Table of Contents

Cover

Title Page

List of Contributors

Foreword

Background
The Book
The Chapters

Chapter 1: Flow Photochemistry – a Green Technology with a Bright Future

1.1 Introduction to Synthetic Organic Photochemistry
1.2 Conventional Batch Photochemistry
1.3 Continuous-Flow Chemistry
1.4 Selected Examples of Photochemical Reactions under Flow Conditions
1.5 Summary, Conclusion, and Outlook
Acknowledgments
References

Chapter 2: Continuous Flow Synthesis Using Recyclable Reaction Media

2.1 Introduction
2.2 Continuous Flow Reactions Using an Ionic Liquid
2.3 Continuous Flow Reactions Using a Fluorous Solvent
2.4 Conclusions
References

Chapter 3: Synthesis and Application of H2O2 in Flow Reactors

3.1 Introduction
3.2 The Synthesis of Hydrogen Peroxide from Hydrogen and Oxygen in Flow Process with Microtechnology
3.3 Application of Hydrogen Peroxide in Microreactors
3.4 Conclusions
Acknowledgments
References

Chapter 4: Scale-Up of Flow Processes in the Pharmaceutical Industry

4.1 Introduction
4.2 Stages of Pharmaceutical Development
4.3 Sustainability of Supply – The Role of Continuous Processing
4.4 Comparison of Batch to Continuous Large-Scale Processing
4.5 Scale-Up of a Flow Process
4.6 Flow Processes in the Manufacture of Pharmaceuticals: Examples of Scale-Up
4.7 Summary and Outlook on Future Scale-Up
References

Chapter 5: Organic Synthesis in Flow: Toward Higher Levels of Sustainability

5.1 Introduction
5.2 Semi-automated Optimization
5.3 Self-Optimizing Microreactor Systems
5.4 Sustainability in Microreactor Technology
5.5 Conclusion
References

Chapter 6: Sustainable Flow Chemistry in Drug Discovery

6.1 Introduction
6.2 Laboratory Equipment
6.3 Advantages of Improved Sustainability
6.4 Sustainable Drug Discovery
6.5 Conclusions and Outlook
References

Chapter 7: Flow Tools to Define Waste/Time/Energy-Minimized Protocols

7.1 Introduction
7.2 Minimization of Solvents and Reuse of Catalytic Systems
7.3 Time/Cost/Energy Saving Examples Using Flow Approach
7.4 Conclusions
Acknowledgments
References

Chapter 8: The Application of Flow Chemistry in the Use of Highly Reactive Intermediates and Reagents

8.1 Introduction
8.2 Hydrogenation Reactions in Flow
8.3 Carbonylation in Flow
8.4 Organometallic Reagents in Flow
8.5 Synthesis of Azides and Diazoacetates in Flow
8.6 The Use of Flow Reactors to Prepare Unstable Intermediates Using Photochemistry
8.7 The Use of Flow Reactors to Prepare Unstable Intermediates Using Electrochemistry
8.8 Fluorination and Trifluoromethylation in Flow
8.9 Conclusions
Acknowledgments
References

Chapter 9: Nonconventional Techniques in Sustainable Flow Chemistry

9.1 Introduction
9.2 Microwave-Assisted Flow Chemistry
9.3 Inductive Heating in Flow Chemistry
9.4 Sonochemistry in Flow Chemistry
9.5 Organic Electrochemistry in Flow Chemistry
9.6 Conclusions
References

Chapter 10: Life Cycle Assessment of Flow Chemistry Processes

10.1 Introduction
10.2 Environmental Sustainability Assessment
10.3 Flow Processes LCA Case Studies
10.4 Conclusions
References

Chapter 11: Solids in Continuous Flow Reactors for Specialty and Pharmaceutical Syntheses

11.1 Introduction
11.2 Mechanisms of Solids Formation in Flow Reactors
11.3 Manufacture of Solids in Flow: Soft Particles and APIs
11.4 Use of Solids Suspension Catalysts in Flow
11.5 Avoiding Blockage of Flow Reactors by Insoluble By-Products: Flow Focusing
11.6 Green Engineering Aspects
Acknowledgments
References

Index

End User License Agreement

List of Illustrations

Chapter 1: Flow Photochemistry – a Green Technology with a Bright Future

Scheme 1.1 Simplified main photoreaction modes.
Figure 1.1 (a) Immersion-well reactor system equipped with a 150 W medium-pressure mercury lamp. (Reproduced with permission of Peschl Ultraviolet GmbH, Germany.) (b) Chamber reactor equipped with 16 × 8 W UVA fluorescent tubes. (Reproduced with permission of Southern New England Ultraviolet Company, USA.)
Figure 1.2 Schematic concept of continuous-flow photochemistry.
Figure 1.3 (a) Dwell device (Mikroglas Chemtech GmbH, Germany) under a 5 × 8 W UVB panel. (EXPO, Luzchem Research Inc., Canada.) (b) Improvised FEP-capillary reactor equipped with a single 8 W UVA fluorescent tube. (James Cook University, Australia.)
Figure 1.4 (a) Photochemistry Module Deep UV. (Reproduced with permission of FutureChemistry Holding BV, The Netherlands.) (b) Vapourtec UV-150 photochemical reactor. (Reproduced with permission of Vapourtec Ltd, UK.)
Scheme 1.2 [2+2]-Photocycloaddition of 1 and 2 to yield 3 as a model reaction for productivity performances.
Scheme 1.3 [5+2]-Photocyclization of 4a,b to 5a,b and estimated productivities.
Figure 1.5 Multi-microcapillary flow reactor (MμCFR; Dublin City University, Ireland). The left fluorescent tube is turned on.
Scheme 1.4 Parallel sensitized addition reactions of alcohols (8a–c) to furanone derivatives (7a–c).
Scheme 1.5 Photobromination of toluene (12) under continuous flow conditions in concentrated sunlight.
Scheme 1.6 Tandem photochemical–thermal synthesis of AKS-186 (17) under continuous flow conditions.
Scheme 1.7 Synthesis of camptothecin derivatives 19a,b through photorearrangement and structures of irinotecan (20a) and topotecan (20b).
Figure 1.6 Flow photochemical production plant. (Oelgemöller 2012 [76]. Reproduced with permission of Wiley.)
Scheme 1.8 Photocatalytic alkylation of benzylamine (21) under continuous flow conditions.
Scheme 1.9 Continuous-flow synthesis of artemisinin (26) from 24 via a tandem photochemical–thermal process.
Scheme 1.10 Photooxygenation of furfural (27) to hydroxyfuranone (28) in sunlight.

Chapter 2: Continuous Flow Synthesis Using Recyclable Reaction Media

Scheme 2.1 A benchtop biphasic flow production system based on recycle of catalyst, reagent, and solvent.
Scheme 2.2 Copper-free Sonogashira coupling reaction using [bmim]PF₆ and a flow microreactor.
Scheme 2.3 Production of butyl cinnamate using a circulatory catalyst recycling flow system.
Scheme 2.4 Structure of the MMP inhibitor 1 and its precursor 2.
Scheme 2.5 One hundred gram scale flow production of the key intermediate 2 of MMP inhibitor 1 using a circulatory catalyst recycling system.
Scheme 2.6 Flow oxidation of cyclohexene catalyzed by Cu(II) complex.
Scheme 2.7 Typical flow reactor setting for carbonylation (MFC: mass flow controller; BPR: back pressure regulator).
Scheme 2.8 Flow carbonylative Sonogashira reaction in an ionic liquid, [bmim]PF₆, using a stainless-steel tubular reactor.
Scheme 2.9 Double carbonylation in [bmim]PF₆ using a stainless-steel tubular reactor.
Scheme 2.10 Cycloaddition of propylene oxide (PO) and CO₂ in a flow system.
Scheme 2.11 Kolbe–Schmitt reaction in a flow system using [bmim]HCO₃ as cosolvent and CO₂ source.
Scheme 2.12 Enzymatic esterification using ionic liquid in a flow system.
Scheme 2.13 Enzymatic synthesis of propyl caffeate using ionic liquid in a flow system.
Scheme 2.14 Microflow bromination of alkenes using Galden® HT135 as bromine support.
Scheme 2.15 Circulatory microflow bromination of cyclohexene using fluorous polyether Galden® HT135 as bromine support.
Scheme 2.16 Photoinduced radical C−H bromination using FC-72 and flow system.
Scheme 2.17 Microflow Suzuki–Miyaura coupling in an aqueous/fluorous biphasic system.
Scheme 2.18 Concept of a thermomorphous double-emulsion system.
Scheme 2.19 Schematic drawing of capillary tube-in-tube coaxial flow setup for double-emulsion formation.
Scheme 2.20 Flow Mizoroki–Heck reaction using a thermomorphous double-emulsion system.
Scheme 2.21 Flow Baeyer–Villiger oxidation using fluorous/aqueous biphasic conditions.
Scheme 2.22 Flow Mukaiyama using fluorous solvent and catalyst.
Scheme 2.23 Flow glycosylation using the fluorous tag method.
Scheme 2.24 Flow synthesis of monosaccharide using the fluorous tag method.

Chapter 3: Synthesis and Application of H2O2 in Flow Reactors

Scheme 3.1 AO process for the synthesis of hydrogen peroxide.
Scheme 3.2 The four reactions in the synthesis of H₂O₂ from H₂ and O₂.
Figure 3.1 Schematic diagram of the 10-channel microreactor. (a) Plane view showing gas distribution (A), gas–liquid contacting area (B), catalyst loading channel (C), reaction channel, and exit section (D). (b) The lines labeled A, B, C, and D correspond to the four cross sections below the microreactor drawing.
Figure 3.2 Design of the glass-fabricated microreactor: (a) whole structure, (b) magnified picture around the inlet, and (c) magnified picture of “dam” structure to retain catalyst particles.
Figure 3.3 Schematic representation of the setup for H₂O₂ formation.
Figure 3.4 Experimental setup for continuous operation of the H₂O₂ direct synthesis process: (1) saturator, (2) flow meter, (3) membrane module, (4) expansion valve, (5) separator, (6) piston pump, (7) control valve, (8) product vessel, (9) fresh solvent vessel, and (10) HPLC pump.
Figure 3.5 Scheme of a microcapillary setup for the direct synthesis of hydrogen peroxide.
Scheme 3.3 Epoxidation of 1-pentene in a catalytic microreactor.
Figure 3.6 Experimental setup for the epoxidation of soybean oil with a sandwich microreactor.
Scheme 3.4 Epoxidation of chalcone in the presence of catalyst.
Scheme 3.5 Epoxidation of chalcone in the absence of catalyst.
Figure 3.7 Microscope photographs of open PEEK reactor (before bonding). (a) Matching PEEK plates which form the reactor after bonding. (b) Herringbone grooves etched on SU-8.
Scheme 3.6 Oxidation of thioanisole with H₂O₂ using [PO₄{WO(O₂)₂}₄]@PIILP as catalyst.
Scheme 3.7 The synthesis of adipic acid from cyclohexene and H₂O₂.
Figure 3.8 Configuration of the micromixing unit. (1) Inlet plate; (2) distributing plate; (3) mixing plate; and (4) outlet plate.
Figure 3.9 Configuration of flow setup for MEKPO synthesis.
Scheme 3.8 Scheme of phenol oxidation with H₂O₂ over TS-1 catalyst.
Figure 3.10 Photographs of catalytic wall microreactor. (a) Assembled device; (b) catalyst plate (catalyst size = ∅32.0 mm (diameter) × 0.5 mm (thickness)); and (c) microchannel plate (channel size = 0.8 mm (height) × 1.0 mm (width) × 16.0 mm (length), channel geometry = 10 straight channels in a radial pattern).
Scheme 3.9 Two-step process for the synthesis of trans-1,2-cyclohexanediol.
Figure 3.11 The schematic diagram of the microreactor setup for step 1 (a) and step 2 (b).
Scheme 3.10 Pd-catalyzed diacetoxylation of alkenes.
Scheme 3.11 Trifluoromethanesulfonic acid-catalyzed diacetoxylation of alkenes with in situ formed peracetic acid.
Figure 3.12 Schematic representation of the hydroboration/oxidation continuous flow setup.

Chapter 4: Scale-Up of Flow Processes in the Pharmaceutical Industry

Figure 4.1 Drivers and factors affecting the scale-up of a continuous manufacturing process toward an active pharmaceutical ingredient.
Figure 4.2 Different stages in the lifetime of an API profit from different features of continuous processing and different reactor concepts: key properties remain unchanged. ^aPatheon traditionally uses homemade designs made of capillaries and T-pieces, ^bfor example, Corning “low-flow” reactor plates, and ^cPatheon uses flow reactors made of silicon carbide on plant scale.
Figure 4.3 Sustainability and its various faces: economic, social, and environmental aspects constitute sustainability as a whole.
Figure 4.4 Methods and devices for process intensification.
Figure 4.5 A representation of the developments in continuous manufacturing based on Gartner's hype cycle, with typical features such as inflated expectations and supplier consolidation.
Figure 4.6 Evaluation of the literature on “continuous process” referenced by CAplus.
Figure 4.7 Even distribution of flow over parallel mixers and channels by upstream throttles. Elements F are flow controllers, M are mixers. The throttles cause the maximum pressure drop.
Figure 4.8 External parallelization with active control of each flow. The large number of control elements (e.g., flow controllers F) causes a comparatively high initial implementation effort.
Figure 4.9 Campaign sizes in batch and flow operation: flow plants can be tuned to required production volume and available time slot.
Figure 4.10 Thermal Overman rearrangement of a trans-2,3-disubstituted 3,6-dihydro-2H-pyrane.
Figure 4.11 Dehydration by a Vilsmeier reagent produced in situ.
Figure 4.12 Deprotonation-alkylation sequence and its translation into a flow setup.
Figure 4.13 Sequence of lithiation and coupling, and its translation into a flow setup.

Chapter 5: Organic Synthesis in Flow: Toward Higher Levels of Sustainability

Scheme 5.1 Synthesis of isoxazole derivatives in continuous flow.
Scheme 5.2 Palladium-catalyzed Sonogashira coupling between bromothiophene derivate 4 and p-tolylacetylene 5.
Figure 5.1 Microreactor setup for semi-automated Sonogashira coupling reaction.
Scheme 5.3 Swern–Moffat oxidation of benzyl alcohol to benzaldehyde. Included are pathways that lead to formation of side-products 8 and 9 via a Pummerer rearrangement.
Scheme 5.4 Imidazole-1-sulfonyl azide hydrochloride-mediated benzyl azide production.
Figure 5.2 Schematic overview for semi-automated benzyl azide production.
Figure 5.3 Graphic presentation of modeled third-order polynomial function. (a) Temperature versus stoichiometric ratio; (b) temperature versus residence time; and (c) stoichiometric ratio versus residence time. (Reproduced with permission of Delville et al., 2012 [21].)
Scheme 5.5 Biodiesel (15) production from plant oils and animal fats.
Scheme 5.6 Solketal production from glycerol and acetone, catalyzed by Amberlyst-36.
Figure 5.4 Graphical representation of the obtained quadratic model. Dependency of yield on (a) temperature and acetone equivalents; (b) temperature and WHSV; and (c) WHSV and acetone equivalents.
Figure 5.5 Microreactor setup for the synthesis of CdSe quantum dots.
Figure 5.6 Three-dimensional parameter space with analyzed data points (colored dots) for the optimization of the synthesis of well-defined CdSe quantum dots.
Scheme 5.7 Possible products for ethanol dehydration in supercritical carbon dioxide (scCO₂).
Figure 5.7 Microreactor setup for reactions in supercritical carbon dioxide (scCO₂).
Figure 5.8 Three-dimensional parameter space consisting of CO₂ flow-rate (ml min⁻¹), pressure (bar), and temperature (°C).
Scheme 5.8 Methylation of 1-pentanol followed by decarbonylation.
Scheme 5.9 Palladium-catalyzed Heck reaction of 4-chlorobenzotrifluoride and 2,3-dihydrofuran.
Figure 5.9 Microreactor setup for the fully automated optimization of a Heck reaction.
Scheme 5.10 Paal–Knorr reaction of 2,5-hexadione and ethanolamine into pyrrole derivative 34.
Scheme 5.11 Knoevenagel condensation of p-anisaldehyde (35) and malononitrile (36).
Figure 5.10 General setup for the optimization of a Knoevenagel condensation (Section 5.3.5.1) and benzyl alcohol oxidation (Section 5.3.5.2).
Scheme 5.12 Oxidation of benzyl alcohol (38) to benzaldehyde (39) by chromium trioxide (CrO₃), followed by over-oxidation to benzoic acid.
Scheme 5.13 Synthesis of m-anisaldehyde (43) from m-bromoanisole (41).
Figure 5.11 Galantamine HBr.

Chapter 6: Sustainable Flow Chemistry in Drug Discovery

Figure 6.1 Examples of starter kit instrumentation from Chemtrix BV (a) (Reproduced with permission of Chemtrix BV.) and Future Chemistry Holding BV (b). (Reproduced with permission of FutureChemistry Holding BV.)
Figure 6.2 Examples of instrumentation for preparation of series of compounds from Syrris Ltd (a) (Reproduced with permission of Syrris Ltd.) and Accendo Corporation (b). (Reproduced with permission of Accendo Corporation.)
Figure 6.3 Examples of integrated instruments from Vapourtec Ltd (a) (Reproduced with permission of Vapourtec Ltd.) and Uniqsis Ltd (b). (Reproduced with permission of Uniqsis Ltd.)
Figure 6.4 Suzuki and Negishi reactions in flow using silica supported catalyst.
Figure 6.5 Continuous synthesis of organozinc halides coupled to Negishi reactions.
Figure 6.6 Continuous catalyst-recycling system using ionic liquids.
Figure 6.7 Continuous carbonylation using phenyl formates.
Figure 6.8 Continuous carbonylation using tube-in-tube reactor.
Figure 6.9 Continuous Bodroux reaction.
Figure 6.10 Preparation of amides from low-nucleophilic amines.
Figure 6.11 Versatile synthesis of alkenes and alkynes trans-1,2-dichloroethane.
Figure 6.12 Flow setup for the lithiation of dibromomethane and reaction with esters.
Figure 6.13 Magnesiation and reaction with electrophiles of functionalized heterocycles and acrylates.
Figure 6.14 Use of diazomethane in flow in the tube-in-tube reactor.
Scheme 6.1 Preparation of benzotriazoles in three steps.
Figure 6.15 Drug Discovery stages.
Figure 6.16 Multistep synthesis of drug-like compounds targeting CCR8. (Petersen et al. [50]. Reproduced with permission of American Chemical Society.)
Figure 6.17 Tetraline derivative with nanomolar affinity for CCR8.
Scheme 6.2 Combined flow-parallel batch synthesis of pyrrolidine analogs.
Figure 6.18 Flow synthesis of thiazole and pyrazole libraries.
Scheme 6.3 Flow synthesis of 3-aminoindolizine library.
Scheme 6.4 Flow synthesis of imidazopyridine library.
Figure 6.19 Novel hits for adrenergic α_1A receptor.
Figure 6.20 Benzyl ethers and sulfonamides screened against T-cell tyrosine phosphatase.
Figure 6.21 Integrated microfluidic platform for in situ click chemistry. (a) Integrated platform and reaction scheme, (b) image of the device, and (c) tube for collecting reaction products. (Wang et al. [66]. Reproduced with permisison of Royal Society of Chemistry.)
Figure 6.22 Cyclofluidic optimization platform. (Czechtizky et al. [67]. Reproduced with permission of American Chemical Society.)
Figure 6.23 Compounds with activity against T315I gatekeeper Abl kinase mutant.
Figure 6.24 Aniline derivatives prepared for BACE1.
Figure 6.25 Affinity chromatography procedure. (Guetzoyan et al. [71]. Reproduced with permission of The Royal Society of Chemistry.)
Scheme 6.5 Synthesis of imidazo[1,2-a]pyridines as potential GABA_A agonists.
Figure 6.26 Triazolopyridazines assayed as BDR9 modulators.
Scheme 6.6 Imidazo[1,2-b]pyridazine analogs prepared as casein kinase I inhibitors.
Scheme 6.7 Adamantane derivatives for P2X₇ biological evaluation.
Figure 6.27 Structure of compound 75.
Figure 6.28 Five-module chemical assembly system. (Ghislieri et al. [78]. Reproduced with permission of Wiley.)
Scheme 6.8 Electrochemical synthesis of drug metabolites of diclofenac 76.

Chapter 7: Flow Tools to Define Waste/Time/Energy-Minimized Protocols

Scheme 7.1 Waste-minimized, cyclic-flow protocol for the Suzuki coupling [9a].
Scheme 7.2 Pd-SILP-catalyzed Heck reaction under cyclic-flow mode [9b].
Scheme 7.3 Michael addition catalyzed by PS-BEMP in flow under SolFC [19].
Scheme 7.4 Hydrophosphonylation of benzaldehyde catalyzed by PS-BEMP in flow under SolFC [20].
Scheme 7.5 Representative example of the phenolysis of epoxides in flow under SolFC [21].
Scheme 7.6 Two-step flow synthesis of 19 on gram-scale [21].
Scheme 7.7 Preparation of γ-nitrocarbonyls in flow under SolFC and relative metrics [6, 22, 23].
Scheme 7.8 Multistep synthesis of β-hydroxy ester 27 in flow [26].
Scheme 7.9 Multistep synthesis of 1,2-azido alcohol 29 in flow [27].
Scheme 7.10 Preparation of β-azido ketones in water under flow conditions [28].
Scheme 7.11 Multistep synthesis of β-amino acids 36 in flow [31].
Scheme 7.12 Cyanosilylation of acetophenone 37 under SolFC in flow [33].
Scheme 7.13 Multistep synthesis of γ-amino alcohols 39 in flow [35].
Scheme 7.14 Aquivion PFSA-catalyzed synthesis of 42 in flow [39].
Scheme 7.15 Preparation of β-nitroacrylates 44 [40].
Scheme 7.16 Aerobic oxidation of 1-phenylethanol 45 to acetophenone on large scale [41].
Scheme 7.17 Hydration of nitriles in flow on large scale [42].
Scheme 7.18 Photochemical bromination of rosuvastatin precursor 48 [43].
Scheme 7.19 Flow microreactors assembly for the synthesis of disubstituted pyridines [44].
Scheme 7.20 Suzuki coupling of phenylboronic acid with 4-bromoanisole under MW and flow conditions [45].
Scheme 7.22 Synthesis of DHA intermediate under flow-microreactor conditions [46].
Scheme 7.21 A continuous-flow three-step synthesis of carbamates 57 [48].
Scheme 7.23 Two reaction continuously using fluoropolymer membrane [49].
Scheme 7.24 Direct oxidative amidation of aromatic aldehydes [50].

Chapter 8: The Application of Flow Chemistry in the Use of Highly Reactive Intermediates and Reagents

Scheme 8.1 Hydrogenation in a falling film microreactor.
Scheme 8.2 Hydrogenation using a tube-in-tube reactor using an iridium catalyst.
Scheme 8.3 Hydrogenation using a tube-in-tube reactor using a rhodium catalyst.
Scheme 8.4 Continuous flow hydrogenation for pyrimidine synthesis.
Scheme 8.5 Continuous flow hydrogenation of pyridine carboxylic acid.
Scheme 8.6 Asymmetric hydrogenation using heterogeneous Rh catalysts.
Scheme 8.7 Methoxycarbonylation in a tube-in-tube flow reactor.
Scheme 8.8 Alkoxycarbonylation in a tube-in-tube reactor.
Scheme 8.9 Carbonylative coupling within a microreactor.
Scheme 8.10 Synthesis of neuropeptide YY5 receptor antagonist in a flow reactor.
Scheme 8.11 Hydroformylation of styrene in a tube-in-tube reactor.
Scheme 8.12 In situ generation of unstable organometallic intermediates.
Scheme 8.13 Synthesis of a substituted pyridine via a halogen–lithium exchange reaction.
Scheme 8.14 Li exchange and Murahashi coupling reactions in continuous flow.
Scheme 8.15 Grignard reaction used in the synthesis of (rac)-tramadol using flow conditions.
Scheme 8.16 Synthesis of a pharmaceutically relevant azide in-flow.
Scheme 8.17 Synthesis of triazoles in continuous flow reactors.
Scheme 8.18 Click cyclization reaction performed in a Cu tube reactor.
Scheme 8.19 Continuous synthesis of 5-substituted 1H-tetrazoles.
Scheme 8.20 In situ preparation of diazomethane under flow conditions.
Scheme 8.21 In situ preparation of ethyl diazoacetate under flow conditions.
Scheme 8.22 Photocycloaddition in a microreactor.
Scheme 8.23 Photochemical chlorination of toluene-2,4-diisocyanate in a falling film reactor.
Scheme 8.24 Photocatalytic synthesis of l-pipecolinic acid in continuous flow.
Scheme 8.25 Paternó–Büchi reaction in a photochemical microreactor.
Scheme 8.26 Synthesis of CpRu(MeCN)₃PF₆ in a photochemical flow reactor.
Figure 8.1 Reactor configuration for the electrochemical generation of cations in continuous flow.
Scheme 8.27 Synthesis of [4+2] adducts under continuous flow.
Scheme 8.28 Electrochemical synthesis of hypervalent iodine reagents in flow.
Scheme 8.29 In situ electrogeneration of o-benzoquinone in a microreactor.
Scheme 8.30 Fluorination in a microreactor.
Scheme 8.31 Sulfur pentafluoride synthesis in a microreactor.
Scheme 8.32 Trifluoromethylation of N-methylpyrrole in a flow reactor.
Scheme 8.33 Trifluoromethylation of thiols in a flow reactor.

Chapter 9: Nonconventional Techniques in Sustainable Flow Chemistry

Scheme 9.1 Degradative hydrolysis of ethyl 2-indolecarboxylic ester 1 in the MBR.
Figure 9.1 Some commercial microwave-system assisted flow reactors.
Scheme 9.2 Methylation of phenol 4 using the FlowSynth instrument. Rate acceleration up to 1900-fold.
Scheme 9.3 Cycloaddition of benzyl azide 6 with dimethyl acetylenedicarboxylate 7.
Scheme 9.4 Nucleophilic aromatic substitution in flow. The yield increased from 20% to 81%.
Scheme 9.5 Suzuki coupling of biphenylboronic acid 12 in flow in a nonresonant cavity.
Scheme 9.6 Hantzsch synthesis of diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate 17 in flow.
Scheme 9.7 Suzuki coupling of p-bromobenzonitrile 18 in a microreactor. Selective heating of the catalyst.
Figure 9.2 Microreactor with a palladium catalyst bed. (He 2004 [17]. Reproduced with permission of Royal Society of Chemistry.)
Scheme 9.8 Suzuki reaction benzofuran 2-boronic acid 21 in flow resulted in dramatic increases in isolated yields and product purity.
Figure 9.3 Flow reactor design with microcapillaries for MACOS. (a) Single capillary system and (b) four capillary system. (Comer 2005 [19]. Reproduced with permission of American Chemical Society.)
Scheme 9.9 Suzuki coupling to obtain p-methoxybiphenyl 25 using the MACOS approach.
Figure 9.4 Setup for flow reactions described by Bagley. (Bagley 2005 [21]. Reproduced with permission of American Chemical Society.)
Figure 9.10 Fisher indole synthesis of 28 in flow.
Figure 9.5 Experimental setup designed by Nishioka. (Nishioka 2014 [22]. Reproduced with permission of American Chemical Society.)
Figure 9.6 Experimental setup designed by Akai. a) Complete flow setup b) Detail of the flow reactor. (Yokozawa 2015 [23]. Reproduced with permission of Royal Society of Chemistry.)
Figure 9.7 Setup for in-line NMR analysis of a flow microwave-assisted reaction. (Gómez 2010 [25]. Reproduced with permission of Royal Society of Chemistry.)
Figure 9.8 NMR optimization and analysis of a Diels–Alder reaction. (Gómez 2010 [25]. Reproduced with permission of Royal Society of Chemistry.)
Figure 9.9 Flow system with induction heating. a) Inductor (up) and 0.4 mm steel beads left and MagSilica 300 (right). b) Diagram of the flow setup..
Figure 9.10 Heating profiles of some magnetic nanoparticles. (Kirschning 2012 [27]. Reproduced with permission of The Chemical Society of Japan.)
Scheme 9.11 Multistep synthesis of the neurolepticum olanzapine 32 in flow conditions.
Scheme 9.12 General reactor setup for KMnO₄-mediated oxidations under flow conditions.
Scheme 9.13 Palladium-catalyzed amination reactions in flow.
Scheme 9.14 1,3-Dipolar cycloaddition reactions.
Figure 9.11 Reaction setup for 1,3-dipolar cycloadditions in continuous flow. (Tu 2012 [32]. Reproduced with permission of Springer.)
Figure 9.12 Schematic diagram of the “cation flow” system. (Suga 2001 [36]. Reproduced with permission of American Chemical Society.)
Figure 9.13 Schematic representation of parallel laminar flow in the micro-flow reactor. (Horii 2007 [37]. Reproduced with permission of American Chemical Society.)
Figure 9.14 Schematic representation of the thin layer cell system. (Horii 2005 [38]. Reproduced with permission of Elsevier.)
Scheme 9.15 Paired electrosynthesis of 2,5-dimethoxy-2,5-dihydrofuran 46.
Figure 9.15 Schematic representation of the micro-gap flow cell. (He 2005 [39]. Reproduced with permission of Elsevier.)
Scheme 9.16 Electrolyte-free electrochemical reduction of 4-nitrobenzyl bromide.
Figure 9.16 Electrochemical microflow system: (a) outside and (b) system diagram. (Horcajada 2005 [40]. Reproduced with permission of Royal Society of Chemistry.)
Scheme 9.17 Anodic methoxylation of p-methoxytoluene 49.
Figure 9.17 Schematic diagram of a Friedel–Crafts reaction using an IMM micromixer. (Suga 2003 [41]. Reproduced with permission of Royal Society of Chemistry.)
Scheme 9.18 Microsystem for polymerization.
Figure 9.18 Schematic representation of a “Flux Module.”
Scheme 9.19 Electrochemical benzylic methoxylation/oxidation.
Scheme 9.20 Di- and trifluoromethylation of acrylates.
Scheme 9.21 Di- and trifluoromethylation of acrylamides.
Scheme 9.22 Formation of complex Cu(IMes)Cl.
Figure 9.19 (a) Photograph of the second-generation electrochemical flow reactor and (b) the shape of the reactor channel through a 1 mm thick Teflon spacer. (Chapman 2015 [47]. Reproduced with permission of Royal Society of Chemistry.)
Scheme 9.23 Hydrosilylation reactions using catalyst Cu(IMes)Cl 65 directly from the electrochemical flow-cell.
Scheme 9.24 NHC-mediated electrochemical oxidative esterification of aldehydes.

Chapter 10: Life Cycle Assessment of Flow Chemistry Processes

Figure 10.1 An illustration of gate-to-gate system boundary for the evaluation of environmental indicators: a single stage in the manufacture of palladium acetate.
Figure 10.2 An illustration of the cradle-to-gate system boundary for the evaluation of environmental indicators.
Figure 10.3 System boundary for LCA studies.
Figure 10.4 Calculation of burdens for a multi-step process.
Figure 10.5 From burdens to mid-point and end-point impact assessments.
Figure 10.6 The methodology of SLCA-based process design. Adapted from [27].
Figure 10.7 Schematic of an innovation funnel.
Scheme 10.1 Buchwald–Hartwig amination reaction studied in this work. Flow and batch process conditions (catalyst and base) are shown.
Figure 10.8 Development of LCIs for manufacture of active pharmaceutical ingredient (API). Reproduced from [42], published by the Royal Society of Chemistry.
Figure 10.9 Comparison of Recipe and CED scores for syntheses of Pd-BINAP and [Pd(IPr*)(cin)Cl] catalysts.
Figure 10.10 Comparison of Recipe 2008 midpoints and CED scores for different process scenarios. Reproduced from [42], published by the Royal Society of Chemistry.
Figure 10.11 Contributions of catalyst manufacture, solvent recycling, base and energy inputs to selected indicators in the batch and the flow processes. Data columns marked with * correspond to scenarios with toluene (solvent) recycling both in batch and in flow processes.
Scheme 10.2 A common route to conversion of artemisinin to artemisinin-based APIs, exemplified by artemether.
Figure 10.12 Schematic process flow scheme for a tandem conversion of dihydroartemisinin (DHA) into artemether. Reprinted from [61] with permission from Elsevier.
Figure 10.13 CML impact scores and CED for artemisinin to DHA reaction. Comparison of flow and batch processes and flow process without THF for superhydride. Reprinted from [61] with permission from Elsevier.
Figure 10.14 Individual processes contributions to CED of artemisinin to DHA reaction in batch and flow conditions. Reprinted from [61] with permission from Elsevier.
Figure 10.15 CML impact scores and CED for DHA to artemether (ARM) reaction. Comparison of flow and batch processes. Reprinted from [61] with permission from Elsevier.
Figure 10.16 Comparison of an industrial scale batch organo-lithium reaction (0%) with the same reaction performed in a microreactor. Variation in CML environmental impact categories. Reproduced from [67] with permission from Elsevier.

Chapter 11: Solids in Continuous Flow Reactors for Specialty and Pharmaceutical Syntheses

Figure 11.1 Gibbs free energy as a function of nuclei radius.
Figure 11.2 5 × 5 Epstein matrix.
Figure 11.3 Deposition and removal mechanism on solid surface.
Figure 11.4 Fouling resistance as a function of time. Inset: Practical fouling curve in the case of asymptotic curve.
Figure 11.5 Interaction energy between particles as a function of the distance between colloidal particles with the same z potential.
Figure 11.6 Mechanism of floc breakage: (a) surface erosion and (b) fragmentation.
Figure 11.7 Schematic diagram of different functions that can be used in the synthesis of soft particles in microfluidics. (a) A droplet generation zone. (b) The region of particle development, manipulation and/or sensing.
Figure 11.8 (a) Comparison of conventional process schematics in the manufacture of drug products versus (b) an alternative process involving fluidized-bed particle impregnation.
Figure 11.9 Schematic of a continuous crystallization oscillatory baffled reactor system.
Figure 11.10 A schematic diagram of a gas–liquid–solid continuous flow reactor with fine catalyst slurry, and a CFD simulation of a recirculation pattern within continuous liquid phase slug.
Figure 11.11 An example of continuous separation of catalytic magnetic nanoparticles in flow. The design of fluid channels is shown schematically in the image (a). Image (b) shows a photograph take in position A, illustrating the absence of nanoparticles and image (c) shows a photograph take in position B in the scheme, with clearly visible nanoparticles.
Scheme 11.1 Scheme of a test-reaction for Buchwald–Hartwig amination and structure of the [Pd(IPr*)(cin)Cl] catalyst. IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl) imidazole-2-ylidene and cin = phenylallyl. The catalyst is described in detail in [112].
Figure 11.12 An image of a PFA tubular reactor with forming inorganic salt, captured during continuous flow catalytic Buchwald–Hartwig amination reaction. The reaction was performed in a 10 ml total volume PFA coil reactor by Vapourtec, with ID = 1 mm at flow rate of 1 ml min⁻¹, and feed concentrations of up to 1 M.
Figure 11.13 Schematic illustration of control of surface nucleation by structuring the liquid flow.
Figure 11.14 Details of a co-current laminar flow reactor for Buchwald–Hartwig amination. (a) Scheme of the reactor. 1 is heat exchanger, 2 is tubular reactor (L = 19.5 cm, ID = 6.6 mm), 3 is injector, 4 is coaxial flow, 5 is water, and 6 is outlet biphasic flow. Horizontal meniscus is organic-aqueous phase boundary; vertical cone lines correspond to diffusion. (b) Photo of the reactor during dye tracer tests with 9,10-dicyanoanthracene. (c) A photograph of the reactor during Buchwald–Hartwig amination reaction. The inner flow rate is 0.1 ml min⁻¹, outer flow rate is 1 ml min⁻¹, temperature is 60 °C. (d) Geometry and boundary conditions used for diffusion simulation in the coaxial flows. (e) Minimal injector length providing the fully developed velocity profile calculated from the CFD simulations as a function of the flow rate in the annular part of the reactor. CFD simulation was performed by Dr Xiaolei Fan using Fluent Ansys.
Figure 11.15 Conversions (a) and TOFs (b) in the laminar flow reactor. Diamonds correspond to the exp. 2; squares represent the exp. 3; triangles shows the data for the exp. 4 and circles are related to the exp. 5 (see Tables 11.1 and 11.2 for the corresponding concentrations, flow rates, and residence times). C₀ represents the overall concentration in the reactor, T = 60 °C.

List of Tables

Chapter 3: Synthesis and Application of H2O2 in Flow Reactors

Table 3.1 Epoxidation of alkenes catalyzed by Candida antarctica lipase B in flow process

Chapter 4: Scale-Up of Flow Processes in the Pharmaceutical Industry

Table 4.1 Factors affecting the environmental footprint and cost of a synthetic route
Table 4.2 Batch processes have more parameters that need to be controlled than continuous flow processes
Table 4.3 Some of the most common measures to slow down chemical reactions and their effect on sustainability
Table 4.4 Disciplines involved in the development of a pharmaceutical manufacturing process
Table 4.5 From laboratory plant to pilot and full-scale production

Chapter 5: Organic Synthesis in Flow: Toward Higher Levels of Sustainability

Table 5.1 Optimized conditions for Swern–Moffat oxidation of benzyl alcohol to benzaldehyde
Table 5.2 Optimized conditions for three-parameter optimization of benzyl azide production in continuous flow
Table 5.3 Three level four factorial Box–Behnken design for the optimization of biodiesel production from soybean oil
Table 5.4 Optimized conditions for CdSe quantum dots that emit with a desired TW (nm)
Table 5.5 Entries 1–4: Initial conditions required for the SMSIM algorithm; entry 5: optimal conditions identified by the SMSIM algorithm
Table 5.6 Entries 1–4: Initial conditions required for the SMSIM algorithm; entry 5: optimal conditions identified by the SMSIM algorithm
Table 5.7 Results for optimization using various algorithms

Chapter 7: Flow Tools to Define Waste/Time/Energy-Minimized Protocols

Table 7.1 Results of the reaction in batch and flow on different substrates [27]
Table 7.2 E-factor values for the preparation of β-azido ketones in batch and flow conditions [28]
Table 7.3 Metrics of the multistep synthesis of β-amino acids 36 [31, 32]
Table 7.4 Metrics of the multistep synthesis of N-Boc-γ-amino alcohols 39 [35]
Table 7.5 Green metrics calculation for the Aquivion PFSA-catalyzed synthesis of 42 in batch and flow conditions [39]
Table 7.6 Energy efficiency study of Suzuki coupling under MW and flow conditions [45]

Chapter 8: The Application of Flow Chemistry in the Use of Highly Reactive Intermediates and Reagents

Table 8.1 Catalyst screening for the asymmetric hydrogenation in a falling film microreactor
Table 8.2 Substrate screening for the asymmetric hydrogenation using heterogeneous Rh catalysts

Chapter 9: Nonconventional Techniques in Sustainable Flow Chemistry

Table 9.1 Penetration depth of microwaves into materials at 2.45 GHz
Table 9.2 Exit temperature of common organic solvents.^a

Chapter 10: Life Cycle Assessment of Flow Chemistry Processes

Table 10.1 Impact categories of CML-2001 method and CED used in the case studies
Table 10.2 A list of impact categories used in Recipe 2008 comparative impact assessment and energy impact assessment
Table 10.3 Stages of process development and the corresponding tools for evaluation of environmental performance indicators
Table 10.4 A summary of experimental results of batch, mini-plant, and a pilot-plant Buchwald–Hartwig amination [42]

Chapter 11: Solids in Continuous Flow Reactors for Specialty and Pharmaceutical Syntheses

Table 11.1 Flow rates and residence times of Buchwald–Hartwig amination experiments carried out in jet flow reactor
Table 11.2 Concentrations used in Buchwald–Hartwig amination experiments performed in the laminar coaxial flow reactor and the corresponding conversions at residence time, τ = 4 min

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List of Contributors

Jesús Alcázar

Janssen-Cilag Lead Discovery, S.A.

Janssen Research and Development

C/Jarama, 75

45007 Toledo

Spain

Antonio de la Hoz

Universidad de Castilla-La Mancha

Departamento de Química Orgánica

Facultad de Ciencias y Tecnologías Químicas

Avd. Camilo José Cela, 10

E-13071 Ciudad Real

Spain

Angel Díaz-Ortiz

Universidad de Castilla-La Mancha

Departamento de Química Orgánica

Facultad de Ciencias y Tecnologías Químicas

Avd. Camilo José Cela, 10

E-13071 Ciudad Real

Spain

Takahide Fukuyama

Osaka Prefecture University

Graduate School of Science

Department of Chemistry

1-1 Gakuen-cho

Nakaku Sakai

Osaka 599-8531

Japan

Akihiro Furuta

Osaka Prefecture University

Graduate School of Science

Department of Chemistry

1-1 Gakuen-cho

Nakaku Sakai

Osaka 599-8531

Japan

Tyler Goodine

James Cook University

College of Science and Engineering

Department of Physical Sciences

Discipline of Chemistry

James Cook Drive

Townsville, QLD 4811

Australia

Stefano Guido

Università di Napoli Federico II

Scuola Politecnica e delle Scienze di Base, Dipartimento di Ingegneria chimica, dei Materiali e della Produzione Industriale

Corso Umberto I, 40

80138 Napoli

Italy

Volker Hessel

Eindhoven University of Technology

Micro Flow Chemistry and Process Technology

Department of Chemical Engineering and Chemistry

De Rondom 70

5612 AP Eindhoven

The Netherlands

Vadym Kozell

Laboratory of Green Synthetic Organic Chemistry

Dipartimento di Chimica, Biologia e Biotecnologie

Università di Perugia

Via Elce di Sotto, 8

06123 Perugia

Italy

Alexei A. Lapkin

University of Cambridge

Department of Chemical Engineering and Biotechnology

Cambridge CB2 0AS

Danny C. Lenstra

Radboud University Nijmegen

Institute for Molecules and Materials

Synthetic Organic Chemistry

Heyendaalseweg 135

6525 AJ Nijmegen

The Netherlands

Konstantin Loponov

University of Cambridge

Department of Chemical Engineering and Biotechnology

Cambridge CB2 0AS

Padmakana Malakar

James Cook University

College of Science and Engineering

Department of Physical Sciences

Discipline of Chemistry

James Cook Drive

Townsville, QLD 4811

Australia

Michael Oelgemöller

James Cook University

College of Science and Engineering

Department of Physical Sciences

Discipline of Chemistry

James Cook Drive

Townsville, QLD 4811

Australia

Peter Poechlauer

Patheon Austria GmbH &Co KG

Sankt-Peter-Straße 25

4020 Linz

Austria

Wolgang Skranc

Patheon Austria GmbH & Co KG

Sankt-Peter-Straße 25

4020 Linz

Austria

Chiara Petrucci

Laboratory of Green Synthetic Organic Chemistry

Dipartimento di Chimica, Biologia e Biotecnologie

Università di Perugia

Via Elce di Sotto, 8

06123 Perugia

Italy

Floris P. J. T. Rutjes

Radboud University Nijmegen

Institute for Molecules and Materials

Synthetic Organic Chemistry

Heyendaalseweg 135

6525 AJ Nijmegen

The Netherlands

Ilhyong Ryu

Osaka Prefecture University

Graduate School of Science

Department of Chemistry

1-1 Gakuen-cho

Nakaku Sakai

Osaka 599-8531

Japan

Minjing Shang

Eindhoven University of Technology

Micro Flow Chemistry and Process Technology

Department of Chemical Engineering and Chemistry

De Rondom 70

5612 AP Eindhoven

The Netherlands

Giovanna Tomaiuolo

Università di Napoli Federico II

Scuola Politecnica e delle Scienze di Base, Dipartimento di Ingegneria chimica, dei Materiali e della Produzione Industriale

Corso Umberto I, 40

80138 Napoli

Italy

Luigi Vaccaro

Laboratory of Green Synthetic Organic Chemistry

Dipartimento di Chimica, Biologia e Biotecnologie

Università di Perugia

Via Elce di Sotto, 8

06123 Perugia

Italy

Paul Watts

Nelson Mandela Metropolitan University

InnoVenton: NMMU Institute for Chemical Technology

PO Box 77 000

Port Elizabeth 6031

South Africa

Eleonora Ballerini

Laboratory of Green Synthetic Organic Chemistry

Dipartimento di Chimica, Biologia e Biotecnologie

Università di Perugia

Via Elce di Sotto, 8

06123 Perugia

Italy

Polina Yaseneva

University of Cambridge

Department of Chemical Engineering and Biotechnology

Cambridge CB2 0AS

Foreword

Background

Flow chemistry is becoming the established first choice in many industrial and academic settings due to the changing commercial and regulatory landscape that promotes moving to a continuous manufacturing paradigm. This interdisciplinary endeavor which draws together elements from several traditionally distinct disciplines such as Chemistry, Chemical engineering, Mathematics, Informatics, and Automation systems, to highlight only a few, is changing the way chemistry is performed and even the type of chemical reactions that can be conducted. We are rapidly approaching a tipping point where flow chemistry is staged to potentially create a significant upheaval in synthetic chemistry. This traditionally highly conservative subject, in which the equipment and approaches have remained essentially static for the greater part of the last three centuries, is being presented with an exciting set of new tools.

Flow chemistry offers many improved approaches to conduct reaction chemistry by employing specifically designed reactors that create fundamentally different processing environments. Greater control and miniaturization of reactive volumes are key elements of these reactors with inherently create better mixing and temperature regulation than can be achieved in classical batch reactors as well as improving operating safety. Another advantage is that reaction parameters can be more readily adjusted thereby impacting kinetics and resulting in higher purities, yields, and selectivity. The often small volume reactors also enable the expansion of the available physical processing windows permitting much higher (lower) temperature and pressure domains to be accessed within a safe and fully monitored unit.

A major difference in the processing environment of a flow reaction is that the continuous reaction stream can be specially resolved as a function of time and, therefore, interrogated along its length to investigate the progressing reaction. Using direct in-line monitoring of the flowing reaction yields real-time data regarding its composition and can, therefore, be used to determine kinetics. Advantageously, alterations in the reactor feed (flow rates/concentrations) or its temperature have an instantaneous impact on the progressing reaction and so any change can be recorded downstream of the origin. This enables rapid screening of conditions for new processes and through integration of design of experiment (DoE) software result in efficient optimization. Likewise, scale up monitoring of consistency and establishment of software failsafe's (PAT) ensure continuous manufacturing of material in a consistent, reliable, and safe manner.

A further feature of the specially defined processing regime is that different elements of a reaction sequence from the chemical reaction to work-up and then into purification can be addressed independently using purpose configured modules that can be linked together in series. This is yet another attractive aspect of flow chemistry and why it so well suited for end-to-end continuous manufacturing scenarios. As a consequence, a great deal of effort has already been expended to assemble cascades of reactions that involve multi-step reactions leading to advanced chemical outputs using in-line quenching, work-up and extractions.

The Book

This book, which encompasses a diverse collection of expert opinions of personnel from both academic and industrial settings, appraises the key benefits of flow chemistry in a structured and logical way. The individual chapters address the current topical aspects of flow chemistry using specific examples and perspectives collated from the author's personal experience as well as from wider scientific literature. Each chapter is well contextualized and can be read in isolation but also forms a valuable collection of reference material with the review style format facilitating easy reading while also presenting additional references for more in depth discovery.

The Chapters

The combined material in this book presents a comprehensive picture of the different elements that are involved in devising practical flow chemistry solutions. This book is an educational read and one I fully recommend not only to researchers already experienced and are knowledgeable in the area of flow chemistry but also to those with minimal experience wishing to get a more detailed overview of this rapidly changing field.

Ian R. Baxendale
Department of Chemistry,
University of Durham,
South Road,
Durham DH1 3LE,
North Carolina