Vol. 9, Issue 11, Part C (2025)

A difficult issue in synthetic organic chemistry is the direct functionalization of inert carbon-hydrogen (C-H) bonds, especially the strong and unactivated C(sp³)-H bonds. While there is great potential in integrating photoredox with hydrogen atom transfer (HAT) catalysis, current systems have limitations such as a restricted substrate range and the inability to activate C-H bonds with electron deficiencies. Here, by combining the strengths of two different HAT mediators, we provide a new photocatalytic platform that gets beyond these restrictions. Achieving site-selective alkylation of an unexpectedly wide range of C-H bonds is achieved by coupling a highly oxidizing acridinium photocatalyst with a quinuclidine-derived radical cation and a thiyl radical. Ethers, non-activated alkanes, and even electron-deactivated systems that were previously thought to be resistant to functionalization may all be effectively treated with this dual HAT system. Stern-Volmer quenching, radical clock experiments, density-functional theory (DFT) calculations, and other mechanistic investigations validate the participation of many radical intermediates and provide light on the complementary process behind the observed selectivity and reactivity. By using this technique to functionalize complicated medicines at the last step and synthesize a bioactive lipid analogue concisely, we show that this technology has synthetic utility. There will likely be extensive use of this work's novel approach to C-H functionalization in synthetic chemistry since it is both generic and innovative.