The ene reaction between 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) and tetramethylethylene has been investigated using QM/MM calculations in water, methanol, DMSO, and acetonitrile. The effects of solvation on the mechanism and rates of reaction are elucidated using two-dimensional potentials of mean force (PMF) simulations utilizing free-energy perturbation theory and Monte Carlo statistical mechanics. A new mechanism is proposed where direct formation of an open dipolar intermediate following the addition of PTAD to the alkene is rate-limiting and the pathway toward ene product is significantly dependent on the reaction medium. In protic solvents, the open dipolar intermediate may proceed directly to the ene product or reversibly form an aziridinium imide (AI) intermediate that does not participate in the reaction. However, in aprotic solvents the open intermediate is short-lived (<10-11 s) and the ene product forms via the AI intermediate. The calculated free energies of activation are in close agreement with those derived from experiment, e.g., DeltaG of 14.9 kcal/mol compared to 15.0 kcal/mol in acetonitrile. Density functional theory calculations at the (U)B3LYP/6-311++G(2d,p) level using the CPCM continuum solvent model were also carried out and confirmed a zwitterionic, and not diradical, open intermediate present in the reaction. Only the QM/MM methodology was able to accurately reproduce the experimental rates and differentiate between the protic and aprotic solvents. Solute-solvent interaction energies, radial distribution functions, and charges are analyzed and show that the major factor dictating the changes in reaction path is hydrogen bond stabilization of the charge separations spanning 2 to 4 atoms in the intermediates and transition states.