QM/MM simulations for Diels-Alder reactions in water: Contribution of enhanced hydrogen bonding at the transition state to the solvent effect

Free energy profiles for Diels-Alder reactions of cyclopentadiene with acrylonitrile, methyl vinyl ketone, and 1,4-naphthoquinone have been computed in the gas phase and in aqueous solution using Monte Carlo simulations in a fully automated, mixed quantum and molecular mechanics (QM/MM) approach. The QM/MM calculations in water featured AM I treatment for the solute in the presence of 500 TIP4P water molecules, and computation of solute-water interactions using scaled CM1A charges for the solute. Free energy perturbation calculations yielded the profiles along a reaction coordinate with all other degrees of freedom sampled. The free energies of activation are reduced on going from the gas phase to water by 1.5, 2.8, and 4.4 kcal/mol for the reactions with acrylonitrile, methyl vinyl ketone, and naphthoquinone, respectively. These values are in good agreement with the corresponding experimental results for transfer from hydrocarbon solvents to water (2.1, 3.8, and 5.0 kcal/mol). The cycloadducts are stabilized less effectively than the transition states by water in all three cases. Therefore, the retro-Diels-Alder reactions are also predicted to be accelerated in water, in accord with related experimental data. These results and consideration of variations in solvent-accessible surface area (SASA) confirm that the rate increases in water arise in part from hydrophobic association of the reactants, but predominantly from enhanced hydrogen bonding between water molecules and the polarized transition states.