QM/MC/FEP,solvent effect,cope elimination ,Kemp decarboxylation,synthesis route development

Abstract

We have been developing the QM/MC method, Monte Carlo simulation using quantum mechanical (QM) calculations in order to investigate solvent effects for chemical reactions. The simulation uses the QM calculations to obtain energies of ensembles. Although MC simulations using fully quantum mechanical calculations are free from classical parameters, it takes long CPU times to obtain energies with statistical meanings. We developed a program which calculates difference of free energy of salvation connected with free energy perturbation (FEP) calculations. Activation free energies in solutions can be calculated using the QM/MC/FEP method. We adopted he droplet model that includes a solute molecule in its center and have solvent molecules around the solute within a radius depending on the sides of solvent molecules. The solute has structures optimized using quantum mechanical calculations. The QM/MC(B3LYP/6-311++G**//MP2/6-31G*,PM3,PM3) calculation gave activation free energies included solvent effects to be 12.7, 13.8 and 15.2 kcal mol-1 in aqueous, methanol and propane solutions, respectively. These results indicate that the rate of the reaction in aqueous solution is much faster than that in propane and is consistent with the experimental data.