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

Abstract

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, β-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 β-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.

DFT calculations in solution systems: solvation energy, dispersion energy and entropy

“…, the [3+2], [3+3] cycloaddition, 156–159 Hetero-Diels-Alder, 160 dehydrogenation/hydrogenation, 161–163 migratory insertion reactions of CO 2 , 164,165 olefin polymerizations, 166 C–O, C–F bond activation, 167,168 and C–C, C–X coupling reactions. 167,169 However, this entropy correction value is still ca. 2.0 kcal mol −1 less than that from the Trouton rule (6.3 kcal mol −1 ).…”

“…Martin introduced a correction factor from the gas-phase frequency calculation at elevated pressure (from 1 atm to 1354 atm) to consider the entropic contribution of the solvent; then, an entropy correction of 14.3 cal mol À1 K À1 was obtained for water solution, which translates to a free-energy contribution of 4.3 kcal mol À1 at room temperature. This correction method has been directly employed to calculate the free-energy profiles for the reactions in organic solutions, e.g., the [3+2], [3+3] cycloaddition, [156][157][158][159] Hetero-Diels-Alder, 160 dehydrogenation/hydrogenation, [161][162][163] migratory insertion reactions of CO 2 , 164,165 olefin polymerizations, 166 C-O, C-F bond activation, 167,168 and C-C, C-X coupling reactions. 167,169 However, this entropy correction value is still ca.…”

“…This correction method has been directly employed to calculate the free-energy profiles for the reactions in organic solutions, e.g., the [3+2], [3+3] cycloaddition, [156][157][158][159] Hetero-Diels-Alder, 160 dehydrogenation/hydrogenation, [161][162][163] migratory insertion reactions of CO 2 , 164,165 olefin polymerizations, 166 C-O, C-F bond activation, 167,168 and C-C, C-X coupling reactions. 167,169 However, this entropy correction value is still ca. 2.0 kcal mol À1 less than that from the Trouton rule (6.3 kcal mol À1 ).…”

Catalytic Addition of Nitroalkanes to Unactivated Alkenes via Directed Carbopalladation

“…Several low-energy conformers of the anti -carbopalladation transition state anti -TS1 were located (Figure S8), all of which feature coordinations of HFIP molecules to both the positively charged sodium cation and the iodide, where negative charge is building up during the carbopalladation event. These transition state structures are stabilized by dative bonds between Na and the oxygen atom on the HFIP and H···I hydrogen bond interactions between HFIP and the iodide . In the most stable conformer of anti -TS1 (Figure B), an electrostatic interaction between Na and I [ d (Na···I) = 3.34 Å] is observed, which further stabilizes the transition state.…”