Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor.

Organic electrochemistry has emerged as an enabling and sustainable technology in modern organic synthesis. Despite the recent renaissance of electrosynthesis, the broad adoption of electrochemistry in the synthetic community, and especially in industrial settings, has been hindered by the lack of general, standardized platforms for high-throughput experimentation (HTE). Herein, we disclose the design of the HTe - Chem, a high-throughput microscale electrochemical reactor that is compatible with existing HTE infrastructure and enables the rapid evaluation of a broad array of electrochemical reaction parameters. Utilizing the HTe - Chem to accelerate reaction optimization, reaction discovery, and chemical library synthesis is illustrated using a suite of oxidative and reductive transformations under constant current, constant voltage, and electrophotochemical conditions.

Introduction

Over the past decade, synthetic electrochemistry has garnered significant interest in the organic chemistry community.[1−6] In an electrochemical reaction, electrons flowing between an anode and a cathode provide the redox equivalents to drive chemical transformations in lieu of traditional chemical oxidants or reductants. Under a sufficient current or potential, substrates can be oxidized or reduced at the electrode to generate reactive intermediates such as radicals and radical ions. The broad potential range of an electrochemical system allows for the activation of inert chemical bonds, thus driving highly endergonic reactions that are otherwise challenging or, sometimes, impossible.[7] Meanwhile, by precisely dialing in a current or potential, chemists can select for a specific electron transfer reaction to occur in the presence of various reactive functional groups and do so with control over the reaction rate. These features make electrochemistry an attractive strategy for discovering fundamentally new chemical transformations and promoting green and efficient synthesis.[1,3−5,7−9]

A myriad of powerful electrochemical reactions developed in the past decade have shown the promise of electrochemistry as an enabling technology in both academic and industrial research. Despite the established advantages, electrochemical methods have seen only limited adoption in the pharmaceutical industry, primarily due to a lack of standardization and experimental flexibility. Without a standardized electrolysis setup, the reproduction of electrochemical reactions can be challenging.[10] To address this issue, reactors for electrosynthesis have been designed and deployed, including an early-generation spatially addressable electrolysis platform (SAEP)[11] and the recently commercialized ElectraSyn 2.0,[12,13] e-Hive, and IKA screening system.[14] These critical technology advancements have substantially accelerated the development and adoption of new electrosynthetic methods in the broader organic chemistry community.[2,15] Despite the success achieved with each of these systems, the ability to easily explore a broad array of electrochemical reaction parameters in a high-throughput fashion remains elusive and highly desirable. In this regard, an ideal standardized reactor platform should allow for convenient and modular programming of various experimental parameters. Although the multitude of reaction parameters present in electrochemical systems open opportunities for reaction discovery, they also pose unique challenges. For example, electrochemical parameters such as cell geometry, mode of operation (constant current or constant voltage), applied current or potential, electrode material, and electrolyte can be leveraged to improve reactivity.[16] Nevertheless, this additional complexity introduces a barrier to begin investigating electrochemical reactions and also increases the number of conditions that need to be evaluated. Thus, the full optimization can require significantly more screening experiments than traditional organic transformations.[17]

High-throughput experimentation (HTE) using standardized 24- or 96-well plates (microtiter plates with standard ANSI/SLAS footprint) is routinely used for reaction discovery, optimization, and library synthesis in the pharmaceutical industry and beyond.[18−22] The parallelization of experiments allows chemists to rapidly explore a large number of reaction parameters, generate a complete data set, and optimize toward global maxima rather than local maxima, the latter of which are often encountered in traditional one-factor-at-a-time (OFAT) optimization.[19,23] The adoption of standardized HTE systems, including parallel plate reactors, multichannel pipettors, liquid and solid handling robots, and stirring systems, has streamlined workflows by ensuring the compatibility of all equipment. This standardization also enables the use of preplated reagent libraries, which is particularly useful for the screening of catalysts, ligands, and reagents.[19,20] Consequently, plate-based HTE, first introduced by the biology community in the 1950s, has today been expanded to virtually all research space in organic synthesis.[5,21,24−28]

The integration of HTE capabilities with organic electrosynthesis has the potential to substantially facilitate the adoption of electrochemistry in organic chemistry research.[29] To this end, we aim to design a reactor platform that is compatible with the current HTE infrastructure and allows for the screening of all common electrochemical reaction parameters. An ideal HTE reactor for electrosynthesis will enable the rapid screening of features unique to electrochemistry such as mode of operation (constant current or constant voltage), applied current or potential, applied charge, and electrode material. In addition, the reactor should be amenable to reactions at different temperatures and under air- and water-free conditions. Furthermore, the reactor will accommodate microscale reactions (<400 μL total reaction volume) to reduce material consumption, minimize cost, and improve safety. Finally, the screening platform should accommodate recent advancements such as electrophotochemistry[2,30] and alternating current electrolysis.[31−33] Notably, despite significant recent advances, a general, standardized HTE reactor that satisfies these desirable criteria remains elusive.[34]

Herein, we report the design of a 24-well plate high-throughput electrosynthesis reactor, namely, HTeChem, that presents all of the aforementioned features and capabilities. By showcasing a selection of electrosynthetic transformations, we demonstrate the versatility of this new reactor for reaction discovery, optimization, and library synthesis in a variety of electrochemical applications.

Design of HTeChem

An important design principle for the HTeChem reactor is that it needs to be based on a standardized commercial platform and should be operationally simple, modular, and chemically resistant. Our investigation commenced with a 24-well microscale HTE photochemistry reactor (F; Figure A), which features a 4 row by 6 column plate with 8 × 30 mm glass vial inserts. This parent reactor has been extensively used in both academic and industrial settings for high-throughput screening experiments and is compatible with standardized equipment and existing infrastructure such as automated reagent addition systems and preplated reagent libraries.[21,35] The reactor block has an insert for a temperature probe and can be heated or cooled using common laboratory temperature-control systems; it is also compatible with both magnetic rotary and tumble stirring. Finally, the base allows for efficient illumination of the vials with commercial HTE photochemistry equipment through the bottom of the reactor. Thus, this parent system provides an ideal platform for our design of a standardized and modular electrochemical HTE reactor.

Figure 1

(A) Design and assembly of the HTe–Chem. PCB, printed circuit board. (B) Picture of the fully assembled HTe–Chem with the constant potential top plate with a US quarter for scale. (C) Cross section of the HTe–Chem.

The HTeChem (Figure ) employs two parallel cylindrical rods each with a diameter of 1.6 mm as the electrodes (E). Numerous conducting materials are commercially available in these dimensions in high purity, including graphite, nickel, stainless steel, copper, titanium, magnesium, zinc, platinum, tin, and aluminum. The electrodes are held closely apart at a 1.54 mm distance (from surface to surface) and can perfectly fit in the microscale cells of the baseplate, resulting in a reaction volume (200–600 μL) of up to 25 times lower than that of a typical electrochemical batch reactor. This compact arrangement reduces reagent usage and ensures sufficient conductivity at a low electrolyte concentration, while the cell geometry resembles that of a traditional batch cell and provides good scaling behavior. To keep the electrodes parallel, we designed an alignment plate (D) made from a chemically resistant and rigid G-10 composite material populated with holes machined with tight tolerances. In addition, a silicone rubber gasket (D2), which functions like a septum, is used to hold the electrodes in place and provides sealing against the glass vial inserts.

A sealing plate (C) made from the same G-10 composite material combined with an additional silicone rubber gasket (C3) was also included. This plate contains contact pins (C2) that are secured using epoxy resin and provide electrical contact between the printed circuit board (PCB; vide infra) and the electrodes while effectively excluding air and water from entering the system through the electrode–G-10 contact. Upon assembly of the HTeChem, the compression of the elastic silicone rubber gasket (D2) pushes the electrodes against the contact pins (C2). Even prolonged heating of the reactor does not result in significant loss of solvent, and the silicone rubber tolerates virtually any reaction conditions without damage or swelling.[36] A detailed discussion of design decisions for the sealing and alignment top plates is outlined in the Supporting Information.

Separating the custom printed circuit board (B) from the electrode array increases the operational flexibility and the longevity of the system. Spring-loaded connectors (B2) on the PCB ensure good electrical contact with the contact pins (C2) on the sealing plate. Two variants of the PCB were designed to enable two distinct modes of operations, constant current electrolysis (CCE) and constant voltage electrolysis (CVE). Constant voltage electrolysis is a technique distinct from constant potential electrolysis (CPE). In the former case, a constant cell voltage is applied between the anode and the cathode while the electrode potentials and current can vary during the reaction course. In the latter case, a CPE requires a three-electrode setup, and a potential is applied between the reference electrode and the working electrode. For both the CCE and CVE setup, an 8-pin connector (A) and a ribbon cable connect the PCB to four controllers, each of which supplies power to one row of the 24-well matrix and allows for accurate control of current (±0.5% at 0.5 mA) or cell voltage (±0.1% at 1.5 V). This setup allows for the screening of 4 discrete currents or 4 discrete cell voltages depending on the mode of operation. One potential pitfall is that, in the case of CCE, 6 cells are connected in series; hence, if one cell fails to conduct, electrolysis will fail in all 6 cells. To address this issue, LEDs were added to the circuit associated with each row of cells as a visual identification of faulty cells. If a faulty cell is detected, our system allows the user to add a “skipper-pin” to the faulty cell to effectively disconnect it from the electric circuit. In addition, this feature allows for critical “no electricity” control experiments to be incorporated within the same experimental design, thus evaluating the necessity of applied current. Furthermore, users can start or stop a single reaction at any given time using the “skipper-pin” without affecting other reactions, which can help the user study the effect of the amount of applied charge on the reaction outcome. Therefore, this PCB design facilitates the flexible screening of up to 6 applied charges at 4 currents.

Importantly, the standardized plate design makes assembling the HTeChem reactor simple and straightforward. Most individual components are commercially available, including the HTE reactor block, silicone gaskets, electrodes, and power controllers. The components that are not yet commercially available, namely, the alignment plate, sealing plate, and custom PCB, are readily manufactured and can be produced in bulk if needed. The complete technical drawings, specifications, troubleshooting advice, along with a video tutorial for the reactor setup are included in the SI.

The modular design of the HTeChem reactor allows for flexibility of the reaction setup because the replacement of a single component is possible. For example, alternating current electrolysis can be easily implemented by substituting the power controllers for a waveform generator. In addition, electrophotochemical reactions can be readily carried out using an external, commercially available LED array (vide infra). Further, the design could, in principle, be extended to a 96-well plate format without major modifications. In the following section, we present the application of the HTeChem for a variety of known and new electrosynthetic transformations and demonstrate its exciting potential to accelerate the broader implementation of electrochemistry in the pharmaceutical industry.

Applications

We investigated the use of the HTeChem in a suite of oxidative and reductive transformations using either constant current or constant voltage conditions, as well as in electrophotocatalytic systems. Potential use cases for reaction discovery, screening, and library synthesis were surveyed.

Oxidative Azidooxygenation under Constant Current Conditions

We set out to demonstrate the reliability and reproducibility of the HTeChem by quantifying the well-to-well variability in a TEMPO-mediated azidooxygenation reaction previously reported by the Lin group.[37,38] This model reaction was carried out in all 24 wells of the reactor under identical conditions using constant current electrolysis. Scaling down the reaction to the microscale (17.5 μmol, 380 μL) with the HTeChem furnished the difunctionalized styrene (2) with an average yield of 89.1%, comparable to the 89% yield obtained in the original report under constant voltage conditions on a 0.2 mmol scale (Scheme ). The relative standard deviation was only 2.2%, and there was no impact on the vial position even using a common rotary stir plate. The reliability of the HTeChem reactor was validated by researchers at both Cornell University and Merck & Co., Inc., Kenilworth, NJ, USA. Finally, we showed that the new azidooxygenation conditions discovered using the HTeChem (with a reduced azide loading and no supporting electrolyte) can be readily translated to a synthetic scale experiment. Specifically, we successfully scaled up this reaction by a factor of 57 (1 mmol scale) with the Electrasyn 2.0 instrument, furnishing 85% of the azidooxygenated styrene.

Scheme 1

Azidooxygenation of 4-Methoxystyrene (1) Adapted from Constant Voltage to Constant Current Conditions on the HTe–Chem

The yields are determined by HPLC using dimethyl terephthalate as the internal standard. The transformation is an innersphere mediated oxidation (ECC) of the styrene via a charge-transfer complex formed between the azide and an oxoammonium cation generated by oxidation of TEMPO.[37]

Reductive Silylation Using a Sacrificial Anode

In many nonmediated electrochemical reactions, identifying the correct electrode material is key to rendering a reaction efficient and selective.[39] As the unique surface chemistry influences the optimal electrochemical parameters, an ideal experimental design would evaluate various electrode materials with a range of current densities or applied voltages. The HTeChem presents precisely such capabilities, which we demonstrate in the further optimization of a reductive allylic silylation reaction recently developed in the Lin lab.[40] This reaction is proposed to undergo an ECEC mechanism wherein trimethylsilyl chloride is first directly reduced to a trimethylsilyl radical, which adds to an allylether (3) to generate a carbon-centered radical. This radical is further reduced to a carbanion and subsequently eliminates phenolate to deliver the allyl silane (4). By screening four currents with six cathode materials, we obtained the desired allylsilane (4) in a highest yield of 98% using platinum cathodes, representing a 23% increase over the original optimal 75% yield obtained on the 1 mmol scale with a graphite cathode (Figure ). Intriguingly, the use of stainless steel and platinum cathodes furnished the highest yields at 1.5–2.0 mA, whereas the employment of graphite cathodes provided high yields at 0.5–1.0 mA. These data highlight that factorial parallel screening allows the optimization toward a global maximum, while the traditional OFAT approach is prone to converging to local maxima (e.g., optimizing the current with a graphite cathode would result in the highest yield of 89%). These trends were replicated on a 1 mmol scale (57-fold scale-up); platinum as the cathode gave a 74% yield at a current density of 3.7 mA/cm2, whereas graphite performed optimally at a lower current density of 1.4 mA/cm2, yielding 75% of the desired allyl silane. Finally, the successful demonstration of this reductive silylation reaction showcased the HTeChem’s compatibility with moisture-sensitive, highly reducing conditions (−3.1 V vs SCE or lower for the reduction of trimethylsilyl chloride[40]).

Figure 2

(A) Reaction conditions for the optimization of the reductive synthesis of allyl silanes. The reaction conditions that are varied on the plate are shown in bold. (B) Plate map and data for the optimization of the reductive synthesis of allyl silanes. The yields are determined by HPLC using 1,3,5-trimethoxybenzene as the internal standard.

Electrophotocatalysis under Constant Voltage Conditions

Electrophotocatalysis has recently emerged as an enabling strategy for new reaction discovery.[2] For example, Lambert et al. disclosed an elegant protocol for the oxidative C–H amination of arenes by means of tandem electro- and photochemical activation of an organic catalyst (8).[41] In this mediated electrochemical reaction, the catalyst (8) is oxidized at the anode to generate the corresponding radical dication, which is then photoexcited and reductively quenched by an arene (5). The resultant highly reactive arene radical cation is trapped by pyrazole (6) to construct the desired C–N bond prior to rearomatization.

Given the HTeChem’s baseplate is designed to accommodate photochemistry, we aimed to leverage the HTeChem to investigate this electrophotochemical transformation. Thus, three cell voltages, three supporting electrolytes, and two different reaction times were surveyed. Furthermore, the capability of 24-well parallel screening allows crucial control experiments to be carried out simultaneously with reaction optimization under identical conditions. Accordingly, we included no electrolysis, no light, no electrolysis with no light, and no catalyst control reactions within the same plate (Figure ). Using the HTeChem provided conditions resulting in a 3-fold rate increase and furnished the desired product (7) in 78% yield after 24 h, as compared to the originally reported 71% yield after 72 h on a 0.4 mmol scale, likely as a result of the improved light penetration and LED optical power. The trend of decreasing yields at long reaction times for LiClO4 and TBAPF6 was likely a result of overoxidation of the product by the highly oxidizing exited state of the trisaminocyclopropenium (TAC) cyclopropenium radical dication catalyst (3.33 V vs SCE).[41] Notably, these reactions are also carried out under constant voltage electrolysis conditions, which is another important capability of the HTeChem reactor. As HTeChem is the first standardized platform for electrophotochemistry, we further established the reproducibility of the protocol. Setting up identical reactions in all 24 wells of the HTeChem gave an average yield of 75.0% with a relative standard deviation of 5.2% (see the SI).

Figure 3

(A) Reaction conditions for the optimization of the oxidative C–H amination of mesitylene (5) with pyrazole (6). The reaction conditions that are varied on the plate are shown in bold. (B) Trisaminocyclopropenium (TAC) (8) organocatalyst. (C) HTe–Chem while running the electrophotocatalytic reaction. The reactor is irradiated by the Lumidox II Gen II 24-position LED array at 445 nm with an optical power of 60 mW per vial. (D) 24-well plate data and experimental design. The yields are determined by HPLC using dimethyl terephthalate as the internal standard.

Discovery and Optimization of the Chlorination of Arylboronic Acids

Building on the successful adaptation of a variety of electrochemical reactions to the HTeChem, we set out to optimize a previously unknown transformation, namely, the electrochemical chlorination of boronic acids. We envisioned an anodically coupled electrolysis mechanism in which the anodic oxidation of an arylboronic acid would give rise to an aryl radical,[42] which could then be intercepted by a persistent chlorine atom source such as [MnIII]–Cl. This MnIII species has been employed in our previous work as an effective Cl-atom transfer catalyst and can also be generated electrochemically from a MnII salt.[43] This methodology would be complementary to reports of electrochemical bromination and iodination[44] of boronic acids and provide a sustainable alternative to known methods using stoichiometric electrophilic chlorination reagents.[45,46]

The reaction was initially developed on a 0.2 mmol scale using homemade electrolysis cells by subjecting 4-tert-butylphenyl boronic acid (12) to our previously reported electrochemical alkene dichlorination conditions (see the SI for details).[47] When the electrolysis was conducted at 65 °C, we detected a moderate yield (∼30%) of the desired 4-tert-butylchlorobenzene (10) in addition to a significant amount of tert-butylbenzene (11) from unproductive protodeborylation.[48] Subsequently, we employed the HTeChem to identify the design parameters that were important for observed reactivities with the goal of optimizing the chlorination reaction while minimizing the detrimental side reaction (Figure ). In a single plate, the substrate and activating agent, chloride source, proton source, catalyst, and necessity of electrolysis were investigated. These data revealed several key insights into the reaction: (1) 11 is not an intermediate en route to product 10 (via electrophilic arene chlorination). (2) Electricity is required to furnish the desired product. (3) Protodeborylation of the boronic acid occurs spontaneously with AcOH but not with the more weakly acidic pyridine·HCl. Notably, by using 4-tert-butylphenyl boronic acid (as opposed to Ar–BF3K) as the substrate and pyridine hydrochloride as the acid and chlorine source, protodeborylation was fully suppressed, giving 71% of the desired product (10) in a procedure with manganese and a comparable 64% yield of 10 in metal-free conditions.

Figure 4

(A) Reaction conditions for the optimization of the electrochemical chlorination of aryl boronic acid (9). The reaction conditions that are varied on the plate are shown in bold. (B) Plate map with reaction yields of the desired 4-chloro-tert-butylbenzene (10) (green) and of tert-butylbenzene (11) (red) (protodeborylation). The yields are determined by HPLC using dimethyl terephthalate as the internal standard.

With these promising results, we carried out additional optimization of various other parameters including the catalyst (none, Mn(OTf)2, Ni(OTf)2, and Fe(OTf)2), applied charges (2, 3, and 4 F), and loading of pyridine·HCl (5 and 20 equiv) on a single plate, which resulted in a further improved, metal-free protocol delivering a quantitative yield (>99%) of 10 (see the SI for details). Scaling this chlorination to the 1 mmol scale (57-fold scale-up) using the Electrasyn 2.0 instrument furnished 4-tert-butylchlorobenzene in 92% yield. These optimization data also showed that our initial mechanistic design employing a Mn catalyst is unnecessary, and that the electrophilic chlorinating agent can be generated directly via anodic oxidation. Finally, we note that the chlorination of boronic acids was rapidly developed through only two plates of screening experiments, thus significantly accelerating the optimization workflow vis-à-vis traditional screening strategies.

Electrochemical C–C Coupling Reactions

Various electrochemical C–C coupling reactions have been reported recently, and adopting such transformations using the HTeChem could enable the rapid generation of diverse product libraries for medicinal chemistry studies. We successfully translated two such reactions, which were originally discovered using larger-scale commercial reactors, to the HTeChem conditions (Scheme ). For example, Baran and Minteer disclosed a reductive ketone–olefin coupling for the synthesis of medicinally relevant scaffolds.[49] This direct cathodic electrolysis adopts an ECEC mechanism wherein a ketyl radical is generated by the cathodic reduction of a ketone (14). This ketyl radical adds to the alkene (15) to form the C–C bond, and the resultant C-centered radical undergoes further reduction and protonation to yield the C–C coupled product. To adapt this method to the HTeChem, we investigated a variety of cathode materials and applied currents and successfully replicated the reported results. Notably, the screening experiments allowed us to identify copper and Chromel (Ni0.9Cr0.1) as alternative cathode materials to tin, which was used in the original report, producing comparable yields of 16 at a higher current (see the SI for details).

Scheme 2

Reductive and Oxidative C–C Cross Coupling Optimized Using the HTe–Chem

The yields are determined by HPLC using 1,3,5-trimethoxybenzene for 16 and 4,4′-di-tert-butylbiphenyl for 19 as the internal standard.

In another report by Waldvogel and co-workers, an oxidative C–H/C–H coupling was achieved to furnish valuable diarylmethanes 19 with hydrogen as the sole byproduct. In this transformation, a convergent paired electrolysis generates a pair of p-quinone methide electrophile (via ECE oxidation of 17) and hexafluoroisopropoxide nucleophile. These intermediates react with one another to yield benzyl hexafluoroisopropyl ether 20. In a subsequent operation in the same pot, the ether undergoes substitution with an electron-rich arene 18 in the presence of trifluoroacetic acid.[50] The original report showed that boron-doped diamond (BDD) electrodes promoted the optimal reactivity, generating product 19 in 93% yield on a 1 mmol scale. Interestingly, the HTeChem screening led us to further improve this methodology at a 17.5 μmol scale and obtain the coupling product in quantitative yield with less expensive graphite electrodes (see the SI for details).

Library Synthesis

In addition to reaction development and optimization, use of the HTe–Chem reactor offers the ability to rapidly generate a 24-membered library of compounds. This capability is of substantial interest to the pharmaceutical industry for parallel library synthesis using electrochemical methods. We demonstrated this capability through the synthesis of 24 hindered primary amines under reductive conditions via the coupling of iminium chlorides with cyanopyridines.[15] The key step of the cathodically coupled electrolysis is the radical coupling between an α-amino radical (cathodic reduction of 21a–21d) and a cyanopyridine radical (proton-coupled cathodic reduction of 22–27). The subsequent loss of a proton and cyanide delivers the hindered amines 22a–27d. To translate the originally reported procedure on a 1 mmol scale to a μmol scale, the applied current was screened (I = 0.5, 1.0, 1.5, and 2.0 mA) using the HTe–Chem reactor which revealed that 0.5 mA with 2 F of charge was optimal for the coupling of model substrates (see the SI for details). These results are consistent with decreasing the current density to minimize the formation of diamine side-products. These optimal conditions were applied to library synthesis by reacting four iminium chlorides with six different cyanopyridines, providing rapid access to 24 primary amines with satisfactory isolated yields at a 38.9 μmol scale (Figure ). The exploration of chemical space with the HTeChem reactor enables the observation of clear trends in the yields as the electronics of the iminium salt is varied, as illustrated in Figure when comparing results down each column.

Figure 5

Reductive library synthesis of hindered amines. The yields shown in the plate map are LCAP. Calibrated yields determined by HPLC range from good to moderate (83–53%). (See the SI for isolated yields and analytical details.)

Conclusion

In sum, we report the design and application of the HTeChem, a high-throughput 24-well reactor for electrosynthesis. The HTeChem was designed to enable the parallel screening of electrochemically relevant parameters, such as electrode material, applied current or voltage, and electrolyte, as well as traditional reaction parameters, such as temperature, solvent, and catalyst. This reactor is based on a standardized commercial platform and is fully compatible with existing high-throughput infrastructure, including reagent-dosing equipment as well as preplated reagent libraries, and the design is expected to be scalable to 96-well systems as well. We have demonstrated that employing this HTE reactor enables rapid optimization of reactions and is complementary to existing standardized electrochemistry systems, such as the ElectraSyn 2.0 and the IKA screening system. Importantly, reaction conditions discovered using the HTeChem on microscales are shown to be readily translatable to synthesis at typical benchtop scales using the ElectraSyn 2.0 instrument. In addition, the HTeChem accelerated the development of a previously unknown electrochemical reaction and was also shown to be compatible with cutting-edge developments in electrochemistry such as electrophotocatalysis. Finally, we show that the new reactor can be employed to rapidly generate chemical libraries relying upon electrochemical coupling reactions. Owing to its accessibility, flexibility, and demonstrated performance, we anticipate that the HTeChem will substantially accelerate the adoption and development of electrochemical techniques in both academic and industrial settings.