The ability to control reaction kinetics is critical to achieving the desired reactivity in organic synthesis. Compared to conventional electroorganic synthetic methods, alternating current electrolysis (ACE) provides two additional parameters, AC frequency, and waveform, for reaction kinetic control. We postulated that ACE could effectively minimize the undesired side reactions in paired electrolysis and achieve electrochemical deracemization. Our study examined the α-amino C–H arylation reaction affords Benzylic amines targets, a common motif found in a range of pharmaceutical drug candidates. We found that the amine is prone to over-oxidization to iminium ion via a two-electron oxidation process at a constant voltage, giving the cyanation side product. In contrast, under AC electrolysis, amine overoxidation can be significantly minimized or entirely avoided by allowing the deprotonation of amine cation radical to α-amino radical place under a reducing environment in the negative half cycle of the AC waveform. Because the product selectivity relies on a delicate balance between the reaction kinetics of amine electrooxidation, amine cation radical deprotonation, radical-radical coupling, and α-amino radical oxidation, it shows a strong dependence on the AC frequency. At the optimal frequency, we could able to minimize or utterly turned off the cyanation pathway. Most excitingly, we discovered a simple electrochemical descriptor from a cyclic voltammetry study, which can be used to predict product selectivity at different AC frequencies. This finding is significant because it dramatically simplifies the reaction condition optimization, moving from the conventional time-consuming trial-and-error approach to the easy-and-quick rational design.

Controlling one or two electron oxidation in electroorganic synthesis by rational design of alternating current frequency

ACS Spring 2022

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