Electrochemical Access to Difluoromethyl Groups: An Overview of Scope, Mechanisms, and Challenges

Abstract

The difluoromethyl (−CF₂H) group has gained considerable significance in synthetic and medicinal chemistry due to its ability to modulate molecular properties, including electronic effects and hydrogen-bonding capability. Traditional difluoromethylation methods often require specialized reagents and demanding reaction conditions, potentially limiting their applicability across diverse substrates. Electrochemical difluoromethylation has emerged as an alternative approach that enables the in situ generation of difluoromethylating species under controlled redox conditions. This Perspective examines recent advancements in electrochemical difluoromethylation, focusing on key mechanistic aspects with substrate scope. Electrochemical strategies have facilitated chemo- and regioselective radical-mediated transformations that are often challenging to achieve using conventional chemical or photochemical methods. Additionally, recent studies have explored defluorinative difluoromethylation, leveraging C–F bond activation to generate CF₂H-containing compounds from abundant CF₃ precursors. Despite these advances, significant challenges remain, including the need for enhanced selectivity and improved reaction scalability. This Perspective aims to provide a critical analysis of the current state of electrochemical difluoromethylation, highlighting its mechanistic underpinnings and potential areas for further development.