Controlling Radical Reactivity for Visible‐Light Bioorthogonal Chemistry

Bioorthogonal chemistry enables selective reactions within complex biological environments. Visible‐light photocatalysis expands this toolbox by generating carbon‐centered radicals through single‐electron transfer under mild conditions, enabling selective bond‐forming transformations with spatiotemporal control. Unlike broader photocatalytic transformations in biology, bioorthogonal radical reactions that selectively couple exogenous partners without reacting with native biological functionalities have not been systematically examined from the perspective of radical reactivity control. The central challenge is to control radical reactivity such that productive coupling outcompetes biological quenching while maintaining chemoselectivity. This review examines two complementary strategies to address this challenge: kinetic trapping of transient alkyl radicals and thermodynamic stabilization of persistent ketyl radicals. Framing representative systems through physical‐organic principles—including radical lifetime, polarity, and reaction kinetics—we highlight applications in nucleic acid and protein modifications, protein–protein cross‐linking, and live‐cell labeling. Finally, we discuss emerging opportunities in biocompatible photocatalysts, long‐wavelength activation, and in vivo applications, providing a conceptual framework for the design of next‐generation visible‐light bioorthogonal chemistries.