Medium effects on the decarboxylation of a biotin model in pure and mixed solvents from QM/MM simulations.

The decarboxylation of imidazolidin-2-one-1-carboxylate anion 2 has been investigated via combined quantum and statistical mechanics methodology. Monte Carlo statistical mechanics simulations utilizing free-energy perturbation theory and PDDG/PM3 for the QM method yielded free-energy profiles for the reaction in water, methanol, acetonitrile, and mixed solvents. The results for free energies of activation are uniformly in close accord with experimental data and reflect large rate accelerations in progressing from protic to dipolar aprotic media. Structural and energetic analyses confirm that the rate retardation in protic solvents comes from loss of hydrogen bonding in progressing from the carboxylate anion 2 to the more charge-delocalized transition state (TS). The structure of the TS is found to be significantly affected by the reaction medium; it occurs at a 0.2-A shorter C-N separation in protic solvents than in acetonitrile. Characterization of the hydrogen bonding for 2 and the TS also provided insights for design of decarboxylase catalysts, namely, it is desirable to have three hydrogen-bond donating groups positioned to interact with the ureido oxygen along with two hydrogen-bond donors positioned to interact with the ureido nitrogen of the breaking C-N bond.