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Scaling-up Electroorganic Synthesis Using a Spinning Electrode Electrochemical Reactor in Batch and Flow ModeClick to copy article linkArticle link copied!
- Nikola PetrovićNikola PetrovićInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, AustriaCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaMore by Nikola Petrović
- Bhanwar K. MalviyaBhanwar K. MalviyaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, AustriaCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaMore by Bhanwar K. Malviya
- C. Oliver Kappe*C. Oliver Kappe*E-mail: [email protected]Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, AustriaCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaMore by C. Oliver Kappe
- David Cantillo*David Cantillo*E-mail: [email protected]Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, AustriaCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaMore by David Cantillo
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Cite this: Org. Process Res. Dev. 2023, 27, 11, 2072–2081
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Abstract
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Technology for the rapid scale-up of synthetic organic electrochemistry from milligrams to multigrams or multi-100 g quantities is highly desirable. Traditional parallel plate flow electrolysis cells can produce large quantities of material, but transfer from batch to this flow technology requires reoptimization of the reaction conditions and fully homogeneous reaction mixtures. Moreover, single-pass processing is often difficult to accomplish due to gas generation and the low flow rates typically used in continuous mode. Herein we present a novel reactor design, based on a rotating cylinder electrode concept, that enables seamless scale up from small scale batch experimentation to gram and even multikilogram per day quantities. The device can operate in batch and flow mode, and it is able to easily process slurries without clogging of the system or fouling of the electrodes. Continuous operation is also demonstrated using three reactors in series that act as a continuous stirred electrochemical reactor cascade, providing kilogram per day productivities in a single pass.
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License Summary*
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Copyright © 2023 The Authors. Published by American Chemical Society
Introduction
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The recent revival of electrochemical synthesis as a safe and sustainable strategy for the preparation organic compounds (1,2) has sparked significant interest in the scale up of this technology. Small scale experimentation and early synthetic methodology development is typically carried out using batch type cells. (3) In particular, traditional “beaker cells” and H-cells are used for undivided and divided operation, respectively. Batch cells are easy to set up and convenient for the preparation of small amounts of material. However, they are unable to produce large amounts of compounds and often fail to provide quantities beyond tens of grams. (4) The main drawback of batch cells in terms of scalability is their relatively low electrode surface area to reactor volume ratio (A/V). More importantly, A/V rapidly decreases as the size of the reactor increases during a scale up attempt. As the efficiency of an electrolytic process is closely related to the A/V of the cell, the efficiency of batch cells consequently decreases with increasing size. Slow mass transfer is also often invoked as a drawback of batch cells, although this factor strongly depends on the mixing technology utilized. (5)
The technology for the scale up of electrochemical processes has been well established for many decades. (6) It relies upon the use of the so-called parallel plate flow cells. Parallel plate reactors consist of flat (plate shaped) electrodes, which are arranged in parallel to each other. The gap between the electrodes is typically small (often <1 mm), which provides very high A/V values. (4−7) For example, for a 1 mm interelectrode gap, A/V = 10, while most low volume batch cells feature A/V < 1. Electrolysis in parallel plate reactors is then carried out by flowing the reaction mixture through the gap between the electrodes, while the desired current density is applied using a suitable power supply. Importantly, parallel plate reactors are readily scalable. The dimensions of the electrodes can be enlarged essentially without limits, and the A/V value remains unchanged through the scale up as long as the interelectrode gap is kept constant. (8) In addition to sizing up the electrodes, scale up can be also readily achieved by stacking several electrode pairs, in a numbering up strategy. (6)
Although parallel plate flow electrolysis cells are well established for the scale up of electrochemical processes, they present several drawbacks (Figure 1a): (1) as in many flow-based reactor systems, the presence of solids in the reaction mixture should be avoided to prevent clogging (9) of the narrow channels of the cell. Prevention of solids in a reaction mixture may undermine the sustainability of the process as diluted conditions could be needed to fully dissolve solid materials. Moreover, the selection of solvents for processing a reaction in a parallel plate cell must consider the solubility of the reagents to generate homogeneous conditions, instead of being solely based on other advantages such as cost, greenness, and efficiency. (2) Many electrochemical reactions release gases at the counter electrode. (10) For example, most anodic oxidation reactions release hydrogen gas at the cathode as a byproduct from the reduction of a proton source. Gas evolution is a significant issue during single pass processing, (7) as large volumes of gas compared to the liquid phase are generated, thus reducing the effective reactor volume and available electrode surface area in contact with the reaction mixture. (3) The mass transfer efficiency depends on the flow rate utilized during processing (in particular, it depends on the flow velocity of the liquid phase with respect to the electrode surface). For this reason, processing of reaction mixtures in recirculation mode (semibatch) benefits from high flow rates. (11) However, single-pass processing (continuous mode) requires relatively low rates to achieve high conversion before the reaction mixture exits the reactor, which significantly undermines the mass transport properties of the cell.
Figure 1
Figure 1. Comparison of the scale-up of electrochemical processes in parallel plate flow cells vs the spinning electrode reactor presented herein.
We envisaged that an electrochemical reactor concept that combines flow processing capabilities with a spinning cylinder electrode design should provide a solution to the aforementioned drawbacks of parallel plate reactors. In particular, an assembly of two concentrical cylindrical electrodes (anode and cathode) in which the central working electrode spins around its axis should provide excellent mixing and thus mass transport, even at very low flow rates, while maintaining a relatively narrow interelectrode gap. (12,13) The efficient mixing attained with the system should also enable working with solid suspensions without the risk of clogging the system or the accumulation of particles. Moreover, the fact that the central electrode is spinning should provoke rapid detachment of any gas bubbles from the surface of the electrodes, facilitating their displacement to the reactor headspace and effectively overcoming the issues of gas evolution during electrolysis.
Herein, we present the design, construction, characterization, and testing of an electrochemical reactor based on the aforementioned spinning concentrical cylindrical electrode concept. The reactor system features an interelectrode gap of 5 mm, analogous to common commercially available small scale undivided cells, (14) which permits the translation of milligram scale batch experiments to multigram quantities without the need for reoptimization of the reaction conditions. The cell was shown to readily handle slurries. Importantly, the scalability of the electrolysis cell has been demonstrated by constructing 3 units of different size, featuring working electrode surfaces of 94 cm2, 475 cm2, and 2466 cm2. The 3 units performed identically for a model electrochemical organic transformation. The spinning electrode reactor versatility permits operation under batch conditions as well as flow mode, both as a semibatch type setup with electrolyte recirculation and as a single-pass continuous flow reactor using a reactor cascade, enabling multi-100-g preparations and productivities of several kilograms per day.
Results and Discussion
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Reactor Design and Construction
The electrochemical reactor is based on a relatively simple assembly consisting of a pipe-shaped counter electrode and a cylindrical working electrode, which are positioned concentrically. The outer electrode is static and, once attached to a circular-based plate made of polyether ether ketone (PEEK), forms the reactor vessel (Figure 2). The cylindrical working electrode is located in the center of the reactor vessel with a mixer attached to the bottom. The inner working electrode is attached to the reactor cap via an electrically conducting shaft, which in turn is connected to a slip ring located within the cap, thus enabling spinning of the electrode during electrolysis. The mixer spins with the electrode, providing vigorous mixing of the reaction mixture.
Figure 2
Figure 2. Computer generated images of the reactor components and assembly.
During the course of this work, we designed and manufactured reactors of three different sizes to demonstrate the scalability of the technology. The cells are denominated Reactor S, Reactor M, and Reactor L (Figure 3). The smallest cell (Reactor S) has a working electrode surface area of 94 cm2 and a volume of 52 mL. The medium-size (Reactor M) and large-size (Reactor L) cells are designed with consecutive 5-fold increases in surface electrode area, with a 25-fold scale-up factor between Reactor S and Reactor L. Thus, the medium-size reactor features an electrode surface area of 475 cm2 and the large size reactor 2466 cm2. The interelectrode gap is 5 mm in all reactors. Importantly, this gap distance was selected to match that of the small scale IKA ElectraSyn 2.0 vials, which enables reproducible results between the two types of reactors even with differences in scale of 3 orders of magnitude. The fact that the interelectrode gap is kept constant in all reactors, combined with the cylindrical geometry of the design, results in increasing A/V values as the reactor becomes larger, which further ensures a smooth scale-up process (Figure 3). The reason for this increase in A/V is that, as the electrode diameter becomes larger, the surface resembles more an ideal planar geometry. Reactors M and L feature a relatively large electrode surface area, which was expected to enable electrolysis under comparatively high currents. To avoid heating of the reactors, they were equipped with a cooling jacket, which was installed in direct contact with the cathode. This feature ensured excellent heat transfer and facile temperature control during electrolysis. The small reactor (Reactor S) was not equipped with a cooling jacket, as its small size and use under lower current permitted release of any heat generated without the need for an external coolant.
Figure 3
Figure 3. Simplified view of the electrode dimension of the 3 electrochemical reactors assembled in this work and photograph of the units.
Most of the experiments described in the following sections were carried out on Reactor M, as the middle-size reactor ensured robust and rapid experimentation with adequate amounts of material. Proof-of-concept of scale-down to Reactor S and scale-up to Reactor L using as a model the electrolysis of a slurry was then demonstrated. All model reactions tested herein used impervious graphite (GAB GPX) as the anode material and 316 stainless steel as the cathode.
The reactor features several fluidic connections that enable the flow processing of reaction mixtures (Figure 4). Connectors for 5/16–24 fittings suitable for 3/16-in. outer diameter tubing were selected to ensure that tubing with sufficient inner diameter to avoid clogging could be installed. One of the connectors is located in the bottom of the reactor, which can serve as input as well as an output to empty the reactor. Three additional ports, located on the reactor cap, can be used as inlet/outlet, to introduce temperature probes or other sensors, as well as to flush the reactor headspace with an inert gas (this is important to dilute any hydrogen generated during anodic oxidations).
Figure 4
Figure 4. Fluidic and electrical connections in the spinning electrode cell.
Flow operation can be readily carried out using the fluidic fitting connectors available, preferentially using the bottom of the reactor for the inlet and the top as outlet. Batch operation can be performed by simply filling the bottom assembly (Figure 2) with the reaction mixture (no more than 250 mL should be added to avoid overflowing of the reactor) and then capping the cell. Alternatively, reaction mixtures can be pumped into the reactor using the ports available and pumped out using the bottom port. All experiments carried out in this work were performed using the latter approach.
Reactor Characterization
Before testing the system with model reactions, the performance of the spinning electrode cell was first evaluated to ascertain its expected behavior during electrolysis in batch and flow mode. As mentioned in the introduction, an advantage of this system with respect to classical parallel plate reactors is that high flow rates are not needed to deliver high mass transfer, as this is provided by the movement of the electrode with respect to the liquid phase instead. This feature was demonstrated by determining the mass transfer of the electrochemical reactor using the limiting current method (15) under different spinning speeds using the middle-size Reactor M (Figure 5) equipped with an impervious graphite anode. For this purpose, we employed a known methodology (16) which consists of electrolyzing an aqueous solution containing K3[Fe(CN)6] and K4[Fe(CN)6]. As the working electrode is the anode in this case, the concentration of the reduced species is lower so that the current limitation arises from the electrode of interest. The cell voltage is scanned linearly from 0 to 3 V in a 2 min interval, while the resulting current is monitored. The limiting current value is identified as a “plateau” in the I vs V graph. In our experiments, a stop flow strategy was used. Thus, the reactor was filled with 200 mL of solution for each experiment (Figure 5a). Once the measurement was collected under the desired spinning speed, the reactor was emptied and filled with a fresh solution.
Figure 5
Figure 5. (a) Schematic view of the setup used to determine the mass transfer of the system under different electrode spinning speeds and (b) mass transfer (km) values obtained in cm/s. Details on the calculation of km from the limiting current experiments are collected in the Supporting Information.
As expected, excellent mass transfer values were obtained, even considering that the electrolyte did not flow during the measurements. Moreover, the limiting current values and thus mass transport increased with the spinning speed (Figure 5b). In principle, this trend means that, if a reaction suffers from lack of selectivity or low current efficiency due to mass transfer limitations, the outcome can be improved by augmenting the spinning speed of the electrode. Such a feature was not demonstrated during the course of this study, as all model reactions evaluated showed excellent selectivity at relatively low spinning speeds (vide infra).
We next turned our attention to the residence time distribution (RTD) of the reactor when it was used in flow mode. Given the good mixing provided by the spinning electrode and the mixer, it was expected that the behavior of the system would be that of a continuous stirred tank reactor (CSTR). (17) In the case of electrochemical cells, they are typically termed continuous stirred tank electrochemical reactors (CSTER). (18) An aqueous solution of potassium hydrogen phthalate (KHP), in conjunction with an inline UV–vis spectrometer at the reactor output, was used for evaluation (Figure 6a). The solution was introduced into the system, which had been filled with water, at a flow rate of 50 mL/min. The working volume of the reactor was set to 200 mL by adjusting the height of the output tubing. Under these conditions, the ideal residence time should be 4 min. The RTD was obtained for two scenarios for comparison purposes: when the input of the reactor is located on top of the reactor (Figure 6b) and when it is located at the bottom (Figure 6c). The experiments were carried out using two different electrode spinning rates (50 and 300 rpm). The results revealed, as expected, that introducing the solution from the bottom of the reactor provides a much better RTD profile, with a mean residence time matching the expected value independently of the spinning rate (4.0 and 4.1 min for 50 and 300 rpm, respectively) (Figure 6c). When the solution was introduced through a top port of the reactor instead, poorer RTD profiles were obtained (Figure 6b). The shorter than expected mean residence time distribution (e.g., 3 min at 300 rpm) might be due to the high flow rate with which the solution is introduced into the reactor (50 mL/min), which pushes the entering solution to the bottom of the reactor, thus, exiting the reactor too early. As the spinning mixer is placed at the bottom of the reactor, this is not an issue when the bottom port is used, because the reaction solution is immediately mixed upon entering the cell. Thus, the bottom of the reactor was used as the input in all flow experiments described herein.
Figure 6
Figure 6. (a) Schematic view of the setup utilized for the evaluation of the residence time distribution in the spinning electrode reactor. KHP: potassium hydrogen phthalate. (b) E curve obtained when the reactor was fed from the top port and (c) from the bottom port. E(t) corresponds to the fraction of particles that stay in the reactor for a given time before exiting.
Reactor Performance and Operation in Flow Recirculation Mode
The performance of the reactor design for electrochemical organic transformations was first evaluated by using a model reaction under homogeneous conditions. In particular, the anodic methoxylation of N-formyl piperidine was used (Figure 7a), as this type of Shono oxidation (19) is often employed to test the performance of flow electrolyzers. (20) General reaction conditions such as substrate and supporting electrolyte concentration were first established using a small scale electrolyzer (IKA ElectraSyn 2.0) (see Table S1 for details). Then, the electrochemical process was transferred to the spinning electrode cell (Reactor M, 475 cm2 electrode surface area, impervious graphite anode, and steel cathode). The electrochemical reaction was initially attempted in batch mode using the reactor. The typical procedure for batch experimentation simply consisted of loading 200 mL of the reaction mixture solution into the reactor using one of the top ports, initiating the electrode spinning (300 rpm) and then turning on the power supply at the desired current. Electrolysis under constant current was carried out until the desired amount of charge (2.2 F/mol) had been passed. Importantly, during the electrolytic process nitrogen gas was constantly flushed through the headspace of the reactor. This measure is critical to dilute the hydrogen gas generated at the cathode for safety reasons. (21) When the electrolysis was completed, the power supply was turned off, and the reactor was emptied through the bottom port. The temperature of the reaction mixture could be readily controlled by simply circulating water through the cooling jacket.
Figure 7
Figure 7. (a) Electrochemical methoxylation of N-formyl piperidine (1) and (b) schematic view of the flow setup with the electrolyte recirculation operation used for the reaction.
Given the current density achieved during the preliminary batch experiments, it was expected that currents of at least 10 A could be applied on the reactor with a 450 cm2 working electrode surface area (20 mA/cm2 × 450 cm2). Indeed, a constant current at 10 A provided excellent conversion and selectivity toward the target methoxylated product 2 (Table 1, entry 1). The current was gradually increased in subsequent experiments to 40 A (84 mA/cm2) (Table 1, entries 2–4). Excellent conversion and selectivity were still achieved. A further increase to 50 A has a negative effect in the reaction selectivity (entry 5), due to the generation of the di- or trimethoxylated side-products.
Table 1. Optimization of the Current Used in the Electrochemical Oxidation of 1 in the Spinning Electrode Reactor in Batch Mode and Transfer to Flow Modea
| entry | Operation mode | current [A] | conversion [%]b | selectivity [%]b |
|---|---|---|---|---|
| 1 | batch | 10 | 100 | 95 |
| 2 | batch | 20 | 100 | 94 |
| 3 | batch | 30 | 99 | 94 |
| 4 | batch | 40 | 99 | 94 |
| 5 | batch | 50 | 98 | 89 |
| 6 | flow-recirculation | 40 | 97 | 95 |
a
Batch conditions: 22.6 g (0.2 mol) of 1 in 200 mL of MeOH with 0.1 M Et4NBF4, constant current, 300 rpm. Flow conditions: 113 g (1 mol) of 1 in 1 L of methanol with 0.1 M Et4NBF4, constant current, 300 rpm, 200 mL/min recirculation flow rate.
b
Determined by HPLC area percentage at 215 nm.
To demonstrate that the reactor can also be used in flow mode, an electrolyte recirculation setup was assembled and evaluated (Figure 7b). In this case, the reaction mixture (1 L volume containing 113 g of the starting material) was placed in a reservoir. The solution was pumped into the reactor from the bottom, and the outlet tubing from the reactor top was directed back to the reservoir. For better control of the headspace volume, the solution was pumped out of the cell using a second pump. Thus, the outlet tube was introduced into the reactor by using a top port to the depth matching the desired level of the liquid, and the output pump was operated at a slightly larger flow rate, keeping the liquid level and headspace volume constant. Once the reactor had been filled with solution and was already returning to the reservoir, electrolysis was initiated under optimal batch conditions (40 A, 2.2 F/mol). Gratifyingly, excellent conversion, selectivity, and current efficiency were also achieved in flow mode (entry 6), analogous to that attained in batch. Workup of the reaction mixture collected in the electrolyte reservoir provided 129 g (93%) of compound 2.
It should be emphasized that the reaction initially optimized in a small-scale cell (3 mL reaction volume) could be readily transferred to the larger reactor without the need for reoptimization of the reaction conditions, apart from process intensification via increase of the current density. Thus, this novel design enables easy and rapid scale-up of electrochemical transformations from milligram quantities to multi-100 g operation.
Continuous Operation Using a Reactor Cascade
Over the past few years, there has been a trend toward the development of single-pass flow electrolysis processes, which enables continuous processing of materials. (7,22) As mentioned above, the spinning electrode cell design behaves as a CSTER when a liquid stream is input from the reactor bottom and output from the top of part of the system. Thus, achieving high conversions in a single-pass reactor requires a cascade of reactors in series. Continuous operation involves matching the current applied to the cell to the flow rate of the reaction mixture and its concentration. To avoid excessively low flow rates, currents and thus current densities may need to be high compared to batch operation conditions. To assess potential issues derived from high current densities, we chose the anodic decarboxylative methoxylation of diphenyl acetic acid as a model reaction to test the reactor in continuous mode. This electrochemical transformation is prone to overoxidation of product 4 to benzophenone if excessive current density or amount of charge is applied. (23)
A set of initial batch reactions, first in a small-scale reactor (3 mL volume in a 5 mL IKA ElectraSyn 2.0 vial) and then in the spinning electrode system, established as an optimal set of reaction conditions: 0.5 M concentration of diphenylacetic acid 3, 0.05 M NaOMe, and a current density of ca. 35 mA/cm2 (see Table S2 and Table S3 in the Supporting Information). With these parameters in mind, and considering the working electrode surface area of Reactor M (475 cm2), we estimated that to be able to apply a relevant flow rate (20 to 25 mL/min) and achieve full conversion a series of three reactors was needed (Figure 8). Thus, the continuous flow setup consisted of a stock solution of 3 (0.5 M in MeOH with 0.05 M NaOMe as a base), which was pumped into the first reactor through its bottom inlet using a peristaltic pump. The outlet of the reactor was connected to the second reactor in the series. To accurately control the current density during the electrolytic process, the outlet tubing was introduced in the first reactor so that the level of the liquid stays constant as it is pumped into the second reactor with another pump. In this manner, the surface area of the electrode in contact with the solution was kept at 470 cm2 in the three reactors. Thus, applying the optimal current density for this transformation involved a total current of 49.2 A. Importantly, the connection between the power supply and the three reactors was carried out in parallel. Under these conditions, the electrical current will preferentially pass through the cell with the lowest resistance, which should be the first one (with the highest substrate concentration). As in all experiments, nitrogen gas was passed through the headspace of the reactors to dilute the hydrogen generated.
Figure 8
Figure 8. Schematic view of a cascade of 3 continuous stirred electrochemical reactors connected in series to achieve single-pass electrolysis of diphenylacetic acid (3). Impervious graphite was used as the anode material, and stainless steel was used as cathode.
The CSTER cascade was run under a constant current of 49.2 A in total and a spinning speed of 300 rpm in each cell. The optimal flow rate of the system was evaluated by gradually increasing the flow rate from 20 to 30 mL/min, which corresponds to decreasing the amount of charged pass through the solution from 3 to 2 F/mol. The output of the flow rig was monitored by HPLC under steady state conditions for each of the flow rates applied. Analysis of the crude reaction mixtures (Table 2) revealed that 24.5 mL/min (2.5 F/mol) provides full conversion of the starting material (3), and excellent selectivity toward 4. Under these conditions, the reactor was run under steady state conditions, and the solution from the output was collected for 5 h. During this period of time, no issues with the system or changes in the composition of the output solution were detected. Workup of the reaction mixture provided 711 g of compound 4 (97% isolated yield), which corresponds to a productivity of 146 g/h, or 3.5 kg per day (24 h).
Processing of a Slurry – Scale Up and Scale Down Demonstration
As mentioned in the introductory remarks, one of the main advantages of the spinning electrode cell is the ease with which it can process slurry reaction mixtures. This possibility can be of significant importance in the design of electrochemical transformations, as more flexibility on the choice of solvents and concentration of the reaction mixture is allowed, thus potentially benefiting the sustainability and cost efficiency of the process. To demonstrate the reactor capability, the reagent-free electrochemical side-chain cleavage of cortisone (5), which results in adrenosterone (6) as product, was selected as the model (Figure 9). (24) Cortisone is poorly soluble in many organic solvents. The optimal solvent mixture to perform the electrolysis in small batch experiments is a mixture of MeCN/H2O in a 40:1 ratio. The solubility of cortisone in this mixture is below 0.05 M. Thus, processing a homogeneous reaction mixture, a typical condition when parallel plate flow electrolysis cells are used, requires very high dilution, which is detrimental to the green chemistry metrics of the process. In contrast, small scale batch experimentation revealed that the amount of cortisone can be significantly increased by 10-fold, in a slurry containing 0.5 mmol of cortisone (180 mg) per mL of solvent. Initial examination of the reaction conditions in a 3 mL volume small scale reaction using the IKA ElectraSyn 2.0 cell indicated that this reaction does not tolerate high current densities. Optimal results were obtained under a constant current of 3.3 mA/cm2.
Figure 9
Figure 9. Electrochemical side-chain cleavage of cortisone in flow recirculation mode using a 450 cm2 surface area spinning electrode reactor.
Processing of a slurry containing cortisone (5) in a flow reactor featuring Reactor M (Figure 9) was carried out in recirculation mode. To avoid clogging of the flow recirculation system with the solid substrate, narrow tubing and connections were avoided thorough the setup. Tubing and fittings with a 3/16 in. diameter and a peristaltic pump were utilized to flow the reaction mixture through the system. For this experiment, 1 L of slurry containing 180 g of cortisone was placed in a magnetically stirred reservoir and recirculated through the cell and back to the reservoir at a flow rate of 200 mL/min. The mixture was electrolyzed under a spinning speed of 300 rpm and a constant current of 1.1 A (which corresponds to 3.3 mA/cm2) until 4 F/mol of charge had been passed. Once the reactor was emptied back into the reservoir, workup of the reaction mixture provided 141 g (94% isolated yield) of pure adrenosterone (6). Importantly, no clogging of the system or settling of particles within the reactor was observed during the process.
Next, we carried out the electrolysis of the slurry containing cortisone (5) using the three different reactor sizes (Reactor S, L, and M, featuring 94 cm2, 475 cm2, and 2466 cm2, respectively) to demonstrate the scalability of the system even in the presence of solid materials in suspension. To produce more comparable results between the three reactor sizes, the electrode spinning speeds were set so that they match the electrode surface velocity. This is because the effect of the rotation motion on the mass transfer during electrolysis depends on the velocity of the electrode surface with respect to the liquid phase rather than the rotational speed. In particular, a linear velocity of the electrode surface of ca. 4200 cm2/s was achieved by setting the spinning speed to 390, 150, and 65 rpm for reactors 1, 2, and 3, respectively (Table 3). (25) Additionally, the current optimal current density of 3.2 mA/cm2–3.3 mA/cm2 was used in the three reactors. In this context, as reactors M and L were not fully loaded (see Table 3), the total currents were adjusted accordingly to achieve the desired current density. Gratifyingly, the results achieved in the three reactors, which were operated in batch mode for these experiments, were nearly identical. Excellent isolated yields of desired product 6 were attained in all cases. It should be further emphasized that, using this technology, a simple set of experiments enables rapid scale-up from 450 mg of adrenosterone (6) production in an IKA ElectraSyn 2.0 experiment to 164 g in batch mode without any reoptimization of the reaction conditions. Translation to flow, as demonstrated above, would readily enable the generation of kilogram quantities of material.
Table 3. Scale-up Demonstration Using Reactors of Three Different Sizes, Using the Electrochemical Synthesis of Adrenosterone (6) as Modela
| reactor | used working electrode surface area (cm2)b | Current [mA] | rpm | isolated material and yield |
|---|---|---|---|---|
| S | 94 | 313 | 390 | 7.2 g (95%) |
| M | 346 | 1100 | 150 | 57 g (95%) |
| L | 2214 | 7100 | 65 | 164 g (91%) |
a
Conditions: 0.5 M cortisone (5), 0.1 M Et4NBF4, MeCN/H2O 40:1 constant current, 300 rpm.
b
The used working electrode surface area for Reactors 2 and 3 are lower than the expected for the setup because the reactors were not operated completely full.
Conclusions
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In summary, we have designed, manufactured, and tested an electrochemical reactor concept based on a spinning cylinder electrode. The working electrode, located in the center of a concentrical electrode assembly, spins around its axis, providing very efficient mixing of the reaction mixture, which, in turn, results in excellent mass transfer and the possibility to handle slurries without electrode fouling, bridging, or clogging of the system. The device has been tested with several model reactions, including homo- and heterogeneous mixtures. In all cases, it has been demonstrated that the reaction conditions can be initially screened and optimized in a small-scale batch cell (3 mL volume) and then transferred to multigram amounts in the spinning electrode cell without the need to reoptimize the reaction conditions. The reactor can be operated in batch and flow mode. Flow operation has been demonstrated with both recirculation and single-pass operation. As the reactor behaves as a continuous stirred tank electrochemical reactor, a cascade of three reactors can be set to achieve continuous processing of a reaction mixture. Importantly, the technology is scalable, as the ratio between the electrode surface area and the reactor volume does not decrease as the reactor size is enlarged if the gap between the electrode (5 mm) is kept constant. Scalability has also been demonstrated by manufacturing cells of three different sizes, with working electrode surface areas of 94 cm2, 475 cm2, and 2466 cm2. Electrolysis of a slurry of cortisone (5) in the three reactors provided nearly identical results when the same current density and the surface velocity of the spinning electrode were kept constant.
The reactor concept enables transfer of a milligram scale electrolysis experiment (e.g., from an IKA ElectraSyn 2.0 cell) to multigram and even multi-100 g quantities in batch mode (Figure 10), independently of the presence of solids in the reaction mixture or gas evolution at the counter electrode, without any reoptimization of the reaction conditions. Further transfer to flow mode enables the preparation of kilogram amounts of material using either a recirculation approach or a reactor cascade. Single-pass continuous generation of 146 g/h of material in the 475 cm2 reactor has been shown herein, which corresponds to a projected amount of 18 kg/day of material in the 2466 cm2 reactor. (26)
Figure 10
Figure 10. Summary of the capabilities of scale-up opportunities using spinning cylinder electrode reactor technology.
Future work will expand the versatility and demonstrate the full potential of the spinning electrode cell by implementing a variety of anode and cathode materials, including flexible and 3D electrodes.
Experimental Section
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General Remarks
1H NMR spectra were recorded on a 300 MHz instrument. 13C NMR spectra were recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as an internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively. GC-FID analysis was performed on a Shimadzu GCFID 2030 with a flame ionization detector, using an RTX-5MS column (30 m × 0.25 mm ID × 0.25 μm) and helium as carrier gas (40 cm sec–1 linear velocity). The injector temperature was set to 280 °C. After 1 min at 50 °C, the temperature was increased by 25 °C min–1 to 300 °C and kept constant at 300 °C for 3 min. The detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality). For HPLC, the separation was carried out on a Macherey-Nagel Nucleodur C18 HTec column (150 mm × 4.6 mm, particle size 5 μm) at 37 °C using mobile phases A (H2O/acetonitrile (9 + 1 v/v) + 0.1% TFA) and B (acetonitrile +0.1% TFA) at a flow rate of 0.6 mL min–1. The following gradient was applied: hold 5% of B for 2 min, then linear increase from 5% B to 20% B in 6 min, followed by a linear increase from 20% B to 100% B in 1 min, then hold 100% B for 1 min, followed by column equilibration time at 5% B for 5 min. The detection of compounds was accomplished by a diode array detector. All chemicals were obtained from standard commercial vendors and were used without any further purification. Small scale electrochemical reactions were carried out in 5 mL IKA ElectraSyn 2.0 vials, equipped with impervious graphite and stainless steel electrodes. Stainless steel electrodes for small scale experimentation were acquired from IKA. Impervious graphite for small scale experimentation were purchased from Graphtek LLC. An impervious graphite cylinder for the spinning electrode reactors was obtained from GAB Neumann. The reactor static electrode, used as the counter electrode, was made of 316 stainless steel, purchased from Edelstahl24 GmbH (Frankfurt, Germany). The spinning electrode reactors were powered with an adjustable BK Precision BK1900B power supply (960 W, max. 16 V, 60 A).
Caution: The electrochemical oxidations described herein produce stoichiometric amounts of H2 gas as byproduct. Appropriate dilution of the gas generated with N2 to a concentration below the explosion limit is highly recommended.
Electrochemical Methoxylation of N-Formyl Piperidine (1) in Batch Mode (Table 1)
An Erlenmeyer flask was loaded with N-formyl piperidine (1) (22.6 g, 200 mmol), Et4NBF4 (4.3 g, 20 mmol), and 200 mL of MeOH. The mixture was stirred until the supporting electrolyte was fully dissolved. Then, the solution was loaded into a spinning cylinder electrochemical reactor equipped with an impervious graphite anode (working electrode, 475 cm2) and a steel cathode. The solution was electrolyzed under the desired constant current by using a spinning speed of 300 rpm. After 2.2 F/mol of charge had been passed (the reaction time to complete the electrolysis depends on the current applied), the power supply was turned off. A 20 μL aliquot of the crude reaction mixture was diluted with MeCN, and the mixture was analyzed by HPLC.
Electrochemical Methoxylation of N-Formyl Piperidine (1) in Flow Recirculation Mode
In a 1 L volumetric flask were placed Et4NBF4 (21.7 g, 0.1 mol), N-formyl piperidine (1) (113.6 g, 1 mol), and MeOH (ca. 500 mL). The mixture was stirred until the supporting electrolyte was fully dissolved and then diluted with additional MeOH “up to the mark”. The solution was then loaded into a 1 L jacketed vessel equipped with a magnetic stirrer (reservoir). The solution was pumped into the bottom port of a spinning cylinder cell (475 cm2) using a peristaltic pump (Masterflex L/S) with a flow rate of 200 mL/min. Simultaneously, an outlet tube connected to a second pump was introduced into the cell via a top port. The second pump was set to a flow rate slightly larger than the input pump to ensure a constant level of liquid within the reactor. The outlet line was connected back to the solution reservoir. Once the system had been filled with liquid and recirculation of the electrolyte was established, the spinning of the electrode was initiated (300 rpm) as well as electrolysis under a constant current of 40 A. When 2.2 F/mol was passed, the power supply was turned off. The input pump was reversed to return all of the reaction mixture to the solution reservoir. Then, the solvent was evaporated under reduced pressure, and the residue was extracted with DCM/water. The organic phase was dried over Na2SO4 and evaporated under reduced pressure, yielding 128.5 g (93%) of 2-methoxypiperidine-1-carbaldehyde 2 as a brown liquid, which was isolated as a 2:1 mixture of rotamers; 1H NMR (300 MHz, chloroform-d) δ 8.14min and 8.13maj (s, 1H), 5.51min and 4.56maj (d, J = 2.8 Hz, 1H), 4.17–4.20maj and 3.38min (m, 1H), 3.24min and 3.18maj (s, 3H), 2.76–2.70maj (m, 0.7H), 1.99–1.38 (m, 6.5H) ppm. 13C NMR(75 MHz, CDCl3) δ 162.3min and 161.3maj, 85.7maj and 78.3min, 55.1min and 54.2maj, 41.9min and 35.9maj, 31.2maj and 29.9min, 25.9min and 24.5maj, 19.3maj and 19.2min ppm. These data agree with those previously reported in the literature. (20c)
Decarboxylative Methoxylation of Diphenylacetic Acid (3) in Flow Recirculation Mode
In a 1 L volumetric flask were placed NaOMe (2.7 g, 0.05 mol), diphenylacetic acid (3) (106.1 g, 0.5 mol), and MeOH (ca. 500 mL). The mixture was stirred until the supporting electrolyte was fully dissolved and then diluted with additional MeOH “up to the mark”. The solution was then loaded into a 1 L jacketed vessel equipped with a magnetic stirrer (reservoir). The solution was pumped into the bottom port of a spinning cylinder cell (475 cm2) using a peristaltic pump (Masterflex L/S) with a flow rate of 200 mL/min. Simultaneously, an outlet tube, connected to a second pump, was introduced into the cell via a top port. The second pump was set to a flow rate slightly larger than the input pump, to ensure a constant level of liquid within the reactor. The outlet line was connected back to the solution reservoir. Once the system had been filled with liquid and recirculation of the electrolyte was established, the spinning of the electrode was initiated (300 rpm) as well as electrolysis under a constant current of 12 A. When 2.2 F/mol was passed, the power supply was turned off. The input pump was reversed to return all the reaction mixture to the solution reservoir. Then, the solvent was evaporated under reduced pressure and the residue was extracted with DCM/water. The organic phase was dried over Na2SO4 and evaporated under reduced pressure, yielding 97.5 g (93%) of (methoxymethylene)dibenzene (2) as a brown liquid. 1H NMR (300 MHz, chloroform-d) δ 7.45–7.28 (m, 10H), 5.33 (s, 1H), 3.46 (s, 3H) ppm. 13C NMR (125 MHz, chloroform-d): δ 142.2, 128.5, 127.5, 126.9, 84.5, 57.1 ppm. These data agree with those previously reported in the literature. (23)
Decarboxylative Methoxylation of Diphenylacetic Acid (3) in a Continuous Stirred Electrochemical Reactor Cascade (CSTER)
The reactor cascade was prepared by connecting three identical spinning electrode cells in series (see Figure 7), using the bottom port as input and one of the top ports as output in all cases. The solution was introduced into the first reactor as well as transferred between reactors, using peristaltic pumps (Vaportec SF-10 or Masterflex L/S). A BK Precision BK1900B power supply (60 A) was connected in parallel to the three reactors. Thus, the power supply provides a fixed amount of current, which is then distributed between the reactors, according to their conductivity. A 0.5 M stock solution of diphenylacetic acid (3) containing 0.05 M of NaOMe in MeOH was prepared by dissolving 955.1 g (4.5 mol) of diphenylacetic acid (3) and 24.3 g (0.45 mol) of NaOMe in MeOH, and diluting the mixture to a total of 9 L of volume. The first pump connecting the stock solution of 3 to the first reactor was set to a flow rate of 24.5 mL/min and initiated. All other pumps were set to a slightly higher flow rate to ensure that the level of liquid in the three cells remains constant. Once the solution started to exit the third reactor spinning of the electrodes was initiated at 300 rpm. Then, the power supply was switched on and operated under a constant current of 49.2 A. The output of the flow setup was put to waste until steady state conditions were achieved (ca. 2 reactor volumes). Then, the reaction mixture was collected from the output of the flow system for 5 h. The solution obtained was evaporated under reduced pressure, and the residue was diluted with 5 L of an aqueous saturated NaHCO3 solution. The aqueous mixture was extracted with DCM and the organic phase dried over Na2SO4, filtered and evaporated under reduced pressure, yielding 711.25 g (97%) of (methoxymethylene)dibenzene (2). The spectroscopic data matched those obtained in a previous experiment.
Electrochemical Synthesis of Adrenosterone (6) in Flow Recirculation Mode
In a 1 L volumetric flask were placed Et4NBF4 (21.7 g, 0.1 mol), cortisone (5) (180.2 g, 0.5 mol), and ca. 500 mL of MeCN/H2O 40:1. The mixture was stirred until the supporting electrolyte was fully dissolved and then diluted with additional MeOH “up to the mark”. The solution was then loaded into a 1 L jacketed vessel equipped with a magnetic stirrer (reservoir). The solution was pumped into the bottom port of a spinning cylinder cell (475 cm2) using a peristaltic pump (Masterflex L/S) with a flow rate of 200 mL/min. Simultaneously, an outlet tube, connected to a second pump, was introduced into the cell via a top port. The second pump was set to a flow rate slightly larger than the input pump, to ensure a constant level of liquid within the reactor. The outlet line was connected back to the solution reservoir. Once the system had been filled with liquid and recirculation of the electrolyte was established, the spinning of the electrode was initiated (300 rpm) as well as electrolysis under a constant current of 1.1 A. When 4.0 F/mol was passed, the power supply was turned off. The input pump was reversed to return all the reaction mixture to the solution reservoir. Then, the solvent was evaporated under reduced pressure and the residue was diluted with aqueous NaHCO3 (sat) and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated under reduced pressure, yielding 141.4 g (94%) of adrenosterone (6) as an off-white solid, mp 204–205 °C (lit. (24) 206–208 °C). 1H NMR (300 MHz, chloroform-d): δ 5.75 (s, 1H), 2.63–2.53 (m, 1H), 2.52–2.43 (m, 3H), 2.38–1.76 (m, 10H), 1.74–1.59 (m, 2H), 1.44 (s, 3H), 1.37–1.27 (m 1H), 0.88 (s, 3H) ppm. 13C NMR (125 MHz, chloroform-d): δ 216.8, 207.6, 199.5, 167.9, 124.8, 63.3, 50.4, 50.4, 49.8, 38.3, 36.3, 35.9, 34.7, 33.7, 31.9, 30.9, 21.6, 17.3, 14.7 ppm. These data agree with those previously reported in the literature. (24)
Scale-down of the Electrochemical Synthesis of Adrenosterone (6) in Batch Mode
An Erlenmeyer flask was loaded with cortisone (5) (9.01 g, 25 mmol), Et4NBF4 (1.09 g, 5 mmol), and 50 mL of MeCN/H2O 40:1. The mixture was stirred until the supporting electrolyte was fully dissolved. Then, the solution was loaded into a smaller version of the spinning cylinder electrochemical reactor equipped with an impervious graphite anode (working electrode, 94 cm2) and a steel cathode. The solution was electrolyzed under a constant current of 333 mA and a spinning speed of 390 rpm. After 4.0 F/mol of charge had been passed, the power supply was turned off. Then, the crude reaction mixture was evaporated under reduced pressure. The residue was diluted with aqueous NaHCO3 (sat) and the extracted with DCM. The organic phase was dried over Na2SO4 and evaporated under reduced pressure, yielding 7.17 g (95%) of adrenosterone (6) as an off-white solid, mp 207–209 °C (lit. (24) 206–208 °C). The spectroscopic data matched those obtained in the previous experiment.
Scale-up of the Electrochemical Synthesis of Adrenosterone (6) in Batch Mode
An Erlenmeyer flask was loaded with cortisone (5) (216.3 g, 0.6 mol), Et4NBF4 (26.05 g, 0.12 mol), and 1.2 L of MeCN/H2O 40:1. The mixture was stirred until the supporting electrolyte was fully dissolved. Then, the solution was loaded into a large version of the spinning cylinder electrochemical reactor equipped with an impervious graphite anode (working electrode, 2466 cm2) and a steel cathode. The solution was electrolyzed under a constant current of 7.1 A and a spinning speed of 65 rpm. After 4.0 F/mol of charge had been passed the power supply was turned off. Then, the crude reaction mixture was evaporated under reduced pressure. The residue was diluted with aqueous NaHCO3 (sat) and then extracted with DCM. The organic phase was dried over Na2SO4 and evaporated under reduced pressure, yielding 163.5 g (91%) of adrenosterone (6) as an off-white solid, mp 201–202 °C (lit. (24) 206–208 °C). The spectroscopic data matched those obtained in the previous experiment.
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Author Information
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- C. Oliver Kappe - Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria;
https://orcid.org/0000-0003-2983-6007;
- David Cantillo - Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria;https://orcid.org/0000-0001-7604-8711;
This work was funded by Austria Wirtschaftsservice Gesellschaft (AWS, Grant number P2119778-WTG02). The Research Center Pharmaceutical Engineering (RCPE) is funded within the framework of COMET - Competence Centers for Excellent Technologies by BMK, BMDW, Land Steiermark and SFG. The COMET program is managed by the FFG.
Acknowledgments
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We gratefully acknowledge Florian Sommer and Elias Hammer for their assistance in the manufacture of the electrochemical reactors.
References
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This article references 26 other publications.
- 1(a) Cohen, B.; Lehnherr, D.; Sezen-Edmonds, M.; Forstater, J. H.; Frederick, M. O.; Deng, L.; Ferretti, A. C.; Harper, K.; Diwan, M. Emerging reaction technologies in pharmaceutical development: Challenges and opportunities in electrochemistry, photochemistry, and biocatalysis. Chem. Eng. Res. Des. 2023, 192, 622– 637, DOI: 10.1016/j.cherd.2023.02.050Google Scholar1ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXks1CisLs%253D&md5=216da4f6fcf8a1c1c24b3556b6d09a26Emerging reaction technologies in pharmaceutical development: Challenges and opportunities in electrochemistry, photochemistry, and biocatalysisCohen, Benjamin; Lehnherr, Dan; Sezen-Edmonds, Melda; Forstater, Jacob H.; Frederick, Michael O.; Deng, Lin; Ferretti, Antonio C.; Harper, Kaid; Diwan, MoizChemical Engineering Research and Design (2023), 192 (), 622-637CODEN: CERDEE; ISSN:1744-3563. (Elsevier B.V.)The challenges and opportunities of developing API manufg. processes continue to grow. Mol. complexity of APIs is increasing, process development times are contracting, and there is a need to make processes greener, more efficient, and less costly. At the same time, emerging chem. technologies provide considerable opportunity to help address these challenges. Given that these are industry-wide challenges, the Enabling Technol. Consortium (ETC) Novel Chem. Reaction Environment Working Group seeks to realize the benefits of these novel technologies in manufg. routes by developing solns. that bridge the gap from the bench hood to the manufg. floor. After a prioritization exercise, the Working Group has focused on electrochem., photochem., and biocatalysis as technologies that the Working Group seeks to impact. In this perspective, members of the working group reflect on opportunities and challenges related to bringing these technologies to a scale-up-ready state, with the purpose of aligning the direction of technol. development among academic labs, equipment manufacturers, and industry partners. In this article, we provide a viewpoint on what issues need to be addressed in these technologies from scalability, safety, and quality perspectives.(b) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319, DOI: 10.1021/acs.chemrev.7b00397Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1WntbzJ&md5=21205e55da92db4e7d27aa393fed486dSynthetic Organic Electrochemical Methods Since 2000: On the Verge of a RenaissanceYan, Ming; Kawamata, Yu; Baran, Phil S.Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.(c) Echeverria, P.-G.; Delbrayelle, D.; Letort, A.; Nomertin, F.; Perez, M.; Petit, L. The Spectacular Resurgence of Electrochemical Redox Reactions in Organic Synthesis. Aldrichimica Acta 2018, 51, 3– 19Google Scholar1chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFeqsLvE&md5=34746d64e625bb4bf2e99391bd545c55The spectacular resurgence of electrochemical redox reactions in organic synthesisEcheverria, Pierre-Georges; Delbrayelle, Dominique; Letort, Aurelien; Nomertin, Fiona; Perez, Marc; Petit, LaurentAldrichimica Acta (2018), 51 (1), 3-19CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)A review. Electrochem. has had a profound impact on green chem. and in applications such as energy conversion and storage, electroplating, water treatment, and environmental monitoring, and it has also been embraced by various industries. It is therefore quite surprising that electrochem. has seldom been used by synthetic org. chemists. This could be partly attributed to the misconception that the electron as a reagent cannot be tamed easily. In recent years, the application of electrochem. to the synthesis of fine chems. has had a resurgence, and many elegant solns. based on electrochem. have been devised to address synthetic challenges with easy-to-use exptl. setups.(d) Waldvogel, S. R.; Janza, B. Renaissance of electrosynthetic methods for the construction of complex molecules. Angew. Chem., Int. Ed. 2014, 53, 7122– 7123, DOI: 10.1002/anie.201405082Google Scholar1dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVShurnK&md5=26e3d87d378216c8479526ed9eca6fdcRenaissance of electrosynthetic methods for the construction of complex moleculesWaldvogel, Siegfried R.; Janza, BirgitAngewandte Chemie, International Edition (2014), 53 (28), 7122-7123CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The article reviewed recent electrochem. developments in selective C-C bond formation in natural products, such as the cation-pool method or exploitation of solvent effects using fluorinated alcs., which provide new tools for efficient cross-coupling reactions which are essentially metal and reagent free. The encouraging results underline the potential of electroorg. synthesis and pave the way for the renaissance of this method. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- 2(a) Schäfer, H. J. Contributions of organic electrosynthesis to green chemistry. C. R. Chim. 2011, 14, 745– 765, DOI: 10.1016/j.crci.2011.01.002Google ScholarThere is no corresponding record for this reference.(b) Frontana-Uribe, B. A.; Little, D. R.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Organic electrosynthesis: a promising green methodology in organic chemistry. Green Chem. 2010, 12, 2099– 2119, DOI: 10.1039/c0gc00382dGoogle Scholar2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyrurfI&md5=974934a06b7b2219fabab86d9dfeba45Organic electrosynthesis: a promising green methodology in organic chemistryFrontana-Uribe, Bernardo A.; Little, R. Daniel; Ibanez, Jorge G.; Palma, Agustin; Vasquez-Medrano, RubenGreen Chemistry (2010), 12 (12), 2099-2119CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Over the last decade, org. electrosynthesis has become recognized as one of the methodologies that can fulfill several important criteria that are needed if society is to develop environmentally compatible processes. It can be used to replace toxic or dangerous oxidizing or reducing reagents, reduce energy consumption, and can be used for the in situ prodn. of unstable and hazardous reagents. These are just a few of the most important attributes that render electrochem. environmentally useful. In this review the main characteristics of electrochem. as a promising green methodol. for org. synthesis are described and exemplified. Herein we provide basic information concerning the nature of electrosynthetic processes, paired electrochem. reactions, electrocatalytic reactions, reactions carried out in ionic liqs., electrogeneration of reactants, electrochem. reactions that use renewable starting materials (biomass), green org. electrosynthesis in micro- and nano-emulsions, the synthesis of complex mols. using an electrosynthetic key step, and conclude with some insights concerning the future. Throughout the review the "green aspects" of these topics are highlighted and their relationship with the twelve green chem. principles is described.(c) Schaub, T. Efficient Industrial Organic Synthesis and the Principles of Green Chemistry. Chem.─Eur. J. 2021, 27, 1865– 1869, DOI: 10.1002/chem.202003544Google Scholar2chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsFKjsro%253D&md5=4df75137add44eb87cfa3243e2c0e6e2Efficient Industrial Organic Synthesis and the Principles of Green ChemistrySchaub, ThomasChemistry - A European Journal (2021), 27 (6), 1865-1869CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)There is no expanded citation for this reference.(d) Cantillo, D. Synthesis of Active Pharmaceutical Ingredients using Electrochemical Methods: Keys to Improve Sustainability. Chem. Commun. 2022, 58, 619– 628, DOI: 10.1039/D1CC06296DGoogle Scholar2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXivVemtLjN&md5=c0c27d6f3a8d103f3996782f4b4f8aabSynthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainabilityCantillo, DavidChemical Communications (Cambridge, United Kingdom) (2022), 58 (5), 619-628CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Org. electrochem. is receiving renewed attention as a green and cost-efficient synthetic technol. Electrochem. methods promote redox transformations by electron exchange between electrodes and species in soln., thus avoiding the use of stoichiometric amts. of oxidizing or reducing agents. The rapid development of electroorg. synthesis over the past decades has enabled the prepn. of mols. of increasing complexity. Redox steps that involve hazardous or waste-generating reagents during the synthesis of active pharmaceutical ingredients or their intermediates can be substituted by electrochem. procedures. In addn. to enhance sustainability, increased selectivity toward the target compd. has been achieved in some cases. Electroorg. synthesis can be safely and readily scaled up to prodn. quantities. For this pupose, utilization of flow electrolysis cells is fundamental. Despite these advantages, the application of electrochem. methods does not guarantee superior sustainability when compared with conventional protocols. The utilization of large amts. of supporting electrolytes, environmentally unfriendly solvents or sacrificial electrodes may turn electrochem. unfavorable in some cases. It is therefore crucial to carefully select and optimize the electrolysis conditions and carry out green metrics anal. of the process to ensure that turning a process electrochem. is advantageous.
- 3(a) Pollok, D.; Gleede, B.; Stenglein, A.; Waldvogel, S. R. Preparative Batch-Type Electrosynthesis: A Tutorial. Aldrichimica Acta 2021, 54, 3– 15Google Scholar3ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisFGisrnN&md5=3c9256d8e5e29d45258138f6196a3a1dPreparative batch-type electrosynthesis: a tutorialPollok, Dennis; Gleede, Barbara; Stenglein, Andreas; Waldvogel, Siegfried R.Aldrichimica Acta (2021), 54 (1Spec.Iss.), 3-15CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)A review. Modern org. chem. emphasizes sustainability in addn. to high performance in synthetic processes. Electroorg. synthesis meets these two criteria well. Herein, beakertype cells for batch-type electrolysis are highlighted along with a tutorial on starting an electrosynthesis with these cells and on how to treat the electrodes.(b) Schotten, C.; Nicholls, T. P.; Bourne, R. A.; Kapur, N.; Nguyen, B. N.; Willans, C. E. Making electrochemistry easily accessible to the synthetic chemist. Green Chem. 2020, 22, 3358– 3375, DOI: 10.1039/D0GC01247EGoogle Scholar3bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVSgtr0%253D&md5=4ff3802412f644f41e9c170a24172f26Making electrochemistry easily accessible to the synthetic chemistSchotten, Christiane; Nicholls, Thomas P.; Bourne, Richard A.; Kapur, Nikil; Nguyen, Bao N.; Willans, Charlotte E.Green Chemistry (2020), 22 (11), 3358-3375CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A review. A significantly renewed interest in synthetic electrochem. is apparent in the increasing no. of publications over the last few years. Electrochem. synthesis offers a mild, green and atom efficient route to interesting and useful mols., thus avoiding harsh chem. oxidising and reducing agents used in traditional synthetic methods. As such, encouraging broader application of electrochem. by synthetic chemists should be a priority. Despite the renewed interest there remains a barrier to widespread adoption of this technol. derived from the extra knowledge and specialised equipment required. This has led to a knowledge gap between experienced electrochemists and those new in the field. In this tutorial we will bridge the knowledge gap by providing an easily accessible introduction which will enable synthetic chemists new to the field to explore electrochem. We will discuss mechanistic considerations, the setup of an electrochem. reaction with all its components, trouble shooting and selected examples from the literature.(c) Hilt, G. Basic Strategies and Types of Applications in Organic Electrochemistry. ChemElectroChem. 2020, 7, 395– 405, DOI: 10.1002/celc.201901799Google Scholar3chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1amurfL&md5=c23253339312ef39fcaf8f3481dca9a9Basic Strategies and Types of Applications in Organic ElectrochemistryHilt, GerhardChemElectroChem (2020), 7 (2), 395-405CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The outlook of this paper is to give a short overview of the basic requirements to perform electro-org. transformations. The aim is to explain the strategies and possible applications in org. electrochem. as simply as possible and is directed to those scientists who are not necessarily trained electrochemists and those that intend to utilize this powerful and, nowadays, very popular tool in their research. Different types of electrolysis performed in a galvanostatic/potentiostatic/a.c. fashion will be presented and the strategies to perform divided/undivided/quasi-divided electrolysis will be covered. The application of direct/indirect/cation-pool electrolysis as well as several variants of paired electrolysis will be briefly explained utilizing selected examples.
- 4(a) Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118, 4573– 4591, DOI: 10.1021/acs.chemrev.7b00360Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2qtrnN&md5=28e56b67959db2e57b7a597a56046014Flow Electrolysis Cells for the Synthetic Organic Chemistry LaboratoryPletcher, Derek; Green, Robert A.; Brown, Richard C. D.Chemical Reviews (Washington, DC, United States) (2018), 118 (9), 4573-4591CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the use of flow electrolysis cells in synthetic org. chem. lab. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a no. of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant soln. through the cell. In addn., the needs of the synthetic org. chemist can often be met by flow cells operating with recycle of the reactant soln. These cells give a high rate of product formation while the reactant concn. is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported.(b) Elsherbini, M.; Wirth, T. Electroorganic Synthesis under Flow Conditions. Acc. Chem. Res. 2019, 52, 3287– 3296, DOI: 10.1021/acs.accounts.9b00497Google Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2mtbrN&md5=b5fa8c132594eaf2915246040f2d91b0Electroorganic Synthesis under Flow ConditionsElsherbini, Mohamed; Wirth, ThomasAccounts of Chemical Research (2019), 52 (12), 3287-3296CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Despite the long history of electroorg. synthesis, it did not participate in the mainstream of chem. research for long time. This is probably due to the lack of equipment and standardized protocols. However, nowadays org. electrochem. is witnessing a renaissance and a wide range of interesting electrochem. transformations and methodologies was developed, not only for academic purposes but also for large scale industrial prodn. Depending on the source of electricity, electrochem. methods can be inherently green, environmentally benign and can be easily controlled to achieve high levels of selectivity. The generation and consumption of reactive or unstable intermediates and hazardous reagents can be achieved in a safe way. Limitations of traditional batch-type electrochem. methods such as the restricted electrode surface, the necessity of supporting electrolytes and difficulties in scaling up can be alleviated using electrochem. flow cells. Microreactors offer high surface-to-vol. ratios and enable precise control over temp., residence time, flow rate and pressure. Efficient mixing, enhanced mass and heat transfer and handling of small vols. leads to simpler scaling-up protocols and minimize safety concerns. Electrolysis under flow conditions reduces the possibility of overoxidn. as the reaction mixt. is flown continuously out of the reactor in contrast to traditional batch-type electrolysis cells. In this account, the authors highlight the authors' contributions in the area of electroorg. synthesis under flow conditions over the past decade. The authors have designed and manufd. different generations of electrochem. flow cells. The 1st-generation reactor was effectively used in developing a simple 1-step synthesis of diaryliodonium salts and used in proof-of-concept reactions such as the trifluoromethylation of electron-deficient alkenes via Kolbe electrolysis of HO2CCF3 in addn. to the selective deprotection of isonicotinyloxycarbonyl (iNoc) group from carbonates and thiocarbonates. The improved 2nd-generation flow cell enabled the development of efficient synthesis of isoindolinones, benzothiazoles and thiazolopyridines, achieving gram-scale of some of the products easily without changing the reactor design or reoptimizing the reaction parameters. The same reactor was used in the development of an efficient continuous flow electrochem. synthesis of hypervalent I reagents. The generated unstable hypervalent I reagents were easily used without isolation in various oxidative transformations in a coupled flow/flow manner and could be easily transformed into bench-stable reagents via quant. ligand exchange with the appropriate acids. The authors' second-generation reactor was further improved and commercialized by Vaportec Ltd. The authors demonstrated the power of online anal. in accelerating optimizations and methodol. development. Online mass spectrometry enabled fast screening of the charge needed for the cyclization of amides to isoindolinones. The power of online 2-dimensional-HPLC combined with a DoE approach empowered the rapid optimization of stereoselective electrochem. alkoxylations of amino acid derivs.
- 5Noël, T.; Cao, Y.; Laudadio, G. The Fundamentals Behind the Use of Flow Reactors in Electrochemistry. Acc. Chem. Res. 2019, 52, 2858– 2869, DOI: 10.1021/acs.accounts.9b00412Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVOhtb3J&md5=820eee82ffc1b68b0f8f2b4ce8374f2cThe Fundamentals Behind the Use of Flow Reactors in ElectrochemistryNoel, Timothy; Cao, Yiran; Laudadio, GabrieleAccounts of Chemical Research (2019), 52 (10), 2858-2869CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. In the past decade, research into continuous-flow chem. has gained a lot of traction among researchers in both academia and industry. Esp., microreactors have received a plethora of attention due to the increased mass and heat transfer characteristics, the possibility to increase process safety, and the potential to implement automation protocols and process anal. technol. Taking advantage of these aspects, chemists and chem. engineers have capitalized on expanding the chem. space available to synthetic org. chemists using this technol. Electrochem. has recently witnessed a renaissance in research interests as it provides chemists unique and tunable synthetic opportunities to carry out redox chem. using electrons as traceless reagents, thus effectively avoiding the use of hazardous and toxic reductants and oxidants. The popularity of electrochem. stems also from the potential to harvest sustainable electricity, derived from solar and wind energy. Hence, the electrification of the chem. industry offers an opportunity to locally produce commodity chems., effectively reducing inefficiencies with regard to transportation and storage of hazardous chems. The combination of flow technol. and electrochem. provides practitioners with great control over the reaction conditions, effectively improving the reproducibility of electrochem. However, carrying out electrochem. reactions in flow is more complicated than just pumping the chems. through a narrow-gap electrolytic cell. Understanding the engineering principles behind the observations can help researchers to exploit the full potential of the technol. Thus, the prime objective of this Account is to provide readers with an overview of the underlying engineering aspects which are assocd. with continuous-flow electrochem. This includes a discussion of relevant mass and heat transport phenomena encountered in electrochem. flow reactors. Next, the possibility to integrate several reaction steps in a single streamlined process and the potential to carry out challenging multiphase electrochem. transformations in flow are discussed. Due to the high control over mass and heat transfer, electrochem. reactions can be carried out with great precision and reproducibility which provide opportunities to enhance and tune the reaction selectivity. Finally, the authors detail on the scale-up potential of flow electrochem. and the importance of small interelectrode gaps on pilot and industrial-scale electrochem. processes. Each principle was illustrated with a relevant org. synthetic example. In general, the authors have aimed to describe the underlying engineering principles in simple words and with a min. of equations to attract and engage readers from both a synthetic org. chem. and a chem. engineering background. Hence, the authors anticipate that this Account will serve as a useful guide through the fascinating world of flow electrochem.
- 6Pletcher, D.; Walsh, F. C. Industrial Electrochemistry; Springer: Netherlands, 1993.Google ScholarThere is no corresponding record for this reference.
- 7Maljuric, S.; Jud, W.; Kappe, C. O.; Cantillo, D. Translating batch electrochemistry to single-pass continuous flow conditions: an organic chemist’s guide. J. Flow Chem. 2020, 10, 181– 190, DOI: 10.1007/s41981-019-00050-zGoogle Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktlyjsbg%253D&md5=b02c30f1d47eb0f455dd0012d2cc1156Translating batch electrochemistry to single-pass continuous flow conditions: an organic chemist's guideMaljuric, Snjezana; Jud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidJournal of Flow Chemistry (2020), 10 (1), 181-190CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)Abstr.: The recent renaissance of electrochem. methods for org. synthesis has also attracted increased interest towards flow electrochem. as the most suitable scale-up strategy. Many electrochem. methods using flow cells are based on recirculation of the electrolyte soln. However, single-pass processing is very attractive as it permits integration of the electrochem. reaction with other synthetic or purifn. steps in a continuous stream. Translation of batch electrochem. procedures to single-pass continuous flow cells can be challenging to beginners in the field. Using the electrochem. methoxylation of 4-methylanisole as model, this paper provides newcomers to the field with an overview of the factors that need to be considered to develop a flow electrochem. process, including advantages and disadvantages of operating in galvanostatic and potentiostatic mode in small scale reactions, and the effect of the interelectrode gap, supporting electrolyte concn. and pressure on the reaction performance. A comparison of the reaction efficiency in batch and flow is also presented. [graphic not available: see fulltext].
- 8Goodridge, F.; Scott, K. Electrochemical Process Engineering – A Guide to the Design of Electrolytic Plant; Springer Science+ Business Media: New York, 1995.Google ScholarThere is no corresponding record for this reference.
- 9Schoenitz, M.; Grundemann, L.; Augustin, W.; Scholl, S. Chem. Commun. 2015, 51, 8213– 8228, DOI: 10.1039/C4CC07849GGoogle Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1Sksrk%253D&md5=995d00439b861408acc56047e7ee83f3Fouling in microstructured devices: a reviewSchoenitz, M.; Grundemann, L.; Augustin, W.; Scholl, S.Chemical Communications (Cambridge, United Kingdom) (2015), 51 (39), 8213-8228CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Microstructured devices are widely used for manufg. products that benefit from process intensification, with pharmaceutical products or specialties of the chem. industry being prime examples. These devices are ideally used for processing pure fluids. Where particulate or non-pure flows are involved, processes are treated with utmost caution since related fouling and blocking issues present the greatest barrier to operating microstructured devices effectively. Micro process engineering is a relatively new research field and there is limited understanding of fouling in these dimensions and its underlying processes and phenomena. A comprehensive review on fouling in microstructured devices would be helpful in this regard, but is currently lacking. This paper attempts to review recent developments of fouling in micro dimensions for all fouling categories (crystn., particulate, chem. reaction, corrosion, and biol. growth fouling) and the sequential events involved (initiation, transport, attachment, removal and aging). Compared to fouling in macro dimensions, an addnl. sixth category is suggested: clogging by gas bubbles. Most of the reviewed papers present very specific fouling investigations making it difficult to derive general rules and parameter dependencies, and comparative or crit. considerations of the studies were difficult. The statistical approach is used to evaluate the research in the field of fouling in microchannels.
- 10Zhao, X.; Ren, H.; Luo, L. Gas Bubbles in Electrochemical Gas Evolution Reactions. Langmuir 2019, 35, 5392– 5408, DOI: 10.1021/acs.langmuir.9b00119Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFCju7g%253D&md5=0823c734a0e02877cd72515545772010Gas Bubbles in Electrochemical Gas Evolution ReactionsZhao, Xu; Ren, Hang; Luo, LongLangmuir (2019), 35 (16), 5392-5408CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)A review. Electrochem. gas evolution reactions are of vital importance in numerous electrochem. processes including H2O splitting, chloralkaline process, and fuel cells. During gas evolution reactions, gas bubbles are vigorously and constantly forming and influencing these processes. In the past few decades, extensive studies were performed to understand the evolution of gas bubbles, elucidate the mechanisms of how gas bubbles impact gas evolution reactions, and exploit new bubble-based strategies to improve the efficiency of gas evolution reactions. In this feature article, the authors summarize the classical theories as well as recent advancements in this field and provide an outlook on future research topics.
- 11Bottecchia, C.; Lehnherr, D.; Lévesque, F.; Reibarkh, M.; Ji, Y.; Rodrigues, V. L.; Wang, H.; Lam, Y.-H.; Vickery, T. P.; Armstrong, B. M.; Mattern, K. A.; Stone, K.; Wismer, M. K.; Singh, A. N.; Regalado, E. L.; Maloney, K. M.; Strotman, N. A. Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up Electrosynthesis. Org. Process Res. Dev. 2022, 26, 2423– 2437, DOI: 10.1021/acs.oprd.2c00111Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1GitbvJ&md5=480f8406fcedc78200ed7bca76e20628Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up ElectrosynthesisBottecchia, Cecilia; Lehnherr, Dan; Levesque, Francois; Reibarkh, Mikhail; Ji, Yining; Rodrigues, Vailankanni L.; Wang, Heather; Lam, Yu-hong; Vickery, Thomas P.; Armstrong, Brittany M.; Mattern, Keith A.; Stone, Kevin; Wismer, Michael K.; Singh, Andrew N.; Regalado, Erik L.; Maloney, Kevin M.; Strotman, Neil A.Organic Process Research & Development (2022), 26 (8), 2423-2437CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Org. electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in org. synthesis. Concerns around the scalability of electrochem. methods remain the biggest reason behind their scarce implementation in manufg. routes for the pharmaceutical industry. To fill this gap, we report a workflow describing the key reaction parameters toward the successful scale-up of an org. electrosynthetic method from milligram to kilogram scale. The reaction used to demonstrate our workflow and scale-up in a flow setting was the oxidn. of a thioether to its corresponding sulfone, a fragment of interest in an active pharmaceutical ingredient under development. The use of online flow NMR spectroscopy, offline ion chromatog., cyclic voltammetry, and d. functional theory calcns. provided insight into the reaction mechanism and side reactions.
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Spinning electrode electrolysis cells, also called rotating cylinder cells, have previously found applications in electrolysis processes such as water waste treatment and metal recovery:
(a) Polcaro, A. M.; Vacca, A.; Mascia, M.; Palmas, S.; Pompei, R.; Laconi, S. Characterization of a stirred tank electrochemical cell for water disinfection processes. Electrochim. Acta 2007, 52, 2595– 2602, DOI: 10.1016/j.electacta.2006.09.015Google Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpslagsw%253D%253D&md5=6fe565a0b4268c83d9d3055dc34a8b6cCharacterization of a stirred tank electrochemical cell for water disinfection processesPolcaro, A. M.; Vacca, A.; Mascia, M.; Palmas, S.; Pompei, R.; Laconi, S.Electrochimica Acta (2007), 52 (7), 2595-2602CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)Lab. expts. were performed to characterize the behavior of an electrochem. cell equipped with boron-doped diamond anodes and to verify its effectiveness in water disinfection. The hydrodynamic regime was detd. when the cell worked either in batch or in continuous mode. Galvanostatic electrolyzes of aq. 1 mM Na2SO4 solns. were performed to investigate the oxidant prodn. in different exptl. conditions. The same solns. contaminated by E. coli, enterococci and coliforms were used as test media to verify the effectiveness of the system in the disinfection process. Exptl. results indicated that the major inactivation mechanism of bacteria in the electrochem. cell is a disinfection by electrochem. generated oxidants, however a cooperative effect of superficial reaction has to be taken into account. The great capability of BDD anode to produce reactive oxygen species (ROS) and other oxidizing species during the electrolysis allows to establish a chlorine-free disinfection process.(b) Hernández-Tapia, J. R.; Vazquez-Arenas, J.; González, I. Electrochemical reactor with rotating cylinder electrode for optimum electrochemical recovery of nickel from plating rinsing effluents. J. Haz. Mater. 2013, 262, 709– 716, DOI: 10.1016/j.jhazmat.2013.09.029Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsl2gsL7E&md5=b74fd36119c4a7c0d1c745deebee8de6Electrochemical reactor with rotating cylinder electrode for optimum electrochemical recovery of nickel from plating rinsing effluentsHernandez-Tapia, J. R.; Vazquez-Arenas, J.; Gonzalez, I.Journal of Hazardous Materials (2013), 262 (), 709-716CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)This study is devoted to analyze the metallic electrochem. recovery of nickel from synthetic solns. simulating plating rinsing discharges, in order to meet the water recycling policies implemented in these industries. These effluents present dil. Ni(II) concns. (100 and 200 ppm) in chloride and sulfate media without supporting electrolyte (397-4202 μS cm-1), which stems poor current distribution, limited mass transfer, ohmic drops and enhancement of parasitic reactions. An electrochem. reactor with rotating cylinder electrode (RCE) and a pH controller were utilized to overcome these problems. The pH control around 4 was crucial to yield high purity nickel, and thus prevent the pptn. of hydroxides and oxides. Macroelectrolysis expts. were systematically conducted to analyze the impacts of the applied c.d. in the recovery efficiency and energy consumption, particularly for very dild. effluents (100 and 200 ppm Ni(II)), which present major recovery problems. Promising nickel recoveries in the order of 90% were found in the former baths using a c.d. of -3.08 mA cm-2, and with overall profits of 9.64 and 14.69 USD kg-1, resp. These estns. were based on the international market price for nickel ($18 USD kg-1).(c) Luis Nava-M. de Oca, J.; Sosa, E.; Ponce de Leon, C.; Oropeza, M.T. Effectiveness factors in an electrochemical reactor with rotating cylinder electrode for the acid-cupric/copper cathode interface process. Chem. Eng. Sci. 2001, 56, 2695– 2702, DOI: 10.1016/S0009-2509(00)00514-5Google ScholarThere is no corresponding record for this reference.(d) Gao, H.; Scheeline, A.; Pearlstein, A. J. Spatially Controlled Microstructural Variation using a Free-Surface Flow Driven by a Rotating Cylinder Electrode: Growth of Anodic Oxide Films on A1 6061. J. Electrochem. Soc. 2002, 149, B248, DOI: 10.1149/1.1471889Google Scholar12dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVGlsLY%253D&md5=f9333754280c9e20e4a7d10de7285becSpatially controlled microstructural variation using a free-surface flow driven by a rotating cylinder electrode growth of anodic oxide films on AA 6061Gao, Husheng; Scheeline, Alexander; Pearlstein, Arne J.Journal of the Electrochemical Society (2002), 149 (6), B248-B255CODEN: JESOAN; ISSN:0013-4651. (Electrochemical Society)Growth and characterization of oxide films with spatially controlled microstructure on AA 6061 using a coaxial rotating, axially translating electrochem. reactor (CRATER) are reported. This electrode/flow combination allows growth of oxide films with spatially controlled microstructure on a single working electrode (WE) under well-defined conditions of mass transfer, electrode potential, and residence time. This is achieved by restricting electro-oxidn. to a "window" of narrow axial extent just below the free surface of an electrolyte whose coaxial inner and outer boundaries are a rotating counter electrode and an axially translating WE, resp. Axial translation of the WE maps temporal variation of a controlled parameter (e.g., applied potential, mass-transfer rate) to axial variation of oxide microstructure on the WE. In the present work the applied potential is scanned linearly in time, leading to each element of the WE undergoing electro-oxidn. over a narrow range of potential. Each element of the WE has the same exposure time in the reactive window and is exposed to the same mass-transfer conditions. This produces an oxide film in which the cell size and pore size vary systematically with potential along the length of the WE. The film displays a high degree of azimuthal uniformity. Continuous scanning of process variables in a single expt. by this approach allows identification of desirable microstructures in narrow ranges of operating conditions. Application of CRATER methodol. to electrodissoln. and electrodeposition is discussed.(e) Gabe, C. R.; Walsh, F. C. The rotating cylinder electrode: a review of development. J. Appl. Electrochem. 1983, 13, 3– 22, DOI: 10.1007/BF00615883Google Scholar12ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXotVCjuw%253D%253D&md5=2f06f58ea90d0e7a45a052d716a510afThe rotating cylinder electrode: a review of developmentGabe, D. R.; Walsh, F. C.Journal of Applied Electrochemistry (1983), 13 (1), 3-21CODEN: JAELBJ; ISSN:0021-891X.A review with 143 refs. is given on the theory and applications of rotating cylinder electrodes. Particular attention is paid to the mass transfer behavior and the development of turbulent flow patterns, and its exploitation in electrochem. reactors for a variety of applications, including metal deposition from waste and effluent liquors. - 13
A Taylor vortex reactor based on the same principle has recently been applied to synthetic organic electrochemistry by George and co-workers:
(a) Love, A.; Lee, D. S.; Gennari, G.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. A Continuous-Flow Electrochemical Taylor Vortex Reactor: A Laboratory-Scale High-Throughput Flow Reactor with Enhanced Mixing for Scalable Electrosynthesis. Org. Process Res. Dev. 2021, 25, 1619– 1627, DOI: 10.1021/acs.oprd.1c00102Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVOrtrvM&md5=6220165911367288feaf2ff23a679da7A Continuous-Flow Electrochemical Taylor Vortex Reactor: A Laboratory-Scale High-Throughput Flow Reactor with Enhanced Mixing for Scalable ElectrosynthesisLove, Ashley; Lee, Darren S.; Gennari, Gabriele; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, MichaelOrganic Process Research & Development (2021), 25 (7), 1619-1627CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The authors report the development of a small footprint continuous electrochem. Taylor vortex reactor capable of processing kilogram quantities of material per day. This report builds upon the authors' previous development of a scalable photochem. Taylor vortex reactor (Org. Process Res. Dev.2017,21,1042;2020,24,201-206). It describes a static and rotating electrode system that allows for enhanced mixing within the annular gap between the electrodes. The size of the annular gap and the rotation speed of the electrode are important for both conversion of the substrate and selectivity of the product exemplified using the methoxylation of N-formylpyrrolidine. The employment of a cooling jacket was necessary for scaling the reaction to manage the heat generated by electrodes at higher currents (up to 30 A, >270 mA cm-2) allowing multimole productivity per day of methoxylation product to be achieved. The electrochem. oxidn. of thioanisole was also studied, and the reactor has the performance to produce up to 400 g day-1 of either of the corresponding sulfoxide or sulfone while maintaining a very high reaction selectivity (>97%) to the desired product. This development completes a suite of vortex reactor designs that can be used for photo-, thermal-, or electrochem., all of which decouple residence time from mixing. This opens up the possibility of performing continuous multistep reactions at scale with flexibility in optimizing processes.(b) Lee, D. S.; Love, A.; Mansouri, Z.; Waldron Clarke, T. H.; Harrowven, D. C.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. W. High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor. Org. Process Res. Dev. 2022, 26, 2674– 2684, DOI: 10.1021/acs.oprd.2c00108Google Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xit1SitrfM&md5=09d57d74577db054ab89c9a756845d9aHigh-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex ReactorLee, Darren S.; Love, Ashley; Mansouri, Zakaria; Waldron Clarke, Toby H.; Harrowven, David C.; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, Michael W.Organic Process Research & Development (2022), 26 (9), 2674-2684CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The authors report the development of a single-pass electrochem. Birch redn. carried out in a small footprint electrochem. Taylor vortex reactor with projected productivities of >80 g day-1 (based on 32.2 mmol h-1), using a modified version of the authors' previously reported reactor [Org. Process Res. Dev.2021, 25, 7, 1619-1627], consisting of a static outer electrode and a rapidly rotating cylindrical inner electrode. The authors used an Al tube as the sacrificial outer electrode and stainless steel as the rotating inner electrode. The authors established the viability of using a sacrificial Al anode for the electrochem. redn. of naphthalene, and by varying the current, the authors can switch between high selectivity (>90%) for either the single ring redn. or double ring redn. with >80 g day-1 projected productivity for either product. The concn. of LiBr in soln. changes the fluid dynamics of the reaction mixt. studied by computational fluid dynamics, and this affects equilibration time, monitored using FTIR spectroscopy. The concns. of electrolyte (LiBr) and proton source (dimethylurea) can be reduced while maintaining high reaction efficiency. The authors also report the redn. of 1-aminonaphthalene, which was used as a precursor to the API Ropinirole. The authors' methodol. produces the corresponding dihydronaphthalene in excellent selectivity and 88% isolated yield in an uninterrupted run of >8 h with a projected productivity of >100 g day-1. - 14Small scale experiments were carried out in an IKA ElectraSyn 2.0 electrochemical reactor: https://www.ika.com/en/Products-LabEq/Electrochemistry-Kit-pg516/ElectraSyn-20-pro-Package-40003261/ (accessed on July 26, 2023).Google ScholarThere is no corresponding record for this reference.
- 15Selman, J. R.; Tobias, C. W. Mass-Transfer Measurements by the Limiting-Current Technique. Adv. Chem. Eng. 1978, 10, 211– 318, DOI: 10.1016/S0065-2377(08)60134-9Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXksF2gurw%253D&md5=59acfe1b0c99808d4f9854d4bd84c375Mass-transfer measurements by the limiting-current techniqueSelman, J. Robert; Tobias, Charles W.Advances in Chemical Engineering (1978), 10 (), 211-318CODEN: ACHEAT; ISSN:0065-2377.A review with 324 refs.
- 16Scott, K.; Lobato, J. Determination of a Mass-Transfer Coefficient Using the Limiting-Current Technique. Chem. Educator 2002, 7, 214– 219, DOI: 10.1007/s00897020579aGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmvFWqt78%253D&md5=f18798b462bce4c78191bcf187586f96Determination of a mass-transfer coefficient using the limiting-current techniqueScott, Keith; Lobato, JustoChemical Educator [online computer file] (2002), 7 (4), 214-219CODEN: CHEDF5; ISSN:1430-4171. (Springer-Verlag New York Inc.)Mass-transfer coeffs. of a cross-corrugated plate have been detd. by the limiting-current technique. A simple Microsoft Excel spreadsheet has been created which allows students to correlate data. Students will be able to calc. the mass-transfer coeff. of different processes, for example, cross-flow membrane filtration processes or membrane reactors. The possibility of using the spreadsheet with different correlations and to discriminate between them is also validated by comparing the model results with published exptl. data available in the recent literature. It is possible as well to study the influence of different turbulence promoters on the flow. Results show that corrugated membranes enhanced the flow and the more advantageous flow regime is reached, suggesting that these membranes can be used to study processes that are normally in the low regime.
- 17Fogler, H. S. Residence time distributions of chemical reactors. In Elements of chemical reaction engineering, 5th ed.; Pearson Education, Inc.: London, 2016.Google ScholarThere is no corresponding record for this reference.
- 18Scott, K. The continuous stirred tank electrochemical reactor. An overview of dynamic and steady state analysis for design and modelling. J. Appl. Electrochem. 1991, 21, 945– 960, DOI: 10.1007/BF01077579Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXms1Ghsbc%253D&md5=d9191cdcb2068bac891ea76db42bc199The continuous stirred tank electrochemical reactor. An overview of dynamic and steady state analysis for design and modelingScott, K.Journal of Applied Electrochemistry (1991), 21 (11), 945-60CODEN: JAELBJ; ISSN:0021-891X.A review with 14 refs. The continuous stirred tank reactor is frequently adopted as a model for electrochem. reactors. This article brings together the various important aspects of the model: dynamics, thermal characteristics, residence time distributions and steady-state characteristics and gives an overview of the design procedures.
- 19Shono, T. Electroorganic chemistry in organic synthesis. Tetrahedron 1984, 40, 811– 850, DOI: 10.1016/S0040-4020(01)91472-3Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXhtlyiur8%253D&md5=86702304b101e67907968d530114e516Electroorganic chemistry in organic synthesisShono, TatsuyaTetrahedron (1984), 40 (5), 811-50CODEN: TETRAB; ISSN:0040-4020.A review with 127 refs.
- 20(a) Birkin, P. R.; Kuleshova, J.; Hill-Cousins, J. T.; Brown, R. C. D.; Pletcher, D.; Underwood, T. J. A simple and inexpensive microfluidic electrolysis cell. Electrochim. Acta 2011, 56, 4322– 4326, DOI: 10.1016/j.electacta.2011.01.036Google Scholar20ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkslCnurk%253D&md5=0942af8b0c5c89b1f236c60d27f6d5ebA simple and inexpensive microfluidic electrolysis cellKuleshova, Jekaterina; Hill-Cousins, Joseph T.; Birkin, Peter R.; Brown, Richard C. D.; Pletcher, Derek; Underwood, Toby J.Electrochimica Acta (2011), 56 (11), 4322-4326CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)A single channel microfluidic electrolysis cell based on inexpensive materials and fabrication techniques is described. The cell is characterised using the electrochem. of the Fe(CN)63-/Fe(CN)64- couple and its application in electrosynthesis is illustrated using the methoxylation reactions of N-formylpyrrolidine and 4-t-butyltoluene. The reactions can be carried out with a good conversion in a single pass. The device, as described, allows the prodn. of several mmol/h of the methoxylated products.(b) Folgueiras-Amador, A. A. A.; Teuten, A. E. E.; Pletcher, D.; Brown, R. C. D. React. Chem. Eng. 2020, 5, 712– 718, DOI: 10.1039/D0RE00019AGoogle Scholar20bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvFylt7w%253D&md5=3a7fb0c0b7a7ba68eae357e2b1f1a5f8A design of flow electrolysis cell for 'Home' fabricationFolgueiras-Amador, Ana A.; Teuten, Alex E.; Pletcher, Derek; Brown, Richard C. D.Reaction Chemistry & Engineering (2020), 5 (4), 712-718CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Despite extensive literature on org. electrosynthesis, it has never become a routine procedure in org. synthesis labs. One reason is certainly a lack of attention to the design of the cell used for the electrolysis; an appropriate cell is the dominant factor in detg. the rate of conversion and the final conversion. Beaker cells predominate in published lab. electrosyntheses but their use can limit reaction performance, and ease of scale-up, particularly where high rates of conversion are required without compromising selectivity for the desired product. This paper describes a simple design of a flow cell for operation in a recycle mode that is straightforward to fabricate and its performance is illustrated with anodic and cathodic electrosyntheses. The advantages of using turbulence promoters in the flow channel and a three dimensional electrode (reticulated vitreous carbon) are demonstrated. The cell allows the prepn. of up to 5 mmol per h of isolated product, and 20 mmol of product can be obtained over 4 h with high conversion of starting material. The cell design is readily scalable to enable the synthesis of larger quantities of product, and provides the capability to introduce a separator for org. electrosynthesis in a divided mode.(c) Jud, W.; Kappe, C. O.; Cantillo, D. ChemElectroChem. 2020, 7, 2777– 2783, DOI: 10.1002/celc.202000696Google Scholar20chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtl2rt7vM&md5=6a382f08990fe714d09c2d410107feb0A Continuous Flow Cell for High-Temperature/High-Pressure Electroorganic SynthesisJud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidChemElectroChem (2020), 7 (13), 2777-2783CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)A flow electrolysis cell that enables operation at high temps. and pressures has been designed and developed. The cell, with a cylindrical shape and concentric electrodes, can be easily assembled using com. available fluidic components. The compact design of the device permits easy temp. control using a com. column heater. Temps. ranging from -10°C to +150°C and pressures up to 70 bar have been successfully applied for long operation periods. The cell performance has been evaluated using the anodic methoxylation of N-formylpiperidine as a model. Very high conversions and selectivities have been achieved with single-pass processing, and high productivities of 73 mmol/h with electrolyte recycling. The high pressure and temp. capabilities of the cell have been used to demonstrate the neg. effect that re-dissolved hydrogen gas can have on hydrogen-releasing electrochem. reactions in undivided cells, owing to undesired anodic oxidn. of hydrogen.
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Sufficient inert gas flow to ensure that the H2 gas concentration is below 4% should be provided:
Najjar, Y. S. H. Hydrogen safety: The road toward green technology. Int. J. Hydrog. Energy 2013, 38, 10716– 10728, DOI: 10.1016/j.ijhydene.2013.05.126Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKntr3K&md5=b91ebca1e933e232ed61e26fb8582170Hydrogen safety: The road toward green technologyNajjar, Yousef S. H.International Journal of Hydrogen Energy (2013), 38 (25), 10716-10728CODEN: IJHEDX; ISSN:0360-3199. (Elsevier Ltd.)A review. With increasing world energy demands, the search for an environmentally-friendly fuel is a must. Hydrogen is a fuel that is energy-efficient and clean, and considered by many as the perfect fuel. The problem arises when it comes to safety considerations. It does not have a good reputation because of some unfortunate accidents during history. In this work the safety of hydrogen during prodn., transmission and use is reviewed. Hydrogen safety issues are mainly discussed in relation to its ignition and combustion characteristics namely: wide flammability range detonation level, low ignition energy, relatively high flame velocity, rapid diffusion and buoyancy, in addn. to it its characteristics in the liq. phase. Hydrogen is the lightest gas (14 times lighter than air), highly flammable, odorless, and burns with a colorless flame. When used as a fuel, it supplies more energy per unit mass, than the popular fuels used today. In producing hydrogen, there are many processes, each one with its hazards, but these are relatively less weighed against hydrogen having the highest energy-carrying abilities. In storing, transmission and using of hydrogen, the main hazard is in its leaking, causing a fire to start. To detect when a leak happens, reliable and economic sensors should be used. High degree of safety, depending on hydrogen properties, is essential in any relevant design, to accelerate toward hydrogen economy. - 22Tanbouza, N.; Ollevier, T.; Lam, K. Bridging Lab and Industry with Flow Electrochemistry. iScience 2020, 23, 101720, DOI: 10.1016/j.isci.2020.101720Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVaktLbO&md5=4ee8002fb08118972e5bbfb044695c46Bridging Lab and Industry with Flow ElectrochemistryTanbouza, Nour; Ollevier, Thierry; Lam, KeviniScience (2020), 23 (11), 101720CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)A review. A revitalization of org. electrosynthesis has incited the org. chem. community to adopt electrochem. as a green and cost-efficient method for activating small mols. to replace highly toxic and expensive redox chems. However, many of the crit. challenges of batch electrosynthesis, esp. for org. synthesis, still remain. The combination of continuous flow technol. and electrochem. is a potent means to enable industry to implement large scale electrosynthesis. Indeed, flow electrosynthesis helps overcome problems that mainly arise from macro batch electro-org. systems, such as mass transfer, ohmic drop, and selectivity, but this is still far from being a flawless and generic applicable process. As a result, a notable increase in research on methodol. and hardware sophistication has emerged, and many hitherto uncharted chemistries have been achieved. To better help the commercialization of wide-scale electrification of org. synthesis, we highlight in this perspective the advances made in large-scale flow electrosynthesis and its future trajectory while pointing out the main challenges and key improvements of current methodologies.
- 23Jud, W.; Kappe, C. O.; Cantillo, D. Development and Assembly of a Flow Cell for Single-Pass Continuous Electroorganic Synthesis Using Laser-Cut Components. Chem. Methods 2021, 1, 36– 42, DOI: 10.1002/cmtd.202000042Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlWit7zK&md5=6d0f5324e12974b1adbc918f8ae7d9e1Development and Assembly of a Flow Cell for Single-Pass Continuous Electroorganic Synthesis Using Laser-Cut ComponentsJud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidChemistry: Methods (2021), 1 (1), 36-41CODEN: CMHEGP; ISSN:2628-9725. (Wiley-VCH Verlag GmbH & Co. KGaA)Flow electrolysis cells are essential for the scale up of synthetic org. electrochem. We have developed a simple and inexpensive parallel plate flow cell that can be easily assembled using a stack of laser-cut Mylar foils, which act as gaskets, insulating material, interelectrode gap and flow channel. The ease with which the laser-cutting pattern can be customized has enabled the development of interelectrode separators with mixing geometries, which improve the mass transfer and thus the current efficiency. The performance of the flow electrolysis cell has been evaluated using the anodic decarboxylative methoxylation of diphenylacetic acid as model transformation. Very high conversions and selectivities have been achieved with single-pass processing, with nearly quant. current efficiency in some cases.
- 24Sommer, F.; Kappe, C. O.; Cantillo, D. Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids. Chem.─Eur. J. 2021, 27, 6044– 6049, DOI: 10.1002/chem.202100446Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVWltbo%253D&md5=73e598b56de269117f284d24d9723f8dElectrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen SteroidsSommer, Florian; Kappe, C. Oliver; Cantillo, DavidChemistry - A European Journal (2021), 27 (19), 6044-6049CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto deriv. Conventional chem. reagents pose significant drawbacks for this synthetic strategy, as large amts. of waste are generated, and quenching of the reaction mixt. and purifn. of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochem. strategies for the prepn. of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidn. has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids [e.g., hydrocortisone I → 17-ketosteroid II (99%)]. In addn., simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of satd. androgens.
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The surface velocity ‘V’ (in cm/s) can be calculated from the spinning speed ‘S’ (in rpm) and the diameter ‘D’ of the working electrode using the following equation: V(cm/s) = π × D(cm) × S(min–1)/60(s/min).
There is no corresponding record for this reference. - 26A previous version of this manuscript has been deposited in ChemRxiv: Petrović, N.; Malviya, B. K.; Kappe, C. O.; Cantillo, D. ChemRxiv 2023, Pre-print. DOI: 10.26434/chemrxiv-2023-6vvnn .Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Comparison of the scale-up of electrochemical processes in parallel plate flow cells vs the spinning electrode reactor presented herein.
Figure 2
Figure 2. Computer generated images of the reactor components and assembly.
Figure 3
Figure 3. Simplified view of the electrode dimension of the 3 electrochemical reactors assembled in this work and photograph of the units.
Figure 4
Figure 4. Fluidic and electrical connections in the spinning electrode cell.
Figure 5
Figure 5. (a) Schematic view of the setup used to determine the mass transfer of the system under different electrode spinning speeds and (b) mass transfer (km) values obtained in cm/s. Details on the calculation of km from the limiting current experiments are collected in the Supporting Information.
Figure 6
Figure 6. (a) Schematic view of the setup utilized for the evaluation of the residence time distribution in the spinning electrode reactor. KHP: potassium hydrogen phthalate. (b) E curve obtained when the reactor was fed from the top port and (c) from the bottom port. E(t) corresponds to the fraction of particles that stay in the reactor for a given time before exiting.
Figure 7
Figure 7. (a) Electrochemical methoxylation of N-formyl piperidine (1) and (b) schematic view of the flow setup with the electrolyte recirculation operation used for the reaction.
Figure 8
Figure 8. Schematic view of a cascade of 3 continuous stirred electrochemical reactors connected in series to achieve single-pass electrolysis of diphenylacetic acid (3). Impervious graphite was used as the anode material, and stainless steel was used as cathode.
Figure 9
Figure 9. Electrochemical side-chain cleavage of cortisone in flow recirculation mode using a 450 cm2 surface area spinning electrode reactor.
Figure 10
Figure 10. Summary of the capabilities of scale-up opportunities using spinning cylinder electrode reactor technology.
References
This article references 26 other publications.
- 1(a) Cohen, B.; Lehnherr, D.; Sezen-Edmonds, M.; Forstater, J. H.; Frederick, M. O.; Deng, L.; Ferretti, A. C.; Harper, K.; Diwan, M. Emerging reaction technologies in pharmaceutical development: Challenges and opportunities in electrochemistry, photochemistry, and biocatalysis. Chem. Eng. Res. Des. 2023, 192, 622– 637, DOI: 10.1016/j.cherd.2023.02.0501ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXks1CisLs%253D&md5=216da4f6fcf8a1c1c24b3556b6d09a26Emerging reaction technologies in pharmaceutical development: Challenges and opportunities in electrochemistry, photochemistry, and biocatalysisCohen, Benjamin; Lehnherr, Dan; Sezen-Edmonds, Melda; Forstater, Jacob H.; Frederick, Michael O.; Deng, Lin; Ferretti, Antonio C.; Harper, Kaid; Diwan, MoizChemical Engineering Research and Design (2023), 192 (), 622-637CODEN: CERDEE; ISSN:1744-3563. (Elsevier B.V.)The challenges and opportunities of developing API manufg. processes continue to grow. Mol. complexity of APIs is increasing, process development times are contracting, and there is a need to make processes greener, more efficient, and less costly. At the same time, emerging chem. technologies provide considerable opportunity to help address these challenges. Given that these are industry-wide challenges, the Enabling Technol. Consortium (ETC) Novel Chem. Reaction Environment Working Group seeks to realize the benefits of these novel technologies in manufg. routes by developing solns. that bridge the gap from the bench hood to the manufg. floor. After a prioritization exercise, the Working Group has focused on electrochem., photochem., and biocatalysis as technologies that the Working Group seeks to impact. In this perspective, members of the working group reflect on opportunities and challenges related to bringing these technologies to a scale-up-ready state, with the purpose of aligning the direction of technol. development among academic labs, equipment manufacturers, and industry partners. In this article, we provide a viewpoint on what issues need to be addressed in these technologies from scalability, safety, and quality perspectives.(b) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319, DOI: 10.1021/acs.chemrev.7b003971bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1WntbzJ&md5=21205e55da92db4e7d27aa393fed486dSynthetic Organic Electrochemical Methods Since 2000: On the Verge of a RenaissanceYan, Ming; Kawamata, Yu; Baran, Phil S.Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.(c) Echeverria, P.-G.; Delbrayelle, D.; Letort, A.; Nomertin, F.; Perez, M.; Petit, L. The Spectacular Resurgence of Electrochemical Redox Reactions in Organic Synthesis. Aldrichimica Acta 2018, 51, 3– 191chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFeqsLvE&md5=34746d64e625bb4bf2e99391bd545c55The spectacular resurgence of electrochemical redox reactions in organic synthesisEcheverria, Pierre-Georges; Delbrayelle, Dominique; Letort, Aurelien; Nomertin, Fiona; Perez, Marc; Petit, LaurentAldrichimica Acta (2018), 51 (1), 3-19CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)A review. Electrochem. has had a profound impact on green chem. and in applications such as energy conversion and storage, electroplating, water treatment, and environmental monitoring, and it has also been embraced by various industries. It is therefore quite surprising that electrochem. has seldom been used by synthetic org. chemists. This could be partly attributed to the misconception that the electron as a reagent cannot be tamed easily. In recent years, the application of electrochem. to the synthesis of fine chems. has had a resurgence, and many elegant solns. based on electrochem. have been devised to address synthetic challenges with easy-to-use exptl. setups.(d) Waldvogel, S. R.; Janza, B. Renaissance of electrosynthetic methods for the construction of complex molecules. Angew. Chem., Int. Ed. 2014, 53, 7122– 7123, DOI: 10.1002/anie.2014050821dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVShurnK&md5=26e3d87d378216c8479526ed9eca6fdcRenaissance of electrosynthetic methods for the construction of complex moleculesWaldvogel, Siegfried R.; Janza, BirgitAngewandte Chemie, International Edition (2014), 53 (28), 7122-7123CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The article reviewed recent electrochem. developments in selective C-C bond formation in natural products, such as the cation-pool method or exploitation of solvent effects using fluorinated alcs., which provide new tools for efficient cross-coupling reactions which are essentially metal and reagent free. The encouraging results underline the potential of electroorg. synthesis and pave the way for the renaissance of this method. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- 2(a) Schäfer, H. J. Contributions of organic electrosynthesis to green chemistry. C. R. Chim. 2011, 14, 745– 765, DOI: 10.1016/j.crci.2011.01.002There is no corresponding record for this reference.(b) Frontana-Uribe, B. A.; Little, D. R.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Organic electrosynthesis: a promising green methodology in organic chemistry. Green Chem. 2010, 12, 2099– 2119, DOI: 10.1039/c0gc00382d2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyrurfI&md5=974934a06b7b2219fabab86d9dfeba45Organic electrosynthesis: a promising green methodology in organic chemistryFrontana-Uribe, Bernardo A.; Little, R. Daniel; Ibanez, Jorge G.; Palma, Agustin; Vasquez-Medrano, RubenGreen Chemistry (2010), 12 (12), 2099-2119CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Over the last decade, org. electrosynthesis has become recognized as one of the methodologies that can fulfill several important criteria that are needed if society is to develop environmentally compatible processes. It can be used to replace toxic or dangerous oxidizing or reducing reagents, reduce energy consumption, and can be used for the in situ prodn. of unstable and hazardous reagents. These are just a few of the most important attributes that render electrochem. environmentally useful. In this review the main characteristics of electrochem. as a promising green methodol. for org. synthesis are described and exemplified. Herein we provide basic information concerning the nature of electrosynthetic processes, paired electrochem. reactions, electrocatalytic reactions, reactions carried out in ionic liqs., electrogeneration of reactants, electrochem. reactions that use renewable starting materials (biomass), green org. electrosynthesis in micro- and nano-emulsions, the synthesis of complex mols. using an electrosynthetic key step, and conclude with some insights concerning the future. Throughout the review the "green aspects" of these topics are highlighted and their relationship with the twelve green chem. principles is described.(c) Schaub, T. Efficient Industrial Organic Synthesis and the Principles of Green Chemistry. Chem.─Eur. J. 2021, 27, 1865– 1869, DOI: 10.1002/chem.2020035442chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsFKjsro%253D&md5=4df75137add44eb87cfa3243e2c0e6e2Efficient Industrial Organic Synthesis and the Principles of Green ChemistrySchaub, ThomasChemistry - A European Journal (2021), 27 (6), 1865-1869CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)There is no expanded citation for this reference.(d) Cantillo, D. Synthesis of Active Pharmaceutical Ingredients using Electrochemical Methods: Keys to Improve Sustainability. Chem. Commun. 2022, 58, 619– 628, DOI: 10.1039/D1CC06296D2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXivVemtLjN&md5=c0c27d6f3a8d103f3996782f4b4f8aabSynthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainabilityCantillo, DavidChemical Communications (Cambridge, United Kingdom) (2022), 58 (5), 619-628CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Org. electrochem. is receiving renewed attention as a green and cost-efficient synthetic technol. Electrochem. methods promote redox transformations by electron exchange between electrodes and species in soln., thus avoiding the use of stoichiometric amts. of oxidizing or reducing agents. The rapid development of electroorg. synthesis over the past decades has enabled the prepn. of mols. of increasing complexity. Redox steps that involve hazardous or waste-generating reagents during the synthesis of active pharmaceutical ingredients or their intermediates can be substituted by electrochem. procedures. In addn. to enhance sustainability, increased selectivity toward the target compd. has been achieved in some cases. Electroorg. synthesis can be safely and readily scaled up to prodn. quantities. For this pupose, utilization of flow electrolysis cells is fundamental. Despite these advantages, the application of electrochem. methods does not guarantee superior sustainability when compared with conventional protocols. The utilization of large amts. of supporting electrolytes, environmentally unfriendly solvents or sacrificial electrodes may turn electrochem. unfavorable in some cases. It is therefore crucial to carefully select and optimize the electrolysis conditions and carry out green metrics anal. of the process to ensure that turning a process electrochem. is advantageous.
- 3(a) Pollok, D.; Gleede, B.; Stenglein, A.; Waldvogel, S. R. Preparative Batch-Type Electrosynthesis: A Tutorial. Aldrichimica Acta 2021, 54, 3– 153ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisFGisrnN&md5=3c9256d8e5e29d45258138f6196a3a1dPreparative batch-type electrosynthesis: a tutorialPollok, Dennis; Gleede, Barbara; Stenglein, Andreas; Waldvogel, Siegfried R.Aldrichimica Acta (2021), 54 (1Spec.Iss.), 3-15CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)A review. Modern org. chem. emphasizes sustainability in addn. to high performance in synthetic processes. Electroorg. synthesis meets these two criteria well. Herein, beakertype cells for batch-type electrolysis are highlighted along with a tutorial on starting an electrosynthesis with these cells and on how to treat the electrodes.(b) Schotten, C.; Nicholls, T. P.; Bourne, R. A.; Kapur, N.; Nguyen, B. N.; Willans, C. E. Making electrochemistry easily accessible to the synthetic chemist. Green Chem. 2020, 22, 3358– 3375, DOI: 10.1039/D0GC01247E3bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVSgtr0%253D&md5=4ff3802412f644f41e9c170a24172f26Making electrochemistry easily accessible to the synthetic chemistSchotten, Christiane; Nicholls, Thomas P.; Bourne, Richard A.; Kapur, Nikil; Nguyen, Bao N.; Willans, Charlotte E.Green Chemistry (2020), 22 (11), 3358-3375CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A review. A significantly renewed interest in synthetic electrochem. is apparent in the increasing no. of publications over the last few years. Electrochem. synthesis offers a mild, green and atom efficient route to interesting and useful mols., thus avoiding harsh chem. oxidising and reducing agents used in traditional synthetic methods. As such, encouraging broader application of electrochem. by synthetic chemists should be a priority. Despite the renewed interest there remains a barrier to widespread adoption of this technol. derived from the extra knowledge and specialised equipment required. This has led to a knowledge gap between experienced electrochemists and those new in the field. In this tutorial we will bridge the knowledge gap by providing an easily accessible introduction which will enable synthetic chemists new to the field to explore electrochem. We will discuss mechanistic considerations, the setup of an electrochem. reaction with all its components, trouble shooting and selected examples from the literature.(c) Hilt, G. Basic Strategies and Types of Applications in Organic Electrochemistry. ChemElectroChem. 2020, 7, 395– 405, DOI: 10.1002/celc.2019017993chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1amurfL&md5=c23253339312ef39fcaf8f3481dca9a9Basic Strategies and Types of Applications in Organic ElectrochemistryHilt, GerhardChemElectroChem (2020), 7 (2), 395-405CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The outlook of this paper is to give a short overview of the basic requirements to perform electro-org. transformations. The aim is to explain the strategies and possible applications in org. electrochem. as simply as possible and is directed to those scientists who are not necessarily trained electrochemists and those that intend to utilize this powerful and, nowadays, very popular tool in their research. Different types of electrolysis performed in a galvanostatic/potentiostatic/a.c. fashion will be presented and the strategies to perform divided/undivided/quasi-divided electrolysis will be covered. The application of direct/indirect/cation-pool electrolysis as well as several variants of paired electrolysis will be briefly explained utilizing selected examples.
- 4(a) Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118, 4573– 4591, DOI: 10.1021/acs.chemrev.7b003604ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2qtrnN&md5=28e56b67959db2e57b7a597a56046014Flow Electrolysis Cells for the Synthetic Organic Chemistry LaboratoryPletcher, Derek; Green, Robert A.; Brown, Richard C. D.Chemical Reviews (Washington, DC, United States) (2018), 118 (9), 4573-4591CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the use of flow electrolysis cells in synthetic org. chem. lab. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a no. of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant soln. through the cell. In addn., the needs of the synthetic org. chemist can often be met by flow cells operating with recycle of the reactant soln. These cells give a high rate of product formation while the reactant concn. is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported.(b) Elsherbini, M.; Wirth, T. Electroorganic Synthesis under Flow Conditions. Acc. Chem. Res. 2019, 52, 3287– 3296, DOI: 10.1021/acs.accounts.9b004974bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2mtbrN&md5=b5fa8c132594eaf2915246040f2d91b0Electroorganic Synthesis under Flow ConditionsElsherbini, Mohamed; Wirth, ThomasAccounts of Chemical Research (2019), 52 (12), 3287-3296CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Despite the long history of electroorg. synthesis, it did not participate in the mainstream of chem. research for long time. This is probably due to the lack of equipment and standardized protocols. However, nowadays org. electrochem. is witnessing a renaissance and a wide range of interesting electrochem. transformations and methodologies was developed, not only for academic purposes but also for large scale industrial prodn. Depending on the source of electricity, electrochem. methods can be inherently green, environmentally benign and can be easily controlled to achieve high levels of selectivity. The generation and consumption of reactive or unstable intermediates and hazardous reagents can be achieved in a safe way. Limitations of traditional batch-type electrochem. methods such as the restricted electrode surface, the necessity of supporting electrolytes and difficulties in scaling up can be alleviated using electrochem. flow cells. Microreactors offer high surface-to-vol. ratios and enable precise control over temp., residence time, flow rate and pressure. Efficient mixing, enhanced mass and heat transfer and handling of small vols. leads to simpler scaling-up protocols and minimize safety concerns. Electrolysis under flow conditions reduces the possibility of overoxidn. as the reaction mixt. is flown continuously out of the reactor in contrast to traditional batch-type electrolysis cells. In this account, the authors highlight the authors' contributions in the area of electroorg. synthesis under flow conditions over the past decade. The authors have designed and manufd. different generations of electrochem. flow cells. The 1st-generation reactor was effectively used in developing a simple 1-step synthesis of diaryliodonium salts and used in proof-of-concept reactions such as the trifluoromethylation of electron-deficient alkenes via Kolbe electrolysis of HO2CCF3 in addn. to the selective deprotection of isonicotinyloxycarbonyl (iNoc) group from carbonates and thiocarbonates. The improved 2nd-generation flow cell enabled the development of efficient synthesis of isoindolinones, benzothiazoles and thiazolopyridines, achieving gram-scale of some of the products easily without changing the reactor design or reoptimizing the reaction parameters. The same reactor was used in the development of an efficient continuous flow electrochem. synthesis of hypervalent I reagents. The generated unstable hypervalent I reagents were easily used without isolation in various oxidative transformations in a coupled flow/flow manner and could be easily transformed into bench-stable reagents via quant. ligand exchange with the appropriate acids. The authors' second-generation reactor was further improved and commercialized by Vaportec Ltd. The authors demonstrated the power of online anal. in accelerating optimizations and methodol. development. Online mass spectrometry enabled fast screening of the charge needed for the cyclization of amides to isoindolinones. The power of online 2-dimensional-HPLC combined with a DoE approach empowered the rapid optimization of stereoselective electrochem. alkoxylations of amino acid derivs.
- 5Noël, T.; Cao, Y.; Laudadio, G. The Fundamentals Behind the Use of Flow Reactors in Electrochemistry. Acc. Chem. Res. 2019, 52, 2858– 2869, DOI: 10.1021/acs.accounts.9b004125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVOhtb3J&md5=820eee82ffc1b68b0f8f2b4ce8374f2cThe Fundamentals Behind the Use of Flow Reactors in ElectrochemistryNoel, Timothy; Cao, Yiran; Laudadio, GabrieleAccounts of Chemical Research (2019), 52 (10), 2858-2869CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. In the past decade, research into continuous-flow chem. has gained a lot of traction among researchers in both academia and industry. Esp., microreactors have received a plethora of attention due to the increased mass and heat transfer characteristics, the possibility to increase process safety, and the potential to implement automation protocols and process anal. technol. Taking advantage of these aspects, chemists and chem. engineers have capitalized on expanding the chem. space available to synthetic org. chemists using this technol. Electrochem. has recently witnessed a renaissance in research interests as it provides chemists unique and tunable synthetic opportunities to carry out redox chem. using electrons as traceless reagents, thus effectively avoiding the use of hazardous and toxic reductants and oxidants. The popularity of electrochem. stems also from the potential to harvest sustainable electricity, derived from solar and wind energy. Hence, the electrification of the chem. industry offers an opportunity to locally produce commodity chems., effectively reducing inefficiencies with regard to transportation and storage of hazardous chems. The combination of flow technol. and electrochem. provides practitioners with great control over the reaction conditions, effectively improving the reproducibility of electrochem. However, carrying out electrochem. reactions in flow is more complicated than just pumping the chems. through a narrow-gap electrolytic cell. Understanding the engineering principles behind the observations can help researchers to exploit the full potential of the technol. Thus, the prime objective of this Account is to provide readers with an overview of the underlying engineering aspects which are assocd. with continuous-flow electrochem. This includes a discussion of relevant mass and heat transport phenomena encountered in electrochem. flow reactors. Next, the possibility to integrate several reaction steps in a single streamlined process and the potential to carry out challenging multiphase electrochem. transformations in flow are discussed. Due to the high control over mass and heat transfer, electrochem. reactions can be carried out with great precision and reproducibility which provide opportunities to enhance and tune the reaction selectivity. Finally, the authors detail on the scale-up potential of flow electrochem. and the importance of small interelectrode gaps on pilot and industrial-scale electrochem. processes. Each principle was illustrated with a relevant org. synthetic example. In general, the authors have aimed to describe the underlying engineering principles in simple words and with a min. of equations to attract and engage readers from both a synthetic org. chem. and a chem. engineering background. Hence, the authors anticipate that this Account will serve as a useful guide through the fascinating world of flow electrochem.
- 6Pletcher, D.; Walsh, F. C. Industrial Electrochemistry; Springer: Netherlands, 1993.There is no corresponding record for this reference.
- 7Maljuric, S.; Jud, W.; Kappe, C. O.; Cantillo, D. Translating batch electrochemistry to single-pass continuous flow conditions: an organic chemist’s guide. J. Flow Chem. 2020, 10, 181– 190, DOI: 10.1007/s41981-019-00050-z7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktlyjsbg%253D&md5=b02c30f1d47eb0f455dd0012d2cc1156Translating batch electrochemistry to single-pass continuous flow conditions: an organic chemist's guideMaljuric, Snjezana; Jud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidJournal of Flow Chemistry (2020), 10 (1), 181-190CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)Abstr.: The recent renaissance of electrochem. methods for org. synthesis has also attracted increased interest towards flow electrochem. as the most suitable scale-up strategy. Many electrochem. methods using flow cells are based on recirculation of the electrolyte soln. However, single-pass processing is very attractive as it permits integration of the electrochem. reaction with other synthetic or purifn. steps in a continuous stream. Translation of batch electrochem. procedures to single-pass continuous flow cells can be challenging to beginners in the field. Using the electrochem. methoxylation of 4-methylanisole as model, this paper provides newcomers to the field with an overview of the factors that need to be considered to develop a flow electrochem. process, including advantages and disadvantages of operating in galvanostatic and potentiostatic mode in small scale reactions, and the effect of the interelectrode gap, supporting electrolyte concn. and pressure on the reaction performance. A comparison of the reaction efficiency in batch and flow is also presented. [graphic not available: see fulltext].
- 8Goodridge, F.; Scott, K. Electrochemical Process Engineering – A Guide to the Design of Electrolytic Plant; Springer Science+ Business Media: New York, 1995.There is no corresponding record for this reference.
- 9Schoenitz, M.; Grundemann, L.; Augustin, W.; Scholl, S. Chem. Commun. 2015, 51, 8213– 8228, DOI: 10.1039/C4CC07849G9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1Sksrk%253D&md5=995d00439b861408acc56047e7ee83f3Fouling in microstructured devices: a reviewSchoenitz, M.; Grundemann, L.; Augustin, W.; Scholl, S.Chemical Communications (Cambridge, United Kingdom) (2015), 51 (39), 8213-8228CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Microstructured devices are widely used for manufg. products that benefit from process intensification, with pharmaceutical products or specialties of the chem. industry being prime examples. These devices are ideally used for processing pure fluids. Where particulate or non-pure flows are involved, processes are treated with utmost caution since related fouling and blocking issues present the greatest barrier to operating microstructured devices effectively. Micro process engineering is a relatively new research field and there is limited understanding of fouling in these dimensions and its underlying processes and phenomena. A comprehensive review on fouling in microstructured devices would be helpful in this regard, but is currently lacking. This paper attempts to review recent developments of fouling in micro dimensions for all fouling categories (crystn., particulate, chem. reaction, corrosion, and biol. growth fouling) and the sequential events involved (initiation, transport, attachment, removal and aging). Compared to fouling in macro dimensions, an addnl. sixth category is suggested: clogging by gas bubbles. Most of the reviewed papers present very specific fouling investigations making it difficult to derive general rules and parameter dependencies, and comparative or crit. considerations of the studies were difficult. The statistical approach is used to evaluate the research in the field of fouling in microchannels.
- 10Zhao, X.; Ren, H.; Luo, L. Gas Bubbles in Electrochemical Gas Evolution Reactions. Langmuir 2019, 35, 5392– 5408, DOI: 10.1021/acs.langmuir.9b0011910https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFCju7g%253D&md5=0823c734a0e02877cd72515545772010Gas Bubbles in Electrochemical Gas Evolution ReactionsZhao, Xu; Ren, Hang; Luo, LongLangmuir (2019), 35 (16), 5392-5408CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)A review. Electrochem. gas evolution reactions are of vital importance in numerous electrochem. processes including H2O splitting, chloralkaline process, and fuel cells. During gas evolution reactions, gas bubbles are vigorously and constantly forming and influencing these processes. In the past few decades, extensive studies were performed to understand the evolution of gas bubbles, elucidate the mechanisms of how gas bubbles impact gas evolution reactions, and exploit new bubble-based strategies to improve the efficiency of gas evolution reactions. In this feature article, the authors summarize the classical theories as well as recent advancements in this field and provide an outlook on future research topics.
- 11Bottecchia, C.; Lehnherr, D.; Lévesque, F.; Reibarkh, M.; Ji, Y.; Rodrigues, V. L.; Wang, H.; Lam, Y.-H.; Vickery, T. P.; Armstrong, B. M.; Mattern, K. A.; Stone, K.; Wismer, M. K.; Singh, A. N.; Regalado, E. L.; Maloney, K. M.; Strotman, N. A. Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up Electrosynthesis. Org. Process Res. Dev. 2022, 26, 2423– 2437, DOI: 10.1021/acs.oprd.2c0011111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1GitbvJ&md5=480f8406fcedc78200ed7bca76e20628Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up ElectrosynthesisBottecchia, Cecilia; Lehnherr, Dan; Levesque, Francois; Reibarkh, Mikhail; Ji, Yining; Rodrigues, Vailankanni L.; Wang, Heather; Lam, Yu-hong; Vickery, Thomas P.; Armstrong, Brittany M.; Mattern, Keith A.; Stone, Kevin; Wismer, Michael K.; Singh, Andrew N.; Regalado, Erik L.; Maloney, Kevin M.; Strotman, Neil A.Organic Process Research & Development (2022), 26 (8), 2423-2437CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Org. electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in org. synthesis. Concerns around the scalability of electrochem. methods remain the biggest reason behind their scarce implementation in manufg. routes for the pharmaceutical industry. To fill this gap, we report a workflow describing the key reaction parameters toward the successful scale-up of an org. electrosynthetic method from milligram to kilogram scale. The reaction used to demonstrate our workflow and scale-up in a flow setting was the oxidn. of a thioether to its corresponding sulfone, a fragment of interest in an active pharmaceutical ingredient under development. The use of online flow NMR spectroscopy, offline ion chromatog., cyclic voltammetry, and d. functional theory calcns. provided insight into the reaction mechanism and side reactions.
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Spinning electrode electrolysis cells, also called rotating cylinder cells, have previously found applications in electrolysis processes such as water waste treatment and metal recovery:
(a) Polcaro, A. M.; Vacca, A.; Mascia, M.; Palmas, S.; Pompei, R.; Laconi, S. Characterization of a stirred tank electrochemical cell for water disinfection processes. Electrochim. Acta 2007, 52, 2595– 2602, DOI: 10.1016/j.electacta.2006.09.01512ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpslagsw%253D%253D&md5=6fe565a0b4268c83d9d3055dc34a8b6cCharacterization of a stirred tank electrochemical cell for water disinfection processesPolcaro, A. M.; Vacca, A.; Mascia, M.; Palmas, S.; Pompei, R.; Laconi, S.Electrochimica Acta (2007), 52 (7), 2595-2602CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)Lab. expts. were performed to characterize the behavior of an electrochem. cell equipped with boron-doped diamond anodes and to verify its effectiveness in water disinfection. The hydrodynamic regime was detd. when the cell worked either in batch or in continuous mode. Galvanostatic electrolyzes of aq. 1 mM Na2SO4 solns. were performed to investigate the oxidant prodn. in different exptl. conditions. The same solns. contaminated by E. coli, enterococci and coliforms were used as test media to verify the effectiveness of the system in the disinfection process. Exptl. results indicated that the major inactivation mechanism of bacteria in the electrochem. cell is a disinfection by electrochem. generated oxidants, however a cooperative effect of superficial reaction has to be taken into account. The great capability of BDD anode to produce reactive oxygen species (ROS) and other oxidizing species during the electrolysis allows to establish a chlorine-free disinfection process.(b) Hernández-Tapia, J. R.; Vazquez-Arenas, J.; González, I. Electrochemical reactor with rotating cylinder electrode for optimum electrochemical recovery of nickel from plating rinsing effluents. J. Haz. Mater. 2013, 262, 709– 716, DOI: 10.1016/j.jhazmat.2013.09.02912bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsl2gsL7E&md5=b74fd36119c4a7c0d1c745deebee8de6Electrochemical reactor with rotating cylinder electrode for optimum electrochemical recovery of nickel from plating rinsing effluentsHernandez-Tapia, J. R.; Vazquez-Arenas, J.; Gonzalez, I.Journal of Hazardous Materials (2013), 262 (), 709-716CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)This study is devoted to analyze the metallic electrochem. recovery of nickel from synthetic solns. simulating plating rinsing discharges, in order to meet the water recycling policies implemented in these industries. These effluents present dil. Ni(II) concns. (100 and 200 ppm) in chloride and sulfate media without supporting electrolyte (397-4202 μS cm-1), which stems poor current distribution, limited mass transfer, ohmic drops and enhancement of parasitic reactions. An electrochem. reactor with rotating cylinder electrode (RCE) and a pH controller were utilized to overcome these problems. The pH control around 4 was crucial to yield high purity nickel, and thus prevent the pptn. of hydroxides and oxides. Macroelectrolysis expts. were systematically conducted to analyze the impacts of the applied c.d. in the recovery efficiency and energy consumption, particularly for very dild. effluents (100 and 200 ppm Ni(II)), which present major recovery problems. Promising nickel recoveries in the order of 90% were found in the former baths using a c.d. of -3.08 mA cm-2, and with overall profits of 9.64 and 14.69 USD kg-1, resp. These estns. were based on the international market price for nickel ($18 USD kg-1).(c) Luis Nava-M. de Oca, J.; Sosa, E.; Ponce de Leon, C.; Oropeza, M.T. Effectiveness factors in an electrochemical reactor with rotating cylinder electrode for the acid-cupric/copper cathode interface process. Chem. Eng. Sci. 2001, 56, 2695– 2702, DOI: 10.1016/S0009-2509(00)00514-5There is no corresponding record for this reference.(d) Gao, H.; Scheeline, A.; Pearlstein, A. J. Spatially Controlled Microstructural Variation using a Free-Surface Flow Driven by a Rotating Cylinder Electrode: Growth of Anodic Oxide Films on A1 6061. J. Electrochem. Soc. 2002, 149, B248, DOI: 10.1149/1.147188912dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltVGlsLY%253D&md5=f9333754280c9e20e4a7d10de7285becSpatially controlled microstructural variation using a free-surface flow driven by a rotating cylinder electrode growth of anodic oxide films on AA 6061Gao, Husheng; Scheeline, Alexander; Pearlstein, Arne J.Journal of the Electrochemical Society (2002), 149 (6), B248-B255CODEN: JESOAN; ISSN:0013-4651. (Electrochemical Society)Growth and characterization of oxide films with spatially controlled microstructure on AA 6061 using a coaxial rotating, axially translating electrochem. reactor (CRATER) are reported. This electrode/flow combination allows growth of oxide films with spatially controlled microstructure on a single working electrode (WE) under well-defined conditions of mass transfer, electrode potential, and residence time. This is achieved by restricting electro-oxidn. to a "window" of narrow axial extent just below the free surface of an electrolyte whose coaxial inner and outer boundaries are a rotating counter electrode and an axially translating WE, resp. Axial translation of the WE maps temporal variation of a controlled parameter (e.g., applied potential, mass-transfer rate) to axial variation of oxide microstructure on the WE. In the present work the applied potential is scanned linearly in time, leading to each element of the WE undergoing electro-oxidn. over a narrow range of potential. Each element of the WE has the same exposure time in the reactive window and is exposed to the same mass-transfer conditions. This produces an oxide film in which the cell size and pore size vary systematically with potential along the length of the WE. The film displays a high degree of azimuthal uniformity. Continuous scanning of process variables in a single expt. by this approach allows identification of desirable microstructures in narrow ranges of operating conditions. Application of CRATER methodol. to electrodissoln. and electrodeposition is discussed.(e) Gabe, C. R.; Walsh, F. C. The rotating cylinder electrode: a review of development. J. Appl. Electrochem. 1983, 13, 3– 22, DOI: 10.1007/BF0061588312ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXotVCjuw%253D%253D&md5=2f06f58ea90d0e7a45a052d716a510afThe rotating cylinder electrode: a review of developmentGabe, D. R.; Walsh, F. C.Journal of Applied Electrochemistry (1983), 13 (1), 3-21CODEN: JAELBJ; ISSN:0021-891X.A review with 143 refs. is given on the theory and applications of rotating cylinder electrodes. Particular attention is paid to the mass transfer behavior and the development of turbulent flow patterns, and its exploitation in electrochem. reactors for a variety of applications, including metal deposition from waste and effluent liquors. - 13
A Taylor vortex reactor based on the same principle has recently been applied to synthetic organic electrochemistry by George and co-workers:
(a) Love, A.; Lee, D. S.; Gennari, G.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. A Continuous-Flow Electrochemical Taylor Vortex Reactor: A Laboratory-Scale High-Throughput Flow Reactor with Enhanced Mixing for Scalable Electrosynthesis. Org. Process Res. Dev. 2021, 25, 1619– 1627, DOI: 10.1021/acs.oprd.1c0010213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVOrtrvM&md5=6220165911367288feaf2ff23a679da7A Continuous-Flow Electrochemical Taylor Vortex Reactor: A Laboratory-Scale High-Throughput Flow Reactor with Enhanced Mixing for Scalable ElectrosynthesisLove, Ashley; Lee, Darren S.; Gennari, Gabriele; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, MichaelOrganic Process Research & Development (2021), 25 (7), 1619-1627CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The authors report the development of a small footprint continuous electrochem. Taylor vortex reactor capable of processing kilogram quantities of material per day. This report builds upon the authors' previous development of a scalable photochem. Taylor vortex reactor (Org. Process Res. Dev.2017,21,1042;2020,24,201-206). It describes a static and rotating electrode system that allows for enhanced mixing within the annular gap between the electrodes. The size of the annular gap and the rotation speed of the electrode are important for both conversion of the substrate and selectivity of the product exemplified using the methoxylation of N-formylpyrrolidine. The employment of a cooling jacket was necessary for scaling the reaction to manage the heat generated by electrodes at higher currents (up to 30 A, >270 mA cm-2) allowing multimole productivity per day of methoxylation product to be achieved. The electrochem. oxidn. of thioanisole was also studied, and the reactor has the performance to produce up to 400 g day-1 of either of the corresponding sulfoxide or sulfone while maintaining a very high reaction selectivity (>97%) to the desired product. This development completes a suite of vortex reactor designs that can be used for photo-, thermal-, or electrochem., all of which decouple residence time from mixing. This opens up the possibility of performing continuous multistep reactions at scale with flexibility in optimizing processes.(b) Lee, D. S.; Love, A.; Mansouri, Z.; Waldron Clarke, T. H.; Harrowven, D. C.; Jefferson-Loveday, R.; Pickering, S. J.; Poliakoff, M.; George, M. W. High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor. Org. Process Res. Dev. 2022, 26, 2674– 2684, DOI: 10.1021/acs.oprd.2c0010813bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xit1SitrfM&md5=09d57d74577db054ab89c9a756845d9aHigh-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex ReactorLee, Darren S.; Love, Ashley; Mansouri, Zakaria; Waldron Clarke, Toby H.; Harrowven, David C.; Jefferson-Loveday, Richard; Pickering, Stephen J.; Poliakoff, Martyn; George, Michael W.Organic Process Research & Development (2022), 26 (9), 2674-2684CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The authors report the development of a single-pass electrochem. Birch redn. carried out in a small footprint electrochem. Taylor vortex reactor with projected productivities of >80 g day-1 (based on 32.2 mmol h-1), using a modified version of the authors' previously reported reactor [Org. Process Res. Dev.2021, 25, 7, 1619-1627], consisting of a static outer electrode and a rapidly rotating cylindrical inner electrode. The authors used an Al tube as the sacrificial outer electrode and stainless steel as the rotating inner electrode. The authors established the viability of using a sacrificial Al anode for the electrochem. redn. of naphthalene, and by varying the current, the authors can switch between high selectivity (>90%) for either the single ring redn. or double ring redn. with >80 g day-1 projected productivity for either product. The concn. of LiBr in soln. changes the fluid dynamics of the reaction mixt. studied by computational fluid dynamics, and this affects equilibration time, monitored using FTIR spectroscopy. The concns. of electrolyte (LiBr) and proton source (dimethylurea) can be reduced while maintaining high reaction efficiency. The authors also report the redn. of 1-aminonaphthalene, which was used as a precursor to the API Ropinirole. The authors' methodol. produces the corresponding dihydronaphthalene in excellent selectivity and 88% isolated yield in an uninterrupted run of >8 h with a projected productivity of >100 g day-1. - 14Small scale experiments were carried out in an IKA ElectraSyn 2.0 electrochemical reactor: https://www.ika.com/en/Products-LabEq/Electrochemistry-Kit-pg516/ElectraSyn-20-pro-Package-40003261/ (accessed on July 26, 2023).There is no corresponding record for this reference.
- 15Selman, J. R.; Tobias, C. W. Mass-Transfer Measurements by the Limiting-Current Technique. Adv. Chem. Eng. 1978, 10, 211– 318, DOI: 10.1016/S0065-2377(08)60134-915https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXksF2gurw%253D&md5=59acfe1b0c99808d4f9854d4bd84c375Mass-transfer measurements by the limiting-current techniqueSelman, J. Robert; Tobias, Charles W.Advances in Chemical Engineering (1978), 10 (), 211-318CODEN: ACHEAT; ISSN:0065-2377.A review with 324 refs.
- 16Scott, K.; Lobato, J. Determination of a Mass-Transfer Coefficient Using the Limiting-Current Technique. Chem. Educator 2002, 7, 214– 219, DOI: 10.1007/s00897020579a16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmvFWqt78%253D&md5=f18798b462bce4c78191bcf187586f96Determination of a mass-transfer coefficient using the limiting-current techniqueScott, Keith; Lobato, JustoChemical Educator [online computer file] (2002), 7 (4), 214-219CODEN: CHEDF5; ISSN:1430-4171. (Springer-Verlag New York Inc.)Mass-transfer coeffs. of a cross-corrugated plate have been detd. by the limiting-current technique. A simple Microsoft Excel spreadsheet has been created which allows students to correlate data. Students will be able to calc. the mass-transfer coeff. of different processes, for example, cross-flow membrane filtration processes or membrane reactors. The possibility of using the spreadsheet with different correlations and to discriminate between them is also validated by comparing the model results with published exptl. data available in the recent literature. It is possible as well to study the influence of different turbulence promoters on the flow. Results show that corrugated membranes enhanced the flow and the more advantageous flow regime is reached, suggesting that these membranes can be used to study processes that are normally in the low regime.
- 17Fogler, H. S. Residence time distributions of chemical reactors. In Elements of chemical reaction engineering, 5th ed.; Pearson Education, Inc.: London, 2016.There is no corresponding record for this reference.
- 18Scott, K. The continuous stirred tank electrochemical reactor. An overview of dynamic and steady state analysis for design and modelling. J. Appl. Electrochem. 1991, 21, 945– 960, DOI: 10.1007/BF0107757918https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXms1Ghsbc%253D&md5=d9191cdcb2068bac891ea76db42bc199The continuous stirred tank electrochemical reactor. An overview of dynamic and steady state analysis for design and modelingScott, K.Journal of Applied Electrochemistry (1991), 21 (11), 945-60CODEN: JAELBJ; ISSN:0021-891X.A review with 14 refs. The continuous stirred tank reactor is frequently adopted as a model for electrochem. reactors. This article brings together the various important aspects of the model: dynamics, thermal characteristics, residence time distributions and steady-state characteristics and gives an overview of the design procedures.
- 19Shono, T. Electroorganic chemistry in organic synthesis. Tetrahedron 1984, 40, 811– 850, DOI: 10.1016/S0040-4020(01)91472-319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXhtlyiur8%253D&md5=86702304b101e67907968d530114e516Electroorganic chemistry in organic synthesisShono, TatsuyaTetrahedron (1984), 40 (5), 811-50CODEN: TETRAB; ISSN:0040-4020.A review with 127 refs.
- 20(a) Birkin, P. R.; Kuleshova, J.; Hill-Cousins, J. T.; Brown, R. C. D.; Pletcher, D.; Underwood, T. J. A simple and inexpensive microfluidic electrolysis cell. Electrochim. Acta 2011, 56, 4322– 4326, DOI: 10.1016/j.electacta.2011.01.03620ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkslCnurk%253D&md5=0942af8b0c5c89b1f236c60d27f6d5ebA simple and inexpensive microfluidic electrolysis cellKuleshova, Jekaterina; Hill-Cousins, Joseph T.; Birkin, Peter R.; Brown, Richard C. D.; Pletcher, Derek; Underwood, Toby J.Electrochimica Acta (2011), 56 (11), 4322-4326CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)A single channel microfluidic electrolysis cell based on inexpensive materials and fabrication techniques is described. The cell is characterised using the electrochem. of the Fe(CN)63-/Fe(CN)64- couple and its application in electrosynthesis is illustrated using the methoxylation reactions of N-formylpyrrolidine and 4-t-butyltoluene. The reactions can be carried out with a good conversion in a single pass. The device, as described, allows the prodn. of several mmol/h of the methoxylated products.(b) Folgueiras-Amador, A. A. A.; Teuten, A. E. E.; Pletcher, D.; Brown, R. C. D. React. Chem. Eng. 2020, 5, 712– 718, DOI: 10.1039/D0RE00019A20bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvFylt7w%253D&md5=3a7fb0c0b7a7ba68eae357e2b1f1a5f8A design of flow electrolysis cell for 'Home' fabricationFolgueiras-Amador, Ana A.; Teuten, Alex E.; Pletcher, Derek; Brown, Richard C. D.Reaction Chemistry & Engineering (2020), 5 (4), 712-718CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Despite extensive literature on org. electrosynthesis, it has never become a routine procedure in org. synthesis labs. One reason is certainly a lack of attention to the design of the cell used for the electrolysis; an appropriate cell is the dominant factor in detg. the rate of conversion and the final conversion. Beaker cells predominate in published lab. electrosyntheses but their use can limit reaction performance, and ease of scale-up, particularly where high rates of conversion are required without compromising selectivity for the desired product. This paper describes a simple design of a flow cell for operation in a recycle mode that is straightforward to fabricate and its performance is illustrated with anodic and cathodic electrosyntheses. The advantages of using turbulence promoters in the flow channel and a three dimensional electrode (reticulated vitreous carbon) are demonstrated. The cell allows the prepn. of up to 5 mmol per h of isolated product, and 20 mmol of product can be obtained over 4 h with high conversion of starting material. The cell design is readily scalable to enable the synthesis of larger quantities of product, and provides the capability to introduce a separator for org. electrosynthesis in a divided mode.(c) Jud, W.; Kappe, C. O.; Cantillo, D. ChemElectroChem. 2020, 7, 2777– 2783, DOI: 10.1002/celc.20200069620chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtl2rt7vM&md5=6a382f08990fe714d09c2d410107feb0A Continuous Flow Cell for High-Temperature/High-Pressure Electroorganic SynthesisJud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidChemElectroChem (2020), 7 (13), 2777-2783CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)A flow electrolysis cell that enables operation at high temps. and pressures has been designed and developed. The cell, with a cylindrical shape and concentric electrodes, can be easily assembled using com. available fluidic components. The compact design of the device permits easy temp. control using a com. column heater. Temps. ranging from -10°C to +150°C and pressures up to 70 bar have been successfully applied for long operation periods. The cell performance has been evaluated using the anodic methoxylation of N-formylpiperidine as a model. Very high conversions and selectivities have been achieved with single-pass processing, and high productivities of 73 mmol/h with electrolyte recycling. The high pressure and temp. capabilities of the cell have been used to demonstrate the neg. effect that re-dissolved hydrogen gas can have on hydrogen-releasing electrochem. reactions in undivided cells, owing to undesired anodic oxidn. of hydrogen.
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Sufficient inert gas flow to ensure that the H2 gas concentration is below 4% should be provided:
Najjar, Y. S. H. Hydrogen safety: The road toward green technology. Int. J. Hydrog. Energy 2013, 38, 10716– 10728, DOI: 10.1016/j.ijhydene.2013.05.12621https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKntr3K&md5=b91ebca1e933e232ed61e26fb8582170Hydrogen safety: The road toward green technologyNajjar, Yousef S. H.International Journal of Hydrogen Energy (2013), 38 (25), 10716-10728CODEN: IJHEDX; ISSN:0360-3199. (Elsevier Ltd.)A review. With increasing world energy demands, the search for an environmentally-friendly fuel is a must. Hydrogen is a fuel that is energy-efficient and clean, and considered by many as the perfect fuel. The problem arises when it comes to safety considerations. It does not have a good reputation because of some unfortunate accidents during history. In this work the safety of hydrogen during prodn., transmission and use is reviewed. Hydrogen safety issues are mainly discussed in relation to its ignition and combustion characteristics namely: wide flammability range detonation level, low ignition energy, relatively high flame velocity, rapid diffusion and buoyancy, in addn. to it its characteristics in the liq. phase. Hydrogen is the lightest gas (14 times lighter than air), highly flammable, odorless, and burns with a colorless flame. When used as a fuel, it supplies more energy per unit mass, than the popular fuels used today. In producing hydrogen, there are many processes, each one with its hazards, but these are relatively less weighed against hydrogen having the highest energy-carrying abilities. In storing, transmission and using of hydrogen, the main hazard is in its leaking, causing a fire to start. To detect when a leak happens, reliable and economic sensors should be used. High degree of safety, depending on hydrogen properties, is essential in any relevant design, to accelerate toward hydrogen economy. - 22Tanbouza, N.; Ollevier, T.; Lam, K. Bridging Lab and Industry with Flow Electrochemistry. iScience 2020, 23, 101720, DOI: 10.1016/j.isci.2020.10172022https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVaktLbO&md5=4ee8002fb08118972e5bbfb044695c46Bridging Lab and Industry with Flow ElectrochemistryTanbouza, Nour; Ollevier, Thierry; Lam, KeviniScience (2020), 23 (11), 101720CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)A review. A revitalization of org. electrosynthesis has incited the org. chem. community to adopt electrochem. as a green and cost-efficient method for activating small mols. to replace highly toxic and expensive redox chems. However, many of the crit. challenges of batch electrosynthesis, esp. for org. synthesis, still remain. The combination of continuous flow technol. and electrochem. is a potent means to enable industry to implement large scale electrosynthesis. Indeed, flow electrosynthesis helps overcome problems that mainly arise from macro batch electro-org. systems, such as mass transfer, ohmic drop, and selectivity, but this is still far from being a flawless and generic applicable process. As a result, a notable increase in research on methodol. and hardware sophistication has emerged, and many hitherto uncharted chemistries have been achieved. To better help the commercialization of wide-scale electrification of org. synthesis, we highlight in this perspective the advances made in large-scale flow electrosynthesis and its future trajectory while pointing out the main challenges and key improvements of current methodologies.
- 23Jud, W.; Kappe, C. O.; Cantillo, D. Development and Assembly of a Flow Cell for Single-Pass Continuous Electroorganic Synthesis Using Laser-Cut Components. Chem. Methods 2021, 1, 36– 42, DOI: 10.1002/cmtd.20200004223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlWit7zK&md5=6d0f5324e12974b1adbc918f8ae7d9e1Development and Assembly of a Flow Cell for Single-Pass Continuous Electroorganic Synthesis Using Laser-Cut ComponentsJud, Wolfgang; Kappe, C. Oliver; Cantillo, DavidChemistry: Methods (2021), 1 (1), 36-41CODEN: CMHEGP; ISSN:2628-9725. (Wiley-VCH Verlag GmbH & Co. KGaA)Flow electrolysis cells are essential for the scale up of synthetic org. electrochem. We have developed a simple and inexpensive parallel plate flow cell that can be easily assembled using a stack of laser-cut Mylar foils, which act as gaskets, insulating material, interelectrode gap and flow channel. The ease with which the laser-cutting pattern can be customized has enabled the development of interelectrode separators with mixing geometries, which improve the mass transfer and thus the current efficiency. The performance of the flow electrolysis cell has been evaluated using the anodic decarboxylative methoxylation of diphenylacetic acid as model transformation. Very high conversions and selectivities have been achieved with single-pass processing, with nearly quant. current efficiency in some cases.
- 24Sommer, F.; Kappe, C. O.; Cantillo, D. Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids. Chem.─Eur. J. 2021, 27, 6044– 6049, DOI: 10.1002/chem.20210044624https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVWltbo%253D&md5=73e598b56de269117f284d24d9723f8dElectrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen SteroidsSommer, Florian; Kappe, C. Oliver; Cantillo, DavidChemistry - A European Journal (2021), 27 (19), 6044-6049CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto deriv. Conventional chem. reagents pose significant drawbacks for this synthetic strategy, as large amts. of waste are generated, and quenching of the reaction mixt. and purifn. of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochem. strategies for the prepn. of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidn. has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids [e.g., hydrocortisone I → 17-ketosteroid II (99%)]. In addn., simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of satd. androgens.
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The surface velocity ‘V’ (in cm/s) can be calculated from the spinning speed ‘S’ (in rpm) and the diameter ‘D’ of the working electrode using the following equation: V(cm/s) = π × D(cm) × S(min–1)/60(s/min).
There is no corresponding record for this reference. - 26A previous version of this manuscript has been deposited in ChemRxiv: Petrović, N.; Malviya, B. K.; Kappe, C. O.; Cantillo, D. ChemRxiv 2023, Pre-print. DOI: 10.26434/chemrxiv-2023-6vvnn .There is no corresponding record for this reference.
Supporting Information
Supporting Information
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Supplementary pictures and tables, 1H NMR and 13C NMR spectra of the prepared products. (PDF)
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