Microreactors in Organic Chemistry and Catalysis, Second Edition 9783527332991, 9783527659722

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Edited by Thomas Wirth Microreactors in Organic Chemistry and Catalysis

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Edited by Thomas Wirth

Microreactors in Organic Chemistry and Catalysis Second, Completely Revised and Enlarged Edition

The Editor Prof. Dr. Thomas Wirth Cardiff University School of Chemistry Park Place Main Building Cardiff CF10 3AT United Kingdom

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for

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Contents Preface to the First Edition XIII Preface to the Second Edition XV List of Contributors XVII 1 1.1 1.1.1 1.1.2 1.2 1.2.1 1.2.2 1.3 1.3.1 1.3.2 1.3.3 1.4 1.5 1.5.1 1.5.1.1 1.5.2 1.5.3 1.5.3.1 1.5.3.2

2 2.1 2.2 2.3 2.4 2.5

Properties and Use of Microreactors 1 David Barrow, Shan Taylor, Alex Morgan, and Lily Giles Introduction 1 A Brief History of Microreactors 1 Advantages of Microreactors 6 Physical Characteristics of Microreactors 7 Geometries 7 Constructional Materials and Their Properties 10 Fluid Flow and Delivery Regimes 16 Fluid Flow 16 Fluid Delivery 20 Mixing Mechanisms 21 Multifunctional Integration 23 Uses of Microreactors 23 Overview 23 Fast and Exothermic Reactions 24 Precision Particle Manufacture 25 Wider Industrial Context 27 Sustainability Agenda 27 Point-of-Demand Synthesis 27 References 28 Fabrication of Microreactors Made from Metals and Ceramic 35 Juergen J. Brandner Manufacturing Techniques for Metals 35 Etching 36 Machining 38 Generative Method: Selective Laser Melting 41 Metal Forming Techniques 42

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2.6 2.7 2.8

Assembling and Bonding of Metal Microstructures 43 Ceramic Devices 46 Joining and Sealing 48 References 49

3

Microreactors Made of Glass and Silicon 53 Thomas Frank How Microreactors Are Constructed 53 Glass As Material 54 Silicon As Material 57 The Structuring of Glass and Silicon 58 Structuring by Means of Masked Etching As in Microsystems Technology 58 Etching Technologies 60 Anisotropic (Crystallographic) Wet Chemical Etching of Silicon (KOH) 61 Isotropic Wet Chemical Etching of Silicon 63 Isotropic Wet Chemical Etching of Silicon 64 Isotropic Wet Chemical Etching of Silicon Glass 65 Other Processes 66 Photostructuring of Special Glass 66 Drilling, Diamond Lapping, Ultrasonic Lapping 68 Micro Powder Blasting 69 Summary 71 Other Processes 72 Sensor Integration 72 Thin Films 72 Bonding Methods 73 Anodic Bonding of Glass and Silicon 73 Glass Fusion Bonding 73 Silicon Direct Bonding (Silicon Fusion Bonding) 74 Establishing Fluid Contact 76 Other Materials 78 References 79

3.1 3.1.1 3.1.2 3.2 3.2.1 3.2.2 3.2.2.1 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.2 3.3.2.1 3.3.3 3.3.4 3.3.5 3.4 3.4.1 3.5 3.6 3.6.1 3.6.2 3.6.3 3.6.4 3.7

4 4.1 4.2 4.3 4.4 4.5 4.6

Automation in Microreactor Systems 81 Jason S. Moore and Klavs F. Jensen Introduction 81 Automation System 84 Automated Optimization with HPLC Sampling 86 Automated Multi-Trajectory Optimization 89 Kinetic Model Discrimination and Parameter Fitting 94 Conclusions and Outlook 97 References 99

Contents

5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8

6

6.1 6.2 6.3 6.3.1 6.3.2 6.4

7 7.1 7.2 7.2.1 7.2.2 7.2.3 7.3 7.4 7.5 7.5.1 7.5.2 7.5.3 7.6 7.6.1 7.7 7.8

Homogeneous Reactions 101 Takahide Fukuyama, Md. Taifur Rahman, and Ilhyong Ryu Acid-Promoted Reactions 101 Base-Promoted Reactions 106 Radical Reactions 108 Condensation Reactions 110 Metal-Catalyzed Reactions 117 High Temperature Reactions 122 Oxidation Reactions 124 Reaction with Organometallic Reagents 125 References 130 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis 133 Paul Watts and Charlotte Wiles Photochemistry in Flow Reactors 133 Electrochemistry in Microreactors 137 Radiopharmaceutical Synthesis in Microreactors 139 Fluorinations in Microreactors 141 Synthesis of 11C-Labeled PET Radiopharmaceuticals in Microreactors 145 Conclusion and Outlook 147 References 147 Heterogeneous Reactions 151 Kiyosei Takasu Arrangement of Reactors in Flow Synthesis 152 Immobilization of the Reagent/Catalyst 155 A Packed-Bed Reactor 155 Monolith Reactors 156 Miscellaneous 157 Flow Reactions with an Immobilized Stoichiometric Reagent 159 Flow Synthesis with Immobilized Catalysts: Solid Acid Catalysts 165 Flow Reaction with an Immobilized Catalyst: Transition Metal Catalysts Dispersed on Polymer 166 Catalytic Hydrogenation 167 Catalytic Cross-Coupling Reactions and Carbonylation Reactions 171 Miscellaneous 175 Flow Reaction with an Immobilized Catalyst: Metal Catalysts Coordinated by a Polymer-Supported Ligand 176 Flow Reactions Using Immobilized Ligands with a Transition Metal Catalyst 179 Organocatalysis in Flow Reactions 183 Flow Biotransformation Reactions Catalyzed by Immobilized Enzymes 186

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Contents

7.9 7.10

Multistep Synthesis 187 Conclusion 191 References 191

8

Liquid–Liquid Biphasic Reactions 197 Matthew J. Hutchings, Batool Ahmed-Omer, and Thomas Wirth Introduction 197 Background 198 Kinetics of Biphasic Systems 199 Biphasic Flow in Microchannels 200 Surface and Liquid–Liquid Interaction 202 Liquid–Liquid Microsystems in Organic Synthesis 207 Micromixer 209 Conclusions and Outlook 218 References 218

8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8

9 9.1 9.2 9.2.1 9.2.1.1 9.2.1.2 9.2.1.3 9.2.1.4 9.2.2 9.2.2.1 9.2.2.2 9.2.2.3 9.2.2.4 9.2.2.5 9.2.3 9.3 9.3.1 9.3.1.1 9.3.1.2 9.3.1.3 9.3.2 9.3.3 9.3.4 9.3.5 9.3.6 9.3.7 9.3.8 9.4

Gas–Liquid Reactions 221 Ivana Dencic and Volker Hessel Introduction 221 Contacting Principles and Microreactors 222 Contacting with Continuous Phases 222 Falling Film Microreactor 222 Continuous Contactor with Partly Overlapping Channels 226 Mesh Microcontactor 227 Annular-Flow Microreactors 229 Contacting with Disperse Phases 231 Taylor-Flow Microreactors 232 Micromixer-Capillary/Tube Reactors 237 Micro-packed Bed Reactors 240 Membrane Microreactors 242 Tube in Tube Microreactor 243 Scaling Up of Microreactor Devices 244 Gas–Liquid Reactions 245 Direct Fluorination of Aromatics 246 Direct Fluorination of Aromatics 246 Direct Fluorination of Aliphatics and Non-C-Moieties 249 Direct Fluorination of Heterocyclic Aromatics 251 Oxidations of Alcohols, Diols, and Ketones with Fluorine 253 Photochlorination of Aromatic Isocyanates 254 Photoradical Chlorination of Cycloalkenes 255 Mono-Chlorination of Acetic Acid 256 Sulfonation of Toluene 257 Photooxidation Reactions 259 Reactive Carbon Dioxide Absorption 263 Gas–Liquid–Solid Reactions 265

Contents

9.4.1 9.4.1.1 9.4.1.2 9.4.1.3 9.4.1.4 9.4.1.5 9.4.1.6 9.4.2 9.4.2.1 9.4.2.2 9.5 9.5.1 9.5.2 9.6 9.6.1 9.6.2 9.7

10

10.1 10.2 10.2.1 10.2.1.1 10.2.1.2 10.2.1.3 10.3 10.3.1 10.3.1.1 10.3.1.2 10.3.1.3 10.3.2 10.3.3 10.3.4 10.3.4.1 10.3.4.2

Hydrogenations 266 Cyclohexene Hydrogenation over Pt/Al2O3 266 Hydrogenation of p-Nitrotoluene and Nitrobenzene over Pd/C and Pd/Al2O3 267 Hydrogenation of Azide 270 Hydrogenation of Pharmaceutical Intermediates 270 Selective Hydrogenation of Acetylene Alcohols 271 Hydrogenation of a-Methylstyrene over Pd/C 272 Oxidations 273 Oxidation of Alcohols 275 Oxidation of Sugars 275 Homogeneously Catalyzed Gas–Liquid Reactions 276 Asymmetric Hydrogenation of Cinnamic Acid Derivatives 276 Asymmetric Hydrogenation of Methylacetamidocynamate 278 Other Applications 281 Segmented Gas–Liquid Flow for Particle Synthesis 281 Catalyst Screening 281 Conclusions and Outlook 282 References 283 Bioorganic and Biocatalytic Reactions 289 Masaya Miyazaki, Maria Portia Briones-Nagata, Takeshi Honda, and Hiroshi Yamaguchi General Introduction 289 Bioorganic Syntheses Performed in Microreactors 292 Biomolecular Syntheses in Microreactors: Peptide, Sugar and Oligosaccharide, and Oligonucleotide 292 Peptide Synthesis 292 Sugar and Oligosaccharide Synthesis 296 Oligonucleotide Synthesis 302 Biocatalysis by Enzymatic Microreactors 304 Classification of Enzymatic Microreactors Based on Application 304 Applications of Microreactors for Enzymatic Diagnostics and Genetic Analysis 304 Application of Microreactors for Enzyme-Linked Immunoassays 308 Applications of Microfluidic Enzymatic Microreactors in Proteomics 312 Enzymatic Microreactors for Biocatalysis 347 Advantages of Microreactors in Biocatalysis 347 Biocatalytic Transformations in Microfluidic Systems 348 Solution-phase Enzymatic Reactions 348 Microfluidic Reactors with Immobilized Enzymes for Biocatalytic Transformations 357

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Contents

10.4 10.5

Multienzyme Catalysis in Microreactors 362 Conclusions 365 References 366

11

Industrial Microreactor Process Development up to Production 373 Ivana Dencic and Volker Hessel Mission Statement from Industry on Impact and Hurdles 373 Screening Studies in Laboratory 375 Peptide Synthesis 375 Hantzsch Synthesis 378 Knorr Synthesis 379 Enamine Synthesis 381 Aldol Reaction 381 Wittig Reaction 382 Polyethylene Formation 382 Diastereoselective Alkylation 383 Multistep Synthesis of a Radiolabeled Imaging Probe 384 Process Development at Laboratory Scale 386 Nitration of Substituted Benzene Derivatives 386 Microflow Azide Syntheses 387 Vitamin Precursor Synthesis 389 Ester Hydrolysis to Produce an Alcohol 391 Synthesis of Methylenecyclopentane 391 Condensation of 2-Trimethylsilylethanol 391 Staudinger Hydration 392 (S)-2-Acetyl Tetrahydrofuran Synthesis 392 Synthesis of Intermediate for Quinolone Antibiotic Drug 393 Domino Cycloadditions in Parallel Fashion 394 Phase-Transfer Catalysis-Mediated Knoevenagel Condensation 396 Ciprofloxazin1 Multistep Synthesis 396 Methyl Carbamate Synthesis 397 Newman–Kuart Rearrangement 398 Ring-Expansion Reaction of N-Boc-4-Piperidone 399 Synthesis of Aldehydes 400 Grignard Reactions and Li–Organic Reactions 402 Continuous Synthesis of Disubstituted Triazoles 404 Production of 6-Hydroxybuspirone 405 Swern–Moffatt Oxidation 406 Pilot Plants and Production 408 Hydrogen Peroxide Synthesis 408 Phenylboronic Acid Synthesis 410 Diverse Case Studies at Lonza 411 Alkylation Reactions Based on Butyllithium 414 Microprocess Technology in Japan 416 Pilot Plant for Methyl Methacrylate Manufacture 417

11.1 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5 11.2.6 11.2.7 11.2.8 11.2.9 11.3 11.3.1 11.3.2 11.3.3 11.3.4 11.3.5 11.3.6 11.3.7 11.3.8 11.3.9 11.3.10 11.3.11 11.3.12 11.3.13 11.3.14 11.3.15 11.3.16 11.3.17 11.3.18 11.3.19 11.3.20 11.4 11.4.1 11.4.2 11.4.3 11.4.4 11.4.5 11.4.6

Contents

11.4.7 11.4.8 11.4.9 11.4.10 11.4.11 11.4.12 11.4.13 11.4.14 11.4.14.1 11.4.14.2 11.4.15 11.4.16 11.4.17 11.4.18 11.4.19 11.4.20 11.4.21 11.4.22 11.4.23 11.4.24 11.4.25 11.5

Grignard Exchange Reaction 417 Halogen–Lithium Exchange Pilot Plant 419 Swern–Moffatt Oxidation Pilot Plant 420 Yellow Nano Pigment Plant 422 Polycondensation 423 H2O2-Based Oxidation to 2-Methyl-1,4-naphthoquinone 424 Friedel–Crafts Alkylation 425 Diverse Studies from Japanese Project Cluster 426 Synthesis of Photochromic Diarylethenes 426 Cross-Coupling in a Flow Microreactor 427 Direct Fluorination of Ethyl 3-Oxobutanoate 428 Deoxofluorination of a Steroid 429 Microprocess Technology in the United States 430 Propene Oxide Formation 432 Diverse Industrial Pilot-Oriented Involvements 433 Production of Polymer Intermediates 435 Synthesis of Diazo Pigments 436 Selective Nitration for Pharmaceutical Production 438 Nitroglycerine Production 439 Fine Chemical Production Process 440 Grignard-Based Enolate Formation 441 Challenges and Concerns 442 References 444 Index 447

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Preface to the First Edition Microreactor technology is no longer in its infancy and its applications in many areas of science are emerging. This technology offers advantages to classical approaches by allowing miniaturization of structural features up to the micrometer regime. This book compiles the state of the art in organic synthesis and catalysis performed with microreactor technology. The term “microreactor” has been used in various contexts to describe different equipment, and some examples in this book might not justify this term at all. But most of the reactions and transformations highlighted in this book strongly benefit from the physical properties of microreactors, such as enhanced mass and heat transfer, because of a very large surface-to-volume ratio as well as regular flow profiles leading to improved yields with increased selectivities. Strict control over thermal or concentration gradients within the microreactor allows new methods to provide efficient chemical transformations with high space– time yields. The mixing of substrates and reagents can be performed under highly controlled conditions leading to improved protocols. The generation of hazardous intermediates in situ is safe as only small amounts are generated and directly react in a closed system. First reports that show the integration of appropriate analytical devices on the microreactor have appeared, which allow a rapid feedback for optimization. Therefore, the current needs of organic chemistry can be addressed much more efficiently by providing new protocols for rapid reactions and, hence, fast access to novel compounds. Microreactor technology seems to provide an additional platform for efficient organic synthesis – but not all reactions benefit from this technology. Established chemistry in traditional flasks and vessels has other advantages, and most reactions involving solids are generally difficult to be handled in microreactors, though even the synthesis of solids has been described using microstructured devices. In the first two chapters, the fabrication of microreactors useful for chemical synthesis is described and opportunities as well as problems arising from the manufacture process for chemical synthesis are highlighted. Chapter 1 deals with the fabrication of metal- and ceramic-based microdevices, and Brandner describes different techniques for their fabrication. In Chapter 2, Frank highlights the microreactors made from glass and silicon. These materials are more known to the organic chemists and have therefore been employed frequently in different

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j Preface to the First Edition laboratories. In Chapter 3, Barrow summarizes the use and properties of microreactors and also takes a wider view of what microreactors are and what their current and future uses can be. The remaining chapters in this book deal with different aspects of organic synthesis and catalysis using the microreactor technology. A large number of homogeneous reactions performed in microreactors have been sorted and structured by Ryu et al. in Chapter 4.1, starting with very traditional, acid- and base-promoted reactions. They are followed by metal-catalyzed processes and photochemical transformations, which seem to be particularly well suited for microreactor applications. Heterogeneous reactions and the advantage of consecutive processes using reagents and catalysts on solid support are compiled by Ley et al. in Chapter 4.2. Flow chemistry is especially advantageous for such reactions, but certain limitations to supported reagents and catalysts still exist. Recent advances in stereoselective transformations and in multistep syntheses are explained in detail. Other biphasic reactions are dealt with in the following two chapters. In Chapter 4.3, we focus on liquid–liquid biphasic reactions and focus on the advantages that microreactors can offer for intense mixing of immiscible liquids. Organic reactions performed under liquid–liquid biphasic reaction conditions can be accelerated in microreactors, which is demonstrated using selected examples. The larger area of gas–liquid biphasic reactions is dealt with by Hessel et al. in Chapter 4.4. After introducing different contacting principles under continuous flow conditions, various examples show clearly the prospects of employing microreactors for such reactions. Aggressive and dangerous gases such as elemental fluorine can be handled and reacted safely in microreactors. The emergence of the bioorganic reactions is described by vanHest et al. in Chapter 4.5. Several of the reactions explained in this chapter are targeted toward diagnostic applications. Although on-chip analysis of biologic material is an important area, the results of initial research showing biocatalysis can also now be used efficiently in microreactors are summarized in this chapter. In Chapter 5, Hessel et al. explain that microreactor technology is already being used in the industry for the continuous production of chemicals on various scales. Although only few achievements have been published by industry, the insights of the authors into this area allowed a very good overview on current developments. Owing to the relatively easy numbering up of microreactor devices, the process development can be performed at the laboratory scale without major changes for larger production. Impressive examples of current production processes are given, and a rapid development in this area is expected over the next years. I am very grateful to all authors for their contributions and I hope that this compilation of organic chemistry and catalysis in microreactors will lead to new ideas and research efforts in this field. Cardiff August 2007

Thomas Wirth

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Preface to the Second Edition The continued and increased research efforts in microreactor and flow chemistry have led to an impressive increase in publications in recent years and even to a translation of the first edition of this book into Chinese. This is reflected not only in an update and expansion of all chapters of the first edition but also in the addition of several new chapters to this second edition. In the first three chapters, Barrow, Brandner, and Frank, respectively, describe properties and fabrication methods of microreactors. In Chapter 4, Moore and Jensen give detailed insights into current methods of online and offline analyses, the potential of rapid optimization of reactions using flow technology, and the combination of analysis and optimization. For better readability, the material on organic synthesis has been split into five different chapters. Ryu et al. have extended their chapter on homogeneous reactions in microreactors, while Watts and Wiles have elaborated the topics of photochemistry, electrochemistry, and radiopharmaceutical synthesis in a new chapter as reactions in these areas are very suitable for being carried out using flow chemistry devices and many publications have recently appeared. Takasu has written a comprehensive chapter on heterogeneous reactions in microreactors and a many different reactions can be found in this part. We have updated our chapter on liquid–liquid biphasic reactions and Hessel et al. have provided an update on the gas–liquid biphasic reactions. The chapter on bioorganic and biocatalytic reactions by Miyazaki et al. is a comprehensive overview of the developments in this area and highlights the advantages that flow chemistry can offer for research in bioorganic chemistry. The final chapter by Hessel et al. on industrial microreactor process development up to production has seen a dramatic increase as in many areas industry is now adopting flow chemistry with all its advantages for research and for small- to medium-scale production. I am again very grateful to all authors for providing updates or completely new contributions and I hope that this compilation of chemistry and catalysis in microreactors will stimulate new ideas and research efforts. Cardiff January 2013

Thomas Wirth

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List of Contributors Batool Ahmed-Omer Cardiff University School of Chemistry Main Building Park Place Cardiff CF10 3AT UK David Barrow Cardiff University Cardiff School of Engineering Laboratory for Applied Microsystems Cardiff CF24 3TF UK Juergen J. Brandner Karlsruhe Institute of Technology Institute for Micro Process Engineering Campus North Hermann-von-Helmholtz-Platz 1 76344 Eggenstein-Leopoldshafen Germany Maria Portia Briones-Nagata Measurement Solution Research Center National Institute of Advanced Industrial Science and Technology 807-1 Shuku, Tosu Saga 841-0052 Japan

Ivana Dencic Eindhoven University of Technology Department of Chemical Engineering and Chemistry Laboratory for Micro-Flow Chemistry and Process Technology STW 1.37 5600 MB, Eindhoven The Netherlands Thomas Frank Porzellanstr. 16 98693 Ilmenau Germany Takahide Fukuyama Osaka Prefecture University Graduate School of Science Department of Chemistry Sakai Osaka 599-8531 Japan Lily Giles Cardiff University Cardiff School of Engineering Laboratory for Applied Microsystems Cardiff CF24 3TF UK

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j List of Contributors Volker Hessel Eindhoven University of Technology Department of Chemical Engineering and Chemistry Laboratory for Micro-Flow Chemistry and Process Technology STW 1.37 5600 MB Eindhoven The Netherlands Takeshi Honda Measurement Solution Research Center National Institute of Advanced Industrial Science and Technology 807-1 Shuku, Tosu Saga 841-0052 Japan Matthew J. Hutchings Cardiff University School of Chemistry Main Building Park Place Cardiff CF10 3AT UK Klavs F. Jensen Massachusetts Institute of Technology Department of Chemical Engineering Room 66-566 77 Massachusetts Avenue Cambridge MA 02139 USA Masaya Miyazaki Measurement Solution Research Center National Institute of Advanced Industrial Science and Technology 807-1 Shuku, Tosu Saga 841-0052 Japan

Jason S. Moore Massachusetts Institute of Technology Department of Chemical Engineering Room 66-566 77 Massachusetts Avenue Cambridge MA 02139 USA Alex Morgan Cardiff University Cardiff School of Engineering Laboratory for Applied Microsystems Cardiff CF24 3TF UK Md. Taifur Rahman Osaka Prefecture University Graduate School of Science Department of Chemistry Sakai Osaka 599-8531 Japan and School of Chemistry and Chemical Engineering David Keir Building Queen’s University Belfast BT9 5AG Northern Ireland UK Ilhyong Ryu Osaka Prefecture University Graduate School of Science Department of Chemistry Sakai Osaka 599-8531 Japan

List of Contributors

Kiyosei Takasu Kyoto University Graduate School of Pharmaceutical Sciences Yoshida Sakyo-ku Kyoto 606-8501 Japan Shan Taylor Cardiff University Cardiff School of Engineering Laboratory for Applied Microsystems Cardiff CF24 3TF UK Paul Watts Research Chair in Microfluidic Bio/Chemical Processing InnoVenton: NMMU Institute for Chemical Technology Nelson Mandela Metropolitan University Port Elizabeth 6031 South Africa

Charlotte Wiles Chemtrix BV Burgemeester Lemmensstraat 358 6163 JT Geleen The Netherlands Thomas Wirth Cardiff University School of Chemistry Main Building Park Place Cardiff CF10 3AT UK Hiroshi Yamaguchi Measurement Solution Research Center National Institute of Advanced Industrial Science and Technology 807-1 Shuku, Tosu Saga 841-0052 Japan

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1 Properties and Use of Microreactors David Barrow, Shan Taylor, Alex Morgan, and Lily Giles

1.1 Introduction

Microreactors are devices that incorporate at least one three-dimensional duct, with one or more lateral dimensions of 20 times post wash treatment [79]. Also, coating of the capillary channel of a microreactor with elemental palladium allowed palladium-catalyzed coupling reactions to be performed very efficiently, and the metal coating also serves as recipient for microwave energy allowing a fast heating of the reaction solution [80]. Another popular coating is TiO2 that is frequently used as a photocatalyst for the degradation of organic pollutants. This has been coated onto prefabricated ZnO nanorods on the internal walls of a glass microreactor and has been shown to significantly increase the surface area for photocatalytic oxidation [81]. As a simpler one-step method of increasing the catalytic surface area, a foamlike porous ceramic containing a catalyst as nanoparticle was formed in a microreactor by direct sol-gelation, thus avoiding any separate coating or impregnation step [82]. The result demonstrated a reasonable pressure drop due to its porosity, high thermal and catalytic stability, and excellent catalytic behavior in forming hydrogen and carbon monoxide-rich syngas from butane. Additionally, zeolite materials can function as a valuable adsorbent and catalyst in microreactors and their precision growth can be pre-seeded from nano-zeolites grafted on to silanised microreactor surfaces such as metal (Figure 1.9 [83]).

1.2 Physical Characteristics of Microreactors

Figure 1.9 Scanning electron microscope pictures of an example surface modification, in this case, a NaA zeolite film grown on seeded porous stainless steel, multichannel plate using chloropropyl trimethoxysilane (CP-TMS) linkers (a), (c), (d), and aminopropyl trimethoxysilane

(AP-TMS) linkers (b) [83]. Source: Reprinted from Yang, G. et al. (2007) A novel method for the assembly of nano-zeolite crystals on porous stainless steel microchannel and then zeolite film growth. J. Phys. Chem. Solids, 68(1), 26–31, with permission from Elsevier.

A porous organic polymer monolith may be formed within a microreactor to act as a support for catalysts, such as palladium. The size, size distribution, and surface area of the pores may be controlled by a porogen, while the chemical properties are controlled by the monomer used. Such supports can be formed and even patterned by the use of ultraviolet light, most cost-effectively using ultraviolet light-emittingdiode arrays [84,85]. Carbon nanofibers can also be deposited within microreactors by homogeneous deposition precipitation and pulsed laser deposition to provide a larger surface area support layer upon which catalysts such as ruthenium catalytic nanoparticles can be attached [86].

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1.3 Fluid Flow and Delivery Regimes 1.3.1 Fluid Flow

Flow in microreactors is typically characterized by a low Reynolds number ðReÞ. The Reynolds number is a dimensionless number that describes the ratio of inertial forces to viscous forces and is calculated by Re ¼

Lvr ; m

ð1:1Þ

where L is the characteristic length, v is the fluid velocity, r is the fluid density, and m is the fluid viscosity. When viscous forces dominate, as it is typical within microreactors, fluid flow is laminar. The threshold at which transition from turbulent to laminar flow occurs is dependent on the geometry of ducts through which the fluid is flowing, but typically, in a smooth channel or capillary, transition occurs between Re value 2000 and 2500 [87,88]. As a result, without the use of special structures or active mechanisms, there is little turbulence-based mixing, and mixing occurs mainly through diffusion. Fick’s Law of diffusion says that where n is the particle density or concentration, D is the diffusion coefficient, and D is the Laplace operator, then, the diffusion flux, J, can be defined as J¼

ð1:2Þ

DDn:

The diffusion can be further described by the Schmidt number (Sc), which is the ratio of kinematic viscosity or momentum diffusivity, V, to mass diffusivity as defined by Sc ¼

V m ¼ : D rD

ð1:3Þ

The Schmidt number is also a dimensionless number but is unrelated to the geometry of the microchannel or capillary. As such, it is a characteristic of the liquid and can be used to determine how diffusion will occur within a certain liquid. Additionally, the rate of mass diffusion can be compared to the advection of a liquid within a microreactor via the Peclet number (Pe) Pe ¼ Re  Sc ¼

vL : D

ð1:4Þ

This number is a measure of the importance of advection in relation to diffusion. As the Peclet number increases so does the dominance of flow forces over that of molecular diffusion with regard to mixing. This number is, therefore, important in determining the conditions in which diffusion is the primary mixing method [89]. To demonstrate how advantageous working at a microscale can be, consider an initially very small spot of tracer in a resting solution [89]. The time (t) taken by this

1.3 Fluid Flow and Delivery Regimes

Figure 1.10 Diffusive mixing in a square cross-sectional (side 500 mm) channel. (a) Two streams of water (colored to indicate the ratio of liquid one to liquid two, 1 on the scale indicating purely liquid one) running at 1 m/s in parallel to each other with mixing through diffusion only (b) Same simulation (as a)

highlighting the region of diffusive mixing or “front” between the two fluids, in this case the lighter region indicates where diffusive mixing has occurred. The width of the front, d, is indicated. Source: Both images obtained via COMSOL Multiphysics1 simulation.

spot to spread over a distance x can be estimated as t

x2 : 4D

ð1:5Þ

This means that for reactions limited by diffusion, reaction time is proportional to the square of the rate limiting distance. Therefore, a reaction in a 10 cm flask could take 1 000 000 times less if undertaken in a 100 mm diameter microreactor. Dramatically reduced reaction times have, arguably, been the most potent driving force behind research in microreactor technology. Figure 1.10 demonstrates the spreading of the “front” between two streams. The width of this front, d, increases through diffusion over time as the fluids travel down the channel [89]. This width can be approximated using pffiffiffiffiffi d ¼ 2 Dt: ð1:6Þ If the width of the front is set to the width of the channel then the time it takes to mix diffusively in a microchannel can be determined. Although the limited levels of mixing in microchannels can be advantageous, sometimes greater levels of mixing are required. There are ways to encourage nondiffusion-based mixing to occur within a microchannel such as introducing an obstacle to induce turbulence-based mixing. An obstacle can cause turbulent flow as it can drastically lower the laminar flow transition threshold (into the region of Re 100 [90]). Adding turns to a channel can also initiate greater levels of mixing. In an enclosed rectangular channel, as fluid travels around a curve at appropriate flow rates, vortices are set up in the upper and lower halves of the channel; these are called Dean vortices (Figure 1.11). These Dean vortices will cause mixing but only across the width of the channel, not from top to bottom (Figure 1.12). (For further information about microreactor mixing see Section 1.3.3.)

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j 1 Properties and Use of Microreactors

Figure 1.11 Cross section of a turning rectangular channel showing Dean vortices caused by the turn. These Dean vortices can be advantageous, for example, in mixing or particle sorting. IW is the inner wall of the turn and OW is the outer wall.

While fluid flow is often continuous and laminar, other regimes exist, such as, for example, in segmented flow. Here, immiscible fluids, or phases, are configured to provide contiguous “trains” of fluid “segments” or “packets” (see also Section 4.3). The flow within these fluid segments may be configured to be such that there occurs an internal vortex that causes rapid mixing within segment contents (Figure 1.13) and counters the lack of mixing normally characteristic of microscale fluid flow [91–94]. This fluid flow regime depends on the absolute velocity of the fluids, the fluid viscosities, their interfacial tension, and the geometry of the channels [95]. Adjacent contiguous segments may enjoy a highly dynamic fluidic interface providing many opportunities for novel interfacial chemical and other reactions. This internal vortex and interpacket dynamic interface may be readily switched to laminar flow (within packets) by simple modulation of the duct cross-sectional geometry, thereby changing the three-dimensional format of the individual fluid packets. Thus, dramatic alterations in mixing and mass transfer may be programmed within a given microreactor circuit configuration. The use of such solvent droplets resulting from controlled segmented flow has been proposed as individual nanoliter-scale reactors for organic synthesis [40,41]. Fluid flow segmentation may be generated for a wide range of immiscible fluid matrices.

Figure 1.12 Two parallel streams of water, A and B, (flowing at 3 m/s) are mixed via Dean vortices in a turn. Mixing before the turn is mostly by diffusion. Source: Image obtained via COMSOL Multiphysics1 simulation.

1.3 Fluid Flow and Delivery Regimes

Figure 1.13 Internal circulations (indicated by the dashed lines) within segmented flow segments. Segments are white; continuous phase is the gray area. (a) Circulation over the whole length of the segment. This occurs within liquid segments suspended in an air continuous phase. (b) In a liquid–liquid system, circulation occurs at the front of the segment. The volume fraction of the circulation zone is dependent on certain parameters. Higher segment velocities increase the volume fraction of the circulation.

This circulation zone can also be increased by using a lower viscosity continuous phase. Low interfacial tension also increases the size. High interfacial tension and viscosity can lead to no circulation at all. (c) At high segment velocities, counter-rotating circulation can be initiated towards the rear of the segment. Circulation zones are always set up in the continuous phase between the segments, irrespective of the other parameters [96].

Fluid packets may (i) contain particulates, including solid support beads, catalysts, and separations media, (ii) be subject to sequential additional reagent delivery through tributary ducts and channel injectors, (iii) be caused to split and/or coalesce, and (iv) be provided with individual identity through the provision of addressable molecular photonic and other codes. Segmented fluid packets as shown in Figures 1.13 and 1.17 may therefore be considered as “test tubes on the move” that are, for instance, transferred seamlessly from one functional high-throughput screening operation to another. The fluid packet format, for example, segmented by inert perfluorinated fluids, can be combined with interpacket liquid–liquid or solidphase extractions [97] and microchannel contactor functions, enabling many possibilities for compound transfer between the different solvent streams of hyphenated functional processes. Collectively, these tools pose a radically different opportunity for synthesis, assay, and characterization procedures to traditional highthroughput screening operations such as in microtiter plate technology, storage, and

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information handling. This new platform paradigm with its inherent opportunities requires exploration through experimentation and modeling. For example, in a gas– liquid carbonylative coupling reaction, an annular flow regime was employed to generate a high interfacial surface area, where a thin film of liquid was forced to the wall surfaces of a microreactor (5 m length, 75 ml capacity) by carbon monoxide gas flow through the center [98]. The laminar stationary flow of an incompressible viscous liquid through cylindrical tubes can be described by Poiseuille’s law. This description was later extended to turbulent flow. Flowing patterns of two immiscible phases are more complex in microcapillaries. Various patterns of liquid–liquid flow are described in more detail in Section 4.3, while liquid–gas flow and related applications are discussed in Section 4.4.

1.3.2 Fluid Delivery

1) Displacement: Hydrodynamic pumping has been the main method of fluid delivery generally used in microreactor systems till date. Hydrodynamic pumping usually employs the use of macro- or microscale peristaltic or positive displacement pumps [99–101]. High pressures can be obtained, as well as aggressive solvents are used. However, peristaltic pumps suffer from fluidflow fluctuations at slow flow rates, and syringe pumps require carefully engineered changeover or refill mechanisms when used in long-duration, continuous-flow synthesis schemes. 2) Electro-osmotic Flow(EOF): Fluid pumping in capillary-scale devices and systems may be readily enabled under certain conditions by electrokinetic flow that has the advantage that low levels of hydrodynamic dispersion are observed [102–104]. A detailed theoretical consideration of chemical reactions in microreactors under electro-osmotic and electrophoretic control has been described in the literature [105] (Figure 1.14). To enable EOF, electrodes are usually placed in reservoirs and voltage is applied, most preferably under computer control, with the magnitude of the voltage being a function of several factors including reactor geometry. Electro-osmotic flow pumping has been demonstrated in capillary-based flow reactors incorporating solid-supported reagents and catalysts [106,107]. Further, an array of parallel microreactors, packed with silica-supported sulfuric acid, was operated under EOF to produce several tetrahydropyranyl ethers, thus demonstrating arithmetic scale out of EOF pumped microreactors [108]. However, EOF does place certain requirements on the microreactor design and surface properties of the constructional materials used. As an additional restriction, not every reaction can be performed in an electrical field as electrochemical side reactions can occur. 3) Centrifugal: Centrifugal forces have for some time been harnessed for the controlled propulsion of reagents in spinning disk microreactors [109]. This mechanism has also been used to control the elution, mixing, and incubation of reagents within enclosed reaction capillaries on rotating-disc platforms [110].

1.3 Fluid Flow and Delivery Regimes

Figure 1.14 Image sequences showing the nature of electro-osmotic flow (a) as compared to pressure-driven flow (b) in a 200 mm id circular cross-section capillary. The transport of the photo-injected cross-stream fluorescent markers illustrates: (a) the plug-like velocity profile characteristic of electro-osmotic flows,

and (b) the parabolic velocity profile characteristic of pressure-driven flows. These images were obtained using caged-fluorescence imaging. Source: Image from Figure 1, Ref. [111] with kind permission from Springer Science and Business Media.

This represents a very innovative approach to chemical synthesis since the technique makes use of both hardware and software systems already developed for a mass-produced commodity. Additionally, the use of centrifugal forces provides an elegant way in which these can be used in combination with hydrophobic, the so-called burst valves to control fluid flow and incubation regimes. 1.3.3 Mixing Mechanisms

Microreactors are usually characterized by geometries with a low Reynolds number. In such capillary-scale ducts, laminar flow is dominant, and mixing relies essentially on diffusion unless special measures are taken, such as to cause turbulence or reduce diffusion time. Equally, laminar flow may be exploited such that laminar flow streams moving in parallel may contain reagents, which are caused to interact by careful control of the flow rate and variations in the

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microreactor geometry. A range of passive and active techniques to induce mixing include (i) complex geometries within microfluidic manifolds to cause repeated fluid twisting and flattening [112], (ii) acoustic streaming [113], (iii) resonant diaphragms, and (iv) acoustic cavitation microstreaming [114,115]. Passive techniques such as split and recombine suffer from the requirement that fluids must usually be in a state of flow, whereas active methodologies enable mixing where there is no flow, such as in microwell reactors and under temporary stopped-flow conditions in microchannel reactors. A variant on this is a stopped-flow, batchmode technique and has been employed to induce mixing on a centrifugal platform [116]. Not dissimilarly, pulsed flow in a microchannel has also been shown to be effective at causing accelerated mixing [117] and is dependent on several factors including the Strouhal number, the Peclet number, phase difference, pulse-to-volume ratio, and microchannel geometry. Microfabricated geometries within the microreactor design and which split and recombine fluids have been shown to cause multilamination and thus reduced diffusion distances [118– 120]. Chaotic advection may also be caused by channels that contain integral staggered, serial, asymmetric rib-like structures [121] or are three-dimensionally twisted [122] (Figure 1.15). Active mechanisms for mixing based on energized, ultrasonically induced transport have been demonstrated [123]. An interesting form of rapid micromixing may also be achieved in liquid–liquid multiphase flow microreactors where within serial contiguous fluid packets there exists an internal vortex flow that counters the laminar flow profile normally characteristic of low Reynolds number geometries [96,124].

Figure 1.15 Advection caused by integral structures. A schematic diagram of a microchannel with square grooves in the bottom wall. Below the channel to the right, the average flow profile in the cross section is

drawn schematically. The ribbon indicates schematically a typical helical streamline in the channel. Source: Adapted with permission from Ref. [125]. Copyright 2002 American Chemical Society.

1.5 Uses of Microreactors

1.4 Multifunctional Integration

Some argue that miniaturized tools for both chemical synthesis and analysis need to be integrated onto a single chip in order to gain the true benefits of miniaturization [126], not least because of the problems associated with subsystem interconnectivity, dead volumes, and chip-to-world interfaces. Demonstrations toward such a goal include, for example, a hyphenated mixing reaction channel coupled to a capillary electrophoresis column [127]. As well as miniaturized reactors, microdevices with other functionalities extend the range of functional capabilities that may be achieved when a systems approach is considered [128]. Such microdevices may include mixers, separators, heat exchangers, heaters, coolers, photoreactors, analysis sub-systems, and devices for the application of pulsed electric fields [129]. Therefore, a wide range of processes including extractions (liquid–liquid, liquid–gas, solid-phase enhanced), crystallizations, distillations, purifications, conversions, phase-changes, phase separations, and identifications may be enabled. Thermal conditions may be more readily monitored throughout a microreaction system by employing a distributed reporter such as a thermochromic dye [130] that can report 104 N/mm2) is not of practical significance as the resistance to breakage of actual articles made of glass always depends on manufacturing defects in their surface. Instances of slight surface damage in the form of fine notches and cracks cause an article to break, because excessive increases in tension develop at the ends

3.1 How Microreactors Are Constructed

1 2

3

4

Figure 3.2 1: Network converters (Na2O), 2: oxygen, making no bridges, 3: oxygen, making bridges, 4: SiO2, making bridges).

of the cracks when they are subjected to mechanical loads. In ductile materials such as metals, a plastic type of flow will dissipate this excess tension. Glass and glass ceramics, on the other hand, behave as if they were brittle. At the temperatures and for the time spent under pressure in “normal use,” these materials do not manifest any plastic flow that would enable the peaks of stress at the tips of cracks and notches to be dissipated. Owing to its chemical resistance, glass is generally excellent for water, saline solutions, acids, organic substances, and even alkalis, so that in all these cases, it is superior to most metals and plastics. The only chemicals that have a noticeably adverse effect on it are hydrofluoric acid, strongly alkaline solutions, and concentrated phosphoric acid, particularly at high temperatures. As its heat conductivity is low (typically 0.9–1.2 W/(m K) at 90  C), changes of temperature within the glass will cause relatively steep temperature gradients. On heating, expansion tends to generate high mechanical tension. Significant is the low capacity for heat conduction and the lack of ductility. This is the cause for the low thermal shock resistance. This disadvantage can be offset by a low coefficient of thermal expansion. Of the various types of glass, fused silica is the one with the lowest specific thermal expansion and the highest resistance to changes in temperature. Glass would only be a second choice in situations where highly efficient heat transfer is required, as its thermal conductivity is low. Despite its high chemical resistance and structural stability, its tendency to fracture under tension and the often inadequate resistance to temperature changes make glass more difficult to be structured using the classic structure-imposing methods. Wet and dry chemical etching is only possible within limits, but it produces good geometric resolution while the depth of the structure remains shallow. Inadequate resistance to temperature changes also complicates laser ablation, which can be used successfully only in the case of fused silica, the type with the lowest coefficient of thermal linear expansion. Of the machining methods, which rely on a shaving process, with few exceptions, it is possible to use only those in which the cutter operates with indefinite geometry, that is, lapping, ultrasound lapping, grinding, and sandblasting on a miniature scale.

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One exception is the special type of photostructurable glass. For the construction of microreactors, the borosilicate types of glass are the most important, but also fused silica.

 Fused silica is a single-component type, which consists in of SiO2. Its technical importance lies mainly in its low coefficient of thermal expansion, its excellent high-temperature resistance (up to 1000  C), its very high resistance to changes of temperature, and its extremely good transparency to ultraviolet light.  Borosilicate glass will contain a higher proportion of SiO2 than most other varieties of silicate glass, together with varying amounts of B2O3, constituting up to 13% of the mass. This type is characterized by high resistance to the influence of chemicals and to differences in temperature. It thus finds application mainly in the chemical and pharmaceutical industry and as domestic ovenproof glass. The chemical composition can vary widely. What will decide the actual properties is mainly the manner in which the boron compounds suited to the glass melt are combined with other metallic oxides. Borosilicate 33 is used particularly often; the 33 stands for the thermal coefficient of expansion, a ¼ 3.3  10 6 K 1, and the trade names often met are Borofloat 33, Duran, and Pyrex.  Photoetchable special glasses belong to the doped lithium-aluminosilicate group. It is characteristic for this group to crystallize on the areas exposed to light if, after masking, they are subjected to UV-irradiation and then heated. The crystallized parts are more easily dissolved in hydrofluoric acid, so that a geometric microstructure can be created on the glass by this means. Some of the types that have made an impact in this field are FOTURAN (made by Schott, Germany) and PEG3 (made by Hoya, Japan). The Department of Inorganic Non-Metallic Materials at the Technische Universit€at Ilmenau is using a type of photostructurable glass (FS21) it has developed for its current research. Table 3.1 shows the most important properties of this glass [1]. Table 3.1 Physical properties.

Physical properties Maximum working temperature ( C) Coefficient of mean thermal expansion a (20–300 C) (10 6 K) Density r (g/cm3) (25  C) Young’s modulus (kN/mm2) Flexural strength s (MPa) Hydrolytic class Acid class Alkali class Specific heat capacity cp (20–100  C) 0.83 kJ/kg K Transformation temperature Tg Thermal conductivity l (90  C) W/(m K)

Fused silica

Borosilicate glass (B33)

Photoetchable special glasses

1100 0.55

450 3.25  10

450  Tg  465 8.4  a  10.6

2.2 66 50 1 1 1 —

2.2 64 25 1 1 A2 0.83

2.34  r  2.37 74  E  81 25 5 2 2 —

— —

525 1.2

450  Tg  465 —

6.

3.1 How Microreactors Are Constructed

Z

Z

Y

Y

X

(100)

Z

X

Y

(110)

X

(111)

Figure 3.3 Layers in the cubic crystal system.

It is available in wafer form but also with a rectangular shape. The structuring methods most often used are described below.

3.1.2 Silicon As Material

Silicon as a material is very common in microsystems engineering as it is suitable not only for microswitches but also successfully applied in the creation of structures for mechanical purposes and fluids. The reasons lie not only in its useful mechanical properties but also in its ready availability and its ease of structuring. Silicon is used in its monocrystalline form. The single crystal is developed by a variety of processes, as a cylindrical ingot, or boule. This cylindrical shape is ground to a nominal diameter and then sliced. The resultant wafers are polished. Silicon crystallizes with a diamond structure. The wafers may have the (100), (110), or (111) orientation; the (100) orientation is most commonly used. Figure 3.3 shows the layers in a cubic crystal system, described by their Miller indices, (6). The most important properties are given in Table 3.2.

Table 3.2 Physical properties of silicon.

Physical properties of silicon Coefficient of mean thermal expansion a (20–300  C) (10 Density r (g/cm3) (25  C Flexural strength s (MPa) Thermal conductivity l (90  C) W/(m K) Young’s modulus (GPa) Melting point ( C)

Silicon 6

K)

2.6 2329 6000 150 130–188 1413

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3.2 The Structuring of Glass and Silicon

In microsystems engineering, another process is important besides the structuring of thin layers, which is the etching of the solid material. This will now be described in more detail. From the point of view of the mechanical characteristics, glass and silicon resemble each other. They have a similar mechanical hardness, are brittle as they lack plasticity, and are thus prone to brittle fracture. Of the standard precision engineering procedures available for shaping, only those that do not use a geometrically defined cutter can be used, such as grinding and lapping. Microengineering techniques are much more efficient but do prove difficult for deeper structures. 3.2.1 Structuring by Means of Masked Etching As in Microsystems Technology

On the whole, microsystems procedures rely on masking, whether the aim is to create the structure by the addition or the subtraction of material. The areas not intended to be affected by the procedure are shielded from it by a protective mask. In the cases described here, through-holes or cavities are produced by subtraction of material. The masking acts as a shield, for instance, against an aggressive etch or the chemical changes associated with the photoresist technique (Figure 3.4). A distinction must be made between the mask for photolithography and the type of masking required for an ensuing process of substance removal. In the case of photolithography, a light pattern is directed onto the surface of the substrate after it Ultraviolet light Mask

Substrate

(a)

(b)

(c) (d)

Figure 3.4 Photolithography: (a)photoresist laid on and exposed with a mask; (b) developing; (c) etched substrate; (d) photoresist removed.

3.2 The Structuring of Glass and Silicon

has been coated with photosensitive material (photoresist), resulting in resolutions on the micrometer scale. For the required structures, this is sufficiently accurate. The mask, or reticle, used in photolithography is a layer of glass or transparent polymer coated with certain absorber structures. For microelectronics, there are procedures available, which can achieve much higher resolution. See Refs [2–4] for more details. The photochemical processes in photoresist may work as a positive resist, enhancing the solubility of the exposed areas, or as a negative resist, reducing the solubility. At a later stage of the manufacturing process, the easier-to-dissolve portions will be removed. It is possible to use this photoresist mask for certain substance-removal procedures, as in the case of the special resist for microsandblasting, or for plasma etching of silicon. Where this is not usable because not selective enough, two-stage masking is necessary. Such is the case for deep wet chemical etching of glass and for anisotropic etching of silicon. Here, a masking layer of several hundred nanometer thickness is painted onto the substrate; for the structuring of glass, the mask is made of CrNi and polysilicon, and for silicon, it is a single SiO2 Si3N4 layer. This coating is then etched with the aid of the photoresist and a suitable etching medium, Figure 3.5. The selectivity achieved with this combined masking layer is much greater than that with photoresist alone. In addition to photolithography, other, more direct types of lithography are possible. The means of masking will be described together with the structuring processes for which they are used. To produce through-holes and cavities in a wafer, special forms of lithography are employed. If it is assumed that a roughly constant amount of material requires to be removed from all over the wafer, the creation in one and the same process of both cavities and holes is not feasible. The only possibility to achieve this is to perform

Figure 3.5 Etching with a second masking layer.

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Figure 3.6 Two-stage (double-sided) lithography.

masking and lithography from both sides and then etch both sides simultaneously. The through-holes will be on both sides but the cavities only on one side. The second option is a two-stage lithography. In the first stage, the cavities are made, and then, the wafer is masked again and the holes are created in the second stage (Figure 3.6). 3.2.2 Etching Technologies

Etching processes are the ones that offer the highest geometrical resolution as far as microtechnology is concerned. With it, structures accurate to 80%

Scheme 5.59

Microreaction technology has already shown a great deal of promises for homogeneous reactions, be thermal, photochemical, or electrochemical methods. Efficient mixing, precise control of reaction temperature, and residence time enable one to manipulate the selectivity issue, tame an ultrafast reaction, or even conduct a highly exothermic reaction at room temperature. To conclude, doors for many fascinating properties of microreaction technology are now open for organic chemists.

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Miyazaki, A., and Yoshida, J. (2012) Angew. Chem., Int. Ed., 51, 3245. Nagaki, A., Kim, H., and Yoshida, J. (2009) Angew. Chem., Int. Ed., 48, 8063. Tomida, Y., Nagaki, A., and Yoshida, J. (2011) J. Am. Chem. Soc., 133, 3744. Kim, H., Nagaki, A., and Yoshida, J. (2011) Nat. Commun., 2, Article No. 264. doi: 10.1038/ncomms1264 Nagaki, A., Tokuoka, S., Yamada, S., Tomida, Y., Oshiro, K., Amii, H., and Yoshida, J. (2011) Org. Biomol. Chem., 9, 7559. Browne, D.L., Baumann, M., Harji, B.H., Baxendale, I.R., and Ley, S.L. (2011) Org. Lett., 13, 3312. Hessel, V., Hofmann, C., L€owe, H., Meudt, A., Scheres, S., Sch€onfeld, F., and Werner, B. (2004) Org. Process Res. Dev., 8, 511.

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6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis Paul Watts and Charlotte Wiles

6.1 Photochemistry in Flow Reactors

Photochemistry can potentially provide an environmental-friendly and green approach to chemical synthesis; however, the ability to scale-up such photochemical processes is marred with problems, which are mainly associated with the power of light sources. The fact that a large number of microreactors are manufactured in glass, quartz, or transparent polymers is ideal for conducting photochemical processes, as the path length of such reactors is small meaning that it is very easy to irradiate the reaction mixture within the channel. Compared to other examples of chemical synthesis in flow reactors, the number of photochemical transformations performed under flow conditions has until recently been very limited. Early examples included benzopinacol formation [1], synthesis of cycloaddition products [2], and photosensitized diastereodifferentiation [3]. Mizuno and coworkers [4] reported an enhancement in reaction efficiency, as well as regioselectivity, by conducting the photocycloaddition of a naphthalene derivative (1) (Scheme 6.1) in a microreactor. The authors found that in batch, irradiation of cyanonaphthalene derivative (1), using a filtered xenon lamp (l > 290 nm), afforded photocycloadducts (2) and (3) in 56% and 17% yield, respectively. In comparison, when conducting the reaction in a microreactor, employing an irradiation time of just 3.4 min, the desired compound (2) was obtained in an increased yield of 59%, while by-product (3) was reduced to 9%. CN

CN

NC O

hv (>290 nm)

O

O

MeCN 1

2

3

Scheme 6.1 Photocycloaddition of naphthalene derivative in a microreactor.

Kitamura [5] demonstrated the photocyanation of pyrene (4) (Scheme 6.2) across an oil–water interface within a microreactor [dimensions, 100 mm (wide)  20 mm Microreactors in Organic Chemistry and Catalysis, Second Edition. Edited by Thomas Wirth. # 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

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j 6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis 5 NC

CN CN

hv (> 330 nm), PC/H2O 4

6

Scheme 6.2 Photocyanation of pyrene an oil–water interface in a microreactor.

(deep)  3.5 cm (length)]. To perform the reaction, an aqueous solution of sodium cyanide and pyrene (4) was added from one inlet and 1,4-dicyanobenzene (5) in propylene carbonate (PC) was introduced from the other inlet. Using a residence time of 3.5 min, while the reactor was irradiated using a high-pressure Hg lamp, the authors reported an optimized 73% conversion of pyrene (4) to 1-cyanopyrene (6). Another photochemical transformation conducted in a microreactor, involving a gaseous reagent, was the photochemical chlorination of toluene-2,4-diisocyanate (7) (Scheme 6.3) [6]. Employing a falling film microreactor [channel dimensions, 600 mm (wide)  300 mm (deep)  6.6 cm (length)] consisting of 32 parallel channels, the authors investigated the irradiation of gaseous chlorine, through a quartz window, generating chlorine radicals in the presence of toluene-2,4-diisocyanate (7) in tetrachloropropane as a solvent. The authors investigated the effect of varying the flow rate of chlorine and toluene-2,4-diisocyanate on the proportion of benzyl chloride-2,4-diisocyanate (8) produced. Maintaining the reactor at 130  C, the authors identified the optimal residence time to be 9 s, affording benzyl chloride-2,4-diisocyanate (8) in 81% conversion. Cl NCO

NCO

Cl2, hv C3H4Cl4

NCO 7

NCO 8

Scheme 6.3 Photochemical chlorination of toluene-2,4-diisocyanate.

Oelgem€oller and coworkers [7] focused on the photodecarboxylative benzylation of phthalimide (Scheme 6.4) as a means of providing access to 3-arylmethyleneisoindolin-1-ones (9) upon dehydration. With problems observed with this reaction using conventional photochemistry, including the formation of the product as a potassium salt and significant by-product formation upon dehydration, the authors investigated the reaction using a microreactor. Irradiating the phthalimide (10) solution, in a mixture of acetone and pH 7 buffer and in the presence of phenyl acetate, the authors obtained the target product (9) in 97% yield. Takei and coworkers [8] demonstrated the synthesis of L-pipecolinic acid (11) from an aqueous solution of L-lysine (12) (Scheme 6.5). To achieve this photochemical

6.1 Photochemistry in Flow Reactors

O

HO

NH + Ar

Ar

hv

CO2K

NH O

O 10

Ar

NH O

9

Scheme 6.4 Addition of phenylacetates to phthalimide (10) and dehydration to afford 3arylmethyleneisoindolin-1-ones (9).

O H2 N

OH

+ N H

NH2

CO2H

12

11

N H

CO2H 13

Scheme 6.5 Photocatalytic synthesis of L-pipecolinic acid.

transformation, the authors fabricated a Pyrex microreactor, in which the cover plate was coated in a 300 nm thick layer of TiO2, which was impregnated with platinum nanoparticles. The reactor was subsequently irradiated using a high-pressure Hg lamp and the selectivity to D-pipecolinic acid (13) and L-pipecolinic acid (11) was investigated. Employing a residence time of 50 s, the authors reported an 87% conversion and 22% selectivity for L-pipecolinic acid (11) synthesis. Using a series of UV-LEDs as the light source, Ryu and coworkers [9,10] demonstrated increased reaction efficiency, compared to the Patern o–B€ uchi reaction performed using a 300 W Mercury lamp. Employing six UV-LED light sources, the authors performed the [2 þ 2] cycloaddition of cyclohexen-2-one (14) with vinyl acetate (15) to afford the cycloadduct (16) (Scheme 6.6). Within a micro channel device [dimensions ¼ 1000 mm (wide)  200 mm (deep)  56 cm (long)], the authors obtained a 200-fold increase in energy efficiency compared to a Mercury lamp and a O

O O hv + 14

O 15

20 oC

OAc 16

Scheme 6.6 Illustration of the Patern o–B€ uchi reaction performed in a photochemical microreactor.

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j 6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis 10-fold increase compared to black lights. With the developed protocol in hand, the authors also demonstrated the generality of the technique by varying the acetate used, affording an array of substituted cyclohexanone derivatives. Other examples from the group include the black light promoted selective halogenation of cycloalkenes, reporting the efficient mono-bromination using Br2 and chlorinations using Cl2 and SOCl2 within a biphasic reaction system, and the Barton nitrite photolysis used for the conversion of nitrite derivative (17) to steroid (18) (Scheme 6.7) [11].

ONO

O

HO

O

O O

hv acetone O

NOH

O

17

18

Scheme 6.7 Illustration of the Barton nitrite photolysis used in the synthesis of a complex saturated alcohol.

As well as organic synthesis, Jamison and colleagues [12] have demonstrated organometallic synthesis in flow reactors exploiting photochemistry. The group fabricated a flow reactor by wrapping PFA tubing (internal diameter, 762 mm (wide), volume ¼ 1000 ml) around a standard 450 W medium-pressure mercury lamp. Reaction of complex (19) in acetonitrile at 0.02 M concentration afforded the desired CpRu(MeCN)3PF6 complex (20) in 99% yield (Scheme 6.8). While batch reactions commonly took 36 h to go to completion, the flow reactor gave the product in a residence time of just 5 min. +

Ru

PF6-

+

MeCN 19

PF6-

hv MeNC

Ru CNMe NCMe 20

Scheme 6.8 Synthesis of CpRu(MeCN)3PF6 in a photochemical flow reactor.

With a view toward synthetic production using flow photochemistry, Freitag and coworkers [13] have reported the construction of multipass flow reactors as a means of increasing photochemical efficiency without the need for large irradiated areas. Incorporation of in-line IR enabled the authors to recirculate the reaction mixture until conversion had reached a preset level, at which point an automatic valve opened and diverted the reaction mixture to a collection vessel. In addition to singlephase photochemical transformations, continuous flow reactors have also been applied to heterogeneous photochemical reactions, using TiO2-coated channels to perform reductions [14], oxidations [15], and alkylations [16].

6.2 Electrochemistry in Microreactors

6.2 Electrochemistry in Microreactors

Electroorganic synthesis also represents an efficient and “green” tool for the formation of complex molecular structures. The use of techniques has however been somewhat limited to small-scale syntheses because of the difficulties again associated with successful scale-up. Using microreactors, several groups have started to address the physical problems that have limited application of this technology, namely an inhomogeneous electric field and energy loss due to Joule heating; with the overall aim being to develop the technology to a stage that it can be used for production of chemicals. One of the most important aspects of electrochemical flow chemistry is efficient incorporation of electrodes into the reactors, an area that numerous authors have investigated with techniques ranging from plate electrodes [17] to micro-imprinted electrodes [18] or grooved electrodes [19]. Of the reactions studied, oxidations represent the most widely investigated, with early examples by Suga et al. [20] demonstrating the potential of the technique dubbed “cation flow” for the formation of C C bonds (Figure 6.1). As an example, methyl pyridinecarboxylate (21) in DCM (0.05 M), along with the supporting electrolyte, was passed through the electrochemical cell to generate the cationic intermediate (22) in situ, which could then be reacted with a wide variety of nucleophiles to afford the substituted pyridinecarboxylate (23) in typical yields of 50–70%. More recently, Yoshida and coworkers [21] have demonstrated the [4 þ 2] cycloaddition of a series of N-acyl iminium ions derived from a-silyl carbamates, with the authors identifying the ability to react the cations (24) with a series of styrene-based dienophiles (25) (Scheme 6.9) to afford heterocycles (26) in high yield, without the formation of the polymeric products obtained in batch. In addition to those examples utilizing electrolytes, a series of examples have featured in the literature where reactions have been performed in the absence of TfOH +

Bu4NBF4

Cathode

H2

Anode N 21 CO2Me +

N CO2Me

22

Bu4NBF4

R N CO2Me

23

Figure 6.1 Illustration of the reactor configuration used for the electrochemical generation of cations under continuous flow.

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j 6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis Bu MeO

N

24 O

Bu

N

O

O

R

R 25

26

Scheme 6.9 Synthesis of [4 þ 2] adducts under continuous flow.

added electrolytes [22–24]. One such example was the electrochemical reduction of 4-nitrobenzyl bromide (27) to afford the coupled product 1,2-bis(4-nitrophenyl) ethane (28) (Scheme 6.10) in 92% conversion with only 6% competing dehalogenation [25]. In an extension to this, the authors investigated the reductive coupling of benzyl bromide with a series of olefins to afford the C C coupling products in high yield and excellent selectivity [26]. NO2 Br

DMF:THF

O2N 27

28

O2N

Scheme 6.10 Electrochemical reduction of 4-nitrobenzyl bromide in a microreactor.

Hypervalent iodine reagents can be used in organic synthesis as mild, nontoxic, and highly selective reagents. However, their synthesis is not trivial and this most commonly involves a two-step synthesis protocol. Wirth [27] has reported a simple one-step synthesis within an electrochemical microreactor. Reaction of a variety of iodoarenes (29) with substituted benzene derivatives (30) afforded diaryliodonium hydrogensulfates (31), which were easily converted to the diaryliodonium iodides (32) using aqueous potassium iodide (Scheme 6.11). Conveniently, the iodides (32) were insoluble in the reaction mixture and could be easily isolated by filtration. A range of products was isolated in up to 72% yield. HSO4 I

Electrolysis

+ R1

R2 29

I

30

MeCN, Ac2O, H2SO4

R1

I I

KI R2

H2O

31

R1

R2 32

Scheme 6.11 Electrochemical synthesis of hypervalent iodine reagents.

Amemiya [28] has reported the use of electrochemical flow allylation, between allylic halides (33) and aldehydes (34) (Scheme 6.12); where in batch it is incredibly difficult to control whether the c-adduct (35) or a-adduct (36) is obtained. The authors report that by altering the order of reagent addition and cathode material, chemoselective control over product formation can be achieved. Pt and Ag worked

6.3 Radiopharmaceutical Synthesis in Microreactors

+ 33

RCHO

Electrolysis

34

R 35

R

OR

OH

j139

36

OH

Scheme 6.12 Electrochemical allylation between allylic halides and aldehydes.

effectively as the cathode material, whereby yields of 49–65% were obtained in up to 76% product selectivity. Kashiwagi [29] has successfully demonstrated that a microreactor is very efficient for the electrochemical generation of the highly unstable o-benzoquinone intermediate. The authors have reported that a two-step reaction process may be efficiently conducted by first reacting catechol (37) within the electrochemical reactor to afford o-benzoquinone (38) in situ, before adding thiol (39) as a nucleophile, for example, to afford the product (40) in high yield (Scheme 6.13). Using a variety of thiols a library of products has been prepared in excellent yield (79–88%), whereas when the same reactions were performed in batch, yields were substantially lower (7–13%). SH OH

O

Electrolysis

O

OH 37

39

38

OH S 40

Scheme 6.13 In situ electrogeneration of o-benzoquinone in a microreactor.

Other recent examples of electrochemical synthesis in continuous flow systems include the TEMPO-mediated electrooxidation of primary and secondary alcohols in a microfluidic electrolytic cell [30]. Under the optimized reaction conditions, the authors report that primary alcohols could be oxidized to aldehydes in yields of up to 81% and that the secondary alcohols were oxidized to ketones in up to 85% yield. Using the same experimental approach, the group have also reported the methoxylation of N-formylpyrrolidine in very high conversion [31].

6.3 Radiopharmaceutical Synthesis in Microreactors

Positron emission tomography (PET) [32,33] is a very powerful diagnostic technique, which can be used in a variety of medical applications including oncology, neurology, and cardiology. The basic principle of PET relies on the incorporation of short-lived positron emitting radioisotopes, most commonly 18 F (half-life of 110 min) or 11 C (half-life of 20 min) into the radiopharmaceutical. The fact that the 18 F and 11 C radioisotopes have such short half-lives is a significant challenge for the synthetic chemist, as the organic reactions used to prepare the molecule of interest must be relatively fast chemical transformations, with the goal being to

OH

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j 6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis prepare, purify, and isolate the desired product in 1–2 half-lives. Hence, in the case of 11 C this means that the chemist must synthesize and isolate the pure target in