Double-Regiodetermining-Stages Mechanistic Model Explaining the Regioselectivity of Pd-Catalyzed Hydroaminocarbonylation of Alkenes with Carbon Monoxide and Ammonium Chloride.

Pd-catalyzed hydroaminocarbonylation (HAC) of alkenes with CO and NH4Cl enables atom-economic and regiodivergent synthesis of primary amides, but the origin of regioselectivity was incorrectly interpreted in previous computational studies. A density functional theory study was performed herein to investigate the mechanism. Different from the previous proposals, both alkene insertion and aminolysis were found to be potential regioselectivity-determining stages. In the alkene insertion stage, 2,1-insertion is generally faster than 1,2-insertion irrespective of neutral or cationic pathways for both P(tBu)3 and xantphos. Such selectivity results from the unconventional proton-like hydrogen of the Pd-H bond in alkene insertion transition states. For less bulky alkenes, aminolysis with P(tBu)3 shows low selectivity, while linear selectivity dominates in this stage with xantphos due to a stronger repulsion between xantphos and branched acyl ligands. It was further revealed that the less-mentioned CO concentration and solvents also influence the regioselectivity by adjusting the relative feasibilities of CO-involved steps and NH3 release from ammonium chloride, respectively. The presented double-regiodetermining-stages mechanistic model associated with the effects of ligands, CO concentration, and solvents well reproduced the experimental selectivity to prove its validity and illuminated new perspectives for the regioselectivity control of HAC reactions.