Assessment of reactivities with explicit and implicit solvent models: QM/MM and gas-phase evaluation of three different Ag-catalysed furan ring formation routes

QM/MM molecular dynamics and static DFT calculations have been performed to evaluate free energy barriers and reaction free energies of a representative silver-catalyzed reaction in DMF. The mechanism developed in a previous work revealed a favorable intramolecular C-O coupling between terminal alkyne and beta-ketoester moieties to yield a furan ring and three possible pathways were scrutinized within the framework of the SMD implicit solvation model. In this study we set out to compare the effect of implicit and explicit solvation on the three possible variations of the furan ring-closure step. The three pathways feature different charge states with bonding topologies characteristic of many silver- and copper-catalyzed reaction steps; hence they can serve as a blueprint for assessing the effects of solvents in a wider set of reactions. Comparison of the results showed that both methodologies could unequivocally determine the most favorable as well as the least likely pathway. Further analysis of the trajectories obtained from the QM/MM simulations indicated neither direct solvent participation in the reaction nor any site-specific interaction of the solvent with the reactant despite the fact that pairwise interactions between the solutes and the highly polar solvent molecules are significant. These insights point to a sufficiently mobile, fluctuating solvent shell which can be efficiently substituted by implicit solvent models at a fraction of computational costs.