Electrochemical Platform for Automated Design-of-Experiment Optimization of Ni-Catalyzed Cross-Electrophile Coupling Reactions

Abstract Electrosynthetic organic reactions have advanced significantly in recent years, but their adoption for large-scale applications remains limited. Here, we report an automated experimental platform designed to facilitate translation of small-scale chemical and electrochemical redox reactions into robust larger-scale electrochemical processes. This platform, which integrates a commercial chemical synthesis workstation, peristaltic pumps, and a potentiostat, is equipped to conduct an automated sequence of batch experiments to optimize standard variables, such as stir rate and temperature, in addition to variables unique to electrosynthesis, such as applied current and total charge passed. Analysis of these variables using a design-of-experiment (DoE) approach accelerates identification of optimal reaction conditions and translation of mg-to-multigram operations. To evaluate the DoE optimization protocol and experimental platform, four Ni-catalyzed C(sp2)–C(sp3) cross-electrophile coupling reactions were selected from the literature that were originally conducted on a 0.2–0.4 mmol scale with chemical or electrochemical reduction methods. Each reaction was successfully scaled by a factor of 30–250, delivering up to 20 g (100 mmol) of isolated product. These results show how small-scale redox reactions may be rapidly translated to scalable electrosynthetic processes.