Microreactors in Organic Chemistry and Catalysis

For the second edition of “Microreactors in Organic Chemistry and Catalysis” all chapters have been revised and updated to reflect the latest developments in this rapidly developing field. This new edition has 60% more content, and it remains a comprehensive publication covering most aspects of the topic. The use of microreactors in homogeneous, heterogeneous as well as biphasic reactions is covered in the main part of the book, together with catalytic, bioorganic and automation approaches. The initial chapters also provide a solid physical chemistry background on fluidics in microdevices. Finally, a chapter on industrial applications and developments covers recent progress in process chemistry. An excellent reference for beginners and experts alike. From the contents: Properties and use of microreactors Fabrication of microreactors made from metals and ceramic Microreactors made of glass and silicon Automation in microreactor systems Homogeneous reactions (including photochemical and electrochemical reactions and  radiopharmaceutical synthesis) Heterogeneous reactions Biphasic reactions (liquid/liquid, liquid/gas) Bioorganic and biocatalytic reactions Industrial microreactor process development up to production

Preface to the First Edition XIII Preface to the Second Edition XV List of Contributors XVII 1 Properties and Use of Microreactors 1 David Barrow, Shan Taylor, Alex Morgan, and Lily Giles 1.1 Introduction 1 1.1.1 A Brief History of Microreactors 1 1.1.2 Advantages of Microreactors 6 1.2 Physical Characteristics of Microreactors 7 1.2.1 Geometries 7 1.2.2 Constructional Materials and Their Properties 10 1.3 Fluid Flow and Delivery Regimes 16 1.3.1 Fluid Flow 16 1.3.2 Fluid Delivery 20 1.3.3 Mixing Mechanisms 21 1.4 Multifunctional Integration 23 1.5 Uses of Microreactors 23 1.5.1 Overview 23 1.5.1.1 Fast and Exothermic Reactions 24 1.5.2 Precision Particle Manufacture 25 1.5.3 Wider Industrial Context 27 1.5.3.1 Sustainability Agenda 27 1.5.3.2 Point–of–Demand Synthesis 27 References 28 2 Fabrication of Microreactors Made from Metals and Ceramic 35 Juergen J. Brandner 2.1 Manufacturing Techniques for Metals 35 2.2 Etching 36 2.3 Machining 38 2.4 Generative Method: Selective Laser Melting 41 2.5 Metal Forming Techniques 42 2.6 Assembling and Bonding of Metal Microstructures 43 2.7 Ceramic Devices 46 2.8 Joining and Sealing 48 References 49 3 Microreactors Made of Glass and Silicon 53 Thomas Frank 3.1 How Microreactors Are Constructed 53 3.1.1 Glass As Material 54 3.1.2 Silicon As Material 57 3.2 The Structuring of Glass and Silicon 58 3.2.1 Structuring by Means of Masked Etching As in Microsystems Technology 58 3.2.2 Etching Technologies 60 3.2.2.1 Anisotropic (Crystallographic) Wet Chemical Etching of Silicon (KOH) 61 3.3 Isotropic Wet Chemical Etching of Silicon 63 3.3.1.1 Isotropic Wet Chemical Etching of Silicon 64 3.3.1.2 Isotropic Wet Chemical Etching of Silicon Glass 65 3.3.2 Other Processes 66 3.3.2.1 Photostructuring of Special Glass 66 3.3.3 Drilling, Diamond Lapping, Ultrasonic Lapping 68 3.3.4 Micro Powder Blasting 69 3.3.5 Summary 71 3.4 Other Processes 72 3.4.1 Sensor Integration 72 3.5 Thin Films 72 3.6 Bonding Methods 73 3.6.1 Anodic Bonding of Glass and Silicon 73 3.6.2 Glass Fusion Bonding 73 3.6.3 Silicon Direct Bonding (Silicon Fusion Bonding) 74 3.6.4 Establishing Fluid Contact 76 3.7 Other Materials 78 References 79 4 Automation in Microreactor Systems 81 Jason S. Moore and Klavs F. Jensen 4.1 Introduction 81 4.2 Automation System 84 4.3 Automated Optimization with HPLC Sampling 86 4.4 Automated Multi–Trajectory Optimization 89 4.5 Kinetic Model Discrimination and Parameter Fitting 94 4.6 Conclusions and Outlook 97 References 99 5 Homogeneous Reactions 101 Takahide Fukuyama, Md. Taifur Rahman, and Ilhyong Ryu 5.1 Acid–Promoted Reactions 101 5.2 Base–Promoted Reactions 106 5.3 Radical Reactions 108 5.4 Condensation Reactions 110 5.5 Metal–Catalyzed Reactions 117 5.6 High Temperature Reactions 122 5.7 Oxidation Reactions 124 5.8 Reaction with Organometallic Reagents 125 References 130 6 Homogeneous Reactions II: Photochemistry and Electrochemistry and Radiopharmaceutical Synthesis 133 Paul Watts and Charlotte Wiles 6.1 Photochemistry in Flow Reactors 133 6.2 Electrochemistry in Microreactors 137 6.3 Radiopharmaceutical Synthesis in Microreactors 139 6.3.1 Fluorinations in Microreactors 141 6.3.2 Synthesis of 11C–Labeled PET Radiopharmaceuticals in Microreactors 145 6.4 Conclusion and Outlook 147 References 147 7 Heterogeneous Reactions 151 Kiyosei Takasu 7.1 Arrangement of Reactors in Flow Synthesis 152 7.2 Immobilization of the Reagent/Catalyst 155 7.2.1 A Packed–Bed Reactor 155 7.2.2 Monolith Reactors 156 7.2.3 Miscellaneous 157 7.3 Flow Reactions with an Immobilized Stoichiometric Reagent 159 7.4 Flow Synthesis with Immobilized Catalysts: Solid Acid Catalysts 165 7.5 Flow Reaction with an Immobilized Catalyst: Transition Metal Catalysts Dispersed on Polymer 166 7.5.1 Catalytic Hydrogenation 167 7.5.2 Catalytic Cross–Coupling Reactions and Carbonylation Reactions 171 7.5.3 Miscellaneous 175 7.6 Flow Reaction with an Immobilized Catalyst: Metal Catalysts Coordinated by a Polymer–Supported Ligand 176 7.6.1 Flow Reactions Using Immobilized Ligands with a Transition Metal Catalyst 179 7.7 Organocatalysis in Flow Reactions 183 7.8 Flow Biotransformation Reactions Catalyzed by Immobilized Enzymes 186 7.9 Multistep Synthesis 187 7.10 Conclusion 191 References 191 8 Liquid–Liquid Biphasic Reactions 197 Matthew J. Hutchings, Batool Ahmed–Omer, and Thomas Wirth 8.1 Introduction 197 8.2 Background 198 8.3 Kinetics of Biphasic Systems 199 8.4 Biphasic Flow in Microchannels 200 8.5 Surface and Liquid–Liquid Interaction 202 8.6 Liquid–Liquid Microsystems in Organic Synthesis 207 8.7 Micromixer 209 8.8 Conclusions and Outlook 218 References 218 9 Gas–Liquid Reactions 221 Ivana Dencic and Volker Hessel 9.1 Introduction 221 9.2 Contacting Principles and Microreactors 222 9.2.1 Contacting with Continuous Phases 222 9.2.1.1 Falling Film Microreactor 222 9.2.1.2 Continuous Contactor with Partly Overlapping Channels 226 9.2.1.3 Mesh Microcontactor 227 9.2.1.4 Annular–Flow Microreactors 229 9.2.2 Contacting with Disperse Phases 231 9.2.2.1 Taylor–Flow Microreactors 232 9.2.2.2 Micromixer–Capillary/Tube Reactors 237 9.2.2.3 Micro–packed Bed Reactors 240 9.2.2.4 Membrane Microreactors 242 9.2.2.5 Tube in Tube Microreactor 243 9.2.3 Scaling Up of Microreactor Devices 244 9.3 Gas–Liquid Reactions 245 9.3.1 Direct Fluorination of Aromatics 246 9.3.1.1 Direct Fluorination of Aromatics 246 9.3.1.2 Direct Fluorination of Aliphatics and Non–C–Moieties 249 9.3.1.3 Direct Fluorination of Heterocyclic Aromatics 251 9.3.2 Oxidations of Alcohols, Diols, and Ketones with Fluorine 253 9.3.3 Photochlorination of Aromatic Isocyanates 254 9.3.4 Photoradical Chlorination of Cycloalkenes 255 9.3.5 Mono–Chlorination of Acetic Acid 256 9.3.6 Sulfonation of Toluene 257 9.3.7 Photooxidation Reactions 259 9.3.8 Reactive Carbon Dioxide Absorption 263 9.4 Gas–Liquid–Solid Reactions 265 9.4.1 Hydrogenations 266 9.4.1.1 Cyclohexene Hydrogenation over Pt/Al2O3 266 9.4.1.2 Hydrogenation of p–Nitrotoluene and Nitrobenzene over Pd/C and Pd/Al2O3 267 9.4.1.3 Hydrogenation of Azide 270 9.4.1.4 Hydrogenation of Pharmaceutical Intermediates 270 9.4.1.5 Selective Hydrogenation of Acetylene Alcohols 271 9.4.1.6 Hydrogenation of a–Methylstyrene over Pd/C 272 9.4.2 Oxidations 273 9.4.2.1 Oxidation of Alcohols 275 9.4.2.2 Oxidation of Sugars 275 9.5 Homogeneously Catalyzed Gas–Liquid Reactions 276 9.5.1 Asymmetric Hydrogenation of Cinnamic Acid Derivatives 276 9.5.2 Asymmetric Hydrogenation of Methylacetamidocynamate 278 9.6 Other Applications 281 9.6.1 Segmented Gas–Liquid Flow for Particle Synthesis 281 9.6.2 Catalyst Screening 281 9.7 Conclusions and Outlook 282 References 283 10 Bioorganic and Biocatalytic Reactions 289 Masaya Miyazaki, Maria Portia Briones–Nagata, Takeshi Honda, and Hiroshi Yamaguchi 10.1 General Introduction 289 10.2 Bioorganic Syntheses Performed in Microreactors 292 10.2.1 Biomolecular Syntheses in Microreactors: Peptide, Sugar and Oligosaccharide, and Oligonucleotide 292 10.2.1.1 Peptide Synthesis 292 10.2.1.2 Sugar and Oligosaccharide Synthesis 296 10.2.1.3 Oligonucleotide Synthesis 302 10.3 Biocatalysis by Enzymatic Microreactors 304 10.3.1 Classification of Enzymatic Microreactors Based on Application 304 10.3.1.1 Applications of Microreactors for Enzymatic Diagnostics and Genetic Analysis 304 10.3.1.2 Application of Microreactors for Enzyme–Linked Immunoassays 308 10.3.1.3 Applications of Microfluidic Enzymatic Microreactors in Proteomics 312 10.3.2 Enzymatic Microreactors for Biocatalysis 347 10.3.3 Advantages of Microreactors in Biocatalysis 347 10.3.4 Biocatalytic Transformations in Microfluidic Systems 348 10.3.4.1 Solution–phase Enzymatic Reactions 348 10.3.4.2 Microfluidic Reactors with Immobilized Enzymes for Biocatalytic Transformations 357 10.4 Multienzyme Catalysis in Microreactors 362 10.5 Conclusions 365 References 366 11 Industrial Microreactor Process Development up to Production 373 Ivana Dencic and Volker Hessel 11.1 Mission Statement from Industry on Impact and Hurdles 373 11.2 Screening Studies in Laboratory 375 11.2.1 Peptide Synthesis 375 11.2.2 Hantzsch Synthesis 378 11.2.3 Knorr Synthesis 379 11.2.4 Enamine Synthesis 381 11.2.5 Aldol Reaction 381 11.2.6 Wittig Reaction 382 11.2.7 Polyethylene Formation 382 11.2.8 Diastereoselective Alkylation 383 11.2.9 Multistep Synthesis of a Radiolabeled Imaging Probe 384 11.3 Process Development at Laboratory Scale 386 11.3.1 Nitration of Substituted Benzene Derivatives 386 11.3.2 Microflow Azide Syntheses 387 11.3.3 Vitamin Precursor Synthesis 389 11.3.4 Ester Hydrolysis to Produce an Alcohol 391 11.3.5 Synthesis of Methylenecyclopentane 391 11.3.6 Condensation of 2–Trimethylsilylethanol 391 11.3.7 Staudinger Hydration 392 11.3.8 (S)–2–Acetyl Tetrahydrofuran Synthesis 392 11.3.9 Synthesis of Intermediate for Quinolone Antibiotic Drug 393 11.3.10 Domino Cycloadditions in Parallel Fashion 394 11.3.11 Phase–Transfer Catalysis–Mediated Knoevenagel Condensation 396 11.3.12 Ciprofloxazin1 Multistep Synthesis 396 11.3.13 Methyl Carbamate Synthesis 397 11.3.14 Newman–Kuart Rearrangement 398 11.3.15 Ring–Expansion Reaction of N–Boc–4–Piperidone 399 11.3.16 Synthesis of Aldehydes 400 11.3.17 Grignard Reactions and Li–Organic Reactions 402 11.3.18 Continuous Synthesis of Disubstituted Triazoles 404 11.3.19 Production of 6–Hydroxybuspirone 405 11.3.20 Swern–Moffatt Oxidation 406 11.4 Pilot Plants and Production 408 11.4.1 Hydrogen Peroxide Synthesis 408 11.4.2 Phenylboronic Acid Synthesis 410 11.4.3 Diverse Case Studies at Lonza 411 11.4.4 Alkylation Reactions Based on Butyllithium 414 11.4.5 Microprocess Technology in Japan 416 11.4.6 Pilot Plant for Methyl Methacrylate Manufacture 417 11.4.7 Grignard Exchange Reaction 417 11.4.8 Halogen–Lithium Exchange Pilot Plant 419 11.4.9 Swern–Moffatt Oxidation Pilot Plant 420 11.4.10 Yellow Nano Pigment Plant 422 11.4.11 Polycondensation 423 11.4.12 H2O2–Based Oxidation to 2–Methyl–1,4–naphthoquinone 424 11.4.13 Friedel–Crafts Alkylation 425 11.4.14 Diverse Studies from Japanese Project Cluster 426 11.4.14.1 Synthesis of Photochromic Diarylethenes 426 11.4.14.2 Cross–Coupling in a Flow Microreactor 427 11.4.15 Direct Fluorination of Ethyl 3–Oxobutanoate 428 11.4.16 Deoxofluorination of a Steroid 429 11.4.17 Microprocess Technology in the United States 430 11.4.18 Propene Oxide Formation 432 11.4.19 Diverse Industrial Pilot–Oriented Involvements 433 11.4.20 Production of Polymer Intermediates 435 11.4.21 Synthesis of Diazo Pigments 436 11.4.22 Selective Nitration for Pharmaceutical Production 438 11.4.23 Nitroglycerine Production 439 11.4.24 Fine Chemical Production Process 440 11.4.25 Grignard–Based Enolate Formation 441 11.5 Challenges and Concerns 442 References 444 Index 447

Thomas Wirth is professor of organic chemistry at Cardiff University. After studying chemistry in Bonn and at the Technical University of Berlin, he obtained his PhD in 1992 with Prof. S. Blechert. After a postdoctoral stay with Prof. K. Fuji at Kyoto University a JSPS fellow, he started his independent research at the University of Basel (Switzerland). In the group of Prof. B. Giese he obtained his habilitation on stereoselective oxidation reactions supported by various scholarships before taking up his current position at Cardiff University in 2000. He was invited as a visiting professor to a number of places including the University of Toronto/Canada (1999), Chuo University in Tokyo/Japan (2000), Osaka University/Japan (2004), and Osaka Prefecture University/Japan (2008) and was awarded the Werner–Prize from the New Swiss Chemical Society (2000). His main interests of research concern stereoselective electrophilic reactions, oxidative transformations with hypervalent iodine reagents including mechanistic investigations and organic synthesis performed in microreactors.