Sustainable Flow Chemistry E-Book
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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
This ready reference not only presents the hot and emerging topic of modern flow chemistry, it is also unique in illustrating the important connection to sustainable chemistry.
Focusing on more sustainable methods and applications, the text extensively covers every important field from reaction time optimization to waste minimization, and
from safety improvements to microwave applications. In addition, green metrics are presented as a key aspect of the book, helping readers to evaluate the efficiency of
flow technologies and their impact on the overall efficiency of a chemical process.
An invaluable handbook for every chemist working in the laboratory, whether in academia or industry.
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Table of Contents
Cover
Title Page
Copyright
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
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Guide
Cover
Table of Contents
Foreword
Begin Reading
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]PF
6
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]PF
6
, using a stainless-steel tubular reactor.
Scheme 2.9 Double carbonylation in [bmim]PF
6
using a stainless-steel tubular reactor.
Scheme 2.10 Cycloaddition of propylene oxide (PO) and CO
2
in a flow system.
Scheme 2.11 Kolbe–Schmitt reaction in a flow system using [bmim]HCO
3
as cosolvent and CO
2
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 H
2
O
2
from H
2
and O
2
.
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 H
2
O
2
formation.
Figure 3.4 Experimental setup for continuous operation of the H
2
O
2
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 H
2
O
2
using [PO
4
{WO(O
2
)
2
}
4
]@PIILP as catalyst.
Scheme 3.7 The synthesis of adipic acid from cyclohexene and H
2
O
2
.
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 H
2
O
2
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.
a
Patheon traditionally uses homemade designs made of capillaries and T-pieces,
b
for example, Corning “low-flow” reactor plates, and
c
Patheon 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-2
H
-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 (scCO
2
).
Figure 5.7 Microreactor setup for reactions in supercritical carbon dioxide (scCO
2
).
Figure 5.8 Three-dimensional parameter space consisting of CO
2
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 (CrO
3
), 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 P2X
7
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 1
H
-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)
3
PF
6
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 KMnO
4
-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). C
0
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
Sustainable Flow Chemistry
Methods and Applications
Edited by Luigi Vaccaro
Editor
Prof. 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
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Print ISBN: 978-3-527-33852-8
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Cover Design Bluesea Design, McLeese Lake, Canada
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
UK
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
UK
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
UK
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 overarching theme of improved safety in the generation of highly reactive intermediates and the application of potentially aggressive or dangerous reagents in flow is widely reviewed. In addition, two exciting and rapidly growing sub-fields, Flow Photochemistry and Microwave-Assisted Flow Chemistry, are presented. These approaches are experiencing renewed interest due to their potential for delivering new and improved chemistry as a result of reactor dimensions that impart distinct processing benefits. Of particular interest to readers wanting to understand more about the benefits of flow processing and weighing the choice of adopting flow approaches in industrial settings are two chapters from practicing pharmaceutical chemists, which offer in depth perspectives on how their organizations are pursing this mission.
Flow processing requires a more holistic consideration and, therefore, several chapters within this book address aspects exploring the wider impact and methods for assessment and establishing best practices. This is particularly important in the scaling of flow processes where early effort is rewarded in generating flow procedures that are truly sustainable and economic. Here, the adoption of many more catalytic and recyclable regents are emphasized along with flow-inspired strategies to maximize the processing benefits. However, the applied chemistry needs to be explored in combination with other considerations such as techniques that minimize resource expenditure and waste production while also allowing for effective time and energy management. Overall, the evaluation of these engineered solutions is considered through comparative metrics as a method to establish Life Cycle Assessments of the potential Flow Chemistry Processes.
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
Chapter 1Flow Photochemistry – a Green Technology with a Bright Future
Michael Oelgemöller, Tyler Goodine and Padmakana Malakar
1.1 Introduction to Synthetic Organic Photochemistry
According to the International Union of Pure and Applied Chemistry (IUPAC), photochemistry is “the branch of chemistry concerned with the chemical effects of ultraviolet, visible, or infrared radiation” [1]. Owing to the multidisciplinary nature of light, photochemistry thus finds widespread applications in the fields of analytical, environmental, food, inorganic, material, medicinal, organic, pharmaceutical, polymer, and physical chemistry [2, 3]. In terms of organic synthesis, light energy is utilized to activate molecules within their chromophoric groups. For multichromophoric substrates, this activation can be selectively achieved [4]. The amount of energy required for activation corresponds to the wavelength of the light as expressed in the Planck relation (Equation (1.1)) [5]:
where E is the energy of light; h, the Planck constant; v, the frequency; c, the velocity of light; λ, the wavelength; and , the wavenumber.
The excited state reached can undergo a multitude of energy- as well as electron-transfer processes, which are commonly shown in a Jablonski diagram [6]. Deactivation processes are common and include fluorescence, phosphorescence, or internal conversion. Alternatively, the excited state energy can be utilized for chemical changes. Owing to the different structural and physicochemical properties of excited states, photochemical reactions can differ significantly from thermal reactions. There are three main photochemical processes (Scheme 1.1) [1]: direct excitation, photosensitization, and photoinduced electron transfer reactions. In the first case, light is absorbed by the substrate and its subsequent excited state can undergo a chemical transformation either on its own or by reaction with another (ground-state) molecule. In the second case, light energy is used to activate a photosensitizer (or photocatalyst) into its excited state. This excess of energy is consequently transferred to another substrate by collision. The latter reagent enters its corresponding excited state and can undergo further chemical changes. In the third reaction mode, an electron is transferred between the excited state of one compound and the ground state of another substrate. The corresponding radical-ion pair can undergo further transformation. In reality, photochemical pathways are often much more complex.
Scheme 1.1 Simplified main photoreaction modes.
The extra energy provided via the excited state often enables chemical transformations that are thermally not feasible. Photochemistry is thus commonly applied to the synthesis of high-energy compounds such as strained rings [7, 8] or complex target molecules such as natural products [9–12]. More generally, photochemical transformations include additions, cleavages, isomerizations, rearrangements, and redox reactions. Many of these conversions proceed with high chemical yields and selectivities [13–16]. In contrast to these “productive chemical pathways,” physical deactivation processes do not yield any “chemical products”; however, they are used extensively in analytical, environmental, forensic, medical, sensory, or spectroscopic sciences.
An important performance parameter in photochemistry is the quantum yield (Φλ), which describes the efficiency of a photochemical pathway at a given wavelength (Equation (1.2)) [17]. This value is unity (Φλ = 1) when each photon absorbed by the substrate yields to the formation of a product molecule. Much smaller quantum yields (Φλ ≪ 1) are typically observed owing to competing deactivation or quenching processes. This low efficiency thus necessitates exhaustive irradiation times although the final chemical yield may still be large. When light is only required for the initiation step as in chain reactions, quantum yields can become very large instead (Φλ ≫ 1). The quantum yield is typically determined experimentally using actinometry [18].
Light absorption within a solution used in photochemical synthesis depends on the concentration of the chromophore and the thickness of the solution. This dependency is expressed in the Beer–Lambert–Bouguer law (Equation (1.3)) [19, 20]. Effective light penetration is thus limited to a narrow layer within the reaction mixture. To minimize this limitation, photochemical conversions are typically performed in high dilutions and in thin reaction vessels. In practice, this approach naturally results in large volumes of solvents.
where A is the absorbance of a solution at a given wavelength; T, the transmittance; I, the intensity of light exiting a medium; I0, the intensity of light entering a medium; ϵ, the molar absorption coefficient; l, the thickness of solution traversed by light (path length); and c, the molar concentration of absorbing species.
1.2 Conventional Batch Photochemistry
1.2.1 Batch Photochemical Technology
Two general types of reactor systems are commonly used for preparative photochemistry on laboratory scales (Figure 1.1): immersion-well and chamber reactors [21, 22]. The two systems typically utilize different light sources [23]. The former incorporates a single low-, medium-, or high-pressure mercury lamp within a double-walled immersion well at its center. The reaction medium surrounds the lamp in a separate reaction vessel. This inside-out irradiation arrangement allows for an effective utilization of light. The entire setup can be operated safely in an enclosing cabinet. Merry-go-round setups with rotating test tubes around an immersion well have also been developed and allow for space-efficient parallel photoreactions. In contrast, chamber reactors combine an external array of fluorescent tubes with internal reaction vessels such as test tubes or Schlenk flasks. This outside-in configuration allows for multiple reaction containers to be used. Cooling is provided by internal fans or by inserting cooling fingers into the reaction vessels. Specialized merry-go-round accessories can be placed inside the reactor chamber as well. In typical research laboratory practice, the total reaction volume is limited to below 1 l in both devices. Both reactor types are well established and in widespread use.
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.)
More advanced photoreactor systems are falling-film [24], “liquid-bell” [25], or spinning-disk reactors [26, 27]. Multilamp immersion well or specialized thin-film reactors are used on industrial scales [28].
1.2.2 Photochemistry and Green Chemistry
Owing to their specialized operating features and protocols, preparative photochemistry is commonly viewed as a “green” methodology par excellence [29–32]. Typical arguments to support this claim are as follows:
Light (or a photon) on its own is a “clean and traceless reagent”.
The energy input is directly controlled with the wavelength.
Most photochemical reactions can be terminated instantly by simply turning off the light source.
Photochemistry offers direct, sensitized (catalyzed), or redox pathway options.
Activation can be often achieved at room (or low) temperature.
Light energy is absorbed selectively by the chromophoric group of a molecule and does typically not affect solvent, other reagents, or product(s).
Protecting groups and subsequently additional synthesis steps can be avoided.
Despite these advantages, there are a number of “non-green” process parameters that hamper the widespread use of photochemistry. Some are caused by the utilization of light itself, while others are linked to the photophysical properties of the reagents. Some of the more serious disadvantages are as follows:
High-energy and intense light sources are hazardous to humans and require strict risk assessments and operation protocols.
Reactor materials, pipes, and gaskets experience extreme light (and heat) stresses and need to be replaced frequently.
The conversion of electrical (or fossil) energy into light comes with significant power losses.
Most light sources generate significant amounts of heat, thus necessitating efficient and energy intensive process cooling.
Optical filters are commonly applied to minimize degradation of reagents and products by polychromatic or broadly emitting lamps, thus further reducing the energy efficiency of the overall process.
The limited lifetime of most lamps (∼2000 h) imposes significant service and replacement costs.
The low quantum yields (Φ
λ
) of most photochemical transformations demand prolonged and continuous irradiations.
Photochemical reactions require inert and transparent solvents and are thus commonly conducted in hazardous benzene, acetonitrile, carbon tetrachloride, or methanol.
Light is typically absorbed within a narrow layer of the reaction mixture and solvents demanding high dilutions are thus required to limit this effect.
Some of these drawbacks can be avoided or minimized by technical developments or reaction designs [30, 33]. New energy-efficient light sources such as monochromatic lasers [34], near-monochromatic excimer lamps [35–37], or narrowly emitting light-emitting diodes (LEDs) [38, 39] and organic light-emitting diodes (OLEDs) [40] are now becoming available, thus avoiding the need for optical filters and reducing electricity costs. Photochemical conversions have also been successfully conducted in alternative and more sustainable reaction media such as water [41–43], micelles [44], ionic liquids [45], or supercritical CO2 [46]. The introduction of suitable leaving groups such as gaseous CO2 [47, 48] and N2 [49] or oxophilic TMS [50] has likewise increased photonic efficiencies and hence shortened reaction times. To address the naturally high energy demand required to power the artificial light sources, selected examples of solar chemical production with sunlight have also been realized [51–55].
These improvements, however, failed to induce any interest in photochemistry as an industrially relevant manufacturing method. With a few exceptions, industrial-scale photoreactions are limited to low-volume (but high-value) fine chemicals such as fragrances, flavors or vitamins, or bulk (but low-value) chemicals such as haloalkanes, oximes, sulfonyl chlorides, and sulfonic acids [56–58].
1.3 Continuous-Flow Chemistry
1.3.1 Introduction to Continuous-Flow Chemistry
In flow chemistry, a chemical reaction is conducted in a continuously flowing stream. Solutions of reagents are pumped from various reservoirs into a reaction channel, where the chemical transformation subsequently takes place [59, 60]. For typical laboratory applications, micro- to mesoreactors are most frequently employed. While their channel widths and depths are typically small (<1 mm for micro- and 1–6 mm for mesoreactors) they can be very long. These inner dimensions result in some significant advantages over batch processes, among which are the following:
Rapid achievement of mixing within very short times [61].
Intensification of heat transfer for cooling or heating owing to the large area-to-volume ratio inside the reactors.
Enabling chemistries that cannot be realized under batch conditions [62].
Increase in operation safety due to favorable temperature control and the absence of evaporated gas [63].
Adjustable reaction volumes for flexible on-demand manufacturing [64].
Easier automation option with possible in-line monitoring and analysis for unattended operation on site [65].
Coupling of continuous processes for multistep reactions without the need for isolation and purification of intermediates [66, 67].
Easy control of the reaction time via the flow rate or pumping speed.
Integration of solid-phase reagents such as catalysts or scavengers [68, 69].
“Greener” operations due to higher yields, selectivities, and smaller scales [70, 71].
Easy scale-up by simply changing the reactor volume or by parallel operation of multiple reactor modules.
As a result, continuous-flow devices have found widespread use in chemical synthesis. Fully automated, mobile container modules for end-to-end manufacturing of pharmaceuticals have also been developed [72].
1.3.2 Continuous-Flow Photochemistry
The design and operation features of flow reactors make them especially attractive for photochemical applications. Furthermore, many early flow devices were manufactured from transparent materials such as glass or organic polymers and thus, could be simply combined with suitable light sources. Other specific benefits of flow photochemistry include the following:
An efficient penetration of light throughout the reaction mixture inside the narrow channels, even for high chromophore concentrations.
The continuous removal of (photoactive) products from the irradiated area and thus minimization of secondary follow-up photoreactions.
