Edited by Thomas Wirth Microreactors in Organic Chemistry and Catalysis Related Titles Reschetilowski, W (ed.) Microreactors in Preparative Chemistry Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more 2013 ISBN: 978-3-527-33282-3 Cornils, B., Herrmann, W A., Wong, C.-H., Zanthoff, H-W (eds.) Catalysis from A to Z A Concise Encyclopedia Fourth, Completely Revised and Enlarged Edition 2013 ISBN: 978-3-527-33307-3 Jess, A., Wasserscheid, P Chemical Technology An Integral Textbook 2013 ISBN: 978-3-527-30446-2 Arpe, H.-J Industrial Organic Chemistry 2010 ISBN: 978-3-527-32002-8 Zecchina, A., Bordiga, S., Groppo, E (eds.) Selective Nanocatalysts and Nanoscience Concepts for Heterogeneous and Homogeneous Catalysis 2011 ISBN: 978-3-527-32271-8 Wirth, T (ed.) Organoselenium Chemistry Synthesis and Reactions 2011 ISBN: 978-3-527-32944-1 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 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 Cover The cover image is based on a photo kindly provided by the Institut für Mikrotechnik Mainz, Germany British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library 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 # 2013 Wiley-VCH Verlag GmbH & Co KGaA, Boschstr 12,69469 Weinheim, Germany All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Print ISBN: 978-3-527-33299-1 ePDF ISBN: 978-3-527-65975-3 ePub ISBN: 978-3-527-65974-6 mobi ISBN: 978-3-527-65973-9 oBook ISBN: 978-3-527-65972-2 Cover Design Simone Benjamin, McLeese Lake, Canada Typesetting Thomson Digital, Noida, India Printing and Binding Markono Print Media Pte Ltd, Singapore Printed in Singapore Printed on acid-free paper jV Contents Preface to the First Edition XIII Preface to the Second Edition XV List of Contributors XVII 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 2.1 2.2 2.3 2.4 2.5 Properties and Use of Microreactors David Barrow, Shan Taylor, Alex Morgan, and Lily Giles Introduction A Brief History of Microreactors Advantages of Microreactors Physical Characteristics of Microreactors Geometries 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 VI j Contents 2.6 2.7 2.8 Assembling and Bonding of Metal Microstructures 43 Ceramic Devices 46 Joining and Sealing 48 References 49 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 3.3.1.1 3.3.1 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 4.1 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 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 6.1 6.2 6.3 6.3.1 6.3.2 6.4 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 jVII VIII j Contents 7.9 7.10 Multistep Synthesis 187 Conclusion 191 References 191 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 9.1 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 jIX j X 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 Index deacetylation 216 – triacetyl-D-glucal flow-through 187 Dean–Stark apparatus 381 Dean vortices 18 deep reactive ion etching (DRIE) 13, 61, 65, 233 degree of completeness 373 dehydration 210 – 3-arylmethyleneisoindolin-1-ones 134 – carbohydrates 210, 211 – 3-pentanol 165 – p-toluenesulfonic acid-catalyzed 102 delay-loop reactor 258 DEMiS pilot reactor 433 dendritic polyglycerol-supported Mn-salen catalyst 180 dendritic polymer catalyst – asymmetric epoxidation 180 de novo transketolase (TK)/v-transaminase (v-TAm)-linked asymmetric amino alcohol synthesis 364 2-deoxy-2-[18F]fluoro-D-glucose 384, 386 2-deoxy-2-fluoro-D-glucose synthesis 385 deoxyribonucleic acid (DNA) 151 design of experiments (DoE) 88 2-desoxy-2-fluoro-D-glucose 299 dextran-modified capillaries 336 diaryliodonium salts, reaction 144 diazo compound, in microreactors 437 diazo pigments synthesis 436–438 DIBAL-H reduction 414 p-dibromobenzene 420 1,3-dicarbonyl compounds 379 2,4-dichloropyrimidine 97 dicyclohexylcarbodiimide (DCC) 376 1,3-dicyclohexylcarbodiimide (DCC) 115 Diels–Alder reaction 122, 123 – flow asymmetric, polymer-supported Lewis acids 178 diethylaminosulfur trifluoride (DAST) 251 diffusion-bonded devices 45 diffusion bonding process chain 45 diffusion coefficient 199 diffusive mixing, square cross-sectional channel 17 digestion proteins 342 dihydroartemisinic acid 262 2,3-dihydrofuran 430 (3S)-1,3-dihydroxypentan-2-one 356 diisobutylaluminum hydride (DIBAL-H) 110, 111, 400 N,N-diisopropylethylamine (DIPEA) 112 1,3-diketones 112 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDCI) 376 4-dimethylaminopyridine (DMAP) 376 – analogs 185 N,N-Di-methylaniline 4-benzyl alcohol 376 dimethylformamide (DMF) solution 293 diols 253, 254 1,4-dioxane/tBuOH solvent system 191 dipeptide synthesis 295, 376 direct fluorinations, limitations 249 disaccharide synthesis 299 disubstituted benzene derivatives 386 3,3-disubstituted 2-oxindoles synthesis 214 4,5-disubstituted ozaxoles 184 disubstituted triazoles 404, 405 1,4-disubstituted 1,2,3-triazoles 404, 405 Dmab ester 115 DMF–water systems 294 DNA – amplification 304 – fragment analysis 307 – oligonucleotides 302 – polymerase 291 – replication 291 – strand 305 – synthesis process 308 domino cycloadditions, in parallel fashion 394, 395 drug candidates, three-step continuous flow synthesis 188 dual-channel reactor 230, 247 – inlet section 231 e EFO-IMER 334 electric-field-oriented enzyme reactor 334 electrochemical flow allylation 138 electrochemical methods 130 electrochemical reduction 138 electron-donating groups 252 electroorganic synthesis 137 electro-osmotic flow 20, 21, 104, 106, 107, 110, 111, 292, 293, 327, 378, 379 – conditions 376 electro-osmotic microreactors 107, 377 electrophilic fluorinating agent 143 electrophilic [18F]XeF2 – synthesis and reaction of 143 electrophilic pathway 246 electrophoretic micro total analysis system 327 j451 452 j Index electrospray ionization-mass spectrometry (ESI-MS) 313, 325 electrospray ionization-time of flight-mass spectrometer (ESI-TOF-MS) 336 embossing technology 43 enamine – intermediates 165 – synthesis 381 enantioselective – addition of ZnEt2 to benzaldehyde 176 – aldol and related reactions under flow conditions 186 – aldol reactions 186 – alkylation under flow conditions 177 – biocatalysts – carbonyl ylide cycloaddition 183 – catalyst for asymmetric Strecker reaction 177 – cyclopropanation of ethyl diazoacetate 182 – deacylation 358 – Diels–Alder reaction 177 – hydrogenation – – of dehydroalanine 170 – – of a-ketoesters 169 – proline-catalyzed 185 – reduction 160 – – ketones 160 – – ketopantolactone and methyl benzoylformate 170 – transesterification of vinyl acetate 361 end-point fluorescence detection 306 energy dissipation factor 267 entrapment method 332 enzymatic microreactors 304 – applications 292, 312 – productivity 366 enzymatic synthetic reactions 364 enzyme immobilization 344 – by adsorption – – in capillary microreactor 344, 345 – – on microchip channel surface 330–332 – in capillary microreactor 335 – – by entrapment 345–347 – by covalent linking in capillary microreactor 335–344 – by cross-linking technique 323, 329, 330 – disadvantages 344 – by encapsulation technique 324 – on microchip channel surface by entrapment 332–334 – in microfluidic chips 314–324 – scheme 337 – techniques in microreactor 334, 335 – using adsorption technique 323 – using covalent technique 323 – using entrapment technique 324 enzyme-immobilized capillary microreactor 345 enzyme-immobilized microchip 325, 327 enzyme-immobilized microreactors 337, 357 – enzymatic reaction, schematic representation 339 enzyme-linked immunosorbent assay (ELISA) 291, 308–312 enzyme membrane, preparation 338 enzyme microreactors 341 – integration 357 enzyme-polymeric membrane 186, 337 enzyme reactor, graphical representation 334 enzymes in microchips, covalent immobilization 325–329 EOF See electro-osmotic flow epibromohydrin, kinetic resolution 179 esterifications – in ionic liquid 216 – isoamyl alcohol and acetic acid 353 – lauric acid 360 – propionic acid and 349, 353 esters – amino acid benzyl ester 116 – b-alanine Dmab ester 115 – boronic acid trimethyl ester 410 – enantioselective hydrogenation 169 – 1H-pyrrole-3-carboxylate ester 113 – hydrogenation of cinnamic methyl ester 276 – hydrolysis 391 – pentafluorophenyl ester derivatives 292, 293, 377, 378 – reaction of malonic ester 212 – reduction 110 – – to aldehydes with 400 – synthesis 110 – – phenylboronic acid from 129 etching 36, 60, 64 – gas mixture 65 – isotropic/anisotropic 60 – natural etch stops 62, 63 – profiles 64 – schematic representation of speed 62 – with second masking layer 59 ethanolamine 90, 112 ethoxylation 213 ethyl 2-chloro-3-oxobutanoate 250 ethyl diazoacetate 182, 399, 400 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) 325 ethylenediamine acetate (EDDA) 112 ethylene-vinyl alcohol copolymer (EVOH) 157 Index ethylmagnesium bromide 417 ethyl 3-oxobutanoate 428, 429 ethyl 2-oxocyclopentane carboxylate 211 – phase transfer alkylation 211 ethyl pyruvate 169, 239, 240, 281 6-exo-dig cyclization 165 exothermic reaction 274, 415 f fabricated polymer-based monolithic enzyme reactors 342 fabrication, microstructure 35 – ceramic devices 46–48 – ceramic materials, joining of 48–49 – generative methods 41–42 – machining 38–41 – metal forming techniques 42–43 – metal microstructures, assembling/ bonding 43–46 – metals, manufacturing techniques 35, 36 – sealing 48, 49 falling film – hydrodynamics 270 – principle 222 falling film microreactor (FFMR) 221, 223, 247, 248, 256, 257 – flow pattern 225 – mass-transfer efficiency 264 fanetizole 111 a-fetoprotein (AFP) 310 [18F]fallypride 144 [18F]fluorocholine 144 2-[18F]fluorodeoxyglucose ([18F]FDG) 142 FFMR See falling film microreactor (FFMR) fiber-based microchip 327 Fick’s law 16 filter cartridges 441 fine chemical production 440, 441 fixed bed reactors 272 18 F label, tagging 142 flame-arrestor effect 409 Fletcher–Reeves conjugate gradient method 90 floating production storage and offloading (FPSO) vessels 435 flow asymmetric – allylic amination reaction 182 – hydrogenation 182 – Strecker reaction 178 flow biotransformation reactions 186, 187 flow capillary microreactor 355 Flow Kumada-Tamao Corriu coupling 180 flow b-lactam synthesis 185 flow metathesis catalysts 181 flow microreactor – cross-coupling in 427, 428 – system 427 flow pattern – characterization 240 – maps 232 flow reactors 155 flow restrictor 223 FlowSafe, by future chemistry 140 flow synthesis, reactors arrangement in 152–154 flow system 153, 165 flow-through immunoassay 311 flow transformation, of alcohols 164 fluid contact, connections 76–78 fluid delivery – centrifugal forces 20, 21 – displacement 20 – electro-osmotic flow(EOF) 20 fluid packets 19 fluorescence resonance energy transfer (FRET) 308 fluorinated apolar solvents 247 fluorinated aromatics 246 fluorination – mannose triflate 142 fluorinations 230, 251, 280, 428, 429 fluorous solid phase extraction (FSPE) 116, 300 Fmoc-b-alanine 378 Food and Drug Administration (FDA) 81 N-formylpyrrolidine 139 Fourier transform infrared spectroscopy (FTIR) 82 fraction collector 152 Friedel–Crafts acylation 105 Friedel–Crafts alkylations 425, 426 fullerene-method 261 fused silica – microfluidic chip – physical properties 56 future–fast–flexible factory 375 g gas–liquid channeling 245 gas–liquid mass transfer 244, 274 gas–liquid micromixers 239 gas–liquid reactions 221–280, 245–265 – acetic acid, mono-chlorination 256, 257 – alcohols, diols, and ketones, with fluorine oxidations 253, 254 – aliphatics and non-C-moieties, direct fluorination 249–251, 253 j453 454 j Index – aromatic isocyanates photochlorination 254, 255 – aromatics, direct fluorination 246–253 – contacting principles, and microreactors 222–245 – cycloalkenes, photoradical chlorination 255, 256 – gas–liquid–solid reactions 265–276 – homogeneously catalyzed gas–liquid reactions 276–280 – photooxidation reactions 259–263 – reactive carbon dioxide absorption 263–265 – toluene sulfonation 257–259 gas–liquid screening 277 gas–liquid–solid reactions 81, 265–276, 410 – acetylene alcohols, selective hydrogenation 271, 272 – alcohols oxidation 275 – azide hydrogenation 270 – cyclohexene hydrogenation over Pt/Al2O3 266, 267 – hydrogenations 266–273 – a-methylstyrene over Pd/C hydrogenation 272, 273 – p-nitrotoluene and nitrobenzene over Pd/C and Pd/Al2O3 hydrogenation 267–270 – pharmaceutical intermediates hydrogenation 270, 271 – sugars oxidation 275, 276 gas-permeable Teflon AF-2400 membrane 243 gel-derived microreactor 333 gel electrophoresis 305 gel matrix 333 genetic algorithm 84 glass – anodic bonding of 73 – borosilicate types 56 – fusion bonding 73, 74 – as material for technological purposes 54–57 – microreactors 53, 54 – – controlled nitration 101 – microstructure 438 – photostructurable types 66 – structuring of 58 – – etching technologies 60–63 – – masked etching, in microsystems technology 58–60 – – photostructuring of 66–68 – thermal bonding of 73 glass–ceramic sealants 48 glass–polymer monoliths 170 Gleevec synthesis 190 glucose – gas–liquid–solid oxidation 276 – oxidation 275 3-glycidoxypropyltrimethoxysilane (3-GLYMO) 345 glycosylation 102, 103, 296 – of asparagine amide 103 – Brønsted acid catalyzed 104 – disaccharide formation by 297 – optimization 298 gold-coated capillary reactor – microwave-assisted benzannulation 176 gradient-based methods 83 green chemistry 347 green fluorescent protein fragment (GFPuv) 303 Grignard-based enolate formation 441–443 Grignard reactions 125, 402– 404, 417–419, 441 Grignard reagent 403, 442 Grubbs-Hoveyda catalyst – mesocellular foam microparticle (MCF)-supported 180 Grubbs olefin metathesis 180 h halogen–lithium exchange 126, 419 – microprocess pilot plant 420 halogen–lithium exchange pilot plant 419, 420 Hantzsch synthesis 378, 379 Hastelloy C-276 alloy 105 H-Cube1system 167, 169 – catalyst cartridges for 168 – hydrogenation conducted on 168 heat-resistant polymers 423 heat treatments 67 Heck reactions 89, 197 – by biphasic flow system 216 helical falling film microreactor 225 1-heptaldehyde 216 heteroaromatic compounds 428 heterocyclic compounds 188 heterogeneous catalyst 174, 182 heterogeneous flow reactions 152 heterogeneous reactions 151–191 – flow biotransformation reactions – – catalyzed by immobilized enzymes 186, 187 – immobilized catalysts, flow reaction with 166–183 – immobilized stoichiometric reagent, flow reactions with 159–164 – monolith reactors 156, 157 – multistep synthesis 187–191 – organocatalysis in flow reactions 183–186 – packed (fixed)-bed reactor 155, 156 Index – reactors arrangement, in flow synthesis 152–154 – reagent/catalyst immobilization 155–159 – solid acid catalysts 165, 166 heterogeneous reagents 191 heterogeneous single-step flow reaction 153 highmolecular-weight dendritic catalyst 180 high-pressure interdigital micromixer 238, 409 high-speed CCD camera 225 high-speed microscopy 233 high temperature reactions 122–124 high-throughput – analysis 304, 314 – portable devices 304 – proteome profiling 330 – reaction 366 – screening – – experiments 364 – – schematic illustration 208 – tube-in-tube microchannel reactor 243 hollow fiber membrane, schematic diagrams 344 homogeneously catalyzed gas–liquid reactions 276–280 homogeneous side reactions 387 Horner–Wadsworth–Emmons olefinations 111, 162 horseradish peroxidase (HRP) 309 Hoveyda-Grubbs catalyst 181 m-HPLC-CEC system 381 HRP-labeled anti-AFP antibody 312 human leukocyte antigen (HLA)-B-27 307 hyaluronic acid (HA) 331 hydrogenations 167, 241, 266–273 – asymmetric, cinnamic acid derivatives 276–280 – cyclohexene hydrogenation over Pt/Al2O3 266, 267 – ethyl nicotinate 169 – a-methylstyrene, over Pd/C 272, 273 – nitrobenzene, over Pd/C and Pd/Al2O3 267–270 – m-nitrotoluene 217 – p-nitrotoluene, over Pd/C and Pd/Al2O3 267–270 – Pd-catalyzed, 3-methyl-1- pentyn-3-ol 272 – Pd(0)-doped monolithic reactor 170 – pharmaceutical intermediates 270, 271 – publicly funded project, on reactions 433 – pyruvater asymmetric hydrogenation 169 – substituted pyridines 169 hydrogen gas 167 hydrogen generator 191 hydrogen peroxide 282, 424 – on-demand production 409 – synthesis 408–410 – – pilot microprocess plant 408 hydrolysis – benzyl cloride 213 – epoxide group 319 – esters 216, 391 – by glycosidase 298 – p-nitrophenyl acetate 24, 211, 360 – p-nitrophenyl-b-D-galactopyranoside 348 – triglyceride 361 – urea 358 hydrophilic interaction chromatography (HILIC) matrix 345 6-hydroxybuspirone 405, 406 hydroxylation 405 N-hydroxysuccinimide (NHS) 325 hypervalent iodine reagents 138 i ibuprofen 105 Imatiniv 190 imines, asymmetric cyanation 176 iminodiacetic acid (IDA) 345 IMM micromixer 107 immobilization approaches 324–347 immobilized catalysts – flow reaction with 166–183 – – catalytic cross-coupling reactions, and carbonylation reactions 172–175 – – catalytic hydrogenation 167–171 – – immobilized ligands, with transition metal catalyst 179–183 – – metal catalysts, polymer-supported ligand 176–183 immobilized enzyme microreactors See immobilized-enzyme reactors (IMERs) immobilized-enzyme reactors (IMERs) 291, 313, 343, 362 – in capillary and applications in proteolysis 319–322 – in microchips and applications in proteolysis 315–318 immobilized enzymes, advantages 314 immobilized metal catalyst 167 immobilized metal-ion chelating capillary microreactor 345 immobilized stoichiometric reagent – flow reactions with 159–164 immobilized trypsin 328 – microreactor 343 j455 456 j Index IMMs micromixer 102 inductively coupled PECVD (ICPECVD) 73 industrial microreactor process – (S)-2-acetyl tetrahydrofuran synthesis 392, 393 – alcohol production, ester hydrolysis to 391 – aldehydes synthesis 400, 401 – aldol reaction 381, 382 – N-Boc-4-piperidone, ring-expansion reaction 399, 400 – butyllithium, alkylation reactions 414–416 – challenges and concerns 442, 443 – Ciprofloxazin1 multistep synthesis 396, 397 – development up to production 373–443 – diastereoselective alkylation 383, 384 – diazo pigments synthesis 436–438 – disubstituted triazoles, continuous synthesis 404, 405 – diverse case studies 411–414 – diverse industrial pilot-oriented involvements 433–435 – diverse studies from Japanese project cluster 426, 427 – domino cycloadditions in parallel fashion 394, 395 – enamine synthesis 381 – ethyl 3-oxobutanoate, direct fluorination 428, 429 – fine chemical production process 440, 441 – flow microreactor, cross-coupling in 427, 428 – Friedel–Crafts alkylation 425, 426 – Grignard-based enolate formation 441, 442 – Grignard exchange reaction 417–419 – Grignard reactions, and Li–organic reactions 402–404 – halogen–lithium exchange pilot plant 419, 420 – Hantzsch synthesis 378, 379 – H2O2-based oxidation to 2-methyl-1,4naphthoquinone 424, 425 – hydrogen peroxide synthesis 408–410 – 6-hydroxybuspirone production 405, 406 – Knorr synthesis 379–381 – methyl carbamate synthesis 397, 398 – methylenecyclopentane synthesis 391 – methyl methacrylate manufacture, pilot plant for 417 – microflow azide syntheses 387–389 – microprocess technology – – in Japan 416 – – in United States 430–432 – mission statement from industry 373–375 – Newman–Kuart rearrangement 398, 399 – nitroglycerine production 439, 440 – peptide synthesis 375–378 – phase-transfer catalysis-mediated Knoevenagel condensation 396 – phenylboronic acid synthesis 410, 411 – pilot plants and production 408–443 – polycondensation 423, 424 – polyethylene formation 382, 383 – polymer intermediates production 435, 436 – process development at laboratory scale 386–407 – propene oxide formation 432, 433 – quinolone antibiotic drug, intermediate synthesis 393, 394 – radiolabeled imaging probe, multistep synthesis 384–386 – screening studies in laboratory 375–386 – selective nitration for pharmaceutical production 438, 439 – Staudinger hydration 392 – steroid deoxofluorination 429, 430 – substituted benzene derivatives, nitration 386, 387 – Swern–Moffatt oxidation 406, 407 – – pilot plant 420–422 – 2-trimethylsilylethanol condensation 391, 392 – vitamin precursor synthesis 389–391 – Wittig reaction 382 – yellow nano pigment plant 422, 423 industrial pilot-oriented involvements 433–435 inlet junction 205 innovation, vision, technology (INVITE) 375 in situ steroid biotransformation 354 integrated flow microreactor systems 427 integrated microfluidic device 384 integrated PCR-CE microdevice – schematics and photographs 306 intensification process, principles 242 interdigital micromixer 238, 422 interfacial – bonding, TEM images 75 – forces 201, 202 interfering fragments 314 interphase mass transfer coefficient 387 iodobenzene 117, 146, 174 – carbonylation reaction 174 IPIT Symposium 2011 375 IR micro flow cell 89 isoamyl acetate 350, 353, 356 4-isobutylpropiophenone 105 Index j Japanese project cluster, diverse studies 426, 427 k Kenics static mixers 394 ketones – asymmetric cyanosilylation of 104 – with fluorine oxidations 253, 254 ketopantolactone – enantioselective reduction 170 kinematic viscosity 16 kinetic model discrimination 94–97 Knoevenagel condensation 86, 395, 396 – efficiency 396 – optimization results 87 Knorr synthesis 379–381 Kryptofix 2.2.2, structure 141 l lab-on-a-chip type microreactors 140 lab-on-chip (LOC) 290 laboratory-scale – continuous-flow reactor 179 – microreactor processing 437 – slit-type interdigital micromixer–reactor 388 Labview monitors 85 a-lactalbumin 340 laminar flow transition threshold 17 lapping 71 laser ablation 55 layer-by-layer (LBL) coatings 331 layer-by-layer nanozeolite-assembled network 242 Lewis acids 103, 178, 255 b-(1!6) linked D-glucopyranoside homotetramer 300 Li-organic reactions 402– 404 liquid-liquid biphasic reactions 197–218 – applications in 197 – biphasic flow in microchannels 200–202 – biphasic systems, kinetics of 189 – liquid–liquid microsystems in organic synthesis 207–209 – micromixer 209–218 – surfaceand liquid–liquidinteraction 202–207 liquid–liquid chemical reactions 207 liquid–liquid microreactor 207 liquid–liquid microsystems, in organic synthesis 207–209 liquid–liquid systems 198, 201, 390 liquid phase oxidation reactions 273 liquid pulse injection 276 lithiation/borylation/Suzuki–Miyaura cross coupling sequence 119 lithiation-electrophilic addition chemistry 128 lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA) 400 lithography 60 lonza continuous small-scale plant 413 lowpressureCVD (LPCVD) 73 LTC-type ceramic material 78 luminescence 307 m macroporous monoliths 156 magnetic nanoparticles 157, 158, 328, 329 – unfunctionalized and functionalized 158 MALDI-TOF-MS 313, 325, 327, 333 – peptide analysis 335 N-(4-maleimidobutyloxy) succinimide (GMBS) 293 malonic ester 212 Mannich reaction 123 mannose triflate 142 masked microabrasives powder blasting, principle 70 mask layers, material of 61 mass spectrometry (MS) 313 mass transfer 266 – resistances 275 Matlab script 85 MCF-supported catalyst 183 mechanical precision machining 39 medium-scale microflow systems 417, 418 Meerwein-Ponndorf-Verley reduction 181 membrane/mesh microcontactor 229 membrane microreactors concept 242 mercury lamp 135 mesh microreactor 272 mesoporous silica 182 metal-catalyzed reactions 117–122 metal-free oxidation method 407 metal-organic frameworks (MOFs) 156 metal oxide 155 metal-stabilized enolates 383 – diastereoselective alkylation 383 metal/stainless steel devices 238 methoxylation 139 3-methoxyphenyllithium 404 3-methoxyphenylmagnesium bromide 403 methylating agent 393 2-methyl-3-butyn-2-ol (MBY) 271 methyl carbamate synthesis 397, 398 methyl chloroformate 398 – exothermic reaction 397 j457 458 j Index methylenecyclopentane 391 methyl methacrylate (MMA) 417 – manufacture, pilot plant for 417 N-methylmorpholine (NMM) 116 N-methylmorpholine N-oxide (NMO) 175 2-methylnaphthalene (2MN) 425 2-methyl-1,4-naphthoquinone 424 3-methyl-1- pentyn-3-ol 272 N-methyl-2-pyrrolidone (NMP) 378 5-methylresorcinol reaction 210 a-methylstyrene 272, 273 Mettler Toledo’s ReactIR micro flow cell 89 Michael additions 294 – of nitroalkanes 107 Michaelis–Menten equation 352 Michaelis–Menten kinetics 354 Michaelis–Menten rate constants 353 microabrasion 69, 70, 71 microarray DNA synthesis technologies 303 microbubble columns 236, 263 microcapillaries, wall surface functionalization 157 microcapillary films (MCFs) 157 microcapillary tube reactor process 389 microchannels 37 – array 237 – biphasic flow in 200–202 – nitrogen/water flows in 234 – processing 395 – reactor 293 – – scheme 352, 355 – schematic diagram 22 – semicircular shape 40 – system 353 microchip – based electrochemical enzyme immunoassay 309 – based PCR 301 – immobilized magnetic enzyme reactor (IMER) 328, 329 – reactor 379, 381 microcolumn array 231 microdevices 227 – mesoscale extension 413 microdrill 39 micro electro discharge machining (mEDM) 223 microelectromechanical systems (MEMS) technology 305 microencapsulated (MC) palladium(0) 170 microfabricated meshes 227 microfabrication 241 micro-fabrication technology 241, 289 microflow azide syntheses 387–389 microflow-lithiation chemistry 129 microflow reversed phase liquid chromatography coupled with tandem mass spectrometry (microRPLC–MS/MS) 342 microflow systems 124, 393, 421 – products synthesized in 419 microflow tools 257 microfluidic approach, advantages 290 microfluidic bioreactors 348 microfluidic components microfluidic devices 302, 309 – graphical presentation 354 microfluidic enzymatic microreactors 312 – applications 312 – – in proteomics 312–347 microfluidic enzymatic reactors, applications 292 microfluidic microchips 325 microfluidic microreaction technology, advantages 312 microfluidic reactors 332, 339 – applications 365 – emergence 291 – enzymatic transformations 358–361 – – in solution phase 349–351 – usages 366 microfluidics-based immunoassays 291 microfluidic synthesis 303 microfluidic systems – biocatalytic transformations in 348–362 – reactors with immobilized enzymes 357–362 – solution-phase enzymatic reactions 348–357 micromechanical machining 38, 40 micromixers 209–218, 237, 425, 426 – based process 388, 442 – sandblasting for 71 – tube rig 411 – types 426 micromixing See micromixers microplants – process flow sheet 258 – systems 28 – for toluene sulfonation 255 microporous tube-in-tube microreactor 244 micro powder blasting 69 microprocess pilot plant – for Grignard exchange reaction 418 – for radical polymerization reaction 417 microprocess production plant – for pharmaceutical nitroglycerine 439 microprocess technology 255, 408, 416, 442, 443 – in Japan 416 – potential 276, 374 Index – in United States 430–432 microreaction chambers – intersectional view 308 microreaction system 390 – schematic diagram 302 microreaction technology 115, 130, 348, 375, 411 microreactors 1, 71, 78, 222–245, 265, 346 – advantages of 6–7 – applications 290, 292, 307 – assisted processing – – temperature diagram 441 – biocatalysis by enzymatic microreactors 304–362 – biomolecular syntheses 292–303 – bioorganic syntheses 292–303 – connecting fluidics, possibilities 76 – construction, materials and microfabrication techniques 12 – for cryogenic operation 415 – fluid delivery 20, 21 – fluid flow 16–20 – glass with front port 77 – 1-hexene-3-ol to ethyl propyl ketone isomerization 208 – history of 1–6 – manifold, schematic 293 – mass transfer efficiency 263 – mixing mechanisms 21, 22 – multienzyme catalysis in 362–365 – multifunctional integration 23 – oligonucleotide synthesis 302, 303 – optimal operation 72 – partial frames 77 – peptide synthesis 292–296 – physical characteristics – – architecture – – constructional materials and properties 10–15 – – geometries 7–10 – – multiplicity 8, – – size 7, – plant, process flow sheet 257 – precision particle manufacture 25–27 – processing 393, 411, 436 – – benefits 260 – sugar and oligosaccharide synthesis 296–302 – systems 4, 5, 7, 397, 422 – technology 276, 373, 415 – test 277, 278 – uses of 23 – – fast/exothermic reactions 24, 25 – wider industrial context 27 – – point-of-demand synthesis 27, 28 – – sustainability agenda 27 microscale flow system – schematic diagram 421 microscale processing techniques 347 microscale tubular reactor 421 microsphere-packed microchip bioreactors – advantages 327 microstructured PASSflow reaction system 362 microstructured reactors 274, 432, 440, 441 microsystems – advantage 208, 290 – efficiency 209 micrototal analysis systems (mTAS) 290 – advances in 290 – applications 380 microwave – assisted continuous-flow conditions 182 – irradiation 113 – organic synthesis 443 – system 165 Mikroglas Dwel device 256 mimetic algorithm 84 miniature miniature-scale flow, advantages 434 miniaturization 290 mini-packed bed reactor 240, 241 Ministry of Economy, Trade and Industry (METI) 416 mixed batch reactors 356 Mizoroki–Heck reaction 117, 172 – heterogeneous/homogeneous flow, comparison 172 – ligand-free Pd-catalyzed 172 momentum diffusivity 16 mono-fluoro toluenes 247 monolithic phosphine reactors 163 monolithic preparation, procedures 330 monolithic supports, advantages 339 monolith reactors 156, 157 mononitrated benzene derivative 387 Mukaiyama Aldol reaction 209 multichannel packed bed reactor 240 multienzyme catalysis 362–365 – immobilized enzyme microreactors 363 multi-injection principle 414 multi-injection reactor 412 multilayered microreactor system 410 multiphase microstructured reactors 246 multipurpose microdevices, special-type 259 multistep enzymatic approach 364 multistep synthesis 187–191 j459 460 j Index Murahashi coupling 121, 427 – microreactor system for 427 Mycobacterium tuberculosis (MTB) 307 myoglobin (MYO) 326, 340 n NaA zeolite film 15 nanoliter enzyme microreactor 340 nanoparticle synthesis 240 nanosized Pd particles 270 NanoTek reactor 146 nanozeolite-assembled network 333, 334 2,3-naphthalenediamine 301 Nef oxidation 125 network converters 55 neuropeptide YY5 receptor antagonist [11C]MK-0233 147 – synthesis of 146 neurotensin 341 Newman–Kuart rearrangement 122, 398, 399 N-heterocyclic carbenes (NHC) 179 N-heterocyclic compounds 111 nickel mesh 228 nine-channel microstructured reactor 428 nitration 101 – substituted benzene derivatives 386, 387 nitrobenzene 267–270 – conversion 263 4-nitrobenzyl bromide 138 p-nitrobenzyl esterase from Bacillus subtilis (BsubpNBE) 187 2-nitrobenzyl triphenylphosphonium bromide 110 nitrogen-containing compounds 270 nitrogen-ethanol system 235 – flow pattern for 235 nitrogen/water system, flow-pattern maps 234 nitroglycerine production 439, 440 p-nitrophenyl acetate 211 – hydrolysis 24 O-(2-nitrophenyl)-N,Ndimethylthiocarbamate 398 p-nitrophenyl-b-D-galactopyranoside 348 4-nitrophenylhydrazine 113 p-nitrotoluene 267–270 m-nitrotoluene 217 non-C-moieties, direct fluorination 249–251 nuclear magnetic resonance (NMR) 82 nucleophilic fluorination 250 numbering-up principle 417 o oil–water interface, in microreactor 134 oligonucleotide synthesis 302, 303 oligosaccharide synthesis 300 on-chip protocol, schematic representation 328 online enzyme reactor, schematic illustration 346 on-line micro-HPLC 337 online process control 237 open-channel microdevices 314 operation window 217 optimal kinetic parameter estimates, uncertainties 98 optimization algorithm performance 92 organic–inorganic hybrid silica monolithic matrix formation 342 organic materials 156 organic solvents 237 organic synthesis 267 organocatalysis 183 – in flow reactions 183–186 organolithium compounds 428 organolithium coupling reaction 412 organometallic reactions 125–130, 410 ouabain hexaacetate 216 oxidations 124, 125 – with fluorine 253, 254 – H2O2-based oxidation to 2-methyl-1,4naphthoquinone 424, 425 – laccase-catalyzed-L-DOPA oxidation 352 – 2-methylnaphthalene (2MN) 425 – PI-Ru catalyst – – flow catalytic oxidations 175 – sugars 275, 276 oxide layers 45 2-oxindoles 214 (Ỉ)-oxomaritidine 189, 190 oxygen-free copper, by micromachining 41 ozonolysis (O-cube) reactions 241 p Paal–Knorr reaction 90, 112 – mechanism 90 – production rate of 91 packed-bed columns 155 packed bed microreactor 267 – biphasic oxidation in 218 – systems 241 packed bed reactor 217, 240 packed (fixed)-bed reactor 155, 156 – advantages 155 packed-bed reactors 156 – drawbacks 156 – flow oxidation using 159 palladium catalyst 268, 269 palladium-catalyzed Index – amination, of aromatic halides 121 – C–F bond formation 160 – hydrogenations 214 palladium–silver membranes 431 parallel genetic analysis 306 parallel microchannels 232 particle synthesis 436 partition coefficient 199 PASSflow microreactor 179 Patern o–B€ uchi reaction 135 PBR ligand 145 Pd-catalyzed Murahashi coupling reaction, of aryl halides 121 Pd/C cartridge 168 Pd(0)-doped monolithic reactor 170 Pd-immobilized glass microchannels 171 Pd(0)-immobilized monoliths 173 Pd-immobilized packed-bed column 174 PDMA 299, 307 – glass–PDMA chip 307 – glass–PDMA hybridmicroIMER 326 Pd-monolith flow Mizoroki–Heck reaction 172 PDMS device 328 PDMS microreactor 143, 331 Pd(0) nanoparticles 170 Peclet number 16 PEG-modified photo-polymerized sol–gel (PSG-PEG) monolith 341 penalized Armijo conjugate gradient method 93 pentaerythritol tetranitrate (PETN) reductase 216, 355 pentafluorobenzene (PFB) 418 pentafluorophenyl ester derivatives 292 pepsin-containing gel 346 peptide analysis 331, 335 peptide mapping 313 peptide synthesis 292–296, 375–378 perflouroalkoxy 14 perfluorination processes, hazardous 250 perfluoroalkoxy perfluoroalkanes (PFA) 111 perfluorodecalin (PFD) 206 perfluoropolyether (PFPE) 302 PET microreactor 331 pharmaceutical nitroglycerine, production plant 439 pharmaceuticals 27 phase-transfer catalysis 212, 215, 389 – mediated Knoevenagel condensation 396 phase-transfer catalysts 210, 211, 396 phenol/hydroxybenzyl alcohol ratio 426 phenols – O-alkylation 215 – controlled nitration 101 phenylacetonitrile 214 phenylboronic acid synthesis 410, 411 – temperature profile 411 phenylethyl Grignard reactant 402, 403 phenyliodine bis(trifluoroacetate) (PIFA) 189 phenylmagnesium bromide 410 phosgene 115 phosphine-functionalized monolith 164 phospholic acid catalyst 165 photochemical efficiency 136 photochemical flow reactor 136 photochemical processes 59 photochemistry, in flow reactors 133–136 photochlorination, aromatic isocyanates 254, 255 photochromic diarylethenes, synthesis scheme 427 photocycloaddition, of naphthalene derivative 133 photoetchable special glasses, physical properties 56 photolithography 58, 69, 229 photooxidation reactions 259–263 photooxygenation 260 photopolymerized sol–gel (PSG) monolith 347 photo reaction 262 photosensitized oxygenation 261 photostructurable glass 56, 67, 68 phthalimide 135 physical vapor deposition (PVD) 72 PID controllers 85 piezoresistive principle 72 pigments, coloristic properties 436 pilot fluorination reactor 250 pilot-size microreactor operation 437 pinching mechanism 206 Ping Pong Bi Bi mechanism 353 L-pipecolinic acid – photocatalytic synthesis of 135 cis-piperidinedicarboxylate 168 N-Boc-4-piperidone – BF3ÁEt2O addition 399 – ring-expansion reaction 399 PI-Ru catalyst 175 planar chip chromatograph, image of plant start-up tests 439 plasma enhanced CVD (PECVD) 73 plastic deformation 73 plastic molding 46 PMMAenzymatic microreactor 355 j461 462 j Index PMMA microchannel 332 PMMA microfluidic chip 326 PMMA surface 333 polyacrylate mesh microreactor 229 polycondensation 423, 424 polycondensation reactions 423 poly(diallyldimethylammonium chloride) (PDDA)-entrapped silica sol–gel matrix 345 polydimethylsiloxane (PDMS) 11 – based microreactor arrays 294 – microchannel 206 polydispersity 222 – index 417 polyetheretherketone (PEEK) 14 polyethylene formation 382, 383 poly(ethylene glycol) (PSG-PEG) 340 poly(ethylene glycol)diacrylate (PEGDA) 329 poly(ethyleneimine) (PEI) 310 poly(ethylene terephthalate) (PET) 331 polyimide (PI)-based film microreactors 105, 108 polymerase chain reaction (PCR) 291 polymer-assisted solution phase synthesis (PASSflow) technique 157 polymer-based monolithic reactor, strategies for 156 polymer catalyst 183 polymeric Pd-nanoparticle membraneinstalled devices 158 polymer industry 435 polymer intermediates production 435, 436 polymerization – catalyst plug-induced microchannel ethylene polymerization 383 – free radical, methyl methacrylate (MMA) 417 polymer matrix 332 polymer membrane 158 polymer-supported amine – flow Knoevenagel condensation 184 polymer-supported amine catalysts 184 polymer-supported chiral organocatalyst 185 polymer-supported ligand-metal complexes 181 polymer-supported ligands, preparation 176, 177 polymer-supported PEPPSI-type catalyst 173 polymer-supported phosphazene base (PS-BEMP) 184 poly(methyl methacrylate) (PMMA) 204 – microreactor 298 polystyrene-based amine polymers 159 – 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD) 159 polystyrene-supported chiral phosphinooxazoline (PHOX) ligand 182 polystyrene-supported chiral secondary amine catalysts 186 polystyrene-supported Rudiarylethylenediamine (DPEN) 181 polytetrafluoroethylene (PTFE) 1, 2, 14 – chip fabrication 26 poly(vinyl pyridine), continuous-flow conditions 173 porous alumina layer, generated by anodic oxidation 48 porous polymer monolith (PPM) 306 porous stainless steel hollow fiber – cross-section 243 positron emission tomography (PET) 139 – dose-on-demand synthesis 144 – radiopharmaceuticals 140 pressure-driven microreactor 353 pristane, multi-kilogram synthesis 102 process intensification methodologies applied to liquid–liquid systems in structured equipment (PILLS) 375 production-type microstructured reactor 435 propene oxide formation 432, 433 propiophenone, enol silyl ether of 106 propylene oxide formation 433 protecting group-free flow synthesis 161 proteinase-K (PK) digestion 329 proteins – direct electro-elution 327 – expression profiling 312 proteolytic enzyme reactors 343 proteolytic enzymes 314 – immobilization 329 pseudo 3-D computational fluid dynamic (CFD) model 226 PSG-PEG monolith surface – functionalization 340 PTFE microreactor 215 PTFE tube reactor 141 publicly funded project 432 – on hydrogenation reactions 433 Pummerer rearrangement 407 pumping system 381 pure numbering up approach 224 pyrazoles 379 pyrene, photocyanation of 134 Pyrex glass capillary tubing 275 Pyrex microreactor 135 2,6-pyridinedicarboxylate 168 pyridine-functionalized monoliths 173 pyridines, two-step synthesis 165 3-pyridin-3-yl-propionic acid Index – methylation of 145 – in microreactor 142 4,40 -(2,4-pyrimidinediyl)bis-morpholine – multistep reaction network 97 1H-pyrrole-3-carboxylate ester 113 pyruvate, asymmetric hydrogenation 169 q quartz glass window 260 quinoline – aromatics, selective fluorination 251 – fluorination 252 quinolone antibiotic drug 393, 394 r racemic amino acids 362 – continuous flow system 362 – enantioselective reaction for 357 racemic epoxides – hydrolytic kinetic resolution 179 racemization, degree of 378 radical reactions 108–110 radiochemistry 144 radiolabeled imaging probe, multistep synthesis 384–386 reaction calorimetry 398, 399 reactive carbon dioxide absorption 263–265 reactor configuration 137 reactor system 239 reagent/catalyst immobilization 155–159 retinol 390 reverse transcription polymerase chain reaction (RT-PCR) 305 Reynolds numbers 16, 22, 200, 201, 208 Reynolds, Osborne 3, 200 Rh/Diop catalytic system 279 rhodium diphosphine complexes 280 rhodium honeycomb catalyst microstructure device 39 rhodium phosphine complexes 278 RIE-etched silicon 65 ring closing metathesis (RCM) 180 ring-type monolith reactor 173 s sandwich ELISA 308 SAR-microreactor, geometric design 301 scanning electron microscopy 227 Schmidt number 16 segmented flow conditions 353 selective laser melting (SLM) 36 – schematic sketch of 42 – stainless steel microstructure cube 42 selective nitration, for pharmaceutical production 438, 439 self-made K-M mixer 426 self-supported chiral titanium cluster (SCTC) catalyst 177 self-supported Rh-BINOL catalyst 182 sensor integration 72 a-(2–6)-sialylation optimization 300 Sigma-Aldrich’s custom synthesis 374 silica capillary 335 silica gel 158 silica-gel-derived microfluidic reactor 333 silicon – anisotropic crystallographic wet chemical etching 61 – anodic bonding of 73 – isotropic wet chemical etching 63–65 – – drilling, diamond lapping, ultrasonic lapping 68, 69 – as material for mechanical purposes 57 – micro powder blasting 69–71 – microreactors 53–54 silicon direct bonding 74, 75 silicone microreactor 271 silicon fusion bonding See silicon direct bonding silicon glass – isotropic wet chemical etching 65, 66 – isotropic wet chemical etching of 66 silicon, isotropic etching 64 silicon microreactors 81, 296 – application 294 – uses for flow systems 81 silicon nitride 64 silicon-on-insulator (SOI)-supported microdevice 431 silicon, physical properties 57 silicon, structuring of 58 – etching technologies 60–63 – masked etching, in microsystems technology 58–60 siloxane bridges 74 silyl enol ether 382 single-channel microreactor 253 – schematic 230 single channel single-channel microreactor 249 single laminar flow, velocity profile 201 single-phase reactions 215 singlet oxygen [4ỵ2]-cycloaddition 259 single-trajectory optimization algorithm 86 single trypsin microreactor 339 j463 464 j Index slit-type interdigital micromixer 394 SLM See selective laser melting (SLM) slug-flow generation 26 sodium dodecyl sulfate 277 sodium nitrotetrazolate – direct multistep synthesis 431 – multistep synthesis, reaction setup for 432 sol–gel entrapment method 314 sol–gel generated catalyst 47 sol–gel layer 47 sol–gel reaction 347 sol–gel wall coatings 410 solid acid catalysts 165, 166 solid-phase chemistry 375 solid phase extraction (SPE) 305 solid phase organic synthesis (SPOS) 151 solid-phase PCR purification 302 solution-phase enzyme reaction 348 Sonogashira coupling reaction 117 – using copper tube flow reactor (CTFR) 118 spark erosion 38 spherical-shaped liquid droplets 198 spinning disk reactors 221 split-and-recombine (SAR)-microreactor 301 split–recombine device 239 split–recombine micromixers 238 (20 S,4R,5S)-3-(20 -methyl-30 -phenylpropionyl)4-methyl-5-phenyloxazolidin-2-one 384 stable noisy optimization by branch and fit (SNOBFIT) algorithm 83 staggered herringbone micromixer (SHM) 355 stainless steel microchannel foils 40 – diffusion-bonded cross-flow arrangement 46 stainless steel microstructure cube 42 stainless steel tubing (SST) 332 StarLam 3000 microstructured mixer 440 StarLam mixer 441 Staudinger-aza-Wittig reaction 163 Staudinger hydration 392 Staudinger phosphinimine formation 189 Staudinger reaction 162 stepping trajectory-based algorithms 82 stereoisomers 298 steroid deoxofluorination 429, 430 stirring systems 397 stoichiometric reactions 161 – using flow monolith reactors 162 stoichiometric reagents 162 stopped-flow techniques 376 Strecker synthesis 176 streptavidin-functionalized capillary immune microreactor 311 structured reaction plates 224 2-substituted pyridines – two-step flow synthesis 166 succinyl-ala-ala-ala-paranitroanilide (SAAAP) 329 sugar and oligosaccharide synthesis 296–302 sugars oxidation 275, 276 sulfonation – microplant for toluene 255 – toluene 257–259 sulfonic acid resin 191 supercritical carbon dioxide (scCO2) 171 supported organocatalysts 184 surface/liquid–liquid interaction 202–207 surface modification scheme 337 surface tension 203 Suzuki–Miyaura coupling 119, 213 – immobilized Pd-salen complex 179 Swern–Moffatt oxidation 406, 407, 422 – pilot plant 420–422 Swern oxidation, for pharmaceutical intermediates 420 synthesis based on affinity separation (SAS) system 297 synthetic missions 154 synthetic-organic chemists 102 synthetic protocols 218 syringe delivery system 209 Syrris glass microreactor 109 t tandem mass spectrometry 343 Taqman assay 306 Taylor-flow microreactors 229, 232, 237 – design 233 Taylor recirculation 81 template-directed primer extension 308 terminal phosphate-labeled fluorogenic nucleotides (TPLFNs) 307 a-terpinene 261 testosterone 407 tetra-N-alkylammonium perruthenate (TPAP) 175 tetrabutylammmonium fluoride (TBAF) 106 tetrabutylammonium acetate (TBAA) 118 tetrabutyl ammonium bromide (TBAB) 211, 214 tetraethoxysilane (TEOS) 341 tetramethylenediamine (TMEDA) 161 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) 185 – catalyst 218 b-tetrapeptide synthesis 296 Index tetrapropyl ammonium bromide (TPAB) 213 tetrazoles 123 Thales nano reactors 242 thermophilic alcohol dehydrogenase (TADH) 355 thin film technology 72, 73 O-thiocarbamate 122 three-member array 395 toluene-2,4-diisocyanate reaction 254 toluene isocyanates 254 toluene sulfonation 257–259 – selectivity for 258 Toray Hi-mixer 126, 418 traditional batch method 431 transesterification 179, 361 transgalactosylation 299 transition metal catalysis 166 transition prediction model 235 transparent microchip reactor 236 tri-O-acetyl-D-glucal – deacetylation 187 triazabicyclodecene (TBD) 185 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD) 159 triazoles 405 tributyltin hydride 108 – mediated radical reaction 109 trickle-bed reactors 267, 406 triethylbenzyl ammonium chloride (TEBA) 214 trifluoroacetic anhydride 421 2-trimethylsilylethanol condensation 391, 392 triple-channel microreactor 261, 262 Tris(trimethylsilyl)silane (TTMSS) 109 trypsin-containing gel 346 trypsin immobilization 336 tryptic peptides 336 T-shaped borosilicate microreactor 104 T-shaped micromixers 239 turbulent flow 200 turnover number (TON) 166 two-stage electroplating method 229 two-stage microreactor continuous-flow system 392 tyrosine-based Ni-nitrilotriacetic acid (Ni-NTA) linker system 186 u uncontrolled fluid dynamics 156 unfunctionalized triphenylphosphine monolith 164 UV-polymerization 26 UV spectrometer 190 v vitamin precursor synthesis 389–391 w wall-coated catalysts 272 water-soluble ionic liquid 122 Weber numbers 202 wet chemically etched foils 44 – arrangement 44 wet chemically etched microchannels 37, 43 wetting vs nonwetting 203 wire spark erosion 38, 40 Wittig reaction 110, 382 x X-Cube1 reactor 173, 187 – flow aminocarbonylation 174 y YbCl3-catalyzed microflow reactions 104 yellow nano pigment plant 422, 423 Y-junction microreactor 54 Young’s equation 203 z zeolite nanoparticles 332 j465 ... Design Simone Benjamin, McLeese Lake, Canada Typesetting Thomson Digital, Noida, India Printing and Binding Markono Print Media Pte Ltd, Singapore Printed in Singapore Printed on acid-free paper... micromachining [61], deep reactive ion etching [62], molding [63], embossing [64,65], casting [66], and milling [67] Advanced microreactors for manufacturing-level chemical production place demanding... 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