Explicit Solvation Matters: Performance of QM/MM Solvation Models in Nucleophilic Addition

Nucleophilic addition onto a carbonyl moiety is strongly affected by solvent, and correctly simulating this solvent effect is often beyond the capability of single-scale quantum mechanical (QM) models. This work explores multiscale approaches for the description of the reversible and highly solvent-sensitive nucleophilic Nl center dot center dot center dot C=O bond formation in an Me2N (CH2)(3)-CH=O molecule. In the first stage of this work, we rigorously compare and test four recent quantum mechanical/molecular mechanical (QM/MM) explicit solvation models, employing a QM description of water molecules in spherical regions around both the oxygen and the nitrogen atom of the solute. The accuracy of the models is benchmarked against a reference QM simulation, focusing on properties of the solvated Me2N-(CH2)(3)-CH=O molecule in its ring-closed form. In the second stage, we select one of the models (continuous adaptive QM/MM) and use it to obtain a reliable free energy profile for the Nl center dot center dot center dot C bond formation reaction. We find that the dual-sphere approach allows the model to accurately account for solvent reorganization along the entire reaction path. In contrast, a simple microsolvation model cannot adapt to the changing conditions and provides an incorrect description of the reaction process.