QM/MM investigation on 1,3-dipolar cycloadditions of the phthalazinium dicyanomethanide with three different dipolarophiles on water and in solution.

An "on water" environment, describing the reactions with insoluble reactants in water, has been reported to give high yields of products compared to organic solvents. The 1,3-dipolar cycloadditions of phthalazinium dicyanomethanide 1 with three different dipolarophiles, methyl vinyl ketone (MVK), methyl acrylate (MAC), and styrene (STY), have been investigated using QM/MM calculations in water, acetonitrile, and acetonitrile-water solvent mixtures, as well as at the vacuum-water interface. Monte Carlo statistical mechanics simulations utilizing the free-energy perturbation theory and PDDG/PM3 for the QM method have been used. The transition structures for all three reactions do not show large variations among different solvents. However, the calculated free energies of activation at the interface are found to be higher than those calculated in bulk water. Computed energy pair distributions and radial distribution functions reveal a uniform loss of hydrogen bonds for the reactants and transitions states in progressing from bulk water to the vacuum-water interface. The hydrophobic effects in the reactions of 1 with MVK and MAC are similar for both, and weaker than the effect in the reaction with STY. According to the results in water-acetonitrile mixtures at different molar ratios, it is clear that the special hydrogen bonding effects are the main reason which leads to the rapid rate enhancement in progressing from a water-acetonitrile molar ratio of 0.9 : 0.1 to pure water. New insights into solvent effects for 1,3-dipolar cycloadditions are presented herein.