Theoretical study of keto–enol tautomerism by quantum mechanical calculations (the QM/MC/FEP method)

Abstract

In this study, the tautomeric equilibrium between the keto and enol forms has been studied for five typical ketones and aldehydes: i‐butanal, acetaldehyde, acetone, acetylacetone, and dimedone. The level of theory used in the gas‐phase calculation was Becke, three‐parameter, Lee–Yang–Parr/6‐311G(d,p)//Becke, three‐parameter, Lee–Yang–Parr/6‐31G(d). The free energies of solvation were included in the calculation by using the free‐energy perturbation method based on Monte Carlo simulation, that is, the quantum mechanical/Monte Carlo/free‐energy perturbation method. Three different models, incorporating no‐water, one‐water, and two‐waters, were adopted. The results showed that in the gas phase the addition of water molecules to the reaction mechanism caused the activation barriers (ΔG‡gas) to decrease by half relative to the water‐free mechanism, but there was no effect on the relative difference in free energy, ΔGgas. The solvation effects (ΔGsol), based on quantum mechanical/Monte Carlo/free‐energy perturbation calculations, were added to those of the gas‐phase results of the one‐water and two‐waters models. The two‐waters model produced values that were very consistent with the experimental data for all of the tautomers. The differences in the relative Gibbs free energy (ΔGrxn) were less than 1.0 kcal mol–1. In summary, the inclusion of solvent molecules in gas‐phase calculations plays a very important role in producing results consistent with experimental data. Copyright © 2012 John Wiley & Sons, Ltd.