Microreactors in preparative chemistry practical aspects in bioprocessing nanotechnology catalysis and more

Edited by Wladimir Reschetilowski Microreactors in Preparative Chemistry Related Titles Dietrich, T Microchemical Engineering in Practice 488 pages 2009 Hardcover ISBN: 978-0-470-23956-8 Wirth, T (ed.) Microreactors in Organic Synthesis and Catalysis 297 pages with 303 figures and 18 tables 2008 Hardcover ISBN: 978-3-527-31869-8 Lưhe, D., Haelt, J (eds.) Microengineering of Metals and Ceramics Set Part I: Design, Tooling, and Injection Molding Part II: Special Replication Techniques, Automation, and Properties 698 pages in volumes with 409 figures and 71 tables 2008 Hardcover ISBN: 978-3-527-32378-4 Hessel, V., Hardt, S., Löwe, H., Müller, A., Kolb, G Chemical Micro Process Engineering Volume Set 1393 pages in volumes with 822 figures and 29 tables 2005 Hardcover ISBN: 978-3-527-31407-2 Brand, O., Fedder, G K (eds.) CMOS-MEMS 608 pages with 312 figures and 32 tables 2005 Hardcover ISBN: 978-3-527-31080-7 Edited by Wladimir Reschetilowski Microreactors in Preparative Chemistry Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more The Editor Prof Wladimir Reschetilowski Technische Universität Dresden Zellescher Weg 19 01069 Dresden Germany 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 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: ePDF ISBN: ePub ISBN: mobi ISBN: oBook ISBN: Cover Design Typesetting Printing 978-3-527-33282-3 978-3-527-65292-1 978-3-527-65291-4 978-3-527-65290-7 978-3-527-65289-1 Formgeber, Eppelheim Thomson Digital, Noida, India Markono Print Media Pte Ltd, Singapore Printed in Singapore Printed on acid-free paper V Contents Preface XI List of Contributors XIII 1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.4 1.5 2.1 2.2 2.3 2.3.1 2.3.2 2.4 2.4.1 2.4.2 2.4.2.1 2.4.2.2 2.4.3 2.4.3.1 2.4.3.2 2.5 2.5.1 2.5.2 Principles of Microprocess Technology Wladimir Reschetilowski Introduction History Basic Characteristics Microfluidics and Micromixing Temperature and Pressure Control Safety and Ecological Impact Industrial Applications Concluding Remarks References 10 Effects of Microfluidics on Preparative Chemistry Processes 13 Madhvanand Kashid, Albert Renken, and Lioubov Kiwi-Minsker Introduction 13 Mixing 15 Heat Management 18 Heat Transfer in Continuous-Flow Devices 19 Heat Control of Microchannel Reactors 22 Mass Transfer and Chemical Reactions 26 Fluid–Solid Catalytic Systems 26 Fluid–Fluid Systems 31 Flow Regimes 32 Mass Transfer 34 Three-Phase Systems 36 Gas–Liquid–Solid Systems 36 Gas–Liquid–Liquid Systems 40 Flow Separation 40 Geometrical Modifications 41 Wettability-Based Flow Splitters 42 VI Contents 2.5.3 2.6 2.7 Conventional Separator Adapted for Microstructured Reactors 44 Numbering-Up Strategy 45 Practical Exercise: Experimental Characterization of Mixing in Microstructured Reactors 46 References 50 Modular Micro- and Millireactor Systems for Preparative Chemical Synthesis and Bioprocesses 55 Frank Schael, Marc-Oliver Piepenbrock, J€orn Emmerich, and Joachim Heck Introduction 55 Modular Microreaction System 57 Examples for Microreactor Applications 60 Synthesis of Vitamin A Acetate 60 Screening of Process Parameters for a Suzuki–Miyaura Reaction 62 Scale-Up of Thermal Rearrangement of Furfuryl Alcohol 64 Online Reaction Monitoring and Automation of Chemical Synthesis and Bioprocesses 66 Laboratory Exercise: Suzuki Reaction in a Modular Microreactor Setup 70 References 73 3.1 3.2 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.4 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.4 4.4.1 4.4.2 4.4.3 4.4.4 4.5 4.6 4.7 4.8 Potential of Lab-on-a-Chip: Synthesis, Separation, and Analysis of Biomolecules 77 Martin Bertau Introduction 77 Learning from Nature: Analogies to Living Cells 77 Microenzyme Reactors 79 Enzyme Immobilization on the Microchannel Surface 80 Enzyme Immobilization on Supports 81 Modes of Operation 81 Enzymatic Conversions 81 Enzymatic Cleavage of Peptides 84 Determination of Inhibitor Properties 84 Cytotoxicity Assessment 87 Microchip Electrophoresis 87 Peptide Analysis 88 Chiral Separation 88 Coupling Biocatalysis and Analysis 88 Determination of Amino Acids in Goods and Foods 89 Microenzyme Membrane Reactor/Micromembrane Chromatography 89 Nucleic Acid Analysis in Microchannels 91 Saccharide Analyses in Microdevices 94 Practical Exercise: Lipase-Catalyzed Esterification Reaction 96 References 97 Contents 5.1 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.2.4.1 5.2.4.2 5.2.4.3 5.2.5 5.3 6.1 6.2 6.2.1 6.2.2 6.2.3 6.3 6.3.1 6.3.2 6.4 7.1 7.2 7.3 7.4 7.5 7.6 7.6.1 7.7 7.7.1 7.7.2 Bioprocessing in Microreactors 101 Fridolin Okkels and Dorota Kwasny Introduction 101 Background 101 Basic Elements of a Biosensor 101 Different Sensing Methods 103 The Effect of Reducing Dimensionality and Length Scales of Biosensors 103 Biosensors Based on Field-Effect Transistors 104 The Main Working Principle of FET Sensors 105 Fabrication of SiNW FET Sensors 106 Functionalization of SiNW FET Sensors Using APTES 107 Shielding by the Buffer: Combined Influence from Ions and Charge Carriers 107 Practical Exercise: Functionalization of Silicon Surface 108 References 113 Synthesis of Fine Chemicals 115 Sandra H€ ubner, Norbert Steinfeldt, and Klaus J€ahnisch Introduction 115 Organic Synthesis in Liquid and Liquid–Liquid Phases 116 Fluorination Reactions 116 Reactions with Diazomethane 127 Ultrasound-Assisted Liquid–Liquid Biphasic and Liquid Reactions 134 Gas–Liquid Biphasic Organic Synthesis 141 Ozonolysis Reactions 141 Photooxygenation Reactions 151 Practical Exercise: Photochemical Generation of Singlet Oxygen and Its [4 ỵ 2] Cycloaddition to Cyclopentadiene 159 References 161 Synthesis of Nanomaterials Using Continuous-Flow Microreactors 165 Chih-Hung Chang Introduction 165 Microfluidic Devices 165 Synthesis of Nanomaterials Using Microreactors 166 Kinetic Studies 180 Process Optimization 183 Point-of-Use Synthesis and Deposition 185 Deposition of Nanomaterials 185 Practical Exercises: Synthesis of Nanocrystals 187 Synthesis of ZnO Nanocrystals 187 Synthesis of CdS Nanoparticles 190 References 192 VII VIII Contents 8.1 8.2 8.2.1 8.2.1.1 8.2.1.2 8.2.2 8.2.3 8.2.4 8.2.5 8.2.5.1 8.2.5.2 8.2.5.3 8.2.6 8.2.6.1 8.2.6.2 8.2.6.3 8.3 8.4 8.4.1 8.4.1.1 8.4.1.2 8.4.2 8.4.2.1 8.4.2.2 8.4.2.3 8.4.2.4 8.5 8.5.1 8.5.2 8.5.3 8.6 9.1 9.2 9.2.1 9.2.2 Polymerization in Microfluidic Reactors 197 Jesse Greener and Eugenia Kumacheva Introduction 197 Practical Considerations 198 Control Over Reaction Conditions 198 Batch Reactors 198 Microreactors 199 Control of Mixing 199 Control of Reagent Concentrations 200 Distance-to-Time Transformation 200 Potential Negative Impacts of Polymerization Reactions on Reactor Operation 201 Buildup in Solution Viscosity 201 Precipitation 202 Adsorption 202 Selection of Materials for Fabrication of MF Reactors 203 Polymer Materials 203 Metals 205 Glass 205 Single-Phase Polymerization 205 Multiphase Polymerization 208 Formation of Polymer Particles 209 Formation of Precursor Droplets 209 Transformation of Precursor Droplets into Polymer Particles 213 Review of Demonstrated Applications 214 Controlled Encapsulation 214 Encapsulation and Delivery 215 Cell Encapsulation 217 Microgels as Model Cells 219 Beyond Synthesis: New Developments for Next-Generation MF Polymerization 220 Scaled-Up MF Synthesis of Polymer Particles 220 In Situ Characterization of Polymerization in MF Reactors 223 Automated Systems for Polymerization Microreactors 223 Practical Exercise: MF Polymerization Reactor Kinetics Studies Using In Situ Characterization 224 References 227 Electrochemical Reactions in Microreactors 231 Jun-ichi Yoshida and Aiichiro Nagaki Introduction 231 Electrode Configuration 232 Serial Electrode Configuration 232 Interdigitated Electrode Configuration 233 Contents 9.2.3 9.3 9.4 9.5 Parallel Electrode Configuration 233 Electrolysis without Supporting Electrolytes 234 Generation and Reactions with Unstable Intermediates 235 Practical Exercise: Electrochemical Reactions in Flow Microreactors 239 References 241 10 Heterogeneous Catalysis in Microreactors 243 Evgeny V Rebrov Introduction 243 Bulk Catalysts 244 Supported Catalysts 246 Macroporous Supports 247 ZnO Support 247 g-Al2O3 Support 247 Catalysts Immobilized onto Polymeric Particles 249 Silica-Supported Catalysts 251 Carbon-Supported Catalysts 253 Mesoporous Supports 256 Mesoporous Titania 258 Mesoporous Silica 260 Mesoporous Alumina 261 Microporous Supports 261 Practical Exercise: PdZn/TiO2-Catalyzed Selective Hydrogenation of Acetylene Alcohols in a Capillary Microreactor 263 References 265 10.1 10.2 10.3 10.3.1 10.3.1.1 10.3.1.2 10.3.1.3 10.3.1.4 10.3.1.5 10.4 10.4.1 10.4.2 10.4.3 10.5 10.6 11 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.8.1 11.8.2 Chemical Intensification in Flow Chemistry through Harsh Reaction Conditions and New Reaction Design 273 Timothy No€el and Volker Hessel Introduction 273 High-Temperature Processing in Microflow 273 High-Pressure Processing in Microflow 278 Solvent Effects in Microflow 280 Ex-Regime Processing and Handling of Hazardous Compounds in Microflow 283 New Chemical Transformations in Microflow 284 Process Integration in Microflow 286 Practical Exercises 288 Claisen Rearrangement at Elevated Temperatures 288 Copper(I)-Catalyzed Azide–Alkyne Cycloaddition with Integrated Copper Scavenging Unit 290 References 292 IX X Contents 12 12.1 12.2 12.3 12.3.1 12.3.2 12.4 12.4.1 12.4.2 12.4.3 12.4.3.1 12.4.3.2 12.4.4 12.5 Modeling in Microreactors 297 Ekaterina S Borovinskaya Introduction 297 Processes in Microreactors and the Role of Mixing 298 Modeling of Processes in Microreactors Based on General Balance Equation 300 Plug Flow Tube Reactor Model 300 Laminar Flow Model 302 Computation of Reaction Flows in Microreactors 308 Computational Fluid Dynamics 308 Single-Phase Modeling 309 Two-Phase Modeling 310 Liquid–Liquid Flow with Chemical Reaction 310 Liquid–Gas Flow with Chemical Reaction 312 Three-Phase Modeling 315 Practical Exercise: Alkylation of Phenylacetonitrile 320 References 323 Index 327 12.5 Practical Exercise: Alkylation of Phenylacetonitrile [3] Figure 12.15 Experimental setup Experimental Setup The microreactor system designed to carry out the alkylation of phenylacetonitrile is shown in Figure 12.15 The experimental setup consists of separate modules, produced by Ehrfeld Mikrotechnik BTS and installed on a plate These modules have standard interfaces and can be combined in different ways, providing flexibility of the setting for various reaction conditions It is crucial to provide efficient mixing of phases for the phase transfer reaction Therefore, the centerpiece of the microreactor system is the micromixer, which separates the flow of reagents into multitude layers to ensure efficient mixing conditions Implementation of a micromixer leads to the large specific interfacial area required for the reaction proceeding on the boundary of phases together with stationarity of the process The micromixer consists of a number of plates that form channels of 70 mm in size, providing a mixing time of several milliseconds After mixing, the reagent mixture enters the microreactor where the reaction takes place The volume of the microreactor does not exceed ml The microreactor, a long thin tube, provides the slug flow Equipment Hewlett Packard 6890 gas chromatograph equipped with a HP-5 0.25 mm, 30 m  0.32 mm capillary column, a thermostat, three flasks for the reaction educts and products, microreactor setup according to Figure 12.15 with two microheat exchangers, a microreactor, three inlet/outlet modules, and a micromixer Extra equipment for the experiments in a batch reactor, such as round-bottom flask equipped with a thermometer, a reflux cooler, a dropping funnel, and a mechanical stirrer, are necessary Chemicals Phenylacetonitrile (79.3 mmol), TEBA (0.79 mmol), ethyl bromide (79.3 mmol), aqueous solution of sodium hydroxide (45%), and n-dodecane as internal standard 321 322 12 Modeling in Microreactors Experimental Procedure in a Microreactor First, all reagents were heated up by thermostat and microheat exchanger to the required temperature of 305 K and then fed to the reaction setting The reaction was performed by pumping methanol containing phenylacetonitrile (79.3 mmol), TEBA (0.79 mmol), ethyl bromide (79.3 mmol), n-dodecane as internal standard, and aqueous solution of sodium hydroxide (45%) through two inlets of the micromixer The residence time of the reactants was determined by volume flow rates of organic and aqueous phases with the phase ratio between 1:3 and 1:10, respectively The reaction mixture was drawn from the outlet of the setup into a flask containing water and ethyl acetate to quench the reaction After phase separation, the organic phase was dried with sodium sulfate and analyzed by GC Experimental Procedure in a Batch Reactor Sodium hydroxide, TEBA, and phenylacetonitrile were placed in a round-bottom flask equipped with a thermometer, a reflux cooler, a dropping funnel, and a mechanical stirrer Ethyl bromide was added dropwise The product mixture was extracted by ethyl acetate and analyzed by GC GC analysis was performed on a Hewlett Packard 6890 gas chromatograph equipped with a HP-5 0.25 m, 30 m  0.32 mm capillary column and a temperature regime from 50 to 180  C in 15 Comments The reaction proceeds smoothly and the alkylation product was obtained in the microreactor with almost 85% yield after 10 of reaction time (Figure 12.16) In the case of the batch reactor with vigorous stirring (1200 rpm), nearly 85% yield was obtained after 60 of reaction time In a batch reactor with a magnetic stirrer, a maximum yield of 65% was achieved after mixing for Figure 12.16 Conversion (filled symbols) and yield (open symbols) as a function of time on stream for alkylation of phenylacetonitrile in various reactors (T ¼ 305 K) (Adapted from Ref [3].) 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236 – parallel laminar microflow system for 238 alkylation 135 – carbanions 320 – b-keto esters 37 – phenylacetonitrile 320–323 alkynes 258, 285, 289 – benzannulation of 245, 246 aluminizing treatment 244 amino acids 89 3-aminopropyltriethoxysilane (APTES) 107, 108 ammonium persulfate (APS) 225 aromatic carbonyls 245, 246 Arrhenius number 24 Artemisia annua 158 aryl triflates, Pd-catalyzed fluorination 279 astaxanthin 68 attenuated total reflection Fourier transform infrared (ATR-FTIR) 203 azeotropic evaporation 124 azobenzene 263 2,2-azobis(isobutylronitrile) (AIBN) 207 azo pigments azoxybenzene 263 b batch reactors 7, 81, 115, 137, 140, 153, 167, 180, 258, 263, 273, 322 o-benzoquinones 239 N-benzyloxycarbonyl protecting groups – deprotection of 255 benzyltriethylammonium chloride (TEBA) 320 bioreceptors 102 biosensors 101, 103, 104 – based on field-effect transistors 104, 105 – function 103 bis(methoxyethyl) aminosulfur trifluoride (Deox-FluorÒ) 116 block copolymers 257 Bodenstein number 304, 305 4-bromoacetophenone 249 4-bromobenzonitrile 277 Brownian motion 299 Brown solution 248 BTMG (2-tert-butyl-1,1,3,3tetramethylguanidine) 125 Buchwald–Hartwig amination reaction 277, 286 c carbon-supported catalysts 253–256 b-carotene 68 catalyst recycling, within flow chemistry 281 catalytic coatings 256 cation flow method – N-acyliminium ion 236 – paired 238 – serial combinatorial synthesis 237 CDF See computational fluid dynamics (CDF) cell-laden microgels 218 CFD simulations 315 – Bercic–Pintar correlation 314, 315 chemical transformations, in microflow 284–286 chemical vapor deposition (CVD) 107, 185 Cheng–Prusoff equation 86 chip-type electrochemical flow microreactors 232 Microreactors in Preparative Chemistry: Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more, First Edition Edited by Wladimir Reschetilowski Ó 2013 Wiley-VCH Verlag GmbH & Co KGaA Published 2013 by Wiley-VCH Verlag GmbH & Co KGaA 328 j Index chiral separation 88 Chlamydomonas reinhardtii 68, 70 Chlorella vulgaris 68 4-chloro-7-nitrobenzofurazan 89 citral, hydrogenation of 259 Claisen rearrangement 274, 288 – of allyl phenyl ether 289 – microfluidic setup for 289 – rate enhancement 275 clogging 25, 56, 58, 81, 130, 134, 137, 138, 281, 286 competitive inhibition 86 composite microgel containing – confocal fluorescence microscopy image of 217 computational fluid dynamics (CDF) 58, 308, 315 continuous-flow devices, heat transfer in 19–22 continuous-flow microreactors 7, 165, 166, 185 continuous-flow PCR (CF-PCR) 92, 93 continuous microreactors control over residence time 226 convection–diffusion equation 306, 312 copper(I)-catalyzed azide-alkyne cycloaddition – microfluidic setup for 291 coupling biocatalysis 88 CsF packed-bed microreactor 278 CsNaX zeolitic coating 263 CuAAC click reaction 291 Cu/ZnO/Al2O3 catalyst 318 CVD See chemical vapor deposition (CVD) 1-cyanopyrene 232 cyclobutane tetracarboxylic dianhydride 137 cyclotron 124 cytotoxicity assessment 87 d Damköhler number 14, 29, 46, 299 DAST See diethylaminosulfur trifluoride (DAST) diazomethane 127 – advantages of processing in microfluidics 128 – Arndt–Eistert-type reaction 134 – dual-channel microreactor 133 – microfluidic setup 128 – phase transfer catalyst (PTC) 132 – precursor N-methyl-N-nitroso-p-toluene sulfonamide synthesis 131 Dibal-H reduction 58 1,2-dichloroethene – lithiation, microfluidic setup 285 dichloromethane 252 1,3-dicyanopyrene 232 Diels–Alder reactions 2, 158 diethylaminosulfur trifluoride (DAST) 116 – deoxofluorination 118, 127 – geminal fluorination of ketone functionality in steroid by 117 – heat experiments with 117 2,5-dimethoxy-2,5-dihydrofuran 234 1,3-diphenyl-2-propynyl piperidine 245 DNA oligomers 214 DNA polymerase 91 droplet generation – microfluidic geometries for 210 – reactor material, surface properties 212 droplets, pulsed release of 217 droplet transformation 213 e Einstein–Smoluchowski relation 299, 300, 305 EISA See evaporation-induced self-assembly (EISA) electrochemical flow microreactor 235, 239 – cyanation of pyrene 232 – generation and reactions of o-benzoquinones using 239 – parallel electrode configuration 234 – parallel laminar microflow system for 238 – stack-type microreactor with interdigitated electrode 233 – without using intentionally added supporting electrolyte 235 electrochemical reactions 231 – in flow microreactors 239–241 electrode configuration – electrolysis without supporting electrolytes 234 – interdigitated 233 – parallel 233, 234 – serial 232 electrolysis – paired 234 – without supporting electrolytes 234, 235 electron-deficient substrates 251 energy conservation equation 318 enzyme immobilization on supports 80, 81 – determination of inhibitor properties 84, 85 – enzymatic cleavage of peptides 84 – enzymatic conversions 81–84 – modes of operation 81 enzymes 77 Index – enantioselectivity 89 – membrane reactor 77, 78 epoxidation 8, 263, 302 – 1-pentene to 1,2-epoxypentane 263 esterification 96, 97, 127, 312 ethyl cinnamate, reduction 254 1-ethyl-3-methylimidazolium ethyl sulfate ([EMIM]EtSO4) 281 ethyl pyridine-3-carboxylate 255 evaporation-induced self-assembly (EISA) 256, 257, 260 f field-effect transistors (FETs) 101 flow-focusing devices (FFDs) – planar MF 211 flow liquid–liquid extraction (FLLEX) module 291 flow splitters for separation – geometrical modifications 40–42 – gravity-based separator 40 – liquid–liquid two phase flow 40 – microstructured reactors, conventional separator adapted for 44, 45 – wettability-based flow splitters 40, 42–44 fluid–fluid systems 31, 32 – flow regimes 32–34 – mass transfer 34–36 fluid–solid catalytic systems 26–30 fluorescence microscopy 110 fluorescent dye, liquid carrying – dispersion of 201 fluorinated compounds 116 fluorination reactions 116–127 – alcohols and carbonyl compounds with DAST 120 – allylic alcohol 120 – ATR–FTIR for process monitoring 118 – azeotropic evaporation 124, 125 – Balz–Schiemann reaction 126 – fluoro-Ritter reaction 120 – Pd-catalyzed fluorination of aryl triflates with CsF 122 – radiosyntheses of [18F] fluoroarenes with [18F] fluoride ions 126 – Seeberger’s microreactor-based 119 – trifluoromethylation of aldehydes 121 1-fluoro-4-nitrobenzene – aromatic nucleophilic substitution of 280 fluoro-Ritter reaction 120 formic acid (FA) 301 Fourier number 305 functionalized pyridines, hydrogenation of 255 furans, anodic oxidation 234 g gas–liquid biphasic organic synthesis 141 – ozonolysis reactions 131–151 – photooxygenation reactions 151–159 gas–liquid–liquid system 40 gas–liquid microreactors 283 gas-liquid slug flow 313 gas–liquid–solid systems 36 gas-phase microreactor system 286 gas-phase reactions 306, 308 gel microcapsules 216 gel permission chromatography (GPC) 206 GEN1 reactors 133 geometric factor 41 Gibbs–Thompson effect 168 glycosylation 115 gold catalyst 245 h Hagen–Poiseuille equation 41, 201 p-halonitrobenzenes 278 hazardous compounds in microflow, handling of 283, 284 heat exchanger assembly 245 heating device, microchip 287 heat management 18, 19 heat transfer 6, 79 Heck coupling reactions 253 – aryl iodide and butyl acrylate 253 – of 4-bromoacetophenone 249 – over Pd catalysts using microwave heating 245 heterogeneous catalysis, in microreactors 243 – advantages 244 – bulk catalysts 244–246 – macroporous supports 247 – – carbon-supported catalysts 253–256 – – catalysts immobilized, onto polymeric particles 249–251 – – c-Al2O3 support 247, 248 – – silica-supported catalysts 251–253 – – ZnO support 247 – mesoporous supports 256–263 – – Ag-doped silica and titania films 257 – – evaporation-induced self-assembly (EISA) 256 j329 330 j Index –– –– –– –– mesoporous alumina 261 mesoporous silica 260, 261 mesoporous titania 258, 259 polymer-templated ordered mesoporous films (PTOMFs) 257 – – sol–gel method 256 – – surfactant removal 256 – microporous supports 261–263 – – Knoevenagel condensation 263 – – Sol–gel hydrothermal synthesis 261 – – Ti silicalite (TS-1) coatings 263 – supported catalysts 246 heterogeneous reaction systems 10 high-pressure gas–liquid microreactor systems 279 high-pressure processing, in microflow 278–280 high-temperature processing in microflow 273–278 Hildebrand solubility parameters 204 homogeneous catalysis 243 hydrogel microbeads – microfluidic encapsulation 215 hydrogenation – catalyzed 264 – citral 259 – cyclohexene 38 – functionalized pyridines 255 – 2-methyl-3-butyne-2-ol 258 – partial, ethyl pyridine-3-carboxylate 255 hydrogen peroxide (HP) 301 hydrolysis – p-nitrophenyl acetate 135 – p-nitrophenyl galactose., 95 hydrophilic dye 40,6-diamidino-2phenylindole (DAPI) 217 i immobilization, of DNA probe 112 immobilized Ru catalyst – ring-closing metathesis 252 inhibitor–agonist interaction 87 interdigitated electrode configuration – stack-type electrochemical flow microreactor 233 k KA oil 287 a-ketoamide 277 Knoevenagel condensation 1, 263 Knudsen number 308, 316 Kolbe–Schmitt reaction 275 l lab-on-a-chip systems 77, 78, 87 – for peptide analysis 85 light emitting diodes (LEDs) 68 lipase-catalyzed esterification reaction 96, 97 liquid–liquid microreactor 310 liquid–liquid separation in MSR 40 liquid-liquid slug flow 311 liquid-phase reactions 297 lithiation, of 1,2-dichloroethene, microfluidic setup 285 LowFlow reactor 133 m maleic anhydride 137 Merrifield resin 250 Merrifield’s approach 249 mES cells, co-encapsulation of 220 mesh reactor 38 mesoporous alumina 261 mesoporous coatings 257 mesoporous films 256 metal nanoparticles (NPs) 165 metal thin film microcapillary reactor – advantages for reactions, with microwave heating 277 – for microwave-assisted flow synthesis 277 methanol conversion 319 methanol oxidation (OX) channels 317 p-methoxybenzaldehyde dimethyl acetal 233 N-methoxycarbonyl pyrrolidine – anodic methoxylation of 235 methoxylation 235 p-methoxytoluene – anodic methoxylation of 239 – anodic oxidation of 233 – electrochemical reaction of 240 – methoxylation of 235 methyl 2-amino-4-bromobenzoate – continuous-flow nitration 284 methylation 127 – benzoic acid 132 2-methyl-3-butyne-2-ol – Pd25Zn75/TiO2-catalyzed hydrogenation of 258, 263 trans-methyl cinnamate 251 N-methyl-N-nitroso-p-toluene sulfonamide 129 N-methyl-N-nitrosourea 129, 133, 333 microbubble reactor 38 microchannel reactors, heat control 22–25 microchannels 78, 79, 247, 317 microchip electrophoresis 87 Index – features 87 – functional principle of 88 micro-energy and chemical systems (MECS) 166 microenzyme membrane reactor (mEMR) 89–91 microenzyme reactors 79, 80, 86 microflow – ex-regime processing and hazardous compounds handling 283, 284 – high-pressure processing in 278–280 – high-temperature processing 273–278 – new chemical transformations 284–286 – process integration 286–288 – solvent effects in 280–283 microfluidic devices 165, 166 microfluidic reactors 115 microfluidic system 4, 283 microgel-based cellular microenvironments 218 microgel diameter 216 micromembrane chromatograph (MMC) 89–91 micro-multichannel reactor 15 micro-PFR 78, 79 – vs cell 79 microreactor applications 60 – modular microreactor setup employed for 61 – Suzuki–Miyaura reaction 62–64 – thermal rearrangement of furfuryl alcohol – vitamin A acetate synthesis 60–62 microreactor-assisted nanomaterial deposition (MANDTM) 185 microreactor-assisted solution deposition (MASD) 185 microreactor channel 89 microreactors 77 See also microstructured reactors – automated operation, monitoring 66–70 – computation of reaction flows in 308–320 – conventional reactors, differences 298 – electrochemical flow 235 – endothermic and exothermic reactions 317 – gas–liquid flow 312 – online monitoring of processes 66 – processes and role of mixing 298–300 (See also microstructured reactors, modeling) – slug flow 309 – steam reforming (SR) 317 microscale saccharide analyzer 95 microstructured devices – advantages 15 – manufactures and engineering companies microstructured glass reactor 49 microstructured heat exchanger/reactor 15 microstructured mixers 49 microstructured reactors (MSRs) 1, 297 – characteristic features 13 – developement of ozonolysis reactions – experimental characterization of mixing 46–50 – gas–liquid–solid reactions 39 – historical perspectives – industrial applications 8, – numbering-up 46 microstructured reactors (MSRs), modeling 297 – laminar flow model 302–307 – phenylacetonitrile, alkylation of 320–323 – plug flow tube reactor (PFTR) model 300–302 – reaction flows, computation 308 – – computational fluid dynamics (CDF) 308 – – single-phase modeling 309, 310 – – three-phase modeling 315–320 – – two-phase modeling 310–315 – role of mixing 298–300 – special flow regimes 297 micro-total analysis systems (mTAS) 91, 92, 166 – applications 166 microwave-assisted flow synthesis 277 miniaturization 89, 124 mixing 15–18 Mizoroki–Heck alkenylations 277 MMRS See modular microreaction system (MMRS) modular microreaction system (MMRS) 57 – continuous-flow Henry reaction, monitoring 67 – designing, rules for 57 – hydrodynamic conditions 59 – low-volume connection method 69 – process applications 58 – screening tool of two-stage reaction, setup 57 – technical details 58 Moffatt–Swern oxidation 58 Mukaiyama aldol reaction 135 multicomponent polymerization reaction 225 multiphase reactions 115 multiple modular microfluidic reactors 222 j331 332 j Index multitubular millireactor (MTMR) 245 myoglobin 101 n nanomaterials synthesis, using microreactors 166 – batch hot injection methods 168 – batch synthesis of poly(lactic-co-glycolic)-bpoly(ethylene glycol) diblock 170 – capillary-based droplet microreactor, synthesis of MOF hollow microsphere 175 – chip-based micromixer, fabrication 169 – chip-based multizone microreactor for synthesis of CdSe nanocrystals 178 – Cu3(BTC)2 MOF growth mechanisms 176 – formation route for fcc, hcp, and epsilon-Co nanoparticles 183 – growth mechanism, and stability of ZnO NCs 180 – kinetic studies 180–183 – monodispersed nanocrystals, productions 168 – optical micrographs of droplet formation 175 – point-of-use synthesis and deposition 185 – – CBD 185, 186 – – CVD 185 – – MANDTM 185 – – MANpD 186 – process optimization 183, 184 – proposed TiO2 nanoparticle growth mechanisms in microreactor 177 – PVP-stabilized Au nanoclusters, within interdigital micromixer 169 – scheme of CdSe nanocrystal synthesis 175 – segmented-flow microreactor/droplet reactor, features 170, 172–174 – shape-controlled synthesis of CdS nanocrystals 167, 168 – synthesis of Ag nanoparticles 178 – synthesis of SnTe nanocrystals 179, 180 – technical challenges 168, 169 nanoscale FET biosensor 105 – change conductance of a p-type NW FET, mechanism 106 – working principle 105 106 nanotechnology 165 nanowires 104 Navier–Stokes equations 310, 312 Na2WO4 catalyst 288 Newtonian fluids 308 NIPAm polymerization 227 nitroglycerol nitroxide-mediated polymerization 207 novel process windows 273, 274 nucleic acid 78 – analysis in microchannels 91–94 nucleophilic fluorination 116 numbering-up of microstructured reactors 46 Nusselt number 5, 20 o ordered mesoporous oxide materials (OMOMs) 260 organic synthesis 116 – fluorination reactions 116–127 – reactions with diazomethane 127–134 – ultrasound-assisted liquid–liquid biphasic and liquid reactions 134–141 ozonolysis reactions – acetic 1-vinyl-hexyl ester 143 – application of microstructure 142 – b-pinene 150 – 16-channel microreactor 143 – cleavage of ozonide 143 – 1-decene 142, 143 – five-channel reactor 148 – nopinone 150 – octylamine 142 – O-cube reactor setup 149 – optimization studies 147 – preparation of vitamin D analogues – product selectivities vs 1-decene conversion in 145 – reaction mechanism for 1-acetic 1-vinyl-hexyl ester 144 – reaction scheme of 1-decene 145 – silicon–Pyrex multichannel microreactor 142 – styrene derivates 150 – thioanisole 149, 150 – triethyl phosphite 142 – vapourtec reactor module 146 p palladium acetate precursor – UV decomposition 248 palladium-catalyzed – aminocarbonylation – – 4-bromobenzonitrile 277 – – of halogenated aryl carboxylic acids 281 – carbonylative cross-coupling reactions 280 – C–F bond formation 278 – Suzuki-Miyaura cross-coupling 282 palladium leaching 249 Index palladium-mediated CÀC bond formation reactions 250 parallel laminar microflow system, for electrochemical generation 238 Parr bombs 279 partial oxidation 13 PDMS (polydimethylsiloxane) chip 124 Pd25Zn75 nanoparticles, preparation of 264 Pd25Zn75/TiO2 catalyst 258 PdZn/ZnO supported catalysts 247 Péclet number 304, 306 pelletized G-66MR catalyst 244 peptide analysis 88 b-peptide synthesis 115 phase transfer catalysis 58, 288 phenylacetonitrile, alkylation of 320–323, 322 phenyl acetylene – copper(I)-catalyzed azide-alkyne cycloaddition of 290 phenyl azide – copper(I)-catalyzed azide-alkyne cycloaddition of 290 photobioreactors 68 photochemistry 55, 67 photooxygenation reactions 151–159 – allylic alcohols 155 – artemisinin formation 158 – b-citronellol 152–154 – continuous photooxygenation of various substrates by singlet oxygen 157 – cyclopentadiene 151, 152 – in dual-channel microreactor 154 – experimental setup in scCO2, 153 – furan 157 – 2-methylfuran 157 – reactor unit used for reactions with singlet oxygen 156 – rose oxide 152 – a-terpinene 151, 153, 154, 156, 157 picolinic acid, hydrogenation of 254 Pigford model 314 pipecolic acid – picolinic acid, hydrogenation of 254 planar device microfabrication 248 plug flow reactors (PFRs) 78 plug flow tube reactor (PFTR) model 300–302 poly(butyl acrylate) synthesized, molecular weight distribution of 199 polydimethylsiloxane (PDMS) 204 polydispersity index (PDI) 198 poly[(ethylene oxide)-block-(2-hydroxypropyl methacrylate)] (PEO-block-PHPMA) 207 poly(GMA-co-EDMA) coating 251 poly(hydroxypropyl methacrylate) 208 polymerase chain reaction (PCR) 91, 92 polymer chain diffusivity 198 polymerization – adsorption 202, 203 – batch reactors 198 – control over reaction conditions 198 – demonstrated applications 214 – – cell encapsulation 217–219 – – controlled encapsulation 214, 215 – – encapsulation and delivery 215, 217 – – microgels, as model cells 219, 220 – distance-to-time transformation 200, 201 – MF polymerization reactor kinetics studies 224–227 – in microfluidic reactors 197 – – fabrication, materials selection 203–205 – microreactors 199 – – automated systems for 223, 224 – mixing, control 199–200 – multiphase 208–214 – polymer particles, formation – – coflowing streams 210 – – cross-flow breakup 210, 211 – – flow focusing 211 – – lithographic approaches 213, 214 – – precursor droplets 209–213 – – reactor material on droplets generation, surface properties 212, 213 – – typical MF droplet generators, emulsification 209, 210 – polymer particles, scaled-up MF synthesis of 220–223 – precipitation 202 – single-phase 205–208 – in situ characterization of 223 – solution viscosity, buildup 201, 202 – user safety 197 polymer-templated ordered mesoporous films (PTOMFs) 257 polysilicon wire 103 poly(tri(propylene glycol) diacrylate) particles – optical microscopy image 209 poly(N-vinylpyrrolidone) 265 positron emission tomography (PET) 124 practical considerations – control over reaction conditions 198 – potential negative impacts of polymerization reactions 201 practical exercises – alkylation of phenylacetonitrile 320–323 – Claisen rearrangement at elevated temperatures 288–290 j333 334 j Index – copper(I)-catalyzed azide-alkyne cycloaddition 290–292 – electrochemical reactions in flow microreactors 239–241 – PdZn/TiO2-catalyzed selective hydrogenation of acetylene alcohols 263–265 – experimental characterization of mixing in microstructured reactors 46–50 – functionalization of silicon surface 108–113 – lipase-catalyzed esterification reaction 96, 97 – MF polymerization reactor kinetics studies 224–227 – photochemical generation of singlet oxygen and [4ỵ2] cycloaddition to cyclopentadiene 159161 Suzuki reaction in a modular microreactor setup 70–73 – synthesis of nanocrystals 187–191 Prandtl number 21 probability density function 305 process integration involves, in microflow 286–288 propane conversions 247 propanoic acid ester – ethyl cinnamate, reduction of 254 Pt-catalyzed ammonia oxidation 302 PtRu5Sn/meso-SiO2 catalysts 260 PtSn/TiO2 catalyst 259 Purpureum cruentum 68 pyrene, cyanation of 232 q quenching 146 r radiofluorination reactions 127 Raman spectroscopy 223 Reynolds number 4, 300, 302, 304 Rh/CeO2 catalyst 304 Ruppert’s reagent (TMS-CF3) 120 – trifluoromethylation of aldehydes with 121 s saccharide analyses in microdevices 94 – applications 94–96 Saccharomyces cerevisiae 87 sample-shunting PCR (SS-PCR) 93, 94 Schmidt number 29, 304 segmented flow gas–liquid–solid reactors 38 – hydrodynamic characteristics 38 rac-sertraline imine – hydrogenation of 254 shape-controlled synthesis of CdS nanocrystals 167 Sherwood number 29 Si/Al ratio 262 sigmatropic rearrangements 274 silianization reaction 108 silica-supported catalysts 251–253 silicon nanowires (SiNWs) 101 SiNW FET sensors – APTES-modified SiNW surface 107 – fabrication 106, 107 – functionalization using APTES 107 – p-doped SiNW FET sensor, sensitivity 108, 109 – silicon functionalization 108, 109 slit plate mixer 58 smearing effect 214 sol–gel hydrothermal synthesis 261 sol–gel method 256 solid catalysts 297 solid-phase organic synthesis (SPOS) 249 solvent effects, in microflow 280–283 sonication 140 Sonogashira coupling 251 space–time yields 277 stack-type electrochemical flow microreactor 233 steam reforming (SR) 317, 318 striations 258 5-substituted 1H-tetrazoles, synthesis of 283 supercritical CO2 (scCO2) 283 surface functionalization, of silicon 112 surface tension 134 Suzuki coupling reaction 1, 62 – of 4-bromobenzonitrile 252 – flow diagram 71 – iodobenzene 249 – of iodobenzene and p-tolylboronic acid 249 – microfixed-bed flow capillary reactor 250 – in modular microreactor setup 70–72 – screening of process parameters 62–64 Suzuki-Miyaura reactions 250, 251, 253 – of p-bromoacetophenone and phenylboronic acid 253 – cross-coupling reaction 281 Swern–Moffatt-type oxidations 115 t taurine 89 Taylor dispersion 201 Taylor flow regime, in microchannels 282 Taylor whirls teflon stack microreactor 286 Index telescoping reactions 285 N,N,N ,N -tetramethylethylenediamine (TEMED) 225 1H-tetrazoles 283 thermal conductivity 3, 5, 20 thin films in photoreactor technology 55 three-phase systems 36–40 timescale of chemical and physical processes 14 Ti silicalite (TS-1) coatings on silicon substrates 263 toluene, direct fluorination 284 p-tolylboronic acid – Suzuki coupling of 249 transglycosylation – of p-nitrophenyl galactose 95 trifluoromethanesulfonic acid (TfOH) 236 triphenylphosphine 146 – two-phase flow regimes 134, 135 – ultrasonic energy introduction 136, 141 – ultrasonic treatment 134 – yield enhancement 137 UV–Vis spectroscopy 279 v vapor pressure 134 Villermaux–Dushman reaction 59 vinyl monomers, temperature-controlled free radical polymerization of 206 vinylogous carbamate – ethyl pyridine-3-carboxylate, partial hydrogenation of 255 viscosity 41, 134 volume of fluid (VOF) method 312 volumetric mass transfer coefficient 313 VOx/TiO2 catalyst 261 u w ultrasonic energy 138 ultrasonic waves 134 ultrasound-assisted liquid–liquid biphasic and liquid reactions 134 – capillary procedure, improvements 141 – clogging avoidance 138, 139 – design and evaluation, flexible experimental setup 136 – hydrolysis of p-nitrophenyl acetate 136 – monoacylation of symmetric diamines 140 – photodimerization of maleic anhydride 137, 138 – results with segmented flow in presence of PTC 136 wall-coated microreactors 244 water gas shift reaction 318 water slug 313 wettability-based separators 43 Wittig–Horner reaction 60 Wittig reaction y Y-shaped separator 43 z zeolite beta coatings 262 zeolite-coated micro-reactors 261, 262 ZSM-5 zeolite membrane 263 j335 ... 978-3-527-31080-7 Edited by Wladimir Reschetilowski Microreactors in Preparative Chemistry Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more The Editor Prof Wladimir Reschetilowski... 12.4.3.2 12.4.4 12.5 Modeling in Microreactors 297 Ekaterina S Borovinskaya Introduction 297 Processes in Microreactors and the Role of Mixing 298 Modeling of Processes in Microreactors Based on... tr ¼ kcmÀ1 1;0 ðmth -order reactionÞ; ð2:1Þ Microreactors in Preparative Chemistry: Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more, First Edition Edited by Wladimir Reschetilowski