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 AM1 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 stabili...