Unraveling the role of counter-cations in Pd-catalyzed carboxylic acid C–H activation

The counter-cation effect has been proved by experiments to be very crucial in the Pd-catalyzed C-H activation of carboxylic acid but its mechanism is still unclear. In this study, the reaction mechanism of the Pd-catalyzed mono-selective <i>β</i>-C(sp³)-H heteroarylation of free carboxylic acids was investigated by the density functional theory (DFT) method and the role of the counter-cation effect in this reaction was unveiled. Different from the general understanding that dimeric or trimeric palladium species are the most stable forms, the calculated results indicate that dimeric palladium species tend to dissociate into monomers under the assistance of counter-cations, and then form more stable <i>κ</i> ¹ coordination palladium species with carboxylic acids rather than <i>κ</i> ² coordination palladium species. This enables the Pd center to activate the target C-H bond effectively and successfully. In the following C-C coupling process, the Pd-Ag-K catalytic model was proposed, which could drive the C(sp³)-H (hetero)arylation of free carboxylic acids instead of the Pd-Ag synergistic model. The critical role of the base is to stabilize heterodimeric Pd(ii)-Ag(i) species. Moreover, this model successfully explains the origin of the mono-selective <i>β</i>-C(sp³)-H heteroarylation observed in experiments, in that the Pd(iv) species formed by the oxidative addition are too stable, thus preventing the reductive elimination in the second <i>β</i>-C(sp³)-H heteroarylation.