Microreactors in organic chemistry and catalysis, second edition

Preface to the First Edition XIII Preface to the Second Edition XV List of Contributors XVII 1 Properties and Use of Microreactors 1 David Barrow, Shan Taylor, Alex Morgan, and Lily Gile

Organic Chemistry and Catalysis

Related Titles

Reschetilowski, W (ed.)

Microreactors in Preparative Chemistry

Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more

Zecchina, A., Bordiga, S., Groppo, E (eds.)

Selective Nanocatalysts and Nanoscience

Concepts for Heterogeneous and Homogeneous Catalysis

Edited by Thomas Wirth

Microreactors in Organic Chemistry and Catalysis

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Preface to the First Edition XIII

Preface to the Second Edition XV

List of Contributors XVII

1 Properties and Use of Microreactors 1

David Barrow, Shan Taylor, Alex Morgan, and Lily Giles

1.2.2 Constructional Materials and Their Properties 10

1.3 Fluid Flow and Delivery Regimes 16

1.5.1.1 Fast and Exothermic Reactions 24

1.5.2 Precision Particle Manufacture 25

1.5.3 Wider Industrial Context 27

2.4 Generative Method: Selective Laser Melting 41

2.5 Metal Forming Techniques 42

2.6 Assembling and Bonding of Metal Microstructures 432.7 Ceramic Devices 46

2.8 Joining and Sealing 48

3.2 The Structuring of Glass and Silicon 58

3.2.1 Structuring by Means of Masked Etching As in

3.3.1.1 Isotropic Wet Chemical Etching of Silicon 64

3.3.1.2 Isotropic Wet Chemical Etching of Silicon Glass 653.3.2 Other Processes 66

3.3.2.1 Photostructuring of Special Glass 66

3.3.3 Drilling, Diamond Lapping, Ultrasonic Lapping 683.3.4 Micro Powder Blasting 69

3.6.1 Anodic Bonding of Glass and Silicon 73

3.6.2 Glass Fusion Bonding 73

3.6.3 Silicon Direct Bonding (Silicon Fusion Bonding) 743.6.4 Establishing Fluid Contact 76

3.7 Other Materials 78

References 79

4 Automation in Microreactor Systems 81

Jason S Moore and Klavs F Jensen

Paul Watts and Charlotte Wiles

6.1 Photochemistry in Flow Reactors 133

7.1 Arrangement of Reactors in Flow Synthesis 152

7.2 Immobilization of the Reagent/Catalyst 155

7.2.1 A Packed-Bed Reactor 155

7.2.2 Monolith Reactors 156

7.2.3 Miscellaneous 157

7.3 Flow Reactions with an Immobilized Stoichiometric Reagent 159

7.4 Flow Synthesis with Immobilized Catalysts: Solid Acid Catalysts 1657.5 Flow Reaction with an Immobilized Catalyst: Transition Metal Catalysts

Dispersed on Polymer 166

7.5.1 Catalytic Hydrogenation 167

7.5.2 Catalytic Cross-Coupling Reactions and Carbonylation Reactions 1717.5.3 Miscellaneous 175

7.6 Flow Reaction with an Immobilized Catalyst: Metal Catalysts

Coordinated by a Polymer-Supported Ligand 176

7.6.1 Flow Reactions Using Immobilized Ligands with a Transition

Metal Catalyst 179

7.7 Organocatalysis in Flow Reactions 183

7.8 Flow Biotransformation Reactions Catalyzed by Immobilized

Enzymes 186

7.9 Multistep Synthesis 187

7.10 Conclusion 191

References 191

8 Liquid–Liquid Biphasic Reactions 197

Matthew J Hutchings, Batool Ahmed-Omer, and Thomas Wirth8.1 Introduction 197

8.3 Kinetics of Biphasic Systems 199

8.4 Biphasic Flow in Microchannels 200

8.5 Surface and Liquid–Liquid Interaction 202

8.6 Liquid–Liquid Microsystems in Organic Synthesis 2078.7 Micromixer 209

8.8 Conclusions and Outlook 218

References 218

9 Gas–Liquid Reactions 221

Ivana Dencic and Volker Hessel

9.1 Introduction 221

9.2 Contacting Principles and Microreactors 222

9.2.1 Contacting with Continuous Phases 222

9.2.1.1 Falling Film Microreactor 222

9.2.1.2 Continuous Contactor with Partly Overlapping Channels 2269.2.1.3 Mesh Microcontactor 227

9.2.2.5 Tube in Tube Microreactor 243

9.2.3 Scaling Up of Microreactor Devices 244

9.3 Gas–Liquid Reactions 245

9.3.1 Direct Fluorination of Aromatics 246

9.3.1.1 Direct Fluorination of Aromatics 246

9.3.1.2 Direct Fluorination of Aliphatics and Non-C-Moieties 2499.3.1.3 Direct Fluorination of Heterocyclic Aromatics 251

9.3.2 Oxidations of Alcohols, Diols, and Ketones with Fluorine 2539.3.3 Photochlorination of Aromatic Isocyanates 254

9.3.4 Photoradical Chlorination of Cycloalkenes 255

9.3.5 Mono-Chlorination of Acetic Acid 256

9.4.1 Hydrogenations 266

9.4.1.1 Cyclohexene Hydrogenation over Pt/Al2O3 266

9.4.1.2 Hydrogenation of p-Nitrotoluene and Nitrobenzene over

Pd/C and Pd/Al2O3 267

9.4.1.3 Hydrogenation of Azide 270

9.4.1.4 Hydrogenation of Pharmaceutical Intermediates 270

9.4.1.5 Selective Hydrogenation of Acetylene Alcohols 271

9.4.1.6 Hydrogenation ofa-Methylstyrene over Pd/C 272

9.4.2 Oxidations 273

9.4.2.1 Oxidation of Alcohols 275

9.4.2.2 Oxidation of Sugars 275

9.5 Homogeneously Catalyzed Gas–Liquid Reactions 276

9.5.1 Asymmetric Hydrogenation of Cinnamic Acid Derivatives 276

9.5.2 Asymmetric Hydrogenation of Methylacetamidocynamate 278

10 Bioorganic and Biocatalytic Reactions 289

Masaya Miyazaki, Maria Portia Briones-Nagata, Takeshi Honda, and

Hiroshi Yamaguchi

10.1 General Introduction 289

10.2 Bioorganic Syntheses Performed in Microreactors 292

10.2.1 Biomolecular Syntheses in Microreactors: Peptide, Sugar and

Oligosaccharide, and Oligonucleotide 292

10.2.1.1 Peptide Synthesis 292

10.2.1.2 Sugar and Oligosaccharide Synthesis 296

10.2.1.3 Oligonucleotide Synthesis 302

10.3 Biocatalysis by Enzymatic Microreactors 304

10.3.1 Classification of Enzymatic Microreactors Based on

Application 304

10.3.1.1 Applications of Microreactors for Enzymatic Diagnostics

and Genetic Analysis 304

10.3.1.2 Application of Microreactors for Enzyme-Linked

Immunoassays 308

10.3.1.3 Applications of Microfluidic Enzymatic Microreactors

in Proteomics 312

10.3.2 Enzymatic Microreactors for Biocatalysis 347

10.3.3 Advantages of Microreactors in Biocatalysis 347

10.3.4 Biocatalytic Transformations in Microfluidic Systems 348

10.3.4.1 Solution-phase Enzymatic Reactions 348

10.3.4.2 Microfluidic Reactors with Immobilized Enzymes for

Biocatalytic Transformations 357

10.4 Multienzyme Catalysis in Microreactors 362

10.5 Conclusions 365

References 366

11 Industrial Microreactor Process Development up to Production 373

Ivana Dencic and Volker Hessel

11.1 Mission Statement from Industry on Impact and Hurdles 37311.2 Screening Studies in Laboratory 375

11.2.9 Multistep Synthesis of a Radiolabeled Imaging Probe 384

11.3 Process Development at Laboratory Scale 386

11.3.1 Nitration of Substituted Benzene Derivatives 386

11.3.2 Microflow Azide Syntheses 387

11.3.3 Vitamin Precursor Synthesis 389

11.3.4 Ester Hydrolysis to Produce an Alcohol 391

11.3.5 Synthesis of Methylenecyclopentane 391

11.3.6 Condensation of 2-Trimethylsilylethanol 391

11.3.7 Staudinger Hydration 392

11.3.8 (S)-2-Acetyl Tetrahydrofuran Synthesis 392

11.3.9 Synthesis of Intermediate for Quinolone Antibiotic Drug 39311.3.10 Domino Cycloadditions in Parallel Fashion 394

11.3.11 Phase-Transfer Catalysis-Mediated Knoevenagel Condensation 39611.3.12 Ciprofloxazin1Multistep Synthesis 396

11.3.13 Methyl Carbamate Synthesis 397

11.3.14 Newman–Kuart Rearrangement 398

11.3.15 Ring-Expansion Reaction ofN-Boc-4-Piperidone 399

11.3.16 Synthesis of Aldehydes 400

11.3.17 Grignard Reactions and Li–Organic Reactions 402

11.3.18 Continuous Synthesis of Disubstituted Triazoles 404

11.3.19 Production of 6-Hydroxybuspirone 405

11.3.20 Swern–Moffatt Oxidation 406

11.4 Pilot Plants and Production 408

11.4.1 Hydrogen Peroxide Synthesis 408

11.4.2 Phenylboronic Acid Synthesis 410

11.4.3 Diverse Case Studies at Lonza 411

11.4.4 Alkylation Reactions Based on Butyllithium 414

11.4.5 Microprocess Technology in Japan 416

11.4.6 Pilot Plant for Methyl Methacrylate Manufacture 417

Xj Contents

11.4.7 Grignard Exchange Reaction 417

11.4.8 Halogen–Lithium Exchange Pilot Plant 419

11.4.9 Swern–Moffatt Oxidation Pilot Plant 420

11.4.10 Yellow Nano Pigment Plant 422

11.4.11 Polycondensation 423

11.4.12 H2O2-Based Oxidation to 2-Methyl-1,4-naphthoquinone 424

11.4.13 Friedel–Crafts Alkylation 425

11.4.14 Diverse Studies from Japanese Project Cluster 426

11.4.14.1 Synthesis of Photochromic Diarylethenes 426

11.4.14.2 Cross-Coupling in a Flow Microreactor 427

11.4.15 Direct Fluorination of Ethyl 3-Oxobutanoate 428

11.4.16 Deoxofluorination of a Steroid 429

11.4.17 Microprocess Technology in the United States 430

11.4.18 Propene Oxide Formation 432

11.4.19 Diverse Industrial Pilot-Oriented Involvements 433

11.4.20 Production of Polymer Intermediates 435

11.4.21 Synthesis of Diazo Pigments 436

11.4.22 Selective Nitration for Pharmaceutical Production 438

11.4.23 Nitroglycerine Production 439

11.4.24 Fine Chemical Production Process 440

11.4.25 Grignard-Based Enolate Formation 441

11.5 Challenges and Concerns 442

References 444

Index 447

Preface to the First Edition

Microreactor technology is no longer in its infancy and its applications in many areas

of science are emerging This technology offers advantages to classical approaches

by allowing miniaturization of structural features up to the micrometer regime Thisbook compiles the state of the art in organic synthesis and catalysis performed withmicroreactor technology The term“microreactor” has been used in various contexts

to describe different equipment, and some examples in this book might not justifythis term at all But most of the reactions and transformations highlighted in thisbook strongly benefit from the physical properties of microreactors, such asenhanced mass and heat transfer, because of a very large surface-to-volume ratio

as well as regularflow profiles leading to improved yields with increased ties Strict control over thermal or concentration gradients within the microreactorallows new methods to provide efficient chemical transformations with high space–time yields The mixing of substrates and reagents can be performed under highlycontrolled conditions leading to improved protocols The generation of hazardousintermediatesin situ is safe as only small amounts are generated and directly react in

selectivi-a closed system First reports thselectivi-at show the integrselectivi-ation of selectivi-appropriselectivi-ate selectivi-anselectivi-alyticselectivi-aldevices on the microreactor have appeared, which allow a rapid feedback foroptimization

Therefore, the current needs of organic chemistry can be addressed much moreefficiently by providing new protocols for rapid reactions and, hence, fast access tonovel compounds Microreactor technology seems to provide an additional platformfor efficient organic synthesis – but not all reactions benefit from this technology.Established chemistry in traditionalflasks and vessels has other advantages, andmost reactions involving solids are generally difficult to be handled in microreactors,though even the synthesis of solids has been described using microstructureddevices

In thefirst two chapters, the fabrication of microreactors useful for chemicalsynthesis is described and opportunities as well as problems arising from themanufacture process for chemical synthesis are highlighted Chapter 1 deals withthe fabrication of metal- and ceramic-based microdevices, and Brandner describesdifferent techniques for their fabrication In Chapter 2, Frank highlights themicroreactors made from glass and silicon These materials are more known tothe organic chemists and have therefore been employed frequently in different

jXIII

laboratories In Chapter 3, Barrow summarizes the use and properties of reactors and also takes a wider view of what microreactors are and what their currentand future uses can be.

micro-The remaining chapters in this book deal with different aspects of organic synthesisand catalysis using the microreactor technology A large number of homogeneousreactions performed in microreactors have been sorted and structured by Ryuet al inChapter 4.1, starting with very traditional, acid- and base-promoted reactions They arefollowed by metal-catalyzed processes and photochemical transformations, whichseem to be particularly well suited for microreactor applications Heterogeneousreactions and the advantage of consecutive processes using reagents and catalysts onsolid support are compiled by Leyet al in Chapter 4.2 Flow chemistry is especiallyadvantageous for such reactions, but certain limitations to supported reagents andcatalysts still exist Recent advances in stereoselective transformations and in multi-step syntheses are explained in detail Other biphasic reactions are dealt with in thefollowing two chapters In Chapter 4.3, we focus on liquid–liquid biphasic reactionsand focus on the advantages that microreactors can offer for intense mixing ofimmiscible liquids Organic reactions performed under liquid–liquid biphasicreaction conditions can be accelerated in microreactors, which is demonstrated usingselected examples The larger area of gas–liquid biphasic reactions is dealt with byHesselet al in Chapter 4.4 After introducing different contacting principles undercontinuousflow conditions, various examples show clearly the prospects of employingmicroreactors for such reactions Aggressive and dangerous gases such as elementalfluorine can be handled and reacted safely in microreactors The emergence of thebioorganic reactions is described by vanHestet al in Chapter 4.5 Several of thereactions explained in this chapter are targeted toward diagnostic applications.Although on-chip analysis of biologic material is an important area, the results ofinitial research showing biocatalysis can also now be used efficiently in microreactorsare summarized in this chapter In Chapter 5, Hesselet al explain that microreactortechnology is already being used in the industry for the continuous production ofchemicals on various scales Although only few achievements have been published byindustry, the insights of the authors into this area allowed a very good overview oncurrent developments Owing to the relatively easy numbering up of microreactordevices, the process development can be performed at the laboratory scale withoutmajor changes for larger production Impressive examples of current productionprocesses are given, and a rapid development in this area is expected over the nextyears I am very grateful to all authors for their contributions and I hope that thiscompilation of organic chemistry and catalysis in microreactors will lead to new ideasand research efforts in thisfield

August 2007

Preface to the Second Edition

The continued and increased research efforts in microreactor andflow chemistryhave led to an impressive increase in publications in recent years and even to atranslation of thefirst edition of this book into Chinese This is reflected not only in

an update and expansion of all chapters of thefirst edition but also in the addition ofseveral new chapters to this second edition

In the first three chapters, Barrow, Brandner, and Frank, respectively, describeproperties and fabrication methods of microreactors In Chapter 4, Moore and Jensengive detailed insights into current methods of online and offline analyses, the potential

of rapid optimization of reactions usingflow technology, and the combination ofanalysis and optimization For better readability, the material on organic synthesis hasbeen split into five different chapters Ryu et al have extended their chapter onhomogeneous reactions in microreactors, while Watts and Wiles have elaborated thetopics of photochemistry, electrochemistry, and radiopharmaceutical synthesis in anew chapter as reactions in these areas are very suitable for being carried out usingflow chemistry devices and many publications have recently appeared

Takasu has written a comprehensive chapter on heterogeneous reactions inmicroreactors and a many different reactions can be found in this part We haveupdated our chapter on liquid–liquid biphasic reactions and Hessel et al haveprovided an update on the gas–liquid biphasic reactions The chapter on bioorganicand biocatalytic reactions by Miyazaki et al is a comprehensive overview of thedevelopments in this area and highlights the advantages thatflow chemistry canoffer for research in bioorganic chemistry

Thefinal chapter by Hessel et al on industrial microreactor process development

up to production has seen a dramatic increase as in many areas industry is nowadopting flow chemistry with all its advantages for research and for small- tomedium-scale production

I am again very grateful to all authors for providing updates or completely newcontributions and I hope that this compilation of chemistry and catalysis inmicroreactors will stimulate new ideas and research efforts

January 2013

jXV

Cardiff School of Engineering

Laboratory for Applied Microsystems

Cardiff CF24 3TF

UK

Juergen J Brandner

Karlsruhe Institute of Technology

Institute for Micro Process

Maria Portia Briones-Nagata

Measurement Solution Research

Center

National Institute of Advanced

Industrial Science and Technology

807-1 Shuku, Tosu

Saga 841-0052

Japan

Ivana DencicEindhoven University of TechnologyDepartment of Chemical

Engineering and ChemistryLaboratory for Micro-Flow Chemistryand Process Technology

STW 1.37

5600 MB, EindhovenThe NetherlandsThomas FrankPorzellanstr 16

98693 IlmenauGermanyTakahide FukuyamaOsaka Prefecture UniversityGraduate School of ScienceDepartment of ChemistrySakai

Osaka 599-8531Japan

Lily GilesCardiff UniversityCardiff School of EngineeringLaboratory for Applied MicrosystemsCardiff CF24 3TF

UK

Volker Hessel

Eindhoven University of Technology

Department of Chemical

Engineering and Chemistry

Laboratory for Micro-Flow Chemistry

and Process Technology

National Institute of Advanced

Industrial Science and Technology

National Institute of Advanced

Industrial Science and Technology

807-1 Shuku, Tosu

Saga 841-0052

Japan

Jason S MooreMassachusetts Institute ofTechnology

Department of ChemicalEngineering

Room 66-566

77 Massachusetts AvenueCambridge

MA 02139USAAlex MorganCardiff UniversityCardiff School of EngineeringLaboratory for Applied MicrosystemsCardiff CF24 3TF

UK

Md Taifur RahmanOsaka Prefecture UniversityGraduate School of ScienceDepartment of ChemistrySakai

Osaka 599-8531Japan

andSchool of Chemistry and ChemicalEngineering

David Keir BuildingQueen’s UniversityBelfast BT9 5AGNorthern IrelandUK

Ilhyong RyuOsaka Prefecture UniversityGraduate School of ScienceDepartment of ChemistrySakai

Osaka 599-8531Japan

XVIIIjList of Contributors

Cardiff School of Engineering

Laboratory for Applied Microsystems

6163 JT GeleenThe NetherlandsThomas WirthCardiff UniversitySchool of ChemistryMain BuildingPark PlaceCardiff CF10 3ATUK

Hiroshi YamaguchiMeasurement Solution ResearchCenter

National Institute of AdvancedIndustrial Science and Technology807-1 Shuku, Tosu

Saga 841-0052Japan

Properties and Use of Microreactors

David Barrow, Shan Taylor, Alex Morgan, and Lily Giles

1.1

Introduction

Microreactors are devices that incorporate at least one three-dimensional duct, withone or more lateral dimensions of<1 mm (typically a few hundred micrometers indiameter), in which chemical reactions take place, usually under liquid-flowingconditions [1] Such ducts are frequently referred to as microchannels, usuallytransporting liquids, vapors, and/or gases, sometimes with suspensions of particu-late matter, such as catalysts (Figure 1.1) [2] Often, microreactors are constructed asplanar devices, often employing fabrication processes similar to those used inmanufacturing of microelectronic and micromechanical chips, with ducts orchannels machined into a planar surface (Figure 1.2c and d) [3] The volume outputper unit time from a single microreactor element (Figure 1.2b, c, d and e) is small,but industrial rates can be realized by having many microreactors working in parallel(Figure 1.2f)

However, microreactor research can be conducted on simple microbore tubingfabricated from stainless steel (Figure 1.2a), polytetrafluoroethylene (PTFE), or anymaterial compatible with the chemical processing conditions employed [4] Forinstance, inexpensivefluoroelastomeric tubing was employed to prepare a packed-bed microreactor for the catalysis of oxidized primary and secondary alcohols [5] Assuch, microreactor technology is related to the much widerfield of microfluidics,which involves an extended set of microdevices and device integration strategies forfluid and particle manipulation [6]

1.1.1

A Brief History of Microreactors

In 1883, Reynolds’ study on fluid flow was published in the Philosophical Transactions

of the Royal Society [7] Reynolds used streams of colored water in glass piping tovisually observe fluid flow over a range of parameters The apparatus used isdepicted in a drawing by Reynolds himself (Figure 1.3), which showsflared glassMicroreactors in Organic Chemistry and Catalysis, Second Edition Edited by Thomas Wirth.

#

j1

tubing within a water-filled tank Using this setup, he discovered that varyingvelocities, diameters of the piping, and temperatures led to transitions between

“streamline” and “sinuous” flow (respectively known as laminar and turbulent flowtoday) This paper was a landmark, which demonstrated practical and philosophicalaspects offluid mechanics that are still endorsed and used in many fields of scienceand engineering today, including microreactor technology [8]

An early example for the use of a microreactor was demonstrated in 1977 by theinventor Bollet, working for Elf Union (now part of Total) [9] The invention involvedmixing of two liquids in a micromachined device In 1989, a microreactor that aimed

at reducing the cost of large heat release reactions was designed by Schmidand Caesar working for Messerschmitt–B€olkow–Blohm GmbH Subsequently, anapplication for patent was made by the company in 1991 [10] In 1993, Benson andPonson published their important paper on how miniature chemical processingplants could redistribute and decentralize production to customer locations [11].Later, in 1996, Alan Bardfiled a US patent (priority 1994) where it is taught how anintegrated chemical synthesizer could be constructed from a number of microliter-capacity microreactor modules, most preferably in a chip-like format, which can beused together, or interchangeably, on a motherboard (like electronic chips), and basedupon thermal, electrochemical, photochemical, and pressurized principles [12]

Figure 1.1 Detailed example of a simple

duct-based microreactor fabricated from

polytetrafluoroethylene (with perfluoralkoxy

capping layer) Reagents 1 and 2 interact by

diffusive mixing within the reaction coil The

reaction product becomes the continuous

phase for an immiscible discontinuous phase,

which initially forms elongate slugs When subject to a capillary dimensional expansion, slugs become spheres, which are then coated with a reagent (that is miscible with the continuous phase) fed through numerous narrow, high aspect ratio ducts made with a femtosecond laser.

Figure 1.3 The original apparatus used by

Osborne Reynolds to study the motion of water

[7] The apparatus consisted of a tank filled with

water and glass tubing within Colored water was injected through the glass tubing, so the characteristics of fluid flow could be observed.

Figure 1.2 Examples of modern-day microreactors and other microfluidic components (a) Source: Reprinted with permission from Takeshi et al (2006) Org Process Res Dev., 10,

1126 –1131 Copyright (2006) American Chemical Society.

1.1 Introductionj3

Following this, a pioneering experiment conducted by Salimi-Moosavi and colleagues(1997) introduced one of thefirst examples of electrically driven solvent flow in amicroreactor used for organic synthesis An electro-osmotic-controlledflow was used

to regulate mixing of reagents,p-nitrobenzenediazonium tetrafluoroborate (AZO)andN,N-di-methylaniline, to produce a red dye [13] One of the first microreactor-based manufacturing systems was designed and commissioned by CPC in 2001for Clariant [14]

Microreactor systems have since evolved from basic, single-step chemicalreactions to more complicated multistep processes Belderet al (2006) claim

to have made the first example of a microreactor that integrated synthesis,separation, and analysis on a single device [15] The microfluidic chip fabricatedfrom fused silica (as seen in Figure 1.4) was used to apply microchip electro-phoresis to test the enantioselective biocatalysts that were created The authorsreported a separation of enantiomers within 90 s, highlighting the high through-put of such devices

Early patents in microreactor engineering have been extensively reviewed byHesselet al (2008) [16] and then later by Kumar et al (2011) [17] From 1999 to 2009,the number of research articles published on microreactor technology rose from 61

to 325 per annum (Figure 1.5a) [17] The United States of America produced themajority of research articles, followed by the People’s Republic of China andGermany (Figure 1.5c) [17] The number of patent publications produced wasalso highest in the United States of America; the data are given in Figure 1.5b[17] The number of patent publications is highest in the field of inorganicchemistry, but of particular interest, organic chemistry comes second out 18fields of chemical applications investigated [16]

Figure 1.4 Fused silica microfluidic chip compared to the size of a D2 coin The chip was the first example of synthesis, separation and analysis combined on a single device Source: Photograph courtesy of Professor D Belder with permission.

Microreactor technology has been widely employed in academia and is alsobeginning to be used in industry where clear benefits arise and are worthy ofnewfinancial investment Companies contributing considerably to the development

of microreactors include Merck Patent GmbH, Battelle Memorial Institute, VelocysInc., Forschungszentrum Karlsruhe, The Institute for Microtechnology Mainz,Chemical Process Systems, Little Things Factory GmbH, Syrris Ltd, Ehrfeld

Figure 1.5 (a) The number of research articles

published on microreactors from the years 1999

to 2009 (b) Distribution of patent publications

produced from 10 different countries.

(EP: European; US: United States;

DE: Germany; JP: Japan; GB: United Kingdom;

FR: France; NL: Netherlands; CH: Switzerland; SE: Sweden) (c) Distribution of published research articles from various countries Source: Images reprinted from Ref [17], with

permission from Elsevier.

1.1 Introductionj5

Mikrotechnik BTC, Micronit BV, Mikroglas chemtech GmbH, Chemtrix BV,Vapourtec Ltd, Microreactor Technologies Inc., Xytel Corporation, and more [16,18].

To place microreactors clearly within an historical context, we can relate theemergence of such devices to their nearest neighbors, these being from the widerfield of microfluidics, which includes the flow of gases With respect to this, we cansee that some of the earliest examples of microfluidic devices go back at least to 1970,when James Lovelock filed patent US3,701,632 describing a planar chip-basedchromatograph fabricated from wet-etched magnesium oxide (Figure 1.6).1.1.2

Advantages of Microreactors

Flow chemistry is long established for manufacturing large quantities of materials[19] However, this can sometimes be time consuming and expensive due to theamount of materials used Also, scaling up a small process to a much largerindustrial sized application can be challenging and often results in batch processing.This type of processing can lead to variances between each batch, ultimately yieldinginconclusive and unreproducible results [19] In contrast, the use of microreactorsenables chemical reactions to be run continuously [20], usually in aflowing stream,and from this the topic of microprocess chemistry was born [21] Microreactors aretherefore seen as the modern-day chemists’ round-bottom flask [19] and can

Figure 1.6 Image of a planar chip

chromatograph, microfabricated from wet

etched magnesium oxide, described in US

patent 3,701,632 filed in 1970 by James

Lovelock Image is a screen capture from a

movie of Dennis Desty talking about innovations in chromatography Source: Courtesy, Prof Peter Myers, Liverpool University UK.

potentially revolutionize the practice of chemical synthesis [4] For instance, usingmicroscale reactors, reactions can be carried out under isothermal conditions withwell-defined residence times, so that undesirable side reactions and productdegradation are limited The distinctivefluid-flow and thermal and chemical kineticbehavior observed in microreactors, as well as their size and energy characteristics,lend their use to diverse applications [22,23] including:

 high-purity chemical products [24],

 highly exothermic reactions [25,26],

 screening for potential catalysts [27,28],

 precision particle manufacture [29],

 high-throughput material synthesis [30],

 emulsification and microencapsulation [31],

 fuel cell construction [32],

 point-of-use, miniature, and portable microplants [33]

These new application horizons are enabled by the following advantages: (i)reduced size through microfabrication, (ii) reduced diffusion distances, (iii)enhanced rates of thermal and mass transfer and subsequent processing yields[34,35], (iv) reduced reaction volumes, (v) controlled sealed systems avoidingcontamination, (vi) use of solvents at elevated pressures and temperatures, (vii)reduced chemical consumption, (viii) facility for continuous synthesis [36], and (ix)increased atom efficiency [37] Microreactor research and development has beenparticularly promoted for high-throughput synthesis in the pharmaceutical industry,where large numbers of potential pharmaceutically beneficial compounds need to

be generated, initially, in small quantities, as a component of the drug discoveryprocess [38] In this chapter, the key functional properties of microreactors arereviewed in the context of use in diversefields

as microwells have been fabricated in an analogous format to traditional titer plates, rendering potential compatibility with existing robotic handling

micro-1.2 Physical Characteristics of Microreactorsj7

systems as used in many high-throughput screening laboratories Extending thenotion of a microreactor, an increasing number of studies are demonstratinghow separated droplets may act as nanoscale-based reactors [39] For instance,the use of solvent droplets resulting from controlled segmentedflow has beenproposed as individual nanoliter reactors for organic synthesis [40–42] Similarly,reverse micellar structures have been shown to provide reactors for the controlledsynthesis of nanometer-scale particulates [43,44] Also, giant phospholipid lipo-somes (10 mm diameter) have been utilized as miniature containers of reagentsand can be manipulated by various external mechanisms, such as optical,electrical, and mechanical displacement and fusion [45] Liposome-based micro-reactors, manipulated in this manner, hold the potential to enable highlycontrolled and multiplexed microreactions in a very small scale [46].

2) Architecture: Geometries employed in microreactor design and fabrication mayrange from simple tubular structures, where perhaps two reagents are intro-duced to form a product, to more sophisticated multicomponent circuits, whereseveral functionalities may be performed, including reagent injection(s), mixing,incubation, quench addition, solvent exchange, crystallization, thermal manage-ment, extraction, encapsulation, or phase separation

3) Multiplicity: Microreactors may comprise single-element structures from whichsmall quantities of reaction products may be obtained, or, massively parallelstructures where output on an industrial scale can be realized Examples ofnumbering-up of microreactors are shown in Figure 1.7 In Figure 1.7a, 10 glassmicroreactors are placed on top of each other to form one single, multileveleddevice [47] The microchannels were produced by photolithography and wet

Figure 1.7 Examples of multiple microreactors used in parallel for higher throughput and yield of products [47,48] Source: Figures reprinted with permission, copyright (2010), American Chemical Society.

etching, and each glass reactor was thermally bonded together The microreactorswere used for the production of amides, and using this numbering-up technique,the authors found a 10 times higher throughput yielding product on the scale ofgrams per hour [47] Figure 1.7b shows another example of paralleled micro-reactors, named the Cambridge Disc Microreactor systems [48] Ten capillaries of200mm in diameter and 30 m in length were lined up and embedded in a polymerfilm and then wound into a disc-shaped device This system can be used to performorganic synthesis reactions at temperatures up to 150C [48].

The principle of numbering-up has been used on an industrial scale for nitrationreactions performed under current good manufacturing practice (cGMP) [49].Historically, in 2001, CPC built and commissioned one of thefirst microreactor-based micromanufacturing plants, which incorporated many parallel microreactors.This was for the manufacture of diazo pigments for the company Clariant Thethree-step manufacturing process, which involved (i) diazotation, (ii) coupling, and(iii) pigmenting (conditioning), was found to improve the product quality throughimproved particle size distribution and dye properties of the diazo pigments Theso-called CYTOS Pilot System used multiples of individual microreactors, so thatproducts developed as small quantities on a laboratory scale could be produced inbulk at a manufacturing level without changing the essential chemical processingconditions The scale of such a system is shown in Figure 1.8

Figure 1.8 Parallel microreactor system (the so-called CYTOS Pilot System) designed and

commissioned by CPC for Clariant in 2001, for the manufacturing of diazo pigments.

Source: Reprinted from Ref [50], Copyright (2007), with permission from Elsevier.

1.2 Physical Characteristics of Microreactorsj9

The engineering of numbering-up solutions for processes involving reactionswith heat/mass transfer usually requires a distribution system from a commonreactant source through many reaction microchannels to a common product outletsuch that the same residence time is experienced in all the reaction microchannels.From an analytical comparison of bifurcating and consecutive source/outlet mani-fold structures, as resistance networks, design guidelines have been derived, whichconsider manufacturing variations in microchannel geometry, microchannel aspectratio, and microchannel blockages incurred during function [51,52] From this, ithas been shown that a distribution system of bifurcating ducts always producesflowequipartition as long as the length of the straight channel after each channel bend issufficient for a symmetrical velocity profile to develop Nevertheless, it is clearlyimportant to be able to detect blockages within channels, but placing sensors inevery channel is not economically feasible However, one scheme has shown that bycareful consideration of circuit design, blockages in any one of a number ofparallelized microreactors can be detected with just two in-lineflow sensors [53].

A long-standing issue in the development of process chemistries is that a reactionscheme developed in a small bench topflask may not scale-up with the same outputparameters when transferred to an industrial production reactor Instead, this problem

is potentially circumvented by arithmetically numbering-up, in parallel operation, themultiplicity of the same microreactors to achieve the target output [1] However, thisengineering challenge is not trivial, since many parallel reactors may be required toachieve significantvolumeoutputs.Pioneeringexamplesofthoseindustrialprocesses,which have been successfully achieved using microreactor technology, are described inChapter 5 Those, which have shown commercial success, appear to represent mostlyhigh-value, relatively low-volume products, products that are particularly dangerous tomanufacture, entirely new class of products, and/or those that have a short shelf life.1.2.2

Constructional Materials and Their Properties

Microfluidic devices, which may be suitable for chemical synthesis according to theprocessing conditions, have been fabricated from a range of materials includingglass [54], elastomers [55], silicon [56], quartz,flouropolymers [57], metals [58], andceramics [59] employing the techniques of laser ablation [60], wet chemical etching[61], abrasive micromachining [61], deep reactive ion etching [62], molding [63],embossing [64,65], casting [66], and milling [67]

Advanced microreactors for manufacturing-level chemical production placedemanding requirements on their integrated functionality and durability Forinstance, thermal tolerance to processing conditions, temporal stability of surfaceenergy, surface chemistry, and activity of incorporated catalysts and compatibilitywith sterilization protocol are important considerations when choosing a construc-tional material Materials are also required to [68]

 be chemically inert,

 have appropriate thermal and electrical properties,

 be compatible with solvents and acids used,

 have some degree of light transparency if on-chip analysis is required,

 be compatible with fabrication protocol employed,

 be usable for extended processing durations

These are further complicated by application- and process-specific requirements.For example, the excitation and control of reactions may require temporal and spatialmodulation of applied energies such as UV, IR, and microwave radiation All theseconsiderations place exacting specifications on the constructional materials in orderthat the required geometries may be fabricated in a manner that is cost-effectivelycompatible with envisaged manufacturing-level scenarios Where massively parallelmicroreactor systems are required for volume outputs, constructional materialsmust be appropriate to the economies and micromanufacturing processes of mass-fabricated parts Equally, levels of specific functional integration must be equatedwith the overall system-level integration strategy and range from monolithic tohybrid solutions Most preferably, this is more of a long-term goal, reconfigurable oraddressable component functions will allow for the creation of application-specificmicroreactor ensembles from a“programmable” platform technology

Table 1.1 gives a brief overview of the different materials, advantages and advantages, fabrication techniques, and applications in microreactor technology.Glass and silicon have been used extensively in earlier microreactors and are slowlybeing supplemented by inexpensive and easy-to-fabricate polymers such as polydi-methylsiloxane (PDMS), at least in academic research laboratories [69] Many copies

dis-of a PDMS microfluidic circuit can be molded from a master made from, forexample, silicon [70] However, there are limitations in its use, and formicroreactors, it is generally the swelling of the PDMS in a solvent, whichfirst limitsits application [71] Glass is still the material of choice for many synthetic applicationsdue to its characteristics described in Table 1.1 [68,72] However, due to its lowthermal conductivity, glass is not quite as suitable for high-temperature and high-pressure reactions Stainless steel, silicon, and ceramics are the alternative materialsthat can be used for these specific reactions [68] More details on particular importantaspects are described in Chapters 2–4 and in the given references

While basic microreactors and arrays may be fabricated from glass, polymers,metals, or ceramics, advanced microreactors with multifunctional and reconfigur-able capability will require construction from a diverse and integrated materials set

As example, focused microwave excitation delivered at multiple resonator nodeswithin afluidic microreactor array will require constructional materials and associ-ated machining processes suitable for both reaction chemistry and the spatialdistribution of microwave energy For this, a set of glass, polymers, and metalsare required each of which might be separately microstructured using one or moretechniques of subtractive machining (etching, ablation), embossing, molding, andcasting Industrial-scale processes in microreactors are often conducted undermedium to high pressures and with the use and production of highly reactivechemicals This may require the use of pressure-, solvent-, and temperature-tolerantstainless steel, ceramic, or glass with associated accessories, such as gaskets and

1.2 Physical Characteristics of Microreactorsj11

interconnects, sometimes fabricated from polytetrafluoroethylene and therketone (PEEK) Althoughfluorous polymers might be an optimal choice formany applications including corrosive or other hazardous chemicals, their micro-manufacturing compatibility must be taken into account For instance, PTFE doesnot lend itself to the mass-fabrication technique of embossing but can be micro-structured using reactive ion etching as used frequently at a wafer level with silicon.

polyethere-In contrast, a thermoplastic variant, perflouroalkoxy, can be molded; it is highlysolvent resistant, has FDA approval for many applications, and is sterilizationcompatible In contrast to the requirements imposed by industrial application,experimental, laboratory chip-based devices for research purposes have also beenfabricated from the same materials but may also include silicon, silicon-pyrex, andoccasionally polymers such as poly(methyl methacrylate), polycarbonate, cyclicolefin copolymer, and polydimethylsiloxane

Many chemical reactions performed in microreactors are conducted at roomtemperature, but in others that require heating and/or cooling, thermal transfer tothe microdevice is an important issue and imparts on the selection of constructionalmaterials [76] In this respect, cooling or heating units have been combined withmicrodevices to allow constant reaction temperatures or controlled temperaturezones [77] In the synthesis of biologically activefluorescent quantum dots, threeseparate microreactor chips were used, at different temperatures for (i) the control ofthe size and spectral properties of cadmium selenide and cadmium telluridenanoparticles at 300C, (ii) their zinc sulfide capping at 110–120C, and (iii) ligandreplacement at 60C These could, of course, be potentially integrated into onelarger chip with zoned temperature control [78]

As well as the basic materials from which a microreactor is fabricated, there may

be additional materials that are included as coating or packing For instance, in aglass-polymer composite continuous-flow microreactor, palladium particles havebeen loaded by ion exchange and reduced This was used in a Heck reactions anddemonstrated to be re-usable for>20 times post wash treatment [79] Also, coating

of the capillary channel of a microreactor with elemental palladium allowedpalladium-catalyzed coupling reactions to be performed very efficiently, and themetal coating also serves as recipient for microwave energy allowing a fast heating ofthe reaction solution [80] Another popular coating is TiO2that is frequently used as

a photocatalyst for the degradation of organic pollutants This has been coated ontoprefabricated ZnO nanorods on the internal walls of a glass microreactor and hasbeen shown to significantly increase the surface area for photocatalytic oxidation[81] As a simpler one-step method of increasing the catalytic surface area, a foam-like porous ceramic containing a catalyst as nanoparticle was formed in a micro-reactor by direct sol-gelation, thus avoiding any separate coating or impregnationstep [82] The result demonstrated a reasonable pressure drop due to its porosity,high thermal and catalytic stability, and excellent catalytic behavior in forminghydrogen and carbon monoxide-rich syngas from butane Additionally, zeolitematerials can function as a valuable adsorbent and catalyst in microreactors andtheir precision growth can be pre-seeded from nano-zeolites grafted on to silanisedmicroreactor surfaces such as metal (Figure 1.9 [83])

A porous organic polymer monolith may be formed within a microreactor to act as

a support for catalysts, such as palladium The size, size distribution, and surfacearea of the pores may be controlled by a porogen, while the chemical properties arecontrolled by the monomer used Such supports can be formed and even patterned

by the use of ultraviolet light, most cost-effectively using ultraviolet diode arrays [84,85] Carbon nanofibers can also be deposited within microreactors

light-emitting-by homogeneous deposition precipitation and pulsed laser deposition to provide alarger surface area support layer upon which catalysts such as ruthenium catalyticnanoparticles can be attached [86]

Figure 1.9 Scanning electron microscope

pictures of an example surface modification, in

this case, a NaA zeolite film grown on seeded

porous stainless steel, multichannel plate using

chloropropyl trimethoxysilane (CP-TMS) linkers

(a), (c), (d), and aminopropyl trimethoxysilane

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

1.2 Physical Characteristics of Microreactorsj15

Re ¼Lvr

whereL is the characteristic length, v is the fluid velocity, r is the fluid density, and m

is thefluid viscosity When viscous forces dominate, as it is typical within reactors,fluid flow is laminar The threshold at which transition from turbulent tolaminarflow occurs is dependent on the geometry of ducts through which the fluid

micro-isflowing, but typically, in a smooth channel or capillary, transition occurs between

Re value 2000 and 2500 [87,88] As a result, without the use of special structures oractive mechanisms, there is little turbulence-based mixing, and mixing occursmainly through diffusion Fick’s Law of diffusion says that where n is the particledensity or concentration,D is the diffusion coefficient, and D is the Laplace operator,then, the diffusionflux, J, can be defined as

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

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

This number is a measure of the importance of advection in relation to diffusion

As the Peclet number increases so does the dominance offlow forces over that

of molecular diffusion with regard to mixing This number is, therefore,important in determining the conditions in which diffusion is the primarymixing method [89]

To demonstrate how advantageous working at a microscale can be, consider aninitially very small spot of tracer in a resting solution [89] The time (t) taken by this

spot to spread over a distancex can be estimated as

This means that for reactions limited by diffusion, reaction time is proportional tothe square of the rate limiting distance Therefore, a reaction in a 10 cmflask couldtake 1 000 000 times less if undertaken in a 100mm diameter microreactor.Dramatically reduced reaction times have, arguably, been the most potent drivingforce behind research in microreactor technology

Figure 1.10 demonstrates the spreading of the“front” between two streams Thewidth of this front, d, increases through diffusion over time as the fluids travel downthe channel [89] This width can be approximated using

it can drastically lower the laminarflow transition threshold (into the region of Re

100 [90]) Adding turns to a channel can also initiate greater levels of mixing In anenclosed rectangular channel, asfluid travels around a curve at appropriate flowrates, vortices are set up in the upper and lower halves of the channel; these arecalled Dean vortices (Figure 1.11)

These Dean vortices will cause mixing but only across the width of the channel,not from top to bottom (Figure 1.12) (For further information about microreactormixing see Section 1.3.3.)

Figure 1.10 Diffusive mixing in a square

cross-sectional (side 500 mm) channel (a) Two

streams of water (colored to indicate the ratio

of liquid one to liquid two, 1 on the scale

indicating purely liquid one) running at 1 m/s in

parallel to each other with mixing through

diffusion only (b) Same simulation (as a)

highlighting the region of diffusive mixing or

“front” between the two fluids, in this case the lighter region indicates where diffusive mixing has occurred The width of the front, d, is indicated Source: Both images obtained via COMSOL Multiphysics1simulation.

1.3 Fluid Flow and Delivery Regimesj17

Whilefluid flow is often continuous and laminar, other regimes exist, such as, forexample, in segmentedflow Here, immiscible fluids, or phases, are configured toprovide contiguous“trains” of fluid “segments” or “packets” (see also Section 4.3).Theflow within these fluid segments may be configured to be such that there occurs

an internal vortex that causes rapid mixing within segment contents (Figure 1.13)and counters the lack of mixing normally characteristic of microscalefluid flow[91–94] This fluid flow regime depends on the absolute velocity of the fluids, thefluid viscosities, their interfacial tension, and the geometry of the channels [95].Adjacent contiguous segments may enjoy a highly dynamic fluidic interfaceproviding many opportunities for novel interfacial chemical and other reactions.This internal vortex and interpacket dynamic interface may be readily switched tolaminar flow (within packets) by simple modulation of the duct cross-sectionalgeometry, thereby changing the three-dimensional format of the individualfluidpackets Thus, dramatic alterations in mixing and mass transfer may be pro-grammed within a given microreactor circuit configuration The use of such solventdroplets resulting from controlled segmentedflow has been proposed as individualnanoliter-scale reactors for organic synthesis [40,41] Fluidflow segmentation may

be generated for a wide range of immisciblefluid matrices

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

Figure 1.12 Two parallel streams of water, A and B, (flowing at 3 m/s) are mixed via Dean vortices in a turn Mixing before the turn is mostly by diffusion Source: Image obtained via COMSOL Multiphysics1simulation.

Fluid packets may (i) contain particulates, including solid support beads, catalysts,and separations media, (ii) be subject to sequential additional reagent deliverythrough tributary ducts and channel injectors, (iii) be caused to split and/or coalesce,and (iv) be provided with individual identity through the provision ofaddressable molecular photonic and other codes Segmentedfluid packets as shown

in Figures 1.13 and 1.17 may therefore be considered as“test tubes on the move”that are, for instance, transferred seamlessly from one functional high-throughputscreening operation to another Thefluid packet format, for example, segmented byinert perfluorinated fluids, can be combined with interpacket liquid–liquid or solid-phase extractions [97] and microchannel contactor functions, enabling manypossibilities for compound transfer between the different solvent streams ofhyphenated functional processes Collectively, these tools pose a radically differentopportunity for synthesis, assay, and characterization procedures to traditional high-throughput screening operations such as in microtiter plate technology, storage, and

Figure 1.13 Internal circulations (indicated by

the dashed lines) within segmented flow

segments Segments are white; continuous

phase is the gray area (a) Circulation over the

whole length of the segment This occurs within

liquid segments suspended in an air continuous

phase (b) In a liquid–liquid system, circulation

occurs at the front of the segment The volume

fraction of the circulation zone is dependent on

certain parameters Higher segment velocities

increase the volume fraction of the circulation.

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

1.3 Fluid Flow and Delivery Regimesj19

information handling This new platform paradigm with its inherent opportunitiesrequires exploration through experimentation and modeling For example, in a gas–liquid carbonylative coupling reaction, an annularflow regime was employed togenerate a high interfacial surface area, where a thinfilm of liquid was forced to thewall surfaces of a microreactor (5 m length, 75ml capacity) by carbon monoxide gasflow through the center [98].

The laminar stationaryflow of an incompressible viscous liquid through drical tubes can be described by Poiseuille’s law This description was later extended

cylin-to turbulentflow Flowing patterns of two immiscible phases are more complex inmicrocapillaries Various patterns of liquid–liquid flow are described in more detail

in Section 4.3, while liquid–gas flow and related applications are discussed inSection 4.4

1.3.2

Fluid Delivery

1) Displacement: Hydrodynamic pumping has been the main method of fluiddelivery generally used in microreactor systems till date Hydrodynamic pump-ing usually employs the use of macro- or microscale peristaltic or positive dis-placement pumps [99–101] High pressures can be obtained, as well asaggressive solvents are used However, peristaltic pumps suffer from fluid-flow fluctuations at slow flow rates, and syringe pumps require carefullyengineered changeover or refill mechanisms when used in long-duration,continuous-flow synthesis schemes

2) Electro-osmotic Flow(EOF): Fluid pumping in capillary-scale devices and systemsmay be readily enabled under certain conditions by electrokineticflow that hasthe advantage that low levels of hydrodynamic dispersion are observed [102–104]

A detailed theoretical consideration of chemical reactions in microreactors underelectro-osmotic and electrophoretic control has been described in the literature[105] (Figure 1.14) To enable EOF, electrodes are usually placed in reservoirs andvoltage is applied, most preferably under computer control, with the magnitude

of the voltage being a function of several factors including reactor geometry.Electro-osmotic flow pumping has been demonstrated in capillary-based flowreactors incorporating solid-supported reagents and catalysts [106,107] Further,

an array of parallel microreactors, packed with silica-supported sulfuric acid, wasoperated under EOF to produce several tetrahydropyranyl ethers, thus demon-strating arithmetic scale out of EOF pumped microreactors [108] However, EOFdoes place certain requirements on the microreactor design and surface proper-ties of the constructional materials used As an additional restriction, not everyreaction can be performed in an electricalfield as electrochemical side reactionscan occur

3) Centrifugal: Centrifugal forces have for some time been harnessed for thecontrolled propulsion of reagents in spinning disk microreactors [109] Thismechanism has also been used to control the elution, mixing, and incubation

of reagents within enclosed reaction capillaries on rotating-disc platforms [110]

This represents a very innovative approach to chemical synthesis since thetechnique makes use of both hardware and software systems already developedfor a mass-produced commodity Additionally, the use of centrifugal forcesprovides an elegant way in which these can be used in combination withhydrophobic, the so-called burst valves to control fluid flow and incubationregimes.

1.3.3

Mixing Mechanisms

Microreactors are usually characterized by geometries with a low Reynoldsnumber In such capillary-scale ducts, laminar flow is dominant, and mixingrelies essentially on diffusion unless special measures are taken, such as to causeturbulence or reduce diffusion time Equally, laminarflow may be exploited suchthat laminar flow streams moving in parallel may contain reagents, which arecaused to interact by careful control of the flow rate and variations in the

Figure 1.14 Image sequences showing the

nature of electro-osmotic flow (a) as compared

to pressure-driven flow (b) in a 200 mm id

circular cross-section capillary The transport of

the photo-injected cross-stream fluorescent

markers illustrates: (a) the plug-like velocity

profile characteristic of electro-osmotic flows,

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

1.3 Fluid Flow and Delivery Regimesj21

microreactor geometry A range of passive and active techniques to induce mixinginclude (i) complex geometries within microfluidic manifolds to cause repeatedfluid twisting and flattening [112], (ii) acoustic streaming [113], (iii) resonantdiaphragms, and (iv) acoustic cavitation microstreaming [114,115] Passive tech-niques such as split and recombine suffer from the requirement thatfluids mustusually be in a state offlow, whereas active methodologies enable mixing wherethere is noflow, such as in microwell reactors and under temporary stopped-flowconditions in microchannel reactors A variant on this is a stopped-flow, batch-mode technique and has been employed to induce mixing on a centrifugalplatform [116] Not dissimilarly, pulsedflow in a microchannel has also beenshown to be effective at causing accelerated mixing [117] and is dependent onseveral factors including the Strouhal number, the Peclet number, phase differ-ence, pulse-to-volume ratio, and microchannel geometry Microfabricated geom-etries within the microreactor design and which split and recombinefluids havebeen shown to cause multilamination and thus reduced diffusion distances [118–120] Chaotic advection may also be caused by channels that contain integralstaggered, serial, asymmetric rib-like structures [121] or are three-dimensionallytwisted [122] (Figure 1.15) Active mechanisms for mixing based on energized,ultrasonically induced transport have been demonstrated [123] An interestingform of rapid micromixing may also be achieved in liquid–liquid multiphase flowmicroreactors where within serial contiguousfluid packets there exists an internalvortexflow that counters the laminar flow profile normally characteristic of lowReynolds number geometries [96,124].

Figure 1.15 Advection caused by integral

structures A schematic diagram of a

microchannel with square grooves in the

bottom wall Below the channel to the right, the

average flow profile in the cross section is

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

Multifunctional Integration

Some argue that miniaturized tools for both chemical synthesis and analysis need to

be integrated onto a single chip in order to gain the true benefits of miniaturization[126], not least because of the problems associated with subsystem interconnectivity,dead volumes, and chip-to-world interfaces Demonstrations toward such a goalinclude, for example, a hyphenated mixing reaction channel coupled to a capillaryelectrophoresis column [127]

As well as miniaturized reactors, microdevices with other functionalities extendthe range of functional capabilities that may be achieved when a systems approach isconsidered [128] Such microdevices may include mixers, separators, heat exchang-ers, heaters, coolers, photoreactors, analysis sub-systems, and devices for theapplication of pulsed electric fields [129] Therefore, a wide range of processesincluding extractions (liquid–liquid, liquid–gas, solid-phase enhanced), crystalliza-tions, distillations, purifications, conversions, phase-changes, phase separations,and identifications may be enabled Thermal conditions may be more readilymonitored throughout a microreaction system by employing a distributed reportersuch as a thermochromic dye [130] that can report<1C temperature variations,albeit over a limited dynamic temperature range

Interconnects to and between such microdevices for laboratory-scale experimentalapparatus have historically been problematical, since a mechanically sound,pressure-resistant, and hermetic juncture with minimal dead volume is usuallyrequired For robust, industry-ready chemical production equipment, stainless-steelfittings are usually employed in microreactor systems For laboratory-scaleapparatus with more delicate chip-based microreactors, a range of microfabricatedsolutions have been explored [131,132], resulting in both miniaturized plug-and-play microconnectors [133] and macroscale interface housings Both adhesive[134] and mechanical [135] solutions have been developed, but it has beenreported that the latter have at least an order of magnitude greater strengththan the former More widely, the issues surrounding the packaging and inter-connectivity of microfluidics and associated devices have been comprehensivelysummarized by Veltenet al [136]