Beyond ring strain: Au–H hydrogen bonding dictates chemo-selectivity in gold-catalyzed C(sp3)–H insertions to cyclobutanones and cyclopentanones

Abstract

The intramolecular insertion of oxidatively generated β-diketone-α-gold carbenes into unactivated C(sp³)–H bonds provides a versatile route to cyclobutanones and cyclopentanones, yet the factors governing the chemoselectivity between these pathways remain poorly understood. Herein, we present a comprehensive DFT study that challenges the conventional ring-strain model and unveils a previously overlooked determinant: a non-classical Au⋯H–C hydrogen bond. We demonstrate that the formation of the gold carbene is the rate-determining step, facilitated by π-stacking interactions. Crucially, the chemoselectivity is kinetically controlled by the strength of a key Au⋯H interaction in the transition state, which exhibits a linear free-energy relationship (LFER) with the activation barrier difference (ΔΔG^‡). This interaction effectively overrides the inherent ring strain of the four-membered ring. Thermodynamic stability dictates the outcome only when kinetic barriers are comparable. This work establishes a new conceptual framework for understanding chemoselectivity in metal-carbene-involved C–H functionalization, highlighting the critical role of metal–ligand cooperative interactions and providing a quantitative basis for predicting selectivity through LFER analysis.