Water-assisted enol-to-keto tautomerism of a simple peptide model: A computational investigation

Abstract

Computational investigations on the enol-to-keto tautomerism of N-methylacetamide (NMA), a simple peptide model, in water are performed by B3LYP and MP2 methods with the 6-311+G(d,p) and 6-311++G(2df,2pd) basis sets. Calculated results indicate that the enol/ trans form is less stable than the keto/ trans form both in the gas-phase and in water. The effects of solvent water are described using the combined supramolecular/continuum approach based on the SCRF/PCM model, in which one, two, and three water molecules are, respectively, used to assist this tautomerism of NMA. Two possible enol-to-keto tautomeric pathways are considered in this study. The first type of pathway is a stepwise process and characterized by the cis/ trans isomerization of the C–N bond. The second type of tautomeric pathway is a concerted mechanism that the hydrogen atom of the enol/ trans NMA migrates directly from O to N atom to form the stable keto/ trans structure. The results show that the rate-limiting step in the stepwise pathway is the enol/ trans-enol/ cis isomerization process where the transition state presents a linear conformation approximatively and the reaction energy barrier is little affected by the solvent. In the concerted pathway, at least three water molecules are needed to assist the proton transfer from O to N atom in NMA. It seems that the concerted process with the participation of three water molecules is the most favorable path for the enol-to-keto tautomerism of NMA, because its Gibbs free energy barrier of activation of 11.9 kcal/mol is lower than those of the other pathways.