Computational Exploration of Mechanistic Avenues in C-H Activation Assisted Pd-Catalyzed Carbonylative Coupling

The detailed mechanism of the intermolecular Pd-catalyzed carbonylative coupling reaction between aryl bromides and polyfluoroarenes relying on C(sp²)-H activation was investigated using state-of-the-art computational methods (SMD-B3LYP-D3(BJ)/BS2//B3LYP-D3/BS1). The mechanism unveils the necessary and important roles of a slight excess of carbon monoxide: acting as a ligand in the active catalyst state, participating as a reactant in the carbonylation process, and accelerating the final reductive elimination event. Importantly, the desired carbonylative coupling route follows the rate-limiting C-H activation process via the concerted metalation-deprotonation pathway, which is slightly more feasible than the decarboxylative route leading to byproduct formation by 1.2 kcal/mol. The analyses of the free energies indicate that the choice of base has a significant effect on the reaction mechanism and its energetics. The Cs₂CO₃ base guides the reaction toward the coupling route, whereas carbonate bases such as K₂CO₃ and Na₂CO₃ switch toward an undesired decarboxylative path. However, K₃PO₄ significantly reduces the C-H activation barrier over the decarboxylation reaction barrier and can act as a potential alternative base. The positional influence of a methoxy substituent in bromoanisole and different substituent effects in polyfluoroarenes were also considered. Our results show that different substituents impose significant impact on the desired carbonylative product formation energetics. Considering the influence of several ligands leads to the conclusion that other phosphine and N-heterocyclic carbene, such as P ⁿBuAd₂ and IMes, can be used as an efficient alternative than the experimentally reported P ^tBu₃ ligand exhibiting a clear preference for C-H activation (ΔΔ^⧧ G_L^S) by 7.1 and 10.9 kcal/mol, respectively. We have also utilized the energetic span model to interpret the experimental results. Moreover, to elucidate the origin of activation barriers, energy decomposition analysis calculations were accomplished for the critical transition states populating the energy profiles.