Applications of Flow Microreactors in Electrosynthetic Processes

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Applications of Flow Microreactors in Electrosynthetic Processes Mahito Atobe,*,† Hiroyuki Tateno,† and Yoshimasa Matsumura‡ †

Department of Environment and System Sciences, Yokohama National University, Tokiwadai 79-7, Hodogaya-ku, Yokohama 240-8501, Japan ‡ Department of Chemistry and Chemical Engineering, Faculty of Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan ABSTRACT: The fundamental advantages and potential benefits of flow microreactor technology include extremely large surface-to-volume ratios, precise control over temperature and residence time, extremely fast molecular diffusion, and increased safety during reactive processes. These advantages and benefits can be applied to a wide range of electrosynthetic techniques, and so the integration of flow microreactors with electrosynthesis has received significant research interest from both academia and industry. This review presents an up-to-date overview of electrosynthetic processes in continuous-flow microreactors. In addition, the advantages of continuous-flow electrochemistry are discussed, along with a thorough comparison of microreactorbased processes and conventional batch reaction systems.

CONTENTS 1. Introduction 2. Structure of an Electrochemical Flow Microreactor 2.1. Undivided and Divided Microreactors 2.2. Electrode Configurations 2.2.1. Serial Electrode Configuration 2.2.2. Interdigitated Electrode Configuration 2.2.3. Parallel Electrode Configuration 2.2.4. Other Electrode Configurations 2.3. Flow Channel Geometry 2.3.1. Channel Network Design for a Chip-type Electrochemical Flow Microreactor 2.3.2. Parallel Electrode Configuration with Multichannel Network 2.3.3. Packed-Bed-Type Electrochemical Flow Microreactors 2.4. Numbering-Up Approach to Electrochemical Flow Microreactor Systems 3. Selected Applications 3.1. Electrolyte-free Organic Electrosynthetic Processes 3.2. Electrogeneration of Unstable Intermediates and Their Efficient Reactions 3.3. C−C Coupling Reactions 3.4. Paired Electrosynthetic Processes 3.5. Integrated Electrosynthesis and Chromatographic Separation 3.6. Cogeneration of Chemical Products and Electricity 3.7. Electrochemical Methoxylation 3.8. Electrochemical Fluorination 3.9. Electrochemical Carboxylation 3.10. Electrochemical Synthesis of Amides 3.11. Electrochemical Synthesis of Diaryl Iodonium Salts © XXXX American Chemical Society

3.12. Electrochemical Synthesis Involving a Nicotinamide Adenine Dinucleotide Cofactor 3.13. Electrochemical Conversion of Dichloroacetic Acid to Chloroacetic Acid 3.14. Polymer Synthesis 3.15. Gas-Phase Substrates and Products 4. Conclusions Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION A microreactor is generally defined as a miniaturized chemical reaction device containing one or more specially fabricated channels.1−14 The characteristic dimensions of such channels typically range from the submicrometer to the submillimeter scale. These channels are often made either on or in metal, glass, silicon, or poly(dimethylsiloxane). Microreactor systems always employ flows of gases, liquids, or gas−liquid combinations, based on the use of pumps, micromixers, microseparators, (micro)heat exchangers, reaction media collection units, and media transfer tubes. One of the most typical characteristics of flow microreactors is an extremely large surface-to-volume ratio compared to classical

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Special Issue: Electrochemistry: Technology, Synthesis, Energy, and Materials Received: June 19, 2017

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DOI: 10.1021/acs.chemrev.7b00353 Chem. Rev. XXXX, XXX, XXX−XXX

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present between the electrodes. For this reason, it may not be necessary to use supporting electrolytes, depending on the intrinsic conductivity of the solvent employed. Thus, a vital aspect of reactor design is the efficient incorporation of electrodes, and various types of electrochemical flow microreactors have been developed to date, each intended for specific applications.

batch-type reactors. As an example, a 1 mL quantity of liquid in a cubic tube with a width of 1 cm will have a contact area between the liquid and the channel walls of 4 cm2. In the case of a 100 μm wide tube, a length of 100 m would be required to accommodate the same quantity of water and the contact area would increase to 400 cm2 (that is, by 2 orders of magnitude). This feature is regarded as the prime advantage of a flow microreactor and allows these devices to provide ideal environments for heterogeneous processes, such as electrochemical reactions based on electron transfer between electronic and ionic conductors. For this reason, various electrochemical systems using flow microreactors have been developed for use in electrosynthesis,15−22 electrochemical analysis and sensing,23−25 fuel cell technology,26−29 and other applications. Thus, the most distinctive feature of such microreactors developed is an interelectrode gap or flow channel width and depth in the range of a few micrometers up to 1 mm. Minimization of the electrode gap is clearly recognized to be an important process parameter, especially in industrial electrochemical synthesis, where electrolyte conductivities are low and where the ohmic drop is a major concern. In the 1960s, Beck and Guthke30 constructed a disc-stack capillary cell with a gap of 0.2−1 mm for anisaldehyde production. A small electrode gap allows one to minimize the ohmic voltage drop in the electrolyte and hence conduct the electrolysis even in a dilute electrolyte solution. This type of cell is still used commercially for the electrochemical synthesis of numerous valuable organic compounds. Prior to the mid-1990s, there was very little research regarding the application of flow microreactors to electrochemistry. Since then, there has been a notable increase in this field, especially in the study of electrochemical synthesis, supported by developments in both microreactor hardware and methodology. This review examines the use of electrochemical flow microreactors for applications related to the electrochemical syntheses of useful chemical compounds. Some fundamentals of electrochemical flow microreactors are provided in section 2 to assist the reader in understanding the basic principles behind this technology. Throughout this review, we have also sought to highlight and explain the differences between batch and flow reactors. Although microreactors have also been successfully applied to electrochemical analysis/sensing and to fuel cells, these topics are outside the scope of this review, and readers are instead referred to other summaries regarding electrochemical analysis and sensing23,31−33 and fuel cell technology.34,35

2.1. Undivided and Divided Microreactors

A proper choice of cell (reactor) design is important for performing desired electrochemical synthesis. Because the cell design is simpler and the ohmic resistance is lower, it is more convenient to use an undivided cell for electrochemical reactions. However, the electrochemical reaction or its products at the counter electrode may interfere with the desired product or the electrode reaction of the working electrode. To avoid this problem, it is necessary to separate the cell into anode and cathode compartments by a diaphragm (a sintered glass or ionexchange membrane) that allows the current to pass but suppresses mixing of anodic and cathodic solutions. Cells of this kind are called divided cells. To operate the divided mode in an electrochemical flow microreactor, a modular system is often employed. By introducing a diaphragm such as a proton exchange membrane (PEM) between stacked electrodes in the modular system, a divided microreactor can be formed. Küpper et al.36 designed and fabricated a divided microreactor as shown in Figure 1 and assessed the applicability of this device

2. STRUCTURE OF AN ELECTROCHEMICAL FLOW MICROREACTOR The appropriate design of an electrochemical flow microreactor is crucial for efficient electrochemical processes. One of the important decisions to be made in planning electrochemical synthesis in a microreactor is whether to use an undivided microreactor, in which the working and counter electrodes are located in the same flow channel (compartment), or a divided microreactor, in which the working and counter electrodes are in separate channels (compartments). In making this decision, we have to consider interference by substrates and products at the counter electrode in synthetic processes. If this does not happen, an undivided microreactor can be used. However, if this does happen, a divided microreactor must be employed. On the other hand, the most important feature of such microreactors is an electrode gap or distance in the range of a few micrometers up to 1 mm, as mentioned in section 1. This small gap eliminates the resistance of the electrolyte that is typically

Figure 1. Exploded view of electrochemical microreactor developed by Küpper et al.36 This is a divided microreactor. Two graphite plates of 189 × 98 mm2 were used for the electrodes. Reprinted with permission from ref 36. Copyright 2003 Elsevier.

to organic electrosynthesis. A divided microreactor with a diaphragm (PEM) is useful to prevent mixing of anodic and cathodic solutions, and hence the anodic and cathodic processes do not influence each other. In addition, this setup can easily be switched to an undivided mode by omitting the PEM, hence increasing the utility of electrosynthesis in a flow microreactor. B


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2.2. Electrode Configurations

with low detection limit, high sampling frequency, and good stability over long-term use. Various electrosynthetic processes have also been performed in this type of flow microreactor. Kitamura and co-workers fabricated a polymeric microchannel chip (100 μm width × 20 μm depth) with integrated electrodes38,39 and applied this unit to the anodic cyanation of pyrene (Figure 3).40 In this system, an

2.2.1. Serial Electrode Configuration. Chip-type electrochemical flow microreactors are very popular, particularly in chemical and biochemical analyses. As an example, a poly(methyl methacrylate) substrate (85 mm × 55 mm × 4.0 mm) having a microchannel (2 cm internal path length) equipped with three electrodes (platinum working and counter electrodes and a miniaturized Ag/AgCl reference electrode) was developed for amperometric determination of glucose by Angnes and coworkers37 (Figure 2). In this device, a glucose oxidase enzyme is immobilized on the channel, and the hydrogen peroxide generated by the enzymatic reaction is detected, employing parallel electric current and sample liquid flow paths. This device was applied to the differential amperometric determination of glucose in soft drinks, and it exhibited good repeatability along

Figure 3. Anodic cyanation of pyrene in an electrochemical flow microreactor with a serial electrode configuration, as developed by Kitamura and co-workers.38−40 This is an undivided microreactor. A fluorinated polystyrene plate (26 mm × 30 mm) was used for a reactor substrate. Electrodes of width 0.5 mm were fabricated perpendicular to the direction of the channel length; thus, the electrode length was equal to the channel width, 0.1 mm.

acetonitrile solution of pyrene (also containing tetrabutylammonium perchlorate) and an aqueous NaCN solution were introduced into the microchip by pressure-driven flow, such that the pyrene was oxidized at the working band electrode in the channel. Subsequently, the resulting pyrene radical cation reacted with a cyanide ion to generate 1-cyanopyrene as the main product with high efficiency (61% yield) under optimal conditions. In this configuration, the cyanation product does not come in contact with the anode, and hence overoxidation of the product is avoided. However, in general, chip-type electrochemical flow microreactors are unsuitable for synthetic purposes because their productivities are usually low due to their smaller electrode areas. 2.2.2. Interdigitated Electrode Configuration. Interdigitated electrode systems, made of arrays of microscopic electrodes formed by metal sputtering or screen-printing of patterns onto a substrate, can now be produced routinely and with extremely small dimensions via advanced lithographic techniques.41 Each electrode has a band geometry with a typical bandwidth of 0.1− 100 μm and a similar gap between electrodes. The behavior of interdigitated electrode systems in conducting sensors42,43 and amperometric detectors44,45 has been well-characterized. An electrochemical flow microreactor having such interdigitated electrodes on an alumina substrate was developed by Belmont and Girault46 (Figure 4), and the effect of flow rate on mass transport was investigated by use of redox probes such as Fe(CN)63−/Fe(CN)64−. The observed current initially increased with electrolyte flow, but eventually a steady-state response (i.e., mass-transport-limited current) was obtained.

Figure 2. (A) Photographic image of the electrochemical microreactor developed by Angnes and co-workers.37 This is an undivided microreactor. (B) Components of the flow system used for glucose quantification: (a) pump, (b) throttle, (c) flask containing carrier electrolyte, (d) injector (peristaltic pump), (e) sample vial, (f) enzymatic reactor, (g) detection cell, (h) potentiostat, (i) microcomputer, and (j) waste. (C) Details of the detection cell: (I) reference electrode, (II) platinum working electrode, (III) platinum counter electrode, (IV) polypropylene spacer, and (V) electrical contacts. Reprinted with permission from ref 37. Copyright 2013 Elsevier. C


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fabrication process, since the electrode materials are restricted to those that can be sputtered or screen-printed.49 In addition, the specific electrode areas provided by the interdigitated design are smaller than those obtainable with the simple parallel electrode configurations that will be discussed in section 2.2.3. 2.2.3. Parallel Electrode Configuration. A parallel plateto-plate electrode configuration is readily fabricated and allows uniform current and potential distributions between the electrodes. In this configuration, the two plate electrodes are separated by isolating spacers, producing a parallel flow channel. The electrodes are plane plates that can be replaced and can therefore be made out of essentially any electrode material. Another merit of this type of reactor is related to its high specific area. The submillimeter interelectrode gaps lead to thin concentration boundary layers, with any flow rate resulting in enhanced mass-transfer rates. This permits operation in a singlepass high-conversion mode, leading to a continuous process without the requirement to recycle the flow. Hence, there are many examples of electrosynthesis in electrochemical flow microreactors having this configuration.16,18,19,21 In addition, because of the sufficiently low cell height in these units, bulk electrolysis is possible without an added electrolyte. Marken and co-workers50 have successfully demonstrated the application of an electrochemical microreactor having a parallel plate-to-plate electrode configuration to the two-electron/two-proton reduction of tetraethyl ethylenetetracarboxylate in ethanol without the addition of a supporting electrolyte (Figure 6). The product (tetraethylethanetetracarboxylate) was obtained in good yield (approaching 92%) simply by solvent evaporation. The reactor employed in this work had a geometry in which the working and auxiliary electrodes directly faced one another. The distance between anode and cathode was 50 μm, so that the diffusion layers of the working and auxiliary electrodes could overlap or couple. These overlapping diffusion layers allowed local in situ electrogeneration of ions between electrodes. These ions functioned as the supporting electrolyte, and so-called selfsupported bulk electrolysis was therefore possible without the addition of a supporting electrolyte. 2.2.4. Other Electrode Configurations. In cases of low concentration of the electroactive species, the specific electrode area and also the mass-transfer coefficient must be maximized in order to reach a reasonable space−time yield. This can be obtained by use of three-dimensional electrodes such as porous electrodes. In fact, porous electrodes have also been employed in electrochemical flow microreactor systems. However, porous electrodes commonly lead to nonuniform electrode potentials and, hence, to a nonuniform current distribution within the electrodes, along with the dimension parallel to the current flow. To overcome this problem, Matlosz and Vallières developed a device incorporating a multisectioned electrode consisting of

Figure 4. Electrochemical flow microreactor with interdigitated electrodes (band electrode gap 0.25, 0.5, or 1.0 mm; band electrode width 0.5 or 1.0 mm; band length 20 mm) on an alumina substrate, as developed by Belmont and Girault.46 This is an undivided microreactor. Reprinted with permission from ref 46. Copyright 1994 Springer.

In the case of hydrodynamic integrated electrodes in a flow microreactor, the diffusion layer thickness can be expressed on the basis of the Nernst diffusion layer model as in eq 1:47 δ = nFADC bulk /Ilim

(1)

In this expression, δ is diffusion layer thickness, n is number of electrons transferred per molecule diffusing to the electrode, F is the Faraday constant, A is electrode area, D is diffusion coefficient, Cbulk is bulk concentration, and Ilim is masstransport-limited current. Therefore, forced convection resulting from flow of the solution can reduce the diffusion layer thickness and so increase the current. This electrode configuration has been shown to be applicable to electrosynthesis and has been employed for successful methoxylation of furan (maximum current efficiency 87%) (Scheme 1),46 epoxidation of propylene Scheme 1. Anodic Methoxylation of Furan

(maximum current efficiency 68%) (Figure 5),48 and electrolysis of seawater.49 The major drawback of this system is the

Figure 5. Reaction scheme for propylene epoxidation. D


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Figure 6. Schematic representation of hydrogenation of an activated olefin in ethanol by use of an electrochemical flow microreactor with a parallel plateto-plate electrode configuration in the absence of a supporting electrolyte. This is an undivided microreactor [channel width 5 mm, length 25 mm, height (interelectrode gap) 0.1 mm].

alternating porous electrodes and insulating zones (Figure 7)51,52 and applied this system to the electrosynthesis of D-arabinose via

Scheme 3. Electrocatalytic Hydrogenation of Toluene

electrolyte, and it was also possible to electrolyze gaseous substances in the PEM reactor. The catalyst layers were composed of noble metals, carbon black, and an ionomer and had a highly porous structure in order to provide an effective triple-phase boundary for electrocatalytic hydrogenation. Toluene was provided to the cathodic chamber, while humidified hydrogen gas was supplied to the anodic chamber. During operation of the unit, hydrogen was electrocatalytically oxidized at the anode to produce protons that were subsequently transported through the proton-conductive polymer. Simultaneously, at the cathode, protons penetrating through the polymer were reduced to monatomic hydrogen on the catalyst surface and then reacted with toluene to give methylcyclohexane, which is a potentially useful organic chemical hydride on the basis of its ready availability, melting point, and low toxicity.54 Electrochemical conversion in this system proceeded with high current efficiency (>90%) and good selectivity (>99%) under mild conditions, thus reducing energy consumption.

Figure 7. Multisectioned porous electrode configuration for electrochemical synthesis as used by Matlosz and Vallières.51,52 This is a divided reactor composed of 10 independent porous graphite slice anodes (each of 5 mm thickness).

Scheme 2. Electrosynthesis of D-Arabinose via Anodic Oxidation of Sodium Gluconate

2.3. Flow Channel Geometry

Both the electrode configuration and the flow channel geometry in an electrochemical flow microreactor can affect electrochemical processes, and with continuing progress in micromechanics, the fabrication of various microchannel geometries has become possible. As a result, there are several methods for constructing microchannel networks in electrochemical microreactors. 2.3.1. Channel Network Design for a Chip-type Electrochemical Flow Microreactor. Chip-type electrochemical flow microreactors having a variety of microchannel networks have been developed with the aim of enhancing electrochemical reactions. Kenis and co-workers55 fabricated Yshaped microreactor channels with multiple outlets and inlets on polycarbonate sheets (Figure 9). In these devices, Au electrodes lining the opposing sides of the interiors of the main microfluidic channel were deposited by sputtering. The performance of these

anodic oxidation of sodium gluconate (Scheme 2).51 The current efficiency during this oxidation was found to increase significantly with increasing sections in the electrode. This improved performance can be attributed to more uniform potential distribution throughout the cell. Atobe and co-workers53 reported the electrocatalytic hydrogenation of toluene to methylcyclohexane using a proton exchange membrane (PEM) flow microreactor, which imitates a polymer electrolyte fuel cell (Scheme 3). As shown in Figure 8, a membrane electrode assembly (MEA) with a 1 × 4 cm2 active area was integrated into the PEM flow-microreactor. The MEA consisted of a proton-conducting polymer sandwiched between a pair of catalyst layers on the anode and cathode sides, having the dual roles of electrode and supporting electrolyte. For this reason, the substrate solution did not require a supporting E


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Figure 8. Schematic drawing of PEM flow microreactor. This is a divided microreactor. A membrane electrode assembly (MEA) with 1 × 4 cm active area was integrated into the PEM flow microreactor. Reprinted with permission from ref 53. Copyright 2016 The Chemical Society of Japan.

microreactors (as determined by reactant conversion at the electrodes) could be increased from 10% to 100% by incorporating multiple outlets or inlets into the channel geometry. This can be ascribed tho the transport rate of reactants to reactive surfaces being enhanced by (i) removing the depleted zone through multiple periodically placed outlets (Figure 9A), (ii) adding fresh reactants through multiple periodically placed inlets along the reactive surface (Figure 9B), or (iii) producing a spiraling transverse flow through the integration of herringbone ridges along the channel walls. Legentilhomme and co-workers56 fabricated two different chip-type electrochemical flow microreactors having crossing channel networks and compared their mixing characteristics by assessing diffusion-limited currents during voltammetry (Figure 10). These reactors were made in two Altuglas plates and featured square minichannels in the upper plate. The individual square cross sections of the channels (1.5 mm along each side) intersected one another at right angles, and the entire test section was 105 mm in length and 52 mm in width. A third bottom plate

Figure 9. (A) Multiple outlet design developed by Kenis and coworkers55 to periodically remove the depleted zone. These are undivided microreactors (height of device 0.1 mm, width of main channel 0.5 mm, length of main channel 30 mm, width of inlet and last outlet 0.5 mm, length of inlet and last outlet 10 mm, width of intermediate outlets and inlets 0.09 mm, spacing between outlets or inlets 10 mm). (Inset) Optical micrograph of removal of a dyed stream. (B) Multiple inlet design to periodically supply fresh reactants to the surface. Reprinted with permission from ref 55. Copyright 2006 The Royal Society of Chemistry.

Figure 10. Two chip-type electrochemical flow microreactors, developed by Legentilhomme and co-workers,56 having crossed channel networks: (A) X-network and (B) T-network. These are undivided microreactors. The whole test section has a length of 105 mm and a width of 52 mm. Reprinted with permission from ref 56. Copyright 2008 Elsevier. F


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was used for both cell types in order to perform electrochemical measurements, incorporating 10 platinum microelectrodes (0.25 ± 0.01 mm in diameter) located at the center of the minichannels preceding the outlet chamber. In Figure 10A, the microelectrodes are numbered from right to left. A calming section containing 2 mm glass spheres improved the fluid distribution in the 10 inlet minichannels of the network. The anode consisted of a nickel grid located at the outlet of the cells. Figure 10A shows the so-called X-network geometry, based on a network of crossing minichannels, while Figure 10B presents the T-network design, which was found to allow superior mixing. The Tnetwork had a converging zone in the first half of the cell, followed by a diverging region in the remaining part of the network, to better distribute the fluid as it moved to the outlet. The decrease in the flow section at the center of the network reduced the distance between the streamlines and the path leading to the mixing process, while several T-shaped parts were integrated into the converging zone to enhance mixing. An analysis of the mixing and hydrodynamics associated with various microreactor geometries demonstrated that the T-network offered superior mixing efficiency compared to the X-network. 2.3.2. Parallel Electrode Configuration with Multichannel Network. To avoid dead volume and improve mass transfer in the thin-layer channel within an electrochemical flow microreactor having a parallel plate-to-plate electrode configuration, the two plate electrodes in the reactor are often separated by a multichannel separator sheet. The separator sheet, having a complicated channel network, functions as a turbulence promoter within reactors. This may lead to efficient mass transfer and reduction of dead zones within reactors. As mentioned in section 2.1, Küpper et al.36 designed and fabricated a divided microreactor (Figure 1) and assessed the applicability of this device to organic electrosynthesis. Each electrode plane in this unit had an electrode area of 113 cm2 and incorporated 75 parallel microchannels with channel length 189 mm, channel width 0.8 mm, and channel height 125 μm on electrodes with dimensions 189 × 98 mm2. The design consisted of layered independent cell modules and was therefore highly extendible and allowed for a wide range of electrode materials (Figure 1). Furthermore, the microchannels were associated with a multichannel separator sheet and so the microchannel geometry could be modified. This design approach allowed the microreactor to operate with high substrate concentrations (e.g., 0.5 M) with or without a supporting electrolyte (e.g., maximum current efficiency for electrosynthesis of D-arabinose = 60%). Birkin and co-workers57 reported the fabrication of a simple and inexpensive microreactor meant for electrochemical syntheses such as the anodic methoxylation of N-formylpyrrolidine (Scheme 4). The reactor had a circular design with 100 mm diameter and incorporated a graphite plate anode and a stainless steel cathode in order to more evenly distribute pressure across the plates and hence prevent leakage of the cell. The starburst-shaped spacer forming the reaction channel was lasercut from a fluoropolymer elastomer (Viton) and gave a total channel length of 600 mm (Figure 11). The resulting starburst-

Figure 11. Schematic illustration of electrochemical flow microreactor developed by Birkin and co-workers.57 This is an undivided microreactor. Two electrodes are 100 mm in diameter. Reprinted with permission from ref 57. Copyright 2011 Elsevier.

shaped narrow channel had many sharp turns and so generated complex, highly disrupted flow with contributions from flow separation and secondary flows. Methoxylation of N-formylpyrrolidine in this device was optimized to give conversions up to 96%, with an isolated yield of 87% for the methoxylated product. The same group also designed and fabricated a microreactor having a different channel geometry in order to conduct high single-pass conversion of the substrate during electrochemical synthesis.58,59 To achieve this, the reactor had a rectangular shape and incorporated a snaking channel design into the spacer, creating a channel length of 700 mm (Figure 12), with a working

Scheme 4. Anodic Methoxylation of N-Formylpyrrolidine

Figure 12. Photographic image of the snaking channel in the spacer designed by Birkin and co-workers.59 This is an undivided microreactor. Reprinted with permission from ref 59. Copyright 2012 Elsevier. G


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Figure 13. Schematic representation of the microstructured electrode developed by Tzedakis and co-workers,60 incorporating 10 reaction microchannels (length 5 mm and depth 50 μm for microchannels and collecting/distributing channels; widths 250 μm for microchannels and 1 mm for collecting/distributing channels). These are undivided microreactors. (A) One possible nonoptimized geometry. (B) Optimized geometry obtained by varying the opening angle θ of the distributing and collecting channels. Reprinted with permission from ref 60. Copyright 2012 Springer.

Scheme 5. Electrochemical Synthesis of Gluconic Acid

electrode area of 1050 mm2. With this new design, the same model reaction (anodic methoxylation of N-formylpyrrolidine) was performed, and it was found that the conversion was improved to almost 100% and a high-purity product was obtained without any organic side products.59 Tzedakis and co-workers60,61 also developed a multichannel microreactor for continuous electrosynthesis (Figure 13). To obtain the most uniform residence time distribution possible among all the microchannels, the distributing and collecting channels had a network structure, as shown in Figure 13. In addition, a heat exchanger was integrated into the microstructured electrode to rapidly remove the heat generated by exothermic reactions or supply the heat required for endothermic reactions. This microreactor effectively promoted thermodynamically unfavorable reactions or reactions with large enthalpy changes.60 2.3.3. Packed-Bed-Type Electrochemical Flow Microreactors. The packed-bed electrochemical reactor has been investigated in order to scale up reactor capacity by introducing a three-dimensional electrode. The packed-bed electrode presents high electroactive area per unit electrode volume and high masstransport characteristics based on the turbulent flow regime within the reactors. Johnson and co-workers62 fabricated two types of packed-bed reactors and applied these devices to paired electrochemical synthesis of gluconic acid and sorbitol from glucose (Schemes 5 and 6). In one reactor the current and solution flows were perpendicular (Figure 14, left), while in the other (Figure 14, right) they were parallel. In the former, the packed beds (9 × 3 ×

1.5 cm3) were separated from one another by a nylon mesh. Glass beads (5 mm) were placed at the exit and entrance to the electrode compartment to ensure uniform flow through the reactor, and reference electrodes were inserted through the body of the device into the cathodic compartment. In contrast, in the case of the parallel flow device, the packed-bed electrodes were 5.7 cm in diameter and 1.2 cm thick and were separated by perforated polypropylene discs held between nylon mesh, although the reference electrodes were again inserted through the body of the reactor. Both reactors were packed with 0.5 cm zinc shot as the cathode, while the anode compartment was packed with cylindrical graphite chips (0.3 cm diameter, 0.3 cm length). The authors compared the model reactions in both reactors and concluded that optimal results were obtained with parallel current and solution flows (maximum current efficiency was 88% for gluconic acid and 39% for sorbitol). 2.4. Numbering-Up Approach to Electrochemical Flow Microreactor Systems

In chemical engineering, scale-up is typically achieved by increasing the dimensions of the apparatus. In contrast, scaleup of microreactor technology occurs through the use of multiple optimized microreactor systems, which has come to be known as the numbering-up approach.4 However, to the best of our knowledge, there have been only a few laboratory-scale studies concerning numbering-up of electrochemical flow microreactors.63,64 Haswell and co-workers63 demonstrated the cathodic coupling of benzyl bromide with dimethylfumarate in four parallel-flow microreactors having a parallel plate-to-plate electrode configuration. This quadruple-flow reactor arrangement gave the same level of product yield (97−98%) obtained with a single reactor under the same conditions. This result indicates that scale-up of such devices can be achieved without loss of performance compared to that obtained from a single reactor. Using a different approach, Beck and Guthke30 constructed a disc-stack capillary-gapped cell with a gap of 0.2−1 mm (Figure

Scheme 6. Electrochemical Synthesis of Sorbitol

H


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Figure 14. Packed-bed-type electrochemical flow microreactors, as developed by Johnson and co-workers,62 with (A) perpendicular and (B) parallel current and solution flows. These are divided microreactors. Reprinted with permission from ref 62. Copyright 1984 Springer.

3. SELECTED APPLICATIONS The integrated use of microreactor technology with electrochemistry has been especially successful in biotechnology and fuel cell technologies but has had limited success in electrosynthetic processes. Electrosynthesis is a powerful means of obtaining a variety of useful chemical products without employing toxic or otherwise hazardous chemical reagents and under relatively mild conditions. However, conventional batch reactors can suffer from a high ohmic drop between the electrodes and insufficient mixing when used for this purpose. In contrast, the high surface area-to-volume ratios of microreactors allow effective heat and mass transport, which can be helpful during electrosynthesis. For this reason, these devices can mitigate some of the problems associated with conventional electrosynthetic processes in batch reactors.16 In addition, microreactors offer higher conversions, product yields, and selectivities in conjunction with shorter residence times (i.e., higher space−time yields) compared to classical electrochemical reactors.18 Therefore, the application of microreactors to electrosynthesis is emerging as an important and highly active field of research.15−22

15). This type of cell can be applied for various commercially important organic electrochemical syntheses that generate

3.1. Electrolyte-free Organic Electrosynthetic Processes

Although electrosynthesis is a powerful technique for obtaining organic compounds, a large quantity of supporting electrolyte has to be added to the solvent to obtain sufficient electrical conductivity in conventional processes. This can lead to difficulties in separating the product during reaction mixture workup and can also present issues related to waste generation. As noted in section 2.2.3, Marken and co-workers50 reported that an electrochemical flow reactor having a plate-to-plate configuration can allow an electrosynthetic process to proceed without addition of electrolyte. The short distance between the electrodes in such units is advantageous with regard to conductivity, while the diffusion layers of the working and auxiliary electrodes are able to overlap or couple. These

Figure 15. Schematic view of an undivided electrochemical capillarygapped cell as used by Beck and Guthke.30 This is an undivided cell. Each circular disc electrode is a few meters in diameter. Reprinted with permission from ref 18. Copyright 2009 Springer.

valuable products. In the majority of these industrial cell types, the interelectrode gap is in the submillimeter range. Therefore, this cell design can be regarded as equivalent to multiple electrochemical flow microreactors having parallel electrode configurations. I


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overlapping diffusion layers result in the localized in situ formation of ions between the electrodes, acting as a supporting electrolyte. Consequently, so-called self-supported bulk electrolysis can be carried out without addition of a supporting electrolyte. Löwe and Ehrfeld65 also fabricated an electrochemical flow microreactor and applied this unit to anodic oxidation of 4methoxytoluene to give 4-methoxybenzaldehyde dimethyl acetal, without using an electrolyte (Scheme 7). The reactor Scheme 7. Anodic Oxidation of 4-Methoxytoluene to 4Methoxybenzaldehyde Dimethyl Acetala

a

Figure 16. Electrochemical flow microreactor developed by Yoshida and co-workers:66 (A) exterior of the device and (B) system diagram. This is a divided microreactor. The two-compartment cell was divided by a diaphragm (diameter 20 mm) of poly(tetrafluoroethylene) (PTFE) membrane (thickness 75 μm, pore size 3 μm). Each compartment was filled with carbon felt electrode made of carbon fibers (6 mm × 6 mm). Reprinted with permission from ref 66. Copyright 2005 The Royal Society of Chemistry.

Reprinted with permission from ref 65. Copyright 1999 Elsevier.

incorporated a plate-to-plate electrode configuration, and the working and counter electrodes were separated by a 75 μm thick polyimide foil. In addition, a multichannel was fabricated within the polyimide foil. This reactor exhibited quantitative conversion when performing anodic oxidation in methanol on a glassy carbon anode in conjunction with 0.1 mol·L−1 KF supporting electrolyte. Efficiencies greater than 98% with respect to formation of 4-methoxybenzaldehyde could be achieved. Furthermore, it should be noted that the oxidation proceeded smoothly even without addtion of a supporting electrolyte, although conversion was significantly reduced. Yoshida and co-workers66 reported a flow-through, porous, thin-gap electrode microreactor for anodic methoxylation of various organic substrates without a supporting electrolyte. In this system, two porous electrodes faced one another, separated (at a distance on the micrometer scale) by a porous spacer, and the electric and liquid flows were parallel (Figure 16). In the methoxylation of p-methoxytoluene, the desired methoxylated product was obtained in more than 90% yield based on consumed starting material. Atobe and co-workers67,68 also developed an electrolyte-free electrosynthetic system for methoxylation of furan using an electrochemical microreactor (Scheme 1) based on a parallel electrode configuration. The distance between the electrodes was sufficiently small to ensure that electrogenerated ions derived from the substrate and the solvent could act as the electrolyte. Consequently, the process was self-supported. In the methoxylation of furan, the desired methoxylated product was obtained in 98% current efficiency. Although the self-supported microreactor systems described above were well-designed, only protic solvents such as methanol and ethanol could be used in these systems, since these were readily oxidized at the anode to give protons. These electrogenerated protons smoothly migrated to the cathode via a hydrogen-bonding network, based on the proton-jump mechanism (or Grotthuss69 mechanism) and were easily reduced at the cathode. Each process proceeded simultaneously in a harmonized manner, and consequently the system operated at a low cell voltage. In the synthetic systems typified by the above examples, either anodic oxidation of the solvent or cathodic reduction of protons is replaced by the desired electrochemical reaction of a substrate. Therefore, solvents such as dimethylformamide

(DMF) and acetonitrile are unsuitable for self-supported microreactor systems due to the extremely high cell voltages. However, if other stable ionic species are generated in situ from the substrate, they can also function as charge carriers instead of protons. Thus, in order to realize a self-supported system with an aprotic solvent, alternative ionic species derived from substrates must be employed as charge carriers. Haswell and co-workers70 reported that the electrochemical cross-coupling reaction of dimethyl fumarate with benzyl bromide was successfully carried out in DMF using a microreactor without the addition of a supporting electrolyte (Figure 17). The desired cross-coupling product was obtained in 98% yield. In this case, bromide ions were released in situ from benzyl bromide throughout the reaction and served as electric charge carriers. Dimethyl fumarate reduction at the cathode and DMF decomposition at the anode proceeded readily at low reduction and oxidation potentials, respectively. Reaction designs such as this enable the system to be self-supporting even when an aprotic solvent is employed. Atobe and co-workers71 reported a self-supported paired electrosynthetic system using acetonitrile as the reaction medium. In this demonstration, the authors employed two substrates: benzyl chloride and 1-phenylethanol (Figure 18). Benzyl chloride was reduced at the cathode while 1-phenylethanol was oxidized at the anode to give the corresponding products toluene and acetophenone in good yields (maximum yield was 87% for toluene and 61% for acetophenone). The substrates released ionic species such as chloride ions and protons following their respective electrode reactions, and these acted as the main charge carriers. Thus, the overall system was self-supporting even without decomposition of the solvent. Recently, Watkins et al.72 developed a simple, electrolyte-free electrosynthesis microreactor system (with a volume of 100 μL and batch sizes up to 10 mg) for reactions at liquid−liquid interfaces, and they demonstrated the reduction of aldehydes and imines. Figure 19A presents a photographic image of the tubular microreactor in a glass capillary, with the carbon nanofiber membrane held in place by silicone. When the reactor (filled with J


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Figure 17. Schematic representation of reductive C−C coupling reaction of dimethyl fumarate with benzyl bromide in DMF by use of a microreactor in the absence of a supporting electrolyte. This is an undivided microreactor [channel width 5 mm, length 9 mm, height (interelectrode gap) 0.16 or 0.32 mm].

Figure 18. Schematic representation of paired electrode reactions of benzyl chloride and 1-phenylethanol in acetonitrile by use of a microreactor in the absence of a supporting electrolyte. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm].

Figure 19. (A) Photographic image of tubular microreactor devised by Watkins et al.72 This is a divided microreactor. (B) Schematic drawing of microreactor capillary with the organic phase in place and the micropropeller immersed, with an amphiphilic carbon nanofiber membrane separating the aqueous electrolyte phase. (C) Schematic drawing of the overall interfacial process during reduction in the organic phase. Reprinted with permission from ref 72. Copyright 2012 Elsevier.

an organic liquid) was immersed in the aqueous phase, a stable interface for triple-phase boundary electrolysis was formed (see Figure 19B). The addition of a high-speed micropropeller ensured effective mixing and fluid transport within the organic phase. In this triple-phase boundary mechanism, the redox-active

species was only reduced at the boundary between solid electrode, aqueous electrolyte, and organic carrier phases, with the concerted insertion of one proton per electron to maintain charge neutrality (Figure 19C). High conversions and interesting selectivity effects have been observed during aldehyde or imine K


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Scheme 8. Cathodic Reduction of Substituted Benzaldehydes and Benzyliminesa

a

Reprinted with permission from ref 72. Copyright 2012 Elsevier.

Figure 20. Schematic diagram of a cation-flow system. A divided-type microreactor is used for electrochemical flow. The two-compartment reactor was divided by a diaphragm of PTFE membrane (pore size 0.1 μm). Each compartment was filled with carbon felt electrode made of carbon fibers (7 mm × 7 mm × 5 mm). Reprinted with permission from ref 73. Copyright 2001 American Chemical Society.

Nu3, and so on. In the next step, a cation precursor is transformed to S2, and the cation generated from S2 is allowed to react with nucleophiles Nu1, Nu2, and Nu3 sequentially. Subsequently, a cation precursor is transformed to S3, and the cation generated from S3 is allowed to react with nucleophiles Nu1, Nu2, and Nu3 sequentially. In this manner, nine compounds are obtained from three precursor N-acyliminium ions and three allylsilanes by simple flow switching. Yoshida and co-workers77 reported that N-acyliminium ions generated electrochemically are useful intermediates in the Friedel−Crafts reaction of aromatic compounds (Figure 22). Although this is not the cation-flow method (which is the method for generating ionic species via flow electrolysis), Nacyliminium ions generated and accumulated by low-temperature electrolysis in a batch-type reactor are used in a flow system for the Friedel−Crafts reaction. In this work, a solution of 1,3,5trimethoxybenzene and N-acyliminium ions generated electrochemically was mixed in the first micromixer, M1, at −78 °C at a flow rate of 8 mL·min−1 and the resulting solution was sent to a microtube reactor (with diameter 1.0 mm and length 1.0 cm). Triethylamine was introduced in the second micromixer, M2, again at a flow rate of 8 mL·min−1, to quench the reaction and give the monoalkylation product in 78% yield, together with the dialkylation product (19%). N-Acyliminium ions generated electrochemically have also been applied to cationic three-component coupling reactions (Figure 23) using essentially the same microreactor system as above at 0 °C.78 In this process, the mixing of 2-t-butyl-3methoxycarbonyloxazole with N-acyliminium ions generated electrochemically in M1 generates intermediate cations in the first microtube reactor, R1 (with a residence time tR of 0.48 s). In M2, these intermediate cations react with allyltrimethylsilane to give the final coupling product in 79% yield. An important point

reduction (Scheme 8) in this reactor (maximum conversion was 100% for aldehyde reduction and 100% for imine reduction). In this preliminary study, the authors did not adopt continuous-flow methods, but they did state that there is the potential for scale-up through the use of continuous-flow methods. 3.2. Electrogeneration of Unstable Intermediates and Their Efficient Reactions

One of the key features of an electrochemical flow microreactor is that it serves as an effective means of generating and using normally unstable reactive species. In such systems, these species are generated in the absence of a reaction partner within the flow and are quickly transferred to the next reactor, where the reaction with the partner takes place. Because the residence time can be shortened significantly, highly unstable species can be used for reactions before they decompose. Yoshida and co-workers73−75 reported that a microflow electrochemical system can perform the oxidative generation of unstable organic cations at low temperatures, in the so-called cation-flow technique. In this process, an electrochemical reactor is equipped with a carbon felt anode and a platinum wire cathode (Figure 20), and the anodic and cathodic chambers are separated by a diaphragm made of PTFE membrane. A solution of methyl pyrrolidinecarboxylate is introduced to the anodic chamber, while the cathodic chamber is filled with a solution of trifluoromethanesulfonic acid as a proton source. The organic cations thus generated are immediately transferred to a vessel in which a nucleophilic reaction takes place to give the desired coupling product (69% conversion, 91% selectivity). The cation-flow method enables sequential combinatorial synthesis by simple flow switching.73,76 As shown in Figure 21, a cation generated from precursor S1 is allowed to react with nucleophile Nu1, such that the nucleophile is transitioned to Nu2, L


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Figure 21. Sequential combinatorial synthesis based on the cation-flow method. Reprinted with permission from ref 76. Copyright 2008 American Chemical Society.

is that this transformation can be accomplished at 0 °C, which is a much higher temperature than that required when a macro-batch reaction is employed (−78 °C). Presumably, the extremely fast mixing in M1 and precise residence time control in R1 are responsible for progression of the reaction at this higher temperature. Yoshida and co-workers79 reported that selective monoiodination of aromatic compounds such as dimethoxybenzene was successfully achieved with anodically generated I+ in a microsystem consisting of a mixer and a microtube reactor (Figure 24). In a macroscale batch reactor, the reaction with I+ generated from 0.625 equiv of I2 (0.0625 M) in 0.3 M Bu4NBF4−CH3CN with 2.1 F·mol−1 (based on I2) of electricity generates the monoiodo compound as the major product (45% yield). However, a significant amount of diiodo compound is also formed (18% yield). In contrast, the efficient mixing in the microsystem greatly improves selectivity for the monoiodo compound (78% yield) and reduces formation of the diiodo compound (4% yield). Yoshida and co-workers80,81 also demonstrated effective glycosylation reactions involving the glycosyl cation intermediate (A in Figure 25) in a microsystem consisting of three T-shaped mixers (M1−M3) and three microtube reactors (R1−R3). In this demonstration, [ArS(ArSSAr)]+, generated electrochemi-

Figure 22. Friedel−Crafts reaction of 1,3,5-trimethoxybenzene with Nacyliminium ions generated electrochemically. Reprinted with permission from ref 77. Copyright 2005 American Chemical Society.

Figure 23. Three-component coupling reaction with an N-acyliminium cation pool. Reprinted with permission from ref 78. Copyright 2010 The Chemical Society of Japan.

M


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in a parallel manner, such that laminar flow prevents the oxidation of 2 at the anode and only the precursor is oxidized to generate N-acyliminium ions, which diffuse through the solution and react with 2. Although the efficiency of this process is very low for the Bu4NBF4/CH3CN system, the Bu4NBF4/TFE (2,2,2trifluoroethanol) system (59% yield) or ionic liquids (62−91% yield) both give the desired product 3. Atobe and co-workers84,85 also reported the electrochemical generation of unstable o-benzoquinone and its rapid use for a subsequent reaction with benzenethiols (Figure 27). Although obenzoquinones are considered to be useful and important synthetic building blocks in organic and medicinal chemistry, they are too reactive and unstable to store and are not easy to handle because they are highly labile. The flow microreactor fabricated for the model process consisted of two parts: an electrolysis zone, for the generation of o-benzoquinone via catechol oxidation, and a chemical reaction zone, for the rapid use of this compound in the Michael addition reaction. By use of this system, the reaction proceeded very efficiently without decomposition of the o-quinones and with selective oxidation (88% yield for the Michael addition product). Nishiyama and co-workers86 demonstrated the efficient generation of methoxy radicals by electrochemical oxidation of MeOH in a flow microreactor with a boron-doped diamond (BDD) anode, followed by immediate use of these radicals for methoxylation of isoeugenol (Scheme 9). In this system, methoxylation was facilitated by high concentrations of methoxy radicals formed at the BDD anode in a flow microreactor system having a parallel electrode configuration (maximum yield was 40% for licarin and 90% for the vicinal substituted product). Atobe and co-workers87,88 also demonstrated that an electrochemical flow microreactor can be extremely useful in terms of controlling reactions involving an electrogenerated base (EGB) such as 2-pyrrolidone anion. The EGB derived cathodically from 2-pyrrolidone can be applied to many organic reactions, although severe reaction conditions such as low temperature and an inert gas atmosphere are usually required. However, using a parallel laminar flow mode in a two-inlet microflow electrochemical reactor, Atobe and co-workers88 were able to perform selective monoalkylation of methyl phenylacetate without the need for extreme reaction conditions (Figure 28). The flow microreactor consisted of three reaction parts: a cathodic reaction zone for generation of 2-pyrrolidone anions, a deprotonation zone for reaction between these anions and methyl phenylacetate, and a final alkylation reaction zone for rapid use of the unstable intermediate to obtain the monoalkylated product formed by reaction with alkyl iodides (85% yield for the monomethoxylated product). An EGB such as 2-pyrrolidone anion can also be used for trichloromethylation of aldehydes with a trichloromethyl anion. The resulting trichloromethylcarbinol derivatives are very important precursors for a number of useful chemicals, such as terminal alkynes, chloromethyl ketones, vinyl dichlorides, and αchloroacetic acids.89−93 Atobe and co-workers87 successfully demonstrated in situ generation of trichloromethyl anions as the EGB and subsequent efficient reaction of these species with benzaldehyde in an electrochemical flow microreactor under ambient conditions (Figure 29). The electrochemical flow microreactor used in the work was composed of three parts: a cathodic reaction zone for generation of 2-pyrrolidone anions from 2-pyrrolidone, a trichloromethyl anion formation region in which reaction between 2-pyrrolidone anions and chloroform took place, and a final reaction zone in which rapid

Figure 24. Selective monoiodination of 1,3-dimethoxybenene by use of micromixing. Micromixing of 1,3-dimethoxybenzene with electrochemically generated I+ was carried out in a microsystem consisting of an IMM single mixer (channel width 0.5 mm) and a microtube reactor (ϕ = 0.5 mm × 2 m) at 0 °C. Reprinted with permission from ref 79. Copyright 2006 The Royal Society of Chemistry.

Figure 25. Glycosylation with electrochemically generated activator [ArS(ArSSAr)]+ in a microsystem consisting of three T-shaped mixers (M1−M3; channel width 0.5 mm) and microtube reactors (for R1, ϕ = 1.0 mm and L = 12.5 cm; for R2, ϕ = 1.0 mm and L = 100 cm; for R3, ϕ = 1.0 mm and L = 50 cm). Adapted with permission from ref 80. Copyright 2011 Wiley.

cally from the disulfide (ArSSAr), was used to activate a thioglycoside in the presence of a nucleophile such as methanol. Specifically, the electrochemical oxidation of ArSSAr (Ar = pFC6H4) was carried out at −78 °C to generate and accumulate [ArS(ArSSAr)]+. A CH2Cl2 solution of the thioglycoside was mixed with [ArS(ArSSAr)]+ obtained electrochemically in M1 to generate glycosyl cations, which reacted with methanol as the nucleophile in M2 and R2. Triethylamine was added at M3 to quench the reaction, giving the desired product in 88% yield as a mixture of α- and β-isomers (α:β = 38:62). Atobe and co-workers82,83 reported that a parallel laminar flow in a two-inlet microflow electrochemical reactor enables effective generation of N-acyliminium ions, followed by trapping with an easily oxidizable carbon-based nucleophile such as allyltrimethylsilane (Figure 26). A solution of the cation precursor (1 in Figure 26) and a solution of allyltrimethylsilane 2 are introduced

Figure 26. Anodic substitution reaction that uses parallel laminar flow in a two-inlet flow microreactor. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.02 mm]. N


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Figure 27. Schematic representation of electrogeneration of o-benzoquinone and the following reaction with benzenethiol in a flow microreactor, as developed by Atobe and co-workers.84,85 This is an undivided microreactor. Reprinted with permission from ref 85. Copyright 2012 The Royal Society of Chemistry.

Scheme 9. Electrochemical Oxidation of MeOHa

This oxidation took place in a flow microreactor with a BDD anode, and the resulting radical was rapidly used for subsequent methoxylation of isoeugenol. a

Figure 28. Schematic representation of electrogeneration of 2-pyrrolidone anions and their immediate application to monoalkylation of methyl phenylacetate in a flow microreactor, as designed by Atobe and co-workers.88 This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm]. Reprinted with permission from ref 88. Copyright 2015 The Royal Society of Chemistry.

trichloromethylation of benzaldehyde proceeded to give 2,2,2trichloro-1-phenylethanol (52% yield).

mentally attractive since only electrons serve as reagents and the reaction proceeds under mild conditions. Haswell and co-workers94 demonstrated cathodic dimerization of 4-nitrobenzyl bromide in an electrochemical flow microreactor having a plate-to-plate electrode configuration in the absence of added supporting electrolyte (Scheme 10). The process was optimized at an interelectrode distance of 160 μm, flow rate of 40 μL·min−1, and current density of 2.4 mA·cm−2, resulting in a yield of 94%. It was also noted that a very small

3.3. C−C Coupling Reactions

C−C coupling is one of the most important aspects of organic synthesis and is the main step in the syntheses of various ligands, polymers, and natural products. Although a number of synthetic approaches to this coupling have been developed to date, electrochemical C−C coupling is economically and environO


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Figure 29. Schematic representation of in situ preparation of unstable trichloromethyl anions from electrogenerated 2-pyrrolidone anions and subsequent reaction with benzaldehyde in an electrochemical flow microreactor, as designed by Atobe and co-workers.87 This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm]. Reprinted with permission from ref 87. Copyright 2016 The Chemical Society of Japan.

allylation.96,97 Electrochemical carbonyl allylation can produce either γ- or α-adducts, depending on whether the aldehyde or the allylic halide is reduced by the cathode. If the aldehyde has a higher reduction potential, the allylic halide is predominantly reduced to give the γ-adduct, whereas the aldehyde is reduced preferentially and the α-adduct is favored if the reduction potential of the allylic halide is higher. Therefore, control over selectivity in C−C cross-coupling products (or regioselectivity in the case of this reaction) requires that either the allylic halides or aldehydes are reduced chemoselectively, regardless of their reduction potentials. To perform this chemoselective cathodic reduction, Atobe and co-workers96,97 employed a liquid−liquid parallel laminar flow in an electrochemical flow microreactor. As shown in Figure 31, when the two solutions (containing allylic chloride and aldehyde) were introduced through their respective inlets (1 and 2), a stable liquid−liquid interface was generated and mass transfer between the input streams occurred only by means of diffusion. Therefore, the substrate introduced through inlet 1 (inflow 1) was predominantly reduced, while reduction of the inlet 2 substrate (inflow 2) was avoided. This system allowed chemoselective cathodic reduction followed by regioselective formation of the cross-coupling product. That is, the desired product could be selected simply by switching the reagent flows (92% selectivity for α-adduct in flow mode a, 87% selectivity for γ-adduct in flow mode b). Wirth and co-workers98 carried out Kolbe electrolysis and anodic trifluoromethylation of olefins in an electrochemical flow

Scheme 10. Electrochemical Reduction of 4-Nitrobenzyl Bromide

amount of 4-nitrotoluene was generated in this system from debromination of 4-nitrobenzyl bromide. Atobe and co-workers95 demonstrated an efficient anodic aromatic C−C cross-coupling reaction using a parallel laminar flow mode in a two-inlet flow microreactor. In this demonstration, they chose the anodic cross-couplings of naphthalene and alkylbenzenes as model reactions. The desired crosscoupling products were obtained via reaction between the electrogenerated radical naphthalene cations and alkylbenzenes as coupling partners. The parallel laminar flow mode was found to be extremely useful for selective anodic oxidation of naphthalene and the subsequent C−C cross-coupling reactions with alkylbenzenes (Figure 30). The desired cross-coupling products were obtained in much higher current yields compared to the same reactions in a conventional batch-type cell (current efficiency was 49% in batch cell and 85% in flow reactor). Employing parallel laminar flow in an electrochemical flow microreactor also enables chemoselective cathodic reduction to control the product regioselectivity in electrochemical carbonyl

Figure 30. Schematic representation of anodic aromatic C−C cross-coupling reaction by use of liquid−liquid parallel laminar flow in a two-inlet electrochemical flow microreactor, as developed by Atobe and co-workers.95 This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.02 mm]. Reprinted with permission from ref 95. Copyright 2015 The Royal Society of Chemistry. P


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Figure 31. Chemoselective cathodic reduction as employed by Atobe and co-workers,96,97 using parallel laminar flow in a two-inlet flow microreactor, showing the flow modes for selective reduction of (a) benzaldehyde and (b) 1-chloro-3-methyl-2-butene. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.02 mm].

Scheme 11. Kolbe Electrolysis of Di- and Trifluoroacetic Acids in the Presence of Various Electron-Deficient Alkenes

microreactor. The microreactor used in these works contained a flow channel sandwiched between two platinum electrodes. Kolbe electrolysis of di- and trifluoroacetic acids in the presence of various electron-deficient alkenes was performed in conjunction with constant current and continuous flow at room temperature (Scheme 11). As a result, di- and trifluoromethylated compounds were effectively produced in yields either equal to or higher than those obtained for identical reactions under batch conditions (yield 11−45% in batch reactor and 11−52% in flow reactor). An anodic phenol−arene C−C cross-coupling reaction was also achieved by Atobe and co-workers99 in inexpensive and sustainable media such as methanol, acetic acid, or formic acid in an electrochemical flow microreactor (90% maximum yield). This device was found to provide better performance under screening conditions than standard beaker-type electrolysis cells (Scheme 12).

Scheme 13. Cathodic Coupling of Activated Olefins with Benzyl Bromidesa

a

Scheme 12. Anodic Phenol−Arene C−C Cross-Coupling Reaction

Reprinted with permission from ref 70. Copyright 2006 Wiley.

electrode distance (320 μm), conversions of 47% and 77% were achieved, with increases in current only increasing the generation of the homocoupling products. Yields of up to 99% were achieved with a variety of substituted benzyl bromides and activated olefins. Haswell and co-workers64 also carried out the synthesis of various substituted phenyl-2-propanones by a one-step electrochemical acylation reaction involving direct electroreductive coupling of benzyl bromides and acetic anhydride in the same microreactor configuration (Scheme 14). This technique gave yields typically in excess of 80% with correspondingly high levels of product selectivity.

Haswell and co-workers70 reported self-supported cathodic coupling of activated olefins with benzyl bromides in an electrochemical flow reactor having a plate-to-plate configuration (Scheme 13). Better results were achieved when the electrodes were closer together (with a gap of 160 μm), allowing a lower voltage and resulting in conversions of >90%. At a greater Q


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Scheme 14. Direct Electroreductive Coupling of Benzyl Bromides and Acetic Anhydride

Figure 32. Electrochemical paired microflow system as developed by Yoshida and co-workers.74 This is a divided microreactor. The two-compartment reactor was divided by a diaphragm of PTFE membrane (pore size 0.1 μm). Each compartment was filled with carbon felt electrode made of carbon fibers (7 mm × 7 mm × 5 mm). Reprinted with permission from ref 74. Copyright 2005 Wiley.

3.4. Paired Electrosynthetic Processes

configuration. In general, efficient sequential oxidation (or reduction) and the following reduction (or oxidation) of a single starting material has been difficult in conventional batch-type reactors because the distance between the anode and cathode is on the centimeter scale. As such, electrochemically generated intermediates require some time to diffuse from the electrode surface to the counter electrode surface, so that complete conversion of intermediates is difficult when the theoretically required amount of electricity is employed. This reduces the efficiency of the electrolysis process as well as the utility of the synthesis. In order to solve this problem, Atobe and coworkers101 employed an electrochemical microreactor. The short distance between the electrodes in the microreactor enabled rapid molecular diffusion from anode to cathode, leading to ideal circumstances for the desired paired electrolysis (Figure 33). In this work, the paired electrosynthetic conversion of a phenol derivative to a diaryl ether in an electrochemical microreactor was employed as a model process. The anodic C−O coupling reaction of phenol to a dienone aryl ether and the following reduction of the ether were accomplished in this device, selectively generating the desired diaryl ether (41% yield, 100% selectivity). In sharp contrast, only the dienone aryl ether intermediate was obtained (20% yield) when a conventional batch reactor was used. Atobe and co-workers100 also demonstrated the paired electrochemical conversion of benzylamine to dibenzylamine in an electrochemical flow microreactor. As shown in Figure 34, in the first step, the oxidative condensation of benzylamine to Nbenzylidenebenzylamine takes place at the anode. Following this, a secondary amine such as dibenzylamine can be obtained in a reasonable yield by cathodic hydrogenation of the Nbenzylidenebenzylamine at the cathode (74% yield). Employing a batch reactor gives the desired product (dibenzylamine) in only low yield (3% yield) and instead generates the intermediate imine (N-benzylidenebenzylamine) as the main product (93% yield). This comparative experiment clearly shows that narrow spacing of the electrodes in a microreactor enables highly efficient sequential redox reactions that dramatically increase the yield of the desired product. Very recently, Waldvogel and co-workers102 reported the development of a highly modular electrochemical flow micro-

Electrosynthesis involves simultaneous reduction at a cathode and oxidation at an anode. In the case of organic electrolysis, synthesis of the desired products is obtained by either a cathodic or anodic reaction and so, in most cases, the reaction products generated at the counter electrode are wasted. Therefore, simultaneous utilization of both cathode and anode reactions for efficient synthesis solely of desired products is preferable. Paired electrosynthesis is based on this concept, and the development of electrochemical flow microreactors has led to new chemical processes based on paired electrode processes. Yoshida and co-workers74 developed a paired microflow electrochemical system in which a reaction between anodically generated organic cations and cathodically generated carboanion equivalents took place to give the corresponding coupling products (Figure 32). In this work, anodic oxidation of a silylsubstituted carbamate to generate a solution of N-acyliminium ions and cathodic reduction of cinnamyl chloride in the presence of chlorotrimethylsilane were carried out under a constant current condition at −78 °C (Scheme 15). The anodically Scheme 15. Paired Electrolysis of Silyl-Substituted Carbamate and Cinnamyl Chloride, Followed by Direct Coupling of Anodic and Cathodic Productsa

a

Reprinted with permission from ref 74. Copyright 2005 Wiley.

generated N-acyliminium ions subsequently reacted with the cathodically generated cinnamyltrimethylsilane downstream to afford the coupling product in a reasonable yield (85% conversion, 79% yield based on consumed silyl-substituted carbamate). Atobe and co-workers100,101 successfully demonstrated sequential paired electrosynthetic reactions in an electrochemical flow microreactor having a parallel plate-to-plate electrode R


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Figure 33. Schematic representation of electrochemical conversion of a dichlorophenol derivative to a diaryl ether in methanol in an electrochemical microreactor, as devised by Atobe and co-workers.101 This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm]. Reprinted with permission from ref 101. Copyright 2014 The Chemical Society of Japan.

Figure 34. Schematic representation of electrochemical conversion of benzylamine to dibenzylamine in an electrochemical flow microreactor. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm].

To demonstrate the potential of process integration, simulations of the functioning of this reactor during direct electrochemical production of arabinose from sodium D-gluconate were performed, as shown in Scheme 2. Experimentally verified models of the reactor and column units were combined with a model of the electrochemical SMB reactor, and a schematic of the integrated system and a simulated concentration profile are presented in Figure 36. Here it is evident that the concentration of substrate decreased in the active area of the system while the product concentration increased. Electrochemical reactions possess the unique ability to be switched on and off with applied current, and so the reactors could be switched off to simulate the moving-bed chromatography and then activated once more, making combination of the two processes possible. The integrated process demonstrated interactions between the reaction and separation that reduced side reactions. Case studies have shown the theoretical feasibility of such integrated processes and, compared to a conventional reactor, utilization of an integrated system has also been found to give higher yields (48% at 99% product purity).

reactor (Figure 35). This innovative setup facilitates adjustment of the electrode distance and rapid exchange of electrode materials and also offers the possibility of easily switching between divided and undivided cells. Another major benefit of this reactor is the exact thermal positioning of the electrode material within a Teflon piece (100 mm × 40 mm × 16 mm). As a result, expensive, nonmachinable electrode materials such as boron-doped diamond or glassy carbon can be readily inserted in the reactor. To demonstrate the applicability and performance of this modular cell, the authors demonstrated a domino oxidation− reduction sequence for synthesis of nitriles from aldoximes (Scheme 16). In this transformation, the oxime is first oxidized at a graphite anode to the corresponding nitrile N-oxide and then reduced directly at a lead cathode to the desired nitrile. An 80% yield of the desired nitrile was achieved at a flow rate of 8.5 mL· h−1 and a current density of 5 mA·cm−2 with a 0.12 mm thick spacer. 3.5. Integrated Electrosynthesis and Chromatographic Separation

To increase the productivity of the electrochemical reactor, Schmidt-Traub and co-workers103 developed a new continuous process combining electrochemical reaction and chromatographic simulated moving-bed (SMB) separation. In this novel continuous process, the electrochemical reaction takes place in an electrochemical flow microreactor coupled to the SMB plant. The reactor design is based on the thin-layer cell technique and employs a miniaturized plate-to-plate electrode configuration.

3.6. Cogeneration of Chemical Products and Electricity

As discussed earlier, the integration of microreactor technology with electrochemistry has also been successful in fuel cell applications. In these cases, the main focus is not the products of the electrochemical processes but rather the generation of electricity. However, for exothermic processes, it is potentially attractive to carry out a chemical synthesis in combination with a S


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Figure 35. (A) Cross-section of the Teflon piece in the Waldvogel reactor, showing the connections for tubing, inlet, and outlet and free space for the electrode. (B) Complete half-cell containing the Teflon piece, the electrode, and a stainless steel plate (open space for electrode 60 mm × 20 mm). (C) Half-cell with a gasket/spacer on top. (D) Exploded drawing of the complete divided cell. In the undivided mode, the Nafion membrane and one gasket/ spacer are omitted. Reprinted with permission from ref 102. Copyright 2017 American Chemical Society.

in an electrochemical flow microreactor. In this case, solid oxide fuel cell (SOFC) technology was adopted for the microreactor construction, and the reactor was electrolyte-supported with a gadolinia-doped ceria (CGO) electrolyte and operated in the temperature range 500−650 °C. The anode was a mixture of a Ni/CGO composite and an iron antimony oxide catalyst, which is known to catalyze the ammoxidation of methanol to HCN. The anode off-gas contained HCN, with a maximum yield of 40% (with respect to methanol input) and selectivity for the conversion of methanol to HCN of 47.5%.

Scheme 16. Domino Oxidation−Reduction Sequence for Synthesis of Nitriles from Aldoximesa

a

Reprinted with permission from ref 102. Copyright 2017 American Chemical Society.

3.7. Electrochemical Methoxylation

fuel cell so as to cogenerate electricity from some of the excess free energy of the reaction.104 Wouters et al.105 constructed a microfluidic fuel cell-type reactor based on a colaminar flow cell (CLFC) design for the electrochemical reduction of nitrobenzene. The CLFC was constructed on the basis of the fuel cell concept of Ferrigno et al.,106 as depicted in Figure 37. With methanol oxidation as the anodic process, this reactor was able to hydrogenate nitrobenzene while generating a small amount of electricity. The highest power density obtained was 0.542 mW·cm−2 at cell potential of 0.217 V and current density of −2.498 mA·cm−2. Methanol conversion of 37% was achieved at a flow rate of 5 μL· min−1 with an average power density of 0.062 mW·cm−2. Hydrogen cyanide (HCN), though highly toxic, is an important building block for a variety of chemicals and is produced in large quantities worldwide. Atkinson and coworkers27 demonstrated HCN synthesis from methanol/ ammonia steam mixtures with cogeneration of electrical energy

Electrochemical methoxylation is important in industrial organic electrochemistry, due to widespread use of the resulting aldehydes as precursors for fragrances and fine chemicals and in pharmaceuticals, dyestuffs, plating additives, pesticides, and flavors.107 For this reason, as noted, many groups have studied electrochemical methoxylation in electrochemical flow microreactors.46,57,59,65−68 Lapicque and co-workers107 demonstrated the anodic oxidation of 4-methoxytoluene to 4-methoxybenzaldehyde dimethyl acetal in this type of device (Scheme 7). In their study, the single-pass thin-gap flow reactor shown in Figure 38 was fabricated, and the selectivity and conversion during the model methoxylation were assessed as functions of composition of the electrolyte solution, flow rate, and applied current. The experimental results indicated that potassium fluoride (currently used for industrial synthesis and providing higher yields than sodium perchlorate) affected the reaction mechanism, such that high KF concentrations facilitated the undesired oxidation of the diacetal. Nevertheless, a feed solution with a substrate T


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Figure 36. Simulated internal concentration profile in an SMB reactor during production of arabinose. Legend: D = desorbant, E = extract, F = feed, R = raffinate. Reprinted with permission from ref 103. Copyright 2003 Springer.

Figure 37. Exploded view of the cogeneration colaminar flow cell designed by Wouters et al.,105 showing (1) poly(oxymethylene) piece with milled flow channels (two channels of Y-shaped form 0.5 mm × 0.5 mm × 10 mm, main channel 1.0 mm × 0.5 mm × 30 mm); (2) electrocatalyst-coated graphite electrodes (available surface 4 × 28 mm2) placed in the polyoxymethylene piece and glued to the electrical wires with conductive epoxy; (3) cyclic olefin copolymer plate and rubber seal covering the channel; (4) poly(methyl methacrylate) piece with holes for nanoports for tubing; and (5) aluminum plates that hold the construction together. This is an undivided microreactor. Reprinted with permission from ref 105. Copyright 2016 Elsevier.

Figure 38. Schematic view of single-pass thin-gap flow reactor designed by Lapicque and co-workers.107 This is an undivided microreactor. The anode (glassy carbon) consisted of ten 1 × 1 cm2 elements, separated from each other by a 1 mm wide insulated section. High-grade stainless steel was chosen as the cathode material. The two electrodes, with a 100 μm interelectrode gap, formed a 1 × 0.01 cm2 channel cross section. Reprinted with permission from ref 107. Copyright 2008 Springer.

concentration of 0.1 M in 0.01 M KF was 90% converted in the 100 μm thin-gap cell when a suitable voltage was applied, with nearly 87% selectivity. The authors stated that this selectivity was substantially higher than that typically observed in conventional electrochemical cells. An electrochemical flow microreactor can also be interfaced with a stand-alone analytical technique such as gas chromatography (GC) or high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS), allowing mechanistic studies of electrochemical reactions that identify intermediate species. A ceramic electrochemical microreactor

devoted to electrosynthesis was developed by Girault and coworkers108 (Figure 39) and directly coupled to the six-port valve of a mass spectrometer, allowing online sampling and analysis of the reaction mixture (Figure 40). As shown in Figure 39, five ceramic layers assembled under pressure and sintered at 850 °C for 1 h constituted the ceramic microreactor. Interdigitated electrodes were screen-printed with platinum ink, and the microreactor chamber was composed of seven channels perpendicular to the electrodes. Electrochemical methoxylation of methyl-2-furoate was carried out, and the effect of residence U


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Figure 39. Schematic representation of the ceramic electrochemical microreactor assembly developed by Girault and co-workers.108 This is an undivided microreactor. Reprinted with permission from ref 108. Copyright 2002 The Royal Society of Chemistry.

Figure 40. (A) Schematic representation of apparatus used by Girault and co-workers108 for online mass spectrometric identification of electrogenerated products. (B) Two configurations of the six-port valve. Reprinted with permission from ref 108. Copyright 2002 The Royal Society of Chemistry.

depending on the manner in which the fluorine atom is delivered, electrochemical fluorination is one of the most promising and reliable methods for selective fluorination.111 Electrochemical fluorination has also been carried out in flow microreactors.60,112,113 Tzedakis and co-workers112 investigated the electrochemical fluorination of both anisole and dimethoxyethane using a filter-press electrochemical microreactor under various working conditions (−10 °C < T < 40 °C). They did not observe anisole fluorination on either the aromatic ring or the methoxy group, but the dimethoxyethane was monofluorinated

time in the microreactor was optimized on the basis of MS analyses. 3.8. Electrochemical Fluorination

Recent progress in organofluorine chemistry has contributed significantly to advances in medicinal, agrochemical, and material sciences.109 Industry sources estimate that as many as 30−40% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.110 Although there are some strategies for the introduction of a single C−F bond into an organic molecule, V


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Approximately 60 mL of this concentrated 18F− solution was subsequently redirected into a microfluidic reaction flow cell for further nucleophilic substitution reactions. Iwata and co-workers 113 carried out nucleophilic 18 F − substitution reactions to obtain [ 18 F]fluoro- D -glucose ([18F]FDG), [18F]fluoro-misonidazole ([18F]FMISO), [18F]flumazenil, and [18F]fluoromethyl bromide (Figure 42). Under optimized conditions, these four 18F-labeled compounds were obtained in yields of 98%, 80%, 20%, and 60%, respectively, all of which were comparable to or higher than those obtained by conventional means.

and two reaction products were obtained (FCH2OCH2CH2OCH3 and CH3OCHFCH2OCH3 with chemical yields of 62% and 38%) in conjunction with a charge of 7 F· mol−1 based on substrates. The same group also demonstrated one-step electrochemical fluorination of 2-deoxy-D-glucose in a multichannel microreactor (Scheme 17).60 However, the yield of the fluorinated product Scheme 17. Electrochemical Fluorination of 2-Deoxy-Dglucose

3.9. Electrochemical Carboxylation

Atobe and co-workers114 reported a novel electrochemical carboxylation system for CO2 fixation reactions with benzyl halides, using a microreactor. Electrochemical fixation of CO2 with organic compounds (often called electrochemical carboxylation) is one of the most useful methods for direct transformation of CO2. However, this technique involves a serious challenge; for the carboxylation to proceed, metal ions generated from sacrificial anodes (such as Mg and Al) are generally required to stabilize the unstable carboxylate ions. From a green chemistry point of view, the potential for metal ion contamination in the reaction mixture is a serious drawback. To address this issue, Atobe and co-workers114 successfully demonstrated that a microreactor is an extremely useful means of controlling electrochemical carboxylations involving unstable carboxylate ions without the need for sacrificial anodes. In their work, electrochemical carboxylation of 1-(chloroethyl)benzene was achieved to give the carboxylated product in 95% yield (Figure 43).

was low and the dimethyl ether solvent was also fluorinated. Therefore, the overall process requires optimization, especially with regard to separating the fluorinating agent and purifying the 2-fluoro-2-deoxy-D-glucose. Iwata and co-workers113 applied an electrochemical flow microreactor to radiosynthesis of 18F-labeled compounds. In this case, the electrochemical flow microreactor was used not for fluorination of the organic compounds but for electrochemical concentration of the reactive 18F−. Figure 41 illustrates the microfluidic platform and shows the reaction setup. Reactive 18F− was supplied by pumping a 1.5 mL aliquot of water containing 18F− through a disposable concentration chip at a flow rate of 0.7 mL·min−1 while a constant electric potential of 10 V was applied between the Pt cathode and the glassy carbon anode. The cell was subsequently flushed with acetonitrile at 1.0 mL·min−1 for 2 min under the same electric potential, after which the voltage was no longer supplied. Subsequently, a solution of [K+/K.222]HCO3 was pumped into the cell, after which the cell was immediately heated to 80 °C while a reverse potential was simultaneously applied for 1 min. Following this step, the [K+/ K.222]HCO3 solution, now containing 18F−, was pumped out of the cell at a flow rate of 0.2 mL·min−1 into a Tefzel loop, with an inner diameter of 0.25 mm and a volume of 100 mL, connected to a 6-way valve and monitored with a radiation sensor.

3.10. Electrochemical Synthesis of Amides

The amide functional group is of fundamental importance as a structural and functional motif in a vast array of natural and synthetic substances, from small-molecule drugs to biopolymers and other materials. Consequently, the synthesis of amides is widely practiced and highly relevant across many areas. Brown and co-workers115 carried out N-heterocyclic carbene (NHC)mediated anodic amidation of aldehydes to give the corresponding amides using an electrochemical flow microreactor. In this process, the NHC was used as an organic catalyst for a range of

Figure 41. Microfluidic platform used by Iwata and co-workers,113 showing the reaction setup incorporating an electrochemical concentration chip and a reaction flow cell. An undivided type is used for the electrochemical flow cell. The inner flow channel is 100 μm high, 4 mm wide, and 40 mm long, with a volume of 16 μL. Reprinted with permission from ref 113. Copyright 2012 Elsevier. W


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Figure 42. Reaction schemes for 18F-labeling of selected radiotracers. Reprinted with permission from ref 113. Copyright 2012 Elsevier.

Figure 43. Electrochemical carboxylation of benzyl chloride via CO2 fixation in a microreactor. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.02 mm]. Reprinted with permission from ref 114. Copyright 2015 The Royal Society of Chemistry.

Scheme 18. N-Heterocyclic Carbene-Mediated Anodic Amidation of Aldehydes

X


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between an arene and an iodoarene was investigated. Sulfuric acid present in the reaction mixture acted both as a counterion during the intermediate formation of diaryl iodonium hydrogen sulfates and also as an electrolyte to carry charge through the solution. Purification of the iodide salt products was not necessary as the diaryl iodonium iodide salts precipitated out of solution once potassium iodide was added (18−72% yields). One advantage of this electrochemical flow microreactor is that it is easily dismantled and reassembled, unlike other systems that are completely sealed and not readily disassembled (Figure 45).

reactions including anodic oxidative conversion of aldehydes to amides (Scheme 18). One significant benefit of performing such reactions within a flow is the ability to easily control reactant/reagent mixing, such that the NHC and Breslow intermediate can be generated in the flow prior to mixing with the amine and before the reaction mixture enters the electrolysis cell (Figure 44). By use of this synthetic system, high yields (71−99%), productivities (up to 2.6 g·h−1), and current efficiencies (65−91%) were realized for 19 amides.

3.12. Electrochemical Synthesis Involving a Nicotinamide Adenine Dinucleotide Cofactor

Many dehydrogenation reactions involve the use of the pyridinic cofactor nicotinamide adenine dinucleotide (NADH) for the synthesis of optically active compounds.117 Because of the high cost of NADH, its regeneration constitutes an economic challenge. Although various regeneration methods have been developed, electrochemistry is a promising tool for NADH regeneration.118 The feasibility of continuous electrogeneration of NADH in an electrochemical filter-press microreactor, with flavin adenine dinucleotide (FAD)/FADH2 as a redox mediator, was experimentally demonstrated by Tzedakis and co-workers.60,119,120 This work also involved mass balance experiments in which electrogenerated NADH was applied to the synthesis of chiral L-lactate from achiral pyruvate (Figure 46). The optimized device allowed quantitative yields to be reached during both nicotinamide dinucleotide (NAD+) conversion and L-lactate production.

Figure 44. NHC-mediated oxidative synthesis of esters from aldehydes in an electrochemical flow microreactor. The undivided microreactor with a snaking channel spacer illustrated in Figure 12 was used for electrolysis. Reprinted with permission from ref 115. Copyright 2016 American Chemical Society.

3.11. Electrochemical Synthesis of Diaryl Iodonium Salts

Iodonium salts are currently being used in three main types of reactions: ligand exchange, reductive elimination, and ligand coupling. This is due to their highly electron-deficient nature and high dissociation rates, both of which make these compounds excellent leaving groups. Wirth and co-workers116 reported a simple procedure for the synthesis of both symmetrical and unsymmetrical diaryl iodonium salts in an electrochemical flow microreactor equipped with platinum electrodes (Scheme 19). The coupling reaction Scheme 19. Electrochemical Synthesis of both Symmetrical and Unsymmetrical Diaryl Iodonium Salts

Figure 46. Schematic representation of enzymatic synthesis of L-lactate involving indirectly electroregenerated NADH cofactor. Reprinted with permission from ref 60. Copyright 2012 Springer.

Figure 45. Electrochemical flow microreactor used by Wirth and co-workers116 for synthesis of both symmetrical and unsymmetrical diaryl iodonium salts. This is an undivided microreactor. The reactor consisted of two aluminum bodies (50 mm diameter, 25 mm height). The electrodes were constructed of two PTFE plates (35 mm diameter, 4 mm height) onto which were placed 0.1 mm platinum foil electrodes. The electrodes are held apart by a FEP (fluorinated ethylene propylene) foil of variable thickness, into which a rectangular reaction channel is cut (3 × 30 mm), giving an overall channel volume of 23 μL (FEP foil 254 μm thick), and the whole device is held together by steel screws and wing nuts. Reprinted with permission from ref 116. Copyright 2011 Beilstein-Institut. Y


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Tzedakis and co-workers121 also applied an electrochemical filter-press microreactor to direct in situ electroregeneration of NAD+ for the enzymatically assisted oxidation of β-alanine (Figure 47). This work first investigated direct electrochemical

demonstrated the electrosynthesis of chloroacetic acid in a series of microfluidic stack reactors. The stack was assembled as described in Figure 48 and consisted of a commercial undivided filter-press flow cell with three or four electrodes, depending on the number of electrolytic chambers. Stacks of several cells in series allowed a substantial increase in process productivity (up to 3.1 mmol·h−1) and operation at higher initial substrate

Figure 47. Indirect electroenzymatic oxidation of Cbz-β-aminopropanol to the corresponding acid (Cbz-β-alanine), catalyzed by HLADH and mediated by the cofactor NAD+, which is regenerated by anodic oxidation. Reprinted with permission from ref 121. Copyright 2017 Elsevier.

regeneration of NAD+, since NADH can be directly oxidized to NAD+ on a gold anode in a filter-press microreactor. The high specific area of the microreactor enabled high (92%) conversion of NADH to NAD+. In addition, the authors studied the enzymatic oxidation of Cbz-β-amino propanol in the presence of horse liver alcohol dehydrogenase (HLADH) and found they could reduce the reaction time. Nevertheless, complexation of the enzyme by the product (Cbz-β-alanine) appeared to introduce a serious drawback into the overall process. 3.13. Electrochemical Conversion of Dichloroacetic Acid to Chloroacetic Acid

Chloroacetic acid, an important reagent for several chemical reactions, is industrially synthesized by hydrolysis of trichloroethylene or chlorination of acetic acid.122 Production of chloroacetic acid via chlorination of acetic acid, the most common route, is accompanied by formation of significant amounts of dichloroacetic acid and, to a lesser extent, trichloroacetic acid.122,123 Recycling of dichloroacetic acid into chloroacetic acid is thus of interest in order to eliminate an unwanted waste product and increase the overall yield.123 Electrochemical reduction of dichloroacetic acid to chloroacetic acid, in particular, has been investigated in detail on both bench and pilot scales, with promising results (Scheme 20).123,124 Scheme 20. Electrochemical Reduction of Dichloroacetic Acid to Chloroacetic Acid

Scialdone et al.125 reported the construction of a filter-press cell equipped with PTFE micrometric spacers for electrosynthesis of chloroacetic acid in water through cathodic reduction of dichloroacetic acid. A microreactor equipped with compact graphite cathodes was found to produce chloroacetic acid in water at low cell potentials with high conversion and good selectivity in a single-pass mode without adding a supporting electrolyte. However, these proof-of-concept experiments involved quite small electrode surface areas (4 cm2 in most cases), thus limiting the productivity of the microreactor and the final concentration of product. Hence, scaling up of the present process is of paramount relevance in order to assess its feasibility for practical applications. To address this issue, Scialdone et al.126

Figure 48. (A) Schematic diagram and (B) photographic image of three microreactors in series as used by Scialdone et al.126 (C, D) Schematic diagrams of stacks with (C) two and (D) three cells. These are undivided cells. Each device was equipped with a compact graphite cathode and Ti/IrO2−Ta2O5 anode (electrode surface 4 cm2, interelectrode gap 0.1 mm). Reprinted with permission from ref 126. Copyright 2015 Wiley. Z


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electronics, such as organic solar cells, organic field-effect transistors, and organic electroluminescent devices, because P3HT has many useful properties including wide solubility, processability, charge mobility, and environmental stability. Molecular weight is closely related to these properties of P3HT, and hence controlling the molecular weight of P3HT during its synthesis is an important issue in this research area. Monomer conversion was much improved by using the flow microreactor (conversion was 13% in batch reactor and 53−68% in microreactor), attributed to better mixing in the flow microreactor. Therefore, electrode reaction of the monomer in the flow microreactor proceeded more efficiently than in the batch reactor. In addition, use of the flow microreactor resulted in a narrower molecular weight distribution (Mw/Mn was 3.5 in batch reactor and 1.7 in microreactor). This can be ascribed to the high volume-to-surface ratio of the reactor causing the absence of hot spots and thus better-defined polymer products. The molecular weight of P3HT could also be controlled by selecting reaction conditions for electrochemical polymerization in the reactor.

concentrations (0.1−0.5 M), in addition to high yields (85− 97%) and selectivity (almost 100%), in simple compact devices. 3.14. Polymer Synthesis

The discovery of controlled/living polymerization was an epochmaking event in polymer science and technology, and the control of molecular weight and molecular weight distribution is still at the forefront in this field. Yoshida and co-workers127 have successfully demonstrated that a combination of a highly reactive cationic initiator, generated anodically, and an extremely fast mixing device enable tuning of polymer molecular weights and molecular weight distributions. In their research, N-acyliminium ions, acting as the cationic initiator, were generated anodically from N-methoxycarbonyl-N(trimethylsilylmethyl)butylamine, followed by efficient mixing with a vinyl ether monomer in a multilamellar microreactor manufactured by Institut fur Mikrotechnik Mainz GmbH (IMM) (Figure 49). This initiated cationic polymerization to give

3.15. Gas-Phase Substrates and Products

It is generally difficult to work with gas-phase substrates and products in electrochemical microreactors because these substances can lead to inhomogeneous local current density distributions inside the reactor. In fact, Bouzek and coworkers129 have reported that bubbles with sizes exceeding 90% of the interelectrode distance in an electrochemical microreactor significantly disturb the current density distribution. Therefore, it will be necessary to devise ways to carry out electrosynthetic processes involving gas-phase substrates and/or products in electrochemical microreactors. For this purpose, Mahmood and Bonanos130 fabricated a three-electrode ceramic electrochemical microreactor equipped with a zirconia solid electrolyte to oxidize methane gas at 800 °C (Figure 51). Upon feeding of a 90%/10% CH4/N2 mixture into this device, a small amount of C2H6 was generated. Kopljar et al.131 demonstrated electrochemical reduction of CO2 to formic acid in a PEM flow microreactor. To mitigate limitations related to the solubility of CO2, gas-diffusion electrodes were developed based on tin as an electrocatalyst, and were used as working electrodes for electrochemical reduction of CO2. This system generated an increased current density of up to 200 mA·cm−2 at a faradic efficiency of 90% before mass-transport limitations came into effect. Direct fluorination of carbon monoxide was also carried out in microreactors by Venturini and co-workers.132 Many previous studies have attempted to obtain a stream of pure COF2 by direct fluorination of carbon monoxide with elemental fluorine or by

Figure 49. Microsystem used by Yoshida and co-workers127for polymerization initiated by N-acyliminium ions generated anodically. Legend: M1 and M2 = micromixers, R1 = microtube reactor (ϕ = 1.0 mm, L = 20 cm). Reprinted with permission from ref 127. Copyright 2004 American Chemical Society.

products with low polydispersity index (PDI) values (from 1.14 to 1.40) relative to those obtained from a batch process (from 2.25 to 2.56). Yoshida and co-workers127 demonstrated that adjusting the flow rates led to rapid mixing of the initiator and monomer, which in turn allowed control over the PDI and also improved the polymerization yields. The degree of mixing in this multilamellar microreactor increased with flow rate, such that lower flow rates also served to increase the PDI, while more efficient mixing at high flow rates yielded the narrowest PDIs. Very recently, Atobe and co-workers128 demonstrated electrochemical synthesis and molecular weight control of π-conjugated polymer poly(3-hexylthiophene) (P3HT) using a flow microreactor based on a parallel electrode configuration (Figure 50). P3HT is one of the most promising materials for photo-

Figure 50. Electrochemical synthesis of poly(3-hexylthiophene) (P3HT) in a flow microreactor. This is an undivided microreactor [channel width 10 mm, length 30 mm, height (interelectrode gap) 0.08 mm]. AA


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Figure 51. Three-electrode ceramic electrochemical microreactor designed by Mahmood and Bonanos.130 This is a divided microreactor. The external diameter of an open-ended zirconia−yttria tube is 9 mm. Reprinted with permission from ref 130. Copyright 1992 Elsevier.

Figure 52. Microstructure of a microtubular reactor: (A) low- and (B) high-magnification SEM images of the electrolysis region. Reprinted with permission from ref 133. Copyright 2017 The Royal Society of Chemistry.

electrochemical fluorination. However, these reactions are highly exothermic and therefore difficult to control, and so can easily lead to thermal runaway with poor selectivity. Venturini and coworkers132 successfully circumvented these critical issues, using a stainless steel parallel-channel microreactor (with a surface/ volume ratio of 1 × 104 m−1 and a residence time of 0.1 s) for direct electrochemical fluorination of carbon monoxide. The microreactor increased the selectivity of the reaction by 15−50%, and carbon monoxide conversion in this system was 30% greater than in the standard reactor. Generation of trifluoromethyl hypofluorite, an unstable byproduct of COF2 synthesis, in the microreactor was also up to 40% lower than in a standard reactor. Lemmon and co-workers133 developed a microtubular reactor (Figure 52) and applied it to high-temperature coelectrolysis of the H 2 O−CO 2 system as well as to low-temperature methanation. A cross-sectional scanning electron microscopic (SEM) image of the electrolysis region is shown in Figure 52A. The outer diameter of this zone was approximately 1.88 mm. It can be seen from Figure 52B that the electrolysis region contained three layers: a porous nickel oxide−yttria-stabilized zirconia (Ni-YSZ) electrode, a dense YSZ electrolyte film and a porous (La0.8Sr0.2)0.95MnO3‑δ (LSM-YSZ) electrode, with thicknesses of approximately 140, 13, and 30 μm, respectively. The Ni-YSZ support exhibits a sandwiched microstructure, with fingerlike macrovoids near the lumen and outer sides and a less porous layer in the middle. The temperature gradient along the microtubular reactor provided favorable conditions for both electrolysis and methanation reactions. Moreover, the microtubular reactor had a high volumetric factor for both electrolysis and methanation processes. When the cathode of this reactor was fed a stream of 10.7% CO2, 69.3% H2, and 20.0% H2O and the electrolysis region was operated at a current of −0.32 A, a remarkably enhanced CH4 yield of up to 21.1% was achieved

(along with a CO2 conversion ratio of 87.7%), compared with the results obtained during operation at an open-circuit voltage. Effects of the inlet gas composition at the cathode on CO2 conversion rate and CH4 yield were also investigated. The highest CH4 yield of 23.1% was achieved when the inlet gas consisted of 21.3% CO2, 58.7% H2, and 20.0% H2O in conjunction with an electrolysis current of −0.32 A. This novel design represents an alternative approach to CO2 utilization and energy storage.

4. CONCLUSIONS Although many studies have reported the use of flow microreactors for conventional chemical syntheses, the integration of microreactors with electrosynthesis remains rare. Consequently, this technology is relatively new and unfamiliar. Further developments in this field will require research and development activities in the following areas: (1) easy-to-handle systems for electrosynthesis in flow microreactors, (2) unique and useful electrosynthetic reactions that can occur in these devices, and (3) economically advantageous and environmentally benign electrosynthetic microreactor-based processes. We believe that this technology offers a potential solution to the present-day limitations that prevent wide-scale commercialization of electrosynthetic processes and therefore represents a useful new approach to industrial electrochemical synthesis. AUTHOR INFORMATION Corresponding Author

*E-mail [email protected]. ORCID

Mahito Atobe: 0000-0002-3173-3608 AB


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Notes

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The authors declare no competing financial interest. Biographies Mahito Atobe was born in Yamanashi, Japan, in 1969. He received his Ph.D. from Tokyo Institute of Technology in 1998. He has held positions at Tokyo Institute of Technology (1996−2011) and Yokohama National University (2011−present). He has been awarded the Young Researcher Award of The Electrochemical Society of Japan (2003), the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology: The Prize for Young Scientists (2009), and so on. Hiroyuki Tateno was born in Tochigi, Japan, in 1989. He spent three years in the Atobe group while earning his Ph.D. and received his Ph.D. from Yokohama National University in 2016. He then joined the Advanced Functional Material Team, Research Center for Photovoltaics (RCPV), National Institute of Advanced Industrial Science and Technology (AIST), as a postdoctoral researcher. Yoshimasa Matsumura was born in Gifu, Japan, in 1987. He received his Ph.D. from Tokyo Institute of Technology in 2015. He worked as a postdoctoral researcher in the Atobe group at Yokohama National University from 2015 until 2016. Currently, he is an assistant professor at Yamagata University. His research interests are polymer synthesis and organic electrochemistry.

ACKNOWLEDGMENTS M.A. has received support from the Council for Science, Technology and Innovation (CSTI), the Cross-ministerial Strategic Innovation Promotion Program (SIP) “Energy Carrier” (funding agency JST), and Grants-in-Aid for Scientific Research (JP15K13691, JP15H05847 and JP15H03843) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). REFERENCES (1) Matlosz, M., Ehrfeld, W., Baselt, J. P., Eds. Microreaction Technology; IMRET 5: Proceedings of the Fifth International Conference on Microreaction Technology; Springer: Berlin, 1998; DOI: 10.1007/978-3-642-56763-6. (2) Haswell, S. J.; Fletcher, P. D. I.; Greenway, G. M.; Skelton, V.; Styring, P.; Morgan, D. O.; Wong, S. Y. F.; Warrington, B. H. In Automated Synthetic Methods for Speciality Chemicals; Royal Society of Chemistry: Cambridge, U.K., 1999; p 26. (3) Manz, A., Becker, H., Eds. Microsystem Technology in Chemistry and Life Sciences; Springer: Berlin, 1999; DOI: 10.1007/3-540-69544-3. (4) Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for Modern Chemistry; Wiley−VCH: Weinheim, Germany, 2000; DOI: 10.1002/3527601953. (5) Jensen, K. F. Microreaction Engineering − Is Small Better? Chem. Eng. Sci. 2001, 56, 293−303. (6) Haswell, S. J.; Middleton, R. J.; O’Sullivan, B.; Skelton, V.; Watts, P.; Styring, P. The Application of Micro Reactors to Synthetic Chemistry. Chem. Commun. 2001, 391−398. (7) Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar, E.; Warrington, B. H.; Watts, P.; Wong, S. Y. F.; Zhang, X. Micro Reactors: Principles and Applications in Organic Synthesis. Tetrahedron 2002, 58, 4735−4757. (8) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Chemistry in Microstructured Reactors. Angew. Chem., Int. Ed. 2004, 43, 406−446. (9) Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Microreactors as Tools for Synthetic Chemists-The Chemists’ Round-Bottomed Flask of the 21st Century? Chem. - Eur. J. 2006, 12, 8434−8442. (10) deMello, A. J. Control and Detection of Chemical Reactions in Microfluidic Systems. Nature 2006, 442, 394−402. AC


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Applications of Flow Microreactors in Electrosynthetic Processes

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