Substrate-Assisted Photochemistry of Thiobenzoic Acids: An Unconventional Mechanism for C–H Deuteration

Abstract

Precision deuterium labeling is pivotal across chemical biology, medicinal chemistry, and materials science. However, conventional methods often necessitate expensive catalysts or high-energy UV irradiation, which restrict their sustainability and broad utility. Herein, we report a photocatalyst-free, visible-light-driven (440 nm) deuteration platform mediated by simple thiobenzoic acid (TBA) under exceptionally mild conditions. Beyond mere synthetic utility, mechanistic studies—combining spectroscopic analysis and DFT calculations—unveil a conceptually distinct "substrate-assisted photoactivation" paradigm. We demonstrate that TBA engages in transient molecular aggregates with substrates, enabling efficient visible-light harvesting and subsequent S–H bond homolysis without external sensitizers. This strategy grants access to diverse deuterated architectures, including formyl, α-amino, and benzylic positions. Most notably, it overcomes the long-standing challenge of direct α-hydroxy C(sp3)–H deuteration, achieving up to 99% D-incorporation with excellent functional group tolerance. The practical robustness is underscored by gram-scale synthesis and efficient D2O recovery, offering a sustainable, operationally simple solution that redefines the boundaries of light-driven radical chemistry.