal properties.

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles In recent years, synthesis and functionalization of tetrazoles gained tremendous attention in synthetic community [12] due wide range of application in medicines, materials, and in agricultural sectors. Therefore, in 2020, Chanda and his research group prepared the IL-supported copper (II) catalyst (IL 1) via sequential three step reactions from 2-methyl imidazole as shown in Scheme 21.1 and applied it (as catalyst) for the synthesis of tetrazole derivatives (3) via [3 + 2] dipolar cycloaddition between organic nitrile (1) and sodium azide (2) under microwave irradiation [13]. After reaction completion, catalyst (IL 1) was recovered and reused up to three cycles without much decrease in the reaction yield and catalytic activity. In their subsequent work, authors again used the same IL catalyst (IL 1) for synthesizing triazole derivatives (6) via microwave-irradiated reaction between benzyl bromide (4), sodium azide (2), and alkynes (6). The reaction of benzyl bromide and sodium azide in situ generated highly explosive benzyl azide intermediate, which

H3C

N

N

Scheme 21.1

2-Chloro acetic acid CH3CN 80 °C, 10 h

H3C N Cl

NaBF4 CH3CN

N HO

O

Synthetic procedure of IL 1.

80 °C, 10 h

H3C

N

BF4

Cu(OAc)2

N HO

O

H2O, 8 h reflux

IL 1

421

422

21 Applications of Ionic Liquids in Heterocyclic Chemistry

underwent [3 + 2] cycloaddition with alkynes to form substituted triazole derivatives (6) [14]. The author found that the solvent methanol acts as a reducing agent and reduces copper (II) of IL 1 to Cu (I). However, 1,4-diphenylbuta-1,3-diyne (Glaser reaction product) was not observed during the reaction (Scheme 21.2). The above-mentioned IL 1, was also used in the multicomponent strategy involving 2,6-difluorobenzyl bromide (7), sodium azide (2), and propiolamide (8) for the synthesis of antiepileptic drug, Rufinamide (9) [14]. Methanol was used as the solvent system under refluxing conditions, which yielded the desired Rufinamide in exceptional amounts (Scheme 21.3). In 2015, Liu and his coworkers developed 1,3-dibutyl-1H-benzo[d][1,2,3]-triazol3-ium bromide (IL2) promoted intra-molecular cross dehydrogenative coupling (CDC) reaction between aldehydic C—H bond and aryl C—H bonds of 5-aryloxy-1H-pyrazole-4-carbaldehydes (10) for the construction of pyrazolone derivatives (11) (Scheme 21.4). This oxidative annulation reaction was performed in a water medium. After completion of the reaction, authors added additional water and ethyl acetate, in the reaction mixture, separated the IL (IL2) from the water

CN

+ NaN3 2

HN N N N

DMF, 130 °C MW, 20 min

1

H3C

N

O Cu O O

O

BF4

3

IL 1

N

N

(a)

N

CH3 BF4

IL 1 Br

+

+

4

NaN3 2

5

(b)

CH3OH, 65 °C

N N N

MW, 10 min IL 1

6

Scheme 21.2 Application of IL 1 for synthesis of a 5-substituted-1H-tetrazole and b 1,4-disubstituted 1,2,3-triazoles. F

Br

F

+ F

O NH2

7

2

NH2

N N N F

reflux, 3 h IL 1

H

BF4

O 70% aq. TBHP [Dbbta]+ Br− (IL 2)

H

X

H2O, 120 °C, 24 h

X = O, S

Scheme 21.4

H CH 3 N

N O O Cu O O IL 1

N

Application of IL 1 for synthesis of Rufinamide.

O N N

H3C

NH

O

Rufinamide (9), 87%

8

Scheme 21.3

+ NaN3

CH3OH

N

N

X X = O, S

Synthesis of pyrazolone derivatives using IL 2.

Bu N N Br N Bu [Dbbta]+ Br− IL 2

BF4

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

layer and reused it after drying in vacuo [15]. The greener IL (IL2) was five times recycled and reused without compromising any yield of the desired product. From mechanistic aspects, the oxidation of anionic portion of IL (Br− ) by tert-butyl hydroperoxide (TBHP) generated a tert-butoxyl radical, bromine, and a hydroxyl anion. The hydroxyl anion forms adduct with cationic part of IL [Dbbta]+ [Br]− , and form [Dbbta]+ [OH]− , concurrently, tert-butoxyl radical (t-BuO• ) abstracted aldehydic hydrogen of 5-aryloxy-1H-pyrazole-4-carbaldehydes (10) and generated acyl radical (i). The acyl radical (i) underwent radical cyclization with aryoxy unit to form radical intermediate (ii). A single electron transfer (SET) between bromide (1/2 Br2 ) and radical intermediate (ii) furnished a cationic intermediate (iii) and Br− . That initially formed hydroxyl anion ([Dbbta]+ [OH]− ), abstracted proton from (iii), and delivered the desired heterocyclic pyrazolone derivatives (11) (Scheme 21.5) [15]. In 2016, Chu and research group prepared N-alkylated 4,5,6,7-tetrahydro[1,2,3] triazolo[1,5-a]pyridine with NTf2 counter ion [16]. The IL [b-4C-Tr][NTf2 ] was prepared from 5-hexyn-1-ol via a sequential five-step reaction. Mesylation of 5-hexyn-1-ol followed by azidation, Hüisgen [3 + 2] intramolecular cycloaddition leads to 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine. N-alkylation of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine using alkyl methanesulfonate and then metathesis of LiNTf2 with triazoliummethanesulfonate salts provided desired ILs (IL 3 and IL 4) (Scheme 21.6) [16]. O H3C N H2O +

Bu N

O

N

Br

t-BuOOH

N Bu

[Dbbta]+ Br–

11

1/2 Br2 + [Dbbta]+ OH–

Br– + [Dbbta]+ OH–

t-BuO

H3C N

CHO N

O

O H3C N

10 N

t-BuOH

O

O

iii H3C

Br–

O

N

H3C N

N

O

N

O i

1/2 Br2 ii

Scheme 21.5 using IL 2.

Probable mechanism for synthesizing chromeno[2,3-c]pyrazol-4(1H)-ones

423

424

21 Applications of Ionic Liquids in Heterocyclic Chemistry MsCl, Et3N OH

Toluene

NaN3, DMF OMs

DCM, rt, 2 h

N3

DMF, rt, 8 h

N N

Reflux, 6 h

N

R-OMs 70–80 °C N N

LiNTf2, H2O

N R

H2O, rt, 13 h

NTf2

R = [IL 3] = Butyl R = [IL 4] = Ethyl

Scheme 21.6

12

N H

N R

OMs R = Butyl, ethyl

Syntheses of IL 3 and IL 4.

O

O O

N N

+ O 13

Scheme 21.7

O

N H

O

DIPEA microwave 100 °C, 30 W 2 mins

N N N H3C NTf2 [IL 3]

N N 14 99% using [IL 3] 98% using [IL 4] O

N N

N

CH3

NTf2 [IL 4]

Synthesis of tryptanthrin using IL 3 and IL 4.

These bicyclic ILs (IL 3 and IL 4) were used as solvents in microwave-assisted synthesis of biologically important natural product tryptanthrin (14), by treating isatoic anhydride (12) and isatin (13) in the presence of equimolar amounts of the base N,N-diisopropylethylamine (DIPEA) (Scheme 21.7) [16]. Since pyrans are very significant set of heterocyclic compounds [17a], possessing different range of medicinal activities, an efficient reaction for the synthesis of pyrano[3,2-c]pyridine derivatives (18) using aromatic aldehydes (15), tert-butyl 2,4-dioxopiperidine-1-carboxylate (17), and N-methyl-1-(methylthio)-2nitroethylen-1-amine (16) as reactants and Et3 N as additive in IL [Bmim]+ [BF4 ]− (IL 5) medium was reported by Rong and research group in 2019. In their work, the research group took 1 mmol of (15), 1 mmol of (17), 1 mmol of (16), 1 ml of (IL 5), 0.05 mmol of Et3 N and stirred the reaction mixture for 7–10 h at 80 ∘ C (Scheme 21.8) [17b]. After completion of the reaction (monitored by TLC) 30 ml of water was added to the reaction mixture, the solid was filtered off and washed with water. Crude product was purified by recrystallization from dimethylformamide (DMF) to give the desired products. Application of readily available starting materials,

CHO

O

O2N + HC 3

15

CH3 N

N H

SCH3

16

+

N

O 17

+ − Boc [Bmim] BF4 (IL 5)

Et3N, 80 °C, 7 h

O O2N

H3C

N H

N O 18

NH

Boc BF4

H3C (IL 5) [Bmim]+BF4−

Scheme 21.8

Synthesis of pyranopyridine derivatives using IL5.

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

MsO

N

O

OMs

3

N

OMs

CH2

48 h, 90 °C, CH3CN

N

H2C

O

O

3

N

OMs N

CH2

TEGBDVIM

H2C CH3

O

N

OH AIBN, DCM, 70 °C, 24 h n

O PEGMA

OMs N N

O 3

N

n PEGMA

N

OMs PEGMA-g-TEGBDIM (IL 6)

AMGEP

Scheme 21.9

Synthesis of IL 6(PEGMA-g-TEGBDIM).

CHO

NO2 + HC 3

15

n

S

N H 16

CH3 +

N N H 19

NH2

PEGMA-g-TEGBDIM (IL 6) Neat, 80 °C, 20 min

NO2 N N H

N

N H

CH3

20

Scheme 21.10 PEGMA-g-TEGBDIM (IL 6)-mediated synthesis of aryl-benzo[4,5] imidazo[1,2-a]pyrimidine amines.

uncomplicated reaction conditions, and green solvent were few added advantages of this protocol. In 2017, Kim and research group prepared polyethylene glycol methacrylategrafted tetra-ethylene glycol-bridged dicationicimidazolium-based IL (PEGMA-gTEGBDIM) (IL 6) by treating tetra-ethylene glycol-bridged 1-vinyl imidazoliummesylate and polyethylene glycol methacrylate in the presence of azobisisobutyronitrile (AIBN) (Scheme 21.9) [18]. The catalytic activity of IL 6 (PEGMA-g-TEGBDIM), was evaluated in the multicomponent reaction (MCR) toward the synthesis of aryl-benzo[4,5]imidazo [1,2-a]pyrimidineamines (20) by reacting variety of aryl or heteroaryl aldehydes (15) with 1H-benzo[d]imidazol-2-amine (19) and (E)-N-methyl-1-(methylthio)-2nitroethenamine (16) in solvent-free (neat) conditions (Scheme 21.10) [18]. The catalyst was recovered and reused up to seven runs without significant loss of the catalytic activity. Interestingly, the reaction does not need column purification. In 2015, Chandramouli and research group reported an IL (1-butyl-3methylimidazolium hydrogen sulfate) [BmIm]+ HSO4 − (IL 7) promoted fourcomponent reaction between dimedone (21), aromatic aldehydes (15), hydrazine hydrate (22), and 1,8-naphthanoic anhydride (23). This MCR delivered naphthalimide-based acridine-1,8-dione derivatives (24) in moderate to high

425

426

21 Applications of Ionic Liquids in Heterocyclic Chemistry O

O R

H3C H3C

21

O O

15

H O

O

H3C H3C

[BmIm]HSO4 (IL 7) 60 °C, 35 min

NH2 NH2

O

R

O

N N

O

O

CH3 N CH3 CH3

N

HSO4

H3C (IL 7) [BmIm]+HSO4−

22

23

24

Synthesis of acridinedione derivatives using ionic liquid [Bmim]+

Scheme 21.11 HSO4 − (IL 7).

yield (Scheme 21.11) [19]. The use of common organic solvents, namely acetonitrile, ethanol, methanol, acetic acid, and acetone, yielded 11–38% of the product in 11–20 h. The use of IL [BmIm]+ HSO4 − (IL 7) not only increased the reaction yield (93%) but also reduced the reaction time to 35 min. After completion of the reaction, the authors recovered the IL (IL 7) and reused it for four more cycles, in each cycle the product yield was slightly decreased and time significantly increased. Chandramouli and research group also documented 1-butyl-3-methylimidazolium hydrogen sulfate [BmIm]+ HSO4 − IL (IL 7)-mediated one-pot MCR between dimethylformamidedimethylacetal (26), acetophenone (25), and 5-aminotetrazole (27) for the synthesis of tetrazolo[1,5-a]pyrimidine (28) (Scheme 21.12) [20]. The reaction took longer time (10–21 h) and very poor yield (14–36%) of the product in common organic solvents such as ethanol, water, acetonitrile, n-propanol, acetic acid, and dimethyl formamide were obtained. The use of acetic IL namely [BmIm]+ HSO4 − decreased reaction time to 2 h and increased the yield up to 92%. The synthesized tetrazolopyrimidine moieties showed potent α-glucosidase inhibitor activity (against antidiabetic). For a particular note, p-methyl- and

O

H3C O CH3

H3C O

25

26

CH3

N + N CH3 O HO S O O [BmIm]+HSO4− (IL 7)

H3C

+ − N N NH [BmIm] HSO4 (IL 7) N N N 70 °C, 2 h N NH2 N N 27 28

CH3 N CH3

OCH3

Representative examples

NO2

O N

HO N

N N N

N N

90% IC50 = 49.8 ± 0.29 µM

N N N

N N

92% IC50 = 85.7 ± 1.2 µM

N N N

N N

91%

N N N

N N

86%

N N N

O

O N N

94%

N N N

N N

88%

N N N

N 86%

Scheme 21.12 IL 7 mediated one-pot multicomponent reaction between dimethylformamidedimethylacetal, acetophenone, and 5-aminotetrazole for the synthesis of pyrimidine derivatives.

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

OH

S SCH3

29 HS

NH2

O CHO O 15 O

30

21

CH3 NH

O

N

IL 8 rt, 2.5−5 h

S

CH3 CH3

CH3 CH3

N 31

H3C

OCH3

CF3

O

[EtSO4]

[Emim]+[EtSO4]− IL 8

CH3

O

O

O

O O

S

O

N 90%

O CH3 CH3

S

N 85%

CH3 CH3

O

F 3C

S

OF C 3

N

S

CH3 CH3

N 22%

91%

Scheme 21.13 Ionic liquid [Emim]+ [EtSO4 ]− mediated synthesis of structurally diverse thiazoloquinolinone scaffolds.

p-methoxy-substituted tetrazolo[1,5-a]pyrimidine derivative originated from acetophenone showed better α-glucosidase inhibition values (IC50 = 49.8 ± 0.29 μM and IC50 = 85.7 ± 1.2 μM, respectively) (Scheme 21.12) [20]. In 2018, Singh and research group demonstrated IL 1-ethyl-3 methylimidazoliumethylsulfate [Emim]+ [EtSO4 ]− (IL 8)-mediated four-component cascade coupling (4CCC) reaction of α-enolicdithioesters (29), aldehydes (15), cysteamine/ 2-aminothiophenols (30), and cyclic 1,3-diketones (21) (Scheme 21.13) [21]. In this 4CCC reaction, five consecutive new bonds (two C—C, two C—N, and one C—S) are formed in a single operation, which leads to highly privileged structurally diverse thiazoloquinolinone scaffolds/derivatives (31). The IL [Emim]+ [EtSO4 ]− (IL 8) was recycled and reused four times without considerable loss of any activity. The above protocol is not effective in neat and common solvents, namely water, methanol, ethanol, dimethyl formamide, and dichloromethane. However, few nonaromatic protic ILs, namely pyrrolidiniumformate [Pyr]+ [HCOO]− , pyrrolidinium nitrate [Pyr]+ [NO3 ]− , 1-methylpiperazinium formate [HMPy]+ [HCOO]− , 1-ethylpiperidinium ethylsulfate [EtPip]+ [EtSO4 ]− , and 1-ethyl-4-methyl piperaziniumethylsulfate [EtMPy]+ [EtSO4 ]− , and aprotic aromatic ILs, such as 1-butyl-3-methylimidazolium bromide [BMIM]+ [Br]− , 1-ethylpyridinium ethylsulfate [EtP]+ [EtSO4 ]− , and 1-methylpyridinium methylsulfate [MeP]+ [MeSO4 ]− , also are equally effective for the above transformation. Siddiqui and research group disclosed that the basic IL, [Bmim]+ [OH]− (IL 9), promoted intramolecular hetero cyclization of o-alkynylphenol (32) for the preparation of benzofurans (33) (Scheme 21.14) [22]. In this transformation, the IL, [bmim]+ [OH]− , played triple role of base, catalyst, and solvent. From mechanistic point of view, anionic part of IL (OH− ) abstracted phenolic OH and at the same time cationic imidazolium ring activated internal alkyne. Then, the phenoxide ion attacked the activated alkyne, which leads to the formation of intramolecular

427

428

21 Applications of Ionic Liquids in Heterocyclic Chemistry

[Bmim]+[OH]− (IL 9) 31 °C, 2.5 h

H3C

O 33

OH 32

N

N CH3

[Bmim]+[OH]− (IL 9)

OH

Scheme 21.14 Synthesis of diverse range of benzofuran derivatives using ionic liquid [BmIm]+ [OH]− (IL 9). Cl

O

CO2CH3

O

NaOCH3, PPh3 210 °C, 4.5 h

39

H3C N

N

CH3

PF6 [Bmim]+[PF6]− (IL 11)

Scheme 21.15 medium.

H3CO2C

O

38 [Bmim]+[PF6]−

H 34

OH

CO2CH3

35 [Mmim]+[MSO4]− L-proline 90 °C, 1h

CO2CH3 O 36

O

CH3SO4 N CH H3C N 3 [Mmim]+[MSO4]− (IL 10)

Synthesis of substituted and unsubstituted coumarins in ionic liquid

heterocyclized benzofuran (33) product. This protocol was a good alternative for an expensive transition-metal-catalyzed intramolecular heterocyclization of o-alkynylphenol. Tojo and research group demonstrated application of IL in the synthesis of (3-methoxycarbonyl)coumarin (36) from salicylaldehyde (34) and diethyl malonate (35) [23]. The authors used an IL, 1,3-dimethylimidazolium methyl sulfate ([Mmim]+ [MSO4 ]− ) (IL 10), as both solvent and catalyst, and L-proline was used as an additional promoter (Scheme 21.15). The reaction provided a very high yield of the product in a shorter reaction time. Alternatively, at a higher temperature (210 ∘ C), 3,4-unsubstituted coumarins (39) were prepared by treating salicylaldehyde (34), methylchloroacetate (38), and triphenylphosphine in the presence of sodium methoxide with the help of an IL, 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim]+ [PF6 ]− ) (IL 11). Jiang and research group disclosed Pd-catalyzed, IL, [C2 OHmim]+ [Cl]− (IL 12), mediated one-pot, three-step tandem annulation reaction protocol for the synthesis of 2,3-difunctionalized benzofuran (42) derivatives by treating 2-alkynylphenol (40) with vinylacetic acid (but-3-enoic acid) (41) or 2,2-dimethylbut-3-enoic acid by employing Cu(TFA)2 ⋅xH2 O as an oxidant (Scheme 21.16). The reaction showed good comparability for a wide range of electron releasing and electron withdrawing substituted 2-alkynylphenol. Even bulky, sterically hindered functionalities on 2-alkynylphenols provided good yield of tandem annulation product. However, the reaction between 2-alkynylphenol, namely 2-(phenylethynyl)-phenol (40), with allylacetic acid (pent-4-enoic acid) (43) failed to deliver tandem annulation product, but provided simple annulation product (44) without the involvement of allylacetic

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles O Cl O

Ph

Ph

43 100 °C

44

OH 40 Pd(TFA)2 (3 mol%) Cu(TFA)2 (2 equiv) [C2OHmim]+[Cl]−

O

O

OH 41 100 °C

OH

O

N

N CH 3

Cl OH [C2OHmim]+[Cl]− IL 12

Ph O 42

Scheme 21.16 Pd-catalyzed, ionic liquid [C2 OHmim]+ [Cl]− mediated one-pot, three-step tandem annulation reaction protocol for the synthesis of benzofuran derivatives.

N

O

Ph 48; 76%

Ph

N HOAc:DMF (3:1) 100 °C, 12 h air OCH3

+

Ph

N

OH

DMSO, air 45 Pd(TFA)2 Ph 80 °C, 8 h (5 mol%) + − OCH3 [C2O2mim] [Cl] (2 equiv) 46

O

Ph N

Ph 47; 85%

O

OH

N CH 3 Cl

[C2O2mim]+[Cl]− IL 13 OCH3

Scheme 21.17 Ionic liquid [C2 O2 mim]+ [Cl]− mediated synthesis of poly functionalized, structurally diverse isoxazoles derivatives.

acid (pent-4-enoic acid). The chlorine in annulation product (44) came from the IL, [C2 OHmim]+ [Cl]− (IL 12) (Scheme 21.16) [24]. In continuation of IL-mediated, palladium-catalyzed cascade annulation reaction, Jiang and research group developed an efficient protocol for the synthesis of poly functionalized, structurally diverse isoxazoles derivatives (47) from alkynone o-methyloximes (45) and terminal alkynes (46) [25]. The IL [C2 O2 mim]+ [Cl]− (IL 13) was weakly acidic in nature. The choice of reaction medium and solvent played a major role in the cascade annulated product formation. The reaction in weak acidic medium with polar aprotic solvent (DMSO) afforded alkynylatedisoxazole (47). Whereas, the combination of IL [[C2 O2 mim]+ [Cl]− (IL 13) with polar protic and aprotic solvent (CH3 COOH:DMF, 3 : 1) leads to the formation of E-alkenylated isoxazole product (48) (Scheme 21.17). In both the cases an IL [C2 O2 mim]+ [Cl]− act as an effective additive and makes the transformation greener. In the abovementioned protocol, aliphatic alkynes were failed to provide alkenylated isoxazole, on the other hand aliphatic alkynes comfortably delivered moderate yield of alkynylated isoxazole. In 2020, Jiang and research group, reported the synthesis of a diverse range of allylisoxazoles (51) and carbonyl isoxazoles (52) from acetylenic oximes (49) using ILs (IL 13, IL 14), palladium-based catalyst, and water as solvent (Scheme 21.18) [26]. In this report, the authors claimed that the IL not only acts as a solvent but also offers excess amount of halide ions to eliminate hydrochloride from acetylenicoximes. Authors carried out reaction of acetylenic oximes (47) (0.2 mmol) and enols (48) (1.2 equiv.) in the presence of NHC-Pd catalyst (0.05 mol%) (a) with IL [C2 O2 mim]+ [Cl]− (IL 13) and 2 ml water to synthesize 4-allyl isoxazoles (51) and (b) with IL 1-cyanopropyl-3-methyl imidazolium tetrafluoroborate [Cpmim]+ [BF4 ]− (IL 14) (2 ml) to synthesize 4-carbonyl isoxazoles (52). This methodology provided a straightforward rapid synthetic protocol for synthesis of structurally diverse

429

430

21 Applications of Ionic Liquids in Heterocyclic Chemistry

N

O

Ph O 52

N

Ph NHC-Pd, H2O 90 °C, air, 6 h N

49

+

+

−

[Cpmim] [BF4] (IL 14)

O

NHC-Pd, H2O Ph 110 °C, air, 12 h

Ph

N CH 3

NC BF4

OH

Ph OH

H3C N

iPr N

N

iPr iPr Pd Cl

Ph

N

COOH Cl [C2O2mim]+[Cl]− (IL 13)

50

iPr

N

CH2 51

Ph NHC-Pd

Scheme 21.18 Synthesis of a diverse range of allylisoxazoles and carbonyl isoxazoles from acetylenicoximes using ionic liquids. O

O

O NH2

CH3

+

NH2 53

H3C N + N

IL15−19 rt, 15 mins

25

OTs SO3H

H3C N + N

IL 15, 98% [BSMIm]+[OTs]− (A)

OTs

CH3

H3C

[PMIm]+[Br]− (D) Representative substrate scope O O NH CH3 X

R = CH3; 98% X = CH2; 92% = Ph; 88% = N; 93%

Scheme 21.19

IL 17, 0%

H3C N + N

Br

IL 18, 0%

N H

H3C N + N

SO3H

IL 16, 84% [BSMIm]+[OTs]− (B)

H3C N + N

NH R N H R

N H 54

NH CH3

SO3

OTs SO3H IL 19, 0%

[DMImB]+[OTs]− (E)

O

N H 88%

O NH CH3

O NH

N H

X = CH2; 93% = O; 87% OH = S; 88%

NH X

N H 89%

Synthesis of quinazolinone derivatives using [BSMIm]+ [OTs]− (IL 15).

isoxazole moieties. Milder reaction conditions, lower catalyst loading, application of water as a greener reaction medium, and recyclability of catalytic system in eight consecutive runs were some of the added advantages of this strategy. Hajra and research group systematically designed structurally diversified imidazolium-based Brønsted acidic ILs (BAILs) for the synthesis of 2,2-disubstituted quinazolin-4(1H)-one (54) from 2-aminobenzamides (53) and ketones (25) (Scheme 21.19) [27]. The author prepared two separate alkyl chains of variable length containing ILs [BSMIm]+ [OTs]− -A (IL 15) and [BSMIm]+ [OTs]− -B (IL 16). They found that the longer alkyl chain containing IL [BSMIm]+ [OTs]− -A (IL 15) showed better conversion of the product than the one containing a shorter chain. Further, to check the role of SO3 H group on the alkyl chain, the author performed the reaction with aprotic imidazolium zwitterionic substrate

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

(IL 17) and Bromo-substituted IL [PMIm]+ [Br]− (IL 18). Both the cases completely failed to provide the cyclized product (54). The research group further checked the effect of C2—H of the imidazole motif by carrying the reaction with C2-methyl-substituted imidazole-based IL (IL 19), and no desired heterocyclic product 2-methyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one was formed. The optimization studies confirm that C2—H of imidazolium cation and acidic proton on appended alkyl chain with appropriate chain length are essential for the efficient transformation. Using this methodology, the research group prepared various 2,2-disubstituted quinazolin-4(1H)-one, including spiroquinazolin-4-(1H)-one and spiroheterocyclic quinazolin-4-(1H)-one derivatives. From mechanistic perspective, the SO3 H group on the alkyl chain activates the carbonyl oxygen of ketone via H-bonding. Eventually, the C2—H of imidazolium gets involved in another hydrogen bonding with amidic carbonyl oxygen. These hydrogen bonding interactions bring both the reactants in closer proximity. The nucleophilic attack of amine at carbonyl site of ketone followed by dehydration leads to the intermediate 20.A. This intermediate facilitates intermolecular cyclization to deliver the desired final product 2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one (52) (Scheme 21.20) [27]. The C2—H of imidazolium cation and acidic proton on appended alkyl chain with appropriate chain length are essential for the efficient transformation. For a particular note, the reaction provided excellent yield of 2,2-disubstituted quinazolin-4(1H)-one without column purification. Water was the only by-product of the reaction. Further, the reaction went smoothly under solvent and metal-free conditions thereby making the overall reaction much greener. In 2021, Trushkov, Ratmanova, and Andreev groups combinedly used 1-methylimidazolium thiocyanate (HMimNCS) a protic ionic liquid (PILs) (IL 20) as a reagent in the construction of substituted pyrrolidine-2-thiones (56) from donor–acceptor cyclopropane (55) (Scheme 21.20) [28]. The PILs (HMimNCS) protonated carbonyl group of the donor–acceptor cyclopropane and induced a ring opening of protonated cyclopropane. The thiocyanate ion undergoes nucleophilic attack on saturated carbon of protonated cyclopropane substrate via either sulfur or nitrogen site attack, which leads to an enol intermediate 21.A or 21.B (Scheme 21.21). An intramolecular attack of enol functionality (21.B) on the isothiocyanate core followed by a proton shift afforded pyrrolidine-2-thione motif (56) (Scheme 21.21). H3C N H O

H3C N

NH2 53

NH2 H3C

Scheme 21.20

HO

O

Ph 25

H

O

OTs S

O O

H2O

N H

N

N H

H CH3 Ph

N

O

OTs O

S O

O

(20.A)

Plausible mechanism for the synthesis of 54.

NH CH3 N H Ph (54)

431

21 Applications of Ionic Liquids in Heterocyclic Chemistry

CO2CH3 CO2CH3

EDG

H3CO2C S C N

+

H N

70 °C, 1 h

N CH3

N H 56 H3CO2C

HMimNCS (IL 20)

55

OCH3 CO2CH3

N CH 3 N C S

S C N path a

O

H N

N

S

CO2CH3 S

EDG

proposed mechanism

path b

432

OCH3 O H Ph CO2CH3 (21.A)

CO2CH3 S

N H 56

OCH3 O H Ph CO2CH3 (21.B)

Scheme 21.21 Synthesis of 5-aryl-2-thioxopyrrolidine-3,3-diester via ring opening of donor acceptor cyclopropaneswith1-methylimidazoliumthiocyanate (IL 20) and its proposed mechanism. O

H

OH H3C N

70 °C, 2 h

57

[4+2] N H

Ph

Ph

Ph N

O C

OH

N C S

O NH S

O

S

58; 67%

HMimNCS (IL 20) N H H3C N

COOH N H

N C S

HMimNCS (IL 20)

150 °C, 1 h

O

N

[3+2]

NH S 59; 52%

Scheme 21.22 Synthesis of [1,3]benzoxazine-2-thione (58) and 3-thioxohexahydro-1H-pyrrolo[1,2-c]imidazol-1-one (59) via an ionic liquid 1-methylimidazolium thiocyanate (IL 20) involved cycloaddition reaction.

The authors further extended the protocol for the synthesis of few other N, O, and S contains heterocycle synthesis. For example, the reaction between 2-hydroxyphenylcontaining donor–acceptor cyclopropane (57) with 1-methylimidazolium thiocyanate (HMimNCS) afforded [1,3]benzoxazine-2-thione (58). Under reflux condition L-proline underwent formal (3 + 2)-cycloaddition with the IL HMimNCS leading to the formation of bicyclic 2-thiohydantoin (59) (Scheme 21.22). Srivastava and coworkers in their work reported synthesis of a highly efficient and basic IL supported on SBA-15 (IL 21) [29]. After synthesis of the catalyst, the research group, carried out a detailed characterization of the catalyst by various analytical techniques like powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), and thermogravimetric analysis (TGA). On concluding the fact

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

CHO

NH2

OH NC

+

CN

CN

O

IL 21 Water/ reflux

+

60 15

61

X

+

IL 21, rt

Y

60/63 X = CN, COOEt Y = CN, COOEt O O NH2 + H H

15

65

X

64

O O Si O

N N

OH N

CH3

SBA-15-pr-bu-triazole-OH (IL 21)

O

IL 21 H2O, rt

66

Scheme 21.23

SBA-15

CHO

62

Y

NH 67

OH

IL 21 catalyzed synthesis of naphthopyrans, styrenes, and carbinolamides.

that the catalyst has been successfully synthesized, they applied the synthesized catalyst for preparing a diverse range of substituted styrenes (64), carbinolamides (67), and naphthopyrans (62) (Scheme 21.23). In all reactions, IL 21 exhibited excellent activities. It is noteworthy to mention that the synthesized catalyst was recyclable and was easily recycled and reused till five consecutive runs. This study revealed that reactivity and basicity of ILs can be tuned by incorporating Lewis base or Brønsted base, which in turn was found responsible for the high activity in various reactions investigated. This study represents a sustainable and eco-friendly catalytic route for the synthesis of pharmaceutically significant molecules. In 2020, Hanoon prepared new Brønsted acidic ionic liquid (BAIL), namely 2-[(1H-imidazol-3-ium-3-yl)methyl]-4-{bis[3-((1H-imidazol-3-ium-3-yl) methyl- (4hydroxyphenyl]methylene}cyclohexa-2,5-dienone trihydrogen sulfate ([2-(imm)-4{b(immh)m}c][HSO4 ]3 ) (IL 22), and the prepared IL was utilized in the synthesis of 2,4,5-trisubstitutedimidazole (70) via three MCRs between aldehydes (15), ammonium acetate (69), and benzyl (68) under ultrasound irradiation at room temperature (Scheme 21.24) [30]. After completion of the reaction, the author recovered the catalyst by simple filtration and washed it with dichloromethane.

CHO

O + O

15 68

Scheme 21.24

NH4OAc (69) IL 22, Ethanol

H N

Ultrasonication

N 70

HSO4 H N N

O N N H HSO4 N

N H HSO4 [2-(imm)- 4-{b(immh)m}c][HSO4]3 (IL 22) HO

OH

BAIL (IL 22)-catalyzed imidazole synthesis under ultrasound irradiation.

433

434

21 Applications of Ionic Liquids in Heterocyclic Chemistry

CHO

O +

NH2 +

O

NH4OAc (69) [DBUH]+[Im]−

N

N

N

N N H [DBUH]+[Im]− (IL 23)

Ethanol

68

15

71

72

H3CO

N

H3CO

N Cl

N

N

N Cl

CH3

N H3CO 72a; 95%

CH3

Scheme 21.25

N H3CO

72b; 96%

72c; 95%

s catalyzed synthesis of substituted imidazoles.

The recovered catalyst was used for three more cycles without losing its catalytic activity. Followed by Hanoon, [30] in 2021, Gill and research group reported tetra substituted imidazole via four component reaction by introducing aniline (71) as a fourth reactant in the Hanoon protocol. The combination of benzyl (68), benzaldehyde (15), ammonium acetate (69), and aniline (71) in a 1,8-diazabicyclo [5.4.0]-undec-7-en-8-ium imidazolate [DBUH]+ [Im]− IL (IL 23) provided highly substituted (1,2,4,5-tetrasubstituted)imidazoles (72) with short reaction time, excellent yield, and very high purity of products at room temperature (Scheme 21.25) [31]. The IL [DBUH]+ [Im]− acted as both catalyst as well as a green solvent medium. The IL [DBUH]+ [Im]− was inexpensive, biodegradable, easily recoverable, and reusable. It was reused for more than five consecutive cycles. Application of this protocol for gram-scale synthesis added to its practical applicability. Synthesized tetra-substituted imidazole derivatives were treated with human tumor cell lines MCF-7, EC-109, PC-3, and HGC-27. 72a revealed inhibition of MCF-7 with IC50 values of 3.54–0.55 μM, close to that of doxorubicin (1.58–0.20 μM). Compound 72c showed higher (three times) inhibitory rate to EC-109 than 5-fluorouracil (IC50 : 24.64–1 μM vs. 397.74–0.89 μM). 2-Hydroxyethylammonium formate IL anchored on Fe3 O4 (IL 24) was synthesized by Khalifeh et al. Fe3 O4 -coated silica nanoparticles were synthesized by Stober’s method. Then it was treated with 2-hydroxy ethyl ammonium formate synthesized from amino ethanol and formic acid, under ultrasonication, followed by its activation at 60 ∘ C. After synthesis, the catalyst was characterized by various analytical techniques like field-emission scanning electron microscopy (FE-SEM), TEM, FT-IR, vibrating sample magnetometer (VSM), TGA, and X-ray diffraction (XRD) analyses. After characterizing the catalyst, it was applied for the synthesis of diverse range of 2,4,5-trisubstituted-1H-imidazole derivatives (70) (Scheme 21.26). The catalytic power of the particular magnetic-nanoparticle-based ILs remained

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

CHO

O

+ NH4OAc

+ O

N

Fe3O4@SiO2-EP-HEAF (IL 24) Ethanol, 80 °C

N H 70

69

68

15

Scheme 21.26

IL 24 catalyzed synthesis of 2,4,5-trisubstituted imidazoles.

Ph CN 1-Naphthol (61) O 62 CHO CN

CN Resorcinol (73)

Ph

CN H

HO

O

O

H O

–H2O

NC

60

CN

H

Ph

O

O 73

O

H

O

CH3 O

H

27C

CN 27A HO

Scheme 21.27

CN

H NC

NH2 NH2

Ph

76

O

CN

O

2-Naphthol (74)

NC 27B H

Ph H H

75 O

27B

CH3 H3C N H3C OH OAc Cholin acetate (IL 25)

CH3 H3C N H3C O

IL 25 rt

60

H3C

Ph

CN + NC

15

NH2

H

Ph

Ph H

CN O

N

HO

O

Ph CN

CN NH

HO

O 75

NH2

Choline acetate (IL 25)-mediated synthesis of 2-amino-4H-chromene.

intact even after five consecutive runs as proved by SEM and TEM analyses of the reused catalyst [32]. In their work, Li and coworkers described an efficient IL-based catalytic system, choline acetate (IL 25), for the preparation of 2-amino-4H-chromene derivatives (62, 75, 76) (Scheme 21.27) [33]. The hydroxyl group on the cation part of the IL increased the electrophilicity of the carbonyl carbon (of aldehyde) by formation of hydrogen bond. Eventually, acetate anion of the IL activated the α-hydrogen of malononitrile (60), thereby forming carbon anion (27.A). This carbon anion goes and attacks the electrophilic carbonyl carbon of aldehyde, thereby forming the Knoevenagel adduct (27.B). Following this, phenol derivatives [1-naphthol (61), resorcinol (73) and 1-naphthol (74)] are dehydrogenated by the IL (IL 25) to produce phenoxy anion (27.C). Finally, phenoxy anion (27.C) reacts with adduct 27.B to give the desired products (62, 75, 76). This IL could be easily prepared from low-cost, biocompatible materials. The reaction was carried out at room temperature without

435

436

21 Applications of Ionic Liquids in Heterocyclic Chemistry O

O

O

O

HN H3C

O

H3C H3C

CH3 21 EtOH:H2O (2:1) reflux, 10–45 min R CN

CHO R 15 + NC 60 CN [H2-DABCO][H2PO4]2 (IL 26) H H2PO4

O 77

Scheme 21.28

NH2

N N H2PO4 H [H2-DABCO][H2PO4]2 (IL 26)

NH X 78

H2O, 75 °C 8-30 min O HN X

R CN

O NH2 N H X = S, O 79

Synthesis of pyran derivatives using IL 26.

the necessary of additional organic solvents, and the work-up procedures were very simple and no column purification was required. Shirini et al. [34] reported synthesis of pyran derivatives using novel acidic DABCO-based ILs 1,4-diazaniumbicyclo[2.2.2]octane dihydrogen phosphate [H2 -DABCO][H2 PO4 ]2 (IL 26). They used various substituted benzaldehydes (15), dimedone (21), and malononitrile (60) as starting materials in water–ethanol (2 : 1) cosolvent mixture under reflux conditions for the synthesis of tetrahydrobenzo[b]pyrans (77) (Scheme 21.28). The developed procedure was also being applied for the synthesis of diverse range of pyrano[2,3-d]pyrimidinones (79) using barbituric acid/thiobarbituric acid (78). The catalyst was prepared using a mixture of phosphoric acid and DABCO. The synthesized catalyst was characterized using various analytical techniques like FT-IR, 1 H and 13 C NMR, melting point, and mass spectrometer. The catalyst was recyclable, and the reusability of the catalyst was tested till four consecutive runs. The same research group further reported another DABCO-based acidic IL catalyst by the treatment of DABCO with sulfuric acid (IL 27) [35]. Purity of the catalyst was determined using FT-IR, NMR, and mass analyses. Appearance of acidic H peak of HSO4 − at around 13.8 ppm in 1 H NMR spectrum and aliphatic 13 C peaks of DABCO in the region of 43 ppm indicated successful formation of the catalyst. After characterizing the catalyst, the research group, employed the catalyst for the synthesis of a library of benzimidazoquinazolinones (80) in good to excellent yields using cyclic 1,3-diketone (21), 2-aminobenzimidazole (19) and aryl aldehydes (15) under solvent-free reaction conditions at 100 ∘ C (Scheme 21.29). Next, the same protocol has been adopted for the synthesis of pyrimido[4,5-b]quinolines (82) (Scheme 21.29). For this, 6-amino-1,3-dimethyluracil (81) was used as the amine source in aqueous ethanol at 75 ∘ C. After completion of reaction, the catalyst was recycled and reused till three consecutive runs. In order to confirm the stability of the reused catalyst (after three consecutive runs), its FT-IR analysis was carried out and was found to be in great agreement to that of the freshly prepared catalyst. The present protocol was found to be better as compared to other reported procedures with high TOFs and good yield.

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles

O H3C H3C

O N

O N CH3

O R

N

HSO4

N NH2 81 CH3

O

IL 27 O

21

Water: ethanol (2:1) 75 °C, 65–150 min

O

H HSO 4

+

(IL 27) 16 mol%

NH

N N H

N NH2 N H 19 (IL 27) 9.7 mol%

RCHO 15

N HN

R

Neat, 100 °C 20–55 min

[H2-DABCO][HSO4]2 (IL 27)

CH CH3 3

N

O H3C

CH3 80

82

Scheme 21.29 [H2 -DABCO][HSO4 ]2 -mediated synthesis of benzimidazoquinazolinones and pyrimido[4,5-b]quinoline derivatives.

O

H N

O H3C Y

N

NH NH

N X N H 85 CH3 Y = O, S

78

O

Y

O

IL 28, H2O, 75 °C Urea or thiourea X = O, S 84

O

CHO

H3C +

15

O

N

O

R R R = H, 83; CH3, 21

O H3C

N NH2 IL 28, H2O, 75 °C O 81 CH3 H ClO N 4 N ClO4 H [H2-DABCO][ClO4]2 (IL 28)

O

N N N H CH3 82

Scheme 21.30 Synthesis of pyrimido[4,5-b]quinolines (82) and pyrimido[4,5-d]pyrimidines (85) using IL 28.

This particular research group reported the synthesis of another new IL, 1,4-diazanium bicyclo[2.2.2]octane perchlorate[H2 -DABCO][ClO4 ]2 (IL 28), which was synthesized using a mixture of perchloric acid and DABCO. The synthesized catalyst was characterized using melting point, FT-IR, NMR, and mass analyses. After successful characterization of the catalyst, the research group employed it for the synthesis of pyrimido[4,5-b]quinolines (82) and pyrimido[4,5-d]pyrimidines (85) (Scheme 21.30). For synthesizing pyrimido[4,5-b]quinolines (82), aromatic aldehydes (15), 1,3-cyclohexadione (83)/dimedone (21), and 6-amino-1,3-dimethyl uracil (81) were used as starting materials. They used water as the reaction medium and stirred the reaction at 75 ∘ C. The scope of the present protocol was also extended for the synthesis of pyrimido[4,5-d]pyrimidines (85) using aromatic aldehydes (15), barbituric acid/thiobarbituric acid (78), 6-amino-1,3-dimethyl uracil (81), and urea or thiourea (84) as shown in Scheme 21.30 [36]. Reusability of the catalyst was checked till three consecutive runs. The Biginelli reaction has received tremendous attention in recent years because of its ability to synthesize biologically important heterocycles [37a, b]. Therefore, one-pot synthesis of dihydropyrimidinone (87) by the Biginelli reaction of aryl/alkyl aldehydes (15), methyl/ethyl acetoacetate (86), and thiourea or urea (84) at 70 ∘ C was reported by Ha-Choi et al. using triethyl ammonium acetate [Et3 NH]+ [OAc]− (IL 29) as the catalytic solvent (Scheme 21.31) [37c]. This particular IL (IL 29) was synthesized using triethyl amine and acetic acid at 70 ∘ C. Further characterized by

437

438

21 Applications of Ionic Liquids in Heterocyclic Chemistry Ph

CHO

X NH2 + H3C + H2N X = O, S 84

15

Scheme 21.31

N

O

O

[Et3NH]+[OAc]− (IL 29) OCH3

86

70 °C, 45 min

NH2 H3C + 89

Scheme 21.32

CH3 N H X = O, S (87)

Triethyl ammonium acetate-catalyzed synthesis of dihydropyrimidinones.

H3C

O N

OCH3

HN X

O

S O

H 88

HEAAc (IL 30)

+ O 21/ 83

R R

90 °C, 2 h

N

N

S

O

HO O

NH3

R O CH3 N R H HEAAc (IL 30) R = H, CH3 90

Application of IL 30 for the synthesis of pyrazolodihydropyridines.

Karl Fischer titration revealed less than 70 ppm of moisture content in IL 29. Further studies on the antibacterial and antioxidant properties of the synthesized derivatives were also performed. Application of hydroxyl ethyl ammonium acetate (HEAAc) (IL 30) as a catalytic solvent was carried out by Patel and research group for the synthesis of pyrazolodihydropyridines (90) (Scheme 21.32) [38]. 3-Methylthiophene-2-carbaldehyde (88), cyclic 1,3-diones (21/83), and 3-methyl-1-phenyl-1H-pyrazole-5-amine (89) were used as starting materials and stirred at 90 ∘ C for 2 h. After completion of the reaction, 60–89% of the desired product was isolated. Industrial applicability of the present protocol was also satisfied as the authors carried out the reaction in large scale (3–10 mmols) and got very good results. Recyclability of the catalyst, cost-effectiveness, and high atom efficiency were few of the added advantages of the present protocol. Synthesized compounds were also screened for various pharmacological activities like antifungal, antibacterial, anticancer and anti-tuberculosis activities. In 2019, Hu et al. reported the synthesis of cyclic carbonates (93) by condensation of epoxide (91) with carbon dioxide (92) in the presence of IL 31 catalyst under neat condition at 90 ∘ C for 30–60 min [39]. The product was isolated in excellent yield (96–99%, Scheme 21.33). The imidazolium aminic nitrogen of IL (which acts as hydrogen bond donor) activated the carbon dioxide followed by nucleophilic attack of NTf2 anion on carbon of 91. This enhanced the ring opening and cyclization with elimination of NTf2 anion to give cyclic carbonate 93. After completion of reaction, the IL-based catalyst was recovered by filtration, washed with dichloromethane (DCM), and reused till six consecutive runs without much decrease in catalytic activity. Further, the group also compared their catalysts and conditions with the reported procedures [40–45] to claim advantages of their protocol. More recently, applications of carbon-based materials as catalytic system have gained tremendous attention in synthetic organic chemistry [46]. These carbon-based materials also serve as a surface for grafting ILs [47, 48]. Veisi and

21.2 Application of Ionic Liquids in the Syntheses of Various Heterocycles O

O PMO@IL-NTf2 (IL 31) + C 90 °C, 30–60 min R O 92 91

N

Si

NTf2 NTf2 PMO@IL-NTf2 (IL 31) O

O

O O

O

O

N

N

O

H3C

O

O

OH

Scheme 21.33

O

O O

O

OCH3

O O

O

O

N

O O Si O

O

O O 93

R

PM

PMO

O

O

O O

O

O O

O

F3C

Cl

Synthesis of cyclic carbonates usingPMO@IL-NTf2 (IL 31).

H N 2

N H 94

97

HN

CHO g-C3N4-SO3H (IL 32) Ethanol, 70 °C, 1 h O O O

H2N

CH3 O CH3 95

+

H N

H N

N

96 CH3

O

N N H 98 CH 3

Scheme 21.34 g-C3 N4 -SO3 H-catalyzed synthesis of bis(indolyl)methanes and pyrazolo[3,4-b]pyridines.

coworkers in their work, reported catalytic activity of sulfonic acid functionalized ILs supported on polymeric graphitic carbon nitride (g-C3 N4 -SO3 H) (IL 32). They applied the catalytic system for synthesizing bis(indolyl)methanes (97) and pyrazolo[3,4-b]pyridines (98). Aromatic aldehydes (15) and indoles (94) were used as starting materials for the synthesis of bis(indolyl)methanes (97) and Meldrum’s acid (95) with 5-methylpyrazol-3-amine (96) was used as starting material for the synthesis of pyrazolo[3,4-b]pyridine derivatives (98) (Scheme 21.34). Graphitic carbon nitride was prepared by thermal decomposition of urea. IL 32 was prepared by dispersion of graphitic carbon nitride (g-C3 N4 ) in DCM, followed by addition of chloro sulfonic acid in the mixture, which was stirred vigorously at 0–5 ∘ C. Then, after successful synthesis and characterization, it was applied in the abovementioned reaction. The catalyst was recycled and reused till five consecutive runs.

439

440

21 Applications of Ionic Liquids in Heterocyclic Chemistry

21.3 Conclusion and Future Prospective After having examined all the abovementioned synthetic procedures for preparing a diverse range of heterocycles, it can be concluded that ILs, because of their nonvolatile, noncorrosive and eco-friendly characteristics, have emerged as one of the best solvent as well as catalytic systems for one-step as well as multi-step reactions. In recent years, ILs have found their applications in several fields, such as electrolytes, polymers, catalysts, and solvents. Because of their broad range of polarities and tunable properties of cations and anions, they are often referred to as “designer solvents”. Even though there are numerous merits of ILs, at the same time they suffer from certain drawbacks, like (i) if not handled carefully, they may undergo undesired reactions at the reaction site, thereby leading to the formation of unwanted products, (ii) certain quaternary ammonium and phosphonium ILs may undergo degradation to form neutral products like ylides via SN 2 mechanism [49], and (iii) the high combustibility of certain ILs (because of positive heat of formation) [50]. There are extensive needs to solve the abovementioned issues as well as research should also be focused toward minimizing the cost of ILs.

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22 Application of Ionic Liquids in Drug Development Partha Dutta, Charu Arora, and Sanju Soni Guru Ghasidas Vishwavidyalaya, Department of Chemistry, Bilaspur, Chhattisgarh 495009, India

22.1 Introduction The magnitude of Coulombic attraction results in a very high lattice enthalpy for ionic solids. This is directly manifested in their melting points. Most of the ionic compounds are formed by counterions balancing the charge to maintain electroneutrality, and these ions are primarily from alkali and alkaline earth metals comprising cations and halides and oxo salts as anions. While some of them show poor solubility in solvents, an increasing polarity of the solvent might alter their solvation enthalpy that overcomes the lattice enthalpy. This solvation leads to the breaking down of the crystal lattice, producing freely moving ions; a similar effect is observed when they are in a molten state. The free mobility of the counterions plays a central role in electrochemical phenomena. Hence, ionic mobility is a direct function of temperature and solubility, and for this reason, certain metals are extracted at very high temperatures. The formation of ion pairs is not limited to elemental ions; in fact, a charge separation may occur in the molecule itself or more precisely, a charge transfer between two molecules, e.g. a proton transfer from an acid to a base [1], one of which is prone to attaining a particular polarity/charge due to various stabilizing factors such as aromaticity and carbo-cationic/anionic stability. These species often do not have the necessary stabilizing parameters, which account for the force of Coulombic attraction to manifest a solid state at ambient temperatures. In other words, they show ionic characters in terms of constituents but are not present in a rigid lattice state between temperature ranges where conventional ionic compounds are solid crystals. These compounds are designated as “ionic liquids”, evidently due to their magnitude of the melting point below 100 ∘ C [1]. The first of its kind (ethylammonium nitrate) was reported way back in 1914 by Paul Walden [2]. In recent times, work in this field has evolved from Colorado, where species like dialkylimidazolium and alky pyridinium were exploited in 1970 [1]. The vapor pressure of these species is typical to that of any ionic salt, being negligible [3], which is regarded as their key property among others. This is the very reason why they are regarded as benign to the environment. Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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22.2 Classification of Ionic Liquids Among the commonly found ionic liquids, the cations are mainly composed of tetraalkylphosphonium, tetraalkylammonium, N-alkylpyridinium, or N,N ′ -dialkylimidazolium. Other examples are C1–18 alkyl groups that include ethyl, butyl, and hexyl derivatives of N-alkyl-N ′ -methylimidazolium and N-alkylpyridinium, as well as pyrrolidinium, pyridazinium, pyrimidinium, pyrazinium, pyrazolinium, triazolium, thiazolium, and oxazolium. The anionic counterpart generally possesses Lewis basicity and the common examples include carboxylates, fluorinated carboxylates, sulfonates, imides, borates phosphates, antimonates, halides, and halometallates [4]. One has to be very specific while classifying any species, since the type of classification solely stands on the property on which they are described. Among the properties worth mentioning are miscibility in water, conductivity, and viscosity; however, how the chemical structures affect these properties of ionic liquids is still poorly understood. The catalytic property of Lewis base by the anions is well exploited through these species [4]. With these criteria in mind, ionic liquids are classified into neutral ions, acidic cations and anions, basic cations and anions, and amphoteric anions. Additionally, the ionic liquids have been further divided into a variety of subcategories, viz., room-temperature ionic liquids, task-specific ionic liquids, and poly(ionic liquids). Also, there are categories representing supported ionic liquids membranes that include composites of ionic liquids supported on metal–organic frameworks [2].

22.3 General Synthetic Methodologies The initial synthetic development of these species witnessed the methodology of bimolecular nucleophilic substitution of a haloalkane by nitrogen- or phosphorouscontaining heterocyclic rings, resulting in formation of a quaternary atom that is balanced by a counteranion whose source is the alkyl halide itself; the resulting ionic liquids were designated as first generation. The choice of alkyl bromide rather than alkyl halide reduces the time of the reaction, but their lesser commercial availability makes the chloro derivative the feasible option [5]. Moreover, the use of open vessels while using alkyl halides is somehow hazardous; the purity of the product is questionable, and additionally, there is a high probability of undesired water absorption by highly hygroscopic products. This limitation has been skillfully avoided by the use of nonconventional methodologies such as microwave and sonochemical synthetic routes that result in the so-called second-generation ionic liquids. The contemporary technological development in the field of electronics has equipped the synthetic chemists with microwave-assisted methodologies, which is a breakthrough in the context of minimizing the time required for synthesis. Also, there is an additional advantage of safe heating sources and solvent-free conditions [6]. Microwaves are the high-frequency electromagnetic waves with a wavelength between 10−3 and 1 m, and the instrumentation uses alternating electric

22.4 An Overview of Applications in Diverse Fields

signals. The energy of these electromagnetic waves is absorbed by the molecular species having permanent dipole moments forcing them to rotate. This leads to a collision with other molecules (reactants) and during this phenomenon they heat up while the rotating molecules loose energy. The theories are well established and have been elaborately reviewed in many publications [6]. Although the microwave irradiation provides an effective synthetic strategy for ionic liquids, it still has some drawbacks. The continuous microwave heating sometimes overheats the reaction medium, leading to the appearance of colored products [7]. The development of an alternate clean energy process [7] in view of the emerging importance of the ionic liquid led to the introduction of synthetic methodology that used sonic energy. When the reacting molecules are exposed to ultrasound waves, there is an accelerated chemical reaction due to adiabatic collapse of the transient cavitation bubbles [7]. There occurs a visible transition of the solution mixture from being transparent to opaque due to emulsification that ultimately leads to the formation of a clear viscous phase or separation of solids [7]. The reactivity is usually found to be in the order of I− > Br− > Cl− similar to that of the normal conventional synthesis; probably due to the poor leaving group capability of the chloride ions also with the bromides and iodides, room temperature synthesis was possible; also the purity of the dicationic salts synthesized via sonication is found to be superior as compared to conventional heating methods [7].

22.4 An Overview of Applications in Diverse Fields (a) Electrochemical application: Since these species have very low volatility and high ionic conductivity, they are considered a preferred candidate for utilization in energy storage devices such as batteries, solar cells, fuel, and cells [8]; their use as solvents for metal electrodeposition has been elaborately documented by researchers [9–11]. Also their use as solvents in batteries such as lithium ion [12], and in some cases, ionic liquid containing polymer inorganic hybrid electrolytes [13, 14]. Due to their high ionic conductivity, these species find a good application in dye-sensitized solar cell (DSSC) as potential electrolytes, and sometimes the use of eutectic ionic liquid mixture had proven a better result [15]. Due to their wide electrochemical window [16] they also find application in supercapacitors as safe alternatives for organic electrolytes [17]. (b) Extraction processes: The process of extraction of an analyte is unavoidable when it comes to collecting and conserving synthetically important samples [18]. Conventional extraction requires a large amount of organic solvent as its principle works on the distribution coefficient of an analyte into two or more solvents. The use of ionic liquids facilitates one to require a much lesser amount of liquid, a technique called microextraction technique [19]. In one of the reports, this technique was used to determine the concentration of Cu2+ and Ni2+ in vegetable oil samples [20]. Additionally, biomass extraction also used the ionic liquid isolate bioactive compounds from microalgae [21, 22].

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This process of microextraction benefits in wastewater treatment technologies, where the use of ionic liquids helps in the extraction of various compounds from water [23]. (c) Chemical reactions/catalysts: The application of ionic liquids in synthetic chemistry as catalysts is a prominent field worth mentioning in detail. The attached functional group with the anion or cation of these species accounts for their activity in catalyzing chemical reactions [24–27]. These are generally termed as task-specific ionic liquids [28]. The acid catalyst derived from combining different useful characteristics of solid acids and mineral acids has almost replaced these traditional mineral acids, since their reusability is a marked property when compared under the pretext of green chemistry. Many organic reactions, such as the Pechmann reaction, Koch carbonylation, and asymmetric aldol condensation, have been catalyzed by ionic liquids behaving as acid catalysts. Other notable examples of ionic liquids as catalysts are the acylation of isobutylbenzene using chloroaluminate-based ionic liquid replacing conventional catalyst AlCl3 [29], the olefinic alkylation of thiophenic sulfur in FCC gasoline using caprolactam-tetrabutylammonium bromide acidic quaternary ammonium ionic liquids [30], and the synthesis of poly(isosorbide carbonate) using amino acid ionic liquids. (d) Advance and smart materials: Certain materials have a unique way of responding to a stimulus. This change in property, usually reversible, can be recorded in terms of signals of voltage fluctuations. They are generally termed as smart materials in modern times. The manufacture of ionic liquid-based stimulus-responsive materials for smart windows is only possible due to the tunable nature of ionic liquids [31]. In this particular case, the thermo-responsive poly(ionic liquids) coupled with electrochromic materials and transition metal-based ionic liquid stimulus-responsive materials are generally considered important components of smart windows. Another interesting example is wearable medical devices for monitoring of vital parameters related to human health. Such devices are generally composed of materials with a friendly interface to the human skin and possess advanced functionalities [32–34]. One of the technological breakthrough in this field of research is the development of actuators or sometimes called artificial muscles which has the capability to mimic natural muscles in terms of changing the stiffness and undergo contraction or expansion in response to external stimulus, i.e. temperature, pressure, or even voltage. A cellulose-acetate-based ecofriendly soft-ionic networking actuator consisting of ionic liquid and other materials demonstrate a beautiful example. (e) Pharmaceutical: One of the most innovative applications of ionic liquids is their utilization in the field of drug synthesis and delivery, which is a major concern in the pharmaceutical science; this has been discussed by Egorova, Gordeev, and Ananikov [35], where the emphasis on the novel active pharmaceutical ingredient, ionic liquid, has been focused. The prime goal of the pharmaceutical industry is to develop drug delivery systems that allow for a prolonged and therapeutically effective drug delivery.

22.5 Specific Applications in the Field of Pharmaceutical Development

22.5 Specific Applications in the Field of Pharmaceutical Development ●

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Drug solubility: The poor solubility of drugs is a crucial challenge faced by the pharmaceutical industry. This is primarily because of the aqueous in-vitro environment of the bio-organisms which hinders the solubility of the formulated pharmaceutically active molecules having substantial non polar characteristics. It is found that this lack of sufficient insolubility accounts for about 60–70% of drug molecules in aqueous medium, leading to low permeability that allow inadequate absorption from the gastrointestinal tract [36]. The pharmacokinetic and pharmacodynamic properties of drugs are the two main areas considered while formulating their composition. Both polar and nonpolar species are well dissolved in ionic liquids; they even proved better than the organic solvents that were a well-accepted medium in the pharmaceutical industry [37]. The standard practice of enhancing the aqueous solubility of any drug is to administer them as salts. Some of the well-known examples are diclofenac, ibuprofen, ketoprofen, naproxen, sulfadiazine, sulfamethoxazole, and tolbutamide [38–43]. A study by T.E. Sintra [44] involving pyridinium, piperidinium, pyrrolidinium, phosphonium, ammonium, and cholinium, ionic liquids improved the solubility of ibuprofen in water due to formation of ionic liquid–drug aggregates. Two poorly water-soluble drugs, paracetamol and sodium diclofenac, have been able to increase their solubility by the use of N-acetyl amino acid- N-alkyl choliniumbased ionic liquids [45]. The low ecotoxicity, easy availability, and better biocompatibility of cholinium-based ionic liquids, viz. choline saccharinate and choline acesulfamate having hydrophilic nature, makes them worthy for a sustainable alternative to the imidazolium-based moieties [46–51]. This has been confirmed experimentally by Jesus et al. [36], where they prepared 16 different N-alkyl cholinium-based ionic liquids and studied the solubility of 2 commercial drugs, paracetamol and sodium diclofenac, in water in the presence of 0.2–1.0 mol% ionic liquids. Their results were in very good agreement with those previously reported in the literature. The choice of anions in the ionic liquids was done keeping in mind the biodegradability of the compounds. In this context, sulfonate is most reported in the literature; among others, sulfate, acetate, and phosphate anions are also potential alternatives. In another study, Michuzzi et al. found the effect ionic liquid cosolvents along with water using three different cations with hexafluorophosphate and tetrafluoroborate as common anions, on four drugs, viz. albendazole, danazol, acetaminophen, and caffeine. Drug transport/delivery: Once there is a satisfaction with the solubility of the prepared pharmaceutical ingredient, the next responsibility is its availability in the intracellular fluid from the point of its introduction in the organism. Usually, the cellular fluids are responsible for this process. There has been a tremendous amount of research on drug delivery routes since 1950 [52], which not only includes oral and injection but also transdermal, topical, and nasal ways were also in practice with target-based drug transport. From the region of

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administration to the target area a pharmacological preparation has to endure different chemical/biological environment, and there is a strict necessity to preserve the potency of the drug [53–57]. Due to the noninvasive nature of delivery, the transdermal route is, needless to say, the most preferred one. The loss of drugs due to metabolism is eradicated. Stable microemulsions and self-assembling systems of a surfactant of mixture of surfactants in two immiscible fluids are well recognized as potential drug carriers due to their nanometer size and stability in the body fluid. In an evaluation [37] of the skin carcinogenesis of mice induced by dimethylbenz(a)anthracene (DMBA)/tetradecanoylphorbol-13-acetate (TPA), the application of ionic liquid-oil microemulsion could treat it in 4 weeks in contrast to an aqueous solution, conventional ointment and commercial cream were ineffective in restoring normal physiological condition. Biocompatibility vs. toxicity: The consideration of ionic liquids as solvents for green synthetic chemistry although fits the title but it lacks superiority when the domain belongs to biology. The biodegradation and toxicity of the pharmaceutical ingredients that are to be administered into the body are the major two crossroads that researchers encounter while analyzing the structure–activity relationship of the molecules. In contrast to the lower vapor pressure of the ionic liquid, the surprisingly better aqueous solubility, sometimes pose substantial hazards [58–65], leading to soil and water pollution. The predominantly aqueous nature of biological assays are not to mention quite susceptible to similar kinds of toxicity [66–71]. Hence, some issues such as good biodegradability, ecotoxicity, bioaccumulation, and environmental fate must be appropriately ensured to satisfaction (Figure 22.1). It was found in several studies that imidazolium, pyridinium, and quinolinium bases in cationic head groups of ionic liquids possess a higher probability of cytotoxicity when compared to their morpholium counterparts. A detailed study also pointed out the significant suppression of ecotoxicity while incorporating shorter side chain length (C < 4) being attached to the cation headgroup. Also, the introduction of a polar functional group into the cations provides an alternative pathway [72]. Amde and coworkers [73] have summarized relative toxicity of the cationic head groups as per the following order: choline < piperidinium < pyrolidinium< morpholinium < pyridinium = imidazolium < ammonium < phosphonium. The ionic liquids containing a short alkyl side chain are found to be less toxic, but they are poorly biodegradable [37]. Hence, there is an inherent conflict between biodegradability and biocompatibility [74, 75]. Apart from cations, there is a significant contribution by the anions toward the biodegradability of ionic liquids. Shorter linear chain anions like ethanoate and propanoate were not readily bio degradable [76]. Whereas longer-chain anions, including butanoate, pentanoate, hexanoate, and octanoate, are completely biodegradable. Also, anions of organic origin like acetate, sulfate, and phosphate are generally biodegradable. Anions like [PF6 ] and [BF4 ] undergo hydrolytic reaction in the biological environment, producing toxic and corrosive HF [77]. Among other moieties that are considered for biocompatibility are amino acids [78–82], nonnutritive sweeteners [49], glucose [83], and

22.5 Specific Applications in the Field of Pharmaceutical Development

High viscosity of ionic liquids may cause difficulty in handling Ionic liquids explored for pharmaceutial applications should have negligible toxicity

Cost should be low in comparison to drug carrier

Figure 22.1

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Challenges for future applications of ionic liquids in drug delivery

Degradability of ionic liquids should be low for efficient use in the pharmaceutical industry

Lack of proper coordination and communication between academia and drug developer industry

Challenges for future applications of ionic liquids in drug delivery.

carboxylic acids [84]. Currently, the most successful approach for the synthesis of biocompatible ionic liquids is the selection of precursor (anions and cations) that are already bio compatible [85, 86]. In parallel, the osmolarity of the solution of ionic liquid also contributes to its consideration of biocompatibility and toxicity in therapeutic applications [87]. Intravenous administrations of ionic liquids of concentrations of ionic liquids higher than that of cellular concentration may result in osmotic shocks in recipients [88, 89]. The Organisation of Economic Co-Operation and Development (OECD) and the International Organization for Standardization (ISO) are the two prime entities that recommend standardized tests for the evaluation of biodegradation profile. As per the outcomes of the tests, they are categorized as primary degradation, inherently biodegradable, readily biodegradable, and mineralization. Drug sequestration/recovery: Recent works by Claudio [66] stressed on the extraction of value-added compounds from biomass using aqueous solutions of ionic liquids due to their hydrotropic nature, and the attempt covered a wide range of biomolecules [90] that even include drugs [91]. The underlining factor behind the stability of coacervates is the synergistic interaction between the oppositely charged macromolecules, which is also accompanied by entropic forces associated with the release and reorganization of small counterions [92, 93]. Additionally,

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surfactant-based coacervates have an advantage over simple coacervates in various factors such as interaction are controllable and predictable. Liang et al. [94] were the first to report the encapsulation of malachite green, crystal violet, and methylene blue dyes within coacervate droplets. With the modernization of medical treatment, our expected lifespan also increased. As a result of their immediate effect, there occurs an enormous quantity of pharmaceutical ingredients being discharged as waste products. There are several factors leading to this waste generation and few to mention are end of shelf life, inadequacy of the package size, and sometime even the failure in the treatment guidelines [95, 96]. But it is found that even the expired drugs hold 90% of active principle in stable form. The extraction of these active ingredients poses a challenge, which is actively undertaken by ionic liquids. The nature of molecular level interaction, viz. hydrogen bonding, hydrophobic, and electrostatic interactions, suggest that, precise selection of ionic liquid structure is crucial in achieving efficient extractions. [97, 98]. An experimental study conducted by Silva et al. for the extraction of commercially available ibuprofen using three different ionic liquids in water and in presence of potassium citrate buffer, generally used in pharmaceutical industry as anionic hydrotropic agents [99]. As per the results, the ability of ionic liquids and ionic liquids in conjunction with the citrate buffer aqueous solution can be ranked as water < [BzCh]Cl < 5 wt% citrate buffer ≈ [C4mim]Cl ≪ [C4mim]Cl + citrate buffer < [BzCh]Cl + citrate buffer < [N4444]Cl < [N4444]Cl + citrate buffer. Sustainability/future prospects: In a large number of situations, structural aspects have shown to play a crucial and unexpected role, so understanding ionic liquids both in terms of their macroscopic properties and also at the molecular level is inevitably necessary. The large diversity of combinations of cations and anions, producing novel ionic liquids with specific properties is astonishing. The use of ionic liquid in the pharmaceutical industry should be encouraged, which might result in the recycling of the drugs that have been put on hold owing to their limited aqueous solubility or polymorphic conversions. Although there is an enormous quantity of research in ionic liquids, the family of bio-ionic liquids has grown in the last few years. The prime factor behind this sudden explosion is the emergent need for “greener”, safer, and less harmful compounds accompanied with sustainable synthetic routes. The production of sensitive, selective, and reproducible electrodes is greatly accomplished by bio-ionic liquid-based composites that have catalytic ability. Recent literature also reports the development of integrated biocompatible batteries into one single, continuous unit, removing the necessity of packaging [100–102]. The removal of ionic liquid after the synthesis of active pharmaceutical ingredients (API) is still a challenging task for the researchers. The use of aqueous solutions of ionic liquids instead of pure forms can be the starting point for acceptance in the pharmaceutical industry. Due to their polymerizable character and polymer solving ability, these species allowed the development of tailored biopolymer drug delivery systems. There is also relevance to stimulus-responsive drug delivery systems, promoted by ionic liquids of polymers [103].

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology Ehiaghe Agbovhimen Elimian 1,2,3 , Fidelis Odedishemi Ajibade 4,5,6 , Temitope Fausat Ajibade 4,6,7 , Hailu Demissie 8,9 , Nathaniel Azubuike Nwogwu 10,11 , Kayode Hassan Lasisi 4,6,7 , Daniel A. Ayetoro 12 , and Ehizonomhen Solomon Okonofua 13 1

University of Benin, Faculty of Life Sciences, Department of Plant Biology and Biotechnology, Benin City, Nigeria University of Nottingham, Faculty of Science and Engineering, Department of Chemical Engineering, Ningbo 315100, PR China 3 Key Laboratory of Urban Pollutant Conversion, & CAS Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China 4 Federal University of Technology, Department of Civil and Environmental Engineering, Akure PMB 704, Nigeria 5 Key Lab of Environmental Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, PR China 6 University of Chinese Academy of Sciences, Beijing 100049, PR China 7 Key Laboratory of Urban Pollutant Conversion, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China 8 Arba Minch University, Department of Chemistry, Arba Minch 1000, Ethiopia 9 State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, PR China 10 Federal University of Technology, Department of Agricultural and Bioresources Engineering, Owerri PMB 1526, Nigeria 11 Auburn University, Department of Biosystems Engineering, Auburn, AL 36849, United States 12 University of Ilorin, Department of Industrial Chemistry, Ilorin, Nigeria 13 University of Benin, Department of Geomatics, Benin City, Nigeria 2

Notation Cationic Chains AMIM AMMorp BMIM+ EMIM+ HMIM+ MMEP+ MMIM MTOA+ N4444 OMIM+ PPMIM+

1-alkyl-3-methylimidazolium N-allyl-N-methylmorpholinium 1-butyl-3-methylimidazolium 1-ethyl-3-methylimidazolium 1-hexyl-3-methylimidazolium 1-methyl-1-(2-methoxyethyl) pyrrolidinium 1,3-dimethylimidazolium methyl trioctylammonium tetrabutylammonium 1-methyl-3-octylimidazolium 1-(3′ -phenylpropyl)-3-methylimidazolium

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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Anionic Chains BF4 − CF3 SO3 dca− EtSO4 − For MeSO4 − OAc− Otf− PF6 − Pro Tf2 N−

tetrafluoroborate trifluoromethanesulfonate dicyanamide ethyl sulfate formate methyl sulfate acetate triflate (or trifluoromethanesulfonate) hexafluorophosphate propionate bis(trifluoromethane)sulfonimide

23.1 Introduction Biocatalysis and biotechnology involve the application of enzymes in biotransformation processes. Enzymes are eco-friendly and sustainable, and are popularly used due to their biological abundance and relatively low cost. Furthermore, the use of inorganic catalysts such as noble metals for biotransformation processes is not favorable due to the high cost of materials and low selectivity [1]. Enzymatic reactions are carried out in water under gentle conditions (physiological pH, ambient temperature, and pressure), without the need for functional group activation or the protection and deprotection stages that are required in classical organic syntheses [2]. Enzymatic reactions can also be carried out in standard batch reactors, avoiding the need for additional investments [2]. Furthermore, since the majority of enzymatic reactions occur at similar temperatures and pressures, it is extremely easy to combine multiple reactions into a catalytic cascade. Whole microbial cells and isolated enzyme cells or cells are the two types of enzyme components used in the biotransformation process. In addition to their natural affinity for water, enzymes perform at their best in organic solvents, and are often used to improve the solubility of reactants and maintain the reaction equilibrium [3]. Ionic liquid introduction into a biological system was first known in 2000, with the pioneer ionic liquid (EtNH3 NO3 ) reported in 1914. The inability of ionic liquids to crystalize at room temperature makes them excellent alternatives to other organic solvents [4, 5]. Ionic liquids have been extensively researched for their low vapor pressure, thermal stability, and adjustable properties, which make them desirable alternatives for organic solvents. Furthermore, ionic liquids can easily be regenerated due to their unusual miscibility properties compared to organic solvents [6].

23.2 Properties of Ionic Liquids Biotechnological process performance is heavily influenced by the physicochemical properties of solvents. In particular, a solution with a high viscosity can affect both the mixing requirements and the overall cost of the process.

23.2 Properties of Ionic Liquids

23.2.1 Hydrophobicity The most common solvent descriptor in organic solvents is log P and it is regarded as a critical indicator for enzyme activity [7]. For instance, solvents with log P values above 3.5 such as hexane are considered and are suitable for enzymatic processes compared to solvents with lower log P values [1, 8]. Russell and coworkers were the first to determine log P for ionic liquids, this was because the dialkylimidazolium-based ionic liquids absorb more at about 211 nm due to the imidazolium ring that is located in it [7]. It indicates that the ionic liquids are very hydrophilic when the value of log P is extremely low (−2.90 to −2.39). The ionic liquid [Bmim][OAc] and [Bmim][NO3 ] having a log P value of −2.77 and −2.90, respectively, are also hydrophobic [9–11]. Hydrophobic ionic liquids were applied as alternative solvents to overcome the challenges posed by nitrile hydratase (NHase)’s low solubility and stability [12]. The electrostatic bonds shared between ionic liquid and NHase improve enzyme stability of the enzyme and preserved the morphology of the active sites even at extreme temperatures. Since ionic liquids are hydrophobic, substrates dissolve and are removed from active sites by solvation.

23.2.2 Polarity The degree of polarity of the solvent determines its ability to solvate a charge. Ionic liquids are highly polar solvents [13]. Ionic liquids are good reaction media due to their high polarity, which falls within the range of 0.6–0.7 compared to water that is set at 1. This property enables the dissolution of a variety of different compounds [14]. Although ionic liquids have a high polarity, they tend not to inactivate enzymes.

23.2.3 Purity The physicochemical properties of ionic liquids are altered by impurities e.g. organic salts and water [14]. Experimental results on the activity of an enzyme in an ionic liquid are not always stable, possibly because an ionic liquid is prepared with impurities [15]. Hygroscopic is the term used to describe ionic liquids with low water miscibility. These liquids are reportedly only soluble in about 1% water (v/v) reaction medium [16]. These water-immiscible ionic liquids contain [BF4 ] or [PF6 ], which can partially hydrolyze the anions to form HF, which inhibits numerous enzymes. For example, even though BMIM [BF4 ] and BMIM [MeSO4 ] are well suited to combine with water, the polarity of BMIM [PF6 ] and BMIM [Tf2 N] seems to indicate that they are likely to combine with tetrafluoroborate [15]. Dialkylimidazolium halide is another impurity that is formed due to partial metathesis, although silver tetrafluoroborate is used to remove it. However, preliminary measurements of the effects of the additives on lipase-catalyzed acetylation showed that silver or acidic impurities cause the reaction to be slow or to stop entirely in some ionic liquids [17]. Consequently, purification methods such as silica gel filtration have been recommended for removing imidazolium halides, as well as the use of aqueous sodium carbonate solution for removing acidic impurities instead of the use of silver salts. [17]. Some methods of purifying ionic liquids included incubating in water accompanied by drying in a vacuum oven. It was found that these purified ionic liquids worked reliably, but the process of purifying ionic liquids needs to be explored further.

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

23.2.4 Miscibility of Ionic Liquids Ionic liquids and water miscibility are highly varied and unpredictable. As mentioned earlier, the ionic liquids [BMIM][MeSO4 ] and [BMIM][BF4 ] readily combine with water compared to [BMIM][Tf2 N] and [BMIM][PF6 ]. There is no significant difference between these ionic liquids in terms of polarity or coordination strengths, and the log P values of hydrophilic ionic liquid [BMIm][PF6 ], and the hydrophobic ionic liquids [BMIm][AcO] and [BMIm][NO3 ] are comparable [7]. Recent studies have indicated that [BF4 ] and [MeSO4 ] have a stronger affinity for hydrogen bonds (= 0.61 and 0.75, respectively) than [PF6 ], which might explain the variance in water miscibility between the two compounds. Water and methanol do not mix at the molecular level, so aqueous mixes of ionic liquids are heterogeneous [18]. On the other hand, the miscibility property of ionic liquids and organic solvents are not readily available, for example, lower alcohols and dichloromethane can combine in [BMIm][Tf2 N], whereas alkanes are not easily miscible [19]. Based on the thermodynamic activity, In [BMPy][BF4 ], benzene, toluene, and styrene dissolve easily compared to alkyl aromantic compounds. Also, [BMIM][PF6 ] and [OMIM][BF4 ] do not mix with supercritical carbon dioxide [20].

23.2.5 Viscosity The viscosity of the reaction medium often affects the mass transfer of reactants and enzyme activity. The viscosity of ionic liquids are higher than conventional organic solvents ranging between 35 and 500 cP, whereas toluene is 0.6 cP, water is 0.9 cP at 25 ∘ C. Viscosity affects an ionic liquid’s ability to form hydrogen and van der Waals bonds. This can be reduced under a higher temperature or by introducing organic solvents as co-substrates. Generally, anionic liquids with large alkyl groups exhibit greater viscosity. Considering their high viscosity, ionic liquids will exhibit slow diffusion although the effect on biocatalytic reaction is negligible, except for extending the duration of the reaction. For instance, assaying of α-chymotrypsin in reaction medium containing [EMIm][Tf2 N] and [MTOA][Tf2 N] results in the reduced activity of α-chymotrypsin which can be attributed to the high viscosity values of the two ionic solvents [21]. Accordingly, ionic liquids with a high viscosity are expected to react at a slower reaction rate. Examples of density and viscosity for typical imidazolium-based ionic liquids are given in Table 23.1. Inorganic synthesis and catalysis are among the many fields where ionic liquids are used as reaction media. Today, a wide range of high-purity ionic liquids are commercially accessible. This factor is important, since it enables the development of ionic liquids for specific circumstances, such as improving the water solubility, selectivity, and reaction rate of the substrate and enzyme. The building blocks for bioactive ionic liquids are shown in Figure 23.1. Ionic liquids are not all ideal for biocatalytic reactions. Ionic liquids consisting of the anions tetrafluoroborate (BF4 ) and hexafluorophosphate (PF6 − ) generally promote enzyme activity, while the presence of nitrate (NO3 ), chloride (Cl− ), trifluoromethanesulfonate (CF3 SO3 ), trifluoroacetate (C2 F3 O2 ), and acetate anions

Cations

Imidazolium

Pyridinium

Piperidinium

R1

N

+

N

F F

− B

F F

+ N

+ N

+ N

R2

Tetrafluoroborate

Anions

Quinolinium

Morpholinium O

H3C

R

H3C

R

Hexafluorophosphate F F

F − F P F

+ N R

H3C

R

Methyl sulfate

Octyl sulfate O

O H3C

O

S O − O

H17C8

O

S O − O

Building blocks for bioactive ionic liquids.

Quaternary phosphonium R4

+ N

R3

R

+ P

Acesulfame O O S O N−

H3C

Quaternary ammonium

R1

R4

R2

R3

+ N

Halides − − − Cl, I, Br

O

F Bis(trifluoromethylsulfonyl)amide O O F3C S − S CF3 N O O

Figure 23.1

Pyrrolidinium

Bis(trifluoromethyl)amide F 3C

− CF3 N

Dicyanamide − N C N C N

Trifluoromethanesulfonate O − S O O CF3

R1 R2

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

Table 23.1

Physical properties of typical ionic liquids [5, 14, 22].

Sample

Viscosity (mPa s)

Density (g/cm3 )

Solubility in water (g L−1 )

Temperature for decomposition

Surface tension (mN m−1 )

[BMIM][PF6 ]

60.9

1.345

21.0

349

45

[BMIM][BF4 ]

—

1.197

—

403

46

[BMIM][NTF2 ]

22.4

1.417

16

439

34

[EMIM][NTF2 ]

16.8

1.513

—

455

—

[N4111 ][NTF2 ]

43.4

1.380

—

—

33

[HMIM][PF6 ]

607

1.29

—

417

42

[HMIM][BF4 ]

102

1.14

—

—

37

[HMIM][NTF2 ]

68

1.37

—

—

32.5

decreases enzyme activity in ionic liquids [7, 15]. It is possible that as a result of the compatibility between the enzyme and the hydrogen-bond basicity is reduced. By decreasing hydrogen-bond basicity, an enzyme’s internal hydrogen bonds are less restricted. Based on this phenomenon, enzymes do not react in [BMIM][Cl] at 65 ∘ C. This is a result of the high hydrogen-bond basicity [15, 23]. Anions cannot be utilized in certain applications, as well as a high hydrogen-bond basicity; for example, there is a reportedly 25% cellulose weight lost in [BMIM][Cl] despite the inability of cellulose to be degraded in the ionic liquid containing [BF4 ] and [PF6 ] [24]. Nonvolatile ionic liquids have incorporated biocatalysis over the years to replace volatile organic solvents. Moreover, ionic liquids’ unusual solvent properties have already led to the development of highly efficient and innovative chemical reaction methods.

23.3 Whole-Cell Biotransformations Whole-cell biotransformation is a process in which an enzyme is applied during the biocatalytic process in a host organism, e.g. yeast or bacteria. The cell’s environment protects the enzyme working as a whole-cell biocatalyst. This method has numerous significant benefits over crude, refined, or immobilized isolated enzymes. It is the most cost-effective approach for producing biocatalysts, thanks to the huge reduction in downstream processes [25, 26]. However, one of the major drawbacks associated with whole-cell biocatalysis is the low water stability and low tolerance toward organic solvents, which results in substrate or product inhibition. As a result of cell metabolism, byproducts are also formed which can inhibit biocatalysts or complicate downstream processing [27, 28]. A two-phase approach has been proposed by combining the enzyme and substrate in aqueous and nonaqueous phases,

23.3 Whole-Cell Biotransformations

although the availability of biocompatible solvent is often challenging as well as the toxicity of organic solvents [29, 30]. The use of ionic liquids is an excellent alternative to many organic solvents since they are considerably more environmentally friendly and safe, and permit highly specific reactions. In whole-cell processes, ionic liquids have primarily been used in the so-called extractive fermentation method, which uses a second water-immiscible liquid phase to remove toxic metabolites in situ to prevent inhibition of the cells. The introduction of ionic liquids as the nonaqueous phases in the two-phase systems and the aqueous phase is used to store the biocatalyst. The transfer of substrates via diffusion between the two phases is very critical is attaining high conversion and product yield. A study by Lye and coworkers was the first attempt to replace organic solvents with the ionic liquid ([BMIM][PF6 ]) [4]. Moreover, 1,3-dicyanobenzene conversion and extraction to erythromycin-A by Rhodococcus R312 was aided by the application of an ionic liquid. According to the literature, cholinium and imidazolium are the most common ionic liquids applied during whole-cell biotransformation. Studies have also focused on the sensitivity of microorganisms to ionic liquids, e.g. Penicillium reportedly displays high tolerance toward ionic liquids, whereas Saccharomyces cerevisiae showed low tolerance to most ionic liquids. The application of cholinium-based ionic liquids are of particular interest as these cationic chains are cost-effective and sourced from nature and display low toxicity [25]. Also, Clostridium butyricum bacterium tolerated a 1,3-propanediol concentration that surpass the inhibitory concentration (65 g l−1 ). In subsequent homogeneous reactions, phosphonium sulfonate ionic was used, which represents a combined biochemical and catalytic process consisting of 1,3-propanedial for converting waste glycerol into valuable products [31]. The phosphonium sulfonate ionic liquid displays very low water solubility and toxicity and can therefore serve as an alternative solvent for whole-cell biotransformation [32] Therefore, the above discussion highlights the potential for ionic liquids to promote the reaction between the enzyme active sites and intermediates as well as decrease the toxic effect associated with the substrates/products during the reaction. The immiscible liquid phase is used for reserving toxic substrates during biotransformation. As a consequence, substrate delivery is limited when thermodynamic equilibrium and cell uptake rate are not balanced [33]. Table 23.2 represents ionic liquids that have been applied in whole-cell biotransformation processes that are integral to agrochemical and drug production industries [38]. An example is the application of S. cerevisiae in ionic liquids to produce 2-phenylethanol. Typically, 2-phenylethanol inhibits the cellular metabolism of S. cerevisiae resulting in a low production yield. However, the introduction of [BMIM][NTF2 ] enhanced the product yield five times more compared to organic solvents [34]. In another similar research, the addition of [BMIM][PF6 ] in the organic phase increased the specific activity of Rhodococcus R312 in the production of 3-cyanobenzamide and derivatives by approximately 10 times higher compared to the application in toluene [4]. The [PF6 ] anion is the most popular solvent studied for ionic liquids for whole-cell processes to date.

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

Table 23.2

Examples of ionic liquids applied in whole-cell reactions using ionic liquids.

Microorganism

Ionic liquid

Saccharomyces cerevisiae

[BMIM][PF6 ] [HMIM][PF6 ]

Reaction process system

Scale (l)

References

2-Phenylethanol synthesis

3 × 10−2

[34]

[OMIM][PF6 ] [BMIM][NTF2 ] Whole cells of Rhodococcus R312

[BMIM][PF6 ]

3-Cyanobenzamide and 3-cyanobenzoic acid synthesis

2.5 × 10–2

[4]

Immobilized Saccharomyces cerevisiae

[BMIM][PF6 ]

Reduction of ketones

1.5 × 10−1

[35]

Immobilized Saccharomyces cerevisiae

[BMIM][PF6 ]

Recovery of n-butanol from fermentation broth

Immobilized Saccharomyces cerevisiae

[BMIM][PF6 ]; [BMIM][BF4 ]

(S)-1Trimethylsilylethanol synthesis

1 × 10−2

[37]

Escherichia coli

[BMIM][PF6 ]

Asymmetric reduction of prochiral ketones

1.4 × 10−3 2 × 10−1

[38]

Chiral alcohol synthesis

4 × 10−3

[39]

[HMIM][PF6 ] [BMIM][NTF2 ]

[36]

[HMIM][NTF2 ] Escherichia coli Saccharomyces cerevisiae

[BMIM][PF6 ] [BMIM][NTF2 ]

Although high compatibility between the ionic liquid and whole-cell catalyst has been reported during biotransformation. There are some reports on low activity and toxicity, resulting in a compromise between the nature of the solvent and the type of whole cell metabolism to achieve commendable results. The use of ionic liquids in multiphase systems presents a significant enhancement in the biotransformation process, which can be attributed to an increase in substrate solubility and product isolation. The strong polarity and resistance to oxidation of ionic liquids make them attractive for redox biocatalysis. Redox reactions are frequently catalyzed using whole-cell biocatalysts due to the need to recycle cofactors. Therefore, whole-cell biocatalysts are often used for these reactions. Since ionic liquids cause less damage to cell membranes, they used to capture insoluble products. A series of ketones were reduced enantioselectively by yeast immobilized in a [BMIM][PF6 ] and water biphasic system. Compared with conventional aqueous-organic media, the system performed relatively well [16].

23.4 Ionic Liquids as Solvents for Enzyme Catalysis

23.4 Ionic Liquids as Solvents for Enzyme Catalysis Proteins can be detached from an organism to serve as charge enzymes. However, change in the reaction environment can result in poisoning, denaturing, or unfolding of the protein, leading to a decrease in enzyme activity. Ionic liquids can be applied as enzyme stabilizers to process the protein extraction either by coating the protein or acting as a nonaqueous phase during protein extraction. Besides, the advancements in enzyme-based technologies enable the easy modification of physiochemical properties of enzymes in ionic liquids [25]. The predication of enzyme activity remains highly unreliable despite substantial research into electrolyte–protein interactions. Alkaline phosphatase activation in aqueous solutions of Escherichia coli can be achieved at 10% [EtNH3 ][NO3 ] ionic liquid. The activity, however, decrease with elevated concentrations, with total of activity recorded at 80% [EtNH3 ][NO3 ] liquid [15, 40]. Lau and coworkers [3] accounted for transesterification and lipid epoxidation reactions in ionic liquids. Depending on the alcohol and ester types, the performance of Candida antarctica lipase B catalyzed in transesterification reaction after incubation in [BMIM][PF6 ] was comparable with organic solvents, displaying good conversion rates. Novozym 435 has also been reported to catalyze the production of cyclohexene by peroctanoic acid in situ from octanoic acid and 60% aqueous H2 O2 in [BMIM][BF4 ] without the need of a volatile solvent or hazardous peroxyacid. After 24 hours, an 83% yield was achieved, which was identical to the yield produced when the same reaction was performed in acetonitrile. Scientists found that ionic liquids are superior to organic solvents for the production of important industrial chemicals by enzyme catalysis [41]. In the study, the utilization of ionic liquids with lipases is demonstrated for the first time. As demonstrated in their experiments, the introduction of lipases as ionic liquids for several biochemical reactions such as ammonolysis, alcoholysis, and perhydrolysis at rates reportedly superior to organic solvents. The application of α-chymotrypsin to catalyze the alcoholysis of N-acetyl-l-amino acid esters in [AMIM] based ionic liquids has been reported with the condition that no water is present [42]. The transesterification performance of [OMIM][PF6 ] and [BMIM][PF6 ] solution was observed to be similar to the organic solvents acetonitrile and/or isooctane, although the transesterification performance was higher in [EMIM][Tf2 N] [21, 42] (Table 23.3). Several studies have shown that enzymes lyophilized from salt solutions or amphiphilic compounds are more active in organic media than enzymes lyophilized from inorganic media. An 82-fold increase in transesterification rate was reported during the colyophilizing of α-chymotrypsin with pentaglyme [57]. The enzyme α-chymotrypsin demonstrated comparable effects in [OMIM][PF6 ] medium compared to polyethylene glycol. [42]. In addition, Pseudomonas lipase co-lyophilized with polyethylene glycol in [HMIM][PF6 ] increased transesterification of ionic liquids by a factor of five [58].

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

Table 23.3

Examples of ionic liquids applied in isolated enzyme catalysis.

Enzyme

Ionic liquid

Reaction

References

Peroxidase

[BMIM][PF6 ]

Guaiacol oxidation

[43]

Formate dehydrogenase

[MMIM][MESO4 ]; [4-MBPY][BF4 ]

NADH regeneration

[44]

Alcohol dehydrogenase

[BMIM][Tf2 N]

Enantioselective reduction of 2-octanone

[45]

Laccase C

[BMIM][PF6 ]

Anthracene oxidation

[46]

Baker’s yeast

[BMIM][PF6 ]–H2 O (10 : 1)

Enantioselective reduction of ketones

[35]

[EMIM][BF4 ]; [BMIM][(CF3 SO2 )2 N]; [BMIM][PF6 ]; [EMIM][(CF3 SO2 )2 N]

Butyl butyrate synthesis by transesterification

[47]

[EMIM][(CF3 SO2 )2 N]

Phenylethanol kinetic resolution in supercritical CO2

[48]

[BMIM][PF6 ]

Alcoholysis, ammonolysis, perhydrolysis

[5]

Oxidoreductase

Lipases CAL-B

[BMIM][BF4 ] CALB

[BMIM][(CF3 SO2 )2 N]

Esterification of 1-octanol in the presence of supercritical CO2

[49]

CALB and PCL

[EMIM][PF6 ]

Kinetic resolution of secondary alcohols

[50]

Allylic alcohols kinetic resolution

[51]

[BMIM][(CF3 SO2 )2 N]

(R,S)-1-Phenylethanol kinetic resolution

[52]

[BMIM][PF6 ]

Transesterification of 1-phenylethanol

[53]

Thermolysin

[BMIM][PF6 ]

Synthesis of Z-aspartame

[54]

α-Chymotrypsin

[BMIM][(CF3 SO2 )2 N]

N-Acetyl-L-phenylalanine ethyl ester transesterification in 1-butanol

[55]

[BMIM][PF6 ] CALB, PCL, CRL, and porcine liver lipase

[BMIM][PF6 ] [BMIM][CF3 SO3 ] [BMIM][BF4 ] [BMIM][(CF3 SO2 )2 N] [BMIM][SBF6 ]

Pseudomonas sp. lipase (PCL) Esterase Bacillus stearothermophilus esterase Protease

23.5 Enzyme Selectivity in Ionic Liquids

Table 23.3

(Continued)

Enzyme

Ionic liquid

Reaction

References

α-Chymotrypsin

[OMIM][PF6 ] [BMIM][PF6 ]

N-Acetyl-L-phenylalanine ethyl ester transesterification in 1-propanol

[42]

[EMIM][BF4 ]

N-Acetyl-L-tyrosine ethyl ester transesterification in 1-propanol

[21]

[BMIM][PF6 ]

Z-Aspartame peptide synthesis

[54]

Bacillus circulans β-galactosidase

[MMIM][MESO4 ]

N-Acetyllactosamine synthesis

[44]

β-Galactosidase, subtilisin

[BMIM][BF4 ]

Hydrolytic activity

[56]

[EMIM][(CF3 SO2 )2 N] [BMIM][BF4 ] [BMIM][PF6 ][MTOA] [(CF3 SO2 )2 N]

Glycosidase

23.5 Enzyme Selectivity in Ionic Liquids A novel characteristic of enzymes in organic solvents is their increased enantioselectivity and regioselectivity, which differs from enzymes in aqueous solutions. Ionic liquids further enhance enantioselectivity and regioselectivity of some enzymes.

23.5.1 Enantioselectivity Higher enantioselectivity has been observed for the application of lipase in kinetic studies involving chiral alcohols indicating that the physiochemical characteristics of ionic liquid determine the degree of enantioselectivity. [50, 55, 59]. For example, the enantioselectivity of lipase-mediated acetylation of racemic P-chiral oxides was up to sixfold higher in [BMIM][PF6 ] than in organic solvents. A greater enantioselectivity was also observed in [BMIM][PF6 ] than in [EMIM][BF4 ] [50]. The high thermostability of lipases from Pseudomonas sp. in [BMIm][Tf2 N] has increased research interest in kinetic reaction at extreme temperatures [55]. In [BMIm][Tf2 N], vinyl acetate did not alter the enantioselectivity of acylation by PsL, which dropped from E = 200 to E = 150 as temperature was elevated to 90 ∘ C. However, the enantioselectivity of the organic solvent TBME at 55 ∘ C, dropping from E = 200 to E = 4. In this case, the decrease in enantioselectivity correlated with the solvent boiling point [55]. N-Acylamino acid esters could be hydrolyzed more efficiently into respective (S)-amino acids using [EPy][TFA]–H2 O (15 : 85) as a substitute for acetonitrile–H2 O (15 : 85) [60].

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

23.5.2 Regioselectivity The greater regioselectivity of ionic liquids such as lipases enables the efficient esterification of carbohydrates compared to organic solvents. For example, Park and Kazlauskas reported that during the product of glucose acetylation, the product 6-o-acetyl glucose was more soluble in [MOEMIm][BF4 ], achieving a 93% product yield compared to the organic solvent, acetone [17]. On the other hand, a low product yield and conversion of 29% and 26% was observed during the acetylation of glucose in [BMIm][PF6], further demonstrating the dependence of dissolution of organic substance such as vitamin C, maltose, ascorbic acid, and cellulose on the degree of regioselective acetylation of the reaction medium [15].

23.6 Ionic Liquid Stability of Enzymes The stable interactions between enzymes and ionic liquids are becoming increasingly important since biological components such as peptides and sugars are trustworthy starting materials for the creation of fine compounds and medicines. Similar to the its application in organic solvents, these enzymes are introduced into the ionic liquid in powder form or attached to a support. The preservation of the activity of several enzymes have been reported; for example, the activity of thermolysin was preserved after 144 hours by incubating in [BMIM][PF6 ], although the enzyme activity reduced by 50% after been kept in ethyl acetate under the same conditions [54]. The greater stability of Bacillus stearothermophilus esterase in [BMIM][BF4 ] and [BMIM][PF6 ] than that in hexane and MTBE at 40 ∘ C has been reported. A half-life greater than 240 hours was achieved in [BMIM][PF6 ], which was 30 and 3 times higher than the half-life in hexane and MTBE, respectively [53]. Similarly, the efficiency of different ionic liquid for the preservation of α-chymotrypsin was investigated in 2% H2 O content (v/v) at a temperature of 50 ∘ C [61]. By fitting the deactivation profiles by first-order kinetic model, the half-life of the enzyme (2.63 hours) was extended in ionic liquid compared to 0.15 hours in 1-propanol. It was equally observed that the extending of half-life was significantly related to the degree of hydrophobicity of the reaction medium. This results strongly indicates that the hydrophobic reaction medium limits the direct interaction between protein and water, thereby enhancing enzyme stability. The result was corroborated by the performance of C. antarctica lipase B during the in ionic liquid and CO2 biphasic system setup for ester synthesis [62]. The authors reported that five ionic liquids with large cation alkyl side chain were able to stabilize the activity and enhance the half-life by 2000 compared to the organic solvent hexane [21]. Furthermore, the half-life of the C. antarctica lipase was 2300 times longer when recycled in the ionic liquid [BMIM][PF6 ] compared to the enzyme recycled without incubation [47]. The substrate’s interaction with the enzyme results in a shift that enables the activation and preservation of the enzyme active sites. Following the results from the above evaluations, enzyme incubation in ionic liquids has been demonstrated to enhance enzyme activity. An evaluation of the

23.7 Application of Ionic Liquids in Bioethanol Production

thermostability of C. antarctica lipase B was performed by setting the enzyme in [BMIM][PF6 ] for a period of time at 80 ∘ C then assessing the residual activity after dilution with water [6]. Both enzyme forms demonstrated a considerable rise in activity: the free enzyme increased by 120% after 20–100 hours of incubation, and Novozym 435 increased by 350% after 40 hours of incubation. Solvatochromic test results and partition coefficient measurements have shown that ionic liquids have a higher polarity and hydrophilicity than organic solvents [7] Ionic liquid studies have shown that lipases are readily stable compared to hexane. The ionic liquids aid in the prevention of adverse responses. Kaftzik et al. [44] investigated galactosylation using β-galactosidase for the synthesis of N-acetyllactosamine from lactose and N-acetylglucosamine from lactose and N-acetylglucosamine. The yield of N-acetyllactosamine from aqueous reaction medium was very low due to the product undergoing further hydrolysis. However, the incorporation of 25% (v/v) [MMIM][MeSO4 ] ionic liquid reduced the further hydrolysis of the product, leading to a higher yield of 58%.

23.7 Application of Ionic Liquids in Bioethanol Production Bioethanol can be produced from lignocellulosic biomass by converting it into fermentable sugars [63]. As a feedstock for biofuel production or other chemical processes, lignocelluloses must be pretreated so the crystalline structure of the cellulose can be broken down, the hemicellulose removed, lignin modified or removed so that cellulose can be accessed more readily, and enzyme attack resistance is reduced. In addition to its complex structure, lignocellulose is resistant to enzymatic hydrolysis, lowering saccharification sugar yields [64]. These parameters that determine the efficiency of the enzymatic hydrolysis of polysaccharides into sugars. To facilitate later enzymatic hydrolysis, the crystalline cellulose structure and hydrogen bonds should be broken to increase the specific surface area and pore texture of cellulose as well as enhancing enzymatic hydrolysis. The pretreatment step in the production of bioethanol is the most difficult one because it disturbs the lignocelluloses’ compact and ordered structure. Several pretreatment approaches have been applied to overcome the drawbacks of lignocellulose’s recalcitrance, enhance enzyme efficiency, and boost monomeric sugar yields. These include diluting acid [65], expansion of ammonia fiber [66], incubating in hot water [67] and organic solvent [68], and pretreating in lime [69]. The abovementioned approaches enhance polysaccharide enzymatic digestibility, but there is a need to establish a cost-effective and efficient procedure, that takes little capital, and has minimal impact on downstream processing. Ionic liquids have recently shown tremendous potential as effective biomass dissolving solvents with facile cellulose recovery after antisolvent addition. Lignocellulose can be pretreated with ionic liquids due to their particular physiochemical properties. An ionic liquid consists of an organic and inorganic cation and anion salt, which maintain a liquid state at low temperatures. During ionic liquid regeneration,

471

23 Application of Ionic Liquids in Biocatalysis and Biotechnology

Lignocellulosic biomass Fractionation Water

Ionic liquid

Pretreatment Heating and stirring Acetone / hot water

Biomass + water + IL

Cellulose

Filtration and washing

Lignin

Water + DMSO/DMF Heating and stirring

Lignin + hemicellulose Filtration and + water + IL washing

Hemicellulose + water + IL

Acetone / ethanol / methanol

IL regeneration

472

Filtration and washing

Hemicellulose

Figure 23.2 Pretreatment of biomass in ionic liquid. Source: Usmani et al. [70]/with permission of Elsevier.

the crystalline nature and breakdown of cellulose are greatly influenced. The treatment and regeneration of lignocellulosic biomass and ionic liquids are shown in Figure 23.2. A profusion of investigations on the selective and complete dissolution of lignocellulosic biomass in ionic liquids have been conducted. Findings of these studies have increased the interest on the application ionic liquids for biomass pretreatment in a biorefinery. The most popularly applied ionic liquids for the experimental research of lignocellulosic biomass treatments have been imidazolium ionic liquids. The cations [EMIM], [AMIM], and [BMIM] are the most common ionic liquids of interest for biocatalytic reaction, although imidazolium acetates such as [EMIM][CH3 COO] is also widely applied. As a source lignocellulosic biomass, agricultural wastes are readily available and can be utilized to produce biofuels and chemicals. However, lignocellulosic biomass is not readily dissolved in organic solvents, making the process of enzyme hydrolysis to release fermentable sugars challenging without adequate pretreatment. Ionic liquid pretreatment of biomass has become an economically viable approach [71, 72].

23.7 Application of Ionic Liquids in Bioethanol Production

Table 23.4 Ionic liquids capable of dissolving cellulose, hemicelluloses, and lignin. Sugar

Ionic liquid

Cellulose

[Emim][OAc] [Emim][Cl] [Amim][Cl] [Bmim][Cl] [BmPy][Cl] [AMMorp][OAc] [N4444][OAc]

Hemicelluloses

[Emim][OAc] [Bmim][OAc] [Bmim][Cl] [Amim][HCOO] [Bmim][Br] [Bmim][I]

Lignin

[Emim][OAc] [Bmim][OAc] [Bmim][Cl] [Bmim][MeSO4 ] [Mmim][MeSO4 ] [Hmim][CF3 SO3 ] [Py][For] [Py][OAc] [Py]Pro

Molecular solubility of cellulose in these ionic liquids is reported to increase linearly with the interaction between available anions and hydrogen in the reaction medium. Ionic liquids are capable of dissolving cellulose efficiently, as shown in Table 23.4. Table 23.5 displays the ionic liquid, biomass loading, and pretreatment conditions of biomass for bioethanol. In this study, chloride-based, acetate-based, and formate-based ionic liquids were able to break down the framework of cellulose. Different characterization and analysis studies of cellulose structure reveal disruption of the cellulose framework [82]. The various types of ionic liquids resulted in different effects on the reducing sugar with [BMIM][HCOO], [EMIM][OAc], and [BMIM][Cl] achieving 88.92%, 90.72%, and 100%, respectively, after heating at a temperature of 50 ∘ C for 5 hours. When compared to untreated substrates, yields and hydrolysis rates appeared to be enhanced after ionic liquid pretreatment [83]. To improve subsequent enzymatic saccharification, the cholinium-based ionic liquids [Ch][CA] with carboxylate anions are included in the pretreatment of lignocellulosic materials. Choline cations were combined with mono- and di-carboxylate anions to produce different [CH][CA] ionic liquids. The efficiency of these various [CH][CA] ionic liquids for the pretreatment of kenaf powder during enzymatic saccharification was evaluated by Ninomiya and colleagues [84].

473

Table 23.5

Pretreatment of biomass for bioethanol production assisted by ionic liquids.

Ionic liquid, biomass, and solid loading

Pretreatment condition

Hemicellulose removal (%)

Delignification (%)

Cellulose conversion (%)

Solid recovery (%)

References

[TEA][HSO4 ]/H2 O, 9% miscanthus loading

120 ∘ C, 1–24 h

44–100

53–88

3–14

46.4–73.5

[73]

[Emim][HSO4 ]/H2 O, 10% wheat straw loading

131 ∘ C, 88 min 120 ∘ C, 1–8 h

76

21

5

60

[74]

51–85

31–61

7–15

52.5–71.8

[75]

120 ∘ C, 6 h 120 ∘ C, 6 h

100

52

49

41.6

[76]

100

43

50

39.8

[76]

25 ∘ C, 15 min 50 ∘ C, 30 min

—

—

86

—

[77]

28.1

[78]

[HBim][HSO4 ]/H2 O, 9% pine loading [Mim][Cl], 4% pine loading [Mim][Cl], 4% eucalyptus loading [Emim][OAc], 4.7% kenaf powders loading [TBA][OH]/H2 O, 5% wheat straw loading

69.5

92.4

—

22

57

61

—

[79]

[Bmim]Cl, sugarcane bagasse, 9%

150 ∘ C, 5 min 130 ∘ C, 30 min

85

—

—

—

[80]

[Bmim]Cl, bagasse pith, 9%

80–130 ∘ C, 10–90 min

40–80

—

—

—

[81]

[Bmim]Cl, 4.7% rice straw loading

23.8 Ionic Liquids Applied in the Synthesis of Biodiesel

[CH][CA] ionic liquids were confirmed to be more biocompatible in comparison with other imidazolium cationic ionic liquids such as [EMIM][OAc]. In order to produce second-generation bioethanol from sugarcane bagasse (SCB), a new pretreatment method was investigated. The surfactants 3% polyethylene glycol and 5% Tween 80 were introduced into the ionic liquid [Bmim][Cl] and improved the dissolution of lignin and enzyme digestion by 12.5% and 96.2% after 12 hours of hydrolysis. The authors concluded that decrease in crystallinity of cellulose as well as the modification of the lattice and efficient delignification contributed in improving the pretreatment process with ionic liquids [85]. The application of [EMIM][OAc] as an efficient medium for lignin degradation is evident by the reduction in cellulose crystalline structure and decrease in the operation temperature. Similar research reported that soaking beech chips in the ionic liquid [EMIM][OAc] at a temperature of 115 ∘ C for 1.5 hours resulted in effective hydrolysis of the cellulose [86]. According to this theory, the ionic liquids might break hydrogen bonds in the cellulose molecules, causing the microcrystalline material to become amorphous. For example, Cl− concentrations above a certain level in ionic liquids promote the dissolution of the cellulose framework by the disruption of the hydrogen bonds. Adding just 1 wt% of water to ILs resulted in a decline in cellulose solubility [24]. Low-basicity ions, such as BF4 − and PF6 − , have difficulty in dissolving and disintegrating cellulose. The solvation of cellulose is strongly dependent on cationic ionic liquids, as evidenced by experiments and molecular simulations [71]. For instance, [EMIM][Cl], [BMIM][Cl], and [HMIM][Cl] are able to dissolve cellulose while [C3 MIM][Cl] and [C5 MIM][Cl] have nearly zero and low solubility, respectively. The possibility could be related to cations’ role in cellulose solvation and dispersion. However, the presence of imidazolium cations in ionic liquids play a crucial role in cellulose degradation by hydrophobic interactions with glucopyranose chains in the substrate, according to molecular simulation studies. Nevertheless, the roles of cations remain controversial, and more research is required. Therefore, ionic liquids are necessary to make cellulose more effective for enzymatic hydrolysis.

23.8 Ionic Liquids Applied in the Synthesis of Biodiesel Biodiesel manufacturing is one of the prospective alternative energy sources that might help to minimize the worldwide use of petroleum-based diesel in energy generation. And the most prevalent process for making biodiesel is transesterification. Several organizations have established enzymatic transesterification in ionic liquids in the production of biodiesel. [87]. The application of the enzymatic transesterification permits the adaptable selection of appropriate enzymes for different reactions as well as reduced energy consumption and water requirements compared to chemical methods that are generally accompanied with the formation of secondary waste products [88]. However, the existing lipase-catalyzed approach has many drawbacks that keep it from becoming commercially viable. These include, among other things, the high cost of enzymes and the inactivation of lipase by acyl acceptors such as methanol and other contaminants. Furthermore,

475

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23 Application of Ionic Liquids in Biocatalysis and Biotechnology

many enzymatic transesterification processes must be carried out in heterogeneous systems with complex liquid–liquid interfaces attributed to the miscibility of oils and methanol [88]. To overcome methanol inhibition of lipases, various strategies are employed, such as the addition of methanol during the reaction and the application of acyl acceptors and/or organic solvents such as ethyl acetate and hexane. Some other strategies involve the use of genetically modified enzymes and substrates containing fatty acids. [88]. Ionic liquids have been found as a viable solution to satisfy the criteria because of their unique and greener features. Several groups have shown that enzymatic transesterification of vegetable oils in ionic solutions may produce biodiesel [89, 90]. Setting enzymes in imidazolium-type ionic liquids resulted in highly active and durable catalysts, due to the ability of ionic liquids to protect the lipase from methanol-induced deactivation. [91]. Figure 23.3 represents schematically the production of biodiesel. MeOH Triolein

IME (only 1st cycle)

1st STEP Enzymatic Methanolysis

5th STEP Hexane Vacuum

60 °C

Hexane + FAMEs

4th STEP Cooling on ice bath

IL Phase

60 °C

FAMEs GlyOH MeOH+

H 2O

IL Phase SOLID

IL Phase

60 °C

Cooling on ice

2nd STEP Liquid–liquid extraction

4–6 °C

MeOH Glycerol FAMEs

IL Phase

FAMEs

60 °C

60 °C

3rd STEP Liquid–liquid extraction

FAMEs

Hexane

IL Phase

MeOH Glycerol in H2O

IL Phase

Figure 23.3 Enzymatic biodiesel process in ionic liquids. Source: Diego et al. [92]/with permission of Elsevier.

23.8 Ionic Liquids Applied in the Synthesis of Biodiesel

Typically, ionic liquids with a short cationic chain such as [BMIM]PF6 or [BMIM][NTf2 ] are mostly applied in a biphasic reaction system containing limited amount of water. Biodiesel could be produced from soybean oil by combining [BMIM][NTf2 ] with lipase for ionic liquid biodiesel synthesis [93]. In contrast to shorter alkyl chain groups, longer alkyl chain imidazolium such as [C16 MIM]NTf2 and [C18 MIM]NTf2 have been applied in a single-phase system for lipase-catalyzed biodiesel production. The enzyme is then stabilized and recycled by limiting interaction with methanol [94]. In addition to providing a nonaqueous system for oil transesterification, these long-chain, lipophilic ionic liquids support a triphasic system following the process, making biodiesel extraction more straightforward [91]. In the presence of [CnMIM] cations, increased viscosity hampered the lipase-catalyzed transesterification, with similar effect been observed on the activity of cellulose. Following the order sequence [PF6 ] > [BF4 ] > [NTf2 ], the anion order was consistent with increasing viscosity [91]. To transesterify triolein with CAL-B as the catalyst, the ionic liquids [C16 MIM] [Tf2 N] and [C18 MIM][Tf2 N] were employed as solvents [92]. To an increase in viscosity and increased alkyl chain length after day 7, [C16 -MIM][Tf2 N] was unable to produce fatty acid methyl ester (FAME), a renewable and ecologically friendly fuel. Although solidification at operating temperatures below 20 ∘ C enabled the recovery of the ionic liquids. However, CAL-B and Pseudomonas fluorescens lipase produce biodiesel in the presence of ionic liquids consisting of [C10 -C18 -MIM]+ and PF4 , PF6 , or Tf2 N as operating solvents [95]. CAL-B immobilized in the ionic liquids [C16 MIM][Tf2 N] exhibited the highest activity. Transesterification produces a nonaqueous environment when these lipophilic ionic liquids are used, although the use of lipophilic liquids leads to higher viscosity and reduced enzyme activity. Several other examples of ionic liquids applied as enzyme-catalyzed transesterification solvents are presented in Table 23.6. Burkholderia cepacia lipase (BCL) is a popular enzyme applied in aqueous and nonaqueous phases [101, 102]. A high-performance biocatalyst has been developed using immobilized BCL for biodiesel production using isooctane with no solvents [103]. The coating of BCL with ionic liquids results in the enhancement of the enantioselectivity for different substrates. In a transesterification process using BCL as a catalyst, 19 ionic liquids were evaluated as solvents [95]. After 12 hours of reaction, [OmPy][BF4 ] produced the highest biodiesel yield of 82.21%, and the lipase catalyzing activity decreased to 58.6% after 3 cycles of reactions among these tested ionic liquids. The high viscosity leads to lower mass transfer rate, permitting a faster reaction rate without decrease in the product yield. In a reaction catalyzed by Novozym 435, Sunitha and colleagues reported approximately 99% yield of sunflower oil fatty acid methyl esters after methanolysis with [BMIM][PF6 ] for 10 hours and [EMIM][PF6 ] by Novozym 435 for less than 10 hours [99] as shown in Table.23.7. Due to their capacity to synthesize lipase, Rhizopus oryzae and Aspergillus oryzae have been employed as whole-cell catalysts for biodiesel production. The entire cell may be employed as the lipase-immobilized matrix in this system, and ionic liquids help prevent the biocatalysts from deactivating. The use of all-salt ionic liquids facilitates methyl ester recovery since the methyl esters and unreacted oil are not

477

478

23 Application of Ionic Liquids in Biocatalysis and Biotechnology

Table 23.6

Ionic liquids applied as solvents for enzyme-catalyzed transesterification.

Feed stocks

Ionic liquids

Enzymes

References

Triolein

[OMIM][PF6 ], [C18 MIM][Tf2 N]

CAL-B

[96]

Triolein

[BMIM][PF6 ]

CAL-B

[97]

Corn oil

[BMIM][PF6 ]

PEL, Novozym 435, Lipozyme TLIM

[90]

Microalgal oil (Chlorella pyrenoidosa)

[BMIM][PF6 ]

CAL-B, PEL

[98]

Sunflower oil

[BMIM][PF6 ], [emim][PF6 ], [HMIM][BF4 ], [bmim][BF4 ]

CAL-B

[99]

Sunflower oil, waste cooking oil

[BMIM][BF4 ], [emim][TfO], [BMIM][BF4 ], [bmp][PF6 ], [BMIM][TfO], [BMIM][Tf2 N], [BDIM][Tf2 N], [EMIM][Tf2 N], [OMIM][Tf2 N], [OMIM][PF6 ]

CAL-B

[100]

Table 23.7 Methanolysis of sunflower oil by Candida antarctica at different concentrations and types of ionic liquids. % Product composition (w/w) Ionic liquid

Oil:ionic liquid (w/w)

FAME

TG

DG

[BMIm][PF6 ]

1:2

97 ± 0.8

1 ± 0.8

2 ± 0.3

1:1

98 ± 0.6

—

1 ± 0.2

4:3

95 ± 0.6

3±1

—

2:1

38 ± 1.5

50 ± 2

8 ± 0.81

4:1

—

98 ± 0.8

1 ± 0.8

[EMIm][PF6 ]

MG

1:2

98 ± 0.8

—

1 ± 0.8

—

1:1

98 ± 1.6

—

1 ± 1.6

—

4:3

96 ± 1.4

2±1

1 ± 1.4

—

2:1

46 ± 3

40 ± 3

6±1

—

4:1

—

99 ± 1

—

1 ± 0.2

[BMIm][BF4 ]

1:2

—

94 ± 1

5±1

—

[HMIm][BF4 ]

1:2

10 ± 2.4

80 ± 2.5

3±2

1 ± 0.2

Methanolysis reaction conditions: Amount of sunflower oil (1 g), amount of methanol (0.4 ml), Candida antarctica weight (0.1 g), temperature: 60 ∘ C, time: 240 min. FAME, fatty acid methyl ester; TG, triacylglycerol; DG, diacylglycerol; MG, monoacylglycerol. Source: Adapted from Sunitha et al. [99].

References

dissolved, resulting in a two-phase system. Furthermore, ionic liquids are predicted to acts as substrates for the extraction of reaction byproducts such as glycerol, which decrease the activity of lipase during biodiesel production [104]. It is evident from the range of examples presented that ionic liquids are capable of supporting and being an effective reaction medium for biodiesel production.

23.9 Conclusion Ionic liquids have been shown to have superior activity, stability, and selectivity than traditional organic solvents when used as biocatalysis solvents. Additionally, various highly polar substrates with low solubility can be transformed using ionic liquids. The fine-tunning of ionic liquids to adapt to various reaction conditions by choosing appropriate cation and anion combinations is highly advantageous. However, a better knowledge of the basics of biocatalysis in ionic liquids is required to effectively utilize these observed benefits. The research focus is currently on the influence of ionic liquids on enzyme selectivity, activity, and durability. Several molecular strategies, such as improving enzyme hydrogen—oxygen bond and altering the nature of the enzyme’s active site, as well as improving the interaction with substrates and products, have been explored. Ionic liquids, in particular, have a unique ionic composition that allows them to interact with enzymes at high-charge levels, which may be a major factor in the enzyme’s activation or inactivation. Given these complexities, characterizing ionic liquids’ impact on enzyme activity using a single property (e.g. polarity) is clearly inaccurate. Hence, a more diverse approach involving different parameters and kinetics might be required to gain deeper insight into the mechanism between the enzyme and the solvent. Other aspects that need critical attention involve the environmental impact of the usage and recycling of ionic liquids, although toxicity studies on imidazolium-based compounds have shown relatively low toxicity. Nonaqueous enzymology is a fascinating and rapidly growing topic that has the potential to open up a whole new field of inquiry.

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489

Index a Ab initio molecular dynamics simulation 396, 399–401 absorption 306 chemical absorption method 306–311 physical absorption 311–313 acetophenone 122, 426, 427 acid–base neutralization reaction 32 acidic ILs 15, 34, 112, 290 acidogenic fermentation 335 acridinedione derivatives 426 active pharmaceutical ingredient ionic liquids (API-ILs) 196, 212, 446 active pharmaceutical ingredients (API) 196, 203, 212, 374 adsorption 314–315, 339 “agro-active” agents 228 aldol condensation 111–113, 335 alkylimidazolium ionic liquids 274 1-alkyl-3-methylimidazolium 265 salts 419 1-alkyl-3-methylimidazolium chloride-aluminium chloride ([Cn C1 im]Cl-AlCl3 ) IL system 5 1-alkyl-3-(propyl-3-sulfonate) imidazolium 152 alkynone o-methyloximes 429 alkynylatedisoxazole 429 allylisoxazoles 429, 430 ambient temperature molten salt 369 2-aminobenzamides 430 6-amino-1,3-dimethyl uracil 437 2-amino-4H-chromene derivatives 435

2-amino-2-methyl-1-propanol 307 5-aminotetrazole 426 ammonium acetate 119, 128, 130, 434 (2-hydroxyethyl)-ammonium lactate based ILs 12 analytical chemistry 268–269 anion exchange 32, 152, 166, 167 anions of ILs 30 aromatic aldehydes 425, 437, 439 artificial muscles 446 aryl-benzo[4,5]imidazo[1,2-a]pyrimidine amines 425 5-aryloxy-1H-pyrazole-4-carbaldehydes 422, 423 5-aryl-2-thioxopyrrolidine-3,3-diester 432 Aspen HYSYS software version 8.8 306 azeotropic mixture 43, 267, 360 azobisisobutyronitrile (AIBN) 425

b background electrolyte (BEG) 268 barbituric acid/thiobarbituric acid 436, 437 basic ILs 15–16, 40, 106, 427, 432 benzaldehyde 34, 128, 434, 436 benzimidazoquinazolinones 436 [1,3]benzoxazine-2-thione 432 benzyl bromide 421 bicyclic ionic liquids 424 Biginelli reaction 117–120, 437 biobutanol 335–340

Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability, First Edition. Edited by Sanchayita Rajkhowa, Pardeep Singh, Anik Sen, and Jyotirmoy Sarma. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

490

Index

bio-carboxylic acids adsorption 359 applications of 353–354 definition 353 distillation process 357–359 evaporation 359 ionic liquid 355–357 market of 354 membrane extraction 359 production of 354–355 reactive extraction process 360–363 separation of 357, 362 solvent extraction 360 biocatalysis and biotechnology biodiesel manufacturing 475–479 bioethanol production 471–475 definition 460 enzyme selectivity enantioselectivity 469 regioselectivity 470 hydrophobicity 461 ionic liquid stability of enzymes 470–471 miscibility 462 polarity 461 properties 460 purity 461 solvents for enzyme catalysis 467–469 viscosity 462–464 whole-cell biotransformations 464–466 biocatalysts, definition 286 biocompatible ionic liquids 256, 449 biodegradation of ILs 293–294 biodiesel manufacturing 475–479 biodiesel production 289, 291–292, 294, 295, 477, 479 bioethanol production 471–475 biofuels 333 first generation 333 fourth generation 334–335 second generation 334 third generation 334 bioherbicide ionic liquids (bio-HILs) 226 bio-ILs 11–12

biomass conversion process enzymatic processes 286 lignin extraction processes 285–286 thermochemical process 285 biomass, organic compounds and fuels sources 284 biomechanics 271–272 biomedical applications 278 protein stabilization 258–259 solubilization of drugs 257–258 bio-oils 285 bio refinery 292 biodegradation of ILs 293–294 toxicity of ILs 293 bioscience 205, 267, 271 biphasic acid scavenging utilizing ionic liquids (BASIL) 6 bis-α-aminophosphonates compounds 125 bis(trifluoromethylsulfonyl)amide 275 bis(indolyl)methanes 439 bis(indolyl)methanes and pyrazolo[3,4-b]pyridines 439 bis-(trifluoromethanesulfonyl)imide ((CF3 SO2 )2 N− ) anions 371 [bmim][PF6 ] mediated Heck coupling 100 bromochloroaluminate 4 Bronsted acidic ionic liquid (BAIL) 430, 433 Brownian particle diffusion 237 [Bu4 N][l-PRO] mediated Heck coupling with 2,3-dihydrofuran 101 butanol production anaerobic fermentation 335 via biochemical conversion 335–336 via petrochemical conversion 336–337 properties 336 recovery techniques adsorption 339 advantages and disadvantages 339 distillation 337

Index

gas-stripping process 338 liquid-liquid extraction process 337–338 perstarction process 338–339 pervaporation 338 world demand 344–345 1-butyl-3-methylimidazolium hydrogen sulphate [BmIm]+ HSO4 426 1-butyl-3-methylimidazolium tricyanomethanide 305 1-butylpyridinium chloride-aluminium chloride ([C4 py]-AlCl3 ) 4

c capillary electrophoresis (CE) ionic liquids 268 carbamate polymerization 307 carbinolamides 433 carbon capture and storage (CCS) 276 carbon-carbon bond formation reactions aldol condensation 111–113 Claise–Schmidt condensation reaction 113–114 cross-coupling reactions 98–111 Diel Alder reaction 114–115 Friedel craft alkylation 114 Henry reaction 115–116 other C-C bond formation reaction 116 carbon dioxide 70, 123, 276, 301 carbon ionic liquid electrodes (CILEs) 184 carbon-nitrogen bond formation reaction Biginelli reaction 117–120 Mannich reaction 121–123 N-allylation reactions 120–121 other 123–131 carbonyl isoxazoles 429, 430 cascade correlation network (CCN) 378 casting and rubbing 184, 185 catalytic performance 112, 184 cation of ILs 30 C–C cross-coupling reactions Heck coupling 98–103

Hiyama coupling 109–111 Sonoghasira coupling 106–108 Stille coupling 109 Suzuki coupling 103–106 cellulose 79, 80, 162, 284 Channel Catfish Ovary (CCO) 379 CHARMM algorithm 240 chemical absorption 276, 306–311 chemical adsorption 310, 314 chemical fixation of CO2 315–317 chiral ephedrinium ILs 11 chiral ILs (CILs) 10–11, 101, 222 chiral imidazolium ILs 11 chlormequat chloride 2-chloroethyltrimethylammonium chloride (CCC) 226 choline acetate 258, 435 choline and geranate (CAGE)-based ILs 74 choline based ILs, structure of 310 chromeno[2,3-c]pyrazol-4(1H)-ones 423 Claisen–Schmidt condensation reaction 113–114 classical polyelectrolytes 163 cloud point extraction (CPE) 269 CL&Pol polarizable force field 242 coarse-grained force field (CGFF) 240 CO2 capture (CC) 302, 316 absorption chemical absorption method 306–311 physical absorption 311–313 adsorption 314–315 cryogenic separation 305–306 membrane separation method 304–305 oxyfuel combustion process 303 post-combustion 303 precombustion process 303 CO2 fixation mechanism, plant leaf 301 conductivity, ILs 56–57 corrosion resistant material 274–275 COSMO-RS 53, 81, 361 Coulombic attraction 443

491

492

Index

cross dehydrogenative coupling (CDC) reaction 422 cryogenic separation 305–306 cyclic carbonates 34, 438, 439 cyclic 1,3-diones 438

d Daphnia magna, 71, 75, 378–380 deep eutectic solvents (DES) 255, 257, 267 density functional theory (DFT) 310, 396–399 density, ILs 52–53 designer solvents 1, 35, 70, 88, 97, 223, 440 dialkylimidazolium-based ionic liquids 461 dialkylimidazolium halide 461 1,3-dialkyl-1,2,3-triazolium-based ILs 37 dibenzothiophene (DBT) 272 1,3-dibutyl-1H-benzo[d][1,2,3]-triazol3-ium bromide 422 (2,4-dichlorophenoxy)acetic acid (2,4-D) 226 Diel–Alder reaction 114–115 diffusion, ILs 60–61 2,6-difluorobenzyl bromide 422 3,4-dihydropyrimidin-2(1H)-ones 118, 120 dihydropyrimidinones (DHPs) 117, 437 dimedone 425, 436, 437 dimethylformamidedimethylacetal 426 dispersive solid phase microextraction (DSPME) 269 distillation 337, 357 2,2-disubstituted quinazolin-4(1H)-one 430 1,4-disubstituted 1,2,3-triazoles 422 doxorubicin-loaded ionic liquid (IL-PDA-DOX) 213 DRAGON 7 380 drug solubility 447 dual-functional ILs 224

e Einstein–Helfand conductivity formalism 406 electric double layer capacitor (EDLC) flat electrode capacitor 409–410 in porous electrode capacitor 410–412 electrochemical applications 445 biomechanics 271–272 bioscience 271 electrodeposition 269–270 energy management 270–271 electrodeposition 34, 185, 269, 270 electroosmotic flow (EOF) 142, 268 electrosynthesis 33, 34 enantioselectivity 112, 113, 122, 469, 477 energetic hydrazinium salts 14 energetic ILs 2, 13 energy management 270–271 enzymatic processes 286, 461 ethanol 53, 57, 79, 105, 118, 333 ethylammonium nitrate ([EtNH3 ][NO3 ]) 370 extractive fermentation method 465

f fatty acid ionic liquids (FAILs) 243 Ferreira–Kiralj hydrophobicity parameter 378 first-generation biofuels 333, 335 first generation of ionic liquids 205 Fischer Tropsch process 285 flat electrode capacitor 409–410 fossil fuels 270, 283, 286, 302, 333 fourth-generation biofuels 334–335 fractional Walden rule 3 Friedel–Craft alkylation 114

g γ-valerolactone 111 gas expanded solvents (GXLs) 267 gas-stripping process 338 g-C3 N4 -SO3 H catalyzed synthesis 439 generalized regression neural networks (GRNN) 378 Global Carbon budget 2021 302

Index

graphene material 409 green biofuel 337 Green Chemistry principles 375–376 green solvents 195, 267, 355

h 1H-benzo[d]imidazol-2-amine 425 [H2 -DABCO][HSO4 ]2 mediated synthesis 437 Heck coupling 98–103 hemicellulose 284 Henry reaction 34, 39, 40, 115–116 Henry’s law 311, 312 heptachlorodialuminate salt, structure of 4 herbicidal ionic liquids (HILs) 226 heterocycles applications 421–439 characteristics 419 definition 419 hexafluorophosphate (PF6 − ) 371, 462 Hiyama coupling 109–111 homopolymeric PILs 166 1H-Pyrazolo[1,2-b]Phthalazine-5,10Dione derivatives 128 hydrazine hydrate 425 hydrodesulfurization (HDS) 272 hydrophilic ionic liquid 462 hydrophobic ionic liquids 344, 462 hydrophobicity 183, 461 2-hydroxyethylammonium formate IL 434 hydroxyl ethyl ammonium acetate (HEAAc) 438

i IL-based sensing layers casting and rubbing 185 direct mixing 184 electrodeposition 185 layer-by-layer method 186 physical adsorption method 185 sandwich-type immunoassay 186 sol-gel encapsulation 185–186 IL-based separation techniques

common value-added compounds 144 liquid-liquid extraction (LLE) 148–149 microwave-assisted extractions 147 simple solid-liquid extractions 146 solid-liquid extraction (SLE) 145–146 ultrasound-assisted extractions 147–148 IL catalyzed Heck reaction 40 IL catalyzed Henry reaction 40 IL catalyzed Michael addition reaction 41 ILs/graphene oxide (GO) membranes 238 imidazo[2,1-a]isoquinolines 126 imidazole and pyrrolidinium-based electrolytes 2 imidazolium-and tetraalkylammonium-based poly-ILs 13 imidazolium-based IL 11 imidazolium-cation based ILs 30 immiscible liquid phase 465 indoles 439 industrial applications 272–273 industrial biorefineries 283 IoNanofluids (IFNs) applications of 85–86 non-toxic and biodegradable 86–87 properties of 82–84 ionic conductivity 182, 404 ionic liquid-based electrochemical biosensors CNMs-ILs based electrochemical biosensor 187 cancer biomarker 189–190 cardiac disease 190 glucose biosensor 191 immunoglobulins 190 neurotransmitter 190 ionic liquid crystals (ILCs) 277 ionic liquid electrolyte Ab initio molecular dynamics simulation 399–401 in batteries

493

494

Index

ionic liquid electrolyte (contd.) additives 407–408 salts 407 solvents 403–407 density functional theory (DFT) 396–399 EDLC 408–409 molecular dynamics simulation 402 multiscale simulation method 396 ionic liquid-like systems 6 ionic liquids (ILs) 339 acidic ILs 15 active pharmaceutical ingredient 196 advance and smart materials 446 advantages 265, 317 anions 30 anticancer potential of 209–213 application as bioactive formulations 228 application of 341–342, 372–375 absorbent in gas capturing 276–277 additives in drilling fluid 275–276 in analytic chemistry 268–269 biomedical 278 corrosion resistant material 274–275 in electrochemical 269 in industrial 272–273 liquid crystalline (LC) phase 277–278 lubricant material 273–274 solvent and catalyst 267–268 applications as green solvents 180 analytical application 42 in biomass utilisation and extraction 78–80 in biomedical applications 81–82 biotechnology 43–44 electrocatalysis 34 electrodeposition 34 electrosynthesis 34 in energy applications 80–81 engineering 42–43 heat transport and storage 41 performance additives 43

separation 41 solvents and catalysis 35 assisted metal nanoparticles 198–200 basic ILs 15–16 benefits 302 biobutanol recovery using 343–344 bio-carboxylic acids 355–357 biodiesel production 291–292 in bio-electrochemical devices 191 bio-ILs 11–12 biological application 196 biomedical applications 257–259 biorefinery 284 brief history 3–6 business and academics 235 cations 30 and anions 255, 256 in chemical and biochemical catalysis 245–247 chemical fixation of CO2 315–316 in chemical processes preamble 245 separation and purification 245 chemical reactions/catalysts 446 chiral ILs 10–11 classification of 444 commercialization of 18–20 conductivity of 256 constituents of 2–3 databases of 380–388 deep eutectic solvents 257 defined 29, 179 as deterrents 227–228 discovery of 265 distribution ratios and selectivities 344 drug delivery 197 dynamic characteristics of self-diffusion 237–238 shear viscosity 238–239 electrochemical application 445 in electrochemistry catalytic performance 184 hydrophobicity 183 ionic conductivity 182

Index

larger electrochemical window 181–182 viscosity 183–184 energetic ILs 13–14 extraction processes 445–446 first generation 205 in force fields and electronic structure 239–241 general characteristics of 143–145 generation and their application 222–224 Green Chemistry principles 375–376 green solvents 69 growth of acid–base neutralization reaction 32 anion exchange 32 direct combination 33 microwave-assisted technique 33 quarternization 30–32 ultrasound-assisted synthesis 33 heterocycles 419 hydrophobic 344 industrial catalytic applications 266 interpretation tool 236 IoNanofluids (IFNs) 82–87 limitations 278–279 low melting points of 255 magnetic ILs 16–17 metallic ILs 14 microwave irradiation 445 miscibility, conductivity and viscosity of 257 mixtures in ionic liquids and interfaces 241–243 ionic liquids and water 243–245 as mobile phase additives in liquid chromatography 149–151 in nano carrier development 198 nanotechnology 197 neutral ILs 16 pharmaceutical 446 pharmaceutical application of 196 of pharmaceutical development

bio compatibility vs toxicity 448–449 drug sequestration/ recovery 449–450 drug solubility 447 drug transport/delivery 447–448 sustainability/future prospect 450 physicochemical properties of 29 conductivity 56–57 density 52–53 diffusion 60–61 melting point 53–56 miscibility 61–62 polarity 60 solubility 58 surface tension (ST) 58–59 thermal stability and decomposition 56 vapor pressure 61 viscosity 59–60 PILs 15 in plant defense mechanisms as an herbicide and plant growth promoters 226–227 as antifungal agent 225–226 as antimicrobial agents 224–225 application of 227 functional activity of 224 poly-ILs 12–13 predictive toxicity models 378–380 production 341 products in future management of agri-industries 229 properties of 163–166, 372 SAR induction mechanism 228–229 scope of 17–18 scope of biodegradable and non-toxic 76–78 second generation 7–8, 205–206, 444 silico modeling 377–378 solubility of 256 solvent properties 179 as solvents 197 structural behavior of 260

495

496

Index

ionic liquids (ILs) (contd.) structural characteristics 369–372 structures of anions commonly used in 205 structures of cations commonly used in 205 supported ILs 16 switchable polarity solvent ILs 11 task-specific ionic liquids (TSILs) 9 third generation 206 toxicities of functionalized cation side chain/degree of functionalization 207–208 length of a cation side chain 207 nature of anion 208–209 nature of cation 208 toxicity and ecotoxicity of 292–294 toxicity assessment of 376–377 toxicological effects and toxicity mechanisms of 71–76 vs. traditional salts 340 types 340 used as surface-bonded stationary phases 151–152 value added organic compounds from biomass 286–290 ionothermal synthesis 37 iristectorin A 148 iristectorin B 148

k Knoevenagel adduct 435 Kraft lignin 285

l LASSBio-294 drug in ILs 200 layer-by-layer method 186 levulinic acid 290, 361 levulinic-acid esters 290 Li10 GeP2 S12 (LGPS) 399 lignin 285 lignin extraction processes 285–286 lignocellulosic biomass 284, 334

lignosulfonates 285 linear discriminant analysis (LDA) 378 liquid crystalline (LC) phase 277–278 liquid 1-ethylpyridinium bromide-aluminium chloride ([C2 py]BrAlCl3 ) 4 liquid-liquid extraction (LLE) 148–149, 337–338 liquid organic salt 369 liquid polymers 267 low melting ionic liquid 255 low temperature molten salt 369 lubricant 273–274 lyotropic LCs 277

m magnetic ILs 2, 16 malononitrile 435 Mannich reaction 121 MCF-7 cancer cell lines 380 MC-supported Cobalt-NHC catalyst 108 mechanochemistry 267 Meldrum’s acid 439 melting point, ILs 53–56 membrane extraction 359 membrane separation method 304–305 metal based ILs 311 metallic ILs 14 methanoic acid (HCOOH) 303 (3-methoxycarbonyl)coumarin 428 methylchloroacetate 428 1-methylimidazolium thiocyanate 432 3-methyl-1-phenyl-1H-pyrazole-5-amine 438 5-methylpyrazol-3-amine 439 methylthiophene-2-carbaldehyde 438 microemulsions (MEs) 259 micro-extraction technique 445 microwave-assisted extractions 147 microwave-assisted technique 33 miscibility, ILs 61–62 model oils (MOs), composition of 272 molecular dynamics simulation 402 monoethanolamine 306

Index

multi-objective genetic algorithm (MOGA) 380 multi-walled carbon nanotubes (MWCNT) 359

n N-alkylated 4,5,6,7-tetrahydro[1,2,3]triazolo [1,5-a]pyridine 423 n-alkyl pyridinium 265 N-allylation reactions 120–121 nanotechnology, ionic liquids 197 1,8-naphthanoic anhydride 425 1-Naphthol 435 naphthopyrans 433 natural deep eutectic solvents (NADESs) 379 natural-derived materials in ILs 221 neoteric 370 N-ethylpyridinium tetrafluoroborate [C2 py][BF4 ] 36 neurotransmitter 190 neutral ILs 16 N-heterocyclic carbenes 10 N-methyl-diethanolamine (MDEA) 309 (E)-N-methyl-1-(methylthio)-2nitroethenamine 425 N-methyl-1-(methylthio)-2-nitroethylen1-amine 424 N-methyl-N-propylpyrrolidinium (Pyr13 ) bis (trifluoromethaanesulfonyl)imide (TFSI) ionic liquid [Pyr13 ][TFSI] 403 N-methyl-2-pyrrolidinium hydrogen sulphate-based IL 33 NMR Fast-Field-Cycling (FFC) relaxometry 238 N,N-diethylethanolamine (DEEA) 309 N,N-diisopropylethylamine (DIPEA) 424 non-toxic ILs 292 nonvolatile ionic liquids 464 North Atlantic Treaty Organization (NATO) 376

NRTL equations 344 N-substituted 1-aryltriazenes 127

o o-alkynylphenol 427 onion-like carbon (OLCs) supercapacitors 411 Onsager relation 406 OPLS force field parameters 240 order-N density functional theory (DFT) 241 ornamental plants species 302 oxidative degradation mechanism, of MEA 308 4-Oxo-6-aryl-2-thioxo-1,2,3,4Tetrahydropyrimidine-5carbonitriles derivatives 119 oxy-synthesis 335

p Paal Knorr reaction 126 Patel–Teja–Valderrama equation 306 performance additives 43 perstarction process 338 pervaporative separation 338–339 pharmaceutical salts-ionic liquids 375 phenol derivatives [1-naphthol] 435 phosphonium-based ionic liquids 361 phosphonium sulfonate ionic liquid 465 physical absorption 311–313 of CO2 313 physical adsorption method 185 plants’ resistance against biotic and abiotic stressors effects 229 poisonous solvents 364 polarity, ILs 60 poly (ionic liquids) (PILs) 15, 51 synthesis of 166–167 types and application of 167 polybenzimidazole (PBI) based polymeric membrane 304 poly(1vinyl-3-alkyl imidazolium) chloride-based polyelectrolyte precursor 166 poly chlorinated biphenyls (PCBs) 279

497

498

Index

polyethylene glycol methacrylate-grafted tetra-ethylene glycol-bridged dicationicimidazolium based IL (PEGMA-g-TEGBDIM) 425 poly-ILs 12–13 polyionic liquids 2 porous electrode capacitor 410–412 post-combustion CO2 303 potassium carbonate 307 predictive toxicity models 378–380 probabilistic neural network (PNN) 378 propiolamide 422 protein stabilization 258–259 protic ionic liquids (PILs) 3, 76, 80 pulsed field gradient (PFG) NMR 238 pyranopyridine 424 pyrazolo[3,4-b]pyridines 439 pyrazolodihydropyridines 438 pyrimido[4,5-b]quinolines 437 pyrimido[4,5-d]pyrimidines 437

q QSAR models 388 quantitative toxicity–toxicity relationship (QTTR) 380 quantum chemistry (QC) methods 236 quantum topological molecular similarity (QTMS) 379

r radial distribution function curve (RDF) 399 reactive distillation column with top-bottom external recycling (RDC-TBER) 359 reactive extraction 360–363 Rectisol process 313 red oil 4 regioselectivity 470 Resorcinol 435 retentate/concentrate 359 room temperature ionic liquids (RTILs) 1, 51, 70, 369

room temperature molten salt 5, 369 rotatable bond number (RBN) 379 Rufinamide 422

s salicylaldehyde 428 sandwich-type immunoassay 186 SAR inducers 225 SAR induction mechanism 228–229 second-generation biofuels 334 second generation ionic liquids 205–206, 444 Selexol 312 self-diffusion 237–238 shear viscosity 238–239 simple solid-liquid extractions 146 single electron transfer (SET) 423 sodium azide 421, 422 solar fuels 334 sol-gel encapsulation 185–186 solid-liquid extraction (SLE) 145–146 solid phase extraction (SPE) 269 solubility, ILs 58 solubilization of drugs 257–258 solvent extraction 360 solvents and catalysis 35 Sonogashira coupling 106–108 spiroheterocyclic quinazolin-4-(1H)-one derivatives 431 spiroquinazolin-4-(1H)-one 431 spiro-1,2,4-triazolidine-5-thiones 127 Stille coupling 109 Stokes-Einstein 237, 238 Stokes-Einstein-Debye relationships 238 structure directing agents (SDAs) 37 styrenes 433 5-substituted-1H-tetrazole 422 sulfolane 308 sulfonic acid functionalized ILs (SO3 H-ILs) catalysts 290 sulfur-containing hydrocarbons 272 3-sulphopropyl triphenyl phosphonium p-toluene sulphonate 9

Index

3-sulphopropyl tri-phenyl phosphonium p-toluene sulphonate, structure of 10 supercritical carbon dioxide (scCO2 ) 267 supported ILs 2, 16 supported ionic liquids membranes (SILMs) 51 surface active ILs (SAILs) 146, 259 surface tension (ST), ILs 58–59 Suzuki coupling 103–106 S. vacuolatus, 379 switchable polarity solvent ILs 11 systemic acquired resistance (SAR) 222

t task-specific ionic liquids (TSILs) 2, 9, 51, 97, 419 tectoridins 148 terpene-based ILs 222 terpenoids 145, 221 tert-butyl 2,4-dioxopiperidine-1-carboxylate 424 tert-butyl hydroperoxide (TBHP) 423 tetraalkyl-ammonium or tetraalkyl-phosphonium ion 265 tetrabutyl-ammonium based ionic liquids (ILs) 78 tetrabutylphosphonium 4-ethoxyvalerate ([TBP][4EtOV]) 107 tetrafluoroborate (BF4) 462 tetramethylphosphonium glycinate [P1111 ][Gly] 311 tetrazolo[1,5-a]pyrimidine 426 theophylline 226 thermochemical methods 285 thermochemical process 285 thermotropic LCs 277 thiourea 437

3-thioxohexahydro-1H-pyrrolo[1,2-c] imidazol-1-one 432 third-generation biofuels 334 third generation ionic liquids 206 time-temperature superposition (TTS) approach 239 toxic catalysts 357 toxicity and ecotoxicity 292–294 tricataionic ionic liquid 314 trifluoroacetate (C2 F3 O2 ) 462 trifluoromethanesulfonate (CF3 SO3 ) 462 trihexyl-(tetradecyl)phosphonium 2-cyanopyrrolide ([P66614 ][2-CNpyr]) 311 1,3,5-triphenylbenzene synthesis using PIL 106 triphenylphosphine 428 2,4,5-trisubstituted imidazoles 435 tryptanthrin 424 two-phase approach 464

u ultrasound-assisted extractions 147–148

v van der Waal’s force of attraction 314 vapor pressure, ILs 61 Vibrio fischeri, 72, 73, 378, 379 vinyl imidazolium-based polymers 166 3-vinyl ketones 39, 40 viscosity, ILs 59–60, 183–184

w Walden rule 3, 4, 57 water and air-stable 1-ethyl-3-methylimidazolium based ILs 5 whole-cell biotransformations 464–466

499