Demystifying Solvent Effects on Diels-Alder Reactions in Pure and Mixed Solvents: A Combined Electronic DFT and QM/MM Study

Although solvent effects on chemical reactions in pure solvents are well elucidated, both reaction mechanisms and solvent effects in mixed solvents remain poorly understood. Herein, the free energy profiles and the solute-solvent energy pair distribution of the Diels-Alder reaction in pure water, acetonitrile (ACN), carbon tetrachloride (CTC), and their mixtures ACNwater and ACN-CTC are calculated using the quantum and molecular mechanical (QM/MM) Monte Carlo method. The results show that the presence of solvent can significantly reduce the reaction free energy barrier, and the barrier in the mixed solvent is intermediate between the two pure solvents. Additionally, the free energy decomposition analysis demonstrated that the QM region dominates the reaction free energy. Electronic DFT calculations are employed to delineate the interactions between reactants and solvent molecules in pure and mixed solvents, with a particular focus on the role of electrostatic potential characteristics and an independent gradient model based on Hirshfeld partition. By rigorously analyzing these interactions, this study demystifies the mechanism underlying the phenomenon of preferential solvation and competition for reacting sites in mixed solvents, which alters the microenvironment of the solute.

Automated summary

This study calculates the free energy profiles and solute-solvent energy pair distribution of the Diels-Alder reaction in pure solvents and mixed solvents using the QM/MM Monte Carlo method. The presence of solvent lowers the reaction free energy barrier, with the barrier in the mixed solvent being intermediate between the two pure solvents. The study also investigates the interactions between reactants and solvent molecules in pure and mixed solvents, providing insights into preferential solvation and competition for reacting sites.