The catalytic generation of alkyl ketyl radicals remains challenging due to the very high reduction potentials of alkyl ketones, which impedes their reduction under catalytic conditions. We first employed a photoexcited palladium species with a sufficiently high reduction potential to enable the single-electron reduction of alkyl ketones. Mechanistic studies revealed that back-electron transfer (BET) competes with the productive radical-coupling pathway, providing a key design principle for ligand optimization. This insight motivated us to use a virtual ligand-assisted screening (VLAS) to computationally map the electronic and steric ligand space required to suppress BET. Among the 38 computationally evaluated candidates, VLAS predicted a narrow region capable of minimizing BET and promoting a productive ketyl radical coupling. Experimental evaluation of only four ligands validated these predictions and identified tri(pmethoxyphenyl)phosphine as the optimal ligand. This theory-first strategy enables the general catalytic generation of alkyl ketyl radicals and establishes a predictive framework for computational ligand design using VLAS.
Tanaka et al. (Wed,) studied this question.