Beyond the Phenothiazine Core: Mechanistic Insights into the Three-Electron Oxidation of Chlorpromazine

This study investigates the electrochemical oxidation mechanisms of chlorpromazine (CPZ), revealing a novel three-electron oxidation pathway that challenges the traditionally accepted two-electron paradigm, offering new insights into CPZ oxidation pathways. Using an integrated approach combining cyclic voltammetry, bulk electrolysis, UV-Vis, FT-IR, 1H-NMR spectroscopy, and LC-MS/MS analysis, we demonstrate that CPZ undergoes sequential oxidation processes involving both the phenothiazine core and the tertiary amine-containing side chain. Our results highlight the critical role of side-chain oxidation in forming nor-CPZ sulfoxide, an often-overlooked metabolite, which may influence CPZ’s metabolic and pharmacological behaviour. Spectroelectrochemical data reveal stable intermediate species, providing insight into the structural rearrangements accompanying oxidation. This work offers a detailed mechanistic understanding of CPZ redox behaviour, contributing to improved interpretations of its pharmacological and metabolic properties.