Potentials of Mean Force and Solvent Effects of the CN- + CH3X (X = F, Cl, Br, and I) Reactions by the N-Side Attack in Aqueous Solution

A combined multilevel quantum mechanics and molecular mechanics approach is performed to investigate the nucleophilic substitution reactions of CN- + CH3X (X = F, Cl, Br, and I) by the N-side attack in aqueous solution. The water molecules are treated microscopically using an explicit SPC/E model, and the potentials of mean force are characterized by both the DFT and CCSD(T) levels of theory for the solute. Calculations demonstrate that the shielding effect of the solvent reduces the nucleophile-substrate and substrate-leaving group interactions in solution, leading to stationary point structures that are quite different from those in the gas phase. The structure and charge evolution along the reaction paths reveal that the reaction is not only a synchronous bonding and bond-breaking Walden-inversion mechanism but also a synchronous charge transfer process. The activation barriers calculated at the CCSD(T) level of theory are 27.5 (F), 22.6 (Cl), 21.7 (Br), and 21.2 (I) kcal/mol, respectively, which are larger than the corresponding experimental values for the C-side attack. The polarization effect of water molecules causing solute polarization contributes to the activation barrier in the order of F > Cl > Br > I. The solvent energy contribution to the activation barrier is in the order of F < Cl < Br < I because the F leaving group has the most compact transition state structure and the I leaving group has the loosest transition state structure. As a result, the total contributions of the solvent effects to the activation barriers are 7.9 (F), 10.7 (Cl), 15.3 (Br), and 15.7 (I) kcal/mol. Our results show that the solvent effects have a significant influence on both the structure and the energetics of the N-side attack reactions in aqueous solution.