Cl Radical-Mediated Electrochemical Site-Selective Functionalization of Cysteine Residues in NaCl Aqueous Media

Abstract

The site-selective modification of cysteine residues remains a significant challenge in synthetic and chemical biology. Herein, we report a green and efficient electrochemical strategy for the precise functionalization of cysteine, mediated by chlorine radicals (•Cl) generated in-situ from NaCl aqueous. Mechanistic studies, including control experiments and cyclic voltammetry, established the essential role of Cl⁻ electrooxidation in initiating the transformation. Radical trapping provided direct evidence for the proposed •Cl-mediated radical chain mechanism. This method operates under mild conditions without metal catalysts or stoichiometric oxidants. It demonstrates excellent functional group tolerance and remarkable scalability. Furthermore, this strategy successfully applied to the site-selective modification of unprotected bovine serum albumin, showcasing its considerable potential for bioconjugation and the construction of biomolecular hybrids.