Flow Chemistry: Volume 1 Flow Chemistry – Fundamentals 9783110289169

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De Gruyter Graduate Darvas, Dormán, Hessel • Flow Chemistry

Also of Interest Sustainable Process Engineering – Prospects and Opportunities Koltuniewicz, 2014 ISBN 978-3-11-030875-4, e-ISBN 978-3-11-030876-1

Chemical Reaction Technology Murzin, 2015 ISBN 978-3-11-033643-6, e-ISBN 978-3-11-033644-3

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Green Processing and Synthesis Hessel (Editor-in-Chief) ISSN 2191-9550

Flow Chemistry

| Volume 1: Fundamentals Edited by Ferenc Darvas, György Dormán, Volker Hessel

Editors Ferenc Darvas Florida International University College of Medicine University Park, 495 11 200 S.W. 8th St. Miami 33 199 USA e-mail: [email protected]

György Dormán ThalesNano Nanotechnology Inc Graphisoft Park Zahony u. 7 Budapest 1031 Hungary e-mail: [email protected] Volker Hessel Eindhoven Univ. of Technology Micro Flow Chem. & Proc. Techn. Group Dept. of Chemistry & Chemical Eng. Den Dolech 2 5600 MB Eindhoven The Netherlands e-mail: [email protected]

ISBN 978-3-11-028915-2 e-ISBN 978-3-11-028916-9 Library of Congress Cataloging-in-Publication Data A CIP catalog record for this book has been applied for at the Library of Congress. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.dnb.de. © 2014 Walter de Gruyter GmbH, Berlin/Boston Typesetting: le-tex publishing services GmbH, Leipzig Printing and binding: Hubert GmbH und Co. KG, Göttingen Cover image: Book cover design by Reka Darvas (www.zenurdel.com) ♾ Printed on acid-free paper Printed in Germany www.degruyter.com

Preface Flow chemistry – the use of small flow reactors to perform chemical synthesis – has matured over the past two decades from early demonstrations of simple chemical transformations in microstructured reactors (microreactors) to complex, multistep synthesis relevant to fine chemistry and pharmaceuticals in commercial systems. This evolution in synthetic methods and equipment has been motivated by advantages inherent to continuous synthesis in small scale, specifically enhanced rates from improved heat and mass transfer along with an expanded space of reactions and process conditions. Continuous operation also eliminates headspace issues and avoids accumulation of reactive or toxic intermediates offering opportunities for telescoping of reactions. Synthesis applications are further enhanced by automated optimization as well as mechanistic and kinetic information gained from integrating reaction components with sensors, actuators, and automated fluid handling. Moreover, the steady-state operation inherent in continuous operation provides robustness, stability, and scalability. The expansion in flow chemistry applications and equipment has been detailed in numerous review papers and monographs, but there has been a longstanding need for a comprehensive coverage of the many concepts underlying flow chemistry for graduate students in chemistry and chemical engineering. The present Graduate Textbook on Flow Chemistry fills the gap in graduate education by covering chemistry and reaction principles along with current practice, including examples of relevant commercial reactions, separation, automation, and analytical equipment. It motivates the reasons for flow chemistry, and importantly, when flow chemistry will and will not be advantageous compared to batch processing. Basic theory and practical considerations are summarized to enable the reader to appreciate the difference between conventional batch chemistry and flow chemistry as well as to implement flow chemistry in the laboratory. A very useful feature is the inclusion of validate reactions that can serve as laboratory test experiments. The subsequent treatment of theoretical foundations for flow chemistry, also know as reaction engineering, provides useful in depth understanding of continuous reactions. The second volume of the Graduate Textbook on Flow Chemistry covers specific reaction classes, concepts, and experimental methods. Homogeneous and heterogeneous catalysis, supercritical processes, photochemistry, green chemistry, and radiolabeled chemistry applications are described in individual chapters along with examples of flow chemistry for nanotechnology and materials science. Practical oriented chapters address (i) analytical techniques, specifically in-line monitoring methods, (ii) examples of automation, (iii) how to build your own flow chemistry set-up as well an overview of commercially available units, and (iv) importantly, safety aspects of flow chemistry systems and processes.

vi | Preface The Editors of this Graduate Textbook on Flow Chemistry, Drs. Ferenc Darvas, Volker Hessel and György Dormán are commended for having taken the initiative to bring together experts from the field to provide a comprehensive treatment of fundamental and practical considerations underlying flow chemistry. It promises to become a useful study text as well as a reference for the graduate students and practitioners of flow chemistry. June 2014

Klavs Jensen Department Head, Massachusetts Institute of Technology, USA

The Editors would like to express their gratitude to the many people who helped to complete this textbook. They are indebted to all the authors for their outstanding contribution and the valuable and constructive suggestions during the planning. They are very grateful to Prof. Dr. Jan van Hest (POAC Committee, Radboud University Nijmegen, The Netherlands); to Prof. Floris Rutjes (Radboud University Nijmegen); to Dr. Varsha Kapoerchan (Organisation for Scientific Research NWO, Advanced Chemical, Technologies for Sustainability (ACTS), The Netherlands) and to Darholding Inc. (Hungary) for their financial support. Prof. Volker Hessel kindly acknowledges the funding provided by the Advanced European Research Council Grant “Novel Process Windows – Boosted Micro Process Technology” (no 267 443). Special thanks should be given to all the instrument suppliers for their contributions to the Microreactor Chapter (Chemtrix, FutureChemistry, Invenios, Microinnova, Syrris, ThalesNano, Uniqsis). The Editors’ thanks is extended to Ms. Szilvia Gilmore (Flow Chemistry Society) for the coordination and monitoring duties during the preparation of the textbook, to Ms. Karin Sora, Editorial Director Chemistry/Materials Science and Ms. Julia Lauterbach, Project Editor STM, DeGruyter Publishing House for their enthusiasm, continuing motivation and technical support as well as to Reka Darvas for the great cover design.

Contents Preface | v About the editors | xiii Abbreviations | xvii Part I

Introduction and outlook

Holger Loewe 1 Introduction and outlook | 3 Part II Theoretical foundations Ferenc Darvas and Dormán György 2 Fundamentals of Flow Chemistry | 9 2.1 Fundamentals of chemical reactions | 9 2.1.1 Thermodynamic requirements for reaction | 9 2.1.2 Kinetic requirements for a reaction | 10 2.1.3 Reaction order and kinetics | 12 2.1.4 Diffusion control | 13 2.1.5 Kinetic versus thermodynamic control | 13 2.1.6 Competing reactions | 15 2.1.7 Initiation and termination of chemical reactions | 15 2.1.8 Exotherm and endoterm reactions | 16 2.1.9 How to accelerate an organic chemical reaction. Shifting the equilibrium towards product formation | 16 2.2 Batch versus flow reactions | 20 2.2.1 Performing chemical reactions in batch and flow | 23 2.2.2 Multistep reactions in batch and flow | 26 2.2.3 The dimensions of batch (flask) and flow (micro) reactors | 26 2.2.4 Mixing in batch versus microreactors | 27 2.2.5 Mass transfer in batch and flow | 28 2.2.6 Temperature control in batch and flow | 29 2.2.7 Heterogeneous catalytic reactions in batch and flow | 32 2.3 Introduction to the basics of microfluidics | 34 2.3.1 Electroosmotic (electrokinetic) flow (EOF) | 34 2.3.2 Hydrodynamic (pressure-driven) pumping | 36 2.3.3 Segmented flow | 37 2.3.4 Centrifugal pumping | 38 2.3.5 Laminar and turbulent flow regimes, the Reynolds number | 38 2.3.6 Axial dispersion versus radial dispersion (Bodenstein and Peclet Numbers) | 41 2.3.7 Mixing versus reaction rate–Damköhler Number | 41 2.3.8 Heat transfer in flow | 42 2.3.9 Flow rates in microreactors | 43

viii | Contents 2.4 2.4.1 2.4.2 2.5 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5

Microreactors in general | 44 General properties of flow reactors | 44 Major flow reactor configurations | 47 Essentials of reaction planning and realization in continuous flow | 49 Classification of chemical reactions based on reaction kinetics | 49 Flash chemistry | 50 High-resolution reaction time control | 51 Novel process windows | 52 Process intensification | 55

Jun-ichi Yoshida 3 Principles of controlling reactions in flow chemistry | 59 3.1 Introduction | 59 3.2 Reactions in a flow microreactor | 59 3.2.1 Reaction time in a batch reactor | 59 3.2.2 Residence time control in a flow reactor | 60 3.2.3 Why micro? | 62 3.3 High-resolution reaction time control of reactions in flow | 68 3.3.1 The principle | 68 3.3.2 Example 1: Phenyllthiums bearing alkoxycarbonyl groups | 70 3.3.3 Temperature–residence time map | 72 3.3.4 Example 2: Control of isomerization. Aryllithiums bearing a nitro group | 76 3.4 Space integration of reactions | 77 3.4.1 The concept | 77 3.4.2 Example 3: Synthesis of disubstituted benzenes from dibromobenzene | 78 3.4.3 Example 4: Synthesis of TAC-101 | 79 3.4.4 Linear integration and convergent integration | 80 3.4.5 Example 5: Synthesis of unsymmetrically-substituted photochromic diarylethenes. Convergent integration | 81 3.4.6 Example 6: Integration of lithiation and cross-coupling | 82 3.4.7 Example 7: Anionic polymerization of styrene and synthesis of block copolymers with a silicon core | 85 3.4.8 Example 8: Anionic block copolymerization of styrene and methyl methacrylate | 88 3.5 Summary | 89 Melinda Fekete and Toma Glasnov 4 Technology overview/Overview of the devices | 95 4.1 General aspects | 95 4.2 Pumps for liquid handling | 96

Contents | ix

4.2.1 4.2.2 4.2.3 4.3 4.4 4.5 4.6 4.6.1 4.6.2 4.7 4.7.1 4.7.2 4.7.3 4.8 4.8.1 4.8.2 4.8.3 4.8.4 4.8.5 4.8.6 4.9 4.10

Syringe pump | 96 Piston pump | 97 Other pumps | 98 Mass-flow controllers | 99 Heating/cooling of the reaction zone | 99 Back-pressure regulators | 100 Mixers | 101 Modular mixers | 102 In-line mixers | 103 Reactors | 105 Coil reactors | 106 Chip reactors | 108 Packed-bed or fixed-bed reactors | 109 Miscellaneous techniques | 112 Tube-in-tube reactor | 112 Segmented flow biphasic reactions | 113 Falling film reactors | 116 Flow microwave reactors | 117 UV reactors | 118 Working with supercritical CO2 | 119 Assembling and using a flow reactor | 120 Commercially available systems for the laboratory use | 123

Patrick Plouffe, Arturo Macchi, and Dominique M. Roberge 5 From batch to continuous chemical synthesis – a toolbox approach | 141 5.1 Chemical process development and scale-up challenges | 141 5.1.1 Batch synthesis: Current profile of the pharmaceutical and fine-chemical industry | 141 5.1.2 Flow chemistry and microreactor technology: a viable alternative? | 142 5.1.3 Modularized process intensification – use the right tool at the right place | 143 5.2 Reaction categories based on rate | 146 5.2.1 Type A reactions | 146 5.2.2 Type B reactions | 146 5.2.3 Type C reactions | 147 5.3 Reacting phases | 147 5.3.1 Single phase systems – mix-then-reside | 147 5.3.2 Liquid-liquid systems – mix-and-reside versus active mixing | 148 5.3.3 Gas-liquid systems – use of pressure | 150 5.3.4 Liquid-solid systems | 150 5.4 Summary | 150

x | Contents Part III Lab and teaching practise Pieter Nieuwland, Kaspar Koch, René Becker, Sándor B. Ötvös, István M. Mándity, and Ferenc Fülöp 6 Experimental procedures for conducting organic reactions in continuous flow | 157 6.1 Flow chemistry calculations | 157 6.1.1 Reaction and microreactor temperature | 157 6.1.2 Determination of flow rates | 157 6.1.3 Example calculation | 158 6.2 Wittig reaction in a continuous-flow microreactor | 159 6.2.1 Continuous-flow design | 159 6.2.2 Basic experiment | 160 6.2.3 Optimization experiment | 161 6.3 Swern–Moffatt oxidation in a continuous-flow microreactor | 163 6.3.1 Continuous-flow design | 163 6.3.2 Basic experiment | 164 6.3.3 Optimization experiment | 166 6.3.4 Optimization experiment on a different substrate | 167 6.4 Synthesis of silver nanoparticles in a continuous-flow microreactor | 168 6.4.1 Continuous-flow design | 169 6.4.2 Basic experiment | 169 6.4.3 Optimization experiment | 172 6.5 1,2,3-triazole synthesis in continuous flow with copper powder and additives | 172 6.5.1 Continuous-flow design | 173 6.5.2 Basic experiment | 174 6.5.3 Optimization experiment | 174 6.6 Heterogeneous catalytic deuteration with D2 O in continuous flow | 176 6.6.1 Continuous-flow design | 176 6.6.2 Basic experiment | 177 6.6.3 Optimization experiment | 178 6.7 Aldol reaction in a continuous-flow microreactor | 178 6.7.1 Continuous-flow design | 179 6.7.2 Basic aldol experiment | 179 6.7.3 Aldol reaction optimization | 180 6.8 Prilezhaev epoxidation in a continuous-flow microreactor | 181 6.8.1 Continuous-flow design | 181 6.8.2 Basic epoxidation experiment | 182 6.9 Peptide catalyzed stereoselective reactions in a continuous-flow reactor | 184 6.9.1 Continuous-flow design | 186

Contents | xi

6.9.2 6.9.3

Basic aldol experiment | 186 Reaction optimization | 187

Robert K. Harmel, Marielle M. E. Delville, and Floris P. J. T. Rutjes 7 Experimental procedures for conducting organic reactions in continuous flow | 191 7.1 Pyrrole synthesis by Paal–Knorr cyclocondensation | 192 7.1.1 Background | 192 7.1.2 The flow process | 193 7.1.3 Experimental procedures | 195 7.2 Diels–Alder Reactions in flow chemistry | 196 7.2.1 Background | 196 7.2.2 The flow process | 196 7.2.3 Experimental procedures | 199 7.3 Copper-catalyzed azide-alkyne cycloaddition in flow using inductive heating | 200 7.3.1 Background | 200 7.3.2 The flow process | 202 7.3.3 Experimental procedures | 203 7.4 Nef Oxidation of nitroalkanes with KMnO | 204 7.4.1 Background | 204 7.4.2 The flow process | 204 7.4.3 Experimental procedures | 206 7.5 Suzuki–Miyaura cross-coupling with palladium-catalysts generated in flow | 207 7.5.1 Background | 207 7.5.2 The flow process | 208 7.5.3 Experimental procedures | 210 7.6 Oxidative amidation of aromatic aldehydes | 211 7.6.1 Background | 211 7.6.2 The flow process | 212 7.6.3 Experimental procedures | 213 7.7 Azide synthesis in flow via diazotransfer | 215 7.7.1 Background | 215 7.7.2 The flow process | 216 7.7.3 Experimental procedures | 217 7.8 Boronic acid/ester synthesis via lithium halogen exchange in a Cryo-Flow Reactor | 219 7.8.1 Background | 219 7.8.2 The flow process | 219 7.8.3 Experimental procedures | 222 7.9 The Ritter Reaction in Continuous Flow | 223 7.9.1 Background | 223

xii | Contents 7.9.2 7.9.3 7.10 7.10.1 7.10.2 7.10.3 7.11 7.11.1 7.11.2 7.11.3 7.12 7.12.1 7.12.2 7.12.3 7.13 7.13.1 7.13.2 7.13.3 7.14

The flow process | 224 Experimental procedures | 225 Vilsmeier–Haack formylation of electron-rich arenes | 226 Background | 226 The flow process | 227 Experimental procedures | 230 Appel reaction using monolithic triphenylphosphine in flow | 230 Background | 230 The flow process | 232 Experimental procedures | 234 Schenck ene reaction in flow using singlet oxygen | 235 Background | 235 The flow process | 236 Experimental procedure | 239 Chemoenzymatic flow synthesis of cyanohydrins | 241 Background | 241 The flow process | 242 Experimental procedures | 243 Summary | 244

C. Oliver Kappe 8 The Microwave-to-flow paradigm: translating batch microwave chemistry to continuous-flow processes | 251 8.1 Microwave chemistry | 251 8.2 Converting microwave to flow chemistry | 252 8.3 Summary | 257 Nicholas E. Leadbeater, Trevor A. Hamlin 9 Incorporation of continuous-flow processing into the undergraduate teaching laboratory: key concepts and two case studies | 259 9.1 Introduction | 259 9.2 Equipment | 260 9.3 Experiments developed for the undergraduate teaching laboratory | 262 9.4 Development of two new experiments for the undergraduate laboratory | 262 9.4.1 The Biginelli Reaction | 264 9.4.2 The Claisen–Schmidt Reaction | 269 9.5 Summary | 273 9.6 Acknowledgements | 273 Answers to the study questions | 277 Index | 291

About the editors Prof. Ferenc Darvas acquired his degrees in Budapest, Hungary (medical chemistry MS, computer sciences BS, degree in patent law, PhD in experimental biology). He has been teaching in Hungary, Spain, Austria, and in the United States of America at different universities, presently serves as associate professor at the Florida International University in Miami. He is author of 140 pre-reviewed papers and 5 books. Dr. Darvas has been involved in introducing microfluidics/flow chemistry methodologies for synthetizing drug candidates since the late 90’s, which led him to found ThalesNano. One of his team’s inventions, the desktop high pressure/high temperature flow hydrogenator H-Cube won several innovation awards in the United States of America and also in Europe, and has been used in more than 60 countries. Dr. Darvas is also the founder and active President of the Flow Chemistry Association located in Switzerland. Prof. György Dormán obtained his Ph.D. in organic chemistry from the Technical University of Budapest in 1986. Between 1986–1988 and 1996–1999 he worked at Sanofi–Chinoin in Budapest. In 1988–1989 he spent a post-doctoral year in the UK (University of Salford). Between 1992 and 1996 he was a Visiting Scientist at the State University of New York, Stony Brook. Between 1999 and 2008 he served ComGenex/AMRI as Chief Scientific Officer. Since 2008 he is responsible for the scientific innovation of ThalesNano. Dr. Dormán is involved in many training courses in the area of (bio)organic and flow chemistry. In 2011 he became Professor at University of Szeged. He is an author of 85 scientific papers and book chapters. He is a member of the editorial board of Molecular Diversity and the advisory board of J. Flow Chemistry. Prof. Volker Hessel studied chemistry at Mainz University (PhD in organic chemistry, 1993). In 1994 he entered the Institut für Mikrotechnik Mainz GmbH (1996: group leader microreaction technology). In 2002, Prof. Hessel was appointed Vice Director R&D at IMM and in 2007 as Director R&D. In 2005 and 2011, he was appointed as part-time and full professor at Eindhoven University of Technology, respectively, for the chair of “Micro Flow Chemistry and Process Technology”. He is (co-)author of more than 270 peer-reviewed publications, with 18 book chapters and 5 books. He received the AIChE award “Excellence in Process Development Research” in 2007 and in 2010 the ERC Advanced Grant “Novel Process Windows”. Prof. Hessel is in the scientific advisory board of the “International Conference on Microreaction Technology”. He is Editor-in-Chief of the journal “Green Processing and Synthesis”.

Contributing authors René Becker Homogeneous, Bioinspired and Supramolecular Catalysis van ’t Hoff Institute for Molecular Sciences University of Amsterdam Science Park 904 1098 XH Amsterdam, The Netherlands e-mail: [email protected] Chapter 6 Ferenc Darvas Florida International University College of Medicine University Park 495 Miami 33 199, USA e-mail: [email protected] Chapter 2 Marielle M. E. Delville Institute for Molecules and Materials Radboud University Nijmegen Nijmegen, The Netherlands e-mail: [email protected] Chapter 7 György Dormán ThalesNano Nanotechnology Inc Graphisoft Park Zahony u 7 Budapest 1031, Hungary e-mail: [email protected] Chapter 2 Melinda Fekete ThalesNano Inc. Zahony u 7 Budapest Hungary 1031 e-mail: [email protected] Chapter 4

Ferenc Fülöp Institute of Pharmaceutical Chemistry University of Szeged Szeged, Hungary e-mail: [email protected] Chapter 6 Toma Glasnov Institute of Chemistry College of C. Doppler Lab. for Flow Chemistry Karl-Franzens University Graz, Austria e-mail: [email protected] Chapter 4 Trevor A. Hamlin Department of Chemistry University of Connecticut Storrs, CT, USA e-mail: mailto:[email protected] Chapter 9 Robert K. Harmel Institute for Molecules and Materials Radboud University Nijmegen Nijmegen, The Netherlands e-mail: [email protected] Chapter 7 C. Oliver Kappe Institute of Chemistry University of Graz Graz, Austria e-mail: [email protected] Chapter 8 Kaspar Koch Future Chemistry Holding BV Nijmegen, The Netherlands e-mail: [email protected] Chapter 6

xvi | Contributing authors Nicholas E. Leadbeater Department of Chemistry University of Connecticut Storrs, CT, USA e-mail: [email protected] Chapter 9

Sándor B. Ötvös Institute of Pharmaceutical Chemistry University of Szeged Szeged, Hungary e-mail: [email protected] Chapter 6

Holger Loewe Fraunhofer ICT-IMM and Institute for Organic Chemistry Johannes Gutenberg-Universtiy Mainz, Germany e-mail: [email protected] Chapter 1

Patrick Plouffe Department of Chemical and Biological Engineering Centre for catalysis Reseach and Innovation University of Ottawa Ottawa, Canada e-mail: [email protected] Chapter 5

Arturo Macchi Department of Chemical and Biological Engineering Centre for catalysis Reseach and Innovation University of Ottawa Ottawa, Canada e-mail: [email protected] Chapter 5

Dominique M. Roberge Process DEVelopment Lonza AG Visp, Switzerland e-mail: [email protected] Chapter 5

István M. Mándity Institute of Pharmaceutical Chemistry University of Szeged Szeged, Hungary e-mail: [email protected] Chapter 6 Pieter Nieuwland Future Chemistry Holding BV Nijmegen, The Netherlands e-mail: [email protected] Chapter 6

Floris P. J. T. Rutjes Institute for Molecules and Materials Radboud University Nijmegen Nijmegen, The Netherlands e-mail: [email protected] Chapter 7 Jun-ichi Yoshida Department of Synthetic Chemistry and Biological Chemistry Graduate School of Engineering Kyoto University Kyoto, Japan e-mail: [email protected] Chapter 3

Abbreviations AC generator Auto-LF BNS Bo BPM BPR CatCart CF CSTR CuAAC Da DCM DIPEA DMF DMSO DoE ee EOF ETFE FEP FID detector FLLEX FT-IR GC GC-FID GC-MS GLC GMP guidelines HL-60 cells HNL HPLC HRMS IMRET IR LC-MS LCD MAOS mCPBA MCPT

Alternating current generator Automated loop filling beta-nitro styrene Bodenstein number Binary Pumping Module Back-pressure regulator Cartridge-like columns Continuous flow Continuous stirrer tank reactor Copper(I)-catalyzed azide-alkyne cycloaddition Damköhler number Dichloromethane N,N-diisopropylethylamine N,N-Dimethylformamide Dimethyl sulfoxide Design of experiment Enantiomeric excess Electroosmotic flow Ethylene tetrafluoroethylene Fuorinated ethylene propylene Flame ionization detector Flow liquid-liquid extraction Fourier transform infrared spectroscopy Gas chromatography Gas-chromatography flame ionization detector Gas chromatography mass spectrometry Gas-liquid chromatography Good manufacturing practices guidelines Human promyelocytic leukemia cells Catalyzed cyanide High-performance liquid chromatography High-resolution mass spectrometry International Conference on Microreaction Technology Infrared Liquid chromatography-mass spectrometry Liquid-crystal display Microwave-assisted organic synthesis metachloro-peroxybenzoic acid Microchemical processing technology

xviii | Abbreviations ME MFC MMA MS MTBE MW (N)-IR NMR NPW Pe PEEK PFA PFE PFR PhLi PI PID controller PMMA Pr PS PTFE QP-TU Re RP-HPLC s-BuLi SM SMR St t-BuBr t-BuLi TAC-101 TFA TFAA THF TPP UV UV-vis

Molar excess ratio Mass-flow controller Methyl methacrylate Mass spectrometry Methyl tert-butyl ether Microwave chemistry Near-infrared Nucelar magnetic resonance Novel Process Windows Peclet number Polyether ether ketone Perfluoroether reactor coil Plug flow reactor Phenyllithium Process intensification Proportional-integral-derivative controller Polymethyl methacrylate Prandtl number Polystyrene Polytetrafluoroethylene QuadraPure Thiourea resin Reynolds number Reversed phase HPLC s-butyllithium Starting material Sulzer Mixer Reactor Styrene t-butyl bromide t-butyllithium (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) Trifluoroacetic acid Trifluoroacetic anhydride Tetrahydrofuran Tetrafluoroethylene Ultraviolet Ultriaviolet-visible spectroscopy

| Part I: Introduction and outlook

Holger Loewe

1 Introduction and outlook

It has now been more than 15 years since the first International Conference on Microreaction Technology (IMRET) and microflow chemistry developed an established pathway for synthesizing high quality chemicals and products at an industrial scale. Nevertheless, the so-called microreactor chemistry was not new at the time. It has been known since the late 1960s, but due to the lack of advanced fabrication technology to produce microreactors, the publications per year stayed very low until the early 1990s. Not only was the technology missing, but also an established journal on microchemistry, which hindered advancements in this field. Because of this, the first book was published in 2001 with the help of many enthusiastic researchers, who by then had been met with skepticism for this re-invented technology [1]. Today, there can be absolutely no doubt about the importance of microreaction technology. Several specialized journals have been established and a variety of books focusing on different challenges have already been written. Theories for computational microfluidics, as well as novel manufacturing techniques were developed, and new reaction pathways were published [2, 3]. These new pathways are summarized and introduced by Prof. Hessel under the topic of “Novel Process Windows”, leading to reactions with high yields, purities, and sometimes “greener” processes with significantly reduced reaction times [4–6]. The question in mind has to be: Is that everything or can we go any further? The answer will be given in a short summary presented below and in detail in this book. Microreactors now introduce the possibility to perform reactions in a confined space, enabling excellent heat transfer and tremendous mass transfer, which could never be met by the established batch chemistry. Keeping the novel process window in mind, it enables completely new processing pathways in chemistry where reactions are possible, which cannot be done in conventional batch/flask systems, such as protecting group-free synthesis and flash chemistry. Keeping the system at the thermal runaway state can be of great interest for highly exothermic reactions with high activation energies [7]. This can be easily combined with heat pipes: To start the reaction, the pipes are heated to the activation temperature of the respective reaction. After reaching the activation energy, the released heat from the reaction behind the mixing chamber is discharged through the heat pipe and injected back to preheat the educts. An excess heat can be easily dissipated by commercial computer cooling systems [8, 9]. Examples for such reactions are nitration reactions without solvents [10], diazomethane synthesis [11] with subsequent in situ reaction to azo dyes, and oxidations with (singlet) oxygen in a falling film reactor [12]. If passive mixing through energy input from the pumps is not sufficient, active mixing

4 | 1 Introduction and outlook can also be enabled by installing ultrasonic or acoustic probes [13]. Other possibilities for active mixing include integrated microvalves, electro wetting, and vibrating membranes, which can also be used for introducing substrates over time or exchanging ions [14]. Another great opportunity for the use of microreactors are research fields where high cross-phase surfaces are needed. For instance, heterogeneous catalysis is of great importance for high-tech chemicals such as liquid crystals for LCDs [4]. Coating microreactors with those catalysts enables surface areas comparable to packed bed reactors with palladium on charcoal packing, but with the advantage of easier recycling of the catalyst, which is removed from the reactor surface by dissolution and recoating of the reactor [7]. For developing new products, this knowledge should be used at the earliest possible stage in industrial research. Facilitating up-scaling due to the retention of process parameters is an important byproduct of applying microchemistry and further process design and engineering. Other factors, such as safety issues and human resource minimization, as well as waste treatment play an important role in life cycle assessments. Safety concerns emerging through the use of high pressure and temperature can be invalidated by energy reflection: The inner volume of a microreactor is usually too small to hold enough substance at one time for an explosion, which could harm people or the building stability. To minimize the personnel needed to operate the facility, automation of these processes is also of great interest. To account for this, a variety of probes monitoring pressure, temperature, and also product quality with in-line high-performance liquid chromatography (HPLC) or near-infrared ((N)-IR) measurements can be installed in the system. Furthermore, the easy installation of computer controlled emergency purges can make the facility almost 100% automated without any need of human intervention. This not only reduces recurring costs but also improves safety due to elimination of human error. These facilities can be built in parts, fitting in a small number of overseas containers, for better portability [5]. Process intensification of already existing batch or continuous processes is not practical in most cases because of substantial investments made for optimizing the parameters. Achieving significantly better space/time-yields or a higher degree of sustainability is not possible by using only standard processing techniques without a total redesigning of the process and reinvestigation of each step. Most of the chemical companies in the European Union are complying with GMP guidelines, which do not allow altering of process parameters and process layouts without external validation of these changes. Combining these presumptions and keeping the cost factor in mind, changing existing and stable running processes in the sense of process intensification can only be of benefit for highly exothermic reactions or systems that rely on excellent mixing quality. However, there is more potential in this field additionally to novel process windows. All these processes, even the “brand new” ones, still deal with standard heat-

Bibliography

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5

ing techniques using oil/water or standard cooling techniques using aggregates. Both techniques are highly energy consuming and can be easily replaced by incorporating existing temperature control setups from other fields. For instance, heating can be achieved in a very ecological way by using solar mirrors designed for solar power plants. Simple cooling can also be realized using the heat pipes designed for high performance cluster computer systems which have already been mentioned above. This would not only reduce the energy needed to operate the facility but also contribute significantly to the sustainability of the process lowering it to dimensions which could not be achieved with any other technology besides microreactor technology. Even so, there is one step to go: novel process windows, intensifying mass and heat transfer capabilities, and temperature control is still not “chemistry at the limit”. This should imply driving the reaction at the absolute kinetic limit, eliminating all decelerating elements which were introduced in the early stages of continuous processing, to keep the reaction controllable with limited heat and mass transfer. For instance, those factors are solvents, limiting the reaction through diffusion control, and heat exchange, limiting the product yield by overheating. Substrates could be used without diluting and heat exchange can be driven to the limit by using vapordriven heat exchangers (heat pipes) in direct contact with the reaction chamber. The last point could be achieved by directly etching the reactor layout into commercially available heat pipes.

Bibliography [1] [2] [3]

[4] [5]

[6]

[7]

[8]

Ehrfeld, W., Hessel, V., Löwe, H.; Microreactors, Wiley-VCH, Weinheim, 2000. Hessel, V., Kralisch, D., Kockmann, N., Noel, T., Wang, Q.; “Novel process windows for enabling, accelerating, and uplifting flow chemistry”, ChemSusChem 6, 5 (2013) 746–789. Hessel, V., Cortese, B., de Croon, M. H. J. M.; “Novel process windows – concept, proposition and evaluation methodology, and intensified superheated processing”, Chem. Eng. Sci. 66, 7 (2011) 1426–1448. Jensen, K. F.; “Microreaction engineering – is small better?” Chem. Engin. Sci. 56 (2001) 293– 303. Kralisch, D., Streckmann, I., Ott, D., Krtschil, U., Santacesaria, E., Die Serio, M., Russo, V., De Carlo, L., Linhart, W., Christian, E., Cortese, B., de Croon, M. H. J. M., Hessel, V.; “Transfer of the epoxidation of Soybean oil from batch to flow chemistry guided by cost and environmantal issues”, Chem. Sus. Chem. 5 (2012) 300–311. Huebschmann, S., Kralisch, D., Löwe, H., Breuch, D., Petersen, J. H., Dietrich, T., Scholz, R.; “Decision support towards green process design in microstructured reactors by accompanying (simplified) life cycle assessment”, Green Chem. 13, 7 (2011) 1694–1707. Kressirer, S., Protasova, L. N., de Croon, M. H. J. M., Hessel, V., Kralisch, A.; “Removal and renewal of catalytic coatings from lab- and pilot-scale microreactors, accompanied by life cycle assessment and cost analysis”, Green Chem. 14 (2012) 3034–3046. Löwe, H., Axinte, R. D., Breuch, D., Hang, T., Hofmann, C.; “Heat pipe cooled microstructured reactor concept for highly exothermal ionic liquid syntheses”, Chem. Eng. Technol. 33, 7 (2010) 1153–1158.

6 | 1 Introduction and outlook [9] [10]

[11] [12] [13] [14]

Ehm, N., Löwe, H.; “Heat pipe mediated control of fast and highly exothermal reactions”, Org. Proc. Res. Dev. 15, 6 (2011) 1438–1441. Hessel, V., Löb, P., Löwe, H.; “Industrial Microreactor Process Development up to Production”, in Wirth, T. (Ed.) Microreactors in Organic Chemistry and Catalysis, pp. 211–275, Wiley-VCH, Weinheim, 2008. Mueller, G., Gaup, T.; “Continuous diazomethane chemistry”, Chem. Files, Vol. 5, 25 August (2005), 8–9. Jähnisch, K., Dingerdissen, U.; “Photochemical generation and [4+2]-cycloaddition of singlet oxygen in a falling-film microreactor”, Chem. Eng. Technol. 28, 4 (2005) 426–427. Yang, Z., Matsumoto, S., Goto, H., Matsumoto, M., Maeda, R.; “Ultrasonic micromixer for microfluidic systems”, Sensor Actuat. A 93 (2001) 266–272. Hessel, V., Löwe, H., Schönfeld, F.; “Micromixers – a review on passive and active mixing principles”, Chem. Eng. Sci. 60, 8–9 (2005) 2479–2501.

| Part II: Theoretical foundations

Ferenc Darvas and Dormán György

2 Fundamentals of Flow Chemistry

2.1 Fundamentals of chemical reactions Objective of this chapter This chapter intends to summarize all the important basic theoretical features of flow chemistry and flow reactors. The detailed discussion of the particular topics can be found in the following chapters. At each section such chapters are highlighted.

2.1.1 Thermodynamic requirements for reaction In order for a reaction to take place spontaneously, the Gibbs free energy of the products must be lower than the free energy of the reactants; that is, 𝐺 must be negative.

Δ𝐺 = Δ𝐻 − 𝑇 ⋅ Δ𝑆 Free energy is made up of two components, enthalpy 𝐻 and entropy 𝑆. 𝐺: free energy, 𝐻: enthalpy, 𝑇: temperature, 𝑆: entropy, Δ: difference (change between original and product).

Free energy

+

ΔGf+ +

ΔGf+

ΔG

Reaction coordinate

Fig. 2.1: Free energy profile of a chemical reaction without having an intermediate.

10 | 2 Fundamentals of Flow Chemistry The enthalpy change in a reaction is essentially the difference in bond energies (including resonance, strain, and solvation energies) between the reactants and the products. The enthalpy change can be calculated by totaling the bond energies of all the bonds broken, subtracting from this the total of the bond energies of all the bonds formed, and adding any changes in resonance, strain, or solvation energies. Entropy changes refer to the disorder or randomness of the system. The less order in a system, the greater the entropy. The preferred conditions in Nature are low enthalpy and high entropy, and in reacting systems, enthalpy spontaneously decreases while entropy spontaneously increases.

2.1.2 Kinetic requirements for a reaction A negative 𝐺 is a necessary, but not a sufficient, condition for a reaction to occur spontaneously. Reactions take place in a reasonable period of time depending on the energy profile of the starting materials (reactants) and the activated complex (transition state) that are taken to be in equilibrium. The transition state is a saddle point on the potential surface between the reactant and the product. According to the transition-state theory, all activated complexes go on to product at the same rate (“falling downhill”) so that the reaction rate depends only on the position of the equilibrium between the starting materials and the activated complex. Activation energy is required to transfer all the reactants into the activated complex. Transition state

Activation energy Reactant Reaction energy Product Fig. 2.2: Free energy profile of a chemical reaction displaying the transition state and activation energy.

2.1 Fundamentals of chemical reactions

|

11

Table 2.1: The temperature dependence of the reaction time (blue and italic: hour region, black: minutes region, blue and upshape: seconds region) Time (°C) 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250

Times – change in letter style represents change in unit (hour/minutes/seconds) 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 0 0 0 0 0

2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 0 0 0 0

4 2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 0 0 0

6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 0 0 0

8 4 2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 0 0

12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 1 0

24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 0

48 24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1

96 48 24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2

172 86 43 22 11 5 3 1 40 20 10 5 3 1 38 19 9 5 2 1 35 18 9 4

The rates of nearly all reactions increase with increasing temperature because the additional energy helps the molecules to overcome the activation energy barrier. The activation energy (enthalpy of activation), is the difference in bond energies, including strain, resonance, and solvation energies, between the starting compounds and the transition state. In many reactions, bonds have been broken or partially broken by the time the transition state is reached. The temperature dependence of the rate constant usually follows the Arrhenius equation, which expresses the dependence of the rate constant 𝑘 of a chemical reaction on the absolute temperature 𝑇 (in Kelvin), where 𝐴 is the pre-exponential factor, 𝐸a is the activation energy, and 𝑅 is the Universal gas constant.

𝑘 = 𝐴e−𝐸a /(𝑅𝑇)

For further details see Volume 2, Chapter 9, Safety Aspects for Flow Chemistry.

12 | 2 Fundamentals of Flow Chemistry

Energy

Ea (no catalyst)

Ea (with catalyst) X, Y Z

ΔG

Reaction progress Fig. 2.3: Free energy profile of a chemical reaction with or without added catalyst.

Catalysts could also increase the rate of a chemical reaction through participation in the reaction. Catalyst is not consumed, thus, it is recycled (regenerated) during the process. With a catalyst, less free energy is required to reach the transition state, but the total free energy from reactants to products does not change.

For Catalysis in flow see Volume 2, Chapter 1, Catalysis in Flow and Chapter 2, Engineering for Catalysis in Flow.

2.1.3 Reaction order and kinetics The rate of a homogeneous reaction is the rate of disappearance of a reactant or appearance of a product. The rate changes with time, since it is proportional to concentration and the concentration of reactants decreases with time.

−𝑑[A] = 𝑘[A] 𝑑𝑡 −𝑑[A] −𝑑[A] = 𝑘[A][B] or Rate = = 𝑘[A]2 Rate = 𝑑𝑡 𝑑𝑡

Rate =

If the rate is proportional to the change in concentration of only one reactant (𝐴), the rate law (the rate of change of concentration of 𝐴 with time 𝑡) is where 𝑘 is the rate constant for the reaction. The minus sign indicates that the concentration of 𝐴 decreases with time (first-order reaction). The rate of a second-order reaction is proportional to the concentration of two reactants, or to the square of the concentration of one.

Concentration

2.1 Fundamentals of chemical reactions

|

13

Products

Reagents

Time Fig. 2.4: The time course of the reagent and product concentration during chemical reaction. However, the rate is not always proportional to the concentration of all reactants.

If any one step of a mechanism is considerably slower than all the others (this is usually the case), the rate of the overall reaction is essentially the same as that of the slow step, which is consequently called the rate determining step.

2.1.4 Diffusion control Some reactions have no free energy of activation at all, as a consequence virtually all collisions lead to chemical reaction. Such processes are diffusion-controlled. S ΔG P

Fig. 2.5: Free energy profile of the ideal diffusion controlled reaction.

A chemical reaction is mixing- or diffusion controlled if its half-life is on the order of, or smaller than, that of the relevant mixing or diffusion process. (Half-life is the time required for one-half of any given quantity of a reactant to be used up).

2.1.5 Kinetic versus thermodynamic control Competing parallel and consecutive reactions: issue of selectivity. There are many cases in which a compound under a given set of reaction conditions can undergo competing reactions to give different products: If neither reaction is reversible, 𝐶 will be formed in a larger amount because it is formed faster. The product is said to be kinetically controlled. However, if the reactions

14 | 2 Fundamentals of Flow Chemistry

k or Dc

k

Dc

Chemical/kinetic control

Diffusion control

Fig. 2.6: Kinetic control and diffusion control regime in various chemical reactions.

+

ΔGB+

+

ΔGC+ A

ΔGC ΔGB

C

B

Fig. 2.7: Free energy profile that illustrates the kinetic and thermodynamic control.

are reversible, this will not necessarily be the case. If such a process is stopped well before the equilibrium has been established, the reaction will be kinetically controlled since more of the faster-formed product will be present. However, if the reaction is permitted to approach equilibrium, the predominant or even exclusive product will be 𝐵. Under these conditions, the 𝐶 that is first formed reverts to 𝐴, while the more stable 𝐵 reverts to 𝐴 in a much less extent, then, the product is under thermodynamical control.

2.1 Fundamentals of chemical reactions

|

15

2.1.6 Competing reactions Parallel reactions

Consecutive reactions

Product 1 k1 Product 2

k2

Product 1

k1

Starting material k2 Product 2

Fig. 2.8: General scheme of the consecutive and parallel competitive reactions (based on Yoshida: Flash Chemistry, [8]).

In competitive parallel reactions, the reaction of the starting material (SM) is to give Product1 that competes with the reaction of SM to give Product2. Both reactions take place simultaneously. If the rate constant 𝑘1 for the first reaction is much larger than 𝑘2 for the second reaction, we expect the predominant formation of Product1 over Product2. In competitive consecutive reactions, a Product1 that is formed in the first reaction from SM undergoes a further reaction to give a Product2. If the rate constant 𝑘1 for the first reaction is much larger than 𝑘2 for the subsequent reaction, it is possible, in principle, to stop the reaction to obtain Product1 predominantly. If 𝑘2 is larger than 𝑘1 , it seems difficult to stop the reaction at the Product1 stage. Selectivity is the ratio of products in competing reactions. It is the discrimination shown by a reagent in a competitive attack on two or more substrates or on two or more positions in the same substrate. It is quantitatively expressed by ratios of rate constants of the competing reactions.

Selectivity =

𝑇𝑃 𝑇𝑃 + 𝐹𝑃

For further details see Volume 1, Chapter 3, Principles of Controlling Reactions in Flow Chemistry.

2.1.7 Initiation and termination of chemical reactions Reactions can be initiated by (a) energy transfer to reach activation energy (heat transfer), (b) light irradiation to reactive excited state (photochenical activation), (c) by electrochemical processes involving electron transfer to or from a molecule or ion changing its oxidation state, (d) by chemical process by generating reactive intermediates. They are usually very short-lived, and most exist only as intermediates that are quickly converted to more stable molecules.

16 | 2 Fundamentals of Flow Chemistry R

R R C

+

R C•

R R C–

R

R

R

A

B

C

R R C:

R N:

D

E

Fig. 2.9: Four types of reactive intermediates.

There are four types of reactive intermediates: carbocations (𝐴), free radicals (𝐵), carbanions (𝐶), and carbenes (𝐷), and nitrenes (𝐸), the nitrogen analogs of carbenes. During the reaction progression the major parameters should be maintained: temperature; pressure; contact of the reagents or catalyst by mixing (diffusion); maintaining the stoichiometry or excess of the reactants; continuous removal of any of the products or by-products to shift the equilibrium; catalyst activation. Continuous reaction monitoring by proper (preferably real-time) analytical techniques would provide information about the progress of the chemical reaction. The chemical reaction can be terminated by quenching and initiating work-up. Quenching terminates the reaction condition necessary for chemical reaction by rapid cooling or decomposing (trapping) residual reactive intermediates, deactivating any unreacted reagents, neutralizing the pH or simply removing the product from the reaction mixture by extraction, distillation or inducing precipitation.

2.1.8 Exotherm and endoterm reactions Hammond postulate states that for any single reaction step, the geometry of the transition state for that step resembles the side to which it is closer in free energy. Thus, for an exothermic reaction (enthalpy or heat of reaction – Δ𝐻 is negative, heat generation) the transition state resembles the reactants more than the products and for endothermic reaction (enthalpy or heat of reaction – Δ𝐻 is positive, heat consumption) it is closer to the product.

2.1.9 How to accelerate an organic chemical reaction. Shifting the equilibrium towards product formation Chemical equilibrium is the state in which both reactants and products are present at concentrations which have no further tendency to change with time. It is demonstrated with arrows pointing both ways in the chemical equation, when 𝐴 and 𝐵 are reactants, 𝑆 and 𝑇 are products, and 𝛼, 𝛽, 𝜎, and 𝜏 are the stoichiometric

2.1 Fundamentals of chemical reactions

|

TS1 TS2 Reactant

+

ΔG1+

+

ΔG2+

ΔG2 P1 ΔG1 P2 Fig. 2.10: Energy profile of the exothermic reaction.

TS1

TS2

P1

P2 +

ΔG1+ +

ΔG2+

ΔG1 ΔG2

Reactant Fig. 2.11: Energy profile of the endothermic reaction.

coefficients of the corresponding reactants and products:

𝛼𝐴 + 𝛽𝐵 󴀔󴀭 𝜎𝑆 + 𝜏𝑇 where 𝐴, 𝐵, 𝑆 and 𝑇 are active masses and 𝑘+ and 𝑘− are rate constants. At equilibrium forward and backward rates are equal:

𝑘+ {𝐴}𝛼 {𝐵}𝛽 = 𝑘− {𝑆}𝜎{𝑇}𝜏 The ratio of the rate constants is also a constant, it is called equilibrium constant.

𝐾𝑐 =

𝑘+ {𝑆}𝜎 {𝑇}𝜏 = 𝑘− {𝐴}𝛼 {𝐵}𝛽

17

18 | 2 Fundamentals of Flow Chemistry Most of the organic chemical reactions are reversible and normally lead to an equilibrium, which can be shifted by applying the Le Chatelier Braun principle. In general, when changing the concentration of any of the reactants, temperature or pressure will shift the equilibrium to the side that would reduce that change in concentration, temperature or pressure. (1) Thus, reducing the concentration of the product or any of the side-products (e.g., water); increasing the concentration of the reactants (excess applied) (2) Elevated temperature if the reaction is endothermic (enthalpy or heat of reaction – Δ𝐻 is positive) or cooling when the reaction is exothermic (enthalpy or heat of reaction – Δ𝐻 is negative)

Fig. 2.12: Temperature over 400 °C.

(3) Increasing the pressure when at activation volume (Δ𝑉‡ ) is negative or vice versa

Fig. 2.13: Pressure over 200 bar.

Acceleration of certain chemical reactions is possible when high-pressure is applied. The rate of a reaction can be expressed in terms of the activation volume, 𝑉‡

𝛿 ln 𝑘 Δ𝑉‡ = 𝛿𝑝 𝑅𝑇 Δ𝑉‡ = (

−𝜕 ln 𝐾𝑝 𝜕Δ𝐺≠ ) =( ) ⋅ 𝑅𝑇 𝜕𝑝 𝑇 𝜕𝑝 𝑇

2.1 Fundamentals of chemical reactions

|

19

The activation volume is the difference in the partial molar volume between the transition state and the initial state. If the volume of activation is negative, the rate of the reaction will be accelerated by increasing pressure (the value of Δ𝑉‡ then decreases). Negative volume of activation occurs when the transition state of a reaction involves bond formation, concentration of charge, or ionization. In particular, reactions in which the molecularity number (number of molecules) decreases when starting materials are converted to products by cycloadditions, condensations; reactions that proceed via cyclic transition states; reactions that take place through dipolar transition states; reactions with steric hindrance. In gas (gas-liquid phase) reactions an increase in system pressure due to decreasing volume causes the reaction to shift to the side with the fewer moles of gas (thus to products). Inversely, a decrease in pressure due to increasing volume causes the reaction to shift to the side with more moles of gas. The transition state is a saddle point on the potential surface between the reactant and the product. The activation energy (enthalpy of activation), is the difference in bond energies, including strain, resonance, and solvation energies, between the starting compounds and the transition state. Arrhenius’ equation expresses the dependence of the rate constant 𝑘 of a chemical reaction on the absolute temperature 𝑇 (in Kelvin), where 𝐴 is the pre-exponential factor, 𝐸𝑎 is the activation energy, and 𝑅 is the Universal gas constant. If any one step of a mechanism is considerably slower than all the others (this is usually the case), the rate of the overall reaction is essentially the same as that of the slow step, which is consequently called the rate determining step. A chemical reaction is mixing- or diffusion controlled if its half-life is on the order of, or smaller than, that of the relevant mixing or diffusion process. (Half-life is the time required for one-half of any given quantity of a reactant to be used up). If neither reaction is reversible, the kinetically controlled product will be formed in larger amount because it is formed faster. If the reaction is permitted to approach equilibrium, the predominant or even exclusive product will be the one has lower energy (𝐵). Under these conditions even though the higher energy product (𝐶) is first formed it reverts to the common intermediate or starting material (𝐴), while the more stable 𝐵 reverts to 𝐴 in a much less extent, then, the product is under thermodynamical control. Selectivity is the ratio of products in competing reactions. Reactions can be initiated by (a) energy transfer to reach activation energy (heat transfer), (b) light irradiation to reactive excited state (photochenical activation), (c) by electrochemical processes involving electron transfer to or from a molecule or ion changing its oxidation state, (d) by chemical process by generating reactive intermediates. Quenching terminates the reaction condition necessary for chemical reaction by rapid cooling or decomposing (trapping) residual reactive intermediates, deactivating any unreacted reagents, neutralizing the pH or simply removing the product from the reaction mixture by extraction, distillation or inducing precipitation.

20 | 2 Fundamentals of Flow Chemistry

Hammond postulate states that for any single reaction step, the geometry of the transition state for that step resembles the side to which it is closer in free energy. Thus, for an exothermic reaction (enthalpy or heat of reaction – Δ𝐻 is negative, heat generation) the transition state resembles the reactants more than the products and for endothermic reaction (enthalpy or heat of reaction – Δ𝐻 is positive, heat consumption) it is closer to the product. Chemical equilibrium is the state in which both reactants and products are present at concentrations which have no further tendency to change with time.

Further readings – Smith, M. B., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, Weinheim, 2013. – Vogel, A. I., Tatchell, A. R., Furnis, B. S., Hannaford, A. J., Smith, P. W. G., Vogel’s Textbook of Practical Organic Chemistry (5th Edition) Prentice Hall, 1996, – Yoshida, J. I., Flash Chemistry: Fast Organic Synthesis in Microsystems, Wiley, New York, Weinheim, 2008. – Razzaq, T., Kappe, C. O., Continuous Flow Organic Synthesis under High-Temperature/Pressure Conditions Chem–Asian J. 2010, 5,1274–1289. Ref: 29

2.2 Batch versus flow reactions The typical operation sequence of traditional flask (batch) reaction in the laboratory practice is shown in Figure 2.14 [1]. The typical continuous-flow apparatus for heterogeneous (liquid-solid) phase reactions. Chemical synthesis in the laboratory has been carried out in standardized glassware and this has not been changed for over a century [2]. There are significant differences between batch and flow processes with respect to the important measures of the reactions. Batch reaction time is determined by how long a reac-

Evaporate

Reaction (heat/cool)

Quench/ Work-up

Pure product

Purify Evaporate

Purify (distill/recryst)

Fig. 2.14: Typical batch laboratory set-up (adapted from Baxendale, I. R., The Integration of Flow Reactors into Synthetic Organic Chemistry. J Chem Technol Biotechnol 2013, 88, 519–552).

2.2 Batch versus flow reactions

Catalyst cartridge

| 21

Heatable block

HPLC pump

p

O HN

R N

S

S

NH HN

O O

O R

OH O

+ H

Ph

O

NO2

H

Ph S R

NO2

R Fig. 2.15: Typical set-up for flow reactions using a fixed-bed reactor (adapted from Ötvös, S., Mandity, P., Fulop, F., Highly Efficient 1,4-Addition of Aldehydes to Nitroolefins: Organocatalysis in Continuous Flow by Solid-Supported Peptidic Catalysts. ChemSusChem 2012, 5, 266–269).

tion vessel is held at a given temperature. In contrast, in continuous processes the residence time, which refers to how long the reactants stay in the reactor zone, is determined by the reactor volume and the bulk flow rate (Figure 2.17). Stoichiometry in flow reactors is defined by the concentration of reagents and the ratio of their flow rate. In batch processes this is defined by the concentration of chemical reagents, and the ratio of their molar quantities. Flow rate A (mL/min)

Flow rate A + B (mL/min) Reactor zone

Flow rate B (mL/min) Fig. 2.16: Mixing 𝐴 and 𝐵 reagents under flow conditions.

22 | 2 Fundamentals of Flow Chemistry Table 2.2: Comparison of the major reaction characteristics in batch and flow.

Stoichiometry Reaction time

Reaction progress Steady state characteristics

Batch

Flow

Concentration/ratio of the molar quantities Time spent under the defined condition

Concentration/ratio of the flow rates Residence time spent in the reaction zone depending on the flow rate and reaction volume Distance traveled in the channel It has a steady but different concentration at each position throughout the length of the reactor

Time spent in the flask It has a uniform concentration at each position within the flask at a particular moment

Examples for the calculation of the ultimate flow rate can be found in Volume 1, Chapter 6, Experimental Procedures for Flow Chemistry, part 1.

V (flow rate: mL/s) S (cross- section: cm2)

L (length: cm)

Residence time (s) =

SxL V

Fig. 2.17: Calculation of the residence time, where 𝑆 is the cross-section, 𝐿 is the length and 𝑉 is the flow rate.

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

The concentration of the reactant decays exponentially with time in the flask reactor [3] (Figure 2.17). In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor. Thus time in a flask reactor equates with distance in a flow reactor. Reactions in laboratory organic synthesis usually take minutes to hours to obtain the desired product [4, 5]. That time interval has been acceptable and convenient for human beings for a long time. However, very recently, strong demand has emerged to improve the efficiency and green-ness of synthetic organic chemistry which certainly drives for a change in the laboratory routine.

2.2 Batch versus flow reactions

|

23

Flow reactor = sequence of well-mixed flasks

[min] Concentration [M]

0.1

Flow reactor

0.08

Time in flask = distance in flow reactor

0.06 0.04

[M] Flask

0.02 0 0

20

40

60

80

100

Time [min] Fig. 2.18: Reactant concentration versus time (flask reactor) or distance (flow reactor) for a simple first-order reaction under well-mixed homogeneous conditions (adapted from Valera, F. E., Quaranta, M., Moran, A., Blacker, J., Armstrong, A., Cabral, J.T., Blackmond, D.G., The Flow’s the Thing...Or Is It? Assessing the Merits of Homogeneous Reactions in Flask and Flow, Angew Chem Int Ed 2010, 49, 2–10).

2.2.1 Performing chemical reactions in batch and flow If reactions are too fast, it is difficult to carry out such reactions manually on a preparative scale in the batch routine. For example, if a reaction is complete after a reaction time of 0.5 s and an overreaction occurs to a significant extent after 1 s, the reaction time can be adjusted in the range between 0.5 and 1 s. It is practically impossible to adjust the reaction time to such a range using traditional batch chemistry. If a reaction is to run in a flask, the concentration of a reactant will decrease as time goes on, while the product concentration will increase. Furthermore, the concentration of a reactant and the product is uniform in the flask at a given time. The same is true for the product concentration. In contrast, in a flow reactor, the reaction proceeds as a reactant travels through the reactor (Figure 2.19). Therefore, the concentration of a reactant decreases with an increase in the distance from the inlet of the reactor and the concentration of a product increases and reaches a maximum at the outlet of the reactor if length and flow rate is optimal for the reaction. The concentrations of a reactant and a product do not change with the progress of operation time under a steady state in a particular position, in other words, no back or forward mixing is possible (it

24 | 2 Fundamentals of Flow Chemistry Batch

11

12

1

11 2

10

3

9 7

6

1

2 3

9

4

8

12

10

4

8

5

7

6

5

Conditions Flow

Starting compounds

Products

4

60

55

5

10

50

45

15

20

60

40

10

50

20

40

35

30

30

25

Fig. 2.19: Comparison of the reaction time in batch and flow (adapted from Wegner, J., Ceylan, S., Kirschning, A., Ten key issues in modern flow chemistry, Chem Commun 2011, 47, 4583–4592).

is easy to understand if we look at the flow reactors as an infinite series continuous tank (flask) reactors that are isolated from each other, see Figure 2.18). Therefore, the reaction time in a flow reactor can correlate to the space position inside of the reactor, thus, the reaction time can be controlled by adjusting the length of a flow reactor, and the flow rate. Reactions normally started by mixing two reaction components at the appropriate activating conditions and are stopped when the maximum conversion is expected to be achieved with maximum selectivity by adding a quenching reagent to terminate the reaction. Therefore, the reaction time is defined as the time between the first mixing and the mixing with a quencher (see Figure 2.20). By using a flow reactor, the reaction time is defined as the residence time between a reagent inlet and the position of the quencher inlet, and can be precisely controlled by adjusting the length between these positions. It is also designated as reaction windows, which is the time course of the reaction between the activation (starting) and the optimal time for quenching (stopping). At a certain flow rate and volume, reaction time is equal to the residence time.

2.2 Batch versus flow reactions

Reagent

|

25

Quenching agent

Reactant

Product Start

Stop Reaction time

Fig. 2.20: The reaction time is defined as the residence time between a reagent inlet and the position of the quencher inlet (adapted from Yoshida, J. I., Flash Chemistry: Flow Microreactor Synthesis Based on High-Resolution Reaction Time Control, The Chemical Record 2010, 10, 332–341).

For further details on this issue please see Volume 1, Chapter 3, Principles of Controlling Reactions in Flow Chemistry.

A 1. Work-up 2. Purify

+

1. Work-up 2. Purify

B

C Batch reactor 1

1. Work-up 2. Purify D

Batch reactor 2

E

Batch reactor 3

Iterative step-by-step batch synthesis intermediates C and D isolated and purified (a) Traditional multi-step synthesis

A + B

Flow reactor 1

Flow reactor 2

Flow reactor 3

E

C and D not isolated a continuous ‘one-flow, multi-step’ synthesis

(b) Continuous flow multi-step synthesis Fig. 2.21: Multistep synthesis strategies in batch and flow (adapted from Webb, D., Jamison, T. F., Continuous flow multistep organic synthesis, Chem Sci 2010, 1, 675–680).

26 | 2 Fundamentals of Flow Chemistry 2.2.2 Multistep reactions in batch and flow Multistep synthesis proceeds in batch through step-by-step transformation of starting materials into desired products. Typically, after each synthetic step products are isolated from the reaction mixture and purified to remove any undesired components that might interfere with the subsequent synthetic transformations. Single line, continuous reactor network, could circumvent the need for the isolation of intermediate products [6]. Solid supported reagents, catalysts and scavengers together with in-line analytics could support the single line flow synthesis [7]. 2.2.3 The dimensions of batch (flask) and flow (micro) reactors At the molecular level, chemical reactions take place in the range of 10−13 –10−12 s, while reaction times range from minutes to hours (102 –105 s) in a flask. The size of molecules is in the range of 10−10 –10−8 m, whereas the size of a flask ranges from 10−2 to 100 m. So, there is a rough correlation between the reaction time and the size of the reaction environment, In flash chemistry, we use a reactor, the size of which ranges from 10−6 to 10−3 m. The timescale for flash chemistry is milliseconds to seconds.

km

Flask chemistry

103

1 m

Flash chemistry

Space 10–3 mm 10–6 μm

Molecular level reaction

10–9 nm

10–18

10–15

10–12

10–9

10–6

10–3

1

103

106

fs

ps

ns

μs

ms

s

min

h

t Fig. 2.22: Time–space relationship for chemical reactions (adapted from Yoshida, J. I., Nagaki, A., Yamada, T., Flash Chemistry: Fast Chemical Synthesis by Using Microreactors. Chem. Eur. J. 2008, 14, 7450–7459).

2.2 Batch versus flow reactions

|

27

2.2.4 Mixing in batch versus microreactors Typically, to run an organic reaction with high yield and selectivity, both mass and heat transport must be carefully controlled. These processes are traditionally mixed by the old practice of stirring. Stirring in classical reactors leads to inhomogeneities and results in turbulence and chaotic mixing. On the other hand, continuously-flowing microreactors allow for rapid and homogeneous mixing because of their small dimensions (channel or capillary diameter is 0.05–0.5 cm) and laminar flow is the predominant. Microreactors can achieve complete mixing in microseconds, whereas classical reactors mix on the timescale of seconds or longer. Slowing down the fast reactions in batch is the only way to control them [8]. Several techniques have conventionally been used. One of the common techniques is to lower the reaction temperature in order to decrease the rate of the reaction to make it slower than the mixing rate. In fact, decreasing the reaction temperature usually leads to an increase in product selectivity in batch. However, it should also be noted that the rate of mixing, or the rate of molecular diffusion, also decreases with a decrease in the temperature, and the viscosity of the solution increases with a decrease in temperature. Another way to lower the reaction rate is the high dilution method. At very low concentrations the reaction rate decreases significantly and again mixing becomes relatively faster than reaction. In flow fast reactions can be carried out at room temperature applying short residence time without reducing the reaction rate. The fast mixing relies on the short diffusion path in microreactors. A molecule in the center of a typical microfluidic channel can reach the wall of that channel in a few seconds. The same molecule in the middle of a reaction flask (batch) would require hours to diffuse to the side wall (without mixing). Marked shortening of the diffusion path in flow (in a microreactor) results in a mixing speed that is unobtainable in batch (Table 2.3). The time (𝑡d ) needed for molecular diffusion is proportional to the square of the length of the diffusion path.

Diffusion time (s) 0.0005 0.005 5 500

size 1 μm 10 μm 100 μm 1 mm

Diffusion time is calculated for 𝐷 (diffusion coefficient)= 1 ×

10−5 cm2 /s

Table 2.3: The correlation between the diffusion time and the diffusion path in flow reactors (adapted from Yoshida, J. I., Flash Chemistry: Fast Organic Synthesis in Microsystems, New York, John Wiley and Sons, 2008. p72).

28 | 2 Fundamentals of Flow Chemistry

𝐿2 𝑡d = 𝐷 𝑘𝑇 𝐷= 6𝜋𝜂𝑟

𝑡d is the diffusion time, 𝐿 [m] is the distance over which diffusion must take place and 𝐷 [m2 s−1 ] is the diffusion coefficient, in which 𝑘 is the Boltzmann constant (1.38 × 10−23 J K−1 ), 𝑇 [K] the absolute temperature, 𝜂 [kg m−1 s−1 ] the absolute (solute) viscosity, and 𝑟 the hydrodynamic radius [m].

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

2.2.5 Mass transfer in batch and flow [9] The small dimensions also facilitates increased mass transfer in microflow reactors. Comparison of the typical liquid–liquid extraction methods in batch and flow (Figure 2.23). While in batch rigorous shaking is necessary to improve the mass transfer between the aqueous and organic phases in the extraction process in flow simple laminar flow with high interfacial surface allows the rapid mass transfer. Examples of bulk scale unit operations

Solution B

Extraction reagent

Shaking Solution A Mixing & reaction

Phase contact

Extraction

Phase separation & fractionation

Micro unit operations (MUOs)

10-100gm Fig. 2.23: Comparison of the mass transfer in batch and flow (adapted from Mawatari, K., Kazoe, Y., Aota, A., Tsukahara, T., Sato, K., Kitamori, T., Microflow Systems for Chemical Synthesis and Analysis: Approaches to Full Integration of Chemical Process J Flow Chem 2011, 1, 3–12).

2.2 Batch versus flow reactions

| 29

2.2.6 Temperature control in batch and flow [10] Heat is transferred between the interior and exterior of a reactor via the reactor surface according to the theory of heat transfer. Therefore, area per unit volume of the reactor is a crucial factor for heat transfer (surface-to-volume ratio). Generally, volume is equal to the length cubed, while surface area is equal to length squared. When the length is shortened, surface-to-volume ratio increases. Thus, microreactors have high surface-to-volume ratio than macroreactors. Because microreactors have a greater surface area per unit volume than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling fast cooling/heating and, hence, precise temperature control [11]. If the size is reduced by 100 fold, the surface-to-volume increases 100 fold (Figure 2.24).

Size

1/100

Surface area

1/10000

Volume

1/1000000

Surface / Volume

100

Fig. 2.24: Comparison of the reduction ratios of the surface area, and volume during 1 to 1/100 size reduction (adapted from Yoshida, J. I., Kim, H., Nagaki, A., Green and Sustainable Chemical Synthesis Using Flow Microreactors, ChemSusChem 2011, 4, 331–340).

Example 1: Heat transfer Q t

= – kS

T1 – T2 d

d

S

T1

Q

T2

Heat transfer per unit time (𝑄 amount of heat transferred; 𝑡 time taken) depends on the following parameters; 𝑘 conductivity of the material; 𝑆 surface area, 𝑑 distance between the two ends; 𝑇1 higher temperature end; 𝑇2 lower temperature end.

30 | 2 Fundamentals of Flow Chemistry

2.5 mL

250

630 mL 200 T [°C]

150 100 50 t [min]

0 0

5

10

15

20

25

30

Fig. 2.25: Temperature profile of a microreactor and batch reactor upon heating (adapted from Glasnov, T. N., Kappe, C. O., The Microwave-to-Flow Paradigm: Translating High-Temperature Batch Microwave Chemistry to Scalable Continuous-Flow Processes, Chem Eur J 2011, 17, 11 956–11 968).

For further details on this issue please see Volume 2, Chapter 9, Safety Aspects for Flow Chemistry and Chapter 2, Engineering for Catalysis in Flow.

A standard microreactor with channel or capillary dimensions of 1 mm is inherently very fast owing to the high surface-to-volume ratio in these systems, especially when using steel- or silicon-based reactor materials possessing high thermal conductivity. Figure 2.25 shows that a 2.5 mL volume microreactor could reach the targeted temperature (250 °C) with less than a minute while a 630 mL flask requires 8 min to reach the same temperature.

Example 2: Heat removal in exothermic reactions Similarly, removing the excess heat in highly exothermic reactions is only feasible in so-called “heat absorbing” microreactors rather than flasks. Figure 2.26 outlines the temperature characteristic of the microreactor (inner volume 2 ml, surface to volume ratio 95) compared to a 100 ml flask (surface to volume ratio 1) in an cryogenic lithium– bromide exchange experiment. Since the inner temperature of the vessel rises up close to the boiling point of the solvent tetrahydrofuran (THF), the cooling system of the microreactor keeps it strictly to 0 °C after a short period of equilibration. In summary: microreactors achieve such efficient input or removal of heat and nearly constant reaction temperatures because of their high surface-to-volume ratios.

2.2 Batch versus flow reactions

| 31

45 40 35 30 25 T [°C]

20 15 10 5 0 –5

–10

t [min] 0

2

4

6

8

Microreactor®

Flask experiment

Thermostate

Fig. 2.26: Temperature growth in the microreactor and 100 ml flask (ice cooling) for the lithium–bromide exchange (adapted from Schwalbe, T., Wille, G., Microreactors as tools for better chemistry and their integration into process optimization and intensification Org Process Res Dev 2004, 8, 440).

Example 3: Precise energy (heat) transfer to achieve selective activation Reactions that offer two potential products from either kinetic or thermodynamic pathways are very sensitive to temperature. Batch reactors often provide broad temperature profiles that can allow access to multiple pathways when only one pathway is desired. Figure 2.27 compares the temperature distributions in batch and in a microreN

Ideal

Potential energy

Leads to formation of C and creats losses of B C’ A C’

MR Batch

Batch MR

T 1 T2

B’

Tdegree

C

A

C’

C

A

B’

B

A C B N

Reaction Coordinate

Fig. 2.27: Energy profile of a competing chemical reaction indicating the effect of a narrow (flow) and broad (batch) temperature distribution profile (adapted from Jahnisch, K., Hessel, V., Lowe, H., Baerns, M., Chemistry in Microstructured Reactors, Angew. Chem., Int. Ed. 2004, 43, 406–446 and references in [12]).

32 | 2 Fundamentals of Flow Chemistry actor to the kinetic energy needed to access a by-product-forming pathway. The batch reactor’s broad temperature distribution allows the production of the undesired product 𝐶, but the narrow temperature distribution in the microreactor (MR) restricts the reaction to the target product 𝐵. [12].

2.2.7 Heterogeneous catalytic reactions in batch and flow [13] Gas–liquid–solid triphasic reaction conditions that are present in heterogeneous catalytic processes involve a gas, a substrate dissolved in a solvent, and an immobilized solid precious metal catalyst. Such reactions require large interfacial areas (high surface-to-volume ratio) are not attainable in normal batch systems. However, flow conditions lead to improvements in conversions, yields, and selectivities. In heterogeneous catalytic flow synthesis the immobilized reagents and catalyst are placed in cartridges (Figure 2.28, also called fixed-bed reactors) thus separated from the reaction media. Thus, catalyst poisoning as well as side reactions are minimized due to the immediate removal of the product from the reactor zone. The reusability (recycling) of the catalysts or reagents is economical and environmentally-sound. Excess reagents can be used to drive reactions to completion without introducing difficult purification steps. Figure 2.29 shows an overview of the comparison of batch and flow processes regarding the reactor size, way of flow, diffusion time and surface-to-volume ratios [14].

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow and Chapter 1, Catalysis in Flow.

30 x 4 mm 55 x 4 mm

70 mm

55 mm

30 mm

70 x 4 mm

Fig. 2.28: Typical reactor cartridges (packedbed reactors) filled with catalysts.

2.2 Batch versus flow reactions

Typical flow regime in channels

Scale of structure

Approx. diffusion time Liquid gas

| 33

Surface area per volume for circular channels

1m

100 μm

Turbulent

Macro-structure

101 m–1

102 m–1

104 s

Transitional

100 s

Diffusional transport dominant

1s 103 m–1

Laminar

1 mm

Some diffusion, some variation of intensity of conditions

Micro-structure

10 mm

Meso-structure

100 mm

In equipment, intensity and conditions vary widely with position

10–2 s 104 m–1

1s

10–4 s 105 m–1

10 μm Fig. 2.29: Summary of the comparison of batch (macro) reactors and flow (micro) reactors (adapted from Klais, O., Westphal, F., Benaissa, W., Carson, D., Guidance on Safety/Health for Process Intensification including MS Design; Part I: Reaction Hazards Chem. Eng. Technol. 2009, 32, 1831–1844).

Stoichiometry in flow reactors is defined by the concentration of reagents and the ratio of their flow rate. Residence time refers to how long the reactants stay in the reactor zone, it is determined by the reactor volume and the bulk flow rate. Surface-to-volume ratio is the area per unit volume of the reactor.

34 | 2 Fundamentals of Flow Chemistry

Further readings – Yoshida, J. I., Flash Chemistry: Fast Organic Synthesis in Microsystems, New York, John Wiley and Sons, 2008. Ref. 8. – Baxendale, I. R., The Integration of Flow Reactors into Synthetic Organic Chemistry. J Chem Technol Biotechnol 2013, 88, 519–552 Ref. 1. – Wegner, J., Ceylan, S., Kirschning, A., Ten key issues in modern flow chemistry, Chem Commun 2011, 47, 4583–4592. Ref. 5. – Yoshida, J. I., Kim, H., Nagaki, A., Green and Sustainable Chemical Synthesis Using Flow Microreactors, ChemSusChem 2011, 4, 331–340. Ref. 10 – Jahnisch, K., Hessel, V., Lowe, H., Baerns, M., Chemistry in Microstructured. Reactors Angew. Chem., Int. Ed. 2004, 43,406–446. Ref. 14.

2.3 Introduction to the basics of microfluidics [15–17] Fluid flow through microfluidic channels is characterized by low Reynolds numbers, a dimensionless parameter, which when less than 2000 results in laminar flow dominating. In this flow regime, the mass transfer of solutes occurs transversely between the characteristic parallel flow profile and mixing occurs by diffusive forces. There are three types of pumping/delivering [18]: electrokinetic, hydrodynamic and centrifugal.

2.3.1 Electroosmotic (electrokinetic) flow (EOF) EOF induces fluid flow by the application of an electrical potential across a microchannel. Ions in solution migrate to the opposite charge lining the channel wall, creating an electrical double layer of counter ions. The velocity profile of electro-osmotic movement in an open channel is flat, exhibiting plug flow. The advantages of EOF are that the velocity profile reduces the diffusional non-uniformity. EOF is applicable only for aqueous or polar systems, low flow rates, and small channel dimensions. Principles of electroosmotic flow. At appropriate pH, a negative surface charge is present on the microreactor walls, which attracts positive ions from solution and forms an electrical double layer. When an electric field is applied along a microreactor’s channel, the mobile cations move toward the negative electrode, dragging along the rest of the solution. The flow velocity profile is nearly flat across the channel except for a thin (few nanometer) diffusive layer immediately adjacent to the channel wall. The EOF fluid velocity [19] (𝜈eof ) is:

𝜈eof = −

𝐸𝜀𝜀0 𝜁 𝜂

2.3 Introduction to the basics of microfluidics

| 35

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – + + + + + + + + + + + + +

+ + + + + + + + + + + + + – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – Fig. 2.30: The flat velocity profile of electroosmotic flow (adapted from Webster, A., Greenman, J., Haswell, S. J., Development of microfluidic devices for biomedical and clinical application. J Chem Technol Biotechnol 2011, 86, 10–17).

Bulk solution

Double layer

+ –

– +

–

+ –

+

–

–

+

+ –

+ + + + + + + + + + + + + + + + +

+

Electric field

Velocity profile

Negative surface charge

Bulk material Fig. 2.31: The principles of electroosmotic flow (adapted from Mason, B. P., Price, K. E., Steinbacher, J. L., Bogdan, A. R., McQuade, D. T., Greener Approaches to Organic Synthesis Using Microreactor Technology, Chem. Rev. 2007, 107, 2300–2318).

where 𝐸 is the electric field (voltage divided by electrode separation), 𝜀 is the relative dielectric constant of the liquid, 𝜀0 is the permittivity of free space, 𝜁 is the zeta potential of the channel wall–solution interface and 𝜂 is the liquid viscosity. Thus, the solvents which possess a high dielectric constant (i.e., polar solvents) and low viscosity (𝜂) will have the higher flow rate. The solvent flow rate is directly proportional to the field strength applied.

36 | 2 Fundamentals of Flow Chemistry

Fig. 2.32: The parabolic velocity profile of hydrodynamic flow (adapted from Webster, A., Greenman, J., Haswell, S. J., Development of microfluidic devices for biomedical and clinical application. J Chem Technol Biotechnol 2011, 86, 10–17).

2.3.2 Hydrodynamic (pressure-driven) pumping Hydrodynamic pumping exploits conventional or microscale pumps, notably syringetype pumps, to deliver solutions around the channel network. In that case, flow allows fluid to be moved via positive or negative displacement, such as syringe or peristaltic pumps. Positive-displacement pumps are pressure oriented and operate by forcing a fixed volume of fluid from the inlet pressure section of the pump into the discharge zone of the pump. Negative-displacement pumps are the centrifugal pumps that are flow oriented pumps in which flow energy is first converted into kinetic energy (velocity energy) and finally converted into the pressure energy. The static nature of the fluid at the boundary produces a parabolic velocity profile within the channel. The parabolic velocity profile has significant implications for the distribution of solutes transported within the channel, leading to non-uniformity of diffusion coefficients and greater dispersion of sample plugs.[20]. Hydrodynamic (pressure-driven) flow is severely affected by the channel dimensions. A flow that is laminar, incompressible, and viscous, in a channel with is length much greater than its diameter – is described by the Hagen–Poiseulle equation.

Δ𝑃 =

12𝜂𝐿𝑄 , 𝜋𝑑4

where Δ𝑃 is the pressure drop across length 𝐿 of channel diameter, for a flow rate 𝑄 of a fluid with viscosity 𝜂. As the channel diameter (𝑑) decreases, the pressure needed to achieve the same flow increases dramatically. (a)

(b)

(c)

Fig. 2.33: Development of the parabolic profile after initiating the flow (adapted from Mason, B. P., Price, K. E., Steinbacher, J. L., Bogdan, A. R., McQuade, D. T., Greener Approaches to Organic Synthesis Using Microreactor Technology, Chem. Rev. 2007, 107, 2300–2318).

2.3 Introduction to the basics of microfluidics

| 37

Parabolic flow profile of hydrodynamic flow at different length and time (see Figure 2.33a). At the beginning of the channel, the velocity vectors are equal across the channel, but further down the channel ( Figure 2.33b,c), fluid flows faster in the center of the channel than near the sides [12].

2.3.3 Segmented flow [21, 22] The segmented flow system delivers pulses of reactants that are segregated by an immiscible solvent into the flow reactor. Each segment can consist of a different combination of reactants for different reactions to occur. A vortex circulation (axial dispersion) is generated within each fluid segment, continuously regenerating the interface. It is believed that the large interface gener-

Reaction pulse

Portion of reaction pulse collected

Portion of reaction pulse to waste

Absorbance

Portion of reaction pulse to waste

Optical threshold level for collection

Time

(a)

Reaction 2

Solvent

Reaction 1

(b) Fig. 2.34: The typical distribution curve and velocity profile of segmented flow (reaction pulse; adapted from John Goodell presentation: http://ccc.chem.pitt.edu/wipf/Frontiers/John_G.pdf).

38 | 2 Fundamentals of Flow Chemistry ated, coupled with the internal vortex mixing, is responsible for the experimentally observed rate acceleration [23]. The slip velocity can be defined as the difference in velocity between two phases. The internal circulation in a slug greatly increases the mixing as compared to what is achieved by molecular diffusion in laminar flow. In segmented flow systems no crosscontamination is observed between the reaction slugs. Internal vortex circulations

Segment Phase A

Segment Phase B

Fig. 2.35: The internal vortex circulation in a slug greatly increases the mixing compared to what is achieved by molecular diffusion in laminar flow (adapted from Ahmed-Omer, B., Barrow, D. A., Wirth, T., Heck reactions using segmented flow conditions. Tetrahedron Lett 2009, 50, 3352–3355).

2.3.4 Centrifugal pumping Centrifugal forces have for some time been harnessed for the controlled propulsion of reagents in spinning disk microreactors. This mechanism has also been used to control the elution, mixing, and incubation of reagents within enclosed reaction capillaries on rotating-disc platforms.

2.3.5 Laminar and turbulent flow regimes, the Reynolds number The flow rate through the single channel determines flow velocity, flow regimes (characterized by the Reynolds number) and pressure loss in the system [24]. Knowing the channel geometry and fluid properties, the mean flow velocity and Reynolds number, Re can be determined in the channel. Both give an indication for the flow regime, pressure drop, and energy dissipation rate in the mixing channel. A substantial effect of reactor miniaturization is that fluid properties become increasingly controlled by viscous forces rather than inertial forces [25]. Reynolds number determines the flow regimes in the channels and is defined as the ratio of momentum (inertial) forces to viscous forces.

2.3 Introduction to the basics of microfluidics

|

39

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

Re =

inertial forces viscous forces

=

𝜌v𝐿 v𝐿 = 𝜇 𝜈

where: – v is the mean velocity of the object relative to the fluid (SI units: m/s) – 𝐿 is a characteristic linear dimension, (traveled length of the fluid; hydraulic diameter when dealing with river systems) (m) – 𝜇 is the dynamic viscosity of the fluid (Pa ⋅ s or N ⋅ s/m2 or kg/(m ⋅ s)) – 𝜈 is the kinematic viscosity (𝜈 = 𝜇/𝜌) (m2 /s) – 𝜌 is the density of the fluid (kg/m3 ). The flow is – laminar when Re < 2300 – transient when 2300 < Re < 4000 – turbulent when 4000 < Re

[mL/min] Log (diameter) [min]

10 0.1

1

5

30 m/s

200

2000

10000

100000

1

0.1 1

10

100

[min] 1000

10000

Log (flow rate) [mL/min] Fig. 2.36: Typical flow rates (mL/min) and Reynolds numbers in rectangular channels with water at 20 °C (adapted from Kockmann, N., Gottsponer, M., Roberge, D. M., Scale-up Concept of SingleChannel Microreactors from Process Development to Industrial Production, Chem Eng J, 2011, 167, 718–726).

40 | 2 Fundamentals of Flow Chemistry Laminar flow

Turbulent flow

Meso flow

Fig. 2.37: The flow profile of the laminar, turbulent and meso flow (adapted from John Goodel: http: //ccc.chem.pitt.edu/wipf/Frontiers/John_G.pdf).

Scale

Characteristic size (m)

FLow regime

Macro Meso Micro Nano

10−3 and larger 10−5 –10−3 10−7 –10−5 10−7 –10−9

Turbulent Laminar Laminar Laminar

Table 2.4: Size scale and flow regime (adapted from Buono, F. G., Gonzalez, M. A., Müslehiddinoglu, J., Flow Reactors, In: Green Techniques for Organic Synthesis and Medicinal Chemistry, Eds: Wei Zhang, Berkeley Cue, New York, John Wiley & Sons, 2012).

For further details on this issue please see Volume 2, Chapter 5, Flow Chemistry for Synthesis of Materials.

2.3.5.1 Requirements for the solvent concerning flow regimes General requirements: low viscosity, odorless (nonvolatile), anhydrous, noncorrosive, biodegradable. Important characteristics regarding flow kinetics: kinematic viscosity, heat conductivity, Prandtl number Table 2.5: Properties of organic solvents in relation to water properties at 22 °C (adapted from Kockmann, N., Gottsponer, M., Roberge, D. M., Scale-up Concept of Single-Channel Microreactors from Process Development to Industrial Production, Chem Eng J, 2011, 167, 718–726).

toulene ethanol THF

295 K 235 K 295 K 235 K 295 K 235 K

𝜈solv 𝜈water 20 °C

𝜆 solv 𝜆 water 20 °C

Prsolv Prwater 20 °C

0.24 0.89 1.63 6.56 0.55 1.44

0.22 0.25 0.28 0.31 0.23 0.45

0.38 1.23 2.50 7.44 1.29 1.35

The Prandtl number, Pr is a dimensionless number; the ratio of momentum diffusivity (kinematic viscosity) to thermal diffusivity. It is defined as:

𝑃𝑟 =

𝜈 viscous diffusion rate 𝑐𝑝 𝜇 = = 𝛼 thermal diffusion rate 𝑘

2.3 Introduction to the basics of microfluidics

| 41

where: – 𝜈: kinematic viscosity, 𝜈 = 𝜇/𝜌, (SI units : m2 /s) – 𝛼: thermal diffusivity, 𝛼 = 𝑘/(𝜌𝑐𝑝 ), (SI units : m2 /s) – – – –

𝜇: dynamic viscosity, (SI units : Pa s = N s/m2 ) 𝑘: thermal conductivity, (SI units : W/(m K)) 𝑐𝑝 : specific heat, (SI units : J/(kg K)) 𝜌: density, (SI units : kg/m3 ).

2.3.6 Axial dispersion versus radial dispersion (Bodenstein and Peclet Numbers) If axial dispersion is not measurable, the microflow reactor is said to operate as an ideal “plug flow reactor” (PFR). Because reactor length in a flow reactor is the equivalent to time in a flask reactor, kinetic results for flask and microflow reactors are identical if the Damköhler number and 𝛽 heat transfer metric are less than one for these reactors. The degree of axial dispersion is evaluated by a Bodenstein number, Bo, which relates the axial convective forces from flow to the backmixing from axial dispersion,

Bo = –

–

𝑈𝐿 𝐷∗

where 𝑈 is the average velocity of the reaction stream, 𝐿 is the length of the reactor, and 𝐷∗ is the dispersion coefficient. Small Bo values indicate that there is a large deviation from plug flow. Radial diffusion can be similarly expressed by the Peclet number, Pe,

Pe = –

𝑈𝐿 𝐷𝐴𝐵

where the molecular diffusion coefficient, 𝐷𝐴𝐵 , is used to characterize the radial diffusion. Because 𝐷∗ is typically much larger than 𝐷𝐴𝐵 , careful attention should be given to the various correlations and formulae used to characterize axial dispersion. If such dispersion (diffusion) will not effect the reaction kinetics their value is < 1 and flow reactors are the method of choice.

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

2.3.7 Mixing versus reaction rate–Damköhler Number Damköhler number, Da, expresses the reaction rate relative to the mass transport rate (e.g., [reaction rate]/[mass transport rate]). The mass transport rate in a microreactor is

42 | 2 Fundamentals of Flow Chemistry the diffusion rate, thus, the Damköhler number can be written for an 𝑛th order reaction as

Da𝐹 = – –

𝑘r 𝐶𝑛−1 0

[ 2𝐷𝑥2𝐴𝐵 ]

where 𝑘r is the specific reaction rate and 𝐶0 is the initial reagent concentration. In general, chemical transformations are reaction rate limited when Da < 1 and mixed mass transport-reaction rate limited when Da ∼ 1. When Da > 1, experimentally measured reaction rates are controlled by mass transport, thus, flow reactors have superiority.

For further details on this issue please see Volume 1, Chapter 5, Toolbox for Flow Chemistry – targeting industrial needs.

2.3.8 Heat transfer in flow For exothermic reactions, the rate of heat transfer in a reaction system is dependent on several factors: – rate of heat generated from the reaction, −𝑟𝛥𝐻rxn ; – rate of heat removed from reaction mixture through conduction or convection to the reactor wall; – rate of heat removed from the reactor wall through conduction to the surroundings. – The heat of reaction (Δ𝐻rxn ), adiabatic temperature rise (Δ𝑇ad ), and reactor dimension (diameter, 𝑑𝑓 ) we can make a useful comparison of heat generation and removal represented by the ratio. (Adiabatic temperature rise (𝛥𝑇ad ) is the increase in temperature of a reaction mixture, when there is no heat transfer to or from the environment.) For flow systems, thermal conduction from the center of the channel to the reactor walls is the driving force for heat transfer. The ratio of heat generation and removal is then estimated as:

𝛽𝐵 =

heat generated heat removed

𝛽𝐵 =

−𝑟Δ𝐻rxn 𝑑2F 4Δ𝑇ad 𝜅

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

–

where 𝑑F is the diameter of the flow reactor channel, and 𝜅 is the thermal conductivity of the reaction mixture. Heat removal can be solved in microreactors when the respective 𝛽 value is less than 1, compared to batch reactors.

2.3 Introduction to the basics of microfluidics

Plate Size

Flow Rate

Quantity

Lab A6 A5 A4

1–10 mL/min (10)50–150 mL/min 100–300 L/min 200–600 mL/min

0.1–300 kG∗ 300–900 kG∗ 900–2500 kG∗

∗

| 43

development tool, few grams

Isolated product per campaign

Fig. 2.38: The flow rate of lab scale, pilot plant scale and industrial flow reactors (adapted from Roberge, D., Industrial Design, Scale-Up, and Use of MicroReactors, FROST3, 2011, Budapest).

2.3.9 Flow rates in microreactors Flow rate is the volume of fluid which passes through a given channel per unit time. Flow rates [26] are measured with micropressure sensors, microflow anemometers, or optical fiber cantilevers. Typically, the lab microreactors have 10–500 μm internal diameter while mesofluidic reactors higher than 500 μm internal diameter up to several mm. EOF induces fluid flow by the application of an electrical potential across a microchannel. Ions in solution migrate to the opposite charge lining the channel wall, creating an electrical double layer of counter ions. Hydrodynamic pumping exploits conventional or microscale pumps, notably syringe-type pumps, to deliver solutions around the channel network. The segmented flow system delivers pulses of reactants that are segregated by an immiscible solvent into the flow reactor. Each segment can consist of a different combination of reactants for different reactions to occur. Reynolds number determines the flow regimes in the channels and is defined as the ratio of momentum (inertial) forces to viscous forces.

Further readings – Goodell, J. R., McMullen, J. P., Zaborenko, N., Maloney, J. R., Ho, C-X., Jensen, K. F., Porco, Jr., J. A., Beeler, A. B., Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1]octanoid Scaffolds. J Org Chem 2009, 74, 6169–6180. Ref: 21 – Chang, C-H., Paul, B. K., Remcho, V. T., Atre, S., Hutchison, J. E., Synthesis and post-processing of nanomaterials using microreaction technology J. Nanoparticle Res, 2008, 10, 6, 965–980. Ref: 22. – Webster, A., Greenman, J., Haswell, S. J., Development of microfluidic devices for biomedical and clinical application. J Chem Technol Biotechnol 2011, 86, 10–17. Ref: 15. – Kockmann, N., Gottsponer, M., Roberge, D. M., Scale-up Concept of Single-Channel Microreactors from Process Development to Industrial Production, Chem Eng J, 2011, 167, 718–726. Ref: 24. – deMello, A. J., Control and detection of chemical reactions in microfluidic systems Nature, 2006, 442, 394–402. Ref: 25

44 | 2 Fundamentals of Flow Chemistry

2.4 Microreactors in general 2.4.1 General properties of flow reactors Continuous flow (micro) reactors [3, 27] consist of a network of miniaturized channels with diameters typically in the range of 10–500 microm constructed of glass, quartz, silicon, polymers, or stainless steel. The effectiveness of the miniaturization can be characterized by the Space Time Yield (kg m−3 s−1 ) which represents the mass of a product 𝑃 formed per volume of the reactor and time.

𝜎𝑃 = – – –

𝑚𝑃 𝑉𝑡

𝑉 – reaction volume 𝑚𝑃 – mass of the product 𝑡 – reaction time

Microreactors are sometimes embedded in a flat surface, referred to as the “chip” or “lab-on-a-chip” systems. In microreactors fluids may be manipulated by electrokinetic, pressure (flow-driven) pumping. The typical ranges for channel diameter, reactor length, and total reaction volume are on the order of microns, meters, and milliliters, respectively. There are various basic reactor formats:

Chip reactors

PS-BEMP

Coil-type reactor

Tube-type reactor, filled with corresponding reagent

Capillary/tube reactor

Fig. 2.39: Various reactor formats applied in flow chemistry (adapted from Glasnov, T. N., Kappe, C. O., Continuous-Flow Syntheses of Heterocycles J Heterocyclic Chem, J Heter Chem 2011, 48, 11–29).

Filled tube reactors are often called as packed-bead reactors.

For further details on this issue please see Volume 2, Chapter 2, Engineering for Catalysis in Flow.

2.4 Microreactors in general

HPLC pump A Reagent A or solvent

Heating coil

Heat exchanger

M

HPLC pump B

| 45

Liquid mixer

P System pressure sensor

System pressure valve Product

Reagent B Fig. 2.40: Typical flow reactor set-up using coil–heated capillary reactors (adapted from Razzaq, T., Glasnov, T. N., Kappe, C. O., Accessing Novel Process Windows in a High-Temperature/Pressure Capillary Flow Reactor. Chem Eng Technol 2009, 32, 1–16).

Quench

A

C

B

Pump

Mixer

Reactor

Fig. 2.41: Typical flow reactor set-up using chip reactors (adapted from John Goodell presentation: http://ccc.chem.pitt.edu/wipf/Frontiers/John_G.pdf).

A typical flow reactor set-up applying pressure driven flow delivery is shown below including the main parts: reservoirs, T-mixer, pumps, reactor zone, heating/cooling units, and back-pressure regulator (Figure 2.40). For fast chemical reactions, quenching is also incorporated into the reaction line, and in this case the reaction zone starts from mixing up to the quenching point (see Figure 2.41).

46 | 2 Fundamentals of Flow Chemistry What is flow? Analysis and feedback Residence time: tR Reagent and solvent inputs

Reactor Microwave

Purification

Ultrasound Cool

Heat

Product

Waste

UV Recycle Fig. 2.42: The typical flow reactor environment (adapted from http://www.beilstein-institut.de/ Bozen2008/Proceedings/Ley/Ley.html).

The typical flow reactor environment is shown in Figure 2.42. Continuous-flow devices are ideal for real-time analysis and feedback which allows rapid automated optimization of the reaction parameters. In-line analytical tools can be UV, IR, HPLC, GLC, Mass spectrometry and/or NMR.

For further details on this issue please see Volume 1, Chapter 4, Fabrication Technology and Devices for Flow Chemistry.

The principle of self-optimization is shown in Figure 2.43.

Product Microreactor

Flow control

Temperature control

Analysis

Computer control and data processing Fig. 2.43: Typical flow reactor environment for automated self-optimization (adapted from Rasheed, M., Wirth, T., Intelligent Microflow: Development of Self-Optimizing Reaction Systems. Angew Chem Int Ed 2011, 50, 357–358).

2.4 Microreactors in general | 47

2.4.2 Major flow reactor configurations Flow reactors can be connected to form a multiple line of reactors in different configurations [28] (Figure 2.44). In a multistep continuous-flow set-up, the flow devices can serve as reactors and purification devices are shown in Figure 2.45. The integration of a continuous-flow synthetic microreactor with a suitable analytical technique is an important issue. Sensitive detection techniques are required that are suitable for continuous-flow monitoring of a reaction mixture, with practical interfacing of the tiny microfluidic device and the lab-scale analytical instrument [7].

For further details on this issue please read Volume 1, Chapter 4, Fabrication Technology and Devices for Flow Chemistry.

Space Time Yield (kg m−3 s−1 ) represents the mass of a product P formed per volume of the reactor and time.

Linear series of flowthrough reactors Input 2

Input 3

Input 1

Product

Divergent set up of flowthrough reactors Product 1 Product 2 Input Product 3 Product 4 Convergent set up of flowthrough reactors Input 2 Input 1 Input 3

Product

Input 4 Fig. 2.44: Basic multistep flow reactor configurations (adapted from Kirschning, A., Solodenko, W., Jas, G., Continuous flow techniques in organic synthesis. Chem. Eur. J. 2003, 5708–5723).

48 | 2 Fundamentals of Flow Chemistry

SM

Product

UV HPLC

(a) Analysis Valve SM

Product

Pump

(b)

Product

SM 1 SM 2 (c)

Reagent/catalyst SM

Product Scavenger SM – Starting material

(d) Fig. 2.45: Multistep flow reactor environment containing purification cartridges (scavengers) and analytical tools (adapted from Baumann, M., Baxendale, I. R., Ley, S. V., The flow synthesis of heterocycles for natural product and medicinal chemistry applications, Mol Divers. 2011, 15, 613–30).

Further readings – Benito-Lopez, F., Egberink, R. J. M., Reinhoudt, D. N., Verboom, W., High pressure in organic chemistry on the way to miniaturization. Tetrahedron 2008, 64, 10023–10040. Ref: 27. – Valera, F. E., Quaranta, M., Moran, A., Blacker, J., Armstrong, A., Cabral, J. T., Blackmond, D. G., The Flow’s the Thing...Or Is It? Assessing the Merits of Homogeneous Reactions in Flask and Flow, Angew Chem Int Ed 2010, 49, 2–10. Ref: 3. – Kirschning, A., Jas, G., Applications of Immobilized Catalysts in Continuous Flow Processes Topics Current Chem 2004, 242, 209–239. Ref: 28. – Baumann, M., Baxendale, I. R., Ley, S. V., The flow synthesis of heterocycles for natural product and medicinal chemistry applications, Mol Divers. 2011, 15, 613–30. Ref: 7.

2.5 Essentials of reaction planning and realization in continuous flow |

49

2.5 Essentials of reaction planning and realization in continuous flow The major criteria for the reaction planning in continuous-flow systems with microreactors: proper control of stoichiometry, proper timing for starting and stopping a reaction, gas-liquid phase reactions, homogenous or heterogenous systems, rapid mixing, length and diameters for the reactions, kinetic or thermodynamic control of the reactions, single step or multistep reactions and so on.

2.5.1 Classification of chemical reactions based on reaction kinetics [24] Classification based on reaction rate and kinetics provides a rough guidance how to select the most appropriate flow reactor. Reaction kinetics and enthalpy determine characteristic reaction time and adiabatic temperature rise of the reagents. Competitive reactions such as consecutive or parallel reactions lead to side-product formation. Based on the characteristic reaction time the following classification was set: Table 2.6: The major characteristics of the Type A, B, C reactions (adapted from D. Roberge talk at FROST3, Budapest). Type A reactions – Very fast (< 1 s) – Controlled by diffusion and mixing – Increase yield through better mixing/heat exchange Type B reactions – Rapid reaction (10 s to 30 min) – Predominantly kinetically controlled – Avoid overcooking and increase yield Type C reactions – Slow reaction (> 30 min) – Batch processes with thermal hazard – Enhance safety

Applying flow chemistry, the reaction time of the Type A and Type B reactions can be reduced by one order of magnitudes by shifting from batch to flow. When a reaction is conducted in a flow microreactor, however, the border between the kinetic regime region and the region limited by mass and heat transfer shifts toward shorter reaction times because of fast transfer. In the expanded region, the reaction becomes controllable, and therefore kinetically based selectivity is obtained and less waste (undesired by-product) is produced [10].

50 | 2 Fundamentals of Flow Chemistry

For further details on this issue please read Volume 1, Chapter 3, Principles of Controlling Reactions in Flow Chemistry and Chapter 5, Toolbox for Flow Chemistry – targeting industrial needs.

Type D reactions are all reactions not belonging to the above-described classes. These reactions can be accelerated by harsh process conditions, such as high reaction temperature, high pressure [29], enhanced reaction activation, or highly active reagents. Rate acceleration of Type D reaction would benefit from the so called Novel Process Windows concept and Process intensification strategies (discussed later).

2.5.2 Flash chemistry Type A reactions can be characterized as very rapid reactions (reaction time below 1 second) and are normally diffusion of mixing controlled. Flash chemistry is a field of chemical synthesis where extremely fast reactions involving short-lived highly reactive intermediates are conducted without deceleration in a highly controlled manner to produce desired compounds with high selectivity by virtue of high-resolution reaction control [4, 11].

Precursor Activation

Highly reactive species

Microflow system

Substrate

Products

Reaction time: ms-s

Fig. 2.46: Typical flow reactor connection to fast chemical reactions (adapted from Yoshida, J. I., Nagaki, A., Yamada, T., Flash Chemistry: Fast Chemical Synthesis by Using Microreactors. Chem. Eur. J. 2008, 14, 7450–7459).

For further details on this issue please see Volume 1, Chapter 3, Principles of Controlling Reactions in Flow Chemistry.

2.5 Essentials of reaction planning and realization in continuous flow

| 51

A highly reactive intermediate reacts with a substrate to generate the product within milliseconds to seconds. In flash chemistry, all reactant molecules in a reactor react at once (it requires minimum activation energy) and the reaction time should be less than several hundred femtoseconds. Highly reactive intermediates commonly initiate highly exothermic reactions. Miniaturized flow devices are ideal for performing such reactions that are carried out at ambient or low temperature due to the excellent mixing and heat transfer properties of these types of reactors.

2.5.3 High-resolution reaction time control The residence time between the addition of a reagent and that of a quenching agent or the next reagent in a flow microreactor is the reaction time, and the reaction time can be greatly reduced by adjusting the length of a reaction channel in a flow microreactor as well as increasing the flow rate. If a reaction has consecutive or multiple elementary steps the potential products or intermediates can be isolated as major products by simply adjusting or focusing the residence time (”reaction window”) to that particular chemical steps. The principle of high-resolution reaction time control is simply adjusting the residence time to a particular step in a multistep reaction sequence. Thus, the 1

2

3

4

3,99 3,49 2,99 2,49 1,99

Residence time

1,49 0,99 0,49 –0,01 1,5

3,5

5,5

7,5

9,5

Min N

N

Ph Ph

N AcOH/H O 2 NH 2

OO Ph

N NH Ph H 1

O

H2O Ph

OH Ph 3

–CO2

Ph

Ph 4

Fig. 2.47: The HPLC trace (product profile) of the multistep reaction of 2 recorded at various residence times (adapted from Kappe, O., “Some Like it Hot” – High-Temperature Flow Chemistry as a Process Intensification Tool, FROST3, Budapest, 2011). In the shown reaction, the flow rate was varied between 0.2–2.0 mL/min (loop reactor, Loop = 4 mL, 𝑇 = 240 °C, 𝑝 = 140 bar).

52 | 2 Fundamentals of Flow Chemistry isolation of the intermediate products could be resolved by the residence time (partial reaction time) which is not possible in batch reactors.

For further details on this issue please see Volume 1, Chapter 3, Principles of Controlling Reactions in Flow Chemistry.

2.5.4 Novel process windows Type C and particularly Type D reactions require significant reaction rate acceleration. All these efforts are expressed in a new holistic and systemic approach “Novel

Heterogeneous catalytic routes Routes bridged by intermediates One flow (‘pot’) multi-step route Direct-one step synthesis

Alternative heating (MW) Pressurized exreflux processes Ex-cryogenic processes

Routes at much elevated temperature New chemical transformations

Routes at much elevated pressure Novel process windows

Process integration and simplification Routes in the explosive or thermal runaway regime

Mixing all-at once Catalyst-free Reduced process expenditure

Routes at much increased concentration or even solvent-free

Solvent-free Hazardous reactants Thermal runaway regime

Solvent-less Alternative solvents (IL, SCF)

Ex regime Fig. 2.48: Major path for Novel Process Windows (adapted from Illg, T., Löb, P., Hessel, V., Flow chemistry using milli- and microstructured reactors – From conventional to novel process windows, Bioorg Med Chem 18 2010, 18, 3707–3719).

2.5 Essentials of reaction planning and realization in continuous flow

| 53

Process Windows” (NPW) [30]. NPW operates at process conditions that are beyond the usual condition; that considerably speed up conversion rates, while maintaining selectivity. This can be achieved by an increase in temperature, pressure or concentration (solvent-free operation), by a simplification of process protocols, or by function integration [31]. Combined high-temperature and high-pressure flow regime, that is, > 200 °C and > 50 bar, is one of the main direction, with many applications focusing on the generation of high-temperature or supercritical water (scH2 O). NPW combines many different techniques including supercritical fluids, ionic liquids, fluorous media, microwaves, ultrasound, high pressure, physico- and electrochemical activation, microreactors, and ball-milling conditions [32].

For further details on this issue please see Volume 1, Chapter 8, Translating Batch Microwave Chemistry to Flow Chemistry and Volume 2, Chapter 9, Safety Aspects for Flow Chemistry.

High temperature/high pressure conditions shifts routine processes to more harsh conditions that became achievable with microreactors. Two emerging areas in NPW are the superheated and supercritical conditions. Transformations in supercritical conditions has significant advantages since all reactants (solvents and gases) can be brought into one phase. Supercritical fluids are gases, and they mix completely with other gases, such as hydrogen. In these cases, the 1.E+05 Novel process windows

Pressure/kPa

1.E+04 Supercritical conditions

1.E+03

Superheated conditions 1.E+02 “Standard” conditions

Cryogenic conditions 1.E+01

VP EtOH VP NMP solid

1.E+00 100

KRP KRP solid 1000

Temperature/K Fig. 2.49: Novel Process Windows shifts the reactions towards high temperature/pressure realization while increasing the reaction rate (adapted from Hessel, V., Adding a Chemical and Process Intensification Field to Flow Chemistry transport-engineered through Microreactors – Novel Process Windows, FROST3, Budapest, 2011).

Pressure

54 | 2 Fundamentals of Flow Chemistry

Compressible liquid

Solid phase

Supercritical fluid

Critical pressure Pcr

Ptp

Critical point

Liquid phase

Superheated vapour

Triple point Gaseous phase

Critical temperature Tcr

Ttp

Temperature Fig. 2.50: The typical temperature/pressure plot displaying superheated and supercritical conditions. Table 2.7: Common organic solvents and their critical temperatures and pressures (adapted from Razzaq, T., Kappe, C. O., Continuous Flow Organic Synthesis under High-Temperature/Pressure Conditions Chem–Asian J. 2010, 5, 1274–1289). Solvent

Critical temperature 𝑇𝑐 [°C]

Critical pressure 𝑝𝑐 [bar]

Solvent

Critical temperature 𝑇𝑐 [°C]

Critical pressure 𝑝𝑐 [bar]

acetic acid acetone acetonitrile benzene 1-butanol chloroform cyclohexane DCM DMF DME dioxane ethanol

322 236 275 289 290 263 280 237 376 263 315 243

58 48 48 49 44 55 41 61 44 39 52 64

ethyl acetate hexane methanol 𝑛-octane 2-propanol pyridine toluene tetrachloromethane THF trifluoroacetic acid water 𝑝-xylene

250 234 240 296 235 347 321 283 267 218 374 345

38 30 80 25 48 57 42 46 52 33 221 34

2.5 Essentials of reaction planning and realization in continuous flow

| 55

access of the gaseous reactant to the catalyst is not limited by mass transfer resistance across a phase boundary [13].

2.5.5 Process intensification [33] Process intensification (PI), is a closely-related term to NPW. It can be defined as the ability to obtain equivalent or better results in terms of purity, selectivity, and yield of the desired product in a reduced period of time and therefore with an enhanced throughput, by increasing parameters such as temperature and pressure [17]. Most chemical reactions are not processed under kinetically controlled, but rather under mass-or heat transfer controlled conditions. The class of such “slow” reactions (mostly Type D) is quite substantial, since it includes many major chemical transformations such as nucleophilic substitutions. Applying process intensification in microreactors, reaction times can be further reduced from the minute to second level by exploiting much faster kinetics, which could be termed “intensified instrinsic kinetics”. Similarly, reaction speed increases were found for the sealed microwaveoperated vessels. That approach was then transferred to superheated processing in pressurized tubes which bridge to the continuous-flow microreactor technology. In summary, many various chemical reactions could be shifted to faster reaction rate category (intensified chemistry) applying NPW and MCPT (micro chemical processing technology) including flow reactions [34]. MCPT: Mass & heat transfer

10–1

μ-Mixing

μ-Heat exchange

1

SN2 reactions

Most reactions

Low-T Grignard

Metal/halogen exchange, Grignard ketone addition 10–2

Effective chemistry

Many, many reactions

Intrinsic chemistry

Intensified chemistry

10

100

ConvMixing

Conv-Heat Mixing

Process protocol times in organic textbooks

NPW: Kinetics

1000

10,000 Time [s]

Fig. 2.51: Process intensification unites novel process windows and microchemical processing technology in order to accelerate reaction rates (adapted from Hessel, V., Cortese, B., deCroon, M. H. J. M., Novel process windows–Concept, proposition and evaluation methodology, and intensified superheated processing Chem Eng Sci 2011, 66, 1426–1448).

56 | 2 Fundamentals of Flow Chemistry

Flash chemistry is a field of chemical synthesis where extremely fast reactions involving shortlived highly reactive intermediates are conducted without deceleration in a highly controlled manner to produce desired compounds with high selectivity by virtue of high-resolution reaction control. The principle of high-resolution reaction time control is simply adjusting the residence time to a particular step in a multistep reaction sequence. “Novel Process Windows” (NPW) operates at process conditions that are beyond the usual condition; that considerably speed up conversion rates, while maintaining selectivity. Process intensification (PI), is a closely-related term to NPW, can be defined as the ability to obtain equivalent or better results in terms of purity, selectivity, and yield of the desired product in a reduced period of time and therefore with an enhanced throughput, by increasing parameters such as temperature and pressure.

Further readings – Yoshida, J. I., Flash Chemistry: Flow Microreactor Synthesis Based on High-Resolution Reaction Time Control, The Chemical Record 10 (2010) 332–341. Ref: 4. – Hessel, V., Cortese, B., deCroon, M. H. J. M., Novel process windows–Concept, proposition and evaluation methodology, and intensified superheated processing Chem Eng Sci 66 (2011) 1426– 1448. Ref: 30 – Razzaq, T., Glasnov, T. N., Kappe, C. O., Accessing Novel Process Windows in a High-Temperature/Pressure Capillary Flow Reactor. Chem Eng Technol 32 (2009) 1–16. Ref: 31. – Stankiewicz, A., Moulijn, J. A., Process Intensification, Ind Eng Chem Res, 41 (2002) 1920–1924. Ref: 33. – Boodhoo, K., Harvey, A., (Eds), Process Intensification for Green Chemistry: Engineering Solutions for Sustainable Chemical Processing, 2013.

Study questions 2.1. How to characterize a reaction? 2.2. How to accelerate the reaction rate of a chemical reaction? 2.3. How to initiate and terminate chemical reactions? 2.4. How to shift the equilibrium of a chemical reaction? 2.5. What are the differences between diffusion, kinetic control, thermodynamic control? 2.6. How to achieve high selectivity in competing and consecutive reactions? 2.7. How to handle stoichiometry in batch and flow? 2.8. How to define the reaction time in batch and flow? 2.9. How to characterize the reaction progress in batch and flow? 2.10. What is surface-to-volume and what is their value in typical macro and micro (flow) reactors? 2.11. Why is there an increased mass transfer in micro (flow) reactors compared with typical batch reactors? 2.12. Why is there an increased heat transfer in micro (flow) reactors compared with typical batch reactors? 2.13. What is the electroosmotic (electrokinetic) flow (EOF) and its velocity profile?

Bibliography

2.14. 2.15. 2.16. 2.17. 2.18. 2.19. 2.20. 2.21. 2.22. 2.23. 2.24. 2.25. 2.26. 2.27. 2.28.

| 57

What is hydrodynamic (pressure-driven) pumping and its velocity profile? What is segmented flow? What is the Reynolds number? What Re numbers characterize the laminar, transient, and turbulent flow? What are the typical flow rates in various flow reactors? What is the typical dimension of continuous-flow (micro) reactors and the typical material they are constructed of? What is the Space Time Yield and its dimension? What is a typical flow reactor set-up and the main parts? What are the typical flow configurations reactors forming multiple line of reactors and what are the typical in-line analytical tools connected? What are the bases for major classification of chemical reactions? What are major characteristics of Type A, B, C reaction classes? What is Flash chemistry? What is the principle of high-resolution reaction time control? What is “Novel Process Windows” (NPW)? What is process intensification (PI)?

Bibliography [1]

Baxendale, I. R., The Integration of Flow Reactors into Synthetic Organic Chemistry. J. Chem. Technol. Biotechnol. 88 (2013) 519–552. [2] Wegner, J., Ceylan, S., Kirschning, A., Flow Chemistry – A Key Enabling Technology for (Multistep) Organic Synthesis, Adv Synth Catal 354 (2012) 17–57. [3] Valera, F. E., Quaranta, M., Moran, A., Blacker, J., Armstrong, A., Cabral, J. T., Blackmond. D. G., The Flow’s the Thing...Or Is It? Assessing the Merits of Homogeneous Reactions in Flask and Flow, Angew. Chem. Int. Edn. 49 (2010) 2–10. [4] Yoshida, J. I., Flash Chemistry: Flow Microreactor Synthesis Based on High-Resolution Reaction Time Control, The Chemical Record 10 (2010) 332–341. [5] Wegner, J., Ceylan, S., Kirschning, A., Ten key issues in modern flow chemistry, Chem Commun 47 (2011) 4583–4592. [6] Bogdan, A. R., Poe, S. L., Kubis, D. C., Broadwater, S. J., McQuade, D. T., Continuous flow synthesis of ibuprofen Angew Chem Int Edn 48 (2009) 8547–8550. [7] Baumann, M., Baxendale IR., Ley, S. V., The flow synthesis of heterocycles for natural product and medicinal chemistry applications, Mol Divers. 15 (2011) 613–630. [8] Yoshida, J. I., Flash Chemistry: Fast Organic Synthesis in Microsystems, New York, John Wiley and Sons, 2008. [9] Mawatari, K., Kazoe, Y., Aota, A., Tsukahara, T., Sato, K., Kitamori T Microflow Systems for Chemical Synthesis and Analysis: Approaches to Full Integration of Chemical Process. J. Flow. Chem. 1 (2011) 3–12. [10] Yoshida, J. I., Kim, H., Nagaki, A., Green and Sustainable Chemical Synthesis Using Flow Microreactors, Chem. Sus. Chem. 4 (2011) 331–340. [11] Yoshida, J. I., Nagaki, A., Yamada T Flash Chemistry: Fast Chemical Synthesis by Using Microreactors. Chem. Eur., J. 14 (2008) 7450–7459. [12] Mason, B. P., Price, K. E., Steinbacher, J. L., Bogdan, A. R., McQuade, D. T., Greener Approaches to Organic Synthesis Using Microreactor Technology, Chem. Rev. 107 (2007) 2300–2318.

58 | 2 Fundamentals of Flow Chemistry [13] Irfan, M., Glasnov, T. N., Kappe, C. O., Heterogeneous Catalytic Hydrogenation Reactions in Continuous-Flow Reactors. ChemSusChem 4 (2011) 300–316. [14] Jahnisch, K., Hessel, V., Lowe, H., Baerns, M., Chemistry in Microstructured. Reactors Angew. Chem., Int. Edn. 43 (2004), 406–446. [15] Webster, A., Greenman, J., Haswell, S. J., Development of microfluidic devices for biomedical and clinical application. J Chem Technol Biotechnol 86 (2011) 10–17. [16] Bogdan, A. R., Mason, B. P., Sylvester, K. T., McQuade, D. T., Improving Solid-Supported Catalyst Productivity by Using Simplified Packed-Bed Microreactors Angew. Chem. Int. Edn. 46 (2007) 1698–1701. [17] Malet-Sanz, L., Susanne, F., Continuous Flow Synthesis. A Pharma Perspective, J Med Chem 55 9 (2012) 4062–4098. [18] Watts, P., Haswell, S. J., Continuous flow reactors for drug discovery. DDT 8 (2003) 586–593. [19] Watts, P., Haswell, S. J., The application of micro reactors for organic synthesis Chem Soc Rev 34 (2005) 235–246. [20] Livak-Dahl, E., Sinn, I., Burns M., Microfluidic Chemical Analysis Systems. Annu Rev Chem Biomol Eng 2 (2011) 325–53. [21] Goodell, J. R., McMullen, J. P., Zaborenko, N., Maloney, J. R., Ho, C-X., Jensen, K. F., Porco, Jr., J. A., Beeler, A. B., Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1]octanoid Scaffolds. J Org Chem 74 (2009) 6169–6180. [22] Chang, C-H., Paul, B. K., Remcho, V. T., Atre, S., Hutchison, J. E., Synthesis and post-processing of nanomaterials using microreaction technology, J Nanoparticle Res, 10 6 (2008) 965–980. [23] Ahmed-Omer, B., Barrow, D. A., Wirth, T., Heck reactions using segmented flow conditions. Tetrahedron Lett 50 (2009) 3352–3355. [24] Kockmann, N., Gottsponer, M., Roberge, D. M., Scale-up Concept of Single-Channel Microreactors from Process Development to Industrial Production, Chem Eng J, 167 (2011) 718–726. [25] deMello, A. J., Control and detection of chemical reactions in microfluidic systems Nature, 442 (2006) 394–402. [26] McMullen, J. P., Jensen, K. F., Integrated Microreactors for Reaction Automation: New Approaches to Reaction Development Annu Rev Anal Chem 3 (2010) 19–42. [27] Benito-Lopez, F., Egberink, R. J. M., Reinhoudt, D. N., Verboom, W., High pressure in organic chemistry on the way to miniaturization. Tetrahedron 64 (2008) 10023–10040. [28] Kirschning, A., Jas, G., Applications of Immobilized Catalysts in Continuous Flow Processes Topics Current Chem 242 (2004) 209–239. [29] Razzaq, T., Kappe, C. O., Continuous Flow Organic Synthesis under High-Temperature/Pressure Conditions Chem–Asian J 5 (2010) 1274–1289. [30] Hessel, V., Cortese, B., deCroon MHJM. Novel process windows–Concept, proposition and evaluation methodology, and intensified superheated processing Chem Eng Sci 66 (2011) 1426–1448. [31] Razzaq, T., Glasnov, T. N., Kappe CO Accessing Novel Process Windows in a High-Temperature/Pressure Capillary Flow Reactor. Chem Eng Technol 32 (2009) 1–16. [32] Illg, T., Löb, P., Hessel, V., Flow chemistry using milli- and microstructured reactors – From conventional to novel process windows, Bioorg Med Chem 18 18 (2010) 3707–3719 [33] Stankiewicz, A., Moulijn, J. A., Process Intensification, Ind Eng Chem Res, 41 (2002) 1920– 1924. [34] Hessel, V., Hardt, S., Löwe, H., Chemical Micro Process Engineering: Fundamentals, Modeling and Reactions, Weinheim, New York, VCH-Wiley, 2004.

Jun-ichi Yoshida

3 Principles of controlling reactions in flow chemistry 3.1 Introduction Compared to conventional batch chemistry, flow chemistry enjoys a number of advantages from the view points of both laboratory synthesis and production in chemical, pharmaceutical, and agrochemical industries [1–11]. In particular, flow chemistry enables various types of reactions that are very difficult or practically impossible to perform in batch chemistry. This is one of the most important and advantageous features of flow chemistry and opens up a new possibility of chemical synthesis in laboratories and industrial production. For example, extremely fast reactions involving highly reactive, unstable short-lived reactive intermediates are usually very difficult to control in flasks in laboratories and batch macroscale reactors in the industry. However, by using flow microreactors such unstable intermediates can be generated and transferred to another location to be used in the next reaction before they decompose in timescales of seconds or less. Therefore, chemical conversions that are very difficult or practically impossible in batch macroscale reactors should become possible using flow microreactors [12]. Such chemistry is called flash chemistry [13, 14]. Flash chemistry is a chemical synthesis using extremely fast reactions based on flow chemistry. Flash chemistry is expected to complement flask chemistry which has been developed extensively and is widely utilized in laboratory synthesis. Flash chemistry is also expected to play important roles in industrial production in the future. In this chapter, we focus on the principles of controlling homogeneous reactions involving unstable intermediates by taking advantage of the characteristic features of flow microreactors. Some selected applications to synthetic reactions and polymerization reactions are also discussed for better understanding of the principles.

3.2 Reactions in a flow microreactor 3.2.1 Reaction time in a batch reactor Before discussing the control of reactions in flow chemistry, let us briefly touch on reactions in conventional batch chemistry. How does a reaction take place in a batch reactor such as a flask? We often start the reaction by adding some reagent or catalyst to a solution of a reactant. The initial concentration of a product is close to zero. The reaction proceeds as time goes, and the concentration of a product increases, whereas that of a reactant decreases with time. However, the concentrations at each part of the

60 | 3 Principles of controlling reactions in flow chemistry

Concentration

Product

Reactant 0 Reaction time

Batch reactor Fig. 3.1: A reaction profile of a reaction in a batch reactor.

reactor are the same if the reaction mixture is well stirred. Therefore, we often take a small part of the reaction mixture at time intervals, determine the concentrations of the reactant and the product by gas chromatography (GC), high-performance liquid chromatography (HPLC), or some other methods, and plot them against the reaction time as shown in Figure 3.1. From such a figure we can understand how the reaction proceeds. When most of the reactant is consumed and the product concentration reaches a maximum if overreaction or decomposition of the product does not occur, we stop the reaction, and isolate the product from the reaction mixture.

3.2.2 Residence time control in a flow reactor How does a reaction take place in a flow reactor under continuous-flow conditions? In a flow reactor, the reaction proceeds as a reactant travels through the reactor. This means that the concentration of a reactant decreases with an increase in the distance from the inlet of the reactor (Figure 3.2). The concentration of a product increases and reaches a maximum at the outlet of the reactor. It should be noted that the concentrations of a reactant and a product at each part of the reactor do not change as time goes. In other words, the concentrations do not change with the progress of operation time in a steady-state under the continuous-flow conditions. However, the concentrations vary with the space position in the reactor. We should keep in mind that the reaction time and operation time are different in flow chemistry, although they are usually

3.2 Reactions in a flow microreactor

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61

Concentration

Product

Reactant 0 Space position Inlet

Outlet

Reactant

Product Flow react ror

Fig. 3.2: A reaction profile of a reaction in a flow reactor [12, 19].

the same in batch chemistry. It is also important to note that the reaction time in a flow reactor can correlate to the space position inside of the reactor. The length of time that the solution remains in the reactor is called the residence time. Therefore, the reaction time can be defined as the residence time. This means that the reaction time can be controlled by adjusting the length of a flow reactor, although the reaction time also changes with the flow speed. One of the most advantageous features of flow chemistry is precise residence time control by adjusting space length of the reactor and the flow speed. The mean residence time in a flow reactor can be easily calculated from the length of the reactor and the flow speed or flow rate. For example, the mean residence time in a flow reactor of length 10 mm at a flow speed of 1 mm/s (linear velocity) is calculated to be 10 s (Figure 3.3 (a)). Of course, there exists the distribution of the residence time because the flow speed inside the reactor is not uniform. The flow speed near the center of the channel or tube is usually faster than that near the wall. However, if the diameter of the reactor channels or tube is small, radial diffusion time should be short because of a short diffusion path. This leads to a narrow residence time distribution. Anyway, hereafter we consider only the mean residence time for simplicity of the discussion. If we want to reduce the residence time to 5 s, we just simply need to reduce the length of the reactor to 5 mm. If we want to increase the residence time to 20 s, we should increase the length of the reactor to 20 mm. Therefore, the important feature of flow reactors is that the residence time can be controlled by adjusting the length of the reactor.

62 | 3 Principles of controlling reactions in flow chemistry 10 mm 10 s 5 mm 5s 20 mm 20 s (a) Flow speed (linear velocity): 1 mm/s 10 mm 10 ms (b) Flow speed (linear velocity): 1 m/s Fig. 3.3: Relationship between the residence time in a flow reactor and the length of the reactor and the flow speed.

The residence time can also be changed by changing the flow speed. For example, if we increase the flow speed to 1 m/s, the residence time in the flow reactor of length 10 mm is 10 ms (Figure 3.3 (b)). The speed of 1 m/s is not very fast from a view point of the motion of human beings. It is equal to 3.6 km/h and is slightly slower than the average human walking speed. The size of 10 mm or 1 cm is not very small for human beings. We can easily handle a reactor of 10 mm length by our hands. However, the time of 10 ms is usually very difficult to control for human beings. We cannot control the reaction time in such a short range manually using a batch reactor. For example, can you imagine that you start a reaction by adding some reagent to a flask containing a reactant very quickly and then after 10 ms you add a quenching agent to stop the reaction? This kind of operation is impossible to do with our hands. Therefore, this thought experiment tells us that we can control the time length that is difficult to control manually by adjusting the flow speed and the length of a reactor in ranges that are easy to handle in flow chemistry. We should take advantage of this simple but important principle of flow chemistry in conducting chemical reactions for synthesis. Flow chemistry enables chemical reactions that cannot be done in batch!

3.2.3 Why micro? 3.2.3.1 The importance of mixing [12, 19] The above discussion can be applied not only to flow microreactors, but also to flow macroreactors. However, micro is essential for the reaction time control of extremely fast reactions. The lengths of reactors are usually not on micrometer order, but on centimeter order. Where is micro necessary? Why? Reactions are often started by mixing

3.2 Reactions in a flow microreactor

Reagent

| 63

Quenching agent

Reactant

Product

Start

Stop Reaction time

Mixing time Fig. 3.4: Reaction time in a flow reactor [12, 19].

two reaction components and are stopped by adding a quenching reagent. Therefore, the reaction time is defined as the time between the first mixing of reaction components and the mixing of the reaction mixture with a quenching reagent. Thus, in a flow reactor, the reaction time is defined as the residence time between the position of a reagent inlet and that of the quencher inlet. Therefore, the reaction time can be precisely controlled by adjusting the length between these positions and the flow speed (Figure 3.4). However, there is another factor that we must consider for the control of reaction time. That is, the time for mixing. If the mixing time of reaction components is longer than the reaction time, the homogeneity of the solution is not achieved during the course of the reaction. The reaction takes place under nonhomogeneous conditions, and therefore the concentrations of the reaction components cannot be defined. This means that we cannot control the reaction by kinetics. Consequently, the mixing time should be shorter, preferably much shorter than the reaction time. For example, if we wish to adjust the reaction time to 1 s, the time for mixing of the reaction components should be much less than 1 s. The same is true for the quenching. Such fast mixing cannot be achieved by conventional batch reactors with stirring (vide infra). Such fast mixing is also difficult to achieve using macroscale flow reactors. It is only possible by mixing using microstructures. The micro is necessary for fast mixing. Let us consider how mixing takes place [13]. Mixing in a solution phase is defined as a phenomenon that creates homogeneity of all species in the solution. Mixing in a batch reactor with stirring is considered to proceed as follows (Figure 3.5). If we add a solution of B to a solution of A, eddies of the solution of B form in the solution of A. In the second step, the eddies diffuse into the solution by stirring. The last part of mixing takes place by molecular diffusion. During this step, the eddies are destroyed to achieve homogeneity of the solution at a molecular level. Because this step is the slowest step in a mixing process, molecular diffusion is the key step in a mixing process. According to the theory of molecular diffusion, the time needed for molecular

64 | 3 Principles of controlling reactions in flow chemistry

+

A

B

Addition of one solution to another

Homogeneous solution

B A

Reaction

B A

Eddy formation by stirring

B

A Eddy diffusion by stirring

Molecular diffusion

Fig. 3.5: Mixing by stirring [13].

diffusion is proportional to the square of the length of the diffusion path. Therefore, the diffusion time depends on the eddy size. The mixing time can be shortened by decreasing the eddy size. For that reason, we usually increase the intensity of turbulence of stirring to get faster mixing. More vigorous stirring leads to faster mixing. However, it is known that the mean minimum radius of eddies in optimal turbulence is approximately 100 to 10 μm. This means that it takes at least 0.05–5 s to obtain a homogeneous solution through molecular diffusion with such lengths of diffusion path for normal liquid. Therefore, the overall mixing time in a batch reactor with conventional stirring seems to be a few to several seconds. This means that we cannot control reactions that complete within a second or less using batch macroreactors equipped with a conventional stirrer. The use of micromixers solves the problem. Extremely fast mixing can be achieved by virtue of a very short diffusion path of small segments of solutions to be mixed, which can be generated inside of micromixers. For example, small segments of solutions in the laminar flow regime are made by the stream distribution using microstructures in multilamination type micromixers such as IMM single mixers [15] (Figure 3.6). Mixing takes place in the stream through the interfaces of the segments of flows by virtue of the short diffusion path, and a homogeneous solution is produced in a short period. The engulfment flow regime [16] caused by stream energy in T-shaped micromixers at high flow speeds is also effective. Small segments of solutions to be mixed are made presumably by shear stress. The diffusion path of such small segments should also be very short. At low flow speeds, however, the laminar flow regime is predominant, and this leads to slower mixing if the size of the channel is not very small. Anyway, the marked shortening of the diffusion path in micromixers results

3.2 Reactions in a flow microreactor

Solution distribution part

| 65

Mixing part

Solution A Solution B

Micro structure

Molecular diffusion

Fig. 3.6: Principle of multilamination-type micromixers [13].

in a mixing speed unobtainable in a macroreactor. Accordingly, micro is essential for the control of reaction times on the timescales of a second or less. Thus, continuous-flow systems equipped with micromixers are essential for precise control of reaction times on the timescales of a second or less. A picture of a typical flow system consisting of two micromixers and two microtube reactors is shown in Figure 3.8. Such flow systems enable short and precise reaction time control, which

Laminar flow regime (low flow speed)

Engulfment flow regime (high flow speed)

Fig. 3.7: Laminar flow regime and engulfment flow regime in a T-shaped mixer [13].

66 | 3 Principles of controlling reactions in flow chemistry Microtube reactor

Micromixer Fig. 3.8: A flow microreactor system consisting of two micromixers and two microtube reactors.

is extremely effective for controlling reactions involving unstable short-lived reactive intermediates. This feature is also useful for conducting reactions giving products that are unstable under the reaction conditions.

3.2.3.2 The importance of heat transfer [13] Fast reactions are usually, but not necessarily, highly exothermic. Therefore, in addition to mixing, heat removal is also an important factor in controlling extremely fast reactions. Heat transfer through the reaction solution occurs by conduction and convection. A short distance in a microreactor is advantageous for conduction. Because the heat generated by the reaction should eventually be removed from the reaction system, an important issue to consider is the heat transfer through the wall of the reactor. In general, volume is equal to length cubed while surface area is equal to length squared. When the length is decreased, the surface-to-volume ratio increases. Thus, one of the characteristic features of microspaces is that they have large surface-tovolume ratios compared with macrospaces. Because heat is transferred between the interior and exterior of a reactor through the reactor wall, heat transfer occurs rapidly by conduction in a microreactor which has greater surface area per unit volume compared to a macroreactor. Consequently, this feature makes fast removal of heat generated by highly exothermic reactions and precise control of the reaction temperature possible.

3.2 Reactions in a flow microreactor

| 67

Fig. 3.9: Cross-section of a shell&tube micro heat exchanger.

Shell & tube micro heat exchangers are often used for fast heat exchange in flow microreactor systems. The heat exchanger consists of one or several microtubes, which are placed in the shell. A coolant is circulated through the shell to maintain the temperature inside the shell [17].

3.2.3.3 Reaction time and reaction regime [18] Chemical reactions are often controlled by kinetics. In such cases we can obtain products based on the kinetics. However, kinetics cannot be used for extremely fast reactions because of the lack of homogeneity of the reaction environment. Reactions are limited by mass transfer and heat transfer, and accordingly it is difficult to obtain products based on kinetics (Figure 3.10). The border of reaction time between the kinetic regime region and the region limited by mass and heat transfer seems to be minutes order in batch macroreactors. When a reaction is conducted in a flow microreactor, however, the border shifts toward shorter reaction times because of fast mass and heat transfer (Figure 3.10). The border of reaction time for flow microreactors seems to range from milliseconds to seconds, although it depends on the size and the nature of the Fast reaction Limited by mass and heat transfer

Slow reaction Kinetic regime

Macro

Micro

ms s min h

Reaction time

Fig. 3.10: Reaction time and reaction regime [18].

68 | 3 Principles of controlling reactions in flow chemistry reactor. In the expanded region, the reactions that are difficult to conduct in a batch macroreactor become controllable, and therefore kinetically-based desired products are obtained in higher selectivity and less undesired byproducts are produced.

3.3 High-resolution reaction time control of reactions in flow 3.3.1 The principle [12, 19] We often encounter a problem of control of fast reactions involving highly unstable short-lived intermediates such as carbocations and carbanions. Let us consider a simple model case shown in Figure 3.11. A is a reactant. I is an unstable reactive intermediate, and it decomposes very quickly to give an undesired by-product B. For simplicity, we assume a sequence of first-order processes (rate constants: 𝑘1 and 𝑘2 ). We also assume that the generation process is faster than the decomposition process (𝑘1 > 𝑘2 ). Otherwise, there is no chance to accumulate the intermediate I in the solution. If we add a suitable quenching reagent before it decomposes, the intermediate I can be transformed into a desired product C. Of course, the quenching reaction of I to give C should be much faster than decomposition of I to B. Otherwise, there is no chance to obtain the desired product C. We also assume that C is obtained in a quantitative yield by quenching I. When 𝑘2 is much smaller than 𝑘1 , we can see that the reaction of A to generate I takes place first and goes nearly to completion before the decomposition of I takes place to give a significant amount of B. After completion of the generation of I from A, the addition of a quenching agent leads to the production of the desired product C. We can add a quenching agent over a wide range of reaction times to get C in a good yield. The increase in the reaction rate 𝑘2 changes the situation even if 𝑘2 is smaller than 𝑘1 . The reaction of A to give I takes place first, but the decomposition of I to give B occurs immediately. Therefore, I is accumulated in acceptable yields only over a limited time range.

A Reactant

Generation k1

I

Decomposition

Intermediate

k2

B

Byproduct

Quenching C Desired product Fig. 3.11: A general scheme of reactions involving unstable intermediates.

3.3 High-resolution reaction time control of reactions in flow

|

69

Time domain for quenching I to obtain C in a high yield I

Concentration

100 80

A

60 40 20

B

0 0.0

0.5

1.0 Time (h)

1.5

2.0

Fig. 3.12: A variation of the concentrations of reaction components (A, I, and B) against time (𝑘1 = 10 h−1 and 𝑘2 /𝑘1 = 0.01) [12, 19].

Time domain for quenching I to obtain C in a high yield I

Concentration

100 80

A

60 40 20 0 0.0

B 0.5

1.0 Time (s)

1.5

2.0

Fig. 3.13: A variation of the concentrations of reaction components (A, I, and B) against time (𝑘1 = 10 s−1 and 𝑘2 /𝑘1 = 0.01) [12, 19].

Let us consider a more quantitative way. First we consider the case where 𝑘1 = 10 h−1 and 𝑘2 /𝑘1 = 0.01. As shown in Figure 3.12, A is consumed within 0.5 h. The concentration of I increases with an increase in reaction time and then decreases gradually because of the decomposition of I to give B. Therefore, the reaction time for the generation of I should be longer than circa 0.3 h, and should be shorter than circa 0.6 h to get the desired product C in a yield higher than 90%. This is easy to do with batch reactors such as flasks. We need to add a quenching agent circa 0.5 h after we started the reaction. The time length of 0.5 h is easy to control manually. When the reaction is much faster, its control becomes much more difficult. For example, when 𝑘1 = 10 s−1 and 𝑘2 /𝑘1 = 0.01, the reaction time for generation of I should be longer than circa 0.3 s and should be shorter than circa 0.6 s to get a yield higher than 90% as shown in Figure 3.13. This means a quenching agent should be added precisely in this time domain. Otherwise, we cannot get the desired product C in a good yield. Time length shorter than a second cannot be controlled and the reaction cannot be done in a controlled way in a batch macroreactor even if 𝑘2 /𝑘1 is the

70 | 3 Principles of controlling reactions in flow chemistry same. In other words, such high-resolution reaction-time control cannot be achieved in flask chemistry. The use of a flow microreactor system equipped with micromixers is essential for this purpose.

3.3.2 Example 1: Phenyllthiums bearing alkoxycarbonyl groups [20, 21] In the following sections we are going into some examples of the control of reactions involving unstable reactive intermediates using flow microreactors. The first example is the generation of phenyllithium species bearing alkoxycarbonyl groups such as an example of the reactions involving unstable reactive intermediates. It is well known that alkoxycarbonyl groups react with phenyllithium species very rapidly. In fact, the reaction of phenyllithium with an alkoxycarbonyl group of an ester gives the corresponding ketone, which further reacts with phenyllithium to give the corresponding alcohol as shown in Figure 3.15. As you can recognize from this example, organolithium species, including phenyllithium suffer from the problem of functional group incompatibility, although they are widely used in organic synthesis because of their high reactivity. High reactivity often leads to low selectivity. In fact, it is difficult to prepare and use aryllithium species bearing electrophilic functional groups such as alkoxycarbonyl groups, because such functional groups rapidly react with aryllithium species. To overcome this problem, generation and reactions with electrophiles are usually conducted at very low temperatures. It is, however, still difficult to prepare aryllithium compounds having highly reactive functional groups, such as methoxycarbonyl and ethoxycarbonyl groups. Methyl and ethyl groups are less bulky than other alkyl groups making the attack on the carbonyl group much easier. Halogen/lithium exchange of aryl halides and butyllithiums are widely used for generation of aryllithium species because many aryl halides are readily available and butyllithiums such as n-butyllithium (n-BuLi) and s-butyllithium (s-BuLi) are comO OR Fig. 3.14: Phenyllithium bearing an alkoxycarbonyl group.

Li

O O + Li

R

OH R

OR’

Fig. 3.15: Reaction of phenyllithium with an ester.

Li

H3O+

R

3.3 High-resolution reaction time control of reactions in flow |

+

+ Li

Br

71

Br

Li

Fig. 3.16: Generation of phenyllithium by Br/Li exchange of bromobenzene using sec-BuLi.

O O

OC2H5

O OC2H5

O OC2H5

Li OC2H5

Br

Li

Byproducts O

Li Br

C2H5OH

Li

O OC2H5 H

Fig. 3.17: Generation of ethyl o-lithiobenzoate.

mercially available. For example, we can generate phenyllithium by Br/Li exchange of bromobenzene with s-BuLi as shown in Figure 3.16. Let us consider the Br/Li exchange reaction of ethyl o-bromobenzoate using s-BuLi to generate ethyl o-lithiobenzoate. Ethyl o-lithiobenzoate is a very unstable species and is known to undergo dimerization to give undesired by-products even at low temperatures (Figure 3.17). However, if we could quench it with a suitable electrophile (in this case proton of ethanol) before it decomposes, the desired products such as ethyl benzoate should be obtained in high yields. This idea works if we use a flow microreactor system consisting of two micromixers (M1 and M2) and two microtube reactors (R1 and R2) as shown in Figure 3.18. Ethyl o-bromobenzoate is mixed with s-BuLi in M1 and the Br/Li exchange reaction takes place in R1. The resulting ethyl o-lithiobenzoate is allowed to react with ethanol at M2 and R2 to obtain the desired protonated product, ethyl benzoate. In Figure 3.18, the yield of ethyl benzoate and the recovery of unchanged starting material (ethyl o-bromobenzoate) at −48 °C are plotted against the logarithm of the residence time in R1. The starting material is consumed within 0.1 s. The yield of the desired product increases with an increase with the residence time until the residence time reaches 0.1 s. A further increase in the residence time causes a decrease in the yield because of the decomposition (presumably dimerization) of the ethyl olithiobenzoate intermediate. An appropriate time domain for quenching the intermediate to get the desired product in high yields is indicated in the figure.

72 | 3 Principles of controlling reactions in flow chemistry O

O OC2H5

OC2H5

Br

Li R1

M1

O OC2H5

R2

M2

s-BuLi

H C2H5OH Fig. 3.18: The Br/Li exchange reaction of ethyl o-bromobenzoate followed by quenching with ethanol using a flow microreactor system.

Appropriate time domain

% 100

O OC2H5

80 H 60

40 O OC2H5

20 Br 0 10–2

10–1.5

10–1

10–0.5 100 Residence time (s)

100.5

101

Fig. 3.19: A variation of the yield of the protonated product and recovery of unchanged starting material with the residence time in R1 at −48 °C.

3.3.3 Temperature–residence time map [20, 21] Because the rates of reactions generally depend on the temperature, it is important to know the effect of the temperature on the reaction profile. Therefore, reactions in flow microreactors are often carried out with varying the temperature as well as the residence time. In Figure 3.20 the yield of the desired ethyl benzoate obtained by using the flow microreactor system is plotted against the reaction temperature and the residence time in R1 (the logarithm of the residence time). Such a map is called a

3.3 High-resolution reaction time control of reactions in flow

|

73

Temperature (°C) 0

65

37

15 9

4

0

84

63

58 48

38

10

–20

–40 64

90

86 80

77

43

–60 56

88

82 77

78

62

33

43

52 56

64

58

10–1.5

10–1 10–0.5 100 Residence time (s)

100.5

Fig. 3.20: A temperature–residence time map for the yield of the product in the Br/Li exchange reaction of ethyl o-bromobenzoate followed by quenching with ethanol using a flow microreactor system [19–21].

temperature–residence time map. In general, temperature–residence time maps, in which a particular outcome of the reaction such as the conversion of a reactant and the yield of a product is plotted against the temperature and the residence time (usually the logarithm of the residence time) serve as useful tools for analyzing reactions under continuous-flow conditions. Let us look at Figure 3.20 in detail. At low temperatures and short residence times, the yield is low because the starting material remains unchanged. The yield increases with an increase in the temperature and the residence time, but a further increase in the temperature and the residence time causes a decrease in the yield because of decomposition of the ethyl o-lithiobenzoate intermediate. In only an appropriate temperature–residence time domain we can obtain the desired product in good yields. It is important to note that the present temperature–residence time map is quite effective in revealing the stability and reactivity of highly reactive intermediates such as aryllithium species bearing electrophilic functional groups. Therefore, the maps serve as powerful tools for mechanistic studies of reactions involving highly unstable intermediates. It is also noteworthy that the temperature–residence time maps provide practical tools for optimizing reaction conditions for synthesis [22]. You can find the optimized residence time and temperature at a glance. A map consisting of 30–40 data points can be made in a day or two by collecting product solutions under various conditions and subsequent GC or HPLC analysis. Under the optimized conditions obtained by using ethanol as a quencher or an electrophile, ethyl o-lithiobenzoate intermediate can be used for the reactions with

74 | 3 Principles of controlling reactions in flow chemistry O OC2H5

C2H5OH

90% H

O

O

O OC2H5

s-BuLi

OC2H5

CH3OSO2CF3

OC2H5 62%

Br

Li

CH3

O

O

H (CH3 )3SiOSO2CF3

OC2H5 79% Si(CH3 )3

O

O OC2H5 OLi H

O H

70%

Fig. 3.21: Generation of ethyl o-lithiobenzoate and its reactions with various electrophiles.

various electrophiles. For example, the reaction with methyl trifluoromethanesulfonate (methyl triflate, CH3 OSO2 CF3 ) gives the corresponding methylated product (62%). It should be noted that the reaction with methyl iodide (CH3 I) gives the same product, but the yield is much lower (12%). Methyl iodide is much less reactive as an electrophile than methyl triflate, and therefore, the decomposition of the intermediate competes with the desired reaction. The reaction with trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate, (CH3 )3 SiOSO2 CF3 )) gives the corresponding silylated product. The reaction with benzaldehyde gives the corresponding lactone. The initial electrophilic addition gives the lithium alkoxide, which reacts with the ethoxycarbonyl group in an intramolecular manner to give the cyclized product. It should be emphasized that these transformations are impossible using conventional macro batch reactors because the intermediate is too unstable. However, high-resolution residence time control using flow microreactors makes such transformations possible. The present flow-microreactor method can be generally applied to the generation and reactions of aryllithiums bearing an alkoxycarbonyl group at 𝑝-, 𝑚-, and 𝑜-positions. Alkyl 𝑝- and 𝑚-lithiobenzoates are generated by the I/Li exchange reaction with phenyllithium (PhLi), although alkyl 𝑜-lithiobenzoates are successfully generated by the Br/Li exchange reaction with s-BuLi. The temperature–residence time maps for various alkyl 𝑝-, 𝑚-, and 𝑜-lithiobenzoates are shown in Figure 3.22,

3.3 High-resolution reaction time control of reactions in flow

R = –C(CH3 )3 0

O

Br

R = CH3 0

41 24 13

4 0

58 48 38

10

50 57 57

36 21 20

90

86 80 77

43

71 74 63

52 45 42

14

88 43

82 77 78 52 56 64

62 58

61 72 62 37 33

62 55 49 41 49 46

33 34

93 93

90 89 84

43

81

70

44 32 20

10

65

37

15 9

75

99

98 99 97

88

87

87

80 79 71

18

84

63

65

94

98 99 96

92

64

81

86 87 83

68

64

54 48

77 48

92 96 97 58 61 76

94 91

59 49

48 41

62 91 85 48 62 65

72 78

56 33

4

0

0

5

–40

O –60

OR Li

10–1.5 10–1 10–0.5 100

O

0

O OR

Temperature/°C

OR

90

90

81 76 56

11

O OR

Temperature/°C

I

39

32

12 9

7

105

10–1.5 10–1 10–0.5 100

3

27

11

5

5

100.5

10–1.5 10–1 10–0.5 100

4

3

5

4

2

1

0

100.5

0

83

95

95 95 91

69

77

69

50 34 24

9

64

65

26 14 7

3

48

56

17 6

4

0

95

83

97 99 97

94

84

81

82 78 64

23

89

77

62 53 39

7

87

63

50 38 25

0

–60 74 48

70 61

97 98 92 75 77 82

98 95

75 54

84 57

89 85 78 68 69 84

43 85

81 70

83 68

80 72 57 75 76 78

31 78

85 68 67 64

61 47 43 62 74 70

4 51

0

OR

10–1.5 10–1 10–0.5 100

–40

10–1.5 10–1 10–0.5 100 Residence time/s

O

100.5

–20

Li

Li

R = CH2CH3

75

–20

OR

I

R = –CH(CH3 )2

|

85

82

76 66 53

100.5

7

10–1.5 10–1 10–0.5 100 Residence time/s 40

28

11 8

7

100.5

2

10–1.5 10–1 10–0.5 100 Residence time/s 19

100.5

8

4 3

2

0

10–1.5 10–1 10–0.5 100 Residence time/s 10

7

5 4

4

105

5

–20 –40 –60

94

95

95 94 90

74

78

69

51 37 27

8

75

65

28 12 6

3

56

45

11 8

5

3

91

92

93 92 93

89

89

85

83 80 73

27

92

90

79 72 55

7

78

64

61 46 16

4

92

90

93 90 93

92

93

94

94 92 88

55

94

91

85 79 79

22

81

68

64 53 47

7

77

60

67 72 76

84

77

71

66 74 80

89

66

69

70 70 76

76

80

67

63 64 67

10–1.5 10–1 10–0.5 100 Residence time/s

100.5

10–1.5 10–1 10–0.5 100 Residence time/s

100.5

10–1.5 10–1 10–0.5 100 Residence time/s

100.5

10–1.5 10–1 10–0.5 100 Residence time/s

55 100.5

Fig. 3.22: A temperature–residence time map for the yield of the protonated product in the halogen/lithium exchange reaction of alkyl 𝑜-, 𝑚-, and 𝑝-halobenzoates using a flow microreactor system [20, 21].

which visualizes the stability of such reactive species. For example, in cases of t-butyl lithiobenzoate, products are obtained in high yields for a wide range of temperatures and residence times, although low yields are also observed in the high-temperature long-residence-time region because of the decomposition of the intermediates. The steric bulkiness of the t-butyl group retards the attack on the carbonyl group giving rise to relatively high stability of the intermediates. In the case of isopropyl esters, a similar reaction profile is observed, but the high-yield region becomes smaller because an isopropyl group is less bulky than t-butyl group. In cases of ethyl and methyl esters, high-yield regions are very small because these groups are sterically less hindered. These results clearly show that the stability of the aryllithium bearing alkoxycarbonyl groups strongly depends on the bulkiness of the alkyl group attached to the carbonyl carbon and decreases in the order of t-butyl > isopropyl > ethyl > methyl. The stability also depends on the position of the lithium. It is important to note that the high-yield region is bigger for 𝑜-lithiobenzoate cases in comparison with those for 𝑝- and 𝑚-lithiobenzoate cases irrespective of the nature of the alkyl group. This seems to be attributed to the coordination of the carbonyl group to Li making the species more stable.

76 | 3 Principles of controlling reactions in flow chemistry High-resolution reaction time control and the temperature–residence time map method can be generally applicable to various reactions involving highly unstable reactive intermediates such as aryllithiums bearing ketone carbonyl [23] and cyano groups [24], pyridyllithiums [25, 26], oxyranyllithiums [27, 28], aziridinyllithiums [29], vinyllithiums [30, 31], propargyllithiums [32], perfluroalkyllithiums [33], alkoxysulfonium ions [34], and onium ions [35, 36].

3.3.4 Example 2: Control of isomerization. Aryllithiums bearing a nitro group [37] The nitro group is also an electrophilic group which survives with difficulty in organolithium reactions. However, flow microreactor systems enable the generation and reactions of nitro-substituted aryllithium species (Figure 3.23). In this case, the combination of aryl iodides and phenyllithium (PhLi) is more suitable for the generation. I/Li exchange reactions of 𝑜-iodonitrobenzene, 𝑚-iodonitrobenzene, and 𝑝-iodonitrobenzene give the corresponding aryllithium species, which are allowed to react with various electrophiles such as methyl triflate, trimethylsilyl triflate, and benzaldehyde to give 𝑜-, 𝑚-, and 𝑝-substituted nitrobenzenes. The reaction of 1-bromo-2,5-dimethoxy-3-nitrobenzene is interesting. The corresponding aryllithium can be generated from the bromide presumably because the coordination of methoxy oxygen to Li facilitates the Br/Li exchange. More importantly, Li migrates after generation and one can control the migration of Li by controlling the residence time (Figure 3.24). The treatment of the starting material with PhLi (residence time = 0.06 s at −48 °C) followed by reaction with an aldehyde gives the desired product where the aldehyde carbon is connected to the carbon to which the bromine atom has been attached. However, an increase of the residence time results in the formation of a significant amount of isomeric product, which is derived from the migration of Li followed by the reaction with the aldehyde. With the residence time equal to 63 s, the isomerized product is obtained exclusively, indicating that the migration is complete in this period. The present result demonstrates that the high-resolution residence time control method using flow microreactors is quite effective for the selective use of either the kinetically-preferred reactive intermediates (non-isomerized NO2 I R1 M1 PhLi

R2 M2

NO2 E

Electrophile Fig. 3.23: Generation and reactions of aryllithium species bearing a nitro group.

3.4 Space integration of reactions

NO2

NO2

MeO

Br

NO2 OMe

OMe

Li

MeO

| 77

OMe

Li

Isomerization

MeO

–48°C 0.06 s

63 s

PhLi H

H

O

O OH

NO2

NO2 OMe

OMe MeO

MeO OH

84% Isomeric purity >99%

68% Isomeric purity >99%

Fig. 3.24: Control of isomerization by adjusting the residence time.

intermediates) or the thermodynamically preferred reactive intermediates (isomerized intermediates) by adjusting the residence time. The concept of the control of isomerization by high-resolution reaction time control can be applied to the control of cis-trans isomerization of oxyranyllithiums [27, 28], epimerization of propargyllithiums in the synthesis of optically active allenes [38], ring opening of aziridinyllithiums [39], and ring opening of heteroaryllithiums [40].

3.4 Space integration of reactions [41] 3.4.1 The concept Complex organic molecules are usually synthesized in a stepwise way by conducting several reactions sequentially with isolating intermediate products prior to a next reaction. However, such step-by-step synthesis should be molting into an integrated synthesis which combines multiple components in a single operation in one-pot or in one-flow, because integration of chemical reactions enhances the power and speed of multistep organic synthesis. Reaction integration can be classified into three types (Figure 3.25). (a) Time and space integration, where all reaction components are mixed at once to perform a sequence of reactions in one-pot (domino, tandem, or cascade reactions), (b) time integration, where a sequence of reactions is conducted in one-

78 | 3 Principles of controlling reactions in flow chemistry R1 R2

A

R1

R1

C

B R2

R2 (a)

B

A

B

C

A

Time (b)

C (c)

Fig. 3.25: Classification of reaction integration: (a) time and space integration, (b) time integration, (c) space integration [36, 41].

pot by adding components at intervals (one-pot sequential synthesis), and (c) space integration, where a sequence of reactions is conducted under the continuous-flow mode by adding components at different places in the flow system (flow chemistry). Although time and space integration is very easy to do, time integration and space integration methods are more flexible as far as choice of reagents and/or catalysts is concerned due to stepwise addition of such reaction components. Flow chemistry enjoys a number of benefits of space integration reactions [42–44]. The concept of flash chemistry enables space integration of reactions using short-lived unstable reactive intermediates. In the following sections we will briefly touch on space integration of reactions using integrated flow microreactor systems.

3.4.2 Example 3: Synthesis of disubstituted benzenes from dibromobenzene [45, 46] Here we see the sequential introduction of two electrophiles into dibromobenzenes based on the Br/Li exchange reaction can be achieved by using an integrated flow microreactor system. This type of transformation serves as one of the most straightforward methods for synthesizing disubstituted benzenes from bromobenzenes, which are commercially available. A flow microreactor system consisting of four T-shaped micromixers (M1, M2, M3, and M4) and four microtube reactors (R1, R2, R3, and R4) (Figure 3.26) is effective for this transformation. For example, a solution of 𝑜-dibromobenzene in tetrahydrofuran (THF) and a solution of n-BuLi in hexane are introduced into M1. The mixture is passed through R1, and the resulting solution containing 𝑜-bromophenyllithium is introduced into M2, where a solution of the first electrophile in THF is also placed. The mixture is passed through R2, and the resulting solution containing the 𝑜-substituted bromobenzene is introduced into M3, where a solution of n-BuLi is also placed. The mixture is passed

3.4 Space integration of reactions

| 79

Br

Br

Li

Br R1

M1

BuLi

R2

M2

Li

BuLi

E1

R3

M3

Electrophile 1

M4

R4

E2 E1

Electrophile 2 Fig. 3.26: The sequential introduction of two electrophiles into 𝑜-dibromobenzene based on the Br/Li exchange reaction using an integrated flow microreactor system.

through R3, and the resulting solution containing the second aryllithium intermediate is introduced into M4, where a solution of the second electrophile is also placed. The mixture is passed through R4. The reaction temperature for microtube reactors R1 and R2 should be −78 °C, because 𝑜-bromophenyllithium is highly unstable and undergoes the elimination of LiBr to form benzyne, which is also a highly unstable intermediate and undergoes subsequent reactions. In contrast, the reaction temperature for R3 and R4 is 0 °C, because the second aryllithium intermediate is expected to be much more stable than 𝑜-bromophenyllithium. The sequential introduction of two electrophiles into 𝑚- and 𝑝-dibromobenzenes is easier because both the first and the second aryllithium intermediates are relatively stable. All the reactions can be done at room temperature.

3.4.3 Example 4: Synthesis of TAC-101 [47] TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a synthetic retinoid having differentiation-inducing activity of human promyelocytic leukemia cells HL60. The conventional batch synthesis of the methyl ester of TAC-101 includes six steps, but such steps can be combined in one flow by space integration. To achieve this an integrated flow microreactor system consisting of six micromixers (M1, . . . . M6) and six microtube reactors (R1, . . . . R6) shown in Figure 3.27 is used. Starting from 1,3,5-tribromobenzene, three sets of Br/Li exchange reactions followed by a reaction with an electrophile are integrated in space. The total residence time from 1,3,5-tribromobenzene to the final product is circa 13 s, and the productivity is 100– 200 mg min−1 . Various TAC-101 methyl ester analogs having two different silyl groups

80 | 3 Principles of controlling reactions in flow chemistry Br

Br

Br M1 BuLi

R1 R2

M2

R3

M3

(CH3)3SiCl BuLi

R4

M4

R5

O

BuLi C

Si(CH3)3

M5

(CH3)3SiCl

M6

H N

R6 (H3C)3Si

N

O 77% aq NaOH

OCH3 O

OCH3 O

Si(CH3)3 H N

(H3C)3Si

OH

O TAC-101

O

Fig. 3.27: Synthesis of TAC-101 using an integrated flow microreactor system.

could be synthesized from 1,3,5-tribromobenzene in one flow. It is important to note that it is very difficult to synthesize compounds bearing two different silyl groups selectively by the conventional batch methods because dilithiation also occurs in the first step. The flow-microreactor method serves as a selective, efficient, versatile, and practical method for the synthesis of TAC-101 and its analogues.

3.4.4 Linear integration and convergent integration Multistep synthesis is an important application of flow chemistry [48]. Multistep synthesis can be classified, in principle, into linear synthesis and convergent synthesis as shown in Figure 3.28, although their combinations are often used for synthesis of complex molecules. Linear synthesis is suitable for iterative strategy, where the same or a similar reaction (or a set of reactions) is repeated to construct a target molecule. This strategy is frequently used for synthesis of peptides and oligosaccharides. However, in general, linear synthesis suffers from the problem that the overall yield quickly

3.4 Space integration of reactions

| 81

Linear synthesis A

B

D

C

E

Target molecule

Convergent synthesis A

B E

C

Target molecule

D

Fig. 3.28: Linear synthesis and convergent synthesis.

drops with an increase in the step number. Convergent synthesis, where two or several fragments are synthesized separately and they are combined to construct a target structure in the late part of synthesis, improves the efficiency of multistep synthesis. The synthesis of TAC-101 methyl ester is an example of linear synthesis. Therefore, integration of reactions used for its synthesis can be called liner reaction integration, where reactions are integrated in a linear fashion. However, the concept of space integration of reactions can be applied to convergent synthesis as well. Therefore, reaction integration for multistep synthesis can also be classified into two types, linear integration and convergent integration. It is interesting that the type of reaction integration, linear or convergent, can be easily recognized by the architecture of an integrated flow system which is used for the synthesis. The following synthesis of diarylethenes serves as a very simple example of convergent integration of reactions.

3.4.5 Example 5: Synthesis of unsymmetrically-substituted photochromic diarylethenes. Convergent integration [49, 50] Some of diarylhexafluorocyclopentenes exhibit remarkable change of color by reversible switching of two distinct isomeric structures, which is accomplished by absorption of different colors of light. Therefore they are promising candidates of photochromic materials. Various derivatives including those having heteroaryl groups such as thiophene, thiazole, benzothiophene, benzofuran, and indole rings have been synthesized so far, and they show different colors. In general, such diarylethenes are synthesized via the generation of heteroaryllithium compounds by halogen/Li exchange reaction of heteroaryl halides followed by the reaction with octafluorocyclopentene. The synthesis using a conventional batch macroreactor should be carried out at low temperatures such as −78 °C or below because heteroaryllithium species often decompose at higher temperatures. The requirement of such low temperatures, however, has been an obstacle to industrial-scale production. Notably, many photochromic diarylethenes reported in the literature are symmetrical, presumably because unsymmetrically-substituted diarylethenes are rather dif-

82 | 3 Principles of controlling reactions in flow chemistry Br

Li

N Ph

F F

N Me

S

Ph

M1

F S

R1

N

n-BuLi

Ph M2

F F

F

Me

Me

F

S R2

F F

F F F F

F

F F M4 F

Me

F

Me N

Br

Ph Ph

F F

F R4

S

Me

Me S

R3

M3

Me

S

Ph

66%

Me

Li

n-BuLi Ph

S

Me

Fig. 3.29: Synthesis of an unsymmetrical diarylethene using an integrated flow microreactor system.

ficult to synthesize under batch conditions. However, the use of integrated flow microreactor systems shown in Figure 3.29 enables easy synthesis of such unsymmetrical diarylethenes. For example, 4-bromo-5-methyl-2-phenylthiazole is mixed with n-BuLi in M1 and the aryllithium species generated in R1 is mixed with octafluorocyclopentene in M2. The monoarylated compound 1-(5-methyl-2-phenyl-4-thiazolyl)heptafluorocyclopentene is generated in R2 and it is transferred to M4. A different aryllithium is also generated in the flow. 3-Bromo-2,4-dimethyl-5-phenylthiophene is mixed with n-BuLi in M3 and the corresponding aryllithium is generated in R3. The second aryllithium is transferred to M4 and is mixed with the monoarylated compound to give the corresponding unsymmetrically-substituted diarylethene in 66% yield. The method can be applicable to synthesis of various unsymmetrically-substituted diarylethenes using two different aryl bromides.

3.4.6 Example 6: Integration of lithiation and cross-coupling [51] The concept of space integration of reactions can be applied to the combination of different types of reactions. The following example shows the space integration of halogen (X)/Li exchange of aryl halides (ArX) and Pd-catalyzed cross-coupling with aryl halides (Ar’X). The palladium-catalyzed cross-coupling reactions of aryl–metal species with organic halides are widely used for carbon-carbon bond formation in the synthesis of

3.4 Space integration of reactions

|

83

a variety of biologically active compounds and functional materials. In particular, the Suzuki–Miyaura cross-coupling reaction using aryl–boron compounds [52] has been used extensively because boronic acids and their derivatives are usually the airand moisture stabile. In contrast, the use of aryllithiums in cross-coupling reactions has been rather limited, although many aryl–metal compounds, including aryl–boron compounds, are often synthesized from aryllithiums. Therefore, the direct use of aryllithiums for the palladium-catalyzed cross-coupling reaction should be considered more seriously, in particular, from the viewpoint of atom- [53] and step economy [54]. The Pd-catalyzed cross-coupling of organolithium compounds with organic halides is known as Murahashi coupling [55]. However, this coupling has not been popular in organic synthesis. One of the major reasons for the lack of synthetic applications seems to be serious side reactions. Let us consider the cross-coupling of 𝑝-methoxyphenyllithium and bromobenzene as an example. The Br/Li exchange of 𝑝methoxybromobenzene with n-BuLi gives 𝑝-methoxyphenyllithium (Figure 3.30 (1)) which is used for the subsequent Pd-catalyzed cross-coupling reaction with bromobenzene (Figure 3.30 (2)), but 1-bromobutane (n-BuBr) is also formed in this process (Figure 3.30 (1)). If the subsequent cross-coupling reaction is slow, n-BuBr reacts with 𝑝-methoxyphenyllithium to give 𝑝-methoxybutylbenzene (Figure 3.30 (3)). Indeed, this is often the case. Typically, Pd-catalyzed cross-coupling reactions take hours to proceed to completion at room temperature or above, whereas reactions of aryllithiums with alkyl halides, such as n-BuBr, are complete within minutes at 0 °C. Therefore, this problem should be solved to achieve the integration of halogen/Li exchange and Murahashi coupling. The use of two equivalents of tert-butyllithium (t-BuLi) does not suffer from such a problem, because t-butyl bromide (t-BuBr) generated by the Br/Li exchange reacts with the second equivalent of t-BuLi to give isobutene, 2-methylpropane, and LiBr. These products do not react with aryllithium species. However, the use of two equivalents of highly reactive t-BuLi, which ignites spontaneously in air even at room temperature, is not suitable for large-scale laboratory synthesis and industrial production. There is another competing side reaction when the cross-coupling reaction is slow. That is, the Br/Li exchange between p-methoxyphenyllithium and bromobenzene to generate 𝑝-methoxybromobenzene and phenyllithium (Figure 3.30 (4)). The reaction of 𝑝-methoxybromobenzene with 𝑝-methoxyphenyllithium gives the corresponding homo-coupling product (Figure 3.30 (5)). Also, the reaction of phenyllithium with bromobenzene gives the homo-coupling product, biphenyl (Figure 3.30 (6)). The rate of the cross-coupling reactions depends upon the nature of the catalyst. Therefore, it is important to search for a catalyst that enables the cross-coupling faster than the side reactions. Although many conventional Pd catalysts such as Pd(Ph3 P)4 and Pd (t-Bu3 P)2 are not effective for the present purpose, the use of Pd catalysts that contain carbene ligands (PEPPSI-IPr and PEPPSI-SIPr) [56] leads to the cross-coupling reaction being much faster than the side reactions, and the cross-coupling products are obtained in good yields.

84 | 3 Principles of controlling reactions in flow chemistry

Li

Br + CH3CH2CH2CH2Li (1)

+ CH3CH2CH2CH2Br

CH3O

CH3O

Li

Br +

Pd catalyst

(2) CH3O

CH3O CH2CH2CH2CH3 LiBr +

Li + CH3CH2CH2CH2Br (3) CH3O

CH3O

Li

Br

Br +

Li

+

(4) CH3O

CH3O OCH3 Br

Li + (5) CH3O

Pd catalyst

CH3O CH3O Br

Li +

Pd catalyst

(6) Fig. 3.30: Unit reactions involved in generation of 𝑝-methoxyphenyllithium by the Br/Li exchange reaction of 𝑝-methoxybromobenzene followed by a Pd-catalyzed cross-coupling reaction with bromobenzene.

An integrated flow microreactor system that consists of three micromixers (M1, M2, and M3) and three microtube reactors (R1, R2, and R3) are used for the integration of Br/Li exchange and the cross-coupling (Figure 3.31). In the first step, 𝑝methoxybromobenzene is mixed with n-BuLi at M1. The reaction temperature for Br/Li exchange at M1 and R1 is 0 °C. The residence time in R1 is 2.62 s. In the second step, the resulting 𝑝-methoxyphenyllithium species is mixed with a solution of bromobenzene and 0.05 equiv of PEPPSI-SIPr as a catalyst at M1. Because the catalyst does not react with bromobenzene, they are mixed prior to introducing to M1. The cross-coupling reaction is carried out in R2 at 50 °C. The residence time in R2 is 94 s. Methanol is added at M3 to destroy unchanged 𝑝-methoxyphenyllithium species and/or n-BuLi, if they are present in the reaction mixture. Thus, overall transformation is complete within 2 min. The reactions can be successfully carried out with various aryl bromides as both the precursors of aryllithium species and the coupling partners.

3.4 Space integration of reactions

Br

|

85

Li

CH3O

CH3O M1 n-BuLi

R1 2.62 s 0°C M2

R2 94 s 50°C

Br M3 Pd catalyst

R3 CH3O

93%

CH3OH Fig. 3.31: Generation of p-methoxyphenyllithium by Br/Li exchange of 𝑝-methoxybromobenzene followed by Pd-catalyzed cross-coupling with bromobenzene using an integrated flow microreactor system.

The halogen/Li exchange reactions can also be integrated with homo-coupling reactions promoted by FeCl3 [57]. In this case the homo-coupling is much faster than the side reactions. Space integration of halogen/Li exchange, borylation, and Pdcatalyzed Suzuki–Miyaura coupling is also possible [58, 59]. High-resolution reaction time control enables the use of functionalized aryl groups [58]. These examples tell us that different types of reactions can be integrated in space using integrated flow microreactor systems. However, we should keep in mind that the desired second reaction should be faster than the side reactions of the intermediate. Another important point is that we can use different temperatures for the first reaction and the second reaction.

3.4.7 Example 7: Anionic polymerization of styrene and synthesis of block copolymers with a silicon core [60, 61] Polymerization is an important field of chemical synthesis and is widely used in industry for making macromolecules of a variety of functions. Flow chemistry serves as a powerful tool for polymerization [62]. Among the various methods of polymerization, anionic polymerization of vinyl monomers serves as an excellent method for the synthesis of polymers of well-defined end structures because the anionic polymer ends are reactive organolithium species and these living polymer ends can be utilized for end functionalization reactions with various electrophiles and block copolymerization. Anionic polymerization can be seen as reactions involving unstable reactive intermediates. Because the living polymer ends are easy to decompose in polar solvents such as THF, conventional anionic polymerization in macro batch reactors

86 | 3 Principles of controlling reactions in flow chemistry using polar solvents should be carried out at low temperatures, such as −78 °C. Such a requirement causes severe limitations in the use of this highly useful polymerization method in industry. The polymerization can be conducted at higher temperatures if we use nonpolar solvents, but much longer reaction time is needed for completion because of lower reactivity of the living polymer ends. This problem of anionic polymerization can be solved by flow chemistry. For example, anionic polymerization of styrenes using polar solvents can be done in a highly controlled manner in a flow microreactor system under noncryogenic conditions such as at 0 °C or room temperature. A very simple flow microreactor system composed of a micromixer M and a microtube reactor R is effectively used for the anionic polymerization styrene. A solution of styrene in THF (2.0 M) and a solution of s-BuLi in hexane (0.2 M) are mixed using M, and the resulting solution is introduced to R, where the polymerization takes place. The outlet solution is quenched with methanol. High level of molecular-weight distribution control is attained (𝑀w/𝑀n = 1.08). Fast initiation by virtue of extremely fast micromixing of a solution of the initiator and a monomer solutions is responsible. Notably, the polymerization can be carried out at 0 °C, which is much higher than the temperature for the batch polymerization. Efficient removal of the heat of polymerization by fast heat transfer by virtue of high surface-to-volume ratio is responsible. The number-average molecular weight 𝑀n increases linearly with an increase in the monomer/initiator ratio ([𝑀]/[𝐼]) as shown in Figure 3.32. [𝑀]/[𝐼] can be easily changed by changing the relative flow rate of the solutions of the monomer and the initiator. Therefore, 𝑀n can be controlled simply by changing the relative flow rate. These results indicate that flow microreactor systems serve as convenient and powerful tools for synthesizing polymers of different molecular weights. The active polymer end can be trapped by a suitable reagent such as chlorotrimethylsilane. For example, the reaction of active polymer end generated by polymerization of styrene with 0.1 equiv of s-BuLi can be trapped with chlorotrimethylsilane using the flow microreactor system shown in Figure 3.33. The residence time in R1, where the polymerization is carried out at 0 and 24 °C, is circa 4 s. The polymers 25000

Mn

20000 15000 10000 5000 0

0

20

40

60

80

100

120

140

160

[M]/[I] Fig. 3.32: Plots of the number-average molecular weight against the monomer/initiator ratio in anionic polymerization of styrene in THF at 0 °C using the flow microreactor system [60].

3.4 Space integration of reactions

|

87

Li

s-Bu n

R1

M1

CH3 s-Bu

s-BuLi

R2

M2

CH3 Si CH3

n

CH3

CH3 Si

CH3

CI

Fig. 3.33: Anionic polymerization of styrene followed by a reaction with chlorotrimethylsilane [60].

can be obtained in quantitative yields with narrow molecular-weight distribution. 1 H NMR analysis indicates that the active polymer end is quantitatively trapped by chlorotrimethylsilane, and therefore the polymer end is really living in the flow microreactor system even at room temperature within the residence time of 4 s at 0 and 24 °C. s-Bu

n

Li CH3 s-Bu

M1

Si

Cl

n

R1

CH3

s-BuLi M2 CH3 Cl

R2

CH3

CH3

Si Cl

M4

M3 R s-BuLi CH3 CH3 R = O Si C CH3 CH3 CH3

R4

s-Bu

Si

CH3 Bu-s

n

m

R

R3 s-Bu

R

R

Li

m

R

R

R

Fig. 3.34: Synthesis of block copolymers having two different polymer chains on a silicon core by anionic polymerization [60].

88 | 3 Principles of controlling reactions in flow chemistry Block copolymers having two different polymer chains on a silicon core can be easily synthesized in an integrated flow microreactor system using another active polymer chain as a second nucleophile (Figure 3.34). For example, the polymerization of styrene using s-BuLi is carried out in micromixer M1 and microtube reactor R1. The resulting active polymer chain is allowed to react with dichlorodimethylsilane (1 equiv based on the active polymer chain) in M2 and R2 to produce a chlorosilane having a single polymer chain. The polymerization of 𝑝-(t-butyldimethylsilyloxy)styrene to obtain another active polymer chain is carried out in M3 and R3. The reaction of this active polymer chain with the chlorosilane having a single polymer chain is carried out in M4 and R4 to give the final product in quantitative yields. This is another example of convergent space integration of reactions. Easy modulation to integrate polymerization reactions and end-functionalization is an advantage of flow-microreactorcontrolled polymerization.

3.4.8 Example 8: Anionic block copolymerization of styrene and methyl methacrylate [63] The synthesis of structurally well-defined polymers is important in the field of functional materials, and highly controlled block copolymerization is key to synthesizing such polymers. Anionic polymerization serves as an excellent method for the synthesis of such polymers, because the anionic reactive polymer ends are living and can be used for the subsequent polymerization with another monomer. Space integration can also be applicable to polymerization by sequential introduction of different types of monomers, which leads to the formation of structurally well-defined block copolymers with high level of molecular weight distribution control. This is an example of linear space integration of reactions. In this section we will discuss anionic block copolymerization of styrene (St) and methyl methacrylate (MMA) using an integrated flow microreactor system. Anionic polymerization of a single monomer such as St and MMA can be easily accomplished using a flow microreactor. The crucial point of block-copolymerization is how to integrate two polymerization reactions. Direct integration of St-polymerization and MMApolymerization is not successful because a polystyrene living polymer end is too reactive and may attack the carbonyl group of MMA. To achieve copolymerization, the polystyrene living polymer end needs to be converted to less reactive, which means more chemoselective, living polymer end by the reaction with 1,1-diphenylethylene prior to the subsequent polymerization with MMA [64]. An integrated flow microreactor system consisting of three micromixers and four microtube reactors is used (Figure 3.35). It should be noted that the suitable temperature for polymerization of St is 0 °C, whereas that for MMA is −28 °C. Therefore, the polymerization of St and the reaction with 1,1-diphenylethylene is carried out at 0 °C, whereas the subsequent polymerization of MMA is carried out at −28 °C.

3.5 Summary

s-Bu n

| 89

Li

s-Bu

Li n

R1 M1 s-BuLi

R2 M2 0°C

R3 M3

s-Bu n CH3OH

H m O OCH3

–28°C O

OCH3

Fig. 3.35: Flow-microreactor-system-controlled block copolymerization of styrene and methyl methacrylate.

The use of 10 equiv of St and 25 equiv of MMA based on s-BuLi leads to the formation of the block copolymer (𝑀n = 3900) with narrow molecular weight distribution (𝑀w/𝑀n = 1.14). The increase in the amount of St causes an increase in the molecular weight, and the increase in the amount of MMA also leads to an increase in the molecular weight. The block copolymerization of substituted styrene such as p-dimethylsilylstyrene and other alkyl methacrylates, such as t-butyl methacrylate (tBuMA) and n-butyl methacrylate (n-BuMA), can also be successfully carried out to produce the corresponding block copolymers with a narrow molecular weight distribution.

3.5 Summary In this chapter we discussed the principles of controlling reactions involving highly unstable reactive intermediates in flow chemistry. High-resolution control of residence time is the key although heat transfer is also important. Fast micromixing is crucial for the control of very fast reactions which are complete within seconds. We looked at some selected examples of such reactions, mainly focusing on organolithium reactions and anionic polymerization. We should keep in mind that we study these reactions not only for their own sake but also for the use of the idea for developing other types of reactions. The principles discussed here can be applicable to a wide range of reactions involving various unstable reactive intermediates.

90 | 3 Principles of controlling reactions in flow chemistry

Study questions 3.1. Design a flow system consisting of micromixers and microreactors suitable for the following transformations.

Br

Br n-BuLi

R1

O

Li 1

R2 OLi

2

R

R

Br n-BuLi

Br 2

R R1

OLi

O 3

R (a)

R1

Li

R2

R1

OLi

R2 OH

CH3OH

4

R

LiO

HO

R3 R4

R3 R4

n-BuLi I

Li

O

O CH3

CH3 I

Li O H

O

O CH3

LiO

(b)

CH3OH

CH3 HO

| 91

Bibliography

3.2.

What is the major side reaction of the organolithium intermediate in the following transformation. O

H OH Li

Br n-BuLi CH3O

(a)

CH3OH

CH3O

CH3O O H

Br

Li

n-BuLi

Br

(b)

OH CH3OH

Br

Br

O H Br

n-BuLi O

Li

OH CH3OH

O O

(c)

OCH3

OCH3

CH3O

Further readings 1. Flow microreactors: Hessle, V., Renken, A., Slhouten, J. C., Yoshida, J., Micro Process Engineering. Vol. 1, 2, and 3, Wiley-VCH, Weinhem, 2009. 2. Flash chemistry: Yoshida, J., Flash Chemistry Fast Organic Synthesis in Microsystems. Wiley, Chichester, 2008. 3. Organometallic chemistry: Schlosser, M., (Ed.), Organometallics in Synthesis A Manual 2nd Edn., Wiley, Chichester, 2002.

Bibliography [1] [2] [3] [4] [5]

McQuade, D. T., Seeberger, P. H., Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis, J. Org. Chem. 78 (2013) 6384–6389. Wiles, C., Watts, P., Continuous flow reactors: a perspective, Green Chem. 14 (2012) 38–54. Wegner, J., Ceylan, S., Kirschning, A., Ten key issues in modern flow chemistry, Chem. Commun. 47 (2011) 4583–4592. Hartman, R. L., McMullen, J. P., Jensen, K. F., Deciding Whether To Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis, Angew. Chem. Int. Ed. 50 (2011) 7502–7519. Ley, S. V., The changing face of organic synthesis, Tetrahedron 66 (2010) 6270–6292.

92 | 3 Principles of controlling reactions in flow chemistry [6] [7] [8]

[9] [10]

[11] [12] [13] [14] [15]

[16] [17] [18] [19] [20] [21]

[22] [23] [24]

[25]

[26]

Webb, D., Jamison, T. F., Continuous flow multi-step organic synthesis, Chem. Sci. 1 (2010) 675–680. Illg, T., Löb, P., Hessel, V., Flow chemistry using milli- and microstructured reactors – From conventional to novel process windows, Bioorg. Med. Chem. 18 (2010) 3707–3719. Tanaka, K., Fukase, K., Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New Paradigm for Natural Products Synthesis, Org. Process Res Dev. 13 (2009) 983– 990. Fukuyama, T., Rahman, M. T., Sato, M., Ryu, I., Adventures in Inner Space: Microflow Systems for Practical Organic Synthesis, Synlett, 151–163, 2008. Roberge, D. M., Zimmermann, B., Rainone, F., Gottsponer, M., Eyholzer, M., Kockmann, N., Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway? Org. Process Res. Dev. 12 (2008) 905–910. Ahmed-Omer, B., Brandt, J. C., Wirth, T., Advanced organic synthesis using microreactor technology, Org. Biomol. Chem. 5 (2007) 733–740. Yoshida, J., Takahashi, Y., Nagaki, A., Flash chemistry: flow chemistry that cannot be done in batch. Chem. Commun. 49 (2013) 9896–9904. Yoshida, J., Flash Chemistry. Fast Organic Synthesis in Microsystems, Chichester, U. K., Wiley, 2008. Yoshida, J., Nagaki, A., Yamada, T., Flash Chemistry: Fast Chemical Synthesis by Using Microreactors, Chem. Eur. J. 14 (2008) 7450–7459. Ehrfeld, W., Golbig, K., Hessel, V., Löwe, H., Richter, T., Characterization of Mixing in Micromixers by a Test Reaction: Single Mixing Units and Mixer Arrays, Ind. Eng. Chem. Res. 38 (1999) 1075–1082. Soleymani, A., Yousefi, H., Turunen, I., Dimensionless number for identification of flow patterns inside a T-micromixer, Chem. Eng. Sci. 63 (2008) 5291–5297. Wakami, H., Yoshida, J., Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant, Org. Process Res. Dev. 9 (2005) 787–791. Yoshida, J., Kim, H., Nagaki, A., Green and Sustainable Chemical Synthesis Using Flow Microreactors, ChemSusChem 4 (2011) 331–340. Yoshida, J., Flow Microreactor Synthesis Based on High-Resolution Reaction Time Control. Chem. Rec. 10 (2010) 332–341. Nagaki, A., Kim, H., Yoshida, J., Aryllithium Compounds Bearing Alkoxycarbonyl Groups: Generation and Reactions Using a Microflow System. Angew, Chem. Int. Ed. 47 (2008) 7833–7836. Nagaki, A., Kim, H., Moriwaki, Y., Matsuo, C., Yoshida, J. A Flow Microreactor System Enables Organolithium Reactions without Protecting Alkoxycarbonyl Groups, Chem. Eur., J. 16 (2010) 11167–11177. Rasheed, M., Wirth, T., Intelligent Microflow: Development of Self-Optimizing Reaction Systems, Angew. Chem. Int. Ed. 50 (2011) 357–358. Kim, H., Nagaki, A., Yoshida, J. A flow microreactor approach to protecting-group-free synthesis using organolithium compounds, Nat. Commun. 2 (2011) 264. Nagaki, A., Kim, H., Usutani, H., Matsuo, C., Yoshida, J., Generation and reaction of cyanosubstituted aryllithium compounds using microreactors, Org. Biomol. Chem. 8 (2010) 1212– 1217. Nagaki, A., Yamada, S., Doi, M., Tomida, Y., Takabayashi, N., Yoshida, J., Flow Microreactor Synthesis of Disubstituted Pyridines from Dibromopyridines via Br/Li Exchange without Using Cryogenic Conditions, Green Chem. 13 (2011) 1110–1113. Nagaki, A., Yamada, D., Yamada, S., Doi, M., Ichinari, D., Tomida, Y., Takabayashi, N., Yoshida, J., Generation and Reactions of Pyridyllithiums via Br/Li Exchange Reactions Using Continuous Flow Microreactor Systems, Aust., J., Chem. 66 (2013) 199–207.

Bibliography

|

93

[27] Nagaki, A., Takizawa, E., Yoshida, J., Generation and Reactions of Oxiranyllithiums by Use of a Flow Microreactor System, Chem. Eur. J. 16 (2010) 14149–14158. [28] Nagaki, A., Takizawa, E., Yoshida, J., Oxiranyl Anion Methodology Using Microflow Systems, J. Am. Chem. Soc. 131 (2009) 1654–1655 and 3787. [29] Nagaki, A., Takizawa, E., Yoshida, J., Generations and Reactions of N-tbutylsulfonylaziridinyllithiums Using Microreactors, Chem. Lett. 38 (2009) 1060–1061. [30] Nagaki, A., Matsuo, C., Kim, S., Saito, K., Miyazaki, A., Yoshida, J., Lithiation of 1,2Dichloroethene in Flow Microreactors. Versatile Synthesis of Alkenes and Alkynes by Precise Residence-Time Control, Angew. Chem. Int. Ed. 51 (2012) 3245–3248. [31] Nagaki, A., Takahashi, Y., Yamada, S., Matsuo, C., Haraki, S., Moriwaki, Y., Kim, S., Yoshida, J., Generation and Reactions of Vinyllithiums Using Flow Microreactor Systems, J. Flow Chem. 2 (2012) 70–72. [32] Tomida, Y., Nagaki, A., Yoshida, J., Carbolithiation of Conjugated Enynes with Aryllithiums in Microflow System and Applications to Synthesis of Allenylsilanes, Org. Lett. 11 (2009) 3614– 3617. [33] Nagaki, A., Tokuoka, S., Yamada, S., Tomida, Y., Oshiro, K., Amii, H., Yoshida, J., Perfluoroalkylation in Flow Microreactor: Generation of Perfluoroalkyllithiums in the Presence and Absence of Electrophiles, Org. Biomol. Chem. 9 (2011) 7559–7563. [34] Kawaguchi, T., Miyata, H., Ataka, K., Mae, K., Yoshida, J., Room Temperature Swern Oxidation Using Micro Flow System, Angew. Chem. Int. Ed. 44 (2005) 2413–2416. [35] Saito, K., Ueoka, K., Matsumoto, K., Suga, S., Nokami, T., Yoshida, J., Indirect Cation Flow Method. Flash Generation of Alkoxycarbenium Ions and Studies on Stability of Glycosyl Cations, Angew. Chem. Int. Ed. 50 (2011) 5153–5156. [36] Suga, S., Yamada, D., Yoshida, J., Cationic Three-component Coupling Involving an Optically Active Enamine Derivative. From Time Integration to Space Integration of Reactions, Chem. Lett. 39 (2010) 404–406. [37] Nagaki, A., Kim, H., Yoshida, J., Nitro-Substituted Aryl Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic Control, Angew. Chem. Int. Ed. 48 (2009) 8063–8065. [38] Tomida, Y., Nagaki, A., Yoshida, J., Asymmetric Carbolithiation of Conjugated Enynes: A Flow Microreactor Enables the Use of Configurationally Unstable Intermediates before They Epimerize, J. Am. Chem. Soc. 133 (2011) 3744–3747. [39] Giovine, A., Musio, B., Degennaro, L., Falcicchio, A., Nagaki, A., Yoshida, J., Luisi, R., Synthesis of 1,2,3,4-Tetrahydroisoquinolines by Microreactor-Mediated Thermal Isomerization of Laterally Lithiated Arylaziridines, Chem. Eur. J. 19 (2013) 1872–1876. [40] Asai, A., Takata, A., Ushiogi, Y., Iinuma, Y., Nagaki, A., Yoshida, J., Switching Reaction Pathways of Benzo[b]thiophen-3-yllithium and Benzo[b]furan-3-yllithium Based on High-Resolution Residence-Time and Temperature Control in a Flow Microreactor, Chem. Lett. 40 (2011) 393– 395. [41] Yoshida, J., Saito, K., Nokami, T., Nagaki, A., Space Integration of Reactions: An Approach to Increase the Capability of Organic Synthesis, Synlett, 1189–1194, 2011. [42] Pastre, J. C., Browne, D. L., Ley, S. V., Chem. Soc. Rev. 42 (2013) 8849–8869. [43] Baxendale, I R. J. Chem. Technol. Biotechnol. 88 (2013) 519–552. [44] Mascia, S., Heider, P. L., Zhang, H., et. al. End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation, Angew. Chem. Int. Ed. 52 (2013) 12359–12363. [45] Usutani, H., Tomida, T., Nagaki, A., Okamoto, H., Nokami, T., Yoshida, J., Generation and Reactions of o-Bromophenyllithium without Benzyne Formation Using a Microreactor J. Am. Chem. Soc. 129 (2007) 3046–3047.

94 | 3 Principles of controlling reactions in flow chemistry [46] Nagaki, A., Tomida, Y., Usutani, H., Kim, H., Takabayashi, N., Nokami, T., Okamoto, H., Yoshida, J., Integrated Micro Flow Synthesis Based on Sequential Br-Li Exchange Reactions of p-, m-, and o-Dibromobenzenes Chem. Asian J. 2 (2007) 1513–1523. [47] Nagaki, A., Imai, K., Kim, H., Yoshida, J., Flash Synthesis of TAC-101 and Its Analogues from 1,3,5-Tribromobenzene Using Integrated Flow Microreactor Systems, RSC Adv. 1 (2011) 758– 760. [48] Webb, D., Jamison, T. F., Continuous flow multi-step organic synthesis, Chem. Sci. 1 (2010) 675–680. [49] Ushiogi, Y., Hase, T., Iinuma, Y., Takata, A., Yoshida, J., Synthesis of Photochromic Diarylethenes Using Microflow System, Chem. Commun. (2007) 2947–2949. [50] Asai, T., Takata, A., Nagaki, A., Yoshida, J., Practical Synthesis of Photochromic Diarylethenes in Integrated Flow Microreactor Systems. ChemSusChem. 5 (2012) 339–350. [51] Nagaki, A., Kenmoku, A., Moriwaki, Y., Hayashi, A., Yoshida, J., Cross-Coupling in a Flow Microreactor: Space Integration of Lithiation and Murahashi Coupling. Angew. Chem. Int. Ed. 49 (2010) 7543–7547. [52] Miyaura, N., Suzuki, A., Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds, Chem. Rev. 95 (1995) 2457–2483. [53] Trost, B. M., Atom Economy – A Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way, Angew. Chem. Int. Ed. Engl. 34 (1995) 259–281. [54] Wender, P. A., Verma, V. A., Paxton, T. J., Pillow, T. H., Function-Oriented Synthesis, Step Economy, and Drug Design, Acc. Chem. Res. 41 (2008) 40–49. [55] Murahashi, S., Yamamura, M., Yanagisawa, K., Mita, N., Kondo, K., Stereoselective synthesis of alkenes and alkenyl sulfides from alkenyl halides using palladium and ruthenium catalysts J. Org. Chem. 44 (1979) 2408–2417. [56] Organ, M. G., Avola, S., Dubovyk, I., Hadei, N., Kantchev, E. A. B., O’Brien, C. J., Valente, C. A User-Friendly, All-Purpose Pd–NHC (NHC=N-Heterocyclic Carbene) Precatalyst for the Negishi Reaction: A Step Towards a Universal Cross-Coupling Catalyst, Chem. Eur. J. 12 (2006) 4749– 4755. [57] Nagaki, A., Uesugi, Y., Tomida, Y., Yoshida, J., Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl3 promoted homocoupling. Beilstein J. Org. Chem. 7 (2011) 1064–1069. [58] Nagaki, A., Moriwaki, Y., Yoshida, J., Flow synthesis of arylboronic esters bearing electrophilic functional groups and space integration with Suzuki–Miyaura coupling without intentionally added base, Chem. Commun. 48 (2012) 11 211–11 213. [59] Noël, T., Kuhn, S., Musacchio, A. J., Jensen, K. F., Buchwald, S. L., Suzuki–Miyaura CrossCoupling Reactions in Flow: Multistep Synthesis Enabled by a Microfluidic Extraction, Angew. Chem. Int. Ed. 50 (2011) 5943–5946. [60] Nagaki, A., Tomida, Y., Yoshida, J., Microflow System Controlled Anionic Polymerization of Styrenes, Macromolecules 17 (2008) 6322–6330. [61] Wurm, F., Wilms, D., Klos, J., Löwe, H., Frey, H., Carbanions on Tap – Living Anionic Polymerization in a Microstructured Reactor, Macromol. Chem. Phys. 209 (2008) 1106–1114. [62] Wilms, D., Klos, J., Frey, H., Microstructured Reactors for Polymer Synthesis: A Renaissance of Continuous Flow Processes for Tailor-Made Macromolecules? Macromol. Chem. Phys. 209 (2008) 343–356. [63] Nagaki, A., Miyazaki, A., Yoshida, J., Synthesis of Polystyrenes-Poly(alkyl methacrylates) Block Copolymers via Anionic Polymerization Using an Integrated Flow Microreactor System, Macromolecules 43 (2010) 8424–8429. [64] Nagaki, A., Tomida, Y., Miyazaki, A., Yoshida, J., Microflow System Controlled Anionic Polymerization of Alkyl Methacrylates, Macromolecules 42 (2009) 4384–4387.

Melinda Fekete and Toma Glasnov

4 Technology overview/Overview of the devices

With the fast development in the area of continuous-flow chemistry in the last few years, more and more commercial instruments are emerging on the market to satisfy the needs of the laboratory chemist. These systems are compact and usually include all that is needed to perform a continuous-flow synthesis. Nevertheless, the homebuilt systems still remain a cheap solution whenever needed. Further in this chapter, the essential parts in a continuous-flow system will be described shortly, in order to provide useful information on how to assemble such instrumentation and successfully carry out experiments.

4.1 General aspects Nowadays, the application of continuous-flow synthesis in the synthetic laboratory requires a basic set of laboratory equipment. Depending on the reaction profile (mainly temperature and time) various instrumental set-ups are possible. The basic continuous-flow reactor includes a pump to process the reaction mixture throughout the setup and a reactor, where the synthetic transformation happens. Such a simple set-up already provides the possibility to perform chemical reactions. However, performing more sophisticated reactions makes the assembling of a properly working set-up more difficult and requires technical understanding to some extent. Carrying out reactions with two or more reagents in separate streams requires the implementation of additional devices into the overall set-up – the so-called mixers. These devices assure that the reagents come in contact so that the reaction can happen. A reaction is either an exo- or endothermic process. For this reason, the reactor usually needs to be either cooled or heated in order to dissipate the excess heat or to provide the needed initial energy in order to start the reaction. On an industrial scale, it is common to use the released heat from one process for heating another one, thus reducing the production cost and making the overall synthesis greener. In a research laboratory there are several possibilities to heat or cool the reaction zone. The simplest of all are the traditional oil baths for heating or ice baths for working at temperatures lower than the room temperature. In all the cases where elevated temperatures and/or pressure are arising or used, an essential piece of the continuous-flow reactor is the back-pressure regulator. This part serves the purpose of keeping the reaction mixture in the reactor zone for the required reaction (residence) time. In some special processes, where a gas is needed: gas-liquid reactions, reactions in supercritical CO2 , reactions under inert

96 | 4 Technology overview/Overview of the devices Mixer (T-Piece) for additional reagent stream

Pumping module

Reactor zone Back-pressure regulator

Piston pump Reservoir

Collection vial

Syringe pump Gear pump

Chip

Coil Fixed-bed

Fig. 4.1: General scheme of a general continuous-flow set-up.

atmosphere – the back-pressure regulator is an obligatory part of the overall reactor set-up (Figure 4.1). This is also the case, when it is intended to work in a temperature regime above the boiling point of the used solvents or reagents.

4.2 Pumps for liquid handling Pumping fluids has been a perpetual problem for mankind over centuries. Overcoming the shortage of water supply has been the main driving force in the development of pumping technology in the past. With the industrial era more complicated problems arose and needed to be solved. Nowadays, as a result, numerous mechanical pumps for fluid transportation exist and these are used for a great many applications in industry as well as in everyday life. The existing pumps can be classified into three main groups by the method used to move the fluid: direct lift, displacement or gravity [1]. Among the many sub-types, few have been considered for application in the synthetic laboratory for performing continuous-flow experiments so far.

4.2.1 Syringe pump A syringe pump works on the principle of a reciprocating positive displacement of a fluid (Figure 4.2). In general, the pump represents a cylinder from different material – polymer, glass, stainless steel and so on, – equipped with a moving plunger. The most simple syringe pump has a single syringe, connected to a motorized pushing mechanism to move the plunger (Figure 4.2) thus providing constant linear flow of the syringe

4.2 Pumps for liquid handling

Plunger

| 97

Tubing

Fig. 4.2: Syringe pump – working principle and a commercial syringe pump (NE-1000, Microfluidics) for continuous-flow applications.

content into the reactor zone. This variation finds applications in medical care for continuous administration of drugs in patients at low speed for a defined time (infusion pumps). For synthetic purposes, a more sophisticated variation comes to use. It consists of at least two syringe pumps that are driven electronically to work synchronously – while the one is charging with fluid from a reservoir, the second is pumping the fluid into the reaction zone. Both syringes are connected to a switch-valve responsible for the accuracy of the system. The whole system is programmable and working at defined flow speed (few μL to mL per minute), thus controlling the residence time of the reaction mixture in the reaction zone. Such a combination can overcome the disadvantages of the single syringe pump system: limited reservoir capacity and lack of mixing possibilities. Based on the volume of the used syringes, different flow speeds are accessible. Depending on the materials used, high pressure working regimes are possible (few hundred bar). A dual syringe pump can provide constant and pulsation-free flow at very low flow rates (μL range) with high precision. The syringe pumps can be obtained separately and later on combined with a switch-valve to design a continuous-flow system. Multiple syringe systems are commercially available in many formats.

4.2.2 Piston pump The piston pump is a type of positive displacement pump and is used in nearly every modern LC-and HPLC-systems (Figure 4.3). Piston pumps use a reciprocating piston, connected to a crank mechanism, force-moving a fluid through a cylindrical chamber. Piston pumps work at high pressure regimes (up to ∼ 140 bar), and are usually considered as the standard choice for a continuous-flow system. The plunger pump (a variation of the piston pump) can achieve up to 2070 bar working pressure. The pump can be made out of different materials: steel, stainless steel, nickel-molybdenum alloys (Hastelloy, Haynes International Inc.) or ceramics. The Hastelloy®and ceramic pump variations provide increased resistance against many commonly used corrosive chemical reagents. A single pump is able to provide an uninterrupted continuous-flow without the need of additional valves if connected

98 | 4 Technology overview/Overview of the devices Flow direction Piston In- and outlet valves

Fig. 4.3: Piston pump – working principle and a commercial double piston pump (SmartLine 100, Knauer) for continuous-flow applications.

to a reservoir with a fluid. However, there are a few disadvantages to be considered when working with a piston pump: – the generated flow is pulsating due to the piston mechanism and thus low flow speeds of few μL can be difficult to be accurately maintained and working in this area is to be avoided. For very low flow rates syringe pumps are preferable. – processing of highly viscous materials is difficult. – processing of slurries or suspensions is problematic. – handling gas-liquid mixtures can lead to interruption in the flow process. It is advisable to introduce the gas into the reaction mixture after the pump by using a mixer unit. Bubbles in the lines before the pump should be avoided.

4.2.3 Other pumps In the chemical industry many varieties of pumps are used. It is worth mentioning that some of these can be considered, or are already used, in the synthetic laboratory to perform continuous-flow experiments. A diaphragm pump (or also known as a membrane pump, Figure 4.4) is a positive displacement pump, using a reciprocating membrane (instead of a piston) which can be made out of different materials to move a fluid. Membrane

Fig. 4.4: Working principle of membrane pump.

4.3 Mass-flow controllers

Low pressure/ inlet

|

99

Elastic tube

High pressure/ outlet

Rotor (a)

(b)

Fig. 4.5: Working principle of a gear pump (a) and a peristaltic pump (b).

The working principle of a gear pump (internal and external types) is illustrated in Figure 4.5 (a). Such a pump is able to transfer viscous fluids and can work at pressures of up to ∼ 200 bars. Furthermore, it can be designed to withstand highly corrosive liquids. Another pump type is the peristaltic pump (Figure 4.5 (b)). Here, the fluid is processed through a flexible tube, which is pressed by a rotating mechanism so that the fluid is brought into motion. This pump closely resembles the gastrointestinal movement in the human body, where the movement of the intestinal content is realized by the muscle contraction. The peristaltic and the gear pumps are rotary pumps.

4.3 Mass-flow controllers A mass-flow controller (MFC) is a device that sets, measures and controls the flow of a particular gas. It is used in flow chemistry to regulate and control the amount of gas entering the reactor per unit time. The principle of MFC is based on a thermal sensor: a small tube with two resistance thermometers wrapped around. During the operation, the two resistances heat up the tube to a given temperature [2]. When gas flows through the sensor tube, the gas flow cools down the tube and creates a temperature difference between the two elements. The sensor measures the temperature difference via the changed resistances. The measured temperature difference is a function of the mass flow, the density and the specific heat of the applied gas.

4.4 Heating/cooling of the reaction zone In terms of heating the reactor or reaction zone a few simple solutions are possible. A straightforward approach is to place the reactor (tube, coil, chip, etc.) into a classical water bath (< 95 °C), oil bath or a thermostat (r. t. – ∼ 250 °C). In either case, precise temperature control is required. Additionally, the thermal resistance of the materials

100 | 4 Technology overview/Overview of the devices used for the fabrication of the reactor, connections and tubing has to be taken into account. An advanced and more reliable way of heating and/or cooling is offered by GCor HPLC-column thermostats/cryostats (column ovens/chillers). These allow very precise control of the set temperature. Temperature programming is also possible and working in temperature regimes of −80 °C up to 450 °C (depending on producer) is feasible, what makes a GC-oven/chiller the heating/cooling device of choice when assembling an in-house continuous-flow reactor. Unfortunately, they are bulky to some extent and will acquire some bench space in a common synthetic laboratory. Similarly, HPLC-column thermostats can be used, although not designed to achieve such temperatures as the GC-ovens and therefore allow working in a temperature range of −10 °C up to 200 °C. The cooling in the HPLC-chillers is based on Peltier elements. A Peltier element is principally a heat pump with compact size that works without the use of cooling liquids. More traditional cooling methods include simply a cooling bath using liquid N2 , dry ice (CO2 ) in combination with various solvents (temperatures down to −78 °C) or ice-salt mixtures. Cryostats (Julabo, Heidolph) provide consistent cooling down to −80 °C. These are bulky in size and require a cooling liquid but are nevertheless a considerable option for in-house reactor set-ups.

4.5 Back-pressure regulators Back-pressure regulators are a one-way type of flow-through valve allowing the precise maintenance of a determined upstream pressure under controlled fluid flow conditions in one direction (Figure 4.6). Back-pressure regulators are unavoidable in gas-liquid reactions, or when gas evolution occurs during the reaction. It is also used to keep the solvent (and reactants) in the liquid phase when using higher temperatures than the boiling point of the liquid. The back-pressure regulators are simple in design and small in size. They are manufactured from different materials but primarily polymers and stainless steel.

(a)

(b)

(c)

Fig. 4.6: (a) Fixed/static pressure valve for different pressures; with a holder, (b): manual backpressure regulator, (c) adjustable back-pressure valve with the sealing element PTFE membrane.

4.6 Mixers

| 101

Those particularly considered for use in a continuous-flow synthesis on a small laboratory scale are: “Fixed” or static flow-through back-pressure regulators – here the term “fixed” means that the device has a set-point at which it will open and release just the excess pressure above the set-point so that the upstream pressure will remain just below the set limit (Figure 4.6 (a)). These are simple built commercial devices and can be obtained from various suppliers (Upchurch, OptimizeTechnologies, Scientific Systems Inc., etc.). They come in different pre-set pressure limits and are very convenient and relatively inexpensive to use. Such static back-pressure regulators (check-valves) are applied for example in the HPLC pumps. “Variable” or adjustable flow-through back-pressure regulators – these devices allow manual or electronical adjusting of the desired pressures and working mostly on the spring-load principle. When the regulator set-point is overcome, it will “crack” open and try to exhaust just the excess pressure above the set-point. Then, with a sensing element the valve resets very close to the original set pressure [3]. They are of rather low cost and various models are available on the market (Swagelok, Tescom, etc.) permitting working regimes of up to ∼ 1034 bar (Figure 4.6).

4.6 Mixers Proper mixing is of utmost importance in a continuous-flow process and directly affects the reaction speed and outcome by improving the efficiency of heat and mass transfer. The mixing processes strictly obey the laws of fluid mechanics and rheology [4]. Mixing by diffusion is commonly associated with microreactors where the flow channels are very small and proper mixing can occur without using any other special element. Chip microreactors are often utilized as mixing devices before the actual flow reactor.

Fig. 4.7: Chip microreactor for mixing or for reaction zone.

102 | 4 Technology overview/Overview of the devices In larger channels and for multiphase reaction mixtures, mixing by diffusion is not efficient. In some cases, mixing by mechanical agitation is used as an option. Very often, special mixing devices need to be developed, in order to satisfy the specific requirements of a single process. For the laboratory use, many standard devices are commercially available.

4.6.1 Modular mixers These elements typically have two (or more) inlets and one outlet. Their function is not only to mix but also to combine the reagent flows. – One of the simplest mixers is the so-called T-mixer or T-piece (named for the letter “T”, for its shape, Figure 4.8). It can be made out of different materials: glass (in the form of a glass chip), polymers or stainless steel. Variations with special design exist to provoke turbulences in the flow for improved mixing. In some cases the T-piece is used only to combine the reagent streams before pumping them in another mixer.

Fig. 4.8: Mixers – T-pieces (polymer and stainless steel) and a Cross mixer.

–

When there is enough turbulence in the reactor tubes, the T-piece can create effective mixing. Turbulence can be improved by high flow rates or by heat evolution during exothermic reactions. When the reaction is biphasic, or only slow flow rates can be used, the T-piece isn’t the choice of mixer. Structured static mixers: The mixer is a chamber with some inner structure (obstacles) that enhances mixing. This type is commonly used for miscible liquids with different viscosities (Figure 4.9).

Fig. 4.9: Dynamic (left) and static (middle) mixer, with their covering element on the right.

4.6 Mixers

|

103

Dynamic mixer: It has a small-size chamber where reagents can mix with the help of a magnetic stirrer bar. It requires the use of a magnetic stirrer underneath, but can be useful for an in-house built flow reactor system. Due to the very small volume of the mixer chamber, it can provide efficient mixing even for nonmiscible liquids (Figure 4.9). Gas-liquid static mixer: The mixing element is a frit (for example titanium, stainless steel, or polytetrafluoroethylene (PTFE), micrometer range) with small pore size. The liquid and gas enter on the same side of the frit and mix when passing through of it. The small pore size of the frit is responsible for the large contact surface by creating very small gas bubbles (Figure 4.10).

–

–

Fig. 4.10: Gas-liquid static mixer with Teflon frit (left) and lid (right). The inlets for gas and liquid aren’t visible on the photo but signed with arrows on the left piece.

4.6.2 In-line mixers These mixers are typically applied in the reaction zone itself. Some companies offer reactors with built-in elements, but most commonly, the reactor zone is filled with the desired mixing elements by the user. – Split-and-recombine mixer: This structure allows intensive mixing in laminar flow regime, typically applied within chip microreactors (Figure 4.11). Out

In

In

Fig. 4.11: Split-and-recombine micromixer [5]. Reproduced with permission from Wiley-VCH Verlag Gmbh & Co.

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Specially-designed static mixers: A static mixer is generally a mechanical obstacle of different shape (wave, spiral, baffles) with a smooth or rough surface and various sizes. It is placed directly inside the reactor tube and serves to induce turbulence flow along the reactor pipe, thus contributing to excellent radial mixing of the fluid streams while maintaining a nearly plug-like profile of the axial flow (Figure 4.12). These static mixers can be obtained from various suppliers in different sizes and shapes. They are produced of plastic, or metal, depending on the application. The type of the filling material has to be chosen considering the viscosity and the reaction phases, just as well the possible pressure drop along the reaction zone. The static mixer element is simply cut to shorter sections and placed into the loop reactor.

Fig. 4.12: Teflon static mixer – stand-alone and inserted into a tube.

–

Foams: Foams are a special type of static in-line mixers. Such a mixing technique is preferred in biphasic reactions, when a high surface-to-volume ratio is required to reach good conversion. In liquid-gas, or liquid-liquid biphasic reactions, the mixing often has to be maintained during the whole reactor loop to prevent phase separation. Foams are very efficient in mixing biphasic reactions due to their small pore size (Figure 4.13). The pressure drop has to be measured after filling the foam into the reactor since this mixer type can cause high pressure drops. Foams are available in metal (titanium, nickel) or plastic (for example PTFE) with different pore sizes.

Fig. 4.13: Magnified photo of a Ni-foam produced by Recemat (Netherlands) [6].

4.7 Reactors

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–

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105

In-house solutions: When a cheap and effective mixing of a biphasic reaction is needed, simple sand, silica gel or glass beads can efficiently do the job [7, 8]. Although the inner structure is not so well defined as that of the foams, they offer a cheap and chemically resistant alternative. Small particles can be filled in columns or loops as well, but it is recommended to sieve the material to avoid very small particles causing plugs or high pressure drop on the system. Multifunctional mixers: our choice of filling can even be multifunctional. For example, when acidic catalyst is needed in a biphasic reaction, instead of the inert static mixer and a separate catalyst, an acidic mineral with the sufficient particle size can be used in the reactor [9]. On Figure 4.14, an industrial scale tube reactor is presented with a static mixer inside. The tube bundle heat exchanger allows highly effective cooling or heating of viscous reaction media besides performing the mixing [10].

Fig. 4.14: The Sulzer Mixer Reactor (SMR) offers to combine effective mixing with controlled heat transfer [10].

4.7 Reactors The term “reactor“ is considered here to assign where in the continuous-flow set-up the actual reaction takes place [11]. In some cases this happens even while mixing the two or more reaction streams that is, in the mixer unit. In such a case the mixer represents the “reactor”. In most cases, however, the actual reaction happens in the heated or cooled zone, where the reagent mixture achieves the pre-set temperature

106 | 4 Technology overview/Overview of the devices and/or catalyst. There are several possible reactor types. Besides heating and cooling, the reactor device can be subjected to a variety of different physical interactions such as sonication/UV light or microwave radiation to facilitate the reaction. Reactor a device in which reactive materials can be brought to undergo a reaction under controlled conditions.

4.7.1 Coil reactors The coil reactor is one of the simplest designs used to perform flow chemistry. In the most uncomplicated cases, for example a homogeneous reaction, the coil reactor is a stainless steel or polymer capillary (or tube) with various diameters (1/32󸀠󸀠 , 1/16󸀠󸀠 or 1/8󸀠󸀠 , standard HPLC-consumable) and lengths (Figure 4.15). Thus, the internal volume can be easily determined as well as the corresponding residence time at a definite flow rate. The selection of material for the coil reactor (stainless steel, Hastelloy or different polymer tubes: PTFE, PEEK, PS, ETFE, etc.) is based on the reaction conditions – temperature, pH, solvent, pressure. Many of the commercially available instruments are provided with coil reactors of specific lengths that can be easily replaced depending on the synthetic needs. The inner diameter of commercially available tubing, which is considered when assembling a home-built reactor, is less than 2 mm. This is usually enough to assure a proper mixing in a homogeneous reaction mixture and no additional mixer is needed. Using metal coils allows working at elevated temperatures (beyond 200 °C) and pressures (few hundred bar). Polymer tubing cannot be used at such conditions. On the other side, the polymer coils are chemically more resistant to acidic or basic conditions when compared to the metal ones. Metal coils may provide catalytic amounts of iron, nickel or other metals under basic or acidic conditions, which might catalytically influence the outcome of the reaction.

Fig. 4.15: Coil reactors – a polymer tube and a stainless steel tube wrapped around a holder.

4.7 Reactors |

107

Addition of C A + B

[P1]

P2 P2 P1

Pump A Pump C Pump B Fig. 4.16: Scheme of a loop reactor for A + B → P1 + C → P2 type reaction.

Metal coils are generally a good option for homogeneous reactions that require high temperature and high pressure, such as Mitsunobu reaction or energy-intensive aromatic nucleophilic substitutions [12]. Polymer tubes are chosen for exothermic reactions where the temperature has to be well controlled. The high surface-to-volume ratio in coil reactors provides very efficient cooling. PTFE tubes can withstand chemically aggressive reagents (for example concentrated acids in nitrations or sulphonations). Introducing gases in the system allows carrying out exothermic and hazardous gas-liquid biphasic reactions such as Swern-oxidation or ozonolysis [12]. One great advantage of the coil reactor is the flexibility of the reaction set-up. Coils can be easily changed to shorter or longer sections, or new reaction lines can be added when required. Very often a reaction has multiple steps, or, the product mixture requires quenching. The different reaction spaces (coil reactors) can be easily connected to each other due to the reaction scheme. For example, the reaction on Figure 4.16 has two steps so it requires two loops. When necessary, the two loops can be placed into different temperature environments. This kind of flexibility is definitely an advantage of coil reactors when compared to chip microreactors (see later). It is important to consider that the volume flow is an additive quantity. Thus, when two (or more) reactants are entering in a coil (or any other type) reactor, the flow rate inside the reactor will be the sum of the flow rates of the single pumps. This will obviously result in a shortened residence time. When using a coil reactor, it is important to have in mind the problem of pressure drop as a result of different factors. Important factors are the viscosity of the pumped solvent as well as the length, inner diameter, the material of the coil reactor and the fluid velocity. All these factors can lead to differences in the pressure along the coil reactor referred to as “pressure drop”.

108 | 4 Technology overview/Overview of the devices

Pressure drop is the pressure difference between two points of the reactor, usually between inlet and outlet of the reactor.

However, when solvents with low viscosity, relatively short coil reactors as well as a low flow speed are used, this problem should not be of significance. Another issue to be taken into consideration is the possibility of blocking the reactor coil due to precipitation inside (e.g., product precipitation). This is nonetheless a general issue in continuous-flow processing and is usually taken care of during the optimization process. A great advantage of the loop reactors is that in case of blockage it is easy and cheap to replace the reactor just by cutting another sufficiently long polymer/metal tube.

4.7.2 Chip reactors Traditionally, chip reactors [13, 14] find applications in synthetic transformations involving ambient or low-temperature conditions in order to safely conduct highly exothermic processes (Figure 4.17). However, depending on the material used in their fabrication, the chip-microreactors can be utilized at high temperatures and pressures as well. Glass, quartz, silicon, various polymers, metal alloys and also ceramics are 1

2

6

9

7

3 5 4

8

1

Reactant A input

4

SOR mixer, A & B mix

7

Quench pre-heating

2

Reactant B input

5

Residence time

8

SOR mixer, quench mixes

3

Reactant A & B pre-heating

6

Quench input

9

Product output

Fig. 4.17: Chip microreactor with quench line (Labtrix).

4.7 Reactors

| 109

used, but glass is the most common material. Different manufacturing techniques are available for the production of the chip microreactors: etching, sintering, 3D-printing, and so on. The internal volume of microreactors can range from significantly below 1 μL up to several μL or even up to 1 ml. There are several advantages when using a chip microreactor: – Very high heat-transfer coefficients of up to 20–30 000 W/m2 K have been measured in chip microreactors that provide very efficient heating/cooling. – Microreactors have inner surface-to-volume ratio of several tens of thousands m2 /m3 . – Due to the small reactor volume, reaction conditions can be optimized using only a small amount of material. – Very efficient mixing due to the small inner diameter. They are often not only seen as microreactors but also as micromixing devices. For this reason, different designs of micromixers have been developed. These can be used separately or connected to another reactor type as to prolong the reaction time if needed. However, chip reactors are not considered as a cheap option for flow chemistry applications, due to the high-precision production technique. When using chip reactors it is even more important to avoid any precipitation as it leads to the cracking of the glass chip.

4.7.3 Packed-bed or fixed-bed reactors Packed-bed reactors include fluidized bed, fixed-bed and structured bed reactors [15] as shown on Figure 4.18. However, the most relevant type for the topic of this book is the fixed-bed reactor and we will discuss this one in detail. Fixed-bed reactors are used on a regular basis in industrial processing [16, 17]. This reactor type can be simply described as a tube, filled with solid particles of different sizes and shapes. Both ends of these so-called cartridges are closed with small pore size filters in order to keep the catalyst material in the cartridge throughout the operation. The catalytic performance is strongly dependent on the particle size of the used catalyst as well as on the loading (the amount of catalyst per amount of bulk material/solid support). The reaction takes place on the surface of the catalyst. The high surface-to-volume ratio assures better conversions per weight of catalyst. When used in a fixed-bed reactor, it is important that the catalyst has the proper particle size and active surface. Too small particles will result in a high pressure drop on the system and may leach into the solution through the filter. Too big particles have low surface-to-volume ratios and will give low conversions.

110 | 4 Technology overview/Overview of the devices Catalyst particle

(a)

Reaction fluid

Reaction fluid

Reaction fluid

Catalyst particle

Catalyzed channel wall

Fluidized bed

Fixed bed

Structured catalyst bed

(b)

(c)

Fig. 4.18: Main types of packed-bed reactors [15]. Reproduced with permission from Elsevier.

– – – – – – –

The major criteria for the packed bed columns are: low pressure drop; high catalyst loading per reactor volume; high external mass transfer rate from bulk fluid onto catalyst surface, and high internal mass transfer rate from catalyst surface to the catalyst inside; no leaching of catalyst; high longevity; suitable particle size (𝑑p ) is dependent on the length (𝐿) and diameter (𝑑r ); in ideal case 𝑑p < 𝐿/25 and 𝑑p < 𝑑r /10 should apply; high space-time yield.

Fig. 4.19: Packed-bed reactors – empty and filled with inert material (stainless steel beads); cartridge-type packed-bed reactor filled with catalyst (ThalesNano).

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Packed-bed reactors are a very good option for liquid-solid, gas-solid or gas-liquidsolid reactions, when the appropriate gas is introduced into the system via a dosing unit or mass-flow controller. Usually, a heating block is attached to the catalyst bed to control the reaction temperature. The pressure in the system is controlled by the back-pressure regulator. The major advantages of the heterogeneous or heterogenized catalysis are: – immobilized reagent/catalyst doesn’t contaminate the reaction solution, no filtration is required; – reusability (recycling) of catalyst is economical, environmentally-sound, and efficient; – high surface area of the catalyst can vary from 0.05 m2 /g to more than 100 m2 /g; – catalyst poisoning as well as side reactions are minimized due to the immediate removal of the product from the reactor zone; – immobilized reagents can be used in excess to drive reactions to completion without introducing difficulties in purification; – easy and safe handling of dangerous materials and gases, such as hydrogen or pyrophoric catalysts; – reagents on solid-support react differently, mostly more effectively and selectively, due to the high surface-to-volume ratio; – high productivity per mass of catalyst is possible resulting in a low-cost production in long-term usage; Nevertheless, a few disadvantages exist: – depending on the radial size of the tubing, thermal gradients may occur in the cartridge; (very thick cartridges are difficult to heat up) – channelling within the catalyst material – especially when the particles are very small – results in reduced conversion rate; – high pressure drop may occur, depending on the physical properties of the catalyst; – leaching of the reagents or catalysts sometimes occurs; Various commercially available supported catalysts exist. The most common catalysts applied in fixed-bed reactors are simple heterogeneous catalysts, such as 10% Pt/C or 5% Pd/C. Most of them were developed for batch reactions, thus, their application in fixed-bed reactors depends on the particle size and might be limited. For some commercial instruments (Thalesnano Inc.) pre-packed cartridges are available, fulfilling the role of a fixed-bed reactor. Obviously, a heterogeneous catalyst that is soluble in the applied solvent is not suitable for fixed-bed reactors. However, since some homogeneous catalysts have unique catalytical properties, attempts have been made to chemically bind these catalysts to inert support materials. The favored supports for the immobilization are polymers. (For example Tetrakis(triphenylphosphine)palladium, polymer-bound,

112 | 4 Technology overview/Overview of the devices available from Sigma-Aldrich.) [18]. Such a modification makes the homogeneous catalyst suitable for application in fixed-bed reactors. Inorganic materials with catalytic activity can also be filled in fixed-beds. For example, acidic zeolites are cheap and environmentally benign catalysts for many applications. Supported reagents are also available on the market for such applications. Particles with integrated acidic, basic or other reactive groups are being used to carry out a reaction, or as scavenger columns – to capture the excess reagent. Several examples of the many existing immobilized reagents are listed here: – polymer-supported bromine – sodium borohydride on silica – azide exchange resin, azide on Amberlite – Triphenylphosphonium chloride, polymer-bound for Wittig reaction With flow chemistry gaining more and more attention, newer and newer supported catalysts are developed. Catalytic materials containing metal nanoparticles on the solid support surface are prepared, e.g. on aluminum oxide or silica gel [19, 20]. These state-of-the-art catalysts often exhibit novel and superior catalytical activity when compared to traditional supported metal catalysts.

4.8 Miscellaneous techniques 4.8.1 Tube-in-tube reactor Another gas-liquid flow reactor applies a tube-in-tube set-up which separates the gas and liquid line with a semi-permeable Teflon AF-2400 membrane (Figure 4.20). Through the membrane, a rapid gas-liquid contact is generated in flow, which affords homogeneous gas solutions within the inner line. Control of the gas flow is by pressure, rather than by metered flow, which makes for simpler control. The reactant gas consumed by the reaction is constantly replaced through the membrane. This control method is helpful when a large excess of gas would change the selectivity of the reaction. Provided pressure is suitably controlled, bubbles of gas can be avoided entirely (gas bubbles are undesirable as they make it O2 R

H

R

H

O2 O2

Glaser-Hay coupling in flow

CuOTf (cat.)

R

R + H2O

Teflon AF-2400 Fig. 4.20: Tube-in-tube reactor for oxidation reaction [21]. Reproduced with permission from WileyVCH Verlag Gmbh & Co.

4.8 Miscellaneous techniques | 113

difficult to accurately assess liquid residence time and result in significant fluctuations in local concentrations). In the presented example (Figure 4.20) the gas flows in the outer tube, but a similar reaction is feasible with the gas in the inner tube instead [22].

4.8.2 Segmented flow biphasic reactions Recently, an interest in applying microreactors utilizing multiphase flow (gas-liquid or liquid-liquid biphasic systems) has emerged. Segmented flow is a very efficient technique to conduct biphasic reactions in microreactors. In a microchannel, the contact interface between immiscible phases (liquids or gas-liquid mixture) can follow various flow patterns, due to the forces at the interface generated from the different physical properties of both phases such as viscosity and surface tension (Figure 4.21).

(a)

(b)

(c)

(d)

(e) Fig. 4.21: Flow regimes in microchannels; (a) bubbly flow, (b) slug/Taylor flow, (c) churn flow, (d) slug/annular flow, (e) annular flow. Modified after reference [23].

114 | 4 Technology overview/Overview of the devices Gas-liquid segmented flow Gas-liquid flow within channels can be broadly categorized as being either annular or segmented. Annular flow is characterized by a rapid gas flow through the center of a channel resulting in a thin film of liquid coating the internal surface of the channel, whilst segmented flow describes the regular and alternating formation of segments of gas and liquid (Figure 4.21). The flow regime obtained is dependent on volumetric flow rates, channel geometries, and the physical properties of the liquid phase. Although an annular flow regime will generate high surface area contact between the gaseous and liquid phases within a microchannel, and therefore often used, the high gas flow rates typically result in undesirably-shortened residence times for the liquid reagents. Besides, the very high gas flow can result in the evaporation of the solvent, precipitation of reactants on the reactor wall, and finally, blockage. The transition between annular and segmented flow is known to be dependent on both the channel size and the fluid properties (viscosity, surface tension). Smaller channel sizes favor the formation of segmented flows. To obtain a good liquid-gas contact, it is important to have very thin and high frequency liquid segments instead of longer segments [24]. By thinning the liquid segments, the contact area between the gas and substrate is improved. The length of the gas-liquid segment can be adjusted by carefully controlling relative flow rates.

Liquid-liquid biphasic reactions in segmented flow The most common mode of liquid-liquid biphasic interface is known as parallel flow in which the respective fluid phases align side-by-side and mixing between them ocPhase A segment

Phase B segment

Microreactor wall Internal vortex circulation Fig. 4.22: Schematic representation of segmented flow in a microchannel: Rapid mixing within a given fluid segment is caused by the internal vortex fluid flow; mass transfer between contiguous fluid segments is enabled by the continuously refreshing interface. Modified after reference [25].

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curs principally via diffusion. For further details on this topic, see Vol. 2, Chapter 5 by McQuade et al. Another multiphase mode, segmented flow (Figure 4.22), can be created in a microchannel when two (or more) fluid phases form serial trains of fluid packets, each phase being separated by the other. (Similar to gas-liquid slug flow.) Once these fluid packets or segments are formed, an internal fluid vortex is generated which causes rapid mixing within a given segment by continuously refreshing the diffusion interface as shown in Figure 4.22. The cross-section must be smaller than the length of the segments, otherwise emulsions are formed. Furthermore, the constructional material of the microchannel plays a significant role in the formation of segments and influences their shape due to the effects of interfacial tension and surface energies. Additionally, the size of the segments will also have an effect on the reaction rate. Shorter segments facilitate the reaction via the increased surface-to-volume ratio.

Example for liquid-liquid biphasic segmented flow reaction OAc

0.5 M NaOH Toluene

O2N 1

ONa O2N 2

Fig. 4.23: Hydrolysis of 4-nitrophenyl acetate.

A solution of substrate 1 in toluene (0.05 M) and an aqueous solution of sodium hydroxide (0.5M) were passed through the two inlets of the microreactor or into T-junction of PTFE tubes using a dual syringe pump [25]. Results of the hydrolysis reaction are presented on Figure 4.24. Figure 4.24 is a nice representation of the advantages of segmented flow reactions. It is especially interesting to compare the lines a and b. The difference between a and b is the length of a liquid segment in a reaction. When short segments were created, contact between the two phases was elevated and this resulted in higher conversions. This figure is also a good example to see once again the advantages of flow reactors instead of conventional round-bottom flasks. Lines f and g represent the same reaction carried out in flasks. The conversion rate is far from those obtained in the loop reactors.

116 | 4 Technology overview/Overview of the devices 100 a 90

2(yield %)

80 70

b

60

c d e

50 40 30 20 10

f g

0 0

20

40 60 Reaction time (s)

80

100

120

Fig. 4.24: Hydrolysis of 1 using different flow types and reaction times: (a) Short segmented flow (approx. 2 mm) under microwave irradiation at 50 °C; (b) long segmented flow (approx. 10 mm) under microwave irradiation at 50 °C; (c) segmented flow in PTFE tubing heated in an oil bath at 50 °C; (d) segmented flow at room temperature in a PMMA reactor; (e) segmented flow at room temperature in PTFE tubing; (f) hydrolysis reaction at 50 °C in flask with stirring; (g) hydrolysis reaction at room temperature in flask with stirring. Figure modified after reference [25]

4.8.3 Falling film reactors The falling film microreactor utilizes a multitude of thin falling films that move by gravity force between two layers of glass sheet [26]. A typical residence time is

Orifices

Liquid reactant

Withdrawal zone (a)

(b)

Fig. 4.25: Assembled IMM falling film microreactor (a) and falling film principle in a multi-channel architecture (b).

4.8 Miscellaneous techniques | 117

seconds up to about one minute. Its unique properties are the good temperature control by an integrated heat exchanger (Figure 4.25) and the specific interface of 20 000–30 000 m2 /m3 . To further improve the surface-to-volume area, one of the glass layers contains grooves (Figure 4.25). A falling film reactor is obviously limited in size. Although such reactors exist with larger dimensions (up to 1 meter), scale-up is more feasible by stacking several of these reactor layers behind each other. The high mass and heat transfer were, for example, exploited when performing direct fluorination of toluene with elemental fluorine in the original version of IMM’s Falling Film Microreactor [27]. This so far uncontrollable and highly explosive reaction could be managed under safe conditions and with control over the reaction mechanism and therewith selectivity. Another special utilization of the falling film reactor is in photochemistry [28]. Due to the very thin glass and liquid layer, the UV light can incorporate in the reactant solution without significant attenuation – which is usually a crucial factor in photochemical reactions.

4.8.4 Flow microwave reactors Microwave chemistry is based on the efficient heating of materials by electromagnetic radiation in the microwave range. Molecules containing electric charges heat up by microwave radiation very fast, while apolar molecules heat up much slower. This selectivity allows some parts of the object to heat more quickly or more slowly than others (for example the reaction vessel). The reaction mixture is heated directly by the radiation and not by heat convection like in an oil bath. This heating method results in a more uniform heating of the mixture. Although microwave reactors are well-known and wide-spread in laboratory use, their use is mostly limited to laboratory applications. However, a couple of flow microwave reactors are already present on the market. The French company SAIREM introduced microwave-assisted continuous-flow reactors that are easy to integrate to a large variety of processes and with capacities that go up to many hundred kilograms per hour [29]. Another industrial-scale microwave assisted-synthesis is described in the following example [30]. Typically 2.45 GHz microwave radiation is applied in microwave reactors that corresponds to a wavelength of 12.2 cm. This means that the diameter of a reactor can’t be larger than 12.2 cm which is the size of the standing wave formed by the microwave radiation and responsible for the effective and homogeneous heating. This dimension limits the scale-up potential of so-called single-mode reactors.

118 | 4 Technology overview/Overview of the devices

~6 cm

~30 cm

~6 cm

Fig. 4.26: Monomode resonator concept for a microwave flow reactor merging the benefits of existing mono- and multimode technologies. Left: monomode flow concept; right: cylindrical waveguide in the fundamental mode. An idealized cylindrical reaction tube is shown in gray. Figure modified after reference [30].

In this particular work, the authors used 2.45 GHz monomode resonators that create a standing wave. To overcome the difficulties of scale-up, the aligning of several modes along the direction of the flow reactor tube was proposed (Figure 4.26).

4.8.5 UV reactors Advantages of flow chemistry can be superbly utilized when combining with photochemistry. Recent developments in flow photochemistry have the potential to allow photochemistry to become the main interest of chemists once again. A typical and simple flow photoreactor can be easily prepared in-house: it consists of a cylindrical UV-emitting lamp and UV-transparent reactor tubing wrapped around [31]. Oxygen segment Oxygen flow

Solution segment UV lamp UV-transparent tubing

Solution flow Oxygen cylinder

HPLC pump

PTFE T-mixer

Fig. 4.27: Schematic of the Seeberger photooxygenation apparatus and sensitized photooxygenation. Figure modified after reference [31].

4.8 Miscellaneous techniques |

1

H

O2 450W Pyrex

H

H O

Tetraporphyrin DCM, 25°C

H O O H

OOH O

OH 3

119

OH 4

O H

O O 5

Fig. 4.28: Sensitized photooxygenation of dihydroartemisinic acid.

The application of slug-flow gas-liquid reaction with photochemistry was combined by Seeberger and co-workers in the synthesis of Artemisinin [32]. This simple but hugely effective reactor configuration addresses all major issues of sensitized photooxygenation reactions: safe, controlled introduction of oxygen to the solution, and efficient irradiation from the light source (Figure 4.27). This first-line antimalaria drug was produced as a continuous-flow process from dihydroartemisinic acid 3 in three consecutive steps. TPP sensitized photooxidation of 3 produced the allylic hydroperoxide 4 at a rate of 1.5 mmol/min in 75% yield (Figure 4.28). This was followed by acid-catalyzed Hock cleavage and triplet-oxygen (3 O2 ) oxidation. The resulting compound underwent a series of spontaneous condensations to give artemisinin (5) in 45% yield. This is a highlight for flow chemistry in general and demonstrates what can be achieved by the marriage of chemistry with technology.

4.8.6 Working with supercritical CO2 Supercritical CO2 (scCO2 ) is a widely used and studied solvent for many operations in the chemical industry due to its unique solvent properties. Supercritical fluids have near-liquid densities that increase the probability of interactions between the fluid and the substrate, similar to a liquid solvent. The gaslike diffusivities of supercritical fluids allow for exceptional mass transfer properties. Moreover, near-zero surface tension as well as low viscosities similar to gases, allow supercritical fluids to easily penetrate a microporous matrix facilitating contact between components [33]. However, working with scCO2 requires several considerations in the reaction setup. Usually, a liquid CO2 cylinder is used to provide the solvent for the pump. The main difference when pumping liquid CO2 compared to conventional liquids is that small pressure and temperature changes during the operation of the pump can cause the liquid CO2 to evaporate in the pump head. This is crucial because certain pump types cannot transport gases and they will stop working. To avoid this, it is important to use a pump that is able to work without fluctuations. For example, reciprocating pumps have pistons with short strokes, so they need

120 | 4 Technology overview/Overview of the devices to refill frequently. Since fluid flow stops during refill, pressure fluctuations and density changes might result. These kind of pumps are not recommended when using scCO2 [33, 34]. Syringe pumps are considered pulseless, so the pressure and flow rates can be more accurately controlled by them and are available from several companies like Supercritical Fluid Technologies Inc., Jasco, Teledyne Isco. For proper operation, CO2 pumps must incorporate some means to remove the developed heat. Most producers are applying cooling jackets or integrated cooling module for this purpose. Using scCO2 as solvent, preparation of the starting solution isn’t feasible in the traditional way. For flow applications, the starting compound is pumped with a second pump and mixed with the solvent (scCO2 ) in a filled column after combining with a T-piece. Co-solvents are used, when the starting material is a solid [35]. Care must be taken when depressurizing the reaction at the end of the reactor set-up, as the CO2 will evaporate immediately and the components may precipitate, causing plugging.

4.9 Assembling and using a flow reactor Fittings and tubings To perform continuous-flow synthesis in the research laboratory the separate parts of the flow system have to be assembled together. Connecting the units into a working flow system requires proper tubing and fittings (Figure 4.29 and Figure 4.30). These are available as standard HPLC-accessories in different sizes and materials. Tubing with 1/8󸀠󸀠 , 1/16󸀠󸀠 and 1/32󸀠󸀠 diameter is generally used. Depending on the temperature and pressure working regimes of the system, either stainless steel or polymer (PTFE, FEP, ETFE, PFA and PEEK) tubing and fittings can be used. The commercial reactor (or an in-house reactor) can be directly connected after preparing the corresponding tubing. The reactor material should be chemically inert, resistant to the chemicals used, and have suitable thermal and electrical properties. It should withstand temperature and pressure that we intend to use during the reaction. If the material is transparent it favors optical inspection.

Fig. 4.29: Various standard commercial fittings and ferrules for continuous-flow applications.

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Back-pressure regulators The use of back-pressure regulators is necessary when a gaseous reagent is used in the reaction or when gas evolution is expected. This also applies for when temperatures above the boiling point of the solvent is used to keep the reaction mixture liquid. Commonly, two back-pressure regulators are needed – one is connected between the pump and the reactor (inlet-pressure) and one after the reactor (system pressure). Using these two pressure regulators allows measuring the pressure drop on the system: inlet pressure minus system pressure – which is an important characteristic of the flow system and should be kept low. Where more streams are combined via a mixing unit, a back-pressure regulator might be placed after each single pump before the mixer. The selection of backpressure regulators is based on the properties of the pumps, the reactor and the intended working regimes (flow rate, temperature, and pressure). Pumps The pump for the continuous-flow system has to be selected based on the envisaged chemical synthesis taking into account chemical resistance, viscosity of the processed materials, working regimes of the pumps, and so on. The pumping mechanism should guarantee a reliable and homogeneous flow rate, independently from the parameters. Usually, the piston pumps can handle only very small gas bubbles in the line before the pump head. If reactive gases are used in the reaction, these have to be introduced in the flow line behind the pump via a mixer unit. Some of the commercially available flow reactor pumps can work with pressures only up to several bars. Before operating the flow instrument, the pumps have to be checked for the accuracy of the flow rate. Starting up An important point is the determination of the dead volume of the system which is the volume of all the connected tubing. The total volume of the continuous-flow set-up minus the dead volume gives the volume of the reactor zone. (Usually, the reactor zone volume is measured alone with the help of a pump, and then the volume of the total system is measured.) From the volume of the reaction zone the residence time of the reaction mixture can be easily determined dividing it by the used flow rate. This also helps to decide when the collection of the processed reaction mixture should start.

Fig. 4.30: Various standard commercial tubes: PEEK, PTFE, stainless steel, for continuous-flow applications.

122 | 4 Technology overview/Overview of the devices Typically, reagent streams can be combined via a static mixer T-piece before being directed into a reactor device (reactor zone or residence time unit). The reactor device is subjected to physical interactions such as heating/cooling, ultrasonication or microwave radiation to initiate the desired transformations. The pumps, back-pressure regulators and the reactors are connected with the tubing by simply tight-screwing of the fittings. When the continuous-flow system is already assembled, it should be free of bubbles and leakages as well. In the case of leakage, the connections have to be checked and made tight. In the simplest case, when a homogeneous reaction is performed, and the complete system is set and prepared for the run, the inlet is switched from the solvent bottle to the vial with the reaction mixture and the processing is started. In a reaction with more than one reagent stream, the pumping of the single streams should be timely synchronized. Depending on the heating or cooling method used, the temperature control can be achieved accurately. If a simple heating/cooling bath is used, it is advisable to use a digital thermometer and to provide enough time to reach a steady temperature state (variation of +/ − 2 °C). After that, the reactor can be placed inside the heated/cooled zone. Before starting with the processing of the reaction mixture through the heated zone, the reactor should also be allowed to reach the working temperature by simply pumping reaction solvent for 10–15 min. The reaction mixture processing can be started at that point.

Product collection Due to diffusion processes occurring in the tubing, it is advisable to start the product collection earlier and extend the collection time until all of the reaction mixture has been processed. The exact point can be estimated from the total volume of the system, or can be measured with an in-line analytical technique. Monitoring the conversion in the collected fractions can be done simply with TLC, or, when available, GC or HPLC. In-line monitoring systems have also been developed to gather real-time data about the reaction. The collected reaction mixture is most commonly worked-up by traditional means – extraction, chromatography, and so on. However, attempts are being made to automate this step as well. In the scientific literature reports already exist, documenting the attempts to implement in-line purification by using pre-packed columns with supported reagents to capture undesired side-products or excess of reagents. Also, an automated column chromatography method exists that allows continuous purification of the crude product. Reaction optimization in a flow system can involve investigating the temperature, pressure, gas and liquid flow rates, concentrations of the reagents and their ratio. A simple pre-optimization in batch to determine temperature regime, reactant ratios and suitable solvents might be useful. Most flow reactors are sensitive to precipitation so it

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is important to reach a homogeneous reaction mixture before transferring the reaction into flow.

More details on this issue can be read in Volume 2, Chapter 8, Lab environment. In-line Separation, Analytics, Automation and Self Optimization.

Shutting down After the reaction has finished, the set-up has to be left to reach room temperature while simply pumping the reaction solvent through the system and just after that the pressure can be released. If the system is not needed further, it can be washed with an organic solvent such as ethanol or 2-propanol.

4.10 Commercially available systems for the laboratory use Due to the growing interest in performing continuous-flow synthesis on a laboratory scale during the recent years, many companies emerged on the market, offering sophisticated instrumentation to the synthetic chemists. In this section, some of these outstanding companies and their most important developments are shortly presented.

Chemtrix (Netherlands) Labtrix® is a flow reactor platform that is either a manually operated (Labtrix® Start) or automated (Labtrix® -S1). The system is based on the use of glass microreactors for the research and optimization of liquid phase reactions with reagents dosed using syringe pumps and thermally controlled using a Peltier with a thermal range of −20 to 195 °C. By varying the number of pumps employed, the platform is used for the evaluation of reactions of the type A + B + Q → P up to A + B = P1 + C = P2 + Q → P. By integrating efficient thermal control and mixing elements into small volume microreactors (1 to 19.5 μl), rapid reaction screening of high value materials can be performed to generate robust process data suitable for scaling to kg-scale and beyond. Typical Labtrix® Applications: – Grignard reactions – Esterifications – Nitrations – Fluoroalkynylations – Hofmann reaction – Knoevenagel & aldol condensations – Radiolabeling

124 | 4 Technology overview/Overview of the devices DESIGN 3224 Reactor with four inlets and one outlet: A+B=P1+C=P2+Q=P • Width channel: • Depth channel: • Reactor volume:

300 μm 120 μm 15 μl (=5+10 μl)

Fig. 4.31: Labtrix® chip microreactor.

KiloFlow® is a scalable, turnkey continuous flow system capable of processing up to 140 liters of reaction mixture per day. Again utilizing glass reactors (0.8 to 19 ml), efficient mixing and thermal control enables the scaling of reaction conditions developed at the lab to provide g to kg material production. The KiloFlow® Basic system comprises of two dual syringe pumps and a reactor holder, which contains a series of glass devices, in which the thermostating and reaction of two reagent feeds (A + B → P) can be performed – however it can be flexibly expanded to incorporate additional pumplines and reaction steps. Positioned within a standard laboratory fume hood, researchers can readily transfer processes from Labtrix® where mg-quantities are produced to KiloFlow® where 10’s g/h can be realized.

Fig. 4.32: Kiloflow chip microreactor set for largescale production.

– – – –

KiloFlow® Applications: Ionic liquid synthesis Eschweiler Clarke reactions Knoevenagel condensations Hantzsch thiazole reactions

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Plantrix® is an industrial flow platform that uses EKasic® silicon carbide (SiC) reactors for the performance of flow reactions at the 10’s (MR260) to 100’s (MR500) litre/h scale. Employing integrated heat exchange and mixing, Plantrix® reactors allow the performance of controlled flow reactors at a scale suitable for chemical manufacture. Exploiting the thermal performance and high chemical resistance of SiC, the flow reactor affords access to processing windows otherwise not accessible in glass, steel or Hastelloy reactors. Plantrix® applications: – Oxidations – Chlorinations – Nitrations – Wolff-Kishner reductions – Addition reactions – Diazotisations Further information is available on the homepage: www.chemtrix.com.

FutureChemistry (Netherlands) FutureChemistry has developed several modules for carrying out flow chemistry at a small scale. The philosophy behind these instruments is low usage of chemical compounds, combined with easy operation and ease of understanding the actual chemical processes. The base module (FlowStart Evo) is built for carrying out reactions in the liquid state. Up to three different stock solutions are placed in syringes (with a typical volume of 5 mL each), operated by syringe pumps. The stock solutions flow through flexible inlet modules (tubing with internal volume circa 100 μL) to a microreactor. The microreactor has integrated mixing channels (with folding flow mixing units) and residence time channels, with a typical combined volume of 100 μL (for normal flow chemistry) or 1 μL (for ultra-fast reactions, also called “flash chemistry”). The microreactor is contacted with a heating/cooling plate which enables a temperature range of −10 to 200 °C. The microreactor is connected to an outlet, which can be complemented with a back-pressure regulator to increase the pressure inside the microreactor up to 500 kPa, sufficient to keep, for example, water in the liquid state up to 155 °C and prevent outgassing of the liquids. Because the syringe pumps can reach a wide range of flow rates (below 1 μL/min up to 2.9 mL/min), residence times of 0.05 s up to an hour can be theoretically reached. In practical situations, times between 0.1 s and 15 min are normally used. Examples of liquid-phase reactions include Prilezhaev dihydroxylations [36], Vilsmeier–Haack formylations [37], while the principle of using gases at a very small scale in continuous mode was introduced, and an example was given with a Grignard

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Outlet

Residenc e time M ixing part part

470 nm

Inlet A Inlet B

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Fig. 4.33: (a) FlowStart Evo with gas module, (b) closeup of microreactor, (c) photochemistry module.

model reaction [38]. The latter example includes direct coupling to FTIR equipment, extensively investigated earlier by Stephen Ley’s group [39]. While photochemical reactions appear to perform very well in continuous flow, especially at the microliter scale [40], no commercial equipment was available at the latter scale. Therefore, FutureChemistry has recently introduced equipment to irradiate microreactors at a 100 μL scale, while being able to reach from low UV (210 nm) up to visible wavelengths. Further information is available on the homepage: www.futurechemistry.com

Uniqsis (United Kingdom) The Uniqsis FlowSyn™ is a compact and flexible, dual channel meso-scale continuous-flow reactor system designed for bench-top use. It utilizes two high pressure pumps to deliver a maximum combined flow rate of 20 ml/min at pressures of up to 200 bar. A larger version of the instrument, the FlowSyn™ Maxi, is also available with a maximum flow rate of 100 ml/min and a 100 bar max pressure rating. FlowSyn™ can be specified with stainless steel or Hastelloy C flow-paths suitable for high pressure or microwave-like chemistry [41, 42], or with a full perfluoropolymer flow-path for optimal chemical resistance [43]. An embedded user-control interface permits individual experiments to be run either automatically or with full manual control. The system is fitted with three pressure transducers and back-pressure regulators which enable priming to be performed “on-the-fly” without needing to first cool/depressurize the reactors. Each channel has a low pressure inlet valve to allow switching between solvent and reagent solution feeds. Reagent solutions may be delivered from stock bottles (passing through the pump heads) or alternatively from sample loops fitted to high pressure injection valves positioned in-line after the pump heads.

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Fig. 4.34: Uniqsis Flowsyn™ stand-alone (a) and with Automated Loop Filling (b, FlowSyn™ Auto-LF).

The unit is fitted with two independent heated reactor modules, a coil reactor heater (𝑇max 260 °C) and a module which can accommodate either column reactors or glass static mixer/reactor chips (𝑇max 150 °C). The latter may be used as mixers which then flow into a coil reactor to extend residence time [44], or as short residence time reactors affording excellent temperature control for rapid exothermic reactions [45]. A wide range of coil reactor sizes fabricated from materials including Hastelloy® C, 316 L stainless steel, Inconel® , PTFE, PFA and copper are available. In addition, gasliquid reactions where the gas is fully dissolved in the reaction mixture can be performed using “tube-in-tube” modules utilizing the semi-permeable fluoropolymer AF2400 [46, 47]. A number of system upgrades are available. The Multi-X package adds a simple fraction collector that allows a sequence of experiments to be run automatically using the same starting reagent solutions [48]. For combinatorial library generation and reaction optimization requiring a variety of starting materials or reagents, the Auto-LF upgrade package adds an independent liquid handler that automatically fills the sample loops according to a preprogrammed list of experiments [49]. For more complex flow chemistry, the number of flow channels can be increased up to a maximum of four either by adding standalone pumps or by the addition of the Uniqsis Binary Pumping Module (BPM) and additional reactor modules such as the ArrheniusOne Flow™ microwave or the innovative Polar Bear Plus Flow™ compact heater/chiller module [50, 51] (−40 °C to 150 °C) can be added. The BPM itself can also be used in combination with standalone reactor modules as a hub around which to build a modular flow reactor system. In this more complex configuration,

128 | 4 Technology overview/Overview of the devices full system control is achieved using FlowControl™ software running on a separate computer. Whilst developed primarily for homogeneous flow chemistry applications, FlowSyn has also been used for the preparation of nanoparticles [52, 53] and engineered silicas [54]. Further information is available on the homepage: www.uniqsis.com

ThalesNano (Hungary) The company ThalesNano is a pioneer in the field and the market leader in microscale flow reactor development. Its R&D 100 awarded H-Cube flow reactor has been utilized worldwide both in academia and industry since its release in 2005, establishing a strong base for the company’s forthcoming products, such as the modular H-Cube Pro™, Phoenix Flow Reactor™ and Gas Module™ instruments. All equipment from ThalesNano are developed to fulfill the needs of performing hazardous reaction safely, opening access to novel chemistries and compounds providing a user-friendly platform for these achievements. The equipments solve many safety and convenience problems. For instance, with the H-Cube™ Series reactor family hydrogen cylinders can be eliminated from laboratory environment by the built-in hydrogen generation system which requires only water for the generation of high pressure (up to 100 bar) hydrogen making the process a greener, safer, faster and easier alternative compared to batch methods. Furthermore, the cartridge technology, what ThalesNano patented in many countries, provides a safe handling of even pyrophoric catalysts. While the

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Fig. 4.35: H-Cube Pro™ hydrogenation reactor with Autosampler, Phoenix Flow Reactor™ and Gas Module™ (a); Ice Cube™ Reactor (b).

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H-Cube Series reactors are mainly used for hydrogenation reactions, they are all capable of performing heterogeneous reactions in flow manner on different scales. ThalesNano with its widest product portfolio on the market focuses on extending the parameter scale up to 450 °C both for homogeneous and heterogeneous reactions (Phoenix Flow Reactor™), and up to 100 bar allowing the use of different gases and maintaining the automation of all the reactors. The portfolio has been extended with the introduction of the IceCube™ reactor in 2013 allowing to conduct low temperature reactions such as diazotation, Swern oxidation and other type of multistep, homogeneous reactions in one reactor system, the modular setting up allows chemists to perform ozonolysis with the small footprint, highly efficient ozone generator, the Ozone Module™. Although all of these systems are extensively used in academia for both research and educational purposes, ThalesNano has recently launched a flow system exclusively for universities. With this new device, the H-Cube Mini™ reactor, universities will have access to an affordable instrument to perform general flow reactions – also hydrogenation – using the built in hydrogenation generator cell, and the catalyst filled cartridges (CatCart® ). From this point all universities can afford to investigate the benefits of flow chemistry and to teach a technique, which is used every day in the industry. ThalesNano is very proud of the more than 200 publications that have been published by satisfied users of instruments and its own chemistry team within less than 6 years. With the continuous development of flow reactors hopefully this number soon reaches 1000. Further information is available on the homepage: http://www.thalesnano.com

Sealed catalyst column O

O O

In-situ hydrogen production

N H Fig. 4.36: ThalesNano’s newest hydrogenation reactor, the H-Cube Mini™.

O N

130 | 4 Technology overview/Overview of the devices Vapourtec (United Kingdom) Vapourtec offers two modular systems for flow chemistry applications. The R Series architecture enables modules to be combined to create the exact system required. Pumping modules, reactors and collection equipment are simply added as the need arises, giving a tailored system of proven high performance components, all in a compact easy-to-use system.

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Fig. 4.37: (a) R Series reactor block with 4 reactor places and with pump module. (b) E Series reactor block with 2 reactor places and V3 pumps.

Vapourtec offers a range of options for feeding reagents into the reaction. Combining two pumping modules can give up to four reagent channels. All pumping modules use a unique continuous automatic monitoring system to monitor performance of pumps to ensure accurate reporting of flow rates and shutdown safely in the event of a leak or blockage. Pumps for strong acidic liquids or light suspensions are also available. The R Series system allows separate temperature control of up to four reactors. These reactors can be combined for multistep synthesis or used to allow increased total reactor volume, for higher throughput or longer residence times. The available reactors are: – Standard PFA coiled tube reactor (Ambient to 150 °C) – High temperature coiled tube reactor (Ambient to 250 °C) – Cooled coil reactor (Ambient to −70 °C) – Standard column reactor (Ambient to 150 °C) – Cooled column reactor (Ambient to −40 °C) – Cu/Ag/Zn tube reactors for catalyzed reactions – Gas-liquid tube-in-tube reactor

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Vapourtec offers further options for expanding the R Series: additional pump channels, Autosampler, Fraction Collector can be purchased as required. An optional Flow Commander™ control software and touch screen is also available. The new E-Series system continues that innovative trend, combining the R-Series forced convection reactor heating system with the robust and easy to use V3 pump design, making simple flow chemistry accessible to a broader range of users, and with a much reduced learning curve. The E-series instruments come with a maximum of three reagent pump and two reactor positions. The two reaction steps are separately temperature controllable. Using the same extensive set of reactors that are available for the high-end Vapourtec R-Series system, the E-Series offers the flexibility to take on a wide range of applications. All models come with useful chemistry tools such as: – Solvent Vapor Pressure Calculator – Arrhenius Reaction Rate Calculator – Residence time calculator – Dispersion and residence time distribution tool

Corning (USA) Made of specialty glass, the material of choice for most chemistries, Corning’s reactors are compatible with a wide variety of chemicals. Corning’s technology integrates mass and heat transfer within each glass fluidic module and maintains precise temperature control at all times. This results in heat exchange performance 10 times that of non-integrated, metallic mixers as well as superior mixing qualities. Glass fluidic modules are combined into specially engineered reactors that can manage several unit operations including feed, pre-mix, reaction, neutralization, and quench. Corning’s Advanced-Flow™ glass reactors feature a variety of process controls at your demand. And, Corning’s Advanced-Flow glass reactors are highly corrosion resistant, practically eliminating clogs and damage seen in older metal technology. Corning’s Advanced-Flow™ glass reactors can be optimized for a specific chemical reaction or portfolio of chemical reactions, some of which have not previously been possible. The fluidic modules in Corning’s reactors are chemically compatible with a wide range of chemicals and solvents over a wide spectrum of temperatures (−60 °C up to 230 °C) and pressures up to 18 bar. Different designs can be made to accommodate multiphase systems that can be sequentially assembled into an engineered reactor, providing mixing of various reactants with appropriate residence times. Reactions that have already benefited from Corning’s Advanced-Flow glass reactors include nitration, oxidation, reduction, coupling, rearrangement, amidation, bromination, and hydrogenation, among others. The technology has also proven effective in single- or multistep processes, including pre-mixing, quenching, and so on. It can be used in mono- or multiphase environ-

132 | 4 Technology overview/Overview of the devices

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Fig. 4.38: (a) Corning® chip reactor for enhanced mixing of components. (b) Modular set-up of Corning® reactors for large-scale production.

ments, such as miscible liquid feeds, nonmiscible liquid feeds (emulsion), liquid and gas feeds, gas release, slurry, and precipitates. Corning’s Advanced-Flow™ glass reactors are designed for manufacturing, not just testing and experimentation. Corning’s modular approach to chemical processing gives customers the flexibility they need to scale up or reduce production quickly and easily. Customers can increase reactor throughput while maintaining performance and operating condition consistency. Corning Advanced-Flow reactors can be integrated into existing chemical processing infrastructures and designed upon request to ATEX and GMP standards. Corning’s reactors can be easily incorporated into industrial systems via standard connectors, helping customers migrate to Corning’s technology with little or no downtime.

Syrris (UK) Syrris is the longest established provider of laboratory scale flow chemistry systems. The current Asia product range is its fourth generation of equipment specifically designed for flow chemistry. Previous flow chemistry systems include Africa (commercialized in 2004) and FRX (commercialized in 2006). The Asia product range, winner of the R&D100 award, features a variety of modules that can be used in stand-alone mode or arranged in any desired system to enable the widest variety of chemical processes. All wetted parts are made from either glass or Teflon, therefore offering maximum chemical compatibility. Each module can be

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controlled either manually or in an automated way using a computer. Key modules of the Asia range include: – The Asia Pump: the first pump designed specifically for flow chemistry. Its patented pumping system enables smooth pumping of solvents or reagents and can be used with low boiling point solvents such as dichloromethane, ether, and so on. – The Asia Flow Liquid-Liquid Extractor (FLLEX): this popular module is the flow equivalent of a separation funnel and is used for continuous work-up or extraction. By using an advanced membrane technology, the FLLEX can separate two phase mixtures in-line [55]. – Microreactors: the Asia range enable the use of all types of microreactors: glass chips, fluoropolymer or metal tube reactors and glass columns. The wide range of volumes and materials gives much needed flexibility to the flow chemist. – The Asia Sampler and Dilutor: this device is used for the sampling in-line of a flow experiment, then dilution and transfer to an analytical device (HPLC, GC-MS, etc. . . .). The modularity and wide range of available modules enable the system to be used for different applications such as organic synthesis [56], process optimization [57], nanoparticle synthesis [58], enzymatic catalysis, biofuel synthesis, transfer of mi-

Asia 330 system configuration

Pressurized input store Enables the use of air sensitive reagents and eliminates bubble formation and cavitation

Chip climate controller Heat or cool glass microreactors from –15°C to +150°C

FLLEX The flow chemistry equivalent of a separatory funnel

Pressure controller Accurate pressure control up to 20 bar (300psi)

Reagent injector 2 Extremely chemically resistant injection valves with sample loops

Automated Collector Allows collection of multiple reactions

Sampler and dilutor Automated sample extraction, dilution and transfer to an analytical system e.g. LCMS or UPLC

Asia manager software Easy to use for total 'walk-away' control

Syringe Pump 2 Extremely chemically resistant continuous flow pumps. Flow rate from 1μl to 10ml/min.

Fig. 4.39: The Asia 330 System Configuration.

Heater (Tube reactor adaptor) Ability to heat solid phase reactors, tube reactors and glass microreactors up to 250°C

134 | 4 Technology overview/Overview of the devices crowave reactions [59], and so on. Asia systems can be modified and expanded as the requirements evolve and new modules (for example: electrochemistry in flow) can be added afterwards with full compatibility.

Invenios (USA) Over the years, Invenios (former mikroglas chemtech GmbH) has developed different processes to microstructure glass material. Glass is an excellent material for components in microprocess technology because of its high chemical resistance against corrosive and hazardous chemicals and its optical properties which qualifies it for a wide range of optical analysis purposes. Invenios has developed a wide range of different mixer and reactor designs to carry out liquid-liquid and gas-liquid reactions under controlled flow and temperature conditions. Our main mixing principles are multilamination and split&recombine mixers. For droplet formation, different T- and Y-mixer designs are available as well. These mixers work in flow ranges starting from μl/min up to several ml/min total flow. The standard pressure limit is 3 bar and the working temperature is up to 120 °C. For higher temperature and pressure applications, specially designed modules are available. To extend the residence time it is possible to add a coiled tube to the mixer or to integrate additional volume by an extended residence time channel directly into the glass chip. For temperature control it is possible to integrate electric heaters (heating only), Peltier elements (active cooling and heating), or liquid heat exchangers into the frame or directly the microfluidic component. With the liquid heat exchanger and a proper

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Fig. 4.40: (a) Interdigital mixer for multilamination, (b) MikroSyn Initio for liquid-liquid reactions.

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insulation of the reactor set-up it is even possible to reach deep temperatures below −40 °C. Besides the mixing/reaction step it becomes more and more important to also separate solvents or by-products from the main feed so that one can carry out multistep reactions without switching from continuous to batch processing. Here, Invenios developed different modules like settler in different scales, capillary separators and modules with integrated membranes. Furthermore, we developed together with the Fraunhofer IST a process to modify the surface properties locally by a plasma process and make the channel hydrophobic. To complete the product range Invenios offers different laboratory systems, starting from compact set-ups just to run a single mixer (mikroSyn Initio) up to fully automated machines for multistep reactions (mikroSyn Flex). These systems come fully equipped with different pumps (rotary piston pumps, micro gear pumps, syringe pumps and HPLC pumps), sensors (temperature, pressure, optical and chemical), valves and other safety devices. The automation can be realized by different systems like Siemens Simatic or National Instruments LabView. For further information about the different fields of application please also see the following literature: [28, 60–62]; or visit the company’s homepage: www.invenios. com.

Microinnova (Austria) MICROINNOVA provides plants from laboratory scale through to pilot scale for continuous-flow chemistry technology. The Flow Miniplant bridges the gap between process developments starting with a benchtop-system and manufacturing with a broad area of applications. The scope of application ranges from easy processes to difficult areas (complex chemical reactions, high complexity of the process, new process windows with high temperature and high pressure). Due to the modular design of the MICROINNOVA Flow Miniplant, a maximum flexibility is ensured. Ready to use modules of various kinds (e.g., feed module, reaction module, product module) for different requirements can be put together in a short time without great effort for the desired process. The module exchange can be easily done by the lab chemist as the system is very easy to use. A set-up for a one step reaction is shown in Figure 4.41. For more step reactions, more modules can be combined. Feed module: The central part of the feed module is the annular gear pump. The flow rate of the module is 0.5−10 l/h. A filter protects the pump from particles. A burst disk protects the plant from overpressure. The flow is set via a mass flow meter by controlling the pump speed. The pressure is measured and the system will be stopped by the automation once the maximal pressure is reached not to cause the opening of the burst disc.

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Fig. 4.41: Example installation with 2 Feed Modules, 1 Reaction Module and 1 Product Module.

Reaction module: The reaction takes place in a microreactor. The reactor consists of ten glass plates submerged in a heating/cooling bath. The first two plates function as heat exchangers; they bring the two reactants to the required reaction temperature. The third plate contains a mixing structure for intensive mixing of the two reactants. The remaining plates are plug flow reactors that provide the residence time for the reaction. The number of the used plates can be chosen freely. Between the plates, temperature measurings are installed. Product module: It contains a tube-in-tube heat exchanger where the product is cooled down or warmed up to room temperature. The flow of the heating/cooling medium is set by a manual control valve. After the heat exchanger, the temperature and the pressure are measured. The pressure is set by a manual pressure regulator. A manual three-way valve enables the user to switch between two outlets, whereas one is usually used to take samples. Automation system: The automation hardware is partly located on the modules. Each module carries the necessary input modules and signal converters. The main control is done on the personal computer by a control software, which allows the full control of the connected modules, logging of the measured values and reporting. For a more demanding purpose, more options are possible. For further information, please visit the homepage: www.microinnova.com.

Study questions 4.1. What are the main parts of a continuous-flow reactor set-up? 4.2. What should be taken into account when assembling a continuous-flow rector set-up for a specific synthetic process? 4.3. You plan to run a reaction similar to the one on Figure 4.16. Components A and B (both 0.1 M) are pumped with 1 ml/min into the reactor. How long is the residence time in the 8 ml loop? 4.4. You decided to use an excess of the B reactant. For this, you increase the flow rate of B to 1.5 ml/min. How long will the residence time be now? 4.5. Unfortunately, you had to realize that with the increased volume flow, the residence time is too short to complete the reaction. You would like to stick to the excess amount of B, but you have to find another solution. What are the possibilities?

Bibliography

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You make another attempt to perform the same reaction, but this time you also would like to quench it. The initial flow rates of A and B are 1 ml/min, (both are 0.1 M). Your quench loop is 10 ml and you would like to have a reaction time of 2 minutes in this loop. What concentration of your quench solution should have, if you want to apply 3 equivalents compared to A?

Further readings Books: – Hessel, V., Schouten, J. C., Renken, A., Wang, Y., Yoshida, J.I., Handbook of Micro Reactors. Chemistry and Engineering, Weily-VCH: Weinheim, 2008. – Kiwi-Minsker, L., Renken, A., Hessel, V., Structured Catalytic Microreactors and Catalysts. 2007. – Wirth, T. (Ed). Microreactors in Organic Synthesis and Catalysis. Wiley-VCH: Weinheim, 2008. – Hessel, V., Renken, A., Schouten, J. C., Yoshida, J. I., (Eds.), Micro Process Engineering: A Comprehensive Handbook. Wiley-VCH: Weinheim, 2009. – Yoshida, J. I., Flash Chemistry: Fast Organic Synthesis in Microsystems. John Wiley & Sons, 2008. – Luis, S. V., Garcia-Verdugo, E. (Eds.), Chemical Reactions and Processes under Flow Conditions. RSC Publishing: Cambridge, 2010. – de la Hoz, A., Loupy, A., Microwaves in Organic Synthesis. 2 Volume Set, John Wiley & Sons, 2013. Databases: – SciFinder – https://www.cas.org/products/scifinder – Reaxys – http://www.elsevier.com/online-tools/reaxys – Search for key words & phrases: microreactor, continuous-flow synthesis, flow reactor, continuous processing. Dedicated journals: – Journal of Flow Chemistry – http://www.jflowchemistry.com – Beilstein Journal of Organic Synthesis (Thematic Series: Chemistry in Flow Systems) – http:// www.beilstein-institut.de/en/journals

Bibliography [1] [2] [3] [4] [5] [6] [7] [8]

Karassik, I. J., Messina, J. P., Cooper, P., Heald, C. C., Pump Handbook. 4th edn. McGraw-Hill Education, 2007. http://www.advanced-energy.com/upload/File/White_Papers/SL--MFCFUND-270-01.pdf. [Online] [Accessed: 2014/27/1.] http://www.documentation.emersonprocess.com/groups/public/documents/bulletins/ debul2008x012.pdf. [Online] [Accessed: 2014/27/1.] Paul, E. L., Atiemo-Obeng, V., Kresta, S. M., (Eds.), Handbook of Industrial Mixing: Science and Practice. John Wiley & Sons, Hoboken 2004. Löbbecke, S., Ferstl, W., Pani’c, S., Türcke, T., Concepts for modularization and automation of microreaction technology. Chem. Eng. Technol., 28 (2005) 484–493. http://www.recemat.nl/eng/. [Online] [Accessed: 2014/27/1.] Parrott, A. J., Bourne, R. A., Akien, G. R., Irvine, D. J., Poliakoff, M., Self-Optimizing Continuous Reactions in Supercritical Carbon Dioxide. Angew. Chem. Int. Edn 50 (2011) 3788–3792. Löwe, H., Axinte, R. D., Breuch, D., Hofmann, C., Petersen, J. H., Pommersheim, R., Wang, A., Flow chemistry: Imidazole-based ionic liquid syntheses in micro-scale. Chemical Engineering Journal, 163 (2010) 429–437.

138 | 4 Technology overview/Overview of the devices [9]

[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

[22]

[23]

[24]

[25] [26] [27]

[28] [29] [30]

Breuch, D., Löwe, H., Heterogenously Catalyzed One-step Alkylation and Carboxylation of N-Methylimidazole with Dimethylcarbonate in Continuous Flow. Green Processing and Synthesis, 1 (2012) 261–267. (http://www.sulzer.com/br/Products-and-Services/Agitators--Mixers-and-Dispensers/StaticMixers/Heat-Exchangers-and-Reactors/SMR. [Online] [Accessed: 2014/27/1.] Fogler, H. S., Elements of Chemical Reaction Engineering. 4th edn. Prentice Hall, 2005. http://thalesnano.com/application-note. [Online] [Accessed: 2014/27/1.] Ehrfehld, W., Hessel, V., Löwe, H., Microreactors: New Technology for Modern Chemistry. Weinheim: Wiley-VCH, 2000. Wiles, C., Watts, P., Micro Reaction Technology in Organic Synthesis. Boca Ratton: CRC PressTaylor & Francis, 2011. Liu, W., Multi-scale catalyst design. Chemical Engineering Science, 62 (2007) 3502–3512. Elvers, B., Hawkins, S., Schultz, G., Principles of Chemical Reaction Engineering and Plant Design; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH, Vol. B4, 1992. Datsevich, L. B., Conventional Three-Phase Fixed-Bed Technologies. Analysis and Critique. New York: Springer, 2012. www.sigmaaldrich.com/chemistry/drug-discovery/product-highlights/palladium-catalysts. html. [Online] [Accessed: 2014/24/1.] Grirrane, A., Corma, A., García, H., Gold-Catalyzed Synthesis of Aromatic Azo Compounds from Anilines and Nitroaromatics. Science, 322 (2008) 1661–1664. Herzing, A. A., Kiely, C. J., Carley, A. F., Landon, P., Hutchings G. J., Identification of Active Gold Nanoclusters on Iron Oxide Supports for CO Oxidation. Science, 321 (2008) 1331–1335. Petersen, T. P., Polyzos, A., O’Brien, M., Ulven, T., Baxendale, I. R., Ley S. V., The OxygenMediated Synthesis of 1,3-Butadiynes in Continuous Flow: Using Teflon AF-2400 to Effect Gas/Liquid Contact. ChemSusChem, 5 (2012) 274–277. Cranwell, P. B., O’Brien, M., Browne, D. L., Koos, P., Polyzos, A., Peña-López, M., Ley, S. V., Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr pyrrole formation and gas concentration measurement by inline flow titration. Org. Biomol. Chem., 10 (2012) 5774–5779. De Loos, S. R. A., Van Der Schaaf, J., Tiggelaar, R. M., Nijhuis, T. A., De Croon, M. H. J. M., Schouten J. C., Gas–liquid dynamics at low Reynolds numbers in pillared rectangular micro channels. Microfluid Nanofluid, 9 (2010) 131–144. Gong, X., Miller, P. W., Gee, A. D., Long, N. J., de Mello, A. J., Vilar, R., Gas–Liquid Segmented Flow Microfluidics for Screening Pd-Catalyzed Carbonylation Reactions. Chem. Eur., J., 18 (2012) 2768–2772. Ahmed-Omera, B., Barrow, D., Wirth, T., Biphasic reactions in microreactors. http://www.4mnet.org/files/papers/4M2008/01-02/01-02.PDF. [Online] [Accessed: 2014/24/1.] http://www.microinnova.com/microreactorpdf/Falling_Film_Microreactor.pdf. [Online] [Accessed: 2014/24/1.] Chambers, R. D., Fox, M. A., Holling, D., Nakano, T., Okazoeb, T., Sandford, G., Elemental fluorine. Part 16. Versatile thin-film gas–liquid multi-channel microreactors for effective scale-out. Lab Chip., 5 (2005) 191–198. Coyle, E. E., Oelgemöller, M., Micro-photochemistry: photochemistry in microstructured reactors. The new photochemistry of the future? Photochem Photobiol Sci., 7 (2008) 1313–1322. http://www.sairem.com/continuous-flow-reactors-61.html. [Online] [Accessed: 2014/24/1.] Morschhäuser, R., Krull, M., Kayser, C., Boberski, C., Bierbaum, R., Püschner, P. A., Glasnov, T. N., Kappe, C. O., Microwave-assisted continuous flow synthesis on industrial scale. Green Process Synth, 1 (2012) 281–290.

Bibliography

| 139

[31] Knowles J. P., Elliott L. D. and Booker-Milburn K. I., Flow photochemistry: Old light through new windows. Beilstein J. Org. Chem., 8 (2012) 2025–2052. [32] Lévesque F., Seeberger P. H., Continuous Flow Synthesis of the Anti-Malaria Drug Artemisinin, Angew. Chem., 51 (2012) 1706–1709. [33] http://www.isco.com/WebProductFiles/Applications/105/Application_Notes/Supercritical_ Fluids%20in_Reaction_Engineering.pdf. [Online] [Accessed: 2014/27/1.] [34] http://www.supercriticalfluids.com/products/supercritical-fluid-extraction-products/sft-10. [Online] [Accessed: 2014/27/1.] [35] Amandi, R., Hyde, J. R., Ross, S. K., Lotz, T. J., Poliakoff, M., Continuous reactions in supercritical fluids; a cleaner, more selective synthesis of thymol in supercritical CO2. Green Chem., 7 (2005) 288–293. [36] Van den Broek, S. B. A., Becker, R., Kössl, F., Delville, M. M., Nieuwland, P. J., Koch, K., & Rutjes, F. P., Prilezhaev Dihydroxylation of Olefins in a Continuous Flow Process. ChemSusChem, 5 (2011) 289–292. [37] Van den Broek, S. B. A., Leliveld, J. R., Becker, R., Delville, M. M., Nieuwland, P. J., Koch, K., Rutjes F. P., Continuous flow production of thermally unstable intermediates in a microreactor with line IR-analysis:controlled Vilsmeier–Haack formylation of electron-rich arenes. Org. Process Res. Dev., 16 (2012) 934–938. [38] Van Gool, J. J. F., van den Broek, S-. A. M. W., Ripken, R. M., Nieuwland, P. J., Koch, K., Rutjes, F. P. J. T., Highly Controlled Gas/Liquid Processes in a Continuous Lab-Scale Device. Chem. Eng. Technol. 36 (2013) 1042–1046. [39] Carter, C. F., Lange, H., Ley, S. V., Baxendale, I. R., Wittkamp, B., Goode J. G., Gaunt, N. L., ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing. Org. Process Res. Dev., 14 (2010) 393–404. [40] Aida, S., Terao, K., Nishiyama, Y., Kakiuchi, K., Oelgemöller, M., Microflow photochemistry – a reactor comparison study using the photochemical synthesis of terebic acid as a model reaction. Tetrahedron Lett., 53 (2012) 5578–5581. [41] Bagley, M. C., Fusillo, V., Jenkins, R. L., Lubinu, M. C., Mason, C., Continuous flow processing from microreactors to mesoscale: the Bohlmann–Rahtz cyclodehydration reaction. Org. Biomol. Chem., 8 (2010) 2245–2251. [42] Warren, R. J. D., Hodgkinson, J. T., Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues. Org. Biomol. Chem., 9 (2011) 57–61. [43] Battilocchio, C., Baxendale, I. R., Biava, M., Kitching, M. O., Ley, S. V., A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid. Org. Proc. Res. Dev., 16 (2012) 798–810. [44] Pieber, B., Martinez, S. T., Cantillo, D., Kappe, C. O., In Situ Generation of Diimide from Hydrazine and Oxygen: Continuous-Flow Transfer Hydrogenation of Olefins. Angew. Chem. Int. Edn., 52 (2013) 10241. [45] Browne, D. L., Baxendale, I. R., Ley, S. V., Piecing together the puzzle: understanding a mild, metal free reduction method for the large scale synthesis of hydrazines. Tetrahedron, 67 (2011) 10296. [46] O’Brien, M., Taylor, N., Polyzos, A. S., Baxendale, I. R., Ley, S. V., Hydrogenation in flow: Homogeneous and heterogeneous catalysis using Teflon AF-2400 to effect gas–liquid contact at elevated pressure. Chem. Sci., 2 (2011) 1250–1257. [47] Mastronardi, F., Gutmann, B., Kappe, C. O., Continuous Flow Generation and Reactions of Anhydrous Diazomethane Using a Teflon AF-2400 Tube-in-Tube Reactor. Org. Proc. Res. Dev., 15 (2013) 5590–5593. [48] Thompson, C. M., Poole, J. L., Cross, J. L., Akritopoulou-Zanze, I., Djuric, S. W., Small Molecule Library Synthesis Using Segmented Flow. Molecules, 16 (2011) 9161–9177.

140 | 4 Technology overview/Overview of the devices [49] Guetzoyan, L., Nikbin, N., Baxendale, I. R., Ley S. V., Flow chemistry synthesis of zolpidem, alpidem and other GABAA agonists and their biological evaluation through the use of in-line frontal affinity chromatography. Chem. Sci., 4 (2013) 764–769. [50] Pastre, J. C., Browne, D. L., O’Brien, M., Ley, S. V., Scaling Up of Continuous Flow Processes with Gases Using a Tube-in-Tube Reactor: Inline Titrations and Fanetizole Synthesis with Ammonia. Org. Process Res. Dev., 17 (2013) 1183–1191. [51] Newby, J. A., Huck, L., Blaylock, D. W., Witt, P. M., Ley, S. V., Browne, D. L., Investigation of a Lithium–Halogen Exchange Flow Process for the Preparation of Boronates by Using a CryoFlow Reactor. Chem. Eur., J., 20 (2014) 263–271. [52] Mehenni, H., Sinatra, L., Mahfouz, R., Katsiev, K., Bakr, O. M., Rapid continuous flow synthesis of high-quality silver nanocubes and nanospheres. RSC Adv., 3 (2013) 22397–22403. [53] Pan, J., El-Ballouli, A. O., Rollny, L., Voznyy, O., Burlakov, V. M., Goriely, A., Sargent, E. H., Bakr, O. M., Automated synthesis of photovoltaic-quality colloidal quantum dots using separate nucleation and growth stages. ACS Nano., 7 (2013) 10158–10166. [54] Patwardhan, S. V., Perry, C. C., Synthesis of enzyme and quantum dot in silica by combining continuous flow and bioinspired routes. Silicon, 2 (2010) 33–39. [55] Tricotet, T. O’Shea, D. F., Automated Generation and Reactions of 3-Hydroxymethylindoles in Continuous-Flow Microreactors. Chem. Eur., J., 16 (2010) 6678–6686. [56] Pagano, N., Herath, A., Cosford, N. D. P., An Automated Process for a Sequential Heterocycle/Multicomponent Reaction: Multistep Continuous Flow Synthesis of 5-(Thiazol-2-yl)3,4-Dihydropyrimidin-2(1H)-ones. J. Flow Chem., 1 (2011) 28–31. [57] Grant, D., Dahl, R., Cosford N. D. P., Rapid Multistep Synthesis of 1,2,4-Oxadiazoles in a Single Continuous Microreactor Sequence. Org. Chem., 73 (2008) 7219–7223. [58] Pacławski, K., Streszewski, B., Jaworski, W., Luty-Błocho, M., Fitzner, K., Gold nanoparticles formation via gold (III) chloride complex ions reduction with glucose in the batch and in the flow microreactor systems. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 413 (2012) 208–215. [59] Reichart, B., Tekautz, G., & Kappe, C. O., Continuous Flow Synthesis of n-Alkyl Chlorides in a High-Temperature Microreactor Environment. Organic Process Research & Development, 17 (2012) 152–157. [60] Hübner, S., Bentrup, U., Budde, U., Lovis, K., Dietrich, T., Freitag, A., Küpper, L., Jähnisch, K., An Ozonolysis-Reduction Sequence for the Synthesis of Pharmaceutical Intermediates in Microstructured Devices. Org. Proc. Res. Dev. 13 (2009) 952–996. [61] Huebschmann, S., Kralisch, D., Loewe, H., Breuch, D., Petersen, J. H., Dietrich, T., Scholz, R., Decision support towards agile eco-design of microreaction processes by accompanying (simplified) life cycle assessment. Green Chemistry, 13 (2011) 1694–1707. [62] Fukuyama, T., Hino, Y., Kamata, N., Ryu, I., Quick Execution of [2+2] Type Photochemical Cycloaddition Reaction by Continuous Flow System Using a Glass-made Microreactor. Chemistry Letters, 33 (2004) 1430–1431.

Patrick Plouffe, Arturo Macchi, and Dominique M. Roberge

5 From batch to continuous chemical synthesis – a toolbox approach

5.1 Chemical process development and scale-up challenges 5.1.1 Batch synthesis: Current profile of the pharmaceutical and fine-chemical industry In the pharmaceutical and fine-chemical industry, new molecules are continuously discovered, developed and investigated. Malet-Sanz and Susanne [1] describe that pharmacokinetics development at Pfizer’s Medicinal Chemistry Department initially requires only a few milligrams of newly discovered drugs, which are quickly scaled to hundreds of grams for further toxicology studies. Afterwards, synthesis may progress to small-scale production; Lonza Process Development [2–4] produces kilograms of material for pre-clinical trials and up to tons for the following clinical trials phases II and III. As depicted above, molecules will be synthesized in increasing amounts when progressing in the development chain. Such scale-up is nontrivial as it covers nine orders of magnitudes from milligrams to tons. This is problematic since heat generated/required scales to the power of three with the equipment’s characteristic dimension (i.e., proportional to the volume) whereas heat transferred scales only to the power of two (i.e., proportional to the area). Temperature is one of the main variables governing reaction kinetics and selectivity, and requires proper control for quality assurance. To compensate or avoid potential hazards, systems can be diluted by a solvent such to dampen the temperature changes. Although this may solve heat transfer problems, it reduces reactant concentration, slowing the reaction rate, increases the amount of separation steps and generates more waste [5]. In addition to very scalable processes, the industry needs versatile equipment that can be used for multiple and widely diverse reactions. While manufacturing lines have dedicated reactors in some cases, the research and development of new molecules is done in a different environment; equipment is set-up for a particular synthesis for weeks before being cleaned and prepared for an alternate synthesis. Only a few, or even none, of the hundreds of candidate molecules may transfer to a commercial manufacturing process. Ultimately, if a drug progresses through all the different screening tests and reaches commercialization, it will be necessary to demonstrate that the large scale process performs similarly, offering at least the same product quality as the clinical

142 | 5 From batch to continuous chemical synthesis – a toolbox approach trials. This can be particularly difficult if the molecular development was performed in batch reactors whereas the commercial process is to operate in a continuous manner.

5.1.2 Flow chemistry and microreactor technology: a viable alternative? The production needs of the industry have been addressed for many years by using batch processes. Jacketed beakers, stirring platforms, extraction bulbs and rotavaps are part of the usual equipment of batch chemistry. They are easily assembled and cleaned and their performances have long been established. However, batch processes present flaws that are incompatible with process intensification and scale-up [4, 6]. The Reynolds Number Osborne Reynolds investigated in 1883 the resistance to flow in a pipe [47]. He observed two distinct behaviors in the relation between pressure drop and flow rate and linked the transition with a dimensionless number that would later be named after him:

Re =

𝜌𝑢𝐷 𝜇

A flow is considered laminar when Re < 2300, turbulent when Re > 4000 and transitional in between. The difference in flow regime has a significant impact on the fluid mechanics of the system and is important for fields as different as geology, meteorology, chemistry, and aeronautics.

To avoid potential dilution and scale-up problems during process development, it is desirable to use continuous processes from the early molecule discovery. This is not without challenges however. Consider a typical 100 kg production campaign extending over four weeks. Under normal working conditions, this represents a production rate of around 10 g/min. Using a standard 1/8󸀠󸀠 tube as the reactor, the Reynolds number will be around 150 (for water at ambient conditions), which is well into the laminar flow regime with diffusion-dominated mixing, mass transfer and heat transfer rates. These modes of transport are relatively slow and undesirable as they limit the control over the mixing of reactants in the channel, reaction speed and selectivity. For a given flow rate, reducing the diameter of a tube increases the Reynolds number, reduces diffusional distances and increases its specific heat transfer area (areato-volume ratio). For a diameter smaller than 1 mm, it increases above 103 m2 /m3 , allowing high heat transfer rates and tight temperature control. Reactors with internal channels of these dimensions are referred to as microreactors and have received increased attention from both academia and industry due to their capacity for process intensification [7–11]. In a tradeoff for better transport properties, the pressure drop through small channels is much higher. For a given flow rate, it may thus not be practical to reduce the reactor channel dimensions to reach turbulent flow and an alternative approach must be used to further increase transfer rates.

5.1 Chemical process development and scale-up challenges |

143

Enhancement of advective over diffusional transport of heat and mass can be achieved using various techniques. It can be challenging to select the best approach, but fortunately they all aim at a similar objective: change the velocity vector field both in magnitude and direction in order to generate secondary flow patterns, stable or unstable, which will create off-stream movements of mass and heat within a channel, resulting in a system that behaves closer to a transitional or turbulent flow rather than laminar [12]. Mixing enhancement techniques are divided into passive and active methods [13]. Passive methods utilize part of the flow energy from the pressure provided by an upstream pump. Flow multilamination is a technique mostly used in laminar flow to greatly reduce the diffusion distance of incoming streams where the dimension of the microstucture dictates the width of the lamellae [14]. This approach can be enhanced by a focusing technique which further stretches the lamellae [15]. For advective methods, flow through curved channels is among the simplest of these techniques, which can generate vortices and droplet/bubble recirculation in multiphase systems [16–20]. Other techniques include splits and recombine, obstructed, re-entering, contracted or packed flow, irregular or rough wall surface, recirculation and colliding jets [21]. Active methods function with an external source of energy. An example is the impeller of a continuous stirrer tank reactor (CSTR) that is driven by an external engine. In mini and microchannels, actuators and pulsing walls work with mechanical energy, while ultrasounds, microwaves and piezoelectric systems have also shown mixing enhancement capabilities [22, 23]. Passive techniques are generally simpler and offer lower possibility of mechanical malfunction and are thus preferred at the smaller scales over miniaturization of active techniques.

5.1.3 Modularized process intensification – use the right tool at the right place Not all unit operations within a process may benefit from continuous flow or miniaturization. Each section of the process must be considered and optimized according to its specific operating conditions and requirements. This is known as modular flow technology and we believe it is the quintessence of process intensification. In order to successfully apply the principles of process intensification, two particular aspects (reaction kinetics/hazards and phases present) are analyzed. Section 5.2 addresses the impact of reaction kinetics/hazards on the selection of reactor volume. Fast reactions will benefit most from heat and mass transfer enhancements in microreactors. Reactions requiring tighter temperature control or with unstable intermediates may also benefit from miniaturization, whereas safe and slow reactions needing large volumes to reach the desired conversion may still be best per-

144 | 5 From batch to continuous chemical synthesis – a toolbox approach

Plate

Coil

CSTR

Fig. 5.1: The three fundamental reactor modules. The third image is to remind readers that a continuous-flow reactor is not a new technology [27].

formed in a batch reactor because of its low cost requirement (scales with volume to the power of 0.3 [24]). To help with this decision, reactions are categorized into Types A, B and C according to common process requirements based on their kinetics and hazards [3, 24–26]. Section 5.3 discusses the reacting phase(s) involved in the system. Single phase operation does not require the same mixing technology as multiphase (liquid-liquid, gas-liquid or solid-liquid) and the appropriate phases contacting strategy must be chosen accordingly. This reaction category/mixing methodology allows to quickly identify inadequate equipment and accelerates commissioning the optimal process configuration in an environment where projects are typically performed for only a few weeks. The outcome of this methodology can be summarized in a tool-box matrix depicted in Table 5.1. Three distinct types of continuous reactors, shown in Figure 5.1, are proposed to address these specific systems: namely Plates, Coils, and continuous stirred tanks (CSTR). Once the row and column of a given reactive system is known, the matrix indicates which reactor module is most appropriate for that combination. The key to this modular tool-box approach is to use continuous flow and/or miniaturization only where appropriate and to couple it with standard semi-batch or batch technology elsewhere.

5.1 Chemical process development and scale-up challenges |

145

Table 5.1: The Reaction/reactor matrix – preferred flow modules for a reaction type. Rates/Phases

Homogeneous

Liquid-Liquid

Gas-Liquid

Solid-Liquid

Type A

Plate SZ Plate SZ Coil

Type C

Static mixer Coil

Plate TG or HEART-shaped Plate TG or HEART-shaped Coil pressure Static mixer Coil pressure

CSTR

Type B

Plate LL or HEART-shaped Plate LL or HEART-shaped Coil pulsated Static mixer Coil pulsated

CSTRs

Coil pulsated

The Damköhler Numbers Gerhard Damköhler defined in 1936 criteria to describe the performance of general chemical processes [48]. His approach was based on the comparison of different characteristic “times” such as the time spent in the reactor (𝑡res ) and required to convert the reactants (𝑡rxn ). The performance would be satisfactory if the former was greater than the later.

𝑡res ∼

𝑉𝑅 𝑄

1 𝑘rxn 𝐶𝑚−1 𝑉 = 𝑘rxn 𝐶𝑚−1 𝑅 𝑄

& 𝑡rxn ∼ 𝑡res 𝑡rxn

𝐷𝑎I =

Different rates of mass and heat transfer can also be transformed into “times” and used to characterize a reactor. In his analysis, he described these performance criteria as simply “I”, “II”, “III” and “IV”, but they were later renamed in his honor.

After the proper reactor module is chosen, the required dimensions (hydraulic diameter of cross-sectional area and length) can be calculated based on transport and reaction kinetics. This is done using the different Damköhler numbers shown in Table 5.2: Damköhler numbers for reactor sizing and performance evaluation. Time or Rate Ratios

Damköhler Number

Residence time/time for consumption

𝐷𝑎I = 𝑘rxn 𝐶𝑚−1 ⋅

Time for mixing/time for consumption

𝐷𝑎II = 𝑡𝑚 ⋅ 𝑘rxn 𝐶𝑚−1 ≪ 1

Rate of heat generation/removal

𝐷𝑎IV = 𝑘rxn 𝐶𝑚 ⋅ Δ𝐻rxn ⋅

𝑉R 𝑄

≫1

4𝜌𝑑ℎ 𝑈Δ𝑇w

≪1

146 | 5 From batch to continuous chemical synthesis – a toolbox approach Table 5.2 [6], which are ratios of different timescales and must be greater or less than unity for satisfactory performance. These criteria depend on, amongst other, fluid velocity and channel size. Thus, it is possible to calculate the proper reactor size for a given design flow rate. If these numbers are kept constant between research steps, the performance of the system (conversion and selectivity) should be conserved. Kockmann et al. [4, 28] used these criteria to develop standard Plate and Coil sizes for the toolbox approach based on a single-channel strategy to avoid parallelization upon scale-up. At further stages of development, the specificity of the system and the approach chosen with Table 5.1 do not change. Thus, the tools previously selected don’t need to be rethought, but only scaled to the new production rates.

5.2 Reaction categories based on rate Whilst each reaction has unique features, it is possible to generalize categories that call for common process requirements. In this work, we define three reaction classes as follows.

5.2.1 Type A reactions Type A reactions are very fast, typically in the millisecond to second range, and their overall rate is mixing/mass transfer controlled. They often involve chlorine, bromide, or amine molecules, neutralizations and organometallic reactions [29]. For fast and exothermic reactions, the use of a microstuctured reactor is necessary for proper thermal control. Small dimensions yield fast and efficient mass and heat transfer necessary to avoid hot spots, undesired products and/or runaway reactions. The industrial microreactors are typically Plate type reactors [3, 26, 28, 30–36] in analogy to the plate type heat exchanger, where an order of magnitude greater heat transfer rate is expected compared to the shell-and-tube exchanger [37]. For Type A reactions, this means a reduction in reactor volume by a factor of 10 leading to an important increase in space-time-yield.

5.2.2 Type B reactions Type B reactions are slower than type A, but still fast enough to require significant heat removal and precise mixing control. They typically need between several seconds and minutes to complete. Reaction kinetics are likely rate-limiting and thus can be accelerated via greater temperatures, pressures and concentrations; although interphase mass transfer may become limiting in multiphase systems. Using conven-

5.3 Reacting phases

| 147

tional heat exchangers can result in large undesired temperature gradients, whereas proper selection of a microreactor may bring enhanced heat transfer performance with sufficient mass transfer at a reasonable pressure loss as demonstrated by Palmieri et al. [38] for a Hofmann rearrangement or by Renken et al. [39] for the synthesis of an ionic liquid. A Plate design with different channel widths can be used to accommodate the reaction evolution, that is, the multiscale approach. For example, a Plate with a small channel width is used at the beginning when heat generation is fast, followed by a gradual increase of the channel width and thus reactant residence time to accommodate slower reaction rates while maintaining the required rate of heat transfer for isothermal operation. Hence, with such a design, heat transfer is optimized while pressure drop is minimized and a reaction volume increase of several mL is achieved. In addition, the Plate can be combined with conventional Coils to gain volume of several liters.

5.2.3 Type C reactions Type C reactions are typically slow and require several minutes and sometimes hours for completion, but also involve potential hazards like autocatalysis or thermal accumulation. Continuous processing may bring clear safety advantages from the beneficial thermal control at any point in space. For such reactions, static mixers can be followed by residence time modules such as Coils that will provide the required reaction time in addition to thermal control. Examples of such reactions are the various protocols developed via microwave chemistry where flow can be exploited as a mean of scale-up [40]. Indeed, flow can mimic the high pressure and temperature conditions of a microwave unit.

5.3 Reacting phases Phase contacting pattern and intensity will impact the temperature and concentration profiles, pressure drop and ultimately reaction conversion and selectivity. Single- and multiphase systems require different mixing approaches and the selection of the right mixer is necessary to obtain optimal reactive conditions.

5.3.1 Single phase systems – mix-then-reside For single phase reactions, a Plate reactor with a “mix-then-reside” approach is usually appropriate [12, 41]. That is the presence of mixing elements at the entrance of the reactor where the streams meet in order to provide fast mixing along with high heat transfer rates. It is followed by an empty rectangular serpentine channel that pro-

148 | 5 From batch to continuous chemical synthesis – a toolbox approach

Fig. 5.2: Lonza FlowPlate® A6 module for mix-then-reside with SZ mixing elements. The SZ elements enable near plug flow conditions [12].

vides sufficient residence time for the completion of the reaction. Such an approach is depicted in Figure 5.2. For the slower reactions, a simple Coil is often sufficient for additional gain in volume. This approach maximizes transport phenomena at the initial point, where high concentration gradients and potentially high heat generation are present, but minimizes the pressure drop afterward, once the reaction rate has slowed down.

5.3.2 Liquid-liquid systems – mix-and-reside versus active mixing For multiphase reactions, a reactor with a “mix-and-reside” approach is preferable [33]. When the previous “mix-then-reside” type reactor is used, the dispersion generated in the mixing zone would likely coalesce upon entering the agitation-free residence time zone, reducing the interfacial area where mass transfer (and reaction) can occur and effectively bringing the reaction towards a halt. This is because the balance between break-up and coalescence of the dispersed phase is a function of the local agitation and energy dissipation rate [42] and, to maintain a dispersion throughout a reactor, it is necessary to continuously mix the phases (e.g., see Figure 5.3). There must also be enough volume to provide sufficient reaction time and reach the desired conversion. The Plate channels must then compromise between being small enough for fast and intense mixing (i.e., rendering the interphase mass transfer resistance negligible) and large enough to obtain sufficient residence time. For the slower multiphase reactions, the “mix-and-reside” approach is still appropriate, but not with Plate reactors. For such systems, the mass transfer rate needs not

5.3 Reacting phases | 149

Fig. 5.3: Corning® Advanced-Flow™ Reactor for mix-and-reside with HEART-shape mixing elements [29, 30].

Conductivity probes

Tracer

Oscillation

Liquid Out Fig. 5.4: A pulsating reactor from NiTech that provides a large gain in reaction volume [42].

to be intense, but rather sustained over a large volume to achieve conversion. Keeping with the passive mixing techniques, this can be completed by a Coil coupled with static mixing elements. However, at larger equipment scales, active mixing techniques might also be suitable. Because they are not linked with the flow rate, the mixing intensity of active methods is decoupled with the fluid residence time, making it possible to adjust these two parameters independently. A promising technology is to pulse the flow, which has been implemented in reactors by NiTech Solutions Ltd (see Fig-

150 | 5 From batch to continuous chemical synthesis – a toolbox approach ure 5.4, [43, 44]) or by AM Technology [45]. The pulsation changes the velocity and shear field in direction and magnitude, as with other mixing techniques, and generates a dispersion throughout the reacting volume.

5.3.3 Gas-liquid systems – use of pressure For gas-liquid reactions, harsher reaction conditions, particularly greater pressures, can be used in tandem with Plate or Coil reactors to improve performance. At elevated pressures, smaller bubbles can be generated resulting in greater interfacial area for mass transfer. Smaller bubbles also result in greater mass transfer coefficients due to reduced diffusional distances. This is particularly useful in the case of fast gasliquid reactions by minimizing the interphase mass transfer resistance. Furthermore, the partial pressure of the gaseous reactant also increases, resulting in a greater solubility, and thus, driving force for mass transfer. For slower gas-liquid reactions, it essentially accelerates the kinetics. In the most ideal case, the gas is pressurized and the mass transfer increases to an extent where the liquid phase saturates and the reaction is considered homogeneous.

5.3.4 Liquid-solid systems Reactions involving solids and precipitations usually cannot be reliably performed in small-scale channels and microreactors due to the risk of plugging. A CSTR is a pragmatic approach to overcome the problem associated with solids handling, but its mixed flow pattern has inherent disadvantages relative to the near plug flow pattern that can be achieved in the Coil and Plate reactors. For reaction orders above zero, the plug flow pattern will allow a greater conversion per unit volume due to a higher volume-averaged reactant concentration. The CSTR flow pattern is quite useful when the reaction is very fast and the selectivity is not negatively influenced by the mixed flow regime, such as for acid-base precipitations [46]. In other cases, pulsated flow may be a viable alternative, since its reciprocating nature reduces the chance of plugging in small channels while maintaining near plug flow conditions.

5.4 Summary Several reactions within the fine chemical and pharmaceutical industry are being conducted batch or semi batchwise and would potentially economically and environmentally benefit from continuous-flow and intensification via miniaturization. Moreover, process development and scale-up would be facilitated by the adoption of continuousflow reactors in the initial stages of molecule discovery and synthesis.

5.4 Summary

| 151

A methodology is introduced to select reactor type (Plate, Coil, or CSTR) and size based on the reaction kinetics/hazards and phases involved. Importantly, not all reactions benefit from continuous flow or miniaturization and thus process intensification should be implemented modularly as reactor geometry and operating conditions invariably affect transport-reaction kinetics interactions and their relative timescales (i.e., Damköhler numbers). Three different reaction classes are presented and categorized according to their process requirements. Type A reactions are mass and heat transfer limited and will greatly benefit from reactor miniaturization and intense energy dissipation. Type B reactions are slower but can be accelerated by more severe reactor operating conditions (e.g., elevated temperature, concentration, and pressure) and enhanced by moderate miniaturization and mixing while maintaining sufficient reactor volume. Hazardous type C reactions require close thermal control, which can be provided by continuous flow and volume reduction. High yields can be achieved for reactions involving miscible fluids through the combination of a shorter energy intensive region, followed by a longer residence time zone where the well-mixed fluids are allowed to react to completion. However, this approach is subject to significant limitations when applied to immiscible fluids as the phases can coalesce downstream of the mixer, reducing interphase mass transfer and slowing the reaction rate. In this case, balancing continuous energy dissipation and residence time via repeated mixing arrangements is the preferred approach. The dynamic nature of multiphase flow, coupling of heat and mass transfer, and incorporation of solids within these systems will be topics of increased interest to both industry and academia in the years ahead. Plate A generally rectangular channel is machined in a plate. The channel cross-sectional dimensions are in the micrometer or millimeter range and may include a passive mixing structure. Heat can be removed or added from the top and/or bottom of the plate using, for example, other adjacent plates in which a heat transfer fluid is circulated. Coil A coiled tube with diameters in the micrometer, millimeter or centimeter range and possibly equipped with internal static mixers. Heat can be removed or added by, for example, submerging the coil in a thermal bath. CSTR A continuously stirred tank reactor generally in the shape of a cylindrical vessel equipped with a magnetic stirrer or impeller blade that agitates the fluid in the reactor. A CSTR has fluid that continuously enters and exits its volume, otherwise the reactor is a semi-batch or batch agitated vessel.

152 | 5 From batch to continuous chemical synthesis – a toolbox approach

Study questions 5.1. A Plate in which the serpentine rectangular channel is 0.5 mm deep and 5 mm wide is used for a single phase reaction. The reaction is exothermic and heat is removed from both the top and bottom of the channel. (a) What is the heat transfer area per unit volume of this channel? (b) An alternate Plate with a serpentine channel that is 1 mm deep and 2 mm wide is proposed. Does this channel design provide a greater area-to-volume ratio due to its smaller width? Demonstrate your answer. 5.2. Water at 293 K and 1 atm is flowing through a straight circular channel at 10 ml/min. What is the largest channel diameter for the flow regime to be considered turbulent? 5.3. The 4th Damköhler number obtained for a given endothermic reaction is approximately four. What does this suggest and is this condition desirable?

Bibliography [1]

Malet-Sanz, L., Susanne, F., Continuous flow synthesis. A pharma perspective. J. Med. Chem. 55 (2012) 4062–4098. [2] Roberge, D. M., Zimmermann, B., Rainone, F., Gottsponer, M., Eyholzer, M., Kockmann, N., Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: Is the revolution underway?, Org. Process Res. Dev. 12 (2008) 905–910. [3] Roberge, D., Gottsponer, M., Eyholzer, M., Industrial design, scale-up, and use of microreactors, Chem. Today. 27 (2009) 8–11. [4] Kockmann, N., Gottsponer, M., Zimmermann, B., Roberge, D. M., Enabling continuous-flow chemistry in microstructured devices for pharmaceutical and fine-chemical production., Chemistry. 14 (2008) 7470–7477. [5] Mason, B. P., Price, K. E., Steinbacher, J. L., Bogdan, A. R., McQuade, D. T., Greener approaches to organic synthesis using microreactor technology., Chem. Rev. 107 (2007) 2300–2318. [6] Kockmann, N., Pressure Loss and Transfer Rates in Microstructured Devices with Chemical Reactions, Chem. Eng. Technol. 31 (2008) 1188–1195. [7] Dummann, G., Quittmann, U., Gröschel, L., Agar, D. W., Wörz, O., Morgenschweis, K., The capillary-microreactor: a new reactor concept for the intensification of heat and mass transfer in liquid–liquid reactions, Catal. Today. 79–80 (2003) 433–439. [8] Ducry, L., Roberge, D. M., Controlled autocatalytic nitration of phenol in a microreactor., Angew. Chem. Int. Ed. Engl. 44 (2005) 7972–7975. [9] Ghaini, A., Kashid, M. N. N., Agar, D. W. W., Effective interfacial area for mass transfer in the liquid–liquid slug flow capillary microreactors, Chem. Eng. Process. Process Intensif. 49 (2010) 358–366. [10] Kashid, M. N., Kiwi-Minsker, L., Microstructured Reactors for Multiphase Reactions: State of the Art, Ind. Eng. Chem. Res. 48 (2009) 6465–6485. [11] Hessel, V., Kralisch, D., Kockmann, N., Noël, T., Wang, Q., Novel process windows for enabling, accelerating, and uplifting flow chemistry., ChemSusChem. 6 (2013) 746–789. [12] Holvey, C. P., Roberge, D. M., Gottsponer, M., Kockmann, N., Macchi, A., Pressure drop and mixing in single phase microreactors: Simplified designs of micromixers, Chem. Eng. Process. Process Intensif. 50 (2011) 1069–1075.

Bibliography

|

153

[13] Steinke, M. E., Kandlikar, S. G., Review of single-phase heat transfer enhancement techniques for application in microchannels, minichannels and microdevices, Int. J. Heat Technol. 22 (2004) 3–11. [14] Hessel, V., Hardt, S., Löwe, H., Schönfeld, F., Laminar mixing in different interdigital micromixers: I. Experimental characterization, AIChE J. 49 (2003) 566–577. [15] Hessel, V., Dietrich, T., Freitag, A., Hardt, S., Hofmann, C., Löwe, H., et al., Fast Mixing in Interdigital Micromixers achieved by Means of Extreme Focusing, in: Proc. IMRET 6, New Orleans, USA, 2002: p. 297. [16] Berger, S. A., Talbot, L., Yao, L. S., Flow in Curved Pipes, Annu. Rev. Fluid Mech. 15 (1983) 461– 512. [17] Rosaguti, N. R., Fletcher, D. F., Haynes, B. S., Laminar Flow and Heat Transfer in a Periodic Serpentine Channel, Chem. Eng. Technol. 28 (2005) 353–361. [18] Fries, D. M., P. R. von Rohr, Liquid mixing in gas–liquid two-phase flow by meandering microchannels, Chem. Eng. Sci. 64 (2009) 1326–1335. [19] Dreher, S., Kockmann, N., Woias, P., Characterization of Laminar Transient Flow Regimes and Mixing in T-shaped Micromixers, Heat Transf. Eng. 30 (2009) 91–100. [20] Jiang, F., Drese, K. S., Hardt, S., Küpper, M., Schönfeld, F., Helical flows and chaotic mixing in curved micro channels, AIChE J. 50 (2004) 2297–2305. [21] Hessel, V., Löwe, H., Schönfeld, F., Micromixers – a review on passive and active mixing principles, Chem. Eng. Sci. 60 (2005) 2479–2501. [22] Castellano, S., Tamborini, L., Viviano, M., Pinto, A., Sbardella, G., Conti, P., Synthesis of 3aryl/benzyl-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole derivatives: a comparison between conventional, microwave-assisted and flow-based methodologies. J. Org. Chem. 75 (2010) 7439–7442. [23] Wilhelm, A. A.-M., Laugier, F., Kidak, R., Ratsimba, B., Delmas, H., Ultrasound to Enhance a Liquid–Liquid Reaction, J. Chem. Eng. JAPAN. 43 (2010) 751–756. [24] Roberge, D. M., Ducry, L., Bieler, N., Cretton, P., Zimmermann, B., Microreactor Technology: A Revolution for the Fine Chemical and Pharmaceutical Industries?, Chem. Eng. Technol. 28 (2005) 318–323. [25] Roberge, D. M. D., An integrated approach combining reaction engineering and design of experiments for optimizing reactions, Org. Process Res. Dev. 8 (2004) 1049–1053. [26] Kockmann, N., Gottsponer, M., Roberge, D. D. M., Scale-up concept of single-channel microreactors from process development to industrial production, Chem. Eng. J. 167 (2011) 718–726. [27] Agricola, G., De re metallica, New ed., New York: Dover Publications, 1950., New York, 1556. [28] Kockmann, N., Roberge, D. M., Scale-up concept for modular microstructured reactors based on mixing, heat transfer, and reactor safety, Chem. Eng. Process. Process Intensif. 50 (2011) 1017–1026. [29] Ducry, L., Roberge, D. M., Dibal-H Reduction of Methyl Butyrate into Butyraldehyde using Microreactors, Org. Process Res. Dev. 12 (2008) 163–167. [30] Georget, E., Sauvageat, J. L., Burbidge, A., Mathys, A., Residence time distributions in a modular micro reaction system, J. Food Eng. 116 (2013) 910–919. [31] Saber, M., Commenge, J. M., Falk, L., Microreactor numbering-up in multi-scale networks for industrial-scale applications: impact of flow maldistribution on the reactor performances, Chem. Eng. Sci. 65 (2010) 372–379. [32] Lavric, E. D., Woehl, P., Advanced-Flow glass reactors for seamless scale-up, Chim. Oggi. 27 (2009) 45–48. [33] Nieves-Remacha, M. J., Kulkarni, A. A., Jensen, K. F., Hydrodynamics of Liquid–Liquid Dispersion in an Advanced-Flow Reactor, Ind. Eng. Chem. Res. 51 (2012) 16251–16262.

154 | 5 From batch to continuous chemical synthesis – a toolbox approach [34] Barthe, P., Guermeur, C., Lobet, O., Moreno, M., Woehl, P., Roberge, D. M., et al., Continuous Multi-Injection Reactor for Multipurpose Production – Part I, Chem. Eng. Technol. 31 (2008) 1146–1154. [35] Su, Y., Zhao, Y., Chen, G., Yuan, Q., Liquid–liquid two-phase flow and mass transfer characteristics in packed microchannels, Chem. Eng. Sci. 65 (2010) 3947–3956. [36] Lee, S. W., Kim, D. S., Lee, S. S., Kwon, T. H., A split and recombination micromixer fabricated in a PDMS three-dimensional structure, J. Micromechanics Microengineering. 16 (2006) 1067– 1072. [37] Gunnarsson, J., Sinclair, I., Alanis, F. J., Compact Heat Exchangers: Improving Heat Recovery, Chem. Eng. (2009) 44–47. [38] Palmieri, A., Ley, S. V., Hammond, K., Polyzos, A., Baxendale, I. R., A microfluidic flow chemistry platform for organic synthesis: the Hofmann rearrangement, Tetrahedron Lett. 50 (2009) 3287–3289. [39] Renken, A., Hessel, V., Löb, P., Miszczuk, R., Uerdingen, M., Kiwi-Minsker, L., Ionic liquid synthesis in a microstructured reactor for process intensification, Chem. Eng. Process. Process Intensif. 46 (2007) 840–845. [40] Damm, M., Glasnov, T. N., Kappe, C. O., Translating High-Temperature Microwave Chemistry to Scalable Continuous Flow Processes, Org. Process Res. Dev. 14 (2010) 215–224. [41] Kashid, M., Renken, A., Kiwi-Minsker, L., Mixing efficiency and energy consumption for five generic microchannel designs, Chem. Eng. J. 167 (2011) 436–443. [42] Lobry, E., Theron, F., Gourdon, C., Le Sauze, N., Xuereb, C., Lasuye, T., Turbulent liquid–liquid dispersion in SMV static mixer at high dispersed phase concentration, Chem. Eng. Sci. 66 (2011) 5762–5774. [43] Lawton, S., Steele, G., Shering, P., Zhao, L., Laird, I., Ni X.-W., Continuous Crystallization of Pharmaceuticals Using a Continuous Oscillatory Baffled Crystallizer, Org. Process Res. Dev. 13 (2009) 1357–1363. [44] Ni, X.-W., Flow chemistry technologies handling solids including crystallisation, in: ACHEMA, Frankfurt, Germany, 2012. [45] Browne, D. L., Deadman, B. J., Ashe, R., Baxendale, I. R., Ley, S. V., Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor, Org. Process Res. Dev. 15 (2011) 693–697. [46] Roberge, D. M., Noti, C., Irle, E., Eyholzer, M., Rittiner, B., Penn, G., et al., Control of Hazardous Processes in Flow: Synthesis of 2-Nitroethanol, J. Flow Chem. 1 (2013) 1. [47] Reynolds, O., An experimental investigation of the circumstances which determine whether the motion of water shall be direct or sinuous, and of the law of resistance in parallel, Philos. Transactions R. Soc. London. 174 (1883) 935–982. [48] Damköhler, G., Einflüsse der Strömung, Diffusion und des Wärmeüberganges auf die Leistung von Reaktionsöfen. I. Allgemeine Gesichtspunkte für die Übertragung eines chemischen Prozesses aus dem Kleinen ins Große, Zeitschrift Für Elektrochemie UndAngew. Phys. Chemie. 42 (1936) 846–862.

| Part III: Lab and teaching practise

Pieter Nieuwland, Kaspar Koch, René Becker, Sándor B. Ötvös, István M. Mándity, and Ferenc Fülöp

6 Experimental procedures for conducting organic reactions in continuous flow

6.1 Flow chemistry calculations The calculation of the output parameters is a straightforward task, but care should be taken that all relations are taken into account. The process of determining the ultimate flow rates is most easily explained in a step-by-step manner.

6.1.1 Reaction and microreactor temperature The reaction temperature is the same as the microreactor temperature, and is controlled by the temperature controller.

6.1.2 Determination of flow rates In order to relate reaction time and microreactor volume, we define the total flow rate (𝜙tot ) as the sum of flow rate 𝐴 (𝜙𝐴 ) and flow rate 𝐵 (𝜙𝐵 ). We can now relate both microreactor volume (𝑉μR ) and reaction time (𝑡R ) to the total flow rate as in 1. The reaction solution that flows through the microreactor (volume 𝑉μR ) with flow 𝜙tot , takes time 𝑡R to go from the start to the end of this volume.

𝜙tot = 𝜙𝐴 + 𝜙𝐵 =

𝑉μR 𝑡R

.

(6.1)

To obtain values for flow rate 𝐴 and 𝐵, we must take into account the molar ratio between 𝐵 and 𝐴 and the concentration of solutions 𝐴 and 𝐵 (𝑐𝐴 and 𝑐𝐵 ). These are related as in Equation (6.2), since by multiplying the concentration (“mmol/mL”) by the flow rate (“mL/min”) we get a measure of the amount of substance per unit time (“mmol/min”). For the quenching flow 𝑄 the same holds (Equation (6.3)). We also introduce the flow ratio between 𝐵 and 𝐴 (𝑅𝐵/𝐴 ) and do the same for 𝑄 and 𝐵.

𝑐𝐵 ⋅ 𝜙𝐵 𝜙 𝑐 → 𝑅𝐵/𝐴 = 𝐵 = 𝑀𝐵/𝐴 ⋅ 𝐴 𝑐𝐴 ⋅ 𝜙𝐴 𝜙𝐴 𝑐𝐵 𝑐𝑄 ⋅ 𝜙𝑄 𝜙𝑄 𝑐 = → 𝑅𝑄/𝐵 = = 𝑀𝑄/𝐵 ⋅ 𝐵 . 𝑐𝐵 ⋅ 𝜙𝐵 𝜙𝐵 𝑐𝑄

𝑀𝐵/𝐴 =

(6.2)

𝑀𝑄/𝐵

(6.3)

158 | 6 Experimental procedures for conducting organic reactions in continuous flow Combining Equation (6.1) and Equation (6.2), we can isolate flow rate 𝐴 as in Equation (6.4).

𝜙𝐵 = 𝑅𝐵/𝐴 ⋅ 𝜙𝐴 → 𝜙tot = 𝜙𝐴 + 𝜙𝐵 = 𝜙𝐴 + 𝑅𝐵/𝐴 ⋅ 𝜙𝐴 = (1 + 𝑅 𝐵 ) ⋅ 𝜙𝐴 𝐴

1 𝜙𝐴 = 𝜙tot ⋅ . 1 + 𝑅𝐵/𝐴

(6.4)

Applying the same trick for flow rates 𝐵 and 𝑄 we get Equation (6.5) and Equation (6.6).

𝑅𝐵/𝐴 1 + 𝑅𝐵/𝐴 𝑅𝐵/𝐴 ⋅ 𝑅𝑄/𝐵 𝜙𝑄 = 𝜙tot ⋅ . 1 + 𝑅𝐵/𝐴 𝜙𝐵 = 𝜙tot ⋅

(6.5) (6.6)

6.1.3 Example calculation Suppose we want to conduct the reaction below at 55 °C, with a reaction time of 1.0 min at a molar excess ratio 𝐵/𝐴 of 2.0. We set the molar excess ratio 𝑄/𝐵 to 2.0 to make sure all leftover reagent is consumed by the quench flow. Main reaction:

2𝐴 + 3𝐵 → 2𝐶

Quenching reaction:

1𝐵 + 1𝑄 → 1𝑅

We now have chosen all the input parameters of the experiment. The stoichiometric ratio 𝐵/𝐴 is 3/2, for 𝑄/𝐵 this is 1. Our fictional continuous-flow experiment uses three stock solutions – solution 𝐴 with a substrate concentration of 0.2 M, solution 𝐵 with a reagent concentration of 0.1 M and solution 𝑄 with a concentration of 1.0 M. The microreactor has an internal volume of 92 μL. We now have defined all the intrinsic parameters of the experiment. With the above equations we can now calculate the output parameters: Calculate total flow rate, molar ratios and flow ratios:

tot

𝑀𝐵/𝐴 𝑅𝐵/𝐴

𝑉μR

92 μL = 92 μL/min 𝑡R 1.0 min 3 = 𝑆𝐵/𝐴 ⋅ ME𝐵/𝐴 = ⋅ 2.0 = 3.0 and 𝑀𝑄/𝐵 = 𝑆𝑄/𝐵 ⋅ ME𝑄/𝐵 = 1 ⋅ 2.0 = 2.0 2 𝑐𝐴 𝑐 0.2 0.1 = 6.0 = 0.2. = 𝑀𝐵/𝐴 ⋅ = 3.0 ⋅ and 𝑅𝑄/𝐵 = 𝑀𝑄/𝐵 ⋅ 𝐵 = 2.0 ⋅ 𝑐𝐵 0.1 𝑐𝑄 1.0 =

=

6.2 Wittig reaction in a continuous-flow microreactor

|

159

Calculate flow rates:

1 1 = 13.1 μL/min = 92 μL/min ⋅ 1 + 𝑅𝐵/𝐴 1 + 6.0 𝑅𝐵/𝐴 6.0 𝜙𝐵 = 𝜙tot ⋅ = 92 μL/min ⋅ = 78.9 μL/min 1 + 𝑅𝐵/𝐴 1 + 6.0 𝑅𝐵/𝐴 ⋅ 𝑅𝑄/𝐵 6.0 ⋅ 0.2 = 15.8 μL/min. = 92 μL/min ⋅ 𝜙𝑄 = 𝜙tot ⋅ 1 + 𝑅𝐵/𝐴 1 + 6.0 𝜙𝐴 = 𝜙tot ⋅

We now have calculated all the output parameters. Now just set the right temperature, set the pumps to the correct flow rates and press start!

6.2 Wittig reaction in a continuous-flow microreactor A convenient and selective way of forming a carbon-carbon double bond is through the Wittig reaction and its modifications [1, 2]. Although easily performed in batch, the Wittig reaction could be incorporated in a total synthesis using continuous flow. The latter has the added advantage of handling all toxic and corrosive reagents inside a closed system [3, 4]. The phosphoniumylide reagent is prepared in batch, by deprotonation of the corresponding Wittig salt. In continuous flow, an aldehyde (1) and a phosphoniumylide (2) are introduced into the microreactor, where they react to form the corresponding unsaturated Wittig product (3). The Wittig reaction is an example of a very selective reaction, producing no side-products. However, the formed double bond can take two configurations: the cis(𝑍) and the trans (𝐸) form. The latter is shown in Figure 6.1. Br – + Ph3P

O OtBu NaOH

OtBu

Ph3P

O (Performed in batch)

O H

+

OtBu

[DCM]

O (2)

(1)

(3)

Fig. 6.1: Wittig reaction scheme.

6.2.1 Continuous-flow design Flow reactor set-up – three syringe pumps (𝐴, 𝐵, 𝑄) – two mixer units (𝑀1 , 𝑀2 ) – microreactor with temperature control (internal volume 𝑉μR = 92 μL in our example)

160 | 6 Experimental procedures for conducting organic reactions in continuous flow Chemicals – tert-butoxycarbonylmethylphosphonium bromide (Wittig salt) – benzaldehyde – sodium hydroxide (0.2 M solution) – acetic acid – dichloromethane (DCM) Stock solutions to be prepared 𝐴: Benzaldehyde (102 μL, 1.00 mmol) dissolved to a total volume of 10 mL with DCM (corresponding to 0.1 M). 𝐵: Stir 457 mg (1.00 mmol) of the Wittig salt (in 5 mL dichloromethane) with 7.5 mL 0.2 M NaOH for 10 minutes. Separate layers, dry, filter and fill up to a total volume of 10 mL with dichloromethane (corresponding to 0.1 M). 𝑄: Acetic acid (1.73 mL, 30.0 mmol) dissolved to a total volume of 10 mL with dichloromethane (corresponding to 3.0 M). Make sure to close the flasks which are used to store the solutions, as some of the components are rather volatile. 6.2.2 Basic experiment To get acquainted with the reaction and the flow reactor set-up, perform an experiment with the following fixed parameters: a reaction time (𝑡R ) of 5.0 min, a temperature of 20 °C, a phosphoniumylide molar excess ratio (ME𝐵 /𝐴 ) of 4.0 and a 𝑄/𝐵 molar excess ratio (ME𝑄 /𝐵 ) of 20. The target volume of solution 𝐴 to be collected is 20 μL, all samples are collected in a vial containing 500 μL DCM. The used set-up can be seen in Figure 6.2. The corresponding flow rates can be calculated according to the known equations. Temperature control Benzaldehyde [DCM] A M1 M2

Phosphonium ylide [DCM] B

Collection and off-line analysis

Microreactor Product

Acetic acid [DCM] Q Fig. 6.2: Flow reactor set-up for the Wittig reaction.

6.2 Wittig reaction in a continuous-flow microreactor

|

161

Procedure – Prepare solutions 𝐴, 𝐵 and 𝑄 – Fill the three syringes with solutions 𝐴, 𝐵 and 𝑄 – Connect the inlet and outlet tubing and the mixer units (𝑀1 and 𝑀2 ) to the microreactor – Connect the inlet tubing to the corresponding syringes, and place the syringes on the pumps – Set the desired flow rates and press start – Let the system stabilize for a short time – Collect your sample for the calculated time – Analyze your sample (e.g., gas chromatography, NMR spectroscopy) and calculate the substrate conversion – Rinse the system by purging the tubing and microreactor with acetone – Empty, clean and dry the syringes afterwards Make sure to close the vial after collecting. This is done because some of the reaction components are rather volatile and readily evaporate from the vial.

Results For the basic experiment, the flow rate of 𝐴 (𝜙𝐴 ) is 3.68 μL/min, flow 𝐵 (𝜙𝐵 ) is 14.72 μL/min and flow 𝑄 (𝜙𝑄 ) is 9.81 μL/min and the collection time is 5:26 minutes. This is calculated according to the following equations:

𝜙total =

𝑉μR 𝑡R

=

92 μL 𝑐 = 18.4 μL ⋅ min−1 = 𝜙𝐴 + 𝜙𝐵 = 𝜙𝐴 ⋅ (1 + 𝐴 ⋅ ME𝐵/𝐴 ) . 5.0 min 𝑐𝐵

(From this it follows that 𝜙𝐴 = 3.68 μL ⋅ min−1 and 𝜙𝐵 = 14.72 μL ⋅ min−1 .)

𝑐𝐵 ⋅ ME𝑄/𝐵 = 9.81 μL ⋅ min−1 𝑐𝑄 𝑉target,𝐴 20 μL = = = 5.43 min = ̂ 5:26 min. 𝜙𝐴 3.68 μL ⋅ min−1

𝜙𝑄 = 𝜙𝐵 ⋅ 𝑡collect

Using the described parameter settings it is expected that a yield of around 60% will be obtained.

6.2.3 Optimization experiment The goal of this experiment is to identify the influence of the reaction parameters on the product yield and/or to find optimal reaction conditions (i.e., parameter settings) for performing the Wittig reaction using flow chemistry. The reaction parameters can

Benzaldehyde conversion

162 | 6 Experimental procedures for conducting organic reactions in continuous flow 100% 80% 60% 40% 20% 0% 0

500 Reaction time [s]

1000

0

5

10

Benzaldehyde conversion

(a)

(b)

80% 60% 40% 20% 0%

Phosphonium ylide molar excess ratio

Benzaldehyde conversion (c)

100%

100% 80% 60% 40% 20% 0%

0

20 Temperature [°C]

40

Fig. 6.3: Influence of reaction time (a), phosphoniumylide molar excess ratio (b) and temperature (c) on benzaldehyde conversion.

be easily varied by adjusting the flow rates and temperature [5]. The latter parameter speaks for itself, while both 𝐵/𝐴 molar excess ratio and reaction time are controlled by setting different flow rates. There are useful ranges for the reaction parameters, and the parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits. Choose the parameter sets you wish to investigate. For all the points in the parameter sets, calculate the flow rates and collection time. Then carry out the experiments in the same way as the introductory experiment. Quenching molar excess ratio (ME𝑄 /𝐵 ) should be fixed to 20 while optimization. Analyze your sample (e.g., gas chromatography, NMR spectroscopy) and calculate the substrate conversion. When

6.3 Swern–Moffatt oxidation in a continuous-flow microreactor

|

163

you have obtained all your measurement data, present them graphically and find the optimal conditions.

Results The results of our univariate optimization study can be seen in Figure 6.3. It shows that conversion increases linearly with reaction time. Phosphoniumylide molar excess ratio does not show a large effect on conversion above 2.0, while temperature shows an exponential-like increase in conversion. Thus, optimum conditions can be found at a phosphoniumylide molar excess ratio of 2.0, reaction time 15 min and a temperature of 30 °C.

6.3 Swern–Moffatt oxidation in a continuous-flow microreactor The Swern–Moffatt oxidation is an adaptation of the Swern oxidation, and selectively oxidizes an alcohol to the corresponding aldehyde or ketone (Figure 6.4) [6]. The reagent is a system comprised of dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride (TFAA), which forms an active species able to oxidize the alcohol. Hünig’s base (𝑁,𝑁-diisopropylethylamine; DIPEA) is used for the final step in the reaction and as a quenching agent to stop the reaction. 1) DMSO/TFAA 2) DIPEA

OH R1

R2

[CH2Cl2]

O R1

R2

R1 = alkyl R2 = alkyl, H

Fig. 6.4: Swern–Moffatt oxidation scheme.

Using batch chemistry, the Swern–Moffatt oxidation is performed at −80 °C [6]. This low temperature is needed to control the reaction, which is highly exothermic and extremely fast. Using continuous-flow chemistry, the contact time of the reagents can be very short and precisely controlled, and the reaction can be performed at temperatures between 0 °C and 60 °C [7, 8].

6.3.1 Continuous-flow design Flow reactor set-up – three syringe pumps (𝐴, 𝐵, 𝑄) – two mixer units (𝑀1 , 𝑀2 ) – microreactor with temperature control (internal volume 𝑉μR = 1.0 μL in our example)

164 | 6 Experimental procedures for conducting organic reactions in continuous flow Temperature control Benzyl alcohol/DMSO [DCM] A M1 M2

TFAA [DCM] B

Collection and off-line analysis

Microreactor Product

DIPEA Q Fig. 6.5: Flow reactor set-up for the Swern–Moffatt oxidation.

Chemicals – dimethyl sulfoxide (DMSO) – trifluoroacetic anhydride (TFAA) – benzyl alcohol – cinnamyl alcohol (only used in optimization experiments 4) – 1-phenyl ethanol (only used in optimization experiments 4) – 𝑁,𝑁-diisopropylethylamine (DIPEA) – dichloromethane (DCM)

Stock solutions to be prepared 𝐴: 207 μL benzyl alcohol¹ (2.00 mmol), 1.29 mL DMSO (18.0 mmol) dissolved to a total volume of 10 mL with DCM (corresponding to 0.2 M) 𝐵: 1.67 mL TFAA dissolved to a total volume of 10 mL with DCM (corresponding to 1.2 M) 𝑄: DIPEA (neat) (corresponding to 6.0 M). Make sure to close the flasks which are used to store the solutions, as some of the components are rather volatile.

6.3.2 Basic experiment To get acquainted with the reaction and the flow reactor set-up, perform an experiment with the following fixed parameters: a reaction time (𝑡R ) of 1.0 sec, a temperature of

1 When other alcohol substrate is used (optimization experiments 4), similar amount (2.00 mmol) should be used for preparation of stock solution.

6.3 Swern–Moffatt oxidation in a continuous-flow microreactor

|

165

20 °C, a trifluoroacetic anhydride (TFAA) molar excess ratio (ME𝐵/𝐴 ) of 6.0 and a 𝑄/𝐵 molar excess ratio (ME𝑄 /𝐵 ) of 2.0. The target volume of solution 𝐴 to be collected is 50 μL, all samples are collected in a vial containing 500 μL DCM. The used set-up can be seen in Figure 6.5. The corresponding flow rates can be calculated according to the known equations.

Procedure – Prepare solutions 𝐴, 𝐵 and 𝑄 – Fill the three syringes with solutions 𝐴, 𝐵 and 𝑄 – Connect the inlet and outlet tubing and the mixer units (𝑀1 and 𝑀2 ) to the microreactor – Connect the inlet tubing to the corresponding syringes, and place the syringes on the pumps – Set the desired flow rates and press start – Let the system stabilize for a short time – Collect your sample for the calculated time – Analyze your sample (e.g., gas chromatography, NMR spectroscopy) and calculate the substrate conversion – Rinse the system by purging the tubing and microreactor with acetone – Empty, clean and dry the syringes afterwards Make sure to close the vial after collecting. This is done because some of the reaction components are rather volatile and readily evaporate from the vial.

Results For the basic experiment the flow rate of 𝐴 (𝜙𝐴 ) is 30.00 μL/min, flow 𝐵 (𝜙𝐵 ) is 30.00 μL/min and flow 𝑄 (𝜙𝑄 ) is 12.00 μL/min and the collection time is 1:40 minutes. This is calculated according to the following equations:

𝜙total =

𝑉μR 𝑡R

=

1.0 μL 𝑐 = 60.00 μL ⋅ min−1 = 𝜙𝐴 + 𝜙𝐵 = 𝜙𝐴 ⋅ (1 + 𝐴 ⋅ ME𝐵/𝐴 ) . 1.0/60 min 𝑐𝐵

(From this it follows that 𝜙𝐴 = 30.00 μL ⋅ min−1 and 𝜙𝐵 = 30.00 μL ⋅ min−1 .)

𝑐𝐵 ⋅ ME𝑄/𝐵 = 12.00 μL ⋅ min−1 𝑐𝑄 𝑉target,𝐴 50 𝜇𝐿 = = = 1.67 min = ̂ 1:40 min. 𝜙𝐴 30.00 μL ⋅ min−1

𝜙𝑄 = 𝜙𝐵 ⋅ 𝑡collect

Using the described parameter settings it is expected that a yield of around 80% will be obtained.

166 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.3.3 Optimization experiment The goal of this experiment is to identify the influence of the reaction parameters on the product yield and/or to find optimal reaction conditions (i.e., parameter settings) for performing the Swern–Moffatt oxidation using flow chemistry. The reaction parameters can be easily varied by adjusting the flow rates and temperature [5]. The latter parameter speaks for itself, while both 𝐵/𝐴 molar excess ratio and reaction time are controlled by setting different flow rates. There are useful ranges for the reaction parameters, and the parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits.

Aldehyde yield

100% 80% 60% 40% 20% 0% 20

0 (a)

40

60

Temperature [°C]

Aldehyde yield

100% 80% 60% 40% 20% 0%

0.0

1.0

(b)

2.0

3.0

Reaction time [s]

Aldehyde yield

100% 80% 60% 40% 20% 0% (c)

0.0

2.0

4.0

6.0

8.0

TFAA/alcohol stoichiometry

10.0

Fig. 6.6: Influence of temperature (a), molar excess ratio (b), and reaction time (c).

6.3 Swern–Moffatt oxidation in a continuous-flow microreactor

|

167

Choose the parameter sets you wish to investigate. For all the points in the parameter sets, calculate the flow rates and collection time. Then carry out the experiments in the same way as the introductory experiment. Quenching molar excess ratio (ME𝑄 /𝐵 ) should be fixed to 2.0 while optimization. Analyze your sample (e.g., gas chromatography, NMR spectroscopy) and calculate the substrate conversion. When you have obtained all measurement data, present them graphically and find the optimal conditions.

Results The results of our univariate optimization study can be seen in Figure 6.6. It shows that yield increases linearly with temperature, but only slightly. Reaction time reaches a maximum after 0.7 sec and the TFAA/alcohol molar excess ratio clearly shows an optimum around 3.0. Possible optimum conditions are found at a TFAA/alcohol molar excess ratio of 3.0, reaction time 1.0 sec and 20 °C.

6.3.4 Optimization experiment on a different substrate The following experiment is the optimization of the Swern–Moffatt oxidation using a different substrate. Apart from benzyl alcohol, tested substrates which were found to work include cinnamyl alcohol and 1-phenyl ethanol. The procedure is inherently the same as the optimization of benzyl alcohol, with the added ability to compare the reaction behavior while using a different substrate. The experiment is conducted in the same way as the previous optimization experiment, and provides insight into the differences between substrates with respect to reaction behavior.

Results Cinnamyl alcohol The optimization results for cinnamyl alcohol follows the same trends as the benzyl alcohol univariate screening, except for a somewhat lower overall yield.

1-Phenyl ethanol The optimization results for 1-phenyl ethanol show different trends (Figure 6.7). Firstly, the optimal stoichiometry (around standard experiment parameters) lies at approximately 5. Secondly, there is a somewhat more pronounced temperature effect, with an optimum around room temperature. The results of this univariate analysis are plotted in Figure 6.7.

168 | 6 Experimental procedures for conducting organic reactions in continuous flow 100% Aldehyde yield

80% 60% 40% 20% 0% 5.0

0.0 (a)

10.0

TFAA/alcohol stoichiometry

Aldehyde yield

100% 80% 60% 40% 20% 0% 0

20

40

60

Temperature [°C]

(b)

Fig. 6.7: Influence of molar excess ratio (a) and temperature (b) on product yield in case of 1-phenyl ethanol as substrate.

6.4 Synthesis of silver nanoparticles in a continuous-flow microreactor Silver nanoparticles are used in a variety of applications, for example as antibacterial and antifungal agents in medical applications [9]. The synthesis of these nanosized metal particles through “wet chemistry” serves as the most practical laboratory technique, as silver salts are easily reduced using common reducing agents in solution [10]. While still being made in batch vessels most of the time, continuous flow can offer significant advantages since precise control of reaction parameters is often necessary to obtain high-quality nanoparticles with good size uniformity [11, 12]. Using continuous-flow chemistry, precise control over the size (diameter) of the formed nanoparticles is possible by varying the residence time, temperature or molar ratio of reagents [13]. In continuous flow, a silver nitrate solution and a sodium borohydride solution are introduced into the microreactor, where they react to form the corresponding nanoparticles (Figure 6.8).

AgNO3

+

NaBH4

Ag

+

BH3

Fig. 6.8: Synthesis of silver nanoparticles scheme.

+

NaNO3

+ 1/2 H2

6.4 Synthesis of silver nanoparticles in a continuous-flow microreactor

|

169

6.4.1 Continuous-flow design Flow reactor set-up – three syringe pumps (𝐴, 𝐵, 𝑄) – two mixer units (𝑀1 , 𝑀2 ) – microreactor with temperature control (internal volume 𝑉μR = 92 μL in our example) Temperature control Silver nitrate A M1 M2

Sodium borohydride B

Collection and off-line analysis

Microreactor Product

Nonidet P-40 Q Fig. 6.9: Flow reactor set-up for the synthesis of silver nanoparticles.

Chemicals – Sodium borohydride – Silver nitrate – Sodium hydroxide – Nonidet P-40

Stock solutions to be prepared 𝐴: Silver nitrate (5.7 mg, 310 𝜇mol) dissolved to a total volume of 1.0 L with water (corresponding to 310 𝜇M) 𝐵: Sodium borohydride (38 mg, 1.0 mmol) dissolved to a total volume of 100 mL with 10 mM NaOH (corresponding to 10 mM) 𝑄: Nonidet P-40 (1% v/v in water)

6.4.2 Basic experiment To get acquainted with the reaction and the flow reactor set-up, perform an experiment with the following fixed parameters: a reaction time (𝑡R ) of 14 sec, a temperature of 20 °C, a sodium borohydride molar excess ratio (ME𝐵/𝐴 ) of 30. The quenching flow is

170 | 6 Experimental procedures for conducting organic reactions in continuous flow kept at roughly 5% of the sum of flow 𝐴 and 𝐵 (that is: 𝜙𝑄 = 0.05 ⋅ (𝜙𝐴 + 𝜙𝐵 )). Roughly 100 μL of the microreactor outflow is collected and diluted to 1.0 mL (10×dilution). The used set-up can be seen in Figure 6.9. The corresponding flow rates can be calculated according to the known equations.

Procedure – Prepare solutions 𝐴, 𝐵 and 𝑄 – Fill the three syringes with solutions 𝐴, 𝐵 and 𝑄 – Connect the inlet and outlet tubing and the mixer units (𝑀1 and 𝑀2 ) to the microreactor – Connect the inlet tubing to the corresponding syringes, and place the syringes on the pumps – Set the desired flow rates and press start – Let the system stabilize for a short time – Collect your sample for the calculated time – Analyze your sample using UV-vis and calculate particle diameter – Rinse the system by purging the tubing and the microreactor with a soap solution (e.g., 5% hand soap in water) and then water – Empty, clean and dry the syringes afterwards

UV-vis analysis method The microreactor outflow is diluted approximately 10 times and measured on a UV spectrophotometer. The resulting spectrum shows two absorption maxima: one for the Nonidet P-40 surfactant (around 270 nm) and one for the silver nanoparticles (around 400 nm). The relation between the diameter of the silver nanoparticles and the absorption maximum is given by the following relation, in which 𝑑 is the particle diameter in nm and 𝜆 max is the absorption maximum of the nanoparticles in nm:

𝑑 = −0.005441 ⋅ 𝜆2max + 5.654 ⋅ 𝜆 max − 1367.

Results For the basic experiment, the flow rate of 𝐴 (𝜙𝐴 ) is 200 μL/min, flow 𝐵 (𝜙𝐵 ) is 200 μL/min and flow 𝑄 (𝜙𝑄 ) is 20 μL/min and the collection time is roughly 15 seconds. This is calculated according to the following equations:

𝜙total =

𝑉μR 𝑡R

=

92 μL 𝑐 ≈ 400 μL ⋅ min−1 = 𝜙𝐴 + 𝜙𝐵 = 𝜙𝐴 ⋅ (1 + 𝐴 ⋅ ME𝐵/𝐴 ) . 14/60 min 𝑐𝐵

6.4 Synthesis of silver nanoparticles in a continuous-flow microreactor

| 171

(From this it follows that 𝜙𝐴 = 200 μL ⋅ min−1 and 𝜙𝐵 = 200 μL ⋅ min−1 .)

𝜙𝑄 = 0.05 ⋅ (𝜙𝐴 + 𝜙𝐵 ) = 20 μL ⋅ min−1 𝑉target,total 100 μL 𝑡collect = = ≈ 15 sec. 𝜙total 420 μL ⋅ min−1 Using the described parameter settings it is expected that particles with a diameter of around 33 nm will be obtained.

35

Diameter [nm]

30 25 20 15 10 5 0

0

10

(a)

20

30

Reaction time [s] 35

Diameter [nm]

30 25 20 15 10 5 0

0

(b)

20

40

60

80

100

Temperature [°C]

Diameter [nm]

40 30 20 10 0 (c)

1

10

100

Equivalents NaBH4

1000

Fig. 6.10: Influence of reaction time (a), temperature (b), and sodium borohydride molar excess ratio (c) on silver nanoparticles diameter.

172 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.4.3 Optimization experiment The goal of this experiment is to identify the influence of the reaction parameters on the particle diameter in the synthesis of silver nanoparticles using flow chemistry. The reaction parameters can be easily varied by adjusting the flow rates and temperature [5]. The latter parameter speaks for itself, while both B/A molar excess ratio and reaction time are controlled by setting different flow rates. There are useful ranges for the reaction parameters, and the parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits. Choose the parameter sets you wish to investigate. For all the points in the parameter sets, calculate the flow rates and collection time. Then carry out the experiments in the same way as the introductory experiment. The quenching flow should be kept at 5% of the sum of flow 𝐴 and 𝐵 while optimization. Measure the samples using UVvis, find the absorption maximum for each sample. When you have obtained all your measurement data, present them graphically.

Results The results of our single-variate optimization study can be seen in Figure 6.10. It shows that diameter increases with molar excess ratio, decreases with temperature and flattens off above 10 sec reaction time.

6.5 1,2,3-triazole synthesis in continuous flow with copper powder and additives A huge number of 1,2,3-triazole-containing compounds have recently been described with various biological effects, such as antibacterial, antiviral, antifungal and anticancer activities [14]. The 1,2,3-triazole moiety is a pharmacophore. It is used extensively in medicinal chemistry to modify known bioactive molecules and to potentiate their biological effects [15]. The Huisgen 1,3-dipolar cycloaddition of organic azides with acetylenes is the simplest way to obtain useful 1,2,3-triazoles. Following only thermal induction, the reaction results in an approximately 1 : 1 mixture of 1,4- and 1,5-disubstituted triazole isomers. However, if Cu(I) catalysis is applied, the reaction becomes regioselective, giving exclusively the 1,4-regioisomer within a short reaction time (Figure 6.11) [16]. For such reactions, the safety aspects associated with the handling of explosive azides and the inherent scalability of continuous-flow processing are particularly appealing. In continuous-flow processing, heterogeneous Cu(I) sources are most popular [17, 18], and sufficient reactivity is usually obtained via heating [19]. However, it has been

6.5 1,2,3-triazole synthesis in continuous flow with copper powder and additives

N3

Cu(I) source

+

N

| 173

N N

Additives or heating

Fig. 6.11: 1,3-Dipolar cycloaddition between benzyl azide and phenylacetylene.

shown that the joint use of basic and acidic additives allows the moderation of the harsh reaction conditions, thereby improving the operational safety of the flow reaction at room temperature [20]. 6.5.1 Continuous-flow design Flow reactor set-up – HPLC pump – stainless steel reaction column – heating unit or an oil bath – backpressure regulator Benzyl azide HPLC pump phenylacetylene additives [DCM]

Heating Cu powder

Back-pressure regulator

N

N N

Fig. 6.12: Flow reactor set-up for the 1,2,3-triazole synthesis.

Chemicals – phenylacetylene – benzyl azide – 𝑁,𝑁-diisopropylethylamine (DIPEA) – glacial acetic acid (AcOH) – dichloromethane (DCM) – Cu powder Stock solutions to be prepared 𝐴: Dissolve the azide (0.84 mmol, 1 equiv) and the alkyne (1.28 mmol, 1.5 equiv) together in DCM (10 mL). 𝐵: Dissolve the azide (0.84 mmol, 1 equiv), the alkyne (1.28 mmol, 1.5 equiv), DIPEA (0.0336 mmol, 0.04 equiv) and AcOH (0.0336 mmol, 0.04 equiv) together in DCM (10 mL). Make sure to homogenize the solution carefully (e.g., by sonication) to avoid blockage in the reactor.

174 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.5.2 Basic experiment To get acquainted with the reaction and the flow reactor set-up, perform an experiment with the following fixed parameters: a flow rate of 0.5 mL/min, a pressure of 50 bar and room temperature. The set-up can be seen in Figure 6.12. Use solution 𝐴 for the first reaction, and then 𝐵 for the next reaction.

Procedure – Prepare solutions 𝐴 and 𝐵 – Add approximately 1 g of Cu powder to the stainless steel reaction column – Connect the inlet of the reaction column to the HPLC pump, and the outlet to the backpressure valve with stainless steel tubing – Lead the inlet of the pump into a measuring cylinder filled with DCM – Set the desired flow rate, pressure and temperature and press start – Let the system stabilize for a short time – Change to the vial containing the stock solution – Collect your sample, bearing in mind the dead volume of the system – After evaporation, analyze the sample with NMR spectroscopy and calculate the conversion – Rinse the system by purging with DCM

6.5.3 Optimization experiment The goal of this experiment is to identify the influence of the reaction parameters on the product yield and/or to find optimal reaction conditions (i.e., parameter settings) for the synthesis of 1,2,3-triazoles using flow chemistry. The reaction parameters can be easily varied by adjusting the flow rate, temperature and pressure [5]. There are useful ranges for the reaction parameters, and the parameters should not be chosen outside these ranges. The reaction has been extensively screened to yield a good experimenting region within these limits. Choose the parameter sets you wish to investigate. Carry out the experiments in the same way as the introductory experiment, utilizing in turn both solution 𝐴 and solution 𝐵. When you have obtained all your measurement data, present them graphically and find the optimal conditions.

Results The results of our optimization study can be seen in Figure 6.13. It shows that the conversion increases slightly on increasing from atmospheric pressure up to 100 bar. In fact, elevation of the pressure not only improves the rate of triazole production, but

6.5 1,2,3-triazole synthesis in continuous flow with copper powder and additives

| 175

Conversion / %

100 80 60 40 20 0

0

10

20

30

40

(a)

50

60

70

80

90

100

p/bar

Conversion / %

100 80 60 40 20 0 20

30

40

50

(b)

60

70

80

90

100

T/°C

Conversion / %

100 80 60 40 20 0 0.5 (c)

1

1.5

2

2.5

3

Flow rate/mL min–1

Fig. 6.13: (a) Pressure dependence; conditions: room temperature, 0.5 mL/min, no additives; (b) temperature dependence; conditions: 100 bar, 0.5 mL/min, no additives, (c) fine-tuning of the flow rate; 󳵳: 100 bar, 100 °C, no additives. ⧫: 100 bar, RT, additives.

also allows the use of higher temperatures without the solvent boiling over. The temperature exerts a great effect on the conversion, particularly above 40 °C. Through adjustment of the flow rate, the residence time on the catalyst bed can be optimized. The reaction is very sensitive to the residence time, as the conversion decreases steeply with enhancement of the flow rate in the absence of additives. When the flow rate is increased with the joint use of both additives, the drop in conversion is not as steep as

176 | 6 Experimental procedures for conducting organic reactions in continuous flow under the high-temperature conditions. This implies that the joint use of DIPEA and AcOH relieves the harsh reaction conditions without heating, and high conversion can be attained at room temperature.

6.6 Heterogeneous catalytic deuteration with D2 O in continuous flow Deuteration is widely applied in chemical research, for example in tracer studies to follow reaction paths [21], or as a tool to investigate pharmacokinetics [22]. Also, deuterium-labeled compounds are used in structural analysis in NMR and mass spectroscopy [23]. However, the batch synthesis of deuterated compounds suffers from several drawbacks. One is the potentially dangerous gas handling, as in the case of hydrogenations. Another is that conventional methods for the production of D2 gas are far from perfect [24]. Catalyst, D2 N H-Cube reactor

NH D

Fig. 6.14: Deuteration of 3,4-dihydroisoquinoline in the H-Cube® flow reactor.

The recently introduced H-Cube® high-pressure flow hydrogenation mesoreactor eliminates the difficulties in gas handling, greatly improving the operational safety, as H2 gas is generated in situ through the electrolytic decomposition of water. The heterogeneous hydrogenation catalyst is packed into cartridge-like columns (CatCart), thereby eliminating potentially dangerous direct catalyst handling. In the H-Cube® reactor, deuterations can be carried out by changing the hydrogen source to deuterated water (Figure 6.14) [25, 26]. The simple, efficient, selective and safe continuous-flow technique eliminates most of the drawbacks of the conventional batch deuteration procedures.

6.6.1 Continuous-flow design Flow reactor set-up – H-Cube® flow hydrogenation reactor – 30 mm CatCartcontaining 5% Pd/BaSO4 – 30 mm CatCartcontaining 5% Pt/Al2 O3

6.6 Heterogeneous catalytic deuteration with D2 O in continuous flow

| 177

Gas-generation unit H2O/D2O reservoir

Backpressure regulator

Electrolysis cell H2/D2 HPLC pump

Starting materials

Product collection

Stainless steel catalyst bed Peltier heating unit Stainless steel reaction line coil

Gas–liquid mixer

Fig. 6.15: Schematic representation of the H-Cube® flow hydrogenation reactor.

Chemicals – 3,4-dihydroisoquinoline – D2 O (heavy water) – ethyl acetate Stock solutions to be prepared Dissolve 20 mg of 3,4-dihydroisoquinoline in 20 mL of ethyl acetate to obtain a 1 mg/mL solution. Make sure to homogenize the solution carefully (e.g., by sonication) to avoid blockage in the reactor.

6.6.2 Basic experiment To get acquainted with the reaction and the H-Cube® flow hydrogenation reactor, perform an experiment with the following fixed parameters: flow rate 1 mL/min, 50 bar, 50 °C, 5% Pd/BaSO4 . Procedure – Prepare the starting solution – Fill the reservoir of the reactor with D2 O – Lead the inlet of the pump into a measuring cylinder filled with ethyl acetate – Set the desired flow rate, pressure and temperature and press start on the touchscreen (according to the user’s manual of the H-Cube® reactor) – Let the system build up the required parameters – Change to the vial containing the stock solution – Collect sample, bearing in mind the dead volume of the reactor – After evaporation, analyze the sample with NMR spectroscopy and calculate the conversion and deuterium incorporation ratio (D%) – Rinse the system by purging with ethyl acetate

178 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.6.3 Optimization experiment The goal of this experiment is to identify the influence of the reaction parameters on the product yield and D% and/or to find the optimal reaction conditions (i.e., the parameter settings) for deuteration with flow chemistry. The reaction parameters can be easily varied by adjusting the flow rate, temperature and pressure [5]. There are useful ranges for the reaction parameters, and the parameters should not be chosen outside these ranges, as the reaction has been extensively screened to yield a good experimenting region within these limits. Choose the parameter sets you wish to investigate. Carry out the experiments in the same way as the introductory experiment. Carry out the reactions with Pd/BaSO4 and with Pt/Al2 O3 . When you have obtained all the measurement data, present them graphically and find the optimal conditions.

Results Through adjustment of the flow rate, the residence time on the catalyst bed can be optimized. Flow rates > 0.5 mL/min are recommended for the deuteration reaction. Higher pressures are accompanied by conversions as pressurizing increases the solubility of gases. Elevation of the pressure not only improves the reaction rate, but also allows the use of higher temperatures without the solvent boiling over. Pt/Al2 O3 is a more active catalyst than Pd/BaSO4 , and allows quantitative conversion at around room temperature.

6.7 Aldol reaction in a continuous-flow microreactor The aldol condensation [1, 27, 28] of benzaldehyde and acetone is a textbook example of an exothermic, spontaneous reaction which is often performed during practical courses at universities and high schools. Due to its exothermic character, the reaction vessel is traditionally cooled in an ice bath, with controlled reagent addition to avoid the formation of side-products and evaporation of acetone. The product dibenzalacetone is used as a UV blocker and as a ligand in organometallic chemistry. Using continuous-flow chemistry, aldol condensations are suitable for largescale, preparative synthesis of hydroxyl aldehydes or unsaturated ketones [29, 30]. In O O

O NaOH

H

+ 2

[H2O/EtOH/MeCN] (1)

(2)

Fig. 6.16: Aldol condensation reaction.

(3)

6.7 Aldol reaction in a continuous-flow microreactor

|

179

Temperature control Acetone A

Collection and off-line analysis

M Benzaldehyde/NaOH B

Microreactor

Product

Fig. 6.17: General continuous-flow set-up for aldol reactions.

continuous flow, a ketone (1) and an aldehyde (2) are introduced into the microreactor, where they react to form the corresponding aldol condensation product (3).

6.7.1 Continuous-flow design The basic flow set-up for aldol condensation reactions is straightforward (Figure 6.16). Material – 2× Pump module – Inlet module – 3× plastic syringe – Basic microreactor (internal volume 𝑉μR = 100 μL)

6.7.2 Basic aldol experiment Stock solutions to be prepared:

𝐴: 128 μl acetone (1.75 mmol) dissolved to a total volume of to 10 mL with acetonitrile/ethanol/water (1 : 1 : 1) (corresponding to 0.18 M) 𝐵: 140 mg sodium hydroxide (3.5 mmol) and 357 μL (3.5 mmol) benzaldehyde dissolved to a total volume of to 10 mL with acetonitrile/ethanol/water (1 : 1 : 1) (corresponding to 0.35 M) 𝑄: 3.2 mL acetic acid diluted to a total volume of 100 mL with acetonitrile/ethanol/ water (1 : 1 : 1) (corresponding to 0.56 M) To get acquainted with the reaction and with flow chemistry in general, a so-called basic experiment is performed. This experiment is the Aldol condensation at fixed parameters – a reaction time (𝑡R ) of 10 min, a temperature of 60 °C and a benzaldehyde molar excess ratio (ME𝐵/𝐴 ) of 2.0. The target volume of solution 𝐴 to be collected is 2.0 μL, all samples are collected in a vial containing 10.0 mL of solution 𝑄. The vial must be wrapped in aluminum foil to prevent degradation.

180 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.7.3 Aldol reaction optimization The goal of this experiment is to identify the influence of reaction parameters on product yield and/or to find optimal reaction conditions (i.e., parameter settings) for performing the Aldol condensation using flow chemistry. Optimization in a three-dimensional space can be done using various mathematical techniques, of which are commonly used: univariate analysis, full-factorial design, 3D simplex. Using flow chemistry, reaction parameters can be easily varied by adjusting the flow rates and temperature. The latter parameter speaks for itself, while both B/A molar excess ratio and reaction time are controlled by setting different flow rates. Results are shown on Figure 6.18. 100%

Yield

80% 60% 40% 20% 0% 0

10

5

(a)

15

20

Reaction time [s] 100%

Yield

80% 60% 40% 20% 0% 0 (b)

2

4

6

8

10

Benzaldehyde molar ratio 100%

Yield

80% 60% 40% 20% 0% 0 (c)

20

40

60

Temperature [°C]

80

Fig. 6.18: Influence of reaction time (a), benzaldehyde molar excess ratio (b), and temperature (c) on dibenzalacetone yield.

6.8 Prilezhaev epoxidation in a continuous-flow microreactor

|

181

There are useful ranges for the reaction parameters. Parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits.

6.8 Prilezhaev epoxidation in a continuous-flow microreactor The synthesis of epoxides is a useful reaction in organic chemistry, as it provides a good pathway towards trans-diols through alkaline hydrolysis. Traditionally, this reaction is difficult to control due to its fast reaction rate and exothermic character. In batch, temperature runaway is largely overcome by controlled reagent addition and the use of milder epoxidation reagents such as metachloro-peroxybenzoic acid (mCPBA), whose synthesis again requires the use of a peroxy compound and are thus less atom-efficient [31, 32]. O 1)

(Performed in batch) O

OH

2) NaSO3

(4)

OH

O + (5)

OAc OH +

(5a)

(5b)

OH

OAc OH +

OAc

(5c)

OH

NaOH

(5a)

Fig. 6.19: Prilezhaev epoxidation reaction.

Epoxidation with peracetic acid poses its limits to batch scale-up, but has been shown to be possible in continuous flow [33, 34]. The latter has the added advantage of handling all toxic and corrosive reagents inside a closed system. In continuous flow, peracetic acid and cyclohexene (4) (Figure 6.19) are introduced into the microreactor, where they react to form a mixture of the corresponding epoxide (5) and the ring-opened products which are either free diol (5a), mono-acetylated diol (5b) or diacetylated diol (5c). This mixture of four compounds can be hydrolyzed in batch by treatment with aqueous sodium hydroxide to yield only the diol (plus any unreacted cyclohexene).

6.8.1 Continuous-flow design The basic flow set-up for Prilezhaev epoxidation reactions is straightforward (Figure 6.20).

182 | 6 Experimental procedures for conducting organic reactions in continuous flow Temperature control Cyclohexene/toluene A M1 M2

Peracetic acid solution B

Collection and off-line analysis

Microreactor Product

Sodium sulphite solution Q Fig. 6.20: General continuous-flow set-up for epoxidation reactions.

Material – 3× Pump module – Inlet module – 3× plastic syringe – Basic microreactor (internal volume 𝑉μR = 100 μL) 6.8.2 Basic epoxidation experiment Stock solutions to be prepared:

𝐴: Cyclohexene/toluene (5 : 1 vol/vol; corresponding to 8.3 M) 𝐵: Peracetic acid (35% w/w solution in diluted acetic acid; corresponding to 5.4 M) 𝑄: Sodium sulfite 1.0 M in water (corresponding to 1.0 M) To get acquainted with the reaction and with flow chemistry in general, a so-called basic experiment is performed. This experiment is the Prilezhaev epoxidation at fixed parameters – a reaction time (𝑡R ) of 2.0 min, a temperature of 60 °C and a peracetic acid molar excess ratio (ME𝐵/𝐴 ) of 1.1. The 𝑄/𝐵 molar excess ratio (ME𝑄/𝐵 ) is set to a fixed value of 1.0. The target volume of solution 𝐴 to be collected is 200 μL, all samples are collected in a GC vial containing 400 μL dichloromethane. The used set-up can be seen in Figure 6.20. The corresponding flow rates can be calculated according to the known equations. After preparation of this experiment, the instructor should check if the calculated flow rates and collection time are correct.

Preparative scale experiment The reaction mixture from the previous microreactor experiment can also be used to synthesize the diol by hydrolysis with sodium hydroxide. To do this, collect a certain

6.8 Prilezhaev epoxidation in a continuous-flow microreactor

| 183

amount of reaction mixture (e.g., 5 mL) and calculate the starting amount (in mmol) of cyclohexene present in this mixture. Remove all excess water, acetic acid, cyclohexene and toluene by rotary evaporation. Add 2 equivalents of sodium hydroxide as a 5 M solution and heat to 60 °C while stirring for 45 minutes. After cooling down, neutralize the solution to pH 7 with diluted aqueous HCl and evaporate to dryness by rotary evaporation. Extract the residue three times with ethyl acetate. Dry the combined organic fractions, filter and remove solvent by rotary evaporation to obtain the crude diol (determine yield). The pure diol can be obtained by recrystallization from ethyl acetate. Determine melting point (lit. 100–104 °C) and take an IR spectrum (see Appendix: IR spectrum of trans-1,2-cyclohexanediol).

Conversion (%)

100 80 60 40 20 0 0.0 (a)

1.0

2.0

3.0

4.0

Peroxyacetic acid molar excess ratio

Conversion (%)

100 80 60 40 20 0 0

50

100

150

200 250

Reaction time [s]

(b)

Conversion (%)

100 80 60 40 20 0 0 (c)

20

40

60

Temperature [°C]

80

Fig. 6.21: Influence of peroxyacetic acid molar excess ratio (a), reaction time (b), and temperature (c) on conversion of cyclohexene.

184 | 6 Experimental procedures for conducting organic reactions in continuous flow Reaction optimization The goal of this experiment is to identify the influence of reaction parameters on product yield and/or to find optimal reaction conditions (i.e., parameter settings) for performing the Prilezhaev epoxidation using flow chemistry. Optimization in a three-dimensional space can be done using various mathematical techniques, of which are commonly used: univariate analysis, full-factorial design, 3D simplex. Using flow chemistry, reaction parameters can be easily varied by adjusting the flow rates and temperature. The latter parameter speaks for itself, while both 𝐵/𝐴 molar excess ratio and reaction time are controlled by setting different flow rates. There are useful ranges for the reaction parameters. Parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits. From this univariate optimization it follows that conversion increases with all three parameters. Reaction time and molar excess ratio reach a maximum after about 2.0 min and 1.0, respectively. Temperature shows a nonlinear relationship with respect to cyclohexene conversion, which is possibly due to changes in solubility over temperature, thereby altering the two-phase system. Depending on the optimization method used, optimum conditions can be found at a peracetic acid molar excess ratio of 1.1, reaction time 2.0 min and a temperature of 60 °C. Higher conversions are obtained by increasing reaction time and molar excess ratio at the same time, which can be achieved through multivariate analysis or by using a different “middle point” in a univariate screening.

6.9 Peptide catalyzed stereoselective reactions in a continuous-flow reactor A variety of enantioselective C–C bond-forming reactions have been achieved through asymmetric organocatalysis in recent years [35]. Proline has been described as a catalyst for reactions involving enamines, generally with moderate yields or enantioselectivities [36]. Whereas small rigid organocatalysts offer only a limited number of sites for structural and functional diversity, peptides have a modular nature, which allows the creation of optimized catalysts. 𝐴 large number of peptidic catalysts have been designed [37], and it has been shown that N-terminal prolyl-peptides efficiently catalyze reactions proceeding via enamine intermediates [38]. Earlier, we reported the first continuous-flow approach for the selective asymmetric synthesis of 𝛾-nitroaldehydes, utilizing solid supported peptidic catalysts readily synthesized and immobilized in a single step [39]. The reactions are outlined in Figure 6.22. In the case of 1,4-addition, there are four possible products because of the two chiral centers: two diastereomeric pairs. In the aldol reaction, there are only two

6.9 Peptide catalyzed stereoselective reactions in a continuous-flow reactor

Me

S

H

NO2

O

NO2

R

R

H

6

O

7

S

H

NO2

S

H

R

10

11

H OH

O Me

O

+ Me

O2N

12

OH

O Me +

S

O Me

R

O2N

O2N

13

NO2

R

Me

Me a)

9 Ph

O

Ph

NO2

S

Me

Me 8

+ H

Ph

O

Ph

O

| 185

14

15

b) Fig. 6.22: (a) Stereoselective 1,4-addition reaction; (b) stereoselective aldol reaction.

HN HN

N O

NH O

N

O

O

HN

HOOC

HOOC a)

16

NH

O

O

b)

HN 17

Fig. 6.23: (a) The peptidic catalyst used for the stereoselective 1,4-addition reaction; (b) the peptidic catalyst used for the stereoselective aldol reaction.

possible products (because of the one chiral center), which are in enantiomeric relationship. This simple and efficient technique permits catalyst reusability, a facile scale-up and ease of product isolation, while avoiding laborious peptide purification. Moreover, the structure of the resulting peptide can be confirmed at the end of the synthesis. The structures of the immobilized catalysts were checked either by means of suspension-phase 13 C NMR measurements, MS or RP-HPLC investigations after cleavage of a small amount of the peptides. The reaction result can be followed by NMR spectroscopy and chiral HPLC. Reaction condition optimization led to dramatically shortened reaction times, high yields and stereoselectivities comparable with those in the batch process [39, 40].

186 | 6 Experimental procedures for conducting organic reactions in continuous flow 6.9.1 Continuous-flow design The basic flow set-up for the stereoselective reactions is straightforward (Figure 6.24). Material – 1× pump module – Catalyst cartridge – Temperature controller – Pressure regulator Heatable block

Catalyst bed

HPLC pump

p

O OH HN

O N O

NH

HN

O

Immobilized peptide catalyst Fig. 6.24: General continuous-flow set-up for stereoselective reactions.

6.9.2 Basic aldol experiment Materials to be prepared: 𝐴: Peptidic catalysts can be prepared by known literature methods [41] 𝐵: CHCl3 /𝑖PrOH 9 : 1 was poured onto a mixture of 0.54 mmol (1 equiv) E-𝛽-nitrostyrene (BNS) and 2.70 mmol aldehyde (5 equiv) in a measuring cylinder, and to give a final volume of 10 mL. The solution was homogenized by sonication for 3 min. To get acquainted with the reaction and with flow chemistry in general, a socalled basic experiment is performed. This experiment is the stereoselective aldol or 1,4-addition reaction at fixed parameters: a temperature of 25 °C, a pressure of 60 bar and a flow rate of 0.1 ml/min. All samples are collected in a vial.

6.9 Peptide catalyzed stereoselective reactions in a continuous-flow reactor

|

187

6.9.3 Reaction optimization The goal of this experiment is to identify the influence of the reaction parameters on the product yield and/or to find the optimal reaction conditions (i.e., parameter settings) for the stereoselective aldol or 1,4-addition reaction by flow chemistry. Optimization in three-dimensional space can be carried out by using various mathematical techniques, commonly used ones include univariate analysis, full-factorial design and 3D simplex. In flow chemistry, reaction parameters can easily be varied by adjusting the flow rate and temperature. The latter parameter speaks for itself, while both molar excess 100

Yield %

80 60 40 20 0 0

0.1

(a)

0.2

0.3

0.4

0.5

0.4

0.5

80

100

Flow rate (ml/min)

Syn/anti ratio

20 15 10 5 0 0

0.1

(b)

0.2

0.3

Flow rate (ml/min) 92 90

Yield %

88 86 84 82 80 78

0 (c)

20

40

60

Pressure (bar)

Fig. 6.25: Influence of flow rate on yield (a) and selectivity (b), and influence of pressure on yield (c).

188 | 6 Experimental procedures for conducting organic reactions in continuous flow ratio and residence time controlled by setting different flow rates. Results are shown in Figure 6.25. There are useful ranges for the reaction parameters. Parameters should not be chosen outside these ranges, as the pump’s flow rate and the substrate’s boiling point impose some of these limits. Also, the reaction has been extensively screened to yield a good experimenting region within these limits.

Study questions 6.1. Find the reaction mechanism for the Wittig reaction, and show the essential (sequential) steps from benzaldehyde and tert-Butoxycarbonylmethylphosphonium bromide (phosphoniumylide) to Wittig product. 6.2. What advantages in performing the Wittig reaction in continuous flow can you think of? Also, can you think of any disadvantages? 6.3. Find the reaction mechanism for the Swern–Moffatt oxidation, and show the essential (sequential) steps from benzyl alcohol and DMSO/TFAA to the corresponding aldehyde or ketone. 6.4. What advantages in performing the Swern–Moffatt oxidation in continuous flow can you think of? Also, can you think of any disadvantages? 6.5. Typically, the Swern–Moffatt oxidation produces a number of side-products. Find out what they are, how they are formed, and how the formation of these products is suppressed in batch chemistry. Also try to explain why these side-products are formed to a much lesser extent in continuous-flow chemistry. 6.6. Flow chemistry is best carried out in a homogeneous, liquid phase (no gases, no solids). The Swern–Moffatt oxidation is an adaptation of the Swern oxidation, where oxalyl chloride is used instead of TFAA. Explain (using the first statement) why the “regular” Swern oxidation might pose problems when performed in a flow system. 6.7. What advantages in performing the synthesis of silver nanoparticles in continuous flow can you think of? Also, can you think of any disadvantages? 6.8. How do you explain the catalytic activity of copper powder in 1,3-dipolar cycloadditions of organic azides with acetylenes? 6.9. What are the advantages of performing the Cu(I)-catalyzed 1,3-dipolar cycloaddition of organic azides with acetylenes in continuous flow? Can you think of any disadvantages? 6.10. Why is ethyl acetate used as solvent? 6.11. In Figure 6.14, no N-D bond is indicated. Can you explain this? 6.12. What are the advantages of performing deuterations in an H-Cube® system? Can you think of any disadvantages? 6.13. Preparation of the experiment: (a) Roughly calculate the cost of the experiment from the prices of the chemicals. In other words, calculate the price (e.g., per gram) of the product. (b) Find the safety aspects (including 𝑅/𝑆 values) of the used chemicals. What advantages in performing the Aldol condensation in continuous flow can you think of? Also, can you think of any disadvantages? 6.14. Preparation of the experiment: (a) Roughly calculate the cost of the experiment from the prices of the chemicals. In other words, calculate the price (e.g., per gram) of the product. (b) Find the safety aspects (including 𝑅/𝑆 values) of the used chemicals. What advantages in performing the Prilezhaev epoxidation in continuous flow can you think of? Also, can you think of any disadvantages?

Bibliography

| 189

6.15. Find the reaction mechanism for the Prilezhaev epoxidation, and show the essential (sequential) steps from cyclohexene and peracetic acid to diol. 6.16. Preparation of the experiment: (a) Roughly calculate the cost of the experiment from the prices of the chemicals. On this basis, calculate the cost (e.g., per gram) of preparation of the product. (b) Find the safety aspects (including 𝑅/𝑆 values) of the chemicals used. What are the advantages of performing the stereoselective Aldol reaction in continuous flow? Can you think of any disadvantages?

Further readings – Mason, P., Price, K. E., Steinbacher, J. L., Bogdan, A. R., McQuade, D. T., Chem. Rev. 107 (2007) 2300–2318. – Wegner, J., Ceylan, S., Kirschning, A., Chem. Commun. 47 (2011) 4583–4592. – Hessel, V., Kralisch, D., Kockmann, N., Noël, T., Wang, Q., ChemSusChem 6 (2013) 746–789. – Wirth, T., Microreactors in Organic Synthesis and Catalysis, Wiley-VCH: 2008. – Luis, S. V., Garcia-Verdugo, E., Chemical Reactions and Processes under Flow Conditions, The Royal Society of Chemistry: 2009. – Wegner, J., Ceylan, S., Kirschning, A., Adv. Synth. Catal. 354 (2012) 17–57. – Hartman, R. L., McMullen, J. P., Jensen, K. F., Angew. Chem. Int. Ed. 50 (2011) 7502–7519.

Bibliography [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Hoffmann, R. W., Angew. Chem. Int. Edn. 40 (2001) 1411–1416. Parvatkar, P. T., Torney, P. S., Tilve, S. G., Curr. Org. Synth. 10 (2013) 288–317. Comer, E., Organ, M. G., J. Am. Chem. Soc. 127 (2005) 8160–8167. Smith, C. J., Smith, C. D., Nikbin, N., Ley, S. V., Baxendale, I. R., Org. Biomol. Chem. 9 (2011) 1927–1937. Wegner, J., Ceylan, S., Kirschning, A., Chem. Commun. 47 (2011) 4583–4592. Tidwell, T. T., Synthesis-Stuttgart (1990) 857–870. Nieuwland, P. J., Koch, K., van Harskamp, N., Wehrens, R., van Hest, J. C. M., Rutjes, F., Chem. Asian J. 5 (2010) 799–805. van der Linden, J. J. M., Hilberink, P. W., Kronenburg, C. M. P., Kemperman, G. J., Org. Process Res. Dev. 12 (2008) 911–920. Chernousova, S., Epple, M., Angew. Chem. Int. Edn. 52 (2013) 1636–1653. Montazer, M., Alimohammadi, F., Shamei, A., Rahimi, M. K., Carbohyd. Polym. 87 (2012) 1706– 1712. Mehenni, H., Sinatra, L., Mahfouz, R., Katsiev, K., Bakr, O. M., RSC Adv. 3 (2013) 22397–22403. Kumar, D. V. R., Kasture, M., Prabhune, A. A., Ramana, C. V., Prasad, B. L. V., Kulkarni, A. A., Green Chem. 12 (2010) 609–615. Silvestrini, S., Carofiglio, T., Maggini, M., Chem. Commun. 49 (2013) 84–86. Agalave, S. G., Maujan, S. R., Pore, V. S., Chem. Asian J. 6 (2011) 2696–2718. Mohan, S., McAtamney, S., Haselhorst, T., von Itzstein, M., Pinto, B. M., J. Med. Chem. 53 (2010) 7377–7391. Meldal, M., Tornøe, C. W., Chem. Rev. 108 (2008) 2952–3015.

190 | 6 Experimental procedures for conducting organic reactions in continuous flow [17] Smith, C. D., Baxendale, I. R., Lanners, S., Hayward, J. J., Smith, S. C., Ley, S. V., Org. Biomol. Chem. 5 (2007) 1559–1561. [18] Fuchs, M., Goessler, W., Pilger, C., Kappe, C. O., Adv. Synth. Catal. 352 (2010) 323–328. [19] Ceylan, S., Klande, T., Vogt, C., Friese, C., Kirschning, A., Synlett (2010) 2009–2013. [20] Ötvös, S. B., Mándity, I. M., Kiss, L., Fülöp, F., Chem. Asian J. 8 (2013) 800–808. [21] Baldwin, J. E., Raghavan, A. S., Hess, B. A., Smentek, L., J. Am. Chem. Soc. 128 (2006) 14854– 14862. [22] Kharasch, E. D., Bedynek, P. S., Park, S., Whittington, D., Walker, A., Hoffer, C., Clin. Pharmacol. Ther. 84 (2008) 497–505. [23] Salzmann, M., Pervushin, K., Wider, G., Senn, H., Wuthrich, K., Proc. Natl. Acad. Sci. USA 95 (1998) 13585–13590. [24] Herber, R. H., Inorganic Isotopic Synthesis, Benjamin (1962). [25] Mándity, I. M., Martinek, T. A., Darvas, F., Fülöp, F., Tetrahedron Lett. 50 (2009) 4372–4374. [26] Ötvös, S. B., Mándity, I. M., Fülöp, F., Mol. Divers. 15 (2011) 605–611. Wade, L. G. Organic Chemistry (6th edn.), Upper Saddle River, New Jersey: Prentice Hall (2005) 1056–1066. [27] Wurtz, C. A., Bull Soc Chim Fr 17 (1872) 436–442. [28] Wurtz, C. A. J Prakt Chem 5 (1872) 457–464. [29] Tanaka, K., Fukase, K., Org Proc Res Dev 13 (2009) 983–990. [30] Stevens, J. G., Bourne, Poliakoff, R. A., Green, M., Chem 11 (2009) 409–416. [31] Jana, N. K., Verkade, J. G., Org Lett 5 (2003) 3787–3790. [32] Porto, R. S., Vasconcellos, M. L. A. A., Ventura, E., Coelho, F., Synthesis (2005) 2297–2306. [33] Wan, Y. S. S., Chau, J. L. H., Yeung, K. L., Gavriilidis, A., J. Catal. 223 (2004) 241–249. [34] van den Broek, B., Becker, R., Kossl, F., Delville, M. M. E., Nieuwland, P. J., Koch, K., Rutjes, F., Chem Sus Chem 5 (2012) 289–292. [35] Weiner, B., Szymanski, W., Janssen, D. B., Minnaard, A. J., Feringa, B. L., Chem. Soc. Rev. 39 (2010) 1656–1691. [36] Northrup, A. B., Mangion, I. K., Hettche, F., MacMillan, D. W. C., Angew. Chem. Int. Edn. 43 (2004) 2152–2154. [37] Fiori, K. W., Puchlopek, A. L. A., Miller, S. J., Nat. Chem. 1 (2009) 630–634. [38] Wiesner, M., Revell, J. D., Wennemers, H., Angew. Chem. Int. Edn. 47 (2008) 1871–1874. [39] Ötvös, S. B., Mándity, I. M., Fülöp, F., Chem Sus Chem 5 (2012) 266–269. [40] Ötvös, S. B., Mándity, I. M., Fülöp, F., J Catal 295 (2012) 179–185. [41] Sewald N., Jakubke, H.-D., Peptides: Chemistry and Biology, Weinheim: Wiley-VCH (2002).

Robert K. Harmel, Marielle M. E. Delville, and Floris P. J. T. Rutjes

7 Experimental procedures for conducting organic reactions in continuous flow

Introduction Education in synthetic organic chemistry involves, on the one hand, mastering theory and mechanisms, and equally importantly, on the other hand, developing the practical skills to be able to safely conduct organic reactions in the chemistry laboratory. In line with the classic textbook organic chemistry, virtually all training in the bachelor’s and master’s programs at colleges and universities focuses on batchwise reactions, carried out in flasks. With the advent of continuous-flow chemistry, however, it is of vital importance for the development of the field, that students in early stages of their degree programs become acquainted with state-of-the-art techniques and therefore learn how to conduct organic reactions in continuous flow. They must learn about the advantages and disadvantages, the scope and limitations of flow chemistry, so that whenever they have to perform new reactions, they should be able to make a deliberate choice between a batchwise and continuous-flow set-up. In this chapter, we are presenting a series of standard organic reactions that have been developed in continuous flow and can be considered textbook examples to train students on the higher bachelor’s and master’s level. These examples are based on literature procedures that have been described over the years, and which include a wide array of reaction types such as nucleophilic substitution, electrophilic aromatic substitution, Pd-catalyzed cross-coupling, chemoenzymatic reactions, oxidation reactions, condensation reactions, and photochemical reactions. In addition, different techniques have been addressed, including the use of inductive heating and the application of immobilized reagents. Each section starts with a description of the background and the mechanism of the reaction involved, followed by an outline of the approach that was chosen to realize the continuous-flow process. This approach in most of the cases involves: (a) design of the reactor, which also includes the analytical technique and the quenching method, (b) reaction optimization, and (c) scale-up and/or determining the scope of the reaction. Each section is concluded by a detailed description of one or two representative flow chemistry procedures, followed by the cited references. An issue that deserves special attention is the standardization of microreactors and flow equipment that has been used in the experiments. In the early years of flow chemistry, research groups would fabricate their own flow devices, which were not very well defined and, for example, made use of various materials to construct the

192 | 7 Experimental procedures for conducting organic reactions in continuous flow microreactors. This large variety of flow devices made it relatively difficult for other chemists to reproduce published results. Over the years, this situation has very much improved due to the fact that a fair number of suppliers are selling dedicated equipment for conducting flow reactions. As a result, flow equipment has become available to the whole organic chemistry community, and the level of reproducibility has considerably improved. In the experimental procedures described in this chapter, it is indicated which commercial equipment has been used by the author. In principle, however, each of these reactions might also be carried out in equipment from an alternative supplier, since dimensions and flow rates have generally been adequately provided in the procedures. Finally, we realize that the set of experiments described in this chapter represent a rather biased selection of all reactions that have been published during the past fifteen years or so. However, we do feel that this is a representative set of experiments, which can be instrumental in training young chemists in the field of continuous flow synthesis. Learning outcomes of this chapter: – Become acquainted with general practical aspects of performing continuous-flow experiments – Gain insight in approaches to optimize reactions using a continuous-flow approach – Become aware of spectroscopic tools to be able to real-time monitor continuousflow reactions

7.1 Pyrrole synthesis by Paal–Knorr cyclocondensation 7.1.1 Background The pyrrole moiety is abundantly present in natural products such as alkaloids and porphyrins [1]. The heterocyclic pyrrole structure also plays a prominent role in various biologically and pharmaceutically active compounds, which renders its synthesis industrially relevant [2]. The Paal–Knorr cyclocondensation of 1,4-diketones with amines or other nitrogen derivatives is a well-established procedure for the preparation of pyrroles and related heterocycles. The mechanism was described by Amarnath and coworkers and involves an equilibrium reaction in the first step. The subsequent cyclization is rate-determining and is followed by two dehydration steps, Figure 7.1 [3, 4]. Starting materials for the Paal–Knorr cyclocondensation are generally commercially available or can be readily prepared in a few synthetic steps. However, the exothermic behavior of the Paal–Knorr reaction is a major drawback especially on an industrial scale, where high concentrations and larger volumes are frequently

7.1 Pyrrole synthesis by Paal–Knorr cyclocondensation | 193

O

O Me + H2N

Me 1

O

Me OH

Me OH

2

HO Me

HN

OH2 Me

N

OH OH B

H Me

N

Me

Me

OH

N

H

H+ Me OH

HO Me

N

Me OH

HO Me

B

N OH

3 Fig. 7.1: Proposed mechanism for the Paal–Knorr cyclocondensation.

applied. Microreactor flow technology provides optimal control over reaction conditions due to the small internal dimensions of the microreactor channels. The high surface-to-volume ratio provides rapid transport of heat out of the system, thereby avoiding the heat problems that may arise in conventional batch reactors. In addition, continuous-flow technology is ideal for efficient and fast screening of reaction parameters. Rutjes and coworkers chose to study this reaction in flow and designed a flow reactor set-up for investigation of the optimal reaction conditions, which was then validated in larger scale production [5].

7.1.2 The flow process The flow process, from design to larger scale production, involves the following four stages: 1. Continuous-flow design The set-up (Figure 7.2) consisted of three syringe pumps P1–P3 and a straightforward microreactor with temperature control and the possibility to quench the reaction on chip. Syringe pump P1 contained a stock solution of 2,5-hexadione (1) and 2-bromotoluene (internal standard for off-line quantitative GC-FID analysis) in methanol [6]. P2 was charged with a solution of ethanolamine (2) in methanol. The stock solutions of P1 and P2 were pumped into a mixer, which was followed by a reaction channel in which the reaction occurred. To accurately determine the reaction time, acetone was transferred with P3 into a mixer behind the reaction channel, in which the reaction was quenched by imine formation. 2. Reaction optimization Monovariate optimization experiments were performed using a commercially available FutureChemistry FlowStart B-200, including three syringe pumps B230, a microreactor holder, a temperature controller (0–90 °C) and FEP tubing.

194 | 7 Experimental procedures for conducting organic reactions in continuous flow Temperature control 2,5-Hexadione (1) P1 Collection and off-line analysis

M Ethanolamine (2)

M P2

Microreactor

Acetone P3

Pyrrole (3)

Fig. 7.2: Continuous-flow design for the Paal–Knorr reaction.

3.

The microreactor was customized by FutureChemistry (dimensions: 𝐿 45 mm, 𝑊 15 mm, 𝐻 15 mm; channel dimensions: 𝐿 1325 mm, 𝐻 55 μm) having an internal volume of 0.13 μL or 7.02 μL. Temperature, reaction time and molar ratio of ethanolamine (2) to 2,5-hexadione (1 in Figure 7.1) were investigated with respect to the substrate conversion. One parameter was varied and the other two were fixed using parameter values based on data from Amarnath and coworkers [3, 4]. The observed conversions ranged from 20 to 100%. Temperature showed minor influence in this example, while prolonged reaction times and higher stoichiometry led to significantly improved conversions. Next, a multivariate full parametric optimization was conducted, covering potential mutual dependency of parameters, in order to determine the shortest reaction time while maintaining 100% conversion. This optimization was investigated using a commercially available FutureChemistry FlowScreen C-300 with a similar design as shown in Figure 7.1. The FlowScreen had additional computer-controlled software to adjust temperature and flow rates to preset screening sequences. The outlet was directly connected to a sampling unit to deliver the outflow to HPLC vials. Reaction time, stoichiometry and temperature were screened simultaneously using D-optimal-based Design of Experiment (Do E).The resulting samples of the different reactions were analyzed by GC-FID, after which the data points were fitted to a three-dimensional polynomial curve using FlowFit software. The optimal conditions were determined to be 20 °C, 100 seconds and 5.0 molar ratio. Validation on larger scale Validation of the optimal reaction conditions was successfully carried out in a commercially available Uniqsis FlowSyn set-up, using HPLC pumps, a temperature controller and a glass microreactor of 2.4 mL internal volume (Micronit Microfluidics) thereby realizing a roughly 1000-fold scale-up.

7.1 Pyrrole synthesis by Paal–Knorr cyclocondensation | 195

4.

Production on larger scale Using the aforementioned FlowSyn set-up, with four 2.4 mL glass microreactors placed in parallel, a larger volume of pyrrole 3 was produced. This reaction was performed without acetone as quencher, and resulted in 100% conversion, with a total feed of 5.4 mL/min and a total isolated yield of 55.8 g/h (96% yield) of pyrrole 3 (Figure 7.1) using the previously identified optimal conditions.

7.1.3 Experimental procedures 2,5-Dimethyl-1-(methylalcohol)-1H-pyrrole (3 in Figure 7.1) The experiment was conducted in a FutureChemistry FlowStart B-200 containing a 7.02 μL FutureChemistry quench microreactor. 2,5-Hexadione (1, 11.0 g, 96 mmol) and 2-bromotoluene (1.78 g, 10.5 mmol, internal standard) were dissolved in methanol (25 mL) and the stock solution (3.84 M) was taken up in a 2 mL syringe and placed in pump P1. Ethanolamine (2, 7.50 g, 166 mmol) and dimethoxyethane (2.17 g, 24.1 mmol, internal standard) were dissolve in methanol (25 mL) and the stock solution (6.64 M) was taken up in a 2 mL syringe and placed in pump P2. 1-Bromonaphthalene (6.00 g, 29.0 mmol, internal standard) was dissolved in acetone (1 L) and the solution was taken up in a 10 mL syringe and placed in pump P3. The syringes were connected to the respective reactor sites and the outlet tubing was held in a collection vial. The temperature was set to 20 °C, the pumps P1, P2 and P3 were set to 1.07 μL/min, 3.14 μL/min and 17.18 μL/min, respectively, turned on and the system was left to stabilize for 4 min. Subsequently, 1 mL of outflow was collected and analyzed by GC (100% conversion). 1 H NMR (400 MHz, CDCl3 ): 𝛿 5.79 (s, 2H), 3.92 (t, 𝐽 = 6.0 Hz, 2H), 3.78 (t, 𝐽 = 6.0 Hz, 2H), 2.24 (s, 6H), 1.60 (br s, 1H, OH). 2,5-Dimethyl-1-(methylalcohol)-1H-pyrrole (3) (preparative scale) A Uniqsis FlowSyn flow reactor was applied using 20 mL/min syringe pumps (Syntics) and a glass microreactor with an internal volume of 9.4 mL consisting of four parallel 2.4 mL microreactors (Micronit Microfluidics). Bottle one was filled with a 4.4 M solution of 2,5-hexanedione (1) in methanol and bottle two was filled with a 8.3 M solution of ethanolamine (2) in methanol (8.3 M). The pump rates were set to 1.53 and 3.87 mL/min, respectively, and the product was collected for 60 min. The resulting mixture was concentrated under reduced pressure, diluted with 50 mL of water and extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with 1 M HCl (150 mL) and brine (50 mL), dried, filtrated and solvent removed under reduced pressure. The resulting yellow oil crystallized to afford 55.8 g (99% yield) of 2,5-dimethyl-1-(methylalcohol)-1𝐻-pyrrole (3). 1 H NMR (400 MHz, CDCl3 ): 𝛿 5.79 (s, 2H), 3.92 (t, 𝐽 = 6.0 Hz, 2H), 3.78 (t, 𝐽 = 6.0 Hz, 2H), 2.24 (s, 6H), 1.60 (br s, 1H, OH).

196 | 7 Experimental procedures for conducting organic reactions in continuous flow

7.2 Diels–Alder Reactions in flow chemistry 7.2.1 Background Diels–Alder reactions constitute an important class of reactions for the formation of six-membered ring systems. A diene and dienophile react by applying heat to form the corresponding cyclohexene cyclization product through the formation of two new C–C bonds. The Diels–Alder reaction was discovered in 1928 by Otto Diels and his student Kurt Alder and follows a concerted mechanism (Figure 7.3) [7, 8].

Δ

Diene

Dienophile

Cyclohexene

Fig. 7.3: Diels–Alder reaction.

Perhaps more than any other reaction, the Diels–Alder reaction has served as a key step in natural product synthesis, [7] but is also key to large-scale industrial processes for the synthesis of fine chemicals and functionalization of carbon materials [9]. Despite the wide applicability, utilization of the Diels–Alder reaction is sometimes complicated by inconvenient conditions (e.g., high pressure, high temperature), dangerous or highly reactive reagents or complex reactions that require extensive optimization. Most of these difficulties can be overcome by flow chemistry using reactors that allow harsh conditions and fast optimization of in situ generation of dangerous reagents. Kappe and Ley studied the Diels–Alder reaction in a continuous-flow set-up. The Kappe group designed a flow reactor that can be operated under high pressure and high temperature and showed its suitability for a particular Diels–Alder reaction [10]. The group of Ley investigated the in situ generation of dangerous reagents, reaction optimization and complex follow-up reactions using on-line mass spectrometry [11].

7.2.2 The flow process 1.

2.

Continuous-flow design The basic flow set-up for Diels–Alder reactions is straightforward (Figure 7.4). Two or more substances are pumped into the temperature-controlled reactor that is heated either by an oven, microwave or heating bath. The outflow is collected for further workup. In case a reaction is executed at high pressure, a back-pressure regulator can be attached behind the reaction channel [12–19]. Diels–Alder reaction under high pressure and temperature Kappe et al. utilized a continuous-flow set-up as depicted in Figure 7.4 to synthesize cyclohexene 3 from acrylonitrile (2) and butadiene (1, Figure 7.5) [10]. Reactions were performed in an X-Cube Flash reactor (ThalesNano) containing an

7.2 Diels–Alder Reactions in flow chemistry

|

197

Temperature control

1

P1

Collection and off-line analysis

M 2

BPR Oven/Micowave/ Heating bath

P2

3 Fig. 7.4: General continuous-flow set-up for Diels–Alder reactions.

CN

CN

Toluene (2.0 M)

+ 250° C, 60 bar 0.8 mL/min 1

2

3

Fig. 7.5: Diels–Alder reaction.

3.

HPLC pump that was connected to a stainless steel coil (SX316 L). The reaction partners were not expected to react at ambient temperature and pressure so a single pump was sufficient. The coil was heated by direct electric resistance and pressurized via a back-pressure regulator. The pressure inside the reactor was monitored by an in-line pressure sensor. Under optimized reaction conditions, quantitative conversion was reached at 60 bar and 250 °C requiring only 5 min of residence time. Similar results were obtained with lower boiling solvents such as THF (42 bar), MeCN (36 bar) and 1,2-dimethoxyethane (33 bar). The observed conditions exceeded the capability of a batch microwave reactor, which are usually restricted to 20 bar and face serious safety issues during scale-up [10, 20]. Diels–Alder reaction with benzyne generated via diazotization A more complex Diels–Alder reaction was recently studied by Ley and coworkers, which involved the use of benzyne [11]. Diels–Alder reactions with benzyne (6) are troublesome in batch. The reactions provide complex product mixtures making characterization and therefore also optimization rather challenging. In addition, the batch preparation of benzyne via benzenediazonium-2-carboxylate (5) can lead to explosions [21, 22]. In microreactor flow chemistry detonation risks are reduced to a minimum allowing the in situ formation of benzyne followed by the subsequent Diels–Alder reaction with furan. Due to the complexity of this reaction, a reactor design was invented with an on-line mass spectrometer for rapid optimization (Figure 7.6). The optimization experiments were executed in a commercially available FlowSyn system (Uniqsis) equipped with HPLC pumps, mixer, heating block, 6-port valve,

198 | 7 Experimental procedures for conducting organic reactions in continuous flow Temperature control Loading loop

CO2H NH2

Collection and off-line analysis

P1 M1

(34 bar)

Contact heater block

P2

O

BPR1

O t-BuONO

6-port valve

Actetonitrile

P3

BPR2 (7 bar)

Mass spectrometer

6-port valve switching Load

P4

M2

Actetonitrile/water 50:50 (v/v) 0.1% formic acid

In-line filter

Flush

Reactor flow Mass spec. flow

Waste

Fig. 7.6: Continuous-flow design for monitoring Diels–Alder reactions with at-line mass spectrometry.

5 μL loading loop, and a back-pressure regulator. The system was coupled to a commercially available 3500 MiD miniature mass spectrometer (Microsaic Systems) and connected to a high pressure Knauer pump P3 (Wissenschaftlicher Gerätebau Dr. Ing. Herbert Knauer). BPR 2 secured the stability of pump P3. After switching the 6-port valve, the sample was pumped towards the mass spectrometer by pump P3 (Figure 7.6) which provided a flow of acetonitrile (0.1 mL/min.).The obtained mass-sample was diluted with a solution containing 50 : 50 (v/v) acetonitrile/water and 0.1% formic acid by pump P4 (0.9 mL/min). Any residual solid particles present in the sample were removed by an in-line filter prior to analysis. 4. Optimization using on-line mass spectrometry The reaction, depicted in Figure 7.7, was optimized by varying temperature and flow rate/reaction time. By mass spectrometry, several compounds including starting material 4, product 7, side products 8–10 and highly reactive intermediates 5, 11 and 12 could be monitored (Figure 7.8). Optimal conditions for the formation of product 7 were determined to be 50 °C and 3–5 minutes residence time. However, a major downside of this set-up is the precipitation of the reagents

CO2H

‒ CO2

t-BuONO

O

+ N2

NH2 4

O

CO2, N2

5

Fig. 7.7: Diazotization and Diels–Alder reaction.

6

7

7.2 Diels–Alder Reactions in flow chemistry

‒ CO2

CO2H

4

5

CO2Ph NH2 7

8

O

O2N

N H 9

‒ CO2

‒ CO2 + N

+

N H 10

199

O

+ N2

NH2

|

11

12

Fig. 7.8: Products detected in the Diels–Alder reaction.

after cooling and mixing with apolar solvents. One has to take care that the formed solid particles do not block the in-line filter causing the system to shut down.

7.2.3 Experimental procedures 3,4-Dimethylcyclohex-3-enecarbonitrile (3) The experiment was executed in an X-Cube Flash reactor (ThalesNano) containing an HPLC pump and a stainless steel heating coil (4 mL, 8.7 m, ID: 1 mm). The pump was attached to a flask with toluene. The parameters were set to 250 °C and 60 bar and the pump was initiated at 0.8 mL/min. The solvent was pumped through the system until the system achieved the desired parameters and stability. A 5 mL flask was charged with acrylonitrile (2, 105 mg, 133 μL, 2 mmol), 2,3-dimethylbuta-1,3-diene (1, 330 mg, 453 μL, 4 mmol) and 1 mL of toluene (2 M). Subsequently, the flask was switched and the reagents were run through the system. After processing, the system was flushed with toluene for 10 min to collect the remaining product. The process mixture was combined with the washings and concentrated under reduced pressure to afford compound 3 (98%, 264 mg) as a pale yellow oil. (HPLC homogeneity at 215 nm: 99%). 1 H NMR (360 MHz, CDCl3 ): 𝛿 1.63 (s, 6H), 1.83–2.26 (m, 6H), 2.77–2.79 (m, 1H). MS (posAPCI): 𝑚/𝑧 136 (100) [M+ ].

Monitoring of 1,4-dihydro-1,4-epoxynaphthalene synthesis (7) The experiment was conducted in a set-up as depicted in Figure 7.4. Pumps P1 and P2, a mixer, a contact heating block wrapped with tubing (5 mL channel), two 6-port valves, a 5 μL loading loop and a back-pressure regulator (BPR1) were provided within the used FlowSyn system (Uniqsis). The provided 6-port valves for loop injections were configured such that only one was used for the sample preparation in the 5 μL

200 | 7 Experimental procedures for conducting organic reactions in continuous flow loading channel. This valve was connected with two ports to the reactor flow channel, with two ports to the loading channel and with two ports to the mass spectrometry flow channel. The mass spectrometry flow channel was equipped with 1/16󸀠󸀠 PEEK capillary tubing of 127 μm, two high pressure Knauer pumps P3 and P4 (Wissenschaftlicher Gerätebau Dr. Ing. Herbert Knauer), mixer, and an in-line filter with subsequent 3500 MiD miniature mass spectrometer (Microsaic Systems plc, Woking, UK). Pump P3 was connected to the loading loop through a back-pressure regulator (BPR2). The temperature was set to 50 °C and left to warm up. Meanwhile, pumps P1– P4 were equipped with a solution of anthranilic acid in acetonitrile (0.20 M), furan and tertiary-butyl nitrite in acetonitrile (0.24 M), pure acetonitrile and a 50 : 50 (v/v) solution of acetonitrile and water with 0.1% formic acid, respectively. The 6-port valve was switched to flush mode, BPR1 and BPR2 were set to 34 and 7 bar, respectively, and pumps P3 and P4 were initiated at 0.1 and 0.9 mL/min respectively. Once the heating block reached the desired temperature and the mass spectrometer was stabilized, pumps P1 and P2 were initiated at the desired flow rate. Optimal conditions used in this system were 0.05 mL/min flow rates for both pumps (residence time 4 min). After system stabilization, the compound was collected or analyzed by mass spectrometry. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.15–7.17 (m, 2H), 6.94 (s, 2H), 6.87–6.89 (m, 2H), 5.63 (s, 2H); 13 C NMR (100 MHz, CDCl3 ) 𝛿 149.0, 143.1, 125.1, 120.3, 82.4, 82.3 [23].

7.3 Copper-catalyzed azide-alkyne cycloaddition in flow using inductive heating 7.3.1 Background Click chemistry, a term introduced by Sharpless in 2001, refers to reactions with a high yield, a wide substrate scope, easy to remove side-products and solvents, and which are stereoselective and simple to perform [24]. One of the most prominent examples, in fact a reaction that is nowadays known as the click reaction, is the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) which has become a widely applied ligation tool in chemistry and biology [24–26]. A tentative mechanism, postulated by Fokin et al. and refined by several other groups later on, is depicted in Scheme 7.9. It commences with the coordination of copper complex 1 to alkyne 2 leading to the formation of copper alkyne complex 4. Azide 5 then coordinates to copper, followed by direct attack of the distal nitrogen onto the alkyne to afford the six-membered metallacycle 7. The ring contracts to copper-triazole 8, followed by proteolysis to release triazole 9 from the catalytic cycle [27]. Azide-alkyne cycloadditions can be readily applied in batch reactions. However, organic azides form a potential safety hazard due to their explosive nature and thereby impede batchwise scale-up. In flow chemistry, relatively small amounts of azides can be generated in situ, followed immediately by a second reaction with an acetyl to form

7.3 Copper-catalyzed azide-alkyne cycloaddition in flow using inductive heating

| 201

R 2

R N

R1

N

+

CuLn‒1

[CuLn]+

N

R

1

9

3 H+

CuLn‒2

R

N

N N

R

CuLn‒1

4

1

R

8 N CuLn‒2

R

R

CuLn‒2 N N

7

N

+ N N

1

R

+ N N 5 ‒ R1

N 1 ‒ R 6

Fig. 7.9: Mechanism of copper(I)-catalyzed triazole synthesis.

R1 NaN3

R Br

R

Copper source N3

R1 N

N N

R

Fig. 7.10: Triazole synthesis via generating an organic azide in situ from the corresponding bromide.

the corresponding triazole, and thus decreasing the risk of detonation to a minimum (Figure 7.10). Additionally, by applying an immobilized copper-catalyst and/or by introducing a scavenger unit, copper contamination of the product can be significantly reduced. These advantages were incorporated by Kirschning and coworkers in a heterogeneous flow set-up by using trapped copper wire and an in-line scavenger [28]. They developed an inductively-heated copper reactor and used optimized conditions for the synthesis of a series of triazoles. Inductive heating in flow has the main advantage of heat generation from the inside through an inductive material like copper. This ensures the rapid and efficient generation of highly elevated temperatures (220 °C in case of copper) and the additional advantage of guaranteed catalyst activation.

202 | 7 Experimental procedures for conducting organic reactions in continuous flow 7.3.2 The flow process 1.

Continuous-flow design Kirschning’s flow set-up (Figure 7.11) includes a six-port valve connected to four flasks A-D of either starting materials or washing solutions. The solutions were transferred by pump P1 (CHELONA GmbH) to a copper reactor (glass reactor filled with copper wire; void volume: 2 mL) fitted in a custom made inductor (IFF GmbH) which was connected to a magnetic field generator. Flask A was charged with a pure DMF-water mixture (5 : 1). Flasks B-D were loaded with solutions of DMF and water (10 : 1) containing alkyne, bromide and NaN3 , respectively. The solutions were mixed within the six-port valve and pumped in the inductivelyheated reactor where the organic azides were synthesized in situ followed by immediate Cu-catalyzed cycloaddition with the alkyne. A scavenger unit was installed behind the reactor to reduce possible copper leaching prior to sample collection. Magnetic field generator

A: DMF:H2O (5:1) B: Alkyne, DMF:H2O (5:1) C: Bromide, DMF:H2O (5:1) D: NaN3, DMF:H2O (5:1)

Inductor 6-port valve P1

Not used Not used

Reactor lined with copper turnings

Quadrapur® TU scavenger

Triazole Fig. 7.11: Kirschning’s flow design for CuAAC reactions.

2.

3.

Optimization The set-up was optimized for the synthesis of triazole 10. The following parameters were investigated: residence time, temperature, concentration and equivalents of alkyl azide. The optimal conditions were identified as being 150 °C at a flow rate of 0.05 mL/min, with 2 equivalents of both sodium azide and the corresponding bromide. Reactions were performed with 0.25 M solutions of the alkyl bromide and sodium azide and 0.125 M solutions of alkyne since higher concentrations led to blockage of the system by precipitation. Scope of the reaction The optimized conditions were applied in the synthesis of a small selection of triazoles 10–14 (Figure 7.12) affording the compounds in 43–99% yield starting from the corresponding bromides/iodides and alkynes. The conditions for the synthesis of triazoles 11 and 12 could be altered to 100 °C and 0.2 mL/min due

7.3 Copper-catalyzed azide-alkyne cycloaddition in flow using inductive heating |

N

N N

N

OH

N N

N CO2Me

HO

203

N N Br

O2N 10 (70%)

11 (99%) No conversion in batch

12 (90%) TBDPSO

N

N N

NHBoc CO2Me

HO

N

N N

HO 13 (57%)

14 (43%)

Fig. 7.12: Triazoles synthesized in a heterogeneous copper reactor.

to the increased reactivity of the starting materials. Interestingly, using the optimized flow conditions with conventional heating in batch, no conversion into triazole 11 could be achieved.

7.3.3 Experimental procedures 2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (10) Four flasks (A–D) were equipped with washing solutions and starting materials. Bottle A was loaded with a mixture containing a 5 : 1 DMF-water mixture. Flasks B–D were charged with solutions of 2-bromoethanol (0.25 M) (B), phenylacetylene (0.125 M) (C) and sodium azide (0.25 M) (D) in 10 : 1 DMF-H2 O. The bottles were connected to a six-port valve via tubing and the valve was connected to an HPLC pump P1 (Chelona GmbH). Copper wire (𝐿 4 mm, 𝑊 1 mm, 𝐻 1 mm; approximately 24 g) was filled in a glass reactor (dimensions: 𝐿 12 cm, ID 8.5 mm, void volume 2 mL), connected to P1 and fitted into an inductor (IFF GmbH) which was connected to an AC generator. The outlet of the reactor was connected to a scavenger cartridge (Quadrapur® TU) and the final outflow directed to a collection vial. The system was flushed with solution A using a flow rate of 0.2 mL/min. The AC generator was set to 15 kHz and the temperature adjusted to 150 °C with a pyrometer. Once a steady state of temperature and flow was established, the pumping was momentarily ceased, bottle A was disconnected and bottles B-D were connected to the system and run for the desired time at 0.05 mL/min. The collected crude product was diluted with H2 O, extracted with EtOAc, dried with MgSO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford2-(4-phenyl-1𝐻-1,2,3-triazol-1-yl)ethan-1-ol (10) in 70% yield.

204 | 7 Experimental procedures for conducting organic reactions in continuous flow

7.4 Nef Oxidation of nitroalkanes with KMnO 7.4.1 Background Potassium permanganate (KMnO4 ) is one of the most versatile and vigorous oxidants in organic chemistry and has been applied in the oxidation of alkanes, alkenes, alkynes, and alcohols [29]. Additionally, KMnO4 has been applied to the Nef oxidation of primary nitroalkanes (1) to give the corresponding aldehydes (2) or carboxylic acids (3), and secondary nitroalkanes (4) which again can be further oxidized to the corresponding ketones (4) (Figure 7.13) [29–31]. These conversion were shown to be useful in the synthesis of 𝛼-amino acids, conjugated diones, carbacyclic nucleoside precursors and (+)-isomintlactone [31].

H NO2

O

R 2

R1

OH R 1

O

R 3

R

R1 NO2

4

O

R 5

Fig. 7.13: Nef oxidation of nitroalkanes to the corresponding carboxylic acids and ketones.

A major drawback of the use of KMnO4 is the highly exothermic reaction upon contact with an organic substance, which in traditional batch reactors causes potential explosion risks [29, 32]. Flow chemistry in microreactors can reduce the safety risks to a minimum through the small internal dimensions that continuously combine relatively small amounts of KMnO4 and organic material. In this continuous and closed environment, heat is efficiently transferred, eliminating hotspot formation. One issue however, which requires special attention, is the formation of manganese oxide (MnO2 ). This salt precipitates from the reaction mixture and may cause clogging of the narrow flow channels. Baumann and coworkers took on the challenge and investigated the Nef oxidation of primary and secondary nitroalkanes 1 and 4 [33]. With the development of a special flow set-up that could handle MnO2 suspensions (Figure 7.13), Bauman and coworkers were able to rapidly optimize the Nef oxidation reaction and synthesized a variety of aldehydes 2, carboxylic acids 3, and ketones 5.

7.4.2 The flow process 1.

Continuous-flow design The Nef oxidations were performed in a set-up that consisted of two pumps P1 and P2, a subsequent T-piece (M) and a temperature-controlled reactor (Figure 7.14). P1 was loaded with a solution of nitroalkane 1 or 4 and KOH (0.25 M) in methanol, and P2 with KMnO4 dissolved in water (0.2 M). Clogging was avoided by immersing

7.4 Nef Oxidation of nitroalkanes with KMnO |

205

1 or 4 + KOH in MeOH P1 M KMnO4 in H2O

Collection and off-line analysis

P2 Ultrasound waterbath

2,3 or 5

Fig. 7.14: Continuous-flow design for KMnO4 -mediated Nef oxidation.

2.

3.

the mixing T-piece and part of the tubing in an ultrasound bath applying constant sonication or occasional pulsing (e.g., 5 s/min). Optimization Optimization experiments for the synthesis of aldehyde 6 (Figure 7.14) were performed using a commercially available Uniqsis FlowSyn, including two pumps and a 14 mL PFA tube reactor. The ultrasonic water bath was purchased from Ultrawave. Solvent, amount of base, residence time, temperature and concentration were all subsequently changed and the results were analyzed off-line by LC-MS and 1 H NMR to account for conversion and purity. The optimal conditions were found to be 5 minutes residence time at ambient temperature using solutions of KMnO4 (0.8 equiv, 0.2 M) in water and nitroalkane 1 (1 equiv, 0.25 M) and KOH (1.2 equiv) in methanol. Bauman et al. do not specifically report on optimization experiments for the primary nitroalkanes 1, but only state that the optimized conditions are 10 minutes of residence time, ambient temperature while using buffered solutions of KMnO4 (2 equiv, 0.5 M) and Na2 HPO4 (2 equiv) in water and primary nitroalkane (1, 1 equiv, 0.25 M) and KOH (1.2 equiv) in methanol. The additional use of Na2 HPO4 kept the pH constant while acids were generated. Scope of oxidation Having established the optimal conditions for primary and secondary nitroalkanes, a total of 14 carbonyl compounds were synthesized under the aforementioned conditions (Figure 7.14). In the current set-up, Bauman et al. successfully synthesized ketones and aldehydes 6–15 and carboxylic acids 16–19 in good to excellent yields (58–97%). Limitations were encountered with nitroalkanes bearing a 𝛽-amino group with respect to the nitro substituent and with nitro-aldol products except for compound 15.

206 | 7 Experimental procedures for conducting organic reactions in continuous flow 7.4.3 Experimental procedures Cylcohexanone (8) The continuous-flow synthesis of cyclohexanone 8 (Figure 7.15) was performed in a Uniqsis FlowSyn set-up. Two HPLC pumps transferred stock solutions through a T-shaped mixer into the reactor of PFA (perfluoroalkoxy) (14 mL internal volume). The system was operating at ambient temperature and the T-shaped mixer was placed in an ultrasound bath. Pump P1 was equipped with a solution of nitrocyclohexane (60.9 μL, 0.50 mmol) and KOH (33.7 mg, 0.60 mmol) in MeOH (2 mL) and pump P2 was equipped with a solution of KMnO4 (64.3 mg, 0.40 mmol) in water (2 mL). The pumps were initiated at 1.40 mL/min (5 min residence time) each and the crude product was collected in a stirred solution of saturated aqueous NaCl (25 mL) and EtOAc (10 mL). To avoid blockage of the T-shape mixer, the ultrasound bath was briefly pulsed every minute for 5 seconds. After the run was completed, the mixture was extracted multiple times with EtOAc and the combined organic layers were concentrated under reduced pressure to afford cyclohexanone (8, 45 mg, 0.46 mmol) in 92% yield. 1 H NMR (400 MHz, CDCl3 ) 𝛿 2.26 (t, 𝐽 = 6.6 Hz, 4H), 1.83–1.75(m, 4H), 1.68–1.61(m, 2H); 13 C NMR (100 MHz, CDCl3 ) 𝛿 210.9, 40.9, 25.9, 23.9.

H MeO

O

O O

MeO

MeO

HO

t

O Bu

O

F3C

H

7 (88%)

MeO 16 (97%)

10 (85%)

O

O

O

HO

O

O

H

H 13 (87%)

12 (86%) OH

9 (92%)

OtBu

MeO

11 (73%)

14 (74%)

N

17 (78%)

O OH 15 (58%)

O

NO2 MeO

F3C

O O

O

MeO

N

MeO

8 (92%)

O

NO2

MeO

O

MeO 6 (95%)

H

O

CN

O

OH O 18 (77%)

Fig. 7.15: Ketones and carboxylic acids synthesized via Nef oxidation of nitroalkanes.

OH 19 (91%)

7.5 Suzuki–Miyaura cross-coupling with palladium-catalysts generated in flow

| 207

3,4-Dimethoxybenzoic acid (16) The continuous-flow synthesis of 3,4-dimethoxybenzoic acid (16, Figure 7.15) was performed in a Uniqsis FlowSyn set-up. Two HPLC pumps transferred stock solutions through a T-shaped mixer into the reactor of PFA (perfluoroalkoxy) (14 mL internal volume). The system was operating at ambient temperature and the T-shaped mixer was placed in an ultrasound bath. Pump P1 was equipped with a solution of 1,2-dimethoxy-4-(nitromethyl)benzene (248 mg, 1.26 mmol) and KOH (85 mg, 1.51 mmol) in MeOH (5 mL) and pump P2 was equipped with a solution of KMnO4 (398 mg, 2.52 mmol) and Na2 HPO4 (358 mg, 2.50 mmol) in water (5 mL). The pumps were initiated at 0.70 mL/min each and the crude product was collected in a stirred solution of saturated aqueous NaCl (25 mL) and EtOAc (10 mL). To avoid blockage of the T-shape mixer, the ultrasound bath was briefly pulsed every minute for 5 seconds. The product stream was eluted into a stirred mixture of 1M HCl (30 mL) saturated with NaCl and sodium thiosulfate (200 mg) and EtOAc (15 mL). After the run, the mixture was extracted multiple times with EtOAc, the combined organic layers were dried and concentrated under reduced pressure to afford 3,4-dimethoxybenzoic acid (16, 221 mg, 1.21 mmol) in 97% yield. 1 H NMR (400 MHz, CDCl3 ) 𝛿 10.47 (br. s, OH), 7.78 (dd, 𝐽 = 8.4, 1.8 Hz, 1H), 7.60 (d, 𝐽 =1.7 Hz, 1H), 6.92 (d, 𝐽 = 8.5 Hz, 1H), 3.95 (s, 6H); 13 C NMR (100 MHz, CDCl3 ) 𝛿 171.9, 153.8, 148.7, 124.6, 121.7, 112.4, 110.4, 56.1, 56.0.

7.5 Suzuki–Miyaura cross-coupling with palladium-catalysts generated in flow 7.5.1 Background Suzuki–Miyaura coupling reactions are palladium-catalyzed C–C bond formations between two sp2 -hybridized carbon atoms. They have been widely applied to the synthesis of heterocycles [34] and natural products [35] and have been frequently used for the coupling between aryl halides (2, Figure 7.16) and aryl boronic acids (4) [36]. The catalytic cycle commences with the oxidative addition of aryl halide 2 on to palladium(0) complex 1. The resulting palladium(II) complex 3 undergoes transmetallation with boronic acid 4, followed by reductive elimination towards the desired biaryl product 6 [37]. The palladium catalyst can either be recovered in its active form or as precatalyst 7 that is reduced in the reaction mixture to 1. Recent catalyst and method developments broadened the scope of Suzuki– Miyaura coupling reactions enormously [37]. Alkyls, alkenyls and alkynyls can be used instead of aryls, triflates instead of halides and boronic acids can be replaced with a variety of organoboron compounds and borinate esters. The key to the wide applicability of Suzuki–Miyaura coupling resides in the development of suitable palladium-ligand systems. The development of more reactive catalyst systems based on monoligated [Pd(0)L] species allowed the use of less reactive substrates, lowered

208 | 7 Experimental procedures for conducting organic reactions in continuous flow Pd(II) + L

1/2 [ Pd(II)L ]2 7

[ Pd(0) ] 1

Ar-X 2 Oxidative addition

Ar1-Ar 6 Reductive elimination

[ Ar-Pd(II)-X ] 3

Transmetallation

[ Ar1-Pd(II)-Ar ]

Ar1-B(OH)2 4

5 Fig. 7.16: Suzuki reaction mechanism.

catalyst loading and enabled cross-coupling reactions at room temperature [37]. The synthesis of these highly reactive but unstable [Pd(0)L] species (L = phosphine ligand) needs to be executed in situ from the corresponding unstable precatalyst [Pd(II)L]2 , which by itself is generated by mixing Pd(II) with L. Recently, Yoshida and coworkers introduced the concept of “flash chemistry” [39] in which extremely fast reactions are conducted in a controlled manner by using continuous-flow microreactors. With this concept, they allow quick generation of unstable reactive species and its direct use in a subsequent reaction before decomposition by virtue of their short residence time. With the investigation of the Suzuki–Miyaura cross-coupling, Yoshida and coworkers show extremely fast and efficient generation of [Pd(II)L]2 as an application of flash chemistry. After developing a suitable flow design for the synthesis of precatalyst [Pd(II)𝑡 Bu3 P]2 (8), the generation of the complex was optimized and applied in several Suzuki–Miyaura couplings [38].

7.5.2 The flow process 1.

Continuous-flow design The reactor set-up (Figure 7.17) consisted of two syringe pumps P1 and P2 (Harvard Apparatus PHD 2200) which were connected to a stainless steel micromixer M1 (250 μm; SUS304 Synko Seiki Co) through stainless steel connecting units. P1 and P2 contained solutions of Pd(OAc)2 and 𝑡 Bu3 P in THF, respectively. The unstable

7.5 Suzuki–Miyaura cross-coupling with palladium-catalysts generated in flow |

Pd(OAc)2 in THF

P1 250 µm

t

Bu3P in THF

209

P2

M1 R1 8

aryl halide in THF aryl boronic acid in THF KOH in H2O Fig. 7.17: Continuous-flow design for flash generation of catalyst.

2.

3.

4.

palladium precatalyst [Pd(II)𝑡 Bu3 P] (8) was generated in a consecutive stainless steel tube reactor R1 (ID 500 μm, 𝐿 50 cm; SUS316 Synko Seiki Co., Inc.). The outflow was directed to a round-bottom flask containing a stirred solution of suitable coupling partners and base (KOH) in THF. The in-flow prepared precatalyst 8 was reduced within the reaction mixture to catalyst [Pd(0)𝑡 Bu3 P] 9, which then underwent subsequent Suzuki–Miyaura couplings. Optimization of precatalyst generation The precatalyst generation was optimized with the coupling between 𝑝-bromotoluene and phenylboronic acid using the set-up depicted in Figure 7.17. Yoshida et al. envisioned the use of a 1 : 1 ratio of Pd(OAc)2 and 𝑡 Bu3 P and optimized the residence time by tracking of the Suzuki coupling by off-line GC. Correlation between yields after 2 minutes and the residence time showed an optimum at 0.33 seconds. Conventional batch techniques include the simultaneous or successive addition of Pd(OAc)2 and 𝑡 Bu3 P solution and showed lower yield or slower product formation compared to Suzuki–Miyaura coupling with flash generated precatalyst. Spectroscopic analysis of the generated precatalyst To gain a deeper understanding of the nature of the generated precatalyst, spectroscopic studies were performed in a related flow set-up containing identical solutions, pumps, tubing and micromixer as used for the optimization. An additional in-line FT-IR (Smiths Chem ID) was installed behind reactor R1 and monitored the generated palladium-species. The results showed that short residence times supported the formation of precatalyst 8 (Figure 7.18). Longer reaction times suggested the degradation of the desired precatalyst 8 into palladacycle 10 which cannot be reduced to the highly active catalyst [Pd(0)𝑡 Bu3 P] 9. Scope of reaction Compounds 11–24 were synthesized in good to excellent yields between 77 and 100% in 5 min at ambient temperature (Figure 7.19). Recently, Yoshida and coworkers also published a subsequent article in which flash generation of this catalyst was combined with in-flow Suzuki–Miyaura couplings [39].

210 | 7 Experimental procedures for conducting organic reactions in continuous flow t

[Pd(OAc)2]

Bu

O O

Bu

Bu

O

t

P t

O

Pd Bu P O t Bu tBu

t

t Bu P tBu

t

Bu

Reduction

Pd

t

Bu

Bu

Pd

Bu

O 8

t

P t

9

AcOH t

Bu tBu O P Pd O

O Pd P O t Bu tBu 10 Fig. 7.18: Formation of catalyst 10.

R3 R2

R3

S

A

A R1

MeO

11: R1 = Me (100%) 16: R2 = Me (97%) 18: R3 = OMe (96%) 20: A = O (100%) 12: R1 = OMe (100%) 17: R2 = H (97%) 19: R3 = F (100%) 21: A = S (100%) 13: R1 = CN (100%) 14:R1 = CO2Me (95%) 15: R1 = COMe (100%)

N H 22: A = O (100%) 23: A = S (100%)

24: (77%)

Fig. 7.19: Biaryls prepared via flow cross-coupling reactions.

7.5.3 Experimental procedures p-Methylbiphenyl (11) The flow reactor consisted of a T-shaped micromixer M1 (250 μm, SUS304 Synko Seiki Co) which was connected with stainless steel fittings (GL Sciences, 1/16OUW) to a stainless steel tube reactor (R1, ID 500 μm, 𝐿 50 cm, SUS316 Synko Seiki Co.). Syringe pumps P1 and P2 (Harvard Apparatus PHD 2200) were connected to M1 by connecting units (ID 1000 μm, 𝐿 100 cm; SUS316 Synko Seiki Co.). A round-bottom flask, equipped with a stir bar, was charged with a solution of 𝑝-bromotoluene in THF (0.267 M, 0.75 mL), a solution of phenylboronic acid in THF (0.16 M, 1.5 mL) and a solution of KOH in H2 O (0.128 M, 2.0 mL). The resulting mixture was stirred for 5 min at 24 °C. Meanwhile, prepared solutions of palladium acetate in THF (2.67 mM) and tri-tert-butylphosphine in THF (2.67 mM) were taken up by syringes and placed in P1 and P2, respectively. Both syringes were fitted to the connecting units and both pumps were initiated at 4.5 mL/min. After a steady-state had been reached in the system, the

7.6 Oxidative amidation of aromatic aldehydes |

211

solution was dripped into the round-bottom flask for 10 seconds. The resulting mixture was stirred for 5 minutes at 24 °C, quenched with 1N HCl and analyzed by GC to reveal quantitative formation of 𝑝-methylbiphenyl (11). 1 H NMR (600 MHz, CDCl3 ): 𝛿 7.58–7.57 (d, 𝐽 = 7.2, 2H), 7.50–7.48 (d, 𝐽 = 7.8, 2H), 7.43–7.41(t, 𝐽 = 7.5, 2H), 7.33–7.30 (t, 𝐽 = 7.5, 1H), 7.25–7.24 (d, 𝐽 = 7.2, 2H), 2.39 (s, 3H); 13 C NMR (75 MHz, CDCl3 ): 𝛿 141.2, 138.4, 137.1, 129.6, 128.8, 127.1, 21.2 [40].

In-line flow FT-IR spectroscopic analysis The flow reactor consisted of a T-shaped micromixer M1 (250 μm, SUS304 Synko Seiki Co) that was connected with stainless steel fittings (GL Sciences, 1/16OUW) to a stainless steel tube reactor (R1, ID 500 μm, 𝐿 varies with residence time, SUS316 Synko Seiki Co.). Syringe pumps P1 and P2 (Harvard Apparatus PHD 2200) were connected to M1 by connecting units (ID 1000 μm, 𝐿 100 cm; SUS316 Synko Seiki Co.). R1 was immersed into a heating bath and an in-line FT-IR (Smiths Chem ID) was installed behind it. Prepared solutions of palladium acetate in THF (0.025 M) and tri-tert-butylphosphine in THF (0.1 M) were taken up by syringes and placed in P1 and P2, respectively. Both syringes were fitted to the connecting units and P1 and P2 were initiated at 2.4 mL/min and 0.6 mL/min, respectively. After a steady-state had been reached in the system, the resulting reaction mixture was analyzed by in-line FT-IR. Variable residence times where obtained by changing the length of R1.

7.6 Oxidative amidation of aromatic aldehydes 7.6.1 Background Amide bonds are ubiquitous in synthetic and naturally-occurring molecules. They exist, for example, in drugs [41] and polymers, [42] but perhaps most importantly are the bonds that peptides and proteins are made of. A prevalent synthetic strategy for amide bond formation is the coupling between activated carboxylic acids (e.g., acid chlorides, (mixed) anhydrides) and amines [43, 44]. If the appropriate carboxylic acid is not available, it can be prepared via oxidation of the corresponding alcohol or aldehyde. However, direct utilization of the alcohol or aldehyde in an oxidative one-step process would result in a more economic synthesis reducing waste and time, and hence lower production costs. In such an oxidative amidation, an aldehyde (1) and an amine (2) are converted into the corresponding amide (3) using an appropriate oxidant (Scheme 7.20) [45, 46]. Hydrogen peroxide is a cheap and environmentally-benign oxidant, but represents a potential safety hazard, especially on larger scale and in higher concentrations. In flow chemistry, the small internal dimensions of the microreactor lower safety risks, reduce waste during optimization and therefore contribute significantly

212 | 7 Experimental procedures for conducting organic reactions in continuous flow O + R

HN

R

O

Oxidant

R

R1

H

R

R1 3

2

1

N

Fig. 7.20: Oxidative amidation.

to the green character of the reaction. Jensen and coworkers successfully studied the oxidative amidation of aromatic aldehydes in a continuous-flow set-up [47]. They constructed their own microreactor, followed by integration in a flow system which allowed rapid screening of the reaction conditions and synthesis of a series of amides in an oxidative manner.

7.6.2 The flow process 1.

Continuous-flow design The set-up (Figure 7.21) included two syringe pumps P1 and P2 (Harvard Apparatus 9801781) connected via Teflon tubing (Upchurch, ID 500 μm) to a silicon-Pyrex microreactor (230 μL) developed by the Jensen laboratory [48]. P1 was loaded with a solution of aldehyde and aqueous hydrogen peroxide in acetonitrile while P2 was charged with a solution of the secondary amine in acetonitrile. Samples were taken by using a 6-port valve (Upchurch, V-451). The waste was collected behind the valve and back-pressure regulator (BPR). Pressure was applied by a N2 highpressure gas cylinder and controlled by a stainless steel vessel (Parr Instrument, N4714B) and adjusted by a micrometering needle valve. Temperature control

1 + H2O2 (aq.) in MeCN

P1 M

2 in MeCN

P2 Cold section Hot section

6-port valve

Product or waste collection

BPR

Sample BPR collection

Microreactor

N2 Needle valve

Pressure regulator Fig. 7.21: Continuous-flow design for oxidative amidation.

7.6 Oxidative amidation of aromatic aldehydes |

O N R1

O

15 (92%)

14 (92%)

O N

MeO

17 (93%)

MeO

N

O Cl

O 13 (93%)

O N

N

N

O

4: R1 = H (86%) 5: R1 = OMe (93%) 6: R1 = Me (92%) 7: R1 = iPr (93%) 8: R1 = F (93%) 9: R1 = Cl (91%) Cl 10: R1 = Br (91%) 11: R1 = CN (93%) 12: R1 = NO2 (92%)

O

O

O MeO

213

O N

18 (92%)

MeO

O N

19 (94%)

16 (93%) Ot-Bu

O N

20 (88%)

Fig. 7.22: Amides synthesized by oxidative amidation.

2.

3.

Optimization Optimization was executed with the aforementioned design (Figure 7.21). Temperature, concentrations and reaction time were rapidly optimized by off-line GC analysis for each substrate individually. Therefore, an internal standard (𝑝-xylene) was added to the solution of P1. The oxidative amidations were successfully executed in 15–40 minutes under temperatures between 70 and 110 °C. Scope of reaction Compounds 4–20 were obtained in good yields between 86 and 94% based on the GC yield analysis (Figure 7.22). Several substituents on the aromatic aldehyde were tolerated in reactions with morpholine as the amine nucleophile. Piperidine, pyrrolidine, phenyl methanamine and proline tert-butyl ester were shown to be suitable amines.

7.6.3 Experimental procedures Morpholino(phenyl)methanone (4) The experiment was performed in a continuous-flow system using a spiral-channel silicon-Pyrex microreactor (230 μL volume) made by Jensen and coworkers. The inlets of the reactor were connected to Teflon tubing (Upchurch, ID 500 μm) and the outlet was connected to a 6-port valve (Upchurch, V-451) for sample collection followed by a 3-port valve that connected two paths with each other. One path was equipped with a back-pressure regulator and collection vial. The other path was equipped with a backpressure regulator followed by an N2 high-pressure gas cylinder in order to provide additional back pressure. The pressure was controlled by a stainless steel vessel (Parr Instrument, N4714B) and adjusted by a micrometering needle valve. In this way, pressures between 20–60 psi could be obtained. The temperature was controlled by a PID controller (Omega, CN7833) that was connected to the heating cartridges inserted into the packaging chuck.

214 | 7 Experimental procedures for conducting organic reactions in continuous flow The reactor was left to warm up to 80 °C and sufficient back pressure was applied to keep acetonitrile from boiling. Glass syringes (Hamilton, GasTight) containing solutions of benzaldehyde (1 M) and aqueous hydrogen peroxide (1.2 M) and 𝑝xylene (0.5 M, internal standard) in acetonitrile and morpholine in acetonitrile (4 M). The syringes were loaded in the corresponding pumps P1 and P2 (Harvard Apparatus, 9801781) and connected to the reactor inlets. Both pumps were initiated at 2.88 μL/min (40 min residence time) and samples were collected for GC analysis with an FID detector. Yields were determined with respect to 𝑝-xylene. 1 H NMR (500 MHz, CDCl3 ), 𝛿 7.44 (m, 5H), 3.79–3.47 (m, 8H); 13 C NMR (125 MHz, CDCl3 ), 𝛿 170.4, 135.3, 129.9, 128.5, 127.1, 66.9, 43.1; IR (thin film) 2855, 1628, 1426, 1277, 1257, 1112, 1067, 1016, 933, 841 cm−1 [49].

p-(Fluorophenyl)(morpholino)methanone (8) The experiment was performed in a continuous-flow system using a spiral-channel silicon-Pyrex microreactor (230 μL volume) made by Jensen and coworkers. The inlets of the reactor were connected to Teflon tubing (Upchurch, ID 500 μm) and the outlet was connected to a 6-port valve (Upchurch, V-451) for sample collection followed by a 3-port valve that connected two paths with each other. One path was equipped with a back-pressure regulator and collection vial. The other path was equipped with a backpressure regulator followed by an N2 high-pressure gas cylinder in order to provide additional back pressure. The pressure was controlled by a stainless steel vessel (Parr Instrument, N4714B) and adjusted by a micrometering needle valve. In this way pressures between 20–60 psi could be obtained. The temperature was controlled by a PID controller (Omega, CN7833) that was connected to the heating cartridges inserted into the packaging chuck. The reactor was left to warm up to 90 °C and sufficient back pressure was applied to keep acetonitrile from boiling. Glass syringes (Hamilton, GasTight) containing solutions of 𝑝-fluorobenzaldehyde (1 M) and aqueous hydrogen peroxide (1.2 M) in acetonitrile and morpholine in acetonitrile (4 M). The syringes were loaded in the corresponding pumps P1 and P2 (Harvard Apparatus, 9801781) and connected to the reactor inlets. Both pumps were initiated at 5.75 μL/min (20 min residence time) and eight samples from the same stock solution were collected. The combined solutions were mixed with water, extracted with DCM and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, DCM:EtOAc = 5 : 1) to afford the product as light yellow crystals. 1 H NMR (400 MHz, CDCl3 ): 𝛿 3.25–3.96 (m, 8H), 7.29–7.35 (m, 4H); 13 C NMR (101 MHz, CDCl3 ): 𝛿 67.0, 128.9, 129.1, 133.8, 136.2, 169.6.

7.7 Azide synthesis in flow via diazotransfer

| 215

7.7 Azide synthesis in flow via diazotransfer 7.7.1 Background Organic azides have shown to be valuable and versatile intermediates in organic synthesis [50–54]. However, trace amounts of acid or certain metal salts may catalyze explosive decomposition due to the formation of molecular nitrogen. In addition, organic azides may also be shock and/or heat sensitive and will generally decompose on exposure to UV light [55, 56]. Organic azides are commonly synthesized via the substitution of a halide with an inorganic azide [57]. However, the applicability of this method is significantly hampered through the requirement of toxic sodium azide [58, 59]. An alternative route to organic azides proceeds via diazotransfer onto amine functionalities (Scheme 7.23). Triflyl azide is generally used as diazotransfer reagent, but is highly explosive in neat form and has a relatively short shelflife, due to its reactive nature, and needs to be prepared directly prior to use [60]. Recently, Goddard-Borger and Stick invented a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride (2) [61], which is nonexplosive, easy to prepare, and eventually, cheaper, compared to triflyl azide. This allows reagent 2 to be prepared in large amounts and handled in neat form rather than in solution.

NH2 1

+

+ – N N N 2

S O N

N

O H N

+

H

N

N

–N

N3

O S O N

3

N

+ O H2N S N O

N

Fig. 7.23: Proposed mechanism for the diazotransfer synthesis of benzylamine.

The synthesis of organic azides in flow strongly illustrates the benefits of microreactor technology, in particular the inherently safe way of conducting chemistry due to small hold-up volumes and the closed system. Converting a known batch reaction into a flow synthesis is quite straightforward but does require some additional investigation. The high surface-to-volume ratio and excellent mass transfer in a microreactor greatly influences the reaction conditions such as temperature and reaction time. Rutjes and coworkers developed a standard protocol to convert a batch process into a continuous-flow process including optimization of the reaction conditions [62].

216 | 7 Experimental procedures for conducting organic reactions in continuous flow 7.7.2 The flow process This protocol, converting a batch process into a gram-scale production flow process, involves the following four stages: 1. Batch scale synthesis Diazotransfer reactions can be performed with catalytic amounts of zinc chloride or copper sulfate [63]. Since both catalysts showed no difference in the formation of benzyl azide (3), Rutjes et al. arbitrarily chose zinc chloride. First, batch-scale experiments were performed to develop a suitable quenching method in order to ensure well-defined residence times in the continuous-flow system. A 1 M solution of hydrochloric acid in ethyl acetate/acetone (1 : 1) was identified as an adequate method. Secondly, an investigation of several analytical techniques led to identification of GC as a fast method that provided prompt and accurate data. 2. Continuous-flow design The reactor set-up is schematically represented in Figure 7.23. It consists of three syringe pumps P1-P3 and a glass microreactor with temperature control and the possibility to quench the reaction on chip. Pump P1 was loaded with a syringe containing a stock solution of benzylamine (1), DIPEA, and zinc chloride (ZnCl2 ) in methanol/dichloromethane. Pump P2 was charged with a syringe containing a solution of imidazole-1-sulfonyl azide HCl (2) and DIPEA in methanol/dichloromethane. The solutions of P1 and P2 were pumped into a mixer followed by a reaction channel. To accurately determine the reaction time, a solution of hydrochloric acid in ethyl acetate and acetone was transferred with P3 to a mixer behind the reaction channel instantly quenching the reaction. 3. Reaction optimization Univariate optimization experiments were performed using a commerciallyavailable FutureChemistry FlowStart B-200, including three syringe pumps, a microreactor holder, a temperature controller (0–90 °C) and FEP tubing. The single glass microreactor (Micronit, channel dimensions: 𝑊 600 μm, 𝐻 500 μm) having an internal volume of 92 μL contained two mixing units M. In case of short reaction times, experiments were performed in custom-made single glass microreactor (channel dimensions: 𝑊 120 μm, 𝐻 55 μm) having an internal volume of 7.0 μL. This channel layout did not contain separate mixing units. Temperature, reaction time and molar ratio of diazotransfer reagent 2 to amine (1) was investigated with respect to the substrate conversion. One parameter was varied and the other two fixed. All three of the parameters were shown to be kinetically critical parameters. Next, a multivariate optimization was conducted, in order to determine mutual dependency of the three parameters. For this investigation, a computer-controlled FutureChemistry FlowScreen C-300 set-up was used. Reaction time, molar ratio and temperature was screened simultaneously using D-optimal-based Design of Experiment (DoE). The 60 resulting samples of the different reactions were an-

7.7 Azide synthesis in flow via diazotransfer

4.

| 217

alyzed by GC-MS, after which the data points were fitted to a three-dimensional polynomial curve using FlowFit software. The theoretical optimal conditions were determined to be 1.8 °C, 535 seconds and 4.6 molar ratio. Production on larger scale Based on the plots obtained from the multivariate optimization, it was determined to choose a second set of optimal parameters. Performing the reaction at room temperature would eliminate the need of additional cooling. At this slightly elevated temperature, less diazotransfer reagent (2) was necessary, only four equivalents instead of 4.6, decreasing production costs. Under these conditions, a reaction time of 600 seconds was required to obtain complete conversion. A gram-scale production was performed in a Uniqsis FlowSyn set-up consisting of 20 mL stainless steel coil and HPLC-pumps. Two bottles containing the stock solutions were prepared and a collection flask containing 230 mL quenching solution. After collecting for 95 min, the mixture was washed and extracted to obtain benzyl azide in 65% yield (solvated in diethyl ether).

7.7.3 Experimental procedures Benzyl azide (3) (Optimization experiment) A FutureChemistry FlowStart set-up was used including three glass syringes with an internal volume of 1 mL for pumps P1–P3. Pump P1 contained a solution of benzylamine (1, 328 μL, 3.0 mmol), diisopropylamine (DIPEA, 1.57 mL, 9.0 mmol), ZnCl2 (183 μL of 2.19 g/L MeOH/CH2 Cl2 (10 : 3), 3.0 μmol), and 2-bromotoluene (250 μL, internal standard A) in MeOH/CH2 Cl2 (10 mL, 10 : 3 v/v). Pump P2 contained a solution of imidazole-1-sulfonylazide hydrochloride (2, 625 mg, 3.0 mmol), DIPEA (524 μL, 3.0 mmol), and 5-bromo-𝑚-xylene (250 μL, internal standard B) in MeOH/CH2 Cl2 (10 mL, 10 : 3 v/v). In order to quench the reaction at the end of the channel, ensuring Temperature control

Benzylamine (1) DIPEA, ZnCl2 MeOH/CH2Cl2 (3:10) P1 M

Imidazole-1-sulfonylazide HCl (2), DIPEA MeOH/CH2Cl2 (3:10)

M P2

Collection and off-line analysis

Microreactor Benzyl azide (3)

HCl/EtOAc/acetone P3 Fig. 7.24: Continuous-flow design for the diazotransfer reaction of benzyl azide.

218 | 7 Experimental procedures for conducting organic reactions in continuous flow well-defined residence times, pump P3 contained a solution of HCl (500 μL, 37% concentrated HCl) in EtOAc/acetone (10 mL, 1 : 1 v/v), which was added to the reaction after the residence time channel (shown as meander channels in Figure 7.24). The product (5 μL) was collected in CH2 Cl2 (100 μL) containing 2‰ cyclooctane as an external standard. 1 H NMR (400 MHz, CDCl3 ): 𝛿 4.36 (s, 2H), 7.34–7.40 (m, 5H); 13 C NMR (400 MHz, CDCl3 ): 𝛿 54.85, 128.28, 128.37, 128.89; IR (neat): 𝜈 3032, 2929, 2089 (C-N3 absorption band), 1738, 1496, 1455, 1349, 1252, 1202, 1078, 1029, 875, 735, 695 cm−1 [64].

Benzyl azide (3) (Preparative Scale) A Uniqsis FlowSyn equipped with a 20 mL stainless steel coil reactor was applied in the preparative synthesis of benzyl azide. With a flow P1 of 0.4 mL/min and flow P2 of 1.6 mL/min, a residence time of 10 min was obtained. The product was collected for 95 min after 15 min of stabilization. Pump P1 continuously pumped a solution of benzylamine (1, 3.28 mL, 30 mmol), DIPEA (15.7 mL, 90 mmol), and ZnCl2 (1.87 mL of 2.19 g/L MeOH/CH2 Cl2 (10 : 3 v/v), 30 μmol) in MeOH/CH2 Cl2 (100 mL, 10 : 3 v/v). Pump P2 was used for the solution containing imidazole-1-sulfonyl azide hydrochloride (2, 12.5 g, 60 mmol) and DIPEA (10.5 mL, 60 mmol) in MeOH/CH2 Cl2 (200 mL, 10 : 3 v/v). In contrast to the optimization set-up, no quench pump was used because the residence time in the larger set-up could easily be determined. In order to stop the reaction, the product was collected in a quenching solution being 1 M HCl in EtOAc/acetone (230 mL, 1 : 1 v/v). After collecting the product for 95 minutes, the reaction mixture was slowly concentrated under reduced pressure (max 200 mbar in a 40 °C water bath) to 30 mL. Care should be taken during this process due to the low vapor pressure of benzyl azide. The residual yellow oil was filtrated over silica (7 × 10 cm) using Et2 O as the eluent. Bulk solvent was gradually removed under reduced pressure (600 mbar in a 40 °C water bath) up to 50 mL and the residual crude product was washed with 1 M HCl (3 × 50 mL) and brine (50 mL), dried over Na2 SO4 , filtrated and concentrated under reduced pressure (600 mbar in a 40 °C water bath). The remaining oil was then diluted with 15 mL Et2 O and again washed with 1 M HCl (3 × 10 mL) dried over Na2 SO4 , filtrated and concentrated under reduced pressure (max 180 mbar in a 40 °C water bath) to yield a solution of 993 mg (7.4 mmol) benzyl azide (3) in Et2 O. This is in accordance with a calculated yield of 65% based on 1 H NMR analysis. 1 H NMR (400 MHz, CDCl3 ): 𝛿 4.36 (s, 2H), 7.34–7.40 (m, 5H); 13 C NMR (400 MHz, CDCl3 ): 𝛿 54.85, 128.28, 128.37, 128.89; IR (neat): 𝜈 3032, 2929, 2089 (C-N3 absorption band), 1738, 1496, 1455, 1349, 1252, 1202, 1078, 1029, 875, 735, 695 cm−1 [64].

7.8 Boronic acid/ester synthesis via lithium halogen exchange in a Cryo-Flow Reactor

|

219

7.8 Boronic acid/ester synthesis via lithium halogen exchange in a Cryo-Flow Reactor 7.8.1 Background Boronic esters and acids are versatile synthetic compounds with a wide application in C–C, C–N and C–O bond formation [65]. Besides their synthetic utility, some boroncontaining compounds show biological activity or employ unique features interesting for organic materials [66]. The most relevant synthetic route to produce aryl boronic esters or acids proceeds via organometal halogen exchange based on magnesium or lithium. This transformation involves the formation of an aryl-metal complex followed by a consecutive borylation (Figure 7.25). O i

PrO–B O

Ar–X

n-BuLi

Ar–BPin

[ Ar–Li ] B(OiPr)3

Ar–B(OH)2

Fig. 7.25: Boronic acid and ester synthesis by lithium halogen exchange.

Lithium halogen exchange syntheses require low temperatures and inert atmospheres to avoid undesired side-reactions of the in situ generated, highly reactive aryl lithium species. Large batch reactors lack the possibility to accurately control homogeneous reaction temperatures. Therefore, scale-up of the organolithium halogen exchange reaction is limited and hampers the wider application of boronic esters and acids on an industrial scale. Continuous-flow technology offers small reactor channels resulting in a high surface-to-volume ratio compared to a batch reactor. Cooling under these conditions is efficient and provides optimal control over the internal reaction temperature. Ley and coworkers investigated the synthesis of boronic esters and acids via lithium halogen exchange in flow [67, 68]. Their reactor design included a cryo-flow reactor that allows highly controlled and efficient cooling to very low temperatures. After the investigation of workable concentrations, the flow set-up was utilized for the synthesis of several boronic acids and rapidly scaled-up [68]. 7.8.2 The flow process 1.

Continuous-flow design The reactor set-up (Figure 7.26) consisted of two pumpsP1 and P2 which each were connected to a 10 mL injection loop via a 3-way valve (?). The subsequent reac-

220 | 7 Experimental procedures for conducting organic reactions in continuous flow Temperature control n-BuLi in hexanes (1.5 equiv) THF 0.5 mL/min

THF 0.5 mL/min

P1 10 mL injection loop connected via a 3-way valve ( ) and a 2-way valve ( ) P2

M

Cryo-flow reactor –60 °C

Collection

Boronic ester (after acidic workup)

Aryl halide in THF (1 equiv) PinBOiPr or B(OiPr)3 in THF (1 equiv) Fig. 7.26: Continuous-flow design for boronic acid synthesis via lithium halogen exchange.

2.

3.

tor consisted of a 1 mL precooling loop for each stream, followed by a mixer and 20 mL reactor coil. The injection loops were charged with 𝑛-BuLi in hexanes and the aryl halide in THF, respectively, with either isopropylboronic acid pinacol ester (PinBO𝑖 Pr) or triisopropyl borate (B(O𝑖 Pr)3 ). During the reactions the pumps were adjusted to a flow of 0.5 mL THF per minute. The collected crude product was purified to give the desired boronic acid or ester after aqueous acidic workup. Investigation of workable concentrations Concentrations were investigated in commercially available pumps from Syrris, Uniqsis or Vapourtec, injection channels consisting of PFA tubing and a commercially available Polar Bear® cryo-reactor. The reactor was especially designed to maintain temperatures as low as −88 °C. The reaction coil was wrapped around a metal cylinder that was cooled from inside and topped with a bell jar (Figure 7.26). Being aware of the formation of insoluble boronate salts complexes and hence potential clogging of the reactor tubing, the concentration of the solutions was initially set to 0.10 M and 0.15 M for the aryl halide and B(O𝑖 Pr)3 and 𝑛-BuLi, respectively, for the formation of boronic acid 1 after acidic work-up. Precipitation was not observed at these concentrations; indeed, this reaction performed well up to 0.40 M loadings of the aryl halide yielding product 1 in 77% yield after acidic work-up. At concentrations above 0.40 M, thick precipitates were observed in the reactor loop and pumping was therefore ceased. Scope of lithiation reaction Having established suitable conditions for the synthesis of boronic acid 1, identical conditions were directly applied in the preparation of the pinacol (Pin) boronate ester analogue 2 by switching the electrophile from B(O𝑖 Pr)3 to PinBO𝑖 Pr yielding boronic ester 2 in 74% yield. Further extension of the scope resulted in the synthesis of boronic esters 3 to 11 all obtained in yields ranging from 78–95%

7.8 Boronic acid/ester synthesis via lithium halogen exchange in a Cryo-Flow Reactor

(a)

|

221

(b)

Fig. 7.27: Polar Bear® (a), reaction channel with tubing (b); Source: www.uniqsis.com.

BPin

B(OH)2 F

F

BPin Cl

BPin ( )n

O Cl

H 1 (77%)

2 (74%)

BPin

3: n = 0 (88%) 4: n = 1 (90%)

5 (95%)

6 (93%)

BPin BPin

BPin

BPin

BPin

S

F3C

Cl 7 (78%)

8 (78%)

9 (93%)

10 (95%)

TMS 11 (90%)

Fig. 7.28: Boronic acids and esters prepared in continuous flow.

4.

on a scale between 540 and 1010 mg after acidic workup (Figure 7.28). During the investigation the cryo-flow reactor was continuously used for 288 hours at 60 °C without frosting or other problems [67]. Continuous production and scale-up The process was scaled-up for the synthesis of 𝑝-trifluoromethylbenzeneboronic ester (7). The injection channels of the original reactor design were insufficient for the increased amount of reagents. Therefore, the channels and pumps were replaced with two K-120 piston pumps that continuously pumped the reagents from the corresponding stock solutions. The tubing and cryo-flow reactor remained identical (Figure 7.29).

222 | 7 Experimental procedures for conducting organic reactions in continuous flow Temperature control n-BuLi in hexanes (1.6 M) 0.2 mL/min

P1 BPin M

p-F3C-Ph-Br, PinBOiPr in THF (0.2 M) 0.8 mL/min

P2

Cryo-flow reactor –60 °C

CF3 7

12.87 g 99% yield

Fig. 7.29: Scale-up continuous-flow design.

In an attempt to directly apply segmented flow conditions to a continuous process, it was found that pumping could only be maintained for approximately 45 min. After this period the cooled reactor coils became blocked by thick slurry, presumably the boronate complex. Unlike the previous procedure, the incoming solvent stream was inefficient. In order to deal with this blockage an obvious solution was to lower the concentration and increase the content of the more polar solvent in the product stream. The optimal conditions were found to be 𝑛-BuLi (1.6 M in hexanes) with a flow rate of 0.2 mL/min and 𝑝-trifluoromethylbromobenzene and PinBO𝑖 Pr (both 0.2 M in THF) with a flow rate of 0.8 mL/min. The resulting solvent ratio and reagent concentrations prevented the system from clogging. After collecting for 5 hours, 𝑝-trifluoromethylbenzeneboronic ester (7) was obtained in 99% yield (12.9 g) after acidic workup.

7.8.3 Experimental procedures 2-(4-Ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) The experiment was performed using Vapourtec R-series pumps, PTFE tubing, and a Polar Bear® cryo-flow reactor (Cambridge Reactor Design). The reactor was set to 60 °C. Pumps P1 and P2 were both positioned in a flask with dry THF and initiated at 0.5 mL/min for 30 min. P1 and P2 were momentarily ceased and both sides of the injection channels were disconnected from the flow system. The termini were diverted to a waste container. In a 12 mL disposable syringe, dry hexanes (7 mL) and 1.6 M 𝑛-BuLi (4 mL, 6.4 mmol) were swirled and the resulting 11 mL solution (0.6 M) was fully injected into the loading channel of P1. A volume of 9.5 mL of a stock solution of 2-isopropoxy4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (0.4 M) was then taken up into a 12 mL syringe and partially dispensed into a vial containing 1-bromo-4-ethylbenzene

7.9 The Ritter Reaction in Continuous Flow |

223

(740 mg, 4 mmol): before being taken up back into the syringe, this process was repeated two more times. The syringe was swirled and the solution was injected into loading channel P2. Both loading channels were reconnected to the reactor and the 3-way valves were switched to connect the pumps to the channels. In the meantime, the desired temperature was reached and the pumps were started at 0.5 mL/min. After approximately 1 hour, the collected material was concentrated in vacuo to a 5 mL solution. Subsequently, 1 M HCl (2 mL) and EtOAc were added and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried with MgSO4 and concentrated in vacuo to afford 2-(4-ethylphenyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) as colorless solid plates (836 mg, 90% yield). 1 H NMR (400 MHz, CDCl3 ): 𝛿 7.74–7.78 (m, 2H), 7.21–7.25 (m, 2H), 2.67 (q, 𝐽 = 7.5 Hz, 2H), 1.35 (s, 12H), 1.26 (t, 𝐽 = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3 ): 𝛿 147.8, 135.0, 127.4, 83.7, 29.2, 24.9, 15.5. 4,4,5,5-Tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (7) A Uniqsis Polar Bear High Performance Chiller Unit was applied which contained two K-120 piston pumps. The reactor was set to 60 °C. Pumps P1 and P2 were positioned in a flask of dry hexanes and THF, respectively, and initiated at 0.5 mL/min. After 15 min, pumping was stopped and the inlet of P1 was switched to a flask containing a solution of 1-bromo-4-(trifluoromethyl)benzene and 2-isopropoxy4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (both 0.2 M). The inlet of P2 was changed to a commercially available flask containing 1.6 M 𝑛-BuLi in hexanes. Subsequently, P1 and P2 were initiated at 0.2 and 0.8 mL/min, respectively, and after 30 min a pale yellow solution was collected for a total of 5 hours. The volume was decrease to 1/10 of the original volume under reduced pressure, water was added and the mixture was extracted with EtOAc. The aqueous phase was treated with 1M HCl (15 mL) and EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layer were dried with MgSO4 and concentrated in vacuo. The residue was coevaporated with Et2 O (40 mL) which afforded 4,4,5,5-tetramethyl-2-(4(trifluoromethyl)phenyl)-1,3,2-dioxaborolane as an off-white solid (12.9 g, 99% yield). 1 H NMR (400 MHz, CDCl3 ): 𝛿 7.90–7.93 (m, 2H), 7.60–7.64 (m, 2H), 1.36 (s, 12H); 13 C NMR (100 MHz, CDCl3 ): 𝛿 135.0, 132.9 (q, 𝐽𝐶−𝐹 = 32 Hz), 124.3 (q, 𝐽𝐶−𝐹 = 4 Hz), 124.2 (q, 𝐽𝐶−𝐹 = 269 Hz), 84.3, 24.9.

7.9 The Ritter Reaction in Continuous Flow 7.9.1 Background The synthesis of amides via trapping carbocation intermediates with organic recognized known as the Ritter reaction [69, 70]. It is a reaction that has been widely applied in organic synthesis and its relevance is also underlined by the application in syntheses of Symmetrel® [71] and Crixivan® [72] on an industrial scale. The mechanism

224 | 7 Experimental procedures for conducting organic reactions in continuous flow H +

R1

R

H

2

OH

R

R

2

R3

1

R R2 R3

R4 +

N

+ R3

1

2

H N

O R4

7

1

R R2 R3

H N

O

H

1

+ N

R1 R2 R3

3

+O

R4

4

H +O

B H

R4 6

1

R R2 R3

H

N H

R4

+ 5

Fig. 7.30: Ritter reaction mechanism starting from tertiary alcohol 1.

involves the nucleophilic attack of nitrile 3 onto carbocation ion 2 which is generally generated from tertiary alcohols or alternatively by alkenes or secondary and activated alcohols under acidic conditions (7.30). The resulting nitrilium ion 4 is then trapped by water, giving rise to partial hydrolysis affording the corresponding amide 7 [72]. Despite the successful industrial application of the Ritter reaction, its exothermic nature, the use of toxic and violently reacting reagents, and the strongly acidic conditions are major concerns [73–75]. Therefore, the scale-up process in large batch reactors is complicated by the chemical or technological solutions that prevent the formation of hot-spots and thermodynamic runaways. This led to the development of more benign versions that focus mainly on the use of catalytic amounts of Brønsted and Lewis acids [76]. On a different note, flow chemistry solutions have been investigated, since micro- and mesoreactors are due to their intrinsic properties highly suited for the use of dangerous reagents or in situ generated toxic intermediates and thereby increasing the safety of such processes. Additionally, the high surface-to-volume ratio is ideal for efficient heat transfer easing scale-up procedures. Wirth and coworkers investigated the possibility of performing the Ritter reaction in a continuous-flow set-up. They envisioned that a flow reactor set-up could be used for rapid optimization and convenient synthesis of sterically hindered amides [77].

7.9.2 The flow process 1.

Continuous-flow design Wirth et al. performed the Ritter reactions in a set-up as depicted in Figure 7.31. Two syringe pumps, P1 and P2, were connected via a Teflon micromixer (Comet X-01,

7.9 The Ritter Reaction in Continuous Flow |

225

Temperature control 85% H2SO4

P1

PTFE tubing M

1, 3, AcOH P2

Heating bath

Collection and off-line analysis

Amide 7

Aq. NaOH Fig. 7.31: Continuous-flow design for Ritter reaction.

2.

3.

Techno Applications Co.) to PTFE tubing, which was immersed in a conventional temperature-controlled heating bath. The resulting product stream was collected in a cooled aqueous sodium hydroxide solution to form the desired amide. P1 was charged with a syringe containing 85% sulfuric acid and P2 was loaded with a syringe containing a mixture of the alcohol and nitrile in acetic acid. The authors have limited the application of their flow set-up to the generation of carbocations from tertiary and secondary alcohols. Reaction optimization Different solvents and acids, previously reported to be useful for the Ritter reaction, were investigated in the conversion of cyclohexanol with acetonitrile. Based on their findings, it was concluded that acetic acid as the solvent combined with concentrated sulfuric acid gave clean and fast conversions at 90 °C. Based on these findings, an optimized procedure was established that required reaction times between 2 and 10 minutes and heating to 45 °C for tertiary and 85 °C for secondary alcohols. Library synthesis With the optimized conditions in hand, the authors were able to synthesize a library of amides starting from tertiary and cyclic secondary alcohols and a series of nitriles and cyanide salts. The Ritter products were obtained in yields varying from 58–81% and tolerated esters, ethers and aryl and alkyl halides (Figure 7.31). The use of cyanide salts provided a safer preparation of formamides compared to analogous batch reactions with HCN.

7.9.3 Experimental procedures N-(tert-Butyl)-2-(2-iodophenyl)acetamide (11) Pump P1 was charged with a syringe containing 85% H2 SO4 (5 mL) and P2 was loaded with a second syringe filled with a solution of tert-butyl alcohol (563 μL, 6 mmol) and

226 | 7 Experimental procedures for conducting organic reactions in continuous flow

H N

H N O

O

8 (65%)

O O

O

12 (64%)

O

O

9 (62%)

H N

I

H N

H N

10 (66%)

11 (80%) H N

H N

Cl O

13 (73%)

H N

H O

14 (81%)

H O

15 (68%)

Fig. 7.32: Product library synthesized by Ritter reaction (representative examples).

2-iodophenylacetonitrile (1.46 g, 6 mmol) diluted in acetic acid (total volume 5 mL). The syringes and a Teflon micromixer (Comet X01, Techno Application Co.) were connected with PTFE tubing. The output of the mixer was also equipped with PTFE tubing (dimensions: 𝐿 2 m, ID 0.5 mm) and immersed into a heating bath adjust to 45 °C. The pumps were initiated at 0.1 mL/min and the crude product was directly quenched by placing the output into a vessel with ice-cold aqueous sodium hydroxide solution (2 M). The tube was flushed with EtOAc after the reaction was finished to collect the residual product from the tubing. The crude mixture was washed with 2 M aqueous sodium hydroxide (80 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO4 , filtered and concentrated under reduced pressure to afford 𝑁-(tert-butyl)-2-(2-iodophenyl)acetamide (11) in 80% yield. 1 H NMR (500 MHz, CDCl3 ): 𝛿 1.31 (s, 9 H), 3.61 (s, 2 H),5.22 (s, 1 H), 6.98 (m, 1 H), 7.34 (m, 2 H),7.86 (d, 𝐽 = 7.7 Hz, 1 H). 13 C NMR (125 MHz, CDCl3 ): 𝛿 28.7, 49.6, 51.4, 101.0, 128.8, 128.9, 130.8, 138.8, 139.8, 168.6. HRMS: 𝑚/𝑧 [M+H]+ calcd. for C12 H17 INO: 318.0349; found: 318.0349. IR (neat) 𝜈: 3378, 3276, 2972, 2960, 1643, 1552, 1466, 1448, 1417, 1360, 1341, 1288, 1259, 1155, 1014 cm−1 .

7.10 Vilsmeier–Haack formylation of electron-rich arenes 7.10.1 Background The Vilsmeier–Haack formylation is an important reaction for the conversion of electron-rich arenes to their corresponding aldehydes or ketones which are valuable synthetic intermediates [78–82]. In the Vilsmeier–Haack reaction, a chloroiminium ion (3, Scheme 7.33) is formed as the reactive species. Although this reactive intermediate can be readily prepared, calorimetric studies have demonstrated specific

7.10 Vilsmeier–Haack formylation of electron-rich arenes | 227

Cl O

POCl3 H

Me2N

P

Cl

O

+ Me2N

1

Cl O + Me2N

H 2

Cl

Cl H

O

P

Cl O

3 H N

4

H N

H O

NaOH

6

H N

+ NMe2 5

Fig. 7.33: Mechanism for the Vilsmeier–Haack formylation.

hazards due to thermal instability and high and fast temperature elevation during heating, possibly resulting in a thermal runaway [83]. By mixing dimethylformaldehyde (DMF, 1) with phosphorous oxychloride (POCl3 ) the reactive Vilsmeier–Haack reagent (3) is formed via the phosphonium salt intermediate (2). The highly electrophilic iminium ion then reacts with the arene (4) followed by the basic hydrolysis with sodium hydroxide to eventually form aldehyde 6 (Figure 7.33). Since the Vilsmeier–Haack reagent has the potential on a thermal runaway, active cooling is required making batchwise scale-up rather troublesome. Rutjes and coworkers therefore envisioned that a flow chemistry approach including in-line analysis and work-up would enable the Vilsmeier–Haack formylation at industrial scale with enhanced safety [84].

7.10.2 The flow process 1.

Continuous-flow design Transforming this three-step synthesis into a continuous-flow process resulted in a microreactor set-up as depicted in Figure 7.34. The design included four syringe pumps P1-P4 and a straightforward glass microreactor with temperature control and the possibility to quench the reaction on chip. Syringe pumps P1 and P2 were charged with a glass syringe containing neat DMF and POCl3 , respectively. These two streams were combined via a T-splitter in order to form the Vilsmeier–Haack reagent (3) in situ in coil C1. Pump P3 was charged with a glass syringe containing

228 | 7 Experimental procedures for conducting organic reactions in continuous flow POCl3 DMF

Temperature control P1 P2

C1 M

Pyrrole (4)

M P3

Collection and off-line analysis

Microreactor Intermediate 5

H2O/EtOH (1:1 v/v)

P4

Product 6

NaOH/EtOH

Fig. 7.34: Continuous-flow design for the Vilsmeier–Haack reaction.

2.

3.

a stock solution of pyrrole in toluene and was mixed on chip with the Vilsmeier– Haack reagent to form intermediate imine 5. The reaction was quenched on-line with H2 O/EtOH (1 : 1 v/v) followed by off-line hydrolysis with NaOH in EtOH/H2 O (2.7 M NaOH in H2 O/EtO𝐻 1 : 1 v/v). In-line IR analysis of phosphonium salt 2 and chloroiminium ion 3 Complete conversion of POCl3 at the end of coil C1 (FEP-tubing, ID 254 μm) was necessary to circumvent unwanted polymerization of pyrrole. Rutjes et al. enabled real-time analysis of the unstable intermediates 2 and 3 by integrating an in-line IR analysis module (Mettler Toledo FlowIR infrared flow cell). Characteristic stretch and bending vibrations were established in order to determine the optimal reaction time required at room temperature. Phosphonium salt 2 was monitored by its P–O–C bending vibration at 804 cm−1 , and chloroiminium ion 3 was followed in time by focusing at the stretch vibration at 769 cm−1 . It was concluded that the Vilsmeier–Haack reagent (3) formation was completed in 90 seconds. Reaction optimization Monovariate optimization experiments of 2-formylpyrrole (6) were performed using a commercially-available FutureChemistry FlowStart B-200, including four syringe pumps B-230, a microreactor holder, a temperature controller (0–90 °C) and FEP tubing. For a schematic representation of the set-up, see Figure 7.34. The microreactor was customized by FutureChemistry (channel dimensions: 𝑊 600 μm, 𝐻 500 μm) having an internal volume of 92 μL. Temperature, reaction time and molar ratio of POCl3 to pyrrole (4) were investigated with respect to the substrate conversion. One parameter was varied while the other two were fixed. The optimal conditions were determined to be 60 °C, 180 seconds and 1.5 molar ratio.

7.10 Vilsmeier–Haack formylation of electron-rich arenes | 229

CHO MeO

Me2N

CHO

CHO N H

7 : 99 > 99 63 > 99 87 > 99(96)[𝑎] 99(94)[𝑎]

[𝑎]

isolated product yield.

ous NaOH as base with PdCl2 /P(Ph3 )4 as catalyst/ligand combination was thus process intensified to 15 min at 160 °C in a 𝑡-BuOH/H2 O 4:1 solvent mixture utilizing 0.25 mol% Pd(PPh3 )4 as catalyst and 1.3 equiv of 𝑡-BuOK as base [9]. Utilizing these conditions, the high-temperature batch microwave Suzuki–Miyaura cross-coupling was remarkably clean with only minute amounts of dehalogenated side-product being observable, and provided 91% isolated yield of the corresponding biaryl. These optimized conditions were readily translated to a continuous-flow protocol providing a similar high biaryl product yield (89%) (Figure 8.2) [9]. In a subsequent step, the selective reduction of the nitro group in 4󸀠 -chloro2-nitrobiphenyl was first evaluated using sealed vessel batch microwave technology. As opposed to employing molecular hydrogen, here the optimum conditions were quickly found using a catalytic transfer hydrogenation protocol utilizing cyclohexene as hydrogen donor. After identifying Pt/C as the catalyst of choice, the batch

Cl

Cl NO2

Pd(PPh3)4, tBuOK t-BuOH, H2O QP-TU

Cl

Cl 10% Pt/C, H2

+ B(OH)2

(1.1 equiv)

160˚C, 16 min 1 mL min‒1

NO2

NH2

30˚C, ~10 s 1 mL min‒1 (77%)

Fig. 8.2: Multistep flow synthesis involving a catalytic hydrogenation as the second step.

8.3 Summary

| 257

microwave conditions were translated to a flow hydrogenation protocol in the H-Cube device. Employing a 10% Pt/C catalyst cartridge and a flow rate of 1.0 mL min−1 at 30 °C, a highly selective flow hydrogenation of 4󸀠 -chloro-2-nitrobiphenyl to 2-amino4󸀠 -chlorobiphenyl was achieved in the same solvent mixture used for the preceding Suzuki–Miyaura cross-coupling step [9]. Importantly, merging the two processes required scavenging of the homogeneous Pd catalyst used in the Suzuki–Miyaura cross-coupling with a QuadraPure Thiourea resin (QP-TU) which otherwise would contaminate the heterogeneous Pt/C hydrogenation catalyst, leading to an undesired over-reduction (Figure 8.2). Ultimately, the desired key intermediate in the Boscalid synthesis, 2-amino-4󸀠-chlorobiphenyl, was obtained in 77% overall yield in a single flow operation combining a Pd-catalyzed Suzuki–Miyaura cross-coupling reaction with a Pt-catalyzed selective heterogeneous hydrogenation step.

8.3 Summary In this chapter a few examples from the recent literature have been reviewed which demonstrate that small-scale homogeneous microwave batch chemistry can be successfully translated to a scalable high-temperature/pressure continuous-flow format utilizing conventionally heated micro- or mesofluidic platforms (more examples can be found in ref. [3]). In many of the published examples discussed herein, the reaction conditions have initially been carefully optimized for short reaction times and reaction homogeneity using microwave batch technology, and subsequently moved to a flow format. This has several key advantages: 1) Compared to a standard microwave batch reactor, higher temperatures and pressures can generally be attained utilizing an appropriate flow device, therefore allowing significant further process intensification. 2) Because of efficient heat transfer through the high thermal conductivity reactor material (often steel or silicon), temperature control in microreactors is very efficient, even in the case of exothermic reactions. 3) Conventionally heated microreactors do not rely on dielectric heating and therefore the microwave absorptivity of the reaction mixture becomes irrelevant, often an issue in microwave chemistry performed on a larger scale. 4) A particularly important advantage of flow chemistry is the direct scalability, a critical problem in microwave-assisted batch transformations.

Summary of the major terms to be learned 1. Basics and advantages of microwave synthesis. – Higher reaction temperatures can be obtained by combining rapid microwave heating with sealed vessel (autoclave) technology. – In many instances, significantly reduced reaction times, higher yields, and cleaner reaction profiles will be experienced. – Lower boiling solvents can be used under pressure (closed vessel conditions) and be heated at temperatures considerably higher than their boiling point.

258 | 8 The Microwave-to-flow paradigm Microwave heating allows direct “in core” heating of the reaction mixture, which results in a faster and more even heating of the reaction mixture. – Easy online control of temperature and pressure profiles is possible, which leads to more reproducible reaction conditions. Arrhenius law: the temperature dependence of a reaction with a specific rate 𝑘 is defined by Equation (8.1). 𝐴 and 𝐸A are the pre-exponential factor and the activation energy, respectively. –

2.

𝐸

A (− 𝑅𝑇 )

𝑘(𝑇) = 𝐴e

.

(8.1)

Study questions 8.1. What are the major advantages of microwave chemistry? 8.2. What is the main reason that sealed vessel microwave chemistry provides faster reaction rates? 8.3. Why is it possible to translate batch microwave chemistry to conventionally heated flow devices obtaining identical results?

Further readings – Kappe, C. O., Glasnov, T. N.: The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous-flow processes. Chem Eur J 17 (2011) 11956– 11968.

Bibliography [1] Kappe, C. O., Stadler, A., Dallinger, D.: Microwaves in organic and medicinal chemistry, 2nd edn. Wiley-VCH, Weinheim, Germany, 2012. [2] Kappe, C. O.: Microwave effects in organic synthesis – myth or reality? Angew Chem Int Edn. 52 (2013) 1088–1094. [3] Kappe, C. O., Glasnov, T. N.: The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous flow processes. Chem Eur J 17 (2011) 11956– 11968. [4] Razzaq, T., Kappe, C. O.: Continuous flow organic synthesis under high temperature/pressure conditions. Chem Asian J 5 (2010) 1274–1289. [5] Damm, M., Glasnov, T. N. Kappe, C. O.: Translating high-temperature microwave chemistry to scalable continuous flow processes. Org Process Res Dev 14 (2010) 215–224. [6] Razzaq, T., Kappe, C. O.: Continuous flow microreactor chemistry under high temperature/pressure conditions. Eur J Org Chem (2009), 1321–1325. [7] Gutmann, B., Roduit, J. P., Roberge, D., Kappe, C. O.: Synthesis of 5-substituted 1𝐻-tetrazoles from nitriles and hydrazoic acid using a safe and scalable high-temperature microreactor approach. Angew Chem Int Edn. 49 (2010) 7101–7105. [8] Glasnov, T. N., Findenig, S., Kappe, C. O.: Heterogeneous versus homogeneous palladium catalysts for ligandless Mizoroki–Heck reactions. A comparison of batch/microwave and continuous flow processing. Chem Eur J 15 (2009) 1001–1015. [9] Glasnov, T. N., Kappe, C. O.: Toward a continuous flow synthesis of Boscalid. Adv Synth Catal 352 (2010) 3089–3097.

Nicholas E. Leadbeater, Trevor A. Hamlin

9 Incorporation of continuous-flow processing into the undergraduate teaching laboratory: key concepts and two case studies

9.1 Introduction Chemistry, being a hands-on subject, requires undergraduate students to develop a range of experimental skills. As such, the chemistry teaching laboratory is a unique environment. Up until the start of the twentieth century, laboratory instruction was almost entirely conducted in demonstration format by the lecturer [1, 2]. Today, individual laboratory work for students is commonplace and the concept of laboratorybased learning has become firmly established in the teachings of chemistry [3]. A look at a standard organic chemistry laboratory manual shows that while a range of reactions are covered, they represent only a few of the many possibilities. In addition, the equipment used in undergraduate organic chemistry laboratories has not changed significantly in the last 50 years. This is very different from industrial chemistry facilities and most academic research laboratories where state-of-the-art equipment is often found. Efforts are now underway to change this. One class of reactions that students often do not gain experience in is those that require extended heating. This is because they often cannot be fit into an average laboratory period of three hours. This rules out a number of synthetic transformations. To overcome this limitation, we have developed a series of experiments for integration into the undergraduate laboratory using microwave heating as a tool [4]. If a reaction is complete within a few minutes of heating, it is possible to use laboratory time more valuably and expose students to new reactions, such as metal-catalyzed couplings, heterocycle synthesis and C–H bond-activation. More recently, our attention has turned to continuous-flow processing. Like microwave heating, flow chemistry is used in both industry and academic research laboratories. To this end, a wide range of companies now produce equipment for both micro- and mesofluidic flow chemistry [5, 6]. Inherent in these devices are aspects of enhanced safety, ease of scale-up, and efficient mixing of reagents [7, 8]. It is not surprising, therefore, that a wide range of synthetic chemistry transformations have been reported using this equipment [9, 10]. With this being a technology of the future, and with undergraduates being the chemists of the future, we sought to develop flow chemistry laboratory-based materials for incorporation into the undergraduate teaching laboratory. In this chapter we overview the equipment we have used to achieve this goal and some of the experiments developed to date. This is then followed by two pro-

260 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab cedures, one for the Biginelli reaction and one for the Claisen–Schmidt reaction, these exemplifying how flow chemistry experiments can be developed. Microwave-assisted organic synthesis the application of microwave radiation to chemical reactions. An alternative tool to conventional heating using oil-baths or heating mantles. C–H bond activation direct introduction of a new functionality (or a new C–C bond) via direct C–H bond cleavage. A highly attractive strategy in covalent synthesis. The range of substrates is virtually unlimited, ranging from hydrocarbons to complex organic compounds.

9.2 Equipment When considering incorporation of flow chemistry into an undergraduate laboratory class, there are some key metrics that arise in every discussion. Modern flow chemistry equipment is built with safety and reproducibly in mind, so these important factors are taken as standard. The initial cost of the apparatus is often considered to be a major obstacle. The cheapest option may be a “build-your-own” design but this can be time-consuming and also takes the instructor into areas of uncertainty when it comes to safety and reliability. Many of the commercially-available flow reactors are out of the budget of an undergraduate teaching laboratory, especially if multiple systems are needed to accommodate the number of students in the laboratory at any one time. Another issue faced with many of the systems is that there is a fairly steep learning curve for their effective use. Priming pumps, avoiding clogging due to particulate matter, issues with pumping and ease of operation of the user-interface are all concerns when considering undergraduate students with little to no background with these types of equipment. Future Chemistry have developed their FlowStart Evo unit for use in a teaching system [11]. It is a reliable, versatile and easy-to-use microreactor platform. It operates at flow rates of 0.012–2.9 mL min−1 and at temperatures up to 200 °C. A series of seven experiments have been developed for use in a teaching setting [12]. They range from a simple Aldol condensation to a more complex Wittig reaction using either homogeneous or biphasic conditions, as well as a Swern–Moffatt oxidation and synthesis of silver nanoparticles. The reactions take between 4–8 hours to perform. In another example of the use of microreactors in the teaching laboratory, a series of six experiments have been developed to show the advantages of flow chemistry as well as, in one case, a direct comparison between batch and flow processing [13]. Microreactor A series of interconnecting channels in a planar surface, usually a chip. Reagents are brought together, mixed, and allowed to react for a specific period of time. Mesoflow Instead of reagents mixing in micrometer -sized channels in a chip, they mix in a tube reactor.

9.2 Equipment |

(a)

(b)

261

(c)

Fig. 9.1: The Vapourtec E-series system showing (a) the whole system, (b) the pump modules and (c) a reactor coil in position (Reproduced with permission from Vapourtec Ltd).

The focus in our laboratory has been on performing reactions on a larger scale – ideally operating at flow rates of 1–5 mL min−1 . An advantage of this from an undergraduate laboratory setting is that throughput can be higher. This means students can make more material per unit time, shortening reaction times and ameliorating the effects of loss of small quantities of product in transfers or work-up stages. We use the Vapourtec E-series flow unit, shown in Figure 9.1 [14]. It is comprised of two or three advanced self-priming peristaltic pumps. Flow rates range from 0.1–10 mL min−1 . A variety of reactors can be used with the system, the most commonly used for educational purposes being 10 mL PFA coils capable of operation up to 150 °C. There are two reactor positions on the E-Series system. Each reactor is attached to the flow unit and held in place with magnets and connects to the heater system airflow at the top and bottom. The reactor also has a temperature sensor connection, which enables the flow unit to detect that a reactor is present, and to provide feedback of the exact reactor temperature. The system can operate up to 10 bar delivery pressure across the whole flow rate range, the pressure being controlled by restricting flow through a small inert tube at the exit of the unit using a screw-like clamp. The screw knob is not tightened until all the air has been pumped out of the system and liquid is passing in an uninterrupted flow through the exit tubing. A collection valve is an optional accessory for the unit. It allows the user to direct the product flow into either a waste vessel or a product vessel as required, without having to manually move the output stream tube while liquid is coming out of it. The flow unit has a touch-screen interface. Flow rate and temperature can be inputted using this and then all parameters monitored during the course of the experiment.

262 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab

9.3 Experiments developed for the undergraduate teaching laboratory Using the Vapourtec E-series flow unit, we have developed a set of ten experiments for incorporation into the undergraduate laboratory [15]. Each experiment is designed to highlight a particular concept in organic chemistry. Many of the experiments reinforce material that is covered in mainstream organic chemistry courses, such as cycloadditions, rearrangements, and the reaction chemistry of carbonyl compounds. It also extends the scope of experiments undergraduates can perform in a laboratory class, such as ring-closing metathesis and metal-catalyzed coupling. The ten experiments are shown in Table 9.1, together with the key learning goals of each.

9.4 Development of two new experiments for the undergraduate laboratory For the purposes of this chapter, we have developed two new experiments for incorporation into the undergraduate laboratory. They have been performed using the E-series flow unit and hence the protocols are written for that instrument. Each pump on the unit uses a short length of pump tubing, of which there are two types; known simply as blue and red. Each tube type is compatible with a wide range of solvents, but neither is compatible with every solvent. Reference to “red” and “blue” pumps in the protocols hence relate to the pump tubing used. In designing experiments for the undergraduate laboratory, introduction of the concepts of green chemistry is becoming popular [16]. Indeed, a report summarizing the contributions from a special session of the 229th National Meeting of the American Chemical Society (ACS) in March 2005 on incorporation of green chemistry into the undergraduate curriculum and laboratory experience stated that “green chemistry is a useful tool to increase awareness and teach sophisticated problem solving skills in the chemistry context” [17]. Using flow chemistry it is possible to heat solvents to above their boiling point safely and easily. This broadens the spectrum of solvents that can be used to include many of those on the ACS Green Chemistry Institute Pharmaceutical Roundtable Solvent Selection Guide [18]. Here we use methanol and ethanol as solvents and, in previous experiments, have used water and acetone extensively. Green Chemistry The design of chemical products and processes that reduce or eliminate the generation of hazardous substances. ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) Solvent Selection Guide A common tool to assist chemists in selecting the greenest solvent for their reaction as well as providing basis for influencing solvent manufacturers to develop greener alternatives

9.4 Development of two new experiments for the undergraduate laboratory

|

263

Table 9.1: Ten experiments developed for the undergraduate teaching laboratory and their key learning goals.

Experiment

Learning Goals

An Introductory Experiment using Flow Chemistry

To configure the E-Class flow unit for two-pump operation To understand the concept of dispersion To understand the parameters needed for effective product collection

Diels–Alder [4+2] Cycloaddition: Preparation of a Bicyclic Lactone

To perform a flow reaction using one pump To perform a Diels–Alder [4+2] cycloaddition reaction To prepare a bicyclic compound

Preparation of a Heterocycle: A Paal–Knorr Pyrrole Synthesis

To perform a flow reaction using one pump To perform a condensation reaction To prepare a heterocyclic compound

Preparation of a Bromoarene: Electrophilic Aromatic Substitution

To perform a flow reaction using one pump To perform a electrophilic aromatic substitution reaction To determine the regiochemical outcome of a reaction

Preparation of a Carbamate: The Hoffmann Rearrangement

To perform a flow reaction using one pump To perform a Hoffmann rearrangement To prepare a carbamate

Preparation of an Ester: Oxidation of an Aldehyde to a Methyl Ester

To perform a flow reaction using two pumps To perform an oxidation reaction To prepare an ester

Preparation of a Coumarin: A Knoevenagel Condensation

To perform a flow reaction using two pumps To gain exposure to condensation chemistry To overcome clogging of a flow stream by the technique of “solvent interception”

Preparation of a Cyclopentene: A Ring-Closing Metathesis Reaction

To perform a flow reaction using one pump To perform a ring-closing metathesis reaction To gain insight into alkene metathesis chemistry

A Nucleophilic Acyl Substitution Reaction: Preparation of an Ester

To perform a flow reaction using two pumps To perform an acid-catalyzed esterification reaction To separate a reactant from product by controlling solubility using pH

Preparation of a Biaryl: A Suzuki Coupling Reaction

To perform a flow reaction using two pumps To gain exposure to metal-catalyzed cross-coupling chemistry To overcome clogging of a flow stream by the technique of “solvent interception”

264 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab When developing teaching materials for flow-based chemistry experiments, we believe it is best to provide step-by-step instructions for performing the reaction, since students may well have not seen the equipment before entering the laboratory that day. It is assumed that the instructor has set up the equipment with the appropriate tubing and reactors so that students can get straight to work, following the steps outlined in the protocol.

9.4.1 The Biginelli Reaction 9.4.1.1 Motivation The acid-catalyzed cyclocondensation of urea, 𝛽-ketoesters and aromatic aldehydes to yield dihydropyrimidines (Biginelli reaction) has received significant attention, the products having pharmacological activity including calcium channel modulation, mitotic kinesin Eg5 inhibition, and antiviral and antibacterial activity [19, 20]. The Biginelli reaction has been the subject of undergraduate experimental procedures before [21, 22]. One of the attractive features is that the mechanism involves three steps, all of which are covered in a typical organic chemistry lecture class and here students apply them in sequence to understand a seemingly complex three-component reaction. In addition, the traditional methodologies can be compared and contrasted with what could be greener alternatives.

9.4.1.2 Reaction optimization The Biginelli reaction has been performed in flow previously as a route to densely functionalized heterocycles using HBr generated in a prior step as the catalyst for the reaction [23]. Copper catalysis has also been used in flow mode for preparing PEGimmobilized dihydropyrimidines [24]. In order to develop a simple flow-based protocol for the teaching laboratory, we decided to screen a set of conditions for the synthesis of 1 by reaction of benzaldehyde, ethyl acetoacetate and urea catalyzed by sulfuric acid (Figure 9.2). We wanted to perform the reaction in methanol. While this dissolves the starting materials, the product is much less soluble. When using flow chemistry, there is the possibility that solids may accumulate in the tubing and, over time, lead to a blockage. To overcome this problem, we have adopted a simple technique whereby we intercept the product stream with a flow of a solvent in which the product is soluble. By doing this, the potential clogging of the flow stream is avoided. The co-solvent is introduced just after the product stream exits the heated zone and before passing through the back-pressure regulator. This is important since it is in the backpressure regulator where blockage would most likely occur. We used in situ Raman spectroscopy as a tool to enable us to optimize reaction conditions rapidly [25]. Using

9.4 Development of two new experiments for the undergraduate laboratory

O

O H

O +

O

O O

+

H2N

|

265

O

H2SO4 NH2

Flow

HN

NH

1

O Fig. 9.2: The Biginelli cyclocondensation of benzaldehyde, ethyl acetoacetate, and urea to yield 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4 dihydropyrimidin-2(1H)-one, 1.

a catalyst loading of 10 mol% of 6 M sulfuric acid and a flow rate of 1 mL min−1 , we monitored the reaction over a temperature range from 25–120 °C. Seeing that the reaction did not reach completion within the 10 min in the heated zone, we then repeated the process at lower flow rates, first at 0.5 mL min−1 and then at 0.25 mL min−1 . Our optimal conditions as determined by Raman monitoring were heating at 120 °C with a flow rate of 0.25 mL min−1 . Performing the reaction again, this time collecting the product, we found that our optimal conditions gave us a product conversion of 89%, as determined by GC analysis, and a product yield of 78% after purification. Solvent interception Prevention of tube blockage by solubilizing either the product or a byproduct by introduction of a stream of co-solvent just after the product stream exits the heated zone and before passing through the back-pressure regulator. In situ Raman monitoring Use of Raman spectroscopy as a tool for monitoring continuous-flow reactions. By passing the product stream through a flow cell, signals from starting material, product and potential by-products can be monitored as a function of time, temperature and other key reaction parameters.

9.4.1.3 Student protocol Preparation of ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine5-carboxylate (Figure 9.3)

Benzaldehyde, ethyl acetoacetate, urea, methanol (MeOH) and sulfuric acid are irritants. Benzaldehyde is mildly corrosive, while sulfuric acid is strongly corrosive. 𝑁, 𝑁-Dimethylformamide (DMF) is harmful if inhaled, ingested or passed through the skin. All the reagents should be dispensed in a fume hood. The use of goggles with side-shields, lab coats and gloves are considered minimum and nondiscretionary safety practices in the laboratory.

266 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab

O

O H

+

O

O O

+ HN 2

10 mol% 6M H2SO4 NH2

Flow at 0.25 mL/min MeOH, 120°C

O

O

HN

NH O

Fig. 9.3: The Biginelli reaction performed in this experiment.

Table of reagents and physical constants Reagent

Equiv.

MW mmol (g mol−1 )

Mass (g)

Density (g mL−1 )

Benzaldehyde C7 H6 O

1

106.12

5

0.503

1.04

0.51

bp 178

Ethyl acetoacetate C6 H10 O3

1

130.14

5

0.65

1.02

0.64

bp 181

Urea CH4 ON2

1

60.06

5

0.30

–

–

mp 133–134

6 M Sulfuric acid H2 SO4 (in methanol)

0.1

98.08

0.5

–

–

≈ 0.02

Methanol CH4 O

–

–

–

–

–

5.00

bp 65

𝑁, 𝑁-Dimethylformamide

–

–

–

–

–

40.00

bp 152

Vol. (mL)

mp/bp°C

–

C3 H7 ON

Prepare the reagent reservoirs: – In a 10-mL capacity test tube, combine benzaldehyde, ethyl acetoacetate, urea and methanol. Label this tube “reagent” – Gently heat the reaction mixture until urea is completely dissolved and the mixture is homogeneous – In a 100-mL capacity bottle, place 40 mL of methanol. Label this bottle “solvent” – In a 100-mL capacity bottle, place 40 mL of 𝑁, 𝑁-dimethylformamide. Label this bottle “solvent intercept”

Set up the flow unit (Figure 9.4): – Equip the flow unit with a 10-mL capacity PFE reactor coil – Fully open the back-pressure regulator

9.4 Development of two new experiments for the undergraduate laboratory

15cm

|

267

6cm 65cm

105cm Reagent A

Solvent A

Waste

Product ! Backpressure regulator

Heated reactor coil

!

Intercept solvent

105cm

32cm !

!

T mixer Union Pump A Blue pump tubing

28cm Blue pump tubing

Pump B

28cm

Do not ! = overtighten connections to BPR Ensure reactor is ! = connected the correct way round

Fig. 9.4: Schematic representation of the apparatus set-up required for this experiment.

– – – – –

– –

Place the exit lines from the “waste” and “collect” ports into individual 100-mL bottles labeled “waste” and “product”, respectively Ensure that the exit stream is set to go to “waste” Select two blue pumps, one for the methanol “solvent” and one for the dimethylformamide “solvent intercept” reaction Connect the output of the “solvent” blue pump to the beginning of the PFE reactor coil After the reactor coil, install a T-piece, which connects the output of the PFE reactor coil to both the output of the “solvent intercept” blue pump and the input of the back-pressure regulator. If using a four-port T-piece, seal the remaining port with a Teflon stopper Place both the solvent and the reagent line for the “solvent” blue pump into the bottle labeled “solvent” Place the solvent line for the “solvent intercept” blue pump into the bottle labeled “solvent intercept”

268 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab – – – – – – – – –

Turn on the flow unit and prime the solvent and reagent lines for the blue pump with methanol from the “solvent” Prime the solvent line for the blue pump with dimethylformamide from the “solvent intercept” Ensure the pump is set back to “solvent” on the screen Carefully move the reagent line from the bottle labeled “solvent” to the tube labeled “reagent” Pass solvent through the reactor coil at a flow rate of 3.0 mL min−1 for both pumps until the entire system of tubing is filled Once the reactor coil is filled, reduce the flow rate for both pumps to 0.25 mL min−1 Adjust the back-pressure regulator carefully to a pressure of 6.5 bar Set the temperature of the reactor coil to 130 °C Once the desired temperature is reached, and the pressure is stable, the unit is ready to run the reaction

Synthesize the ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxylate: – Add the sulfuric acid catalyst to the tube labeled “reagent” and mix the solution using a pipette – Once thoroughly mixed, switch the pump from “solvent” to “reagent” – Set the exit stream to go to “collect” – When the contents of the “reagent” tube are completely loaded into the reactor, switch the pump from “reagent” back to “solvent” – Continue collecting for another 60 min – Once all the reagents have exited the flow unit, the reaction is complete – Press the “stop reaction” button

Purify the crude product: – When the reaction is complete, transfer the contents of the “product” bottle to a 500 mL separatory funnel – Dilute the material in the funnel with diethyl ether (50 mL) and quench the reaction with saturated sodium bicarbonate (50 mL) and deionized water (50 mL) – Separate the layers and extract the aqueous layer with diethyl ether (3 × 100 mL) – Combine the organic layers and wash with brine (2 × 100 mL) – Dry organic layer with sodium sulfate (∼ 5 g) – Remove the solvent under reduced pressure – While the solvent is being removed, set up a filtration system with a Hirsch funnel, side-arm flask, rubber collar and a length of rubber vacuum tubing – Once the solvent has been removed an off-white powder should result

9.4 Development of two new experiments for the undergraduate laboratory

– – – – – – – –

|

269

Connect the filtration system to a vacuum and place the correct filter paper size in the Hirsch funnel Filter the reaction mixture by pouring the contents into the Hirsch funnel; transfer as much solid as possible Add a small amount of cold methanol (5 mL) to the product flask and pour this into the Hirsch funnel to ensure all the product is removed from the flask Rinse the resulting solid with cold methanol (20 mL) to remove any impurities Allow the product to air dry on the Hirsch funnel for several minutes under vacuum Transfer the filter cake to a large piece of filter paper to dry completely Allow the product to air dry until a constant weight is reached Calculate the yield and percent yield

Characterize the product: – Obtain 1 H–NMR and 13 C–NMR spectra in CDCl3 if instructed to do so – Obtain a GC–MS of your compound if instructed to do so

9.4.2 The Claisen–Schmidt Reaction 9.4.2.1 Motivation The base-mediated synthesis of chalcones from aromatic aldehydes and enolizable acetophenones is a typical preparation included in many introductory organic chemistry teaching laboratories [26, 27]. It showcases the aldol condensation reaction, a cornerstone of organic synthesis [28]. The chalcone products are important compounds in their own right, displaying interesting biological properties such as antioxidant, anticancer, and anti-inflammatory activity [29, 30]. They are also useful starting materials for further experiments in the organic teaching laboratory, for example in the synthesis of highly-fluorescent cyanopyridine and deazalumazine dyes [31] or for catalytic transfer hydrogenation reaction using ammonium formate and Pd/C [32].

9.4.2.2 Reaction optimization The Claisen–Schmidt reaction has been performed in flow previously using a microchip assembly [33]. For our development of a flow-based protocol for the teaching laboratory, we decided to screen a set of conditions for the reaction of benzaldehyde with acetophenone to yield chalcone (2), catalyzed by sodium hydroxide and using ethanol as the solvent (Figure 9.5). In this case, both the starting materials and product are soluble in ethanol meaning that no solvent interception was necessary. We again used in situ Raman spectroscopy to optimize reaction conditions rapidly [25]. Using a catalyst loading of 10 mol% of 2 M sodium hydroxide, our optimal conditions as

270 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab O

O

O H

NaOH

+

2

Flow Fig. 9.5: Scheme 2: The Claisen–Schmidt reaction of benzaldehyde and acetophenone to yield chalcone, 2.

determined by Raman monitoring were heating at 65 °C with a flow rate of 1 mL min−1 , this corresponding to a product conversion of 90%, as determined by GC analysis.

9.4.2.3 Student protocol Preparation of (E)-1,3-diphenyl-2-propen-1-one (Figure 9.6) O

O H

+

O 10 mol% 2M NaOH Flow at 1 mL/min EtOH, 65°C

Fig. 9.6: The Claisen-Schmidt reaction performed in this experiment.

Benzaldehyde, acetophenone and sodium hydroxide are irritants. Benzaldehyde is mildly corrosive, ethanol is flammable and sodium hydroxide is strongly caustic. All the reagents should be dispensed in a fume hood. The use of goggles with side-shields, lab coats and gloves are considered minimum and nondiscretionary safety practices in the laboratory.

Table of reagents and physical constants Prepare the reagent reservoirs: – In a 25-mL capacity test tube, combine benzaldehyde, acetophenone and ethanol. Label this tube “reagent” – Swirl the contents of the tube to ensure adequate mixing of the reagents – In a 100-mL capacity bottle place 80 mL of ethanol. Label this bottle “solvent”

Set up the flow unit (Figure 9.7): – Equip the flow unit with a 10-mL capacity PFE reactor coil – Fully open the back-pressure regulator – Place the exit lines from the “waste” and “collect” ports into individual 100-mL bottles labeled “waste” and “product”, respectively – Ensure that the exit stream is set to go to “waste” – Select one blue pump for performing the reaction

9.4 Development of two new experiments for the undergraduate laboratory

|

271

Table 9.2: Table of reagents and physical constants Reagent

Equiv.

MW mmol (g mol−1 )

Mass (g)

Density (g mL−1 )

Benzaldehyde C7 H6 O

1

106.12

5.0

0.54

1.04

0.52

bp 178

Acetophenone C8 H8 O

1

120.15

5.0

0.6

1.03

0.58

bp 202

2 M Sodium hydroxide NaOH (in ethanol)

0.1

–

0.5

–

–

≈ 0.06

Ethanol C2 H6 O

–

–

–

–

–

20

15cm

Vol. (mL)

mp/bp °C

–

bp 78

6cm 65cm

105cm Reagent A

Solvent A

Waste

Product ! Backpressure regulator

Heated reactor coil

V3 Pump Pump A Blue pump tubing

!

!

!

Union

Union

28cm

32cm

Do not ! = overtighten connections to BPR Ensure reactor is ! = connected the correct way round

Fig. 9.7: Schematic representation of the apparatus set-up required for this experiment.

272 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab – – – – – – – – – –

Connect the output of the blue pump to the beginning of the PFE reactor coil Place both the solvent line and the reagent line for the pump into the bottle labeled “solvent” Turn on the flow unit and prime the solvent and reagent lines for the pump with methanol from the “solvent” Carefully move the reagent line from the bottle labeled “solvent” to that labeled “reagent” Ensure the pump is set back to “solvent” on the screen Pass solvent through the reactor coil at a flow rate of 3.0 mL min−1 for both pumps until the entire system of tubing is filled Once the reactor coil is filled, reduce the flow rate to 1.0 mL min−1 Adjust the back-pressure regulator carefully to a pressure of 6.5 bar Set the temperature of the reactor coil to 65 °C Once the desired temperature is reached, and the pressure is stable, the unit is ready to run the reaction

Synthesize the 1,3-diphenyl-2-propen-1-one: – Add the sodium hydroxide catalyst to the tube labeled “reagent” and mix the solution via a pipette – Once thoroughly mixed, switch the pump from “solvent” to “reagent” – Set the exit stream to go to “collect” – When the contents of the “reagent” tube are completely loaded into the reactor, switch the pump from “reagent” back to “solvent” – Continue collecting for another 15 min – Once all the reagents have exited the flow unit, the reaction is complete – Press the “stop reaction” button Purify the crude product: – When the reaction is complete, transfer the contents of the “product” bottle to a 500 mL beaker containing ice (200 g) – The product should immediately precipitate out of solution – Use cold deionized water (5 mL) to rinse the collection flask and facilitate the transfer – Stir the ice mixture for 20 min to ensure complete precipitation of product – While stirring, set up a filtration system with a Hirsch funnel, side-arm flask, rubber collar and a length of rubber vacuum tubing – Connect the filtration system to a vacuum and place the correct filter paper size in the funnel – Filter the reaction mixture by pouring the contents into the funnel; transfer as much solid as possible – Add a small amount of cold ethanol (5 mL) to the product flask and pour this into the funnel to ensure all the product is removed from the flask

9.5 Summary

– – – – –

| 273

Wash the solid material with cold ethanol (10 mL) to remove impurities Allow the product to air dry on the filter funnel for several minutes under vacuum Transfer the filter cake to a large piece of filter paper to dry completely Allow the product to air dry until a constant weight is reached Calculate the yield and percent yield

Characterize the product: – Obtain 1 H–NMR and 13 C–NMR spectra in CDCl3 if instructed to do so – Obtain a GC–MS of your compound if instructed to do so

9.5 Summary By incorporating new techniques such as flow chemistry into the undergraduate teaching laboratory, students can be exposed to a wider array of tools before they graduate. Anecdotal evidence from our laboratory has shown that students who have had experience working with modern synthetic chemistry equipment such as microwave and flow chemistry tools prove to be highly sought after by the chemical industry. They are also well prepared for graduate school; these new tools meaning that they have broad horizons and, since the equipment is new to them, they have to develop problem-solving skills to overcome issues that may arise during their laboratory periods. The incorporation of the basic tenets of green chemistry into the course is an added benefit. With the increased productivity, the ability to run a wider range of experiments and the positive, enthusiastic student participation that results, flow chemistry is proving its place as a valuable tool in the undergraduate teaching laboratory.

9.6 Acknowledgements The work outlined here, together with our other efforts in the area of incorporation of flow chemistry into the undergraduate teaching laboratory would not have been possible without equipment and technical support from Vapourtec. In particular, Duncan Guthrie, David Griffin, and Andrew Mansfield are thanked. Our initial series of ten experiments were designed, developed, coauthored, tested and re-tested by two graduate students in the research group, Christopher Kelly and Michael Mercadante. We are also grateful to undergraduate interns in the group that tested some of the reactions. We thank the National Science Foundation for funding our educational innovations work (CAREER award CHE-0847262).

274 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab

Study questions 9.1. Monastrol, the structure of which is shown below, is an important medicinal compound. Devise a synthesis of this compound.

O

O

HN

NH

OH

S 9.2.

9.3.

9.4.

Monastrol

Another three-component reaction is the synthesis of 1,4-dihydropyridines from an aldehyde, 𝛽-ketoester and ammonia. Write a reaction scheme for this reaction, using an aldehyde and 𝛽-ketoester of your choice. Having done this, draw a schematic diagram (like the flow-unit setup diagrams in the two experiments above) for how you would make your dihydropyridine using the flow reactor. One of the “Twelve Principles of Green Chemistry” is that of “maximum atom economy”. Atom economy is an evaluation of the degree to which the reactants are incorporated into the product. If all the atoms from the reactants end up in the product, then the atom economy is 100%. Reactions with high atom economy are usually preferred because they are less wasteful. Discuss the atom economy of the Biginelli and the Claisen–Schmidt reactions. How can flow chemistry make reactions “greener”? Hint: Consider the “Twelve Principles of Green Chemistry” and determine in which of these flow chemistry can assist in.

Further readings 1. Leadbeater, N. E., An Introduction to Flow Chemistry: A Practical Laboratory Course, Vapourtec Ltd, 2013 2. McQuade, D. T., Seeberger, P. H., Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis. J. Org. Chem. 78 (2013) 6384–6389. 3. Wegner, J., Ceylan, S., Kirschning, A., Ten key issues in modern flow chemistry, Chem. Commun. 47 (2011) 4583–4592. 4. Zhu, J., Bienaymé, A. (Eds.), Multicomponent Reactions, Weinheim, Germany, Wiley-VCH, 2005

Bibliography [1] [2] [3] [4] [5]

Leicester, H. M., The Historical Background of Chemistry. New York, NY, USA, Wiley, 1956. Blick, D. J., The purpose and character of laboratory instruction. J. Chem. Educ. 32 (1955) 264– 266. Domin, D. S., A Review of Laboratory Instruction Styles. J. Chem. Educ. 76 (1999) 543–547. Leadbeater, N. E., McGowan, C. B., Laboratory Experiments Using Microwave Heating. Chichester, UK, CRC Press, 2013. Wiles, C., Watts, P., Micro Reaction Technology in Organic Synthesis, Boca Raton, FL, USA, CRC Press, 2011.

Bibliography

[6] [7]

[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

[21] [22]

[23]

[24] [25]

[26] [27]

| 275

Luis, S. V., Garcia-Verdugo E. (Eds.) Chemical Reactions and Processes under Flow Conditions, Cambridge, UK, Royal Society of Chemistry, 2010. van den Broek, S. A. M. W., Leliveld, J. R., Delville, M. M. E., Nieuwland, P. J., Koch, K., Rutjes, F. L. J. T., Continuous Flow Production of Thermally Unstable Intermediates in a Microreactor with Inline IR-Analysis: Controlled Vilsmeier–Haack Formylation of Electron-Rich Arenes, Org. Process Res. Dev. 16 (2012) 934–938. Anderson, N., Using Continuous Processes to Increase Production, Org. Process Res. Dev. 16 (2012) 852–869. Baxendale, I. R., The integration of flow reactors into synthetic organic chemistry, J. Chem. Technol. Biotechnol. 88 (2013) 519–552. Malet-Sanz L, Susanne, F., Continuous flow synthesis. A pharma perspective, J. Med. Chem. 55 (2012) 4062–4098. Future Chemistry. (Accessed January 1, 2014, at http://www.futurechemistry.com/home.html). Flow Chemistry Course. (Accessed January 1, 2014, at http://www.futurechemistry.com/flowchemistry-course.html). König, B., Kreitmeier, P., Hilgers, P., Wirth, T., Flow Chemistry in Undergraduate Organic Chemistry Education, J. Chem. Educ. 90 (2013) 934–936. Vapourtec E-Series. (Accessed January 1, 2014, at http://vapourtec.co.uk/products/ eseriessystem). Flow Chemistry Guide. (Accessed January 1, 2014, at http://vapourtec.co.uk/news/ FlowChemistryGuide). Anastas, P. T., Warner, J. C., Green Chemistry: Theory and Practice. New York, NY, USA, Oxford University Press, 1998. Haack, J., Hutchinson, J., Kirchhoff, M., Levy, I., Going Green: Lecture Assignments and Lab Experiences for the College Curriculum, J. Chem. Educ. 82 (2005) 974–976. ACS GCI Pharmaceutical Roundtable (Accessed January 1, 2014, at http://www.acs.org/ content/acs/en/greenchemistry/industriainnovation/roundtable.html). Suresh, Sandhu, J. S., Past, present and future of the Biginelli reaction: a critical perspective ARKIVOC, 2012, 66–133. Singh, K., Arora, D., Singh, K., Singh, S., Genesis of dihydropyrimidinone calcium channel blockers: recent progress in structure-activity relationships and other effects, Mini Rev. Med. Chem. 9 (2009) 95–106. Holden, M. S., Crouch, R. D., The Biginelli Reaction, J. Chem. Educ. 78 (2001) 1104–1105. Aktoudianakis, E., Chan, E., Edward, A. R., Jarosz, I., Lee, V., Mui, L., Thatipamala, S. S., Dicks, A. P., Comparing the Traditional with the Modern: A Greener, Solvent-Free Dihydropyrimidone Synthesis, J. Chem. Educ. 86 (2009) 730–732. Pagano, N., Herath, A., Cosford, N. D. P., An Automated Process for a Sequential Heterocycle/Multicomponent Reaction: Multistep Continuous Flow Synthesis of 5-(Thiazol-2-yl)3,4-Dihydropyrimidin-2(1H)-ones, J. Flow Chem. 1 (2011) 28–31. Prosa, N., Turgis, R., Piccardi, R., Scherrmann, M. C., Soluble Polymer-Supported Flow Synthesis: A Green Process for the Preparation of Heterocycles, Eur. J. Org. Chem. (2012) 2188–2200. Hamlin, T. A., Leadbeater, N. E., Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions, Beilstein J. Org. Chem. 9 (2013) 1843–1852. Palleros, D. R., Solvent-Free Synthesis of Chalcones, J. Chem. Educ. 81 (2004) 1345–1347. Vyvyan, J. R., Pavia, D. L., Lampman, G. M., Kriz, G. S., Preparing Students for Research: Synthesis of Substituted Chalcones as a Comprehensive Guided-Inquiry Experience, J. Chem. Educ. 79 (2002) 1119–1121.

276 | 9 Incorporation of continuous-flow processing into the undergraduate teaching lab [28] Garcia, A.-Raso, Garcia, J.-Raso, Sinisterra, J. V., Mestres, R., Michael addition and aldol condensation: A simple teaching model for organic laboratory, J. Chem. Educ. 63 (1986) 443. [29] Batovska, D. I., Todorova, I. T., Trends in utilization of the pharmacological potential of chalcones, Curr. Clin. Pharmacol. 5 (2010) 1–29. [30] Dickson, J., Flores, L., Stewart, M., LeBlanc R, Pati, H. N., Lee, M., Holt, H., Synthesis and Cytotoxic Properties of Chalcones: An Interactive and Investigative Undergraduate Laboratory Project at the Interface of Chemistry and Biology, J. Chem. Educ. 83 (2006) 934–936. [31] Bowman, M. D., Jacobson, M. M., Blackwell, H. E., Discovery of fluorescent cyanopyridine and deazalumazine dyes using small molecule macroarrays, Org. Lett. 8 (2006) 1645–1648. [32] Hammond, C. N., Schatz, P. F., Mohrig, J. R., Davidson, T. A., Synthesis and Hydrogenation of Disubstituted Chalcones. A Guided-Inquiry Organic Chemistry Project, J. Chem. Educ. 86 (2009) 234–239. [33] Mu, J.-X., Yin, X.-F., Wang, Y.-G., The Claisen–Schmidt Reaction Carried Out in Microfluidic Chips, Synlett (2005) 3163–3165.

Answers to the study questions Chapter 2: Fundamentals of Flow Chemistry 2.1.

A chemical reaction takes place spontaneously, when the Gibbs free energy of the products is lower than the free energy of the reactants; therefore, G must be negative.

Δ𝐺 = Δ𝐻 − 𝑇 ⋅ Δ𝑆 . Free energy is made up of two components, enthalpy 𝐻 and entropy 𝑆. 𝐺: free energy, 𝐻: enthalpy, 𝑇: temperature, 𝑆: entropy, Δ: difference (change between original and product). The enthalpy change in a reaction is essentially the difference in bond energies (including resonance, strain, and solvation energies) between the reactants and the products. The preferred conditions in Nature are low enthalpy and high entropy, and in reacting systems, enthalpy spontaneously decreases while entropy spontaneously increases. A negative 𝐺 is a necessary, but not a sufficient, condition for a reaction to occur spontaneously. Reactions take place in a reasonable period of time depending on the energy profile of the starting materials (reactants) and the activated complex (transition state) that are taken to be in equilibrium. Activation energy is required to transfer all the reactants into the activated complex. 2.2. Chemical reactions (reaction rate) can be accelerated with increasing the temperature and/or applying catalysts. The temperature dependence of the rate constant usually follows the Arrhenius equation, which expresses the dependence of the rate constant 𝑘 of a chemical reaction on the absolute temperature 𝑇 (in Kelvin), where 𝐴 is the pre-exponential factor, 𝐸𝑎 is the activation energy, and R is the Universal gas constant. Catalysts could also increase the rate of a chemical reaction through participation in the reaction. Catalyst is not consumed, thus, it is recycled (regenerated) during the process. With a catalyst, less free energy is required to reach the transition state, but the total free energy from reactants to products does not change. 2.3. Reactions can be initiated by a) energy transfer to reach activation energy (heat transfer), b) light irradiation to reactive excited state (photochenical activation), c) by electrochemical processes involving electron transfer to or from a molecule or ion changing its oxidation state, d) by chemical process by generating reactive intermediates. The chemical reaction can be terminated by quenching and initiating work-up. Quenching terminates the reaction condition necessary for chemical reaction by rapid cooling or decomposing (trapping) residual reactive intermediates, deactivating any unreacted reagents, neutralizing the pH or simply removing the product from the reaction mixture by extraction, distillation or inducing precipitation.

278 | Answers to the study questions 2.4. Most of the organic chemical reactions are reversible and normally lead to an equilibrium, which can be shifted by applying the Le Chatelier Braun principle. In general, changing the concentration, any of the reactants, temperature or pressure will shift the equilibrium to the side that would reduce that change in concentration, temperature or pressure. – Thus, reducing the concentration of the product or any of the side-products (e.g., water); increasing the concentration of the reactants (excess applied) – Elevated temperature if the reaction is endothermic (enthalpy or heat of reaction – Δ𝐻 is positive) or cooling when the reaction is exothermic (enthalpy or heat of reaction – Δ𝐻 is negative). – Increasing the pressure when at activation volume (Δ𝑉‡ ) is negative or vice versa 2.5. Diffusion control: a chemical reaction is mixing- or diffusion controlled if its halflife is on the order of, or smaller than, that of the relevant mixing or diffusion process. Kinetical control: if there are competing reactions that are not reversible such product will be formed in larger amount which is formed faster. The product is said to be the kinetic product, but not the most stable one. Thermodynamical control: if there are competing reactions that are permitted to approach equilibrium, the predominant or even exclusive product is the one that could reach lower free energy level. During the reaction, the faster formed product will revert to the more stable product. 2.6. Selectivity is the ratio of products in competing reactions. In competitive parallel reactions, the reaction of the starting material (SM) is to give Product1 that competes with the reaction of SM to give Product2. Both reactions take place simultaneously. If the rate constant 𝑘1 for the first reaction is much larger than 𝑘2 for the second reaction, we expect the predominant formation of Product1 over Product2. In competitive consecutive reactions, a Product1 that is formed in the first reaction from SM undergoes a further reaction to give a Product2. If the rate constant 𝑘1 for the first reaction is much larger than 𝑘2 for the subsequent reaction, it is possible, in principle, to stop the reaction to obtain Product1 predominantly. If 𝑘2 is larger than 𝑘1 , it seems difficult to stop the reaction at the Product1 stage. 2.7. In batch processes stoichiometry is defined by the concentration of chemical reagents, and the ratio of their molar quantities. Stoichiometry in flow reactors is defined by the concentration of reagents and the ratio of their flow rate. 2.8. Reaction time in batch is the time spent under the defined condition, while in flow reaction time equals to residence time spent in the reaction zone depending on the flow rate and reaction volume. 2.9. Reaction progress can be characterized by the time spent in the flask while in flow by the distance traveled in the channel.

Answers to the study questions

| 279

2.10. Surface-to-volume ratio: area per unit volume of the reactor is a crucial factor for heat ad mass transfer. Generally, volume is equal to the length cubed, while surface area is equal to length squared. When the length is shortened, surface-tovolume ratio increases. Thus, microreactors have higher surface-to-volume ratio than macroreactors.

Size Surface area Volume Surface/Volume

2.11.

2.12.

2.13.

2.14.

2.15.

1/100 1/10000 1/1000000 100

If the size is reduced by 100 fold, the surface-to-volume increased 100 fold. Continuously-flowing microreactors allow for rapid and homogeneous mixing because of their small dimensions (channel or capillary diameter is 0.05–0.5 cm) and laminar flow is the predominant. Microreactors can achieve complete mixing in microseconds, whereas classical reactors mix on the timescale of seconds or longer. The fast mixing relies on the short diffusion path in microreactors. A molecule in the center of a typical microfluidic channel can reach the wall of that channel in a few seconds. The same molecule in the middle of a reaction flask (batch) would require hours to diffuse to the side wall (without mixing). The time (𝑡d ) needed for molecular diffusion is proportional to the square of the length of the diffusion path. Marked shortening of the diffusion path in flow (in a microreactor) results in a mixing speed that is unobtainable in batch. Because microreactors have a greater surface area per unit volume than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling fast cooling/heating and, hence, precise temperature control. EOF induces fluid flow by the application of an electrical potential across a microchannel. Ions in solution migrate to the opposite charge lining the channel wall, creating an electrical double layer of counter ions. The velocity profile of electroosmotic movement in an open channel is flat. Hydrodynamic pumping exploits conventional or microscale pumps, notably syringe-type pumps, to deliver solutions around the channel network. The static nature of the fluid at the boundary produces a parabolic velocity profile within the channel. The segmented flow system delivers pulses of reactants that are segregated by an immiscible solvent into the flow reactor. Each segment can consist of a different combination of reactants for different reactions to occur.

280 | Answers to the study questions 2.16. Reynolds number determines the flow regimes in the channels and is defined as the ratio of momentum (inertial) forces to viscous forces. 2.17. The flow is – laminar when Re < 2300 – transient when 2300 < Re < 4000 – turbulent when 4000 < Re 2.18. – Lab scale: 1–10 mL/min – Pilot plant scale: 50–150 mL/min – Industrial scale: 200–600 mL/min 2.19. Continuous-flow (micro) reactors consist of a network of miniaturized channels with diameters typically in the range of 10–500 microm constructed of glass, quartz, silicon, polymers, or stainless steel. 2.20. Space Time Yield (kg m−3 s−1 ) which represents the mass of a product 𝑃 formed per volume of the reactor and time. 2.21. A typical flow reactor set-up applying pressure driven flow delivery includes the following main parts: reservoirs, T-mixer, pumps, reactor zone, heating/cooling units, and back-pressure regulator. 2.22. Flow reactors can be interconnected to form a multiple line of reactors in different configurations including parallel and consecutive set-ups (please give examples, please draw it). Continuous-flow devices can be linked with in-line analytical tools such as UV, IR, HPLC, GLC, mass spectrometry and/or NMR for real-time analysis and feedback which allows rapid automated optimization of the reaction parameters. 2.23. Classification can be based on reaction rate and kinetics provides a rough guidance how to select the most appropriate flow reactor. Reaction kinetics and enthalpy determine characteristic reaction time and adiabatic temperature rise of the reagents. Competitive reactions such as consecutive or parallel reactions lead to side-product formation. Based on the characteristic reaction time the following classification was set: Type A, Type B or Type C reactions. 2.24. Type A reactions – Very fast (< 1 s) – Controlled by diffusion and mixing – Increase yield through better mixing/heat exchange Type B reactions – Rapid reaction (10 s to 30 min) – Predominantly kinetically controlled – Avoid overcooking and increase yield Type C reactions – Slow reaction (> 30 min) – Batch processes with thermal hazard – Enhance safety

Answers to the study questions

| 281

2.25. Flash chemistry is a field of chemical synthesis where extremely fast reactions involving short-lived highly reactive intermediates are conducted without deceleration in a highly controlled manner to produce desired compounds with high selectivity by virtue of high-resolution reaction control 2.26. High-resolution reaction time control is simply adjusting the residence time to a particular step in a multistep reaction sequence. Thus, the isolation of the intermediate products could be resolved by the residence time (partial reaction time) which is not possible in batch reactors. 2.27. Novel Process Windows (NPW) operates at process conditions that are beyond the usual condition; that considerably speed up conversion rates, while maintaining selectivity. This can be achieved by an increase in temperature, pressure or concentration (solvent-free operation), by a simplification of process protocols, or by function integration. Combined high-temperature and high-pressure flow regime, that is, > 200 °C and > 50 bar, is one of the main direction, with many applications focusing on the generation of high-temperature or supercritical water (scH2 O) 2.28. Process intensification (PI) can be defined as the ability to obtain equivalent or better results in terms of purity, selectivity, and yield of the desired product in a reduced period of time and therefore with an enhanced throughput, by increasing parameters such as temperature and pressure.

282 | Answers to the study questions

Chapter 3: Principles of controlling reactions in flow chemistry 3.1. Br

R1

M1

Br

R2

n-BuLi

M2 O M3 R

1

R3

2

R

n-BuLi

R4

M4

R2 R1

O

M1 – M5: Micromixer R1 – R5: Microreactor

3

R

R

4

M5 CH3OH

HO

(a)

R4

I

R3

R1

M1

R2

n-BuLi

M2

O

R3 CH3

I

M1 – M4: Micromixer R1 – R4: Microreactor

O

M3 O M4 H CH3OH

(b)

OH

R5

R4

CH3 HO

Answers to the study questions |

283

3.2. Br

(a)

CH3O

Li

n-BuBr CH3O

Br (b)

n-BuLi

n-BuLi

n-BuBr

Bu-n CH3O

Li Several products Br

Br

Li O Br

(c)

n-BuLi

OCH3

Li

O

O

OCH3

OCH3

Li O O

Several products

OCH3

Chapter 4: Technology overview/Overview of the devices 4.1. Pump, reactor – for example coil or chip, heating/cooling, and backpressure regulator. 4.2. The reaction conditions – residence/reaction time, temperature regime, pressure regime, strong basic or acidic conditions, possible chemical interactions with the used reactor materials, and toxicity of the reagents, products and side products. 4.3. 4 minutes 4.4. 3.2 min 4.5. You prepare a solution of B with concentration of 0.15 M. Alternatively, you can change the reaction loop to a longer one: a 10 ml loop would provide 4 minutes residence time. 4.6. 0.1 M, flow rate: 3 ml/min

Chapter 5: From batch to continuous chemical synthesis – a toolbox approach 5.1.

If the channel is 𝐿 m long and 𝑊 m wide, the area for heat transfer is 𝐴 = 2 𝑊 ⋅ 𝐿 m2 (from both top and bottom). The channel is 𝐻 m deep and so its volume is 𝑉 = 𝑊 ⋅ 𝐿 ⋅ 𝐻 m3 . The area-to-volume ratio is then 𝐴/𝑉 = 2𝑊𝐿/𝑊𝐿𝐻 = 2/𝐻 m2 /m3 . (a) The area-to-volume ratio for the 0.5 mm deep channel is 4000 m2 /m3 .

284 | Answers to the study questions (b)

The alternate channel is deeper (1 mm). Its resulting area-to-volume ratio is

2000 m2 /m3 , which is lower even though its width is smaller. But at equal flow rate, this channel may generate better mixing conditions via a smaller hydraulic diameter and thus greater Reynolds number. 5.2. The average superficial velocity in a circular channel is 𝑢 = (4𝑄)/(𝜋𝐷2 ). The Reynolds number can then be calculated as Re = (4𝜌𝑄)/(𝜋𝜇𝐷). To obtain turbulent flow in a straight tube, the Reynolds number must be above 4000. Rearranging to find the diameter, this yields 𝐷 = 4𝜌𝑄/𝜋𝜇Re = 4 ⋅ 1000 ⋅ (1.667 ⋅ 10−7 )/𝜋 0.001 ⋅ 4000 = 5 ⋅ 10−5 m. For this 50 μm diameter channel, the water velocity would then be 300 km/h causing an excessively large pressure gradient (3 GPa/m). 5.3. A 𝐷𝑎IV value lower than 1 is desired. Since this is an endothermic reaction, the amount of heat required (at these concentrations) is four times greater than the amount supplied by heating. The temperature will drop and the reaction will decelerate or even stop. A potential solution would be to use a heating fluid that is hotter or a reactor size that is smaller.

Chapter 6: Experimental procedures for conducting organic reactions in continuous flow 6.1. The sequential steps are: (a) Ylide attack on the carbonyl carbon of benzaldehyde; formation of cyclic intermediate. (b) Elimination of triphenylphosphine oxide; formation of alkene (𝐸 or 𝑍). O

O–PPh3

PPh3 H

O OtBu

O O

OtBu

OtBu (E-isomer)

– PPh3O +

O

(Z-isomer) OtBu

6.2. Example (dis)advantages: (a) Advantages: i. By decreasing the contact time of the reagents, the selectivity of the reaction is increased (almost no Z-isomer is formed). (b) Disadvantage: i. For every substrate, the reaction has to be tested for viability. ii. Continuous-flow equipment is not available in every laboratory, unlike common glassware.

Answers to the study questions |

285

6.3. The sequential steps are: (a) Formation of the oxidative sulfonium species from TFAA and DMSO (b) Substitution of the trifluoroacetate group by the alcohol (c) Proton abstraction by the base ‒ O

O

S +

S

O F3C O

CF3

O

CF3

O

S +

O

OH R1

S+

O R1

R2

O R2

R1

H

S

N

O

‒ R2

+ H

R1

R2

6.4. Example (dis)advantages: (a) Advantages: i. By decreasing the contact time of the reagents, the formation of sideproducts is largely suppressed. ii. Through very controlled reagent addition and efficient heat transfer, reaction runaway is fully suppressed. (b) Disadvantage: i. For every substrate, the reaction has to be tested for viability. ii. Continuous-flow equipment is not available in every laboratory, unlike common glassware. 6.5. Side-products: the trifluoroacetyl ester and thiomethyl ether, both (typically) formed at high temperatures. By decreasing the contact time of the reagents, the formation of these side-products is largely suppressed. 6.6. In the “regular” Swern oxidation, gas (CO) is liberated. This makes the determination of reaction time much more difficult, since it is never exactly known how much fluid resides in the microreactor at a certain moment. 6.7. Example (dis)advantages: (a) Advantages: i. Reaction parameters (and thereby particle diameter) are very easily controlled. ii. Since the reaction is almost instantaneous, homogenization (and thus mixing) of the reaction mixture is of utmost important in obtaining mono-disperse size distributions.

286 | Answers to the study questions (b)

6.8.

6.9.

6.10. 6.11. 6.12.

6.13.

6.14.

Disadvantage: i. Continuous-flow equipment is not available in every laboratory, unlike common glassware. Copper undergoes constant oxidation when exposed to air, and the non-self-protecting layers of different oxides, including Cu2 O, formed on its surface can promote the reaction. Example (dis)advantages: (a) Advantages: i. Faster reaction parameter optimization. ii. Safer when handling azides as potentially explosive substances. iii. Allows straightforward scale-up. (b) Disadvantage: i. Continuous-flow equipment is not available in every laboratory, unlike common glassware. Because it is an aprotic solvent, prevents D–H exchange and maximizes deuterium incorporation through the reaction. No N–D bond can be detected, as any N–D bond formed instantly changes to N–H due to reaction with moisture (H2 O) on exposure to air. Example (dis)advantages: (a) Advantages: i. It is safer, as D2 is generated in situ through the decomposition of D2 O. ii. It allows extended parameter space (high pressure/temperature). iii. It allows rapid parameter optimization and automation. (b) Disadvantage: i. The H-Cube® system is not available in every laboratory, unlike common glassware. (a) Advantages: By decreasing the contact time of the reagents, the formation of sideproducts is largely suppressed. (b) Disadvantage: Continuous-flow equipment is not available in every laboratory, unlike common glassware. (a) Advantages: i. By decreasing the contact time of the reagents, the formation of sideproducts is largely suppressed. ii. Through very controlled reagent addition and efficient heat transfer, reaction runaway is fully suppressed. (b) Disadvantage: i. For every substrate, the reaction has to be tested for viability. ii. Continuous-flow equipment is not available in every laboratory, unlike common glassware.

| 287

Answers to the study questions

6.15. The sequential steps are: (a) Epoxidation of cyclohexene to the epoxide by peracetic acid. (b) Ring-opening of the epoxide by either: i. Water (yields the diol 5a, Figure A), ii. One molecule of acetic acid (yields the mono-acetylated product 5b), or iii. Two molecules of acetic acid (yields the di-acetylated product 5c).

H O

O O

(4)

O H O O

'Butterfly' transition state

O H

O

H

O O

O

(5)

H

O H

O

O

O

(5)

(5)

O

O O

OH

O OH

OH

(5a)

H O

(5b)

O

O

(5c)

Fig. A: Mechanism and side-product formation of Prilezhaev epoxidation reaction.

6.16. (a)

(b)

Advantages: – By decreasing the contact time of the reagents, the selectivity and yield can be enhanced considerably. – The reaction is orders of magnitude faster than a batch reaction, while giving the same or even better results. Disadvantage: – Unlike common glassware, continuous-flow equipment is not available in every laboratory.

Chapter 7: Experimental procedures for conducting organic reactions in continuous flow 7.1.

7.2.

If the reaction is not quenched, the reagents will continue to react before the actual analysis will take place. The quench in fact is an on-chip workup procedure, such that, first of all, the residence time (reaction time) can be accurately determined, and secondly, a reliable analysis of the conversion in the chip can be obtained. In continuous-flow experiments, the reaction time is equal to the residence time. The residence time can be calculated by dividing the inner volume of the mi-

288 | Answers to the study questions

7.3.

7.4.

7.5.

croreactor (or tubing) by the combined flow of the solutions that are pumped through the chip. Hence, it is really important to know the internal volume of the microreactor. Homogeneous reactions: Advantages: – Microreactor can be reused – Reagents can be readily analyzed – Residence times can be easily calculated – This is the more conventional way of conducting reactions Disadvantages: – More difficult to reuse expensive reagents (catalysts): in particular with higher flow rates, larger amounts of reagents will be lost – Mixing is different for smaller and larger channels Heterogeneous reactions (immobilized reagents) Advantages: – Reagents can be reused after recycling – Reactions will be similar for small and larger channels (no diffusion limitations) Disadvantages: – More difficult to (reproducibly) prepare packed micoreactors – Packed microreactors can be used for a single type of reaction – Solid phase reactions are more difficult to monitor in-line Generally, the smaller the dimensions of the microchannels, the quicker the channels will clog. Therefore, in case you expect solids to be formed, one should use somewhat larger channels. Furthermore, it may be important to filter reagents and/or substrates prior to use. A critical aspect may also be the quenching reagent that is used: sometimes solids will be formed that precipitate and clog the chip. In those cases, use of different types of acids (or bases) thereby creating different counterions may offer a solution. Diffusion may or may not – depending on the dimensions of the channel – be a rate determining factor in a given reaction. Describe in general terms in what cases diffusion could and could not play a role and how diffusion limitations can be possibly overcome. In microchannels of small dimensions (< 100 μm diameter), diffusion will generally not be rate-limiting: even in case of biphasic laminar flow, or a slug flow, diffusion will be sufficiently fast to go from one phase to the other. However, with increasing dimensions of the chip, diffusion will become rate-limiting. Therefore, in microreactors of larger dimension, active mixing needs to be realized. This is typically achieved by incorporating mixing elements in the design of the microreactor.

Answers to the study questions

| 289

Chapter 8: The Microwave-to-flow paradigm: translating batch microwave chemistry to continuous-flow processes 8.1. Dramatically enhanced reaction rates, better yields and enhanced process control for sealed vessel (autoclave) experiments. 8.2. The autoclave conditions allow superheating of the reaction mixture to far above the boiling point of the reaction mixture. Therefore, based on the Arrhenius law, the reactions proceed faster. 8.3. Since heat transfer in a microreactor environment is very fast, the high temperatures typically generated in a microwave instrument by dielectric heating can be mimicked in a microreactor/flow device fitted with a back-pressure regulator.

Chapter 9: Incorporation of continuous-flow processing into the undergraduate teaching laboratory: key concepts and two case studies 9.1.

Preparation of monastrol:

O

O

O

O

HO

H

OH HN

S

O

+

+

O

H2N

NH2

NH S

Monastrol

9.2. Preparation of a 1,4-dihydropyridine and design of a flow approach: O H

O +

O

O

O O

+ NH3

Δ OEt

EtO N H

1,4-dihydropyridine

NH4OH(aq)

Ethyl acetate

O

O

O H

O +

In ethanol

O

Heated zone O

OEt

EtO N H

290 | Answers to the study questions 9.3. Atom economy of the Biginelli and Claisen–Schmidt reactions: Both reactions are atom efficient, the only byproduct being water. 9.4. Flow chemistry can particularly facilitate: – Prevention – for example, flow chemistry can reduce byproduct formation – Less hazardous chemical syntheses – for example, smaller volumes of material in the reactor vs batch, in-flow generation and use of hazardous reagents – Safer solvents and auxiliaries – for example, use of greener solvents that can be superheated in flow to allow access to a wide temperature range – The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used – for example, solvent-free processing, catalyst-free transformations – Design for energy efficiency – for example, process intensification – Unnecessary derivatization (use of blocking groups, protection/deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste – for example, sometimes protecting groups are not needed – Catalysis – for example, use of homogeneous or heterogeneous catalysts – Catalytic reagents (as selective as possible) are superior to stoichiometric reagents – as above – Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances – for example, range of in situ spectroscopic tools can be interfaced with flow reactors – Inherently safer chemistry for accident prevention – as before, smaller volumes of material in the reactor versus batch, in-flow generation and use of hazardous reagents

Index 1,3-Dipolar cycloaddition 172, 173, 188 1,4-addition 185–187 10% Pt/C catalyst 111 A activated complex 10, 277 activation – energy 3, 10, 11, 15, 19, 51, 258, 277 – volume 18, 19, 278 alcohol 70, 163, 164, 167, 188, 195, 204, 211, 224, 225, 230–235, 238, 239, 285 aldehyde 21, 74, 76, 159, 160, 162, 163, 178–180, 184, 186, 188, 204, 205, 211–214, 226, 227, 241, 243, 263–266, 269–271, 274, 284 aldol reaction 178–180 amidation 131, 211–213 amides 212, 213, 223–225 ammonia 274 anionic polymerization 85–89 Arrhenius law 251, 258, 289 artemisinin 119, 236, 238–241 asymmetric 184 automated optimization v, 46, 280 automation v, 4, 129, 135, 136, 286 axial dispersion 37, 41 azide 172, 188, 200, 202, 215, 286 B backmixing 41 back-pressure regulator 45, 100, 111, 125, 126, 196, 198, 200, 239, 252, 280 batch microwave chemistry 30, 251, 252, 258 benzyne 79, 197 Biginelli reaction 260, 264 biodegradable 40 biphasic reactions 104, 107, 113, 114 block copolymer 85, 87–89 Bodenstein number 41 bond energies 10, 11, 19, 277 bromination 131 C capillary 27, 30, 45, 56, 106, 135, 200, 252, 253, 279

carbanion 16, 68 carbene 16 carbocation 16, 68, 225 carbon-carbon double bonds 159 catalysis v, 4, 12, 111, 133, 137, 172, 264, 290 catalyst 4, 12, 16, 21, 26, 32, 48, 55, 59, 78, 83, 84, 105, 106, 109–112, 128, 129, 137, 175, 176, 178, 184–186, 201, 207–210, 216, 232, 255, 256, 264, 268, 269, 272, 277, 288, 290 chalcone 269, 270 channel 22, 27, 30, 34–40, 42–44, 51, 61, 64, 101, 102, 111, 113–115, 125–127, 130, 131, 134, 135, 193, 194, 196, 199, 204, 213, 214, 216, 217, 219–222, 228, 237, 241–244, 252, 260, 264, 278–280, 288 chemical reaction 9–16, 18, 19, 23, 26, 31, 43, 45, 49, 50, 55–57, 62, 67, 77, 95, 126, 131, 135, 137, 189, 191, 251, 260, 277, 278 chemistry v, vi, 191 chemoenzymatic synthesis 241, 242 chip reactor 45, 108, 109, 132 Claisen–Schmidt reaction 260, 269, 270, 274, 290 clogging 204, 220, 222, 241, 260, 263, 264 coil 45, 99, 197, 199, 217, 253, 261, 266–268, 270, 272 – reactor 106, 107, 127, 130, 218, 255 column reactor 127, 130 consecutive reaction 13, 15, 56, 278 continuous tank (flask) reactors 24 control of stoichiometry 49 corrosion 131 cross-coupling 82–85, 191, 208, 210, 255, 257, 263 cyanide 225, 241–243 cyanohydrin 241–243 cycloaddition 19, 200, 202, 235, 253, 254, 262, 263 D Damköhler number 41 diazomethane 3 diazotation 129 diazotization 197, 198 diazotransfer 215–217

292 | Index dielectric – constant 35 – heating 251, 252, 257, 289 Diels–Alder reaction 196–199 diffusion 5, 13, 14, 16, 19, 61, 101, 102, 115, 122, 244, 288 dihydropyrimidine 264 dispersion 36, 131, 263 dynamic mixer 103 E electroosmotic 34, 35, 56 emulsion 115 enantiomeric excess 241 enantioselective 184, 241 endothermic reaction 16, 17, 20 engulfment flow regime 64, 65 enthalpy 9–11, 16, 18–20, 49, 277, 278, 280 entropy 9, 10, 277 environment 26, 32, 42, 46, 48, 67, 107, 204, 211, 254, 259, 289 enzyme 241–243 equilibrium 10, 14, 16–20, 56, 192, 231, 277, 278 excited state 15, 19, 235, 277 exothermic 3, 4, 16–18, 20, 30, 42, 51, 66, 102, 107, 108, 127, 163, 178, 181, 192, 204, 224, 257, 278 explosive 117, 172, 200, 215, 254, 286 F falling film – microreactor 116, 117 – reactor 3, 116, 117 FEP 120, 193, 216, 228, 230, 237, 239 first-order reaction 12, 23 fitting 4, 120, 122, 210, 211 fixed-bed reactor 21, 32, 109, 111 flammable 270 flash chemistry 3, 15, 20, 25–27, 34, 50, 51, 56, 57, 59, 78, 91, 125, 137, 208, 281 flask (batch) reaction 20 flow v, vi, 157, 191, 251, 259 – chemistry v, vi, 3, 9, 24, 34, 44, 49, 52, 53, 59, 60, 62, 78, 80, 85, 89, 157, 161, 163, 166, 168, 172, 174, 178–180, 182, 184, 186–188, 191, 196, 197, 200, 204, 211, 224, 227, 236, 244, 252, 257, 259, 260, 262–264, 273, 274, 290

– rate 21–24, 33–36, 38, 39, 43, 51, 57, 61, 86, 97, 98, 102, 106, 107, 114, 120–122, 125, 126, 130, 135–137, 157–162, 165–167, 170, 172, 174, 175, 177, 178, 180–182, 184, 186–188, 192, 194, 198, 200, 202, 203, 222, 233, 235, 237, 240, 243, 245, 253, 256, 257, 260, 261, 265, 268, 270, 272, 278, 283, 288 – regime 34, 38, 40, 43, 53, 113, 114, 252, 255, 280, 281 – set-up 47, 96, 105, 121, 179, 181, 182, 186, 196, 197, 201, 202, 204, 209, 212, 219, 224, 225, 232, 233, 237, 239, 242 – technology 193, 219 fluorination 117 fluorine 117 fluorous media 53 free energy profile 9, 10, 12–14 free radicals 16 G Gibbs free energy 9, 277 glass 20, 44, 96, 102, 105, 108, 109, 116, 117, 123–125, 127, 131–134, 136, 194, 195, 202, 203, 214, 216, 217, 227, 229, 232, 234, 236, 239, 242, 243, 280, 284–287 GMP 4, 132 green chemistry v, 56, 262, 273, 274 green-ness 22 H Hagen–Poiseulle equation 36 half-life 13, 19, 278 halogen/lithium exchange 70, 75 Hammond postulate 16, 20 harsh conditions 53, 196 hazard 33, 49, 107, 128, 134, 200, 211, 227, 254, 262, 280, 290 hazardous reagents 290 H-Cube 128, 129, 176, 177, 188, 257, 286 heat – conductivity 40 – exchange 5, 49, 280 – exchanger 5, 67, 105, 117, 134, 136, 253, 255 – removal 30, 42, 66 – transfer 3, 5, 15, 19, 29, 41, 42, 49, 51, 55, 56, 66, 67, 86, 89, 105, 117, 131, 224, 251–253, 257, 277, 279, 285, 286, 289

Index |

heterogeneous v, 4, 20, 32, 111, 129, 172, 176, 201, 203, 257, 288, 290 high pressure 4, 48, 50, 53, 97, 104, 105, 107, 109, 111, 126, 128, 135, 196, 198, 200, 286 high temperature 53, 107, 108, 130, 135, 196, 252, 285, 289 high-resolution reaction time control 51, 56, 57, 68, 76, 77, 85, 281 HNL 241–243 homogeneous reaction 12, 23, 48, 59, 106, 107, 122, 123, 129, 219, 288 HPLC pump 101, 135, 173, 174, 194, 197, 199, 203, 206, 207, 229, 232, 240 hydrazoic acid 254 hydrogen 53, 111, 128, 211, 212, 214, 241 hydrogenation 128, 129, 131, 176, 177, 256, 269 I immobilized 32, 48, 111, 112, 184, 185, 191, 201, 244, 264, 288 in translating organic synthesis 252 Inductive heating 191, 200, 201 In-line IR analysis 228 integration 20, 28, 31, 34, 47, 53, 212, 259, 281 intensified instrinsic kinetics 55 ionic liquid 53, 124 isomerization 76, 77 K kinematic viscosity 39–41 kinetically controlled 13, 19, 49, 55, 280 L laminar flow 27, 28, 34, 38, 64, 65, 103, 242, 279, 288 Le Chatelier Braun principle 18, 278 leaching 110, 111, 202 Life Cycle Assessment 4 liquid–liquid extraction 28 lithium halogen exchange 219, 220 M mass – transfer v, 3, 5, 28, 34, 55, 56, 67, 101, 110, 114, 119, 215, 279 – transport 41, 42 membrane pump 98 meso flow 40 methyl iodide 74

293

microchemical processing technology 55 microchip 269 microfluidic 3, 34, 97, 194, 195, 229 – device 22, 35, 36, 43, 47 micromixer 64–66, 70, 71, 78, 79, 84, 86, 88, 90, 103, 109, 208–211, 224, 226 microreactor 3–5, 25–27, 29–32, 34–36, 38–44, 47, 49–51, 53, 55, 56, 59, 62, 66, 67, 70–76, 78–80, 82, 84–86, 88–91, 101, 103, 107–109, 113, 157, 191, 193–195, 197, 204, 208, 211–216, 227–230, 238, 241–245, 253, 254, 257, 260, 279, 288, 289 microwave 30, 53, 55, 106, 116, 196, 251, 259, 260, 273 – chemistry 117 – reactor 117, 197, 251, 252 microwave-assisted organic synthesis (MAOS) 251 miniaturization 38, 44, 48 mixing 3, 4, 13, 16, 19, 21, 23, 24, 27, 34, 38, 62–64, 66, 86, 89, 97, 101–106, 109, 114, 115, 121–125, 131, 132, 134–136, 199, 205, 208, 216, 227, 236, 241, 259, 260, 270, 285, 288 molecular diffusion 27, 38, 41, 63, 279 Monolith 230, 232–235 multicomponent reaction 274 multistep synthesis 25, 26, 130

N nanoparticle 128, 168–172, 188, 260 nanotechnology v narrow temperature distribution 32 Nef oxidation 204–206 nitration 3, 107, 123, 125, 131 nitrene 16 noncorrosive 40 Novel Process Windows 3–5, 45, 50, 52, 53, 55, 56 numbering-up 252, 253

O on-line mass spectrometry 196, 198 operation time 23, 60 optical properties 134 optimization 31, 127, 161–164, 166, 167, 172, 174, 178, 184, 286

294 | Index Organic Synthesis 20, 22, 25, 27, 34–36, 40, 47, 54, 70, 77, 91, 133, 137, 189, 215, 223, 230, 260, 269 organocatalysis 21, 184 organometallic 91, 178 oxidation 3, 15, 19, 107, 112, 163, 164, 166, 167, 181, 191, 260, 263, 277 ozone 129 ozonolysis 107, 129 P Paal–Knorr cyclocondensation 192 parabolic velocity profile 36, 279 parallel 13, 15, 34, 49, 114, 195, 252, 278, 280 parameter optimization 286 particle diameter 170, 172, 285 Peclet number 41 peracetic acid 181, 182, 184, 189, 287 peristaltic pump 36, 99, 261 pharmaceutical v, 59, 192, 262 phosphine ligand 208 photochemistry v, 117–119, 126 photooxidation 119 photooxygenation 118, 119 piston pump 97, 98, 121, 135, 221, 223 plate 125, 136, 223, 251 plug flow 34, 41, 136 polymers 44, 85, 86, 88, 89, 100, 102, 108, 211, 280 Prandtl number 40 precipitation 16, 19, 108, 109, 114, 122, 198, 202, 220, 272, 277 preparative scale 23, 182, 195, 218, 239 Prilezhaev epoxidation reaction 181 process intensification 4, 33, 50, 51, 53, 55–57, 253, 257, 281, 290 pyrrole synthesis 192, 263 Q quartz 44, 108, 280 quenching 16, 19, 24, 45, 51, 62, 63, 68, 69, 71–73, 107, 157, 162, 163, 167, 169, 172, 191, 216–218, 229, 243, 244, 254, 277, 288 R rate – acceleration 38, 50, 52 – constant 11, 12, 15, 17, 19, 68, 253, 277, 278

– determining step 13, 19 – law 12 reaction – optimization 122, 180, 187, 191, 193, 196, 216, 225, 228, 264, 269 – planning 49 – pulse 37 – time 3, 11, 20, 22–26, 44, 49–51, 59, 60, 62, 63, 65, 67, 109, 116, 137, 157, 158, 160, 162–164, 166, 167, 169, 171, 172, 179, 180, 182–185, 193, 194, 198, 209, 213, 215–217, 225, 228, 242, 244, 251–253, 255, 257, 261, 283, 285, 287 reactive intermediate 15, 16, 19, 50, 51, 56, 59, 66, 68, 70, 73, 76, 78, 85, 89, 198, 226, 277, 281 reactor – volume 21, 33, 109, 110, 130, 157 – zone 21, 32, 33, 45, 95, 97, 103, 111, 121, 122, 280 real-time analysis 46, 280 recycling 4, 32, 111, 233, 288 reduction 29, 125, 131, 232, 255, 256 reproducibility 192 reservoir 45, 97, 98, 177, 266, 270, 280 residence time 21, 22, 24, 25, 27, 33, 51, 56, 60–63, 71–77, 79, 84, 86, 89, 97, 106, 107, 113, 114, 116, 121, 122, 125, 127, 130, 131, 134, 136, 168, 175, 178, 188, 197, 198, 200, 202, 205, 206, 208, 209, 211, 214, 216, 218, 252–255, 278, 281, 283, 287, 288 reusability 32, 111, 185 Reynolds number 34, 38, 39, 43, 57, 280 Ritter reaction 223–226 runaway 3, 181, 224, 227

S safety v, 4, 33, 49, 128, 135, 172, 176, 188, 189, 197, 200, 204, 211, 224, 227, 259, 260, 265, 270, 280 scalability v, 172, 252, 257 scale-up 39, 40, 43, 117, 118, 181, 185, 191, 194, 200, 219, 221, 222, 224, 227, 238, 253, 259, 286 scavenger 26, 48 Schenck ene reaction 235–238 segmented flow 37, 38, 43, 57, 113–116, 222, 279

Index |

selectivity 13, 15, 19, 24, 27, 49, 50, 53, 55, 56, 68, 70, 112, 117, 187, 235, 243, 255, 278, 281, 284, 287 self-optimization 46 silicon 30, 44, 85, 87, 88, 108, 125, 212–214, 252, 257, 280 singlet oxygen 235, 236 slug-flow 119 solid support 26, 109, 184 solvent-free operation 53, 281 space integration of reactions 77, 78, 81, 82, 88 Space Time Yield 44, 47, 57, 280 stabilization 200, 218, 243 static mixer 102–105, 127 steady state v, 22, 23, 60, 203, 210, 211 stoichiometry 16, 21, 22, 33, 167, 194 supercritical v, 53, 54, 95, 119, 253, 281 – fluids 53, 119 surface area 4, 29, 66, 111, 114, 236, 279 surface-to-volume 104, 107, 109 – ratio 29, 30, 32, 33, 66, 86, 109, 111, 193, 215, 219, 224, 236, 252, 279 sustainability 4, 5 Suzuki–Miyaura coupling 85 T teaching 259, 260, 262–264, 269, 273

295

temperature – control 5, 29, 99, 117, 122, 127, 130, 131, 134, 157, 159, 163, 169, 186, 193, 194, 216, 227–229, 232, 257, 279 – dependence 11, 175, 258, 277 tetraphenylporphyrine 239, 240 thermodynamical control 14, 19, 278 timescale 26 T-mixer 45, 102, 240, 280 toxic v, 159, 181, 215, 224, 241, 254, 283 transition state 10–12, 16, 19, 20, 277 triazoles 172, 174, 201–203 – synthesis 172, 173, 201 triplet oxygen 236 tube-in-tube 112, 127, 136 – reactor 112, 130 turbulent flow 38, 57 type D reaction 50, 52 U ultrasound 53, 205–207 undergraduate 259–264, 273 V velocity profile 34, 35 Vilsmeier–Haack formylation 125, 226, 227 viscosity 27, 28, 35, 36, 39, 104, 107, 113, 114, 121 vortex circulation 37, 38