The transition metal catalyzed cycloaddition reaction is one of the most powerful tools for the construction of carbon- and heterocycles. Comprehensive computational studies are employed to investigate the mechanism and...

Transition-metal catalyzed coupling reactions of carbonyl compounds using simple chemical feedstocks have become a cornerstone of modern synthetic organic chemistry. The mechanisms and origins for ligand-controlled palladium-catalyzed regioselective α- and γ-arylation of α,β-unsaturated ketones with aryl halides have been investigated by density functional theory (DFT) calculations. Computational results have confirmed our proposed catalytic cycle, which includes four steps: oxidative addition, transmetallation, deprotonation/protonation, and reductive elimination. The Heck-type mechanism for α-arylation of α,β-unsaturated ketones is proved to be less feasible due to the high energy barrier for the insertion step. While reductive elimination is the rate-determining step (RDS), the critical process responsible for the regioselectivity depends upon the direction of protonation step, where the base function as a proton shuttle to facilitate H migration. Distortion/interaction analysis, natural bond orbital (NBO) analysis, and bur-ied volume calculations indicate that the regioselectivity is primarily controlled by the steric hindrance at the region of the ligand close to the enone. The indole ring of the phosphine ligand lay upward or downward, varying the space crowding in the region, thus leading to different protonation products followed by corresponding reductive elimination. The phenomenon of [1,5]-H trans-fer discovered in the γ-arylation of β-alkoxy cyclohexenones is also well rationalized by the proton shuttle model.