Insight into the Mechanism and Regioselectivity of Pd(OAc)2-Catalyzed C-O Bond Activation via a β-O Elimination Approach: A Computational Study

The density functional theory investigations were carried out to elucidate the mechanism and the origin of regioselectivity for the Pd(OAc)(2)-catalyzed carbon-oxygen bond activation in the reaction between 4-phenoxy-N-(quinolin-8-yl) butanamide and N-methylindole. The reaction proceeded through four main stages in succession: C-H activation, beta-O elimination, nucleo-palladation of the new C-C bond formation, and proto-depalladation steps. A total of six pathways were considered since there were two possible forms of C-O bond breaking in the beta-O elimination step and six reaction channels of nucleophilic attack in the crucial nucleo-palladation step. The computational results indicate that the common first step (C-H bond activation step) occurs via a concerted metalation deprotonation (CMD) mechanism. The nucleo-palladation was the rate-determining step for all six reaction pathways. The results also show that the most favorable pathway for the whole reaction is the one (denoted as path b1) in which phenol was removed in the second stage and the hydrogen atom of N-methylindole attacked the oxygen atom of acetate group of the intermediate in the third stage. According to the analyses of noncovalent interaction (NCI) and the reduced density gradient (RDG), the most favored pathway benefits from the strong attractive interaction and weak repulsive interaction in its key transition state. Furthermore, structural, natural bond orbital charge, and energy analyses of the transition states reveal the origin of the regioselectivity. This is a good explanation of the experimental phenomenon and benefits future design of a new strategy for a similar reaction.