Low-Temperature Flow Electrolysis for Efficient Trichloromethylation Aided by Electrogenerated Base

Abstract

This study introduces a novel low-temperature electrochemical flow reactor for the efficient trichloromethylation of benzaldehyde using electrogenerated bases (EGBs). The setup achieved precise temperature control by leveraging a Peltier-cooled system and a divided flow reactor with carbon-felt electrodes without requiring external cooling baths. Optimization of reaction parameters, including flow rate, temperature, and charge passed, resulted in a maximum yield of 67 % for 2,2,2-trichloro-1-phenylethanol, demonstrating significantly enhanced stability and reactivity of EGBs. This system exhibits a productivity of 1.01 mmol h⁻¹, which is 6.7 times higher than that of a prior microflow reactor approach, and successfully scales up to reactions involving 5 mmol of substrate. Cooling was identified as a critical factor in stabilizing the reactive intermediates, while further experiments confirmed the inefficacy of external cooling components alone. This robust and scalable reactor design highlights the potential for advancing low-temperature electrochemical synthesis and unlocking new reaction pathways.

Electrochemical flow reactors have many advantages, such as a large electrode surface area per unit volume, controllable reaction time, scalability, and the ability to conduct multistep reactions continuously. Therefore, several studies have been conducted on this topic, including those by our group.^1–9 Among these studies, the flash use of active species, such as those generated by electrolysis, has attracted significant attention as an effective methodology because it allows the rapid utilization of these generally unstable species before their decomposition.^10–15

For example, our group reported the synthesis of 2,2,2-trichloro-1-phenylethanol using the 2-pyrrolidone anion as an electrogenerated base (EGB).¹⁰ In that study, the liquid-liquid parallel flow inhibited the reoxidation of EGB, enabling the continuous synthesis and utilization of the trichloromethyl anions (CCl₃⁻) produced by the reaction with EGB and chloroform. However, this method required a carefully constructed handmade flow reactor to enable the parallel liquid–liquid flow. In addition, the relatively small surface area of the plate electrode (ca. 3 cm²) resulted in low productivity (Fig. 1A). Furthermore, the yield increased as the flow rate increased, indicating the importance of discharging the generated EGB from the reactor before its decomposition.¹⁰ Therefore, we thought that generating EGB more stably and flowing it to the subsequent reaction could improve the yield.

Figure 1.

(A) Synthesis of 2,2,2-trichloro-1-phenylethanol using microflow reactor (previous work). (B) Reaction using low temperature flow electrochemical reactor (this work).

Low-temperature electrolysis is an effective approach for stabilizing active species, as represented by the cation pool method. Low-temperature flow electrolysis could be an effective method for utilizing active species; however, a few reports still exist in this field.^12,14,16 Importantly, the availability of devices for low-temperature flow electrolysis is limited, as no commercialized electrochemical flow reactors or cooling devices exist for this purpose.

In this study, we developed a novel low-temperature electrochemical flow reactor and cooling device and applied it to the trichloromethylation of benzaldehyde using EGB (Fig. 1B). This system is composed of a divided flow reactor in contact with a Peltier temperature controller, eliminating the need for a cooling bath for the electrolyte. The flow reactor was equipped with a carbon felt electrode as the working electrode, achieving high productivity and making it applicable to the reaction with 5 mmol of substrate.

First, we presented an overview of the developed reaction system. This reaction system comprised three main components: a flow reactor, a Peltier temperature controller, and an aluminum block that conducted the heat between the flow reactor and the Peltier temperature controller (Fig. 2A). The aluminum block also had a cooling chamber that cools the inlet PTFE tube in advance (Fig. 2B). The structure of the flow reactor was divided into two types: a counter electrode (CE) chamber and a working electrode (WE) chamber, separated by membranes. The working electrode chamber was filled with carbon felt, which allowed the introduced electrolyte to contact the electrodes efficiently (Fig. 2D). The working electrode chamber was made of carbon-coated titanium, which guaranteed efficient heat conduction and electrical conductivity as a current collector.

Figure 2.

(A) Front view of reaction system; (B) Top view of reaction system; (C) Front view of flow reactor; (D) Sectional view of flow reactor; (E) Thermography of reaction system and flow reactor; (F) Optimization of trichloromethylation of benzaldehyde: i) Flow rate, ii) Temperature, iii) Amount of charge passed, iv) Electrolyte; Yields were determined by ¹H nuclear magnetic resonance (NMR) using 1,3,5-trimethoxybenzene as an internal standard.¹⁷

The surface temperature was measured using a thermographic camera to verify that the reactor was effectively cooled according to the temperature controller settings (Fig. 2E). First, the entire reaction system was observed. The temperature controllers were set to 313, 283, 273, and 263 K, and the results showed that the surface temperatures were generally in line with the set temperatures, with a maximum difference of 7 K between the surface and set temperatures. The entire reaction system was found to be heated or cooled uniformly.

Next, to confirm that the flow reactor itself was heated or cooled to the set temperature, the surface temperature was measured immediately after the reactor was removed from the aluminum block. Similar to the previous measurements, the surface temperature was measured at four different temperature settings, and the maximum difference between the surface and set temperatures was +4 K. Since the reactor was heated by the surrounding air from the moment it was removed from the block, the temperature inside the aluminum block was cooled to almost the same temperature as the set temperature. The lower part of the flow reactor, where the working electrode chamber was located, was cooled the most. In addition, the solution discharged from the reactor was cooled sufficiently (see SI, Fig. S4). Therefore, the solution inside the reactor was cooled down to the set temperature.

Using this reaction system, we next conducted the trichloromethylation of benzaldehyde (Fig. 2F). First, under the optimal conditions of the previous study (flow rate: 6 ml h⁻¹, current flow rate: 3.1 F mol⁻¹, 298 K), the electrosynthesis was conducted, and 2,2,2-trichloro-1-phenylethanol was successfully obtained in 26 % yield. Next, the flow rate was optimized. Consequently, under 18.1 and 30 ml h⁻¹, the target product was obtained in 50 % yield (Fig. 2F-i). This was due to the faster flow rate, which allowed the EGB to react with chloroform before decomposition. However, the yield decreased at flow rates higher than 42 ml h⁻¹. This decrease was plausibly due to the increase in current with the increased flow rate, which elevated the cathode potential and led to side reactions, such as the reduction of the solvent and supporting electrolyte. These side reactions likely resulted in decreased reaction efficiency and inhibition of the desired reaction.

The reaction temperature was then examined under an optimized flow rate (30 mL h⁻¹) (Fig. 2F-ii). Consequently, the yield increased with decreasing temperature, and the target product successfully obtained a 67 % yield at 263 K. This was attributed to the increased stability of EGB at lower reaction temperatures, which contributed to a higher yield.

Next, the effect of the amount of electricity was investigated using the optimized flow rate and reaction temperature (30 mL h⁻¹, 263 K) (Fig. 2F-iii). Consequently, 3.1 F mol⁻¹ was found to be optimal. This result indicated that as the amount of electricity increased, the amount of EGB produced also increased, subsequently increasing the amount of trichloromethyl anions produced. However, when charge passed significantly increased, the cathode potential also increased, causing side reactions.

The supporting electrolyte was also examined (Fig. 2F-iv). However, increasing the amount of Bu₄NClO₄ did not improve the yield. The target product was not detected when Li⁺ salt was used. This result indicated that using a supporting electrolyte with bulky cations was crucial for this reaction.

Next, we calculated the productivity P (mmol h⁻¹) from Eq. 1. (The solution concentration is M (mM), the flow rate is F (L h⁻¹), and the yield is Y.)

  

\begin{equation} P = M F Y \end{equation} (1)

Under optimized conditions, the productivity using this reaction system was 1.01 mmol h⁻¹, which was approximately 6.7 times higher than the productivity using a microflow reactor (0.15 mmol h⁻¹).¹⁰ These results highlighted the significantly enhanced productivity of the cooling electrochemical flow reactor.

In this reaction, unstable trichloromethyl anions were produced in the micromixer. Therefore, we hypothesized that the yield could be improved by cooling the micromixer to stabilize them. However, no noticeable increase in the yield occurred (Fig. 3A, Entries 2 and 3). Additionally, when both the micromixer and Solution ii were cooled or when only Solution ii was cooled, no increase in yield was observed (Fig. 3A, Entries 1, 2, 4, and 6). These results implied that the trichloromethyl anions reacted immediately with the excess benzaldehyde. Thus, cooling the reactor, rather than micromixer or Solution ii, is essential in this reaction. It is also noteworthy that when only solution i was cooled, the yield was similar to that obtained at 298 K (Fig. 3A, Entries 1 and 5). This is presumably because the solution was warmed up due to the long residence time in the reactor. This result indicates the advantage of this reaction system, which can cool not only the electrolyte but also the flow reactor itself.

Figure 3.

(A) Effects of the cooling parts; (B) Setup and result of scale up; Yields were determined by ¹H NMR using 1,3,5-trimethoxybenzene as an internal standard.¹⁷

Finally, we scaled up this reaction system, taking advantage of its high productivity, and successfully obtained the target product in 50 % yield by electrolysis using 5 mmol of the starting material. This result demonstrated that the reaction system was readily scalable for electrochemical reactions involving active species such as EGB and CCl₃⁻ (Fig. 3B).

In this study, we developed an easily usable cooling electrochemical flow reactor and investigated its application to the trichloromethylation of benzaldehyde with EGB. Thermography showed that the reaction system and flow reactor were well-cooled, and experiments showed that stabilizing EGB by cooling improved the yield. In addition, the flow reactor was 6.7 times more productive than that in previous works using an electrochemical microflow reactor. In addition, using this reaction system, continuous synthesis on a 5 mmol scale was achieved. We hope that this easy-to-use low-temperature electrochemical flow reaction system will lead to more active investigation of new reactions and scale-up.

Acknowledgment

This work was financially supported by JSPS KAKENHI Grant Numbers 21H05215 (Digi-TOS), 23K23386, and 23K17370.

Data Availability Statement

The data that support the findings of this study are openly available under the terms of the designated Creative Commons License in J-STAGE Data at https://doi.org/10.50892/data.electrochemistry.27977223.

• 1) This study introduces a novel low-temperature electrochemical flow reactor for the efficient trichloromethylation of benzaldehyde using electrogenerated bases (EGBs). The setup achieved precise temperature control by leveraging a Peltier-cooled system and a divided flow reactor with carbon-felt electrodes without requiring external cooling baths. Optimization of reaction parameters, including flow rate, temperature, and charge passed, resulted in a maximum yield of 67 % for 2,2,2-trichloro-1-phenylethanol, demonstrating significantly enhanced stability and reactivity of EGBs. This system exhibits a productivity of 1.01 mmol h⁻¹, which is 6.7 times higher than that of a prior microflow reactor approach, and successfully scales up to reactions involving 5 mmol of substrate. Cooling was identified as a critical factor in stabilizing the reactive intermediates, while further experiments confirmed the inefficacy of external cooling components alone. This robust and scalable reactor design highlights the potential for advancing low-temperature electrochemical synthesis and unlocking new reaction pathways.

CRediT Authorship Contribution Statement

Tatsuya Morimoto: Data curation (Lead), Investigation (Lead), Writing – original draft (Lead)

Su-Gi Chong: Data curation (Supporting), Investigation (Supporting), Writing – review & editing (Supporting)

Masashi Fujita: Data curation (Equal), Investigation (Equal)

Naoki Shida: Conceptualization (Lead), Data curation (Lead), Investigation (Equal), Supervision (Equal), Writing – review & editing (Lead)

Mahito Atobe: Conceptualization (Equal), Funding acquisition (Equal), Supervision (Lead), Writing – review & editing (Equal)

Conflict of Interest

M.F. is the CEO of EC Frontier Co., Ltd., a supplier of the electrochemical flow reactor, cooling device, and potentiogalvanostat used in this study.

Funding

Japan Society for the Promotion of Science: 21H05215

Japan Society for the Promotion of Science: 23K23386

Japan Society for the Promotion of Science: 23K17370

Footnotes

M. Fujita and N. Shida: ECSJ Active Members

M. Atobe: ECSJ Fellow

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