Interpreting terminal selectivity in undirected C(sp³)–H functionalization: kinetic insights and mechanistic implications

Undirected terminal C(sp³)–H functionalization represents a fundamental challenge in organic synthesis. Although early transition-metal-, enzyme-, and zeolite-based platforms have achieved high terminal selectivity through well-defined steric control mechanisms, a unifying mechanistic framework remains elusive for rationalizing such selectivity in the rapidly expanding radical-mediated C(sp³)–H functionalization manifold. This review introduces a stepwise kinetic analysis that deconstructs the origins of terminal selectivity into two major kinetic regimes: (1) “Front-end Attack Control”, wherein selectivity is predominantly governed by the initial C–H bond cleavage event; and (2) “Back-end Capture Control”, which arises during the functionalization step following non-selective, reversible C–H bond cleavage. Furthermore, for systems that transcend this binary classification, we further examine “synergistic control” in multi-step relay catalysis and the “intermediate regime”, wherein selectivity emerges from combined kinetic and thermodynamic effects. Through systematic analysis of diverse catalytic platforms and representative case studies, we aim to elucidate the mechanistic origins of site selectivity and establish a theoretical foundation for the rational design of precision C(sp³)–H functionalization systems, thereby facilitating the transition from post hoc rationalization to predictive catalyst design.