Theoretical study of a nucleophilic addition reaction in the gas phase and in aqueous solution: peptide bond hydrolysis

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Nucleophilic addition of hydroxide anion to N, N-dimethyl acetamide in the gas phase and in solution was elucidated using a combination of ab initio molecular orbital theory and self-consistent reaction field model. The gas phase reaction is exothermic, with a tetrahedral adduct being the product. An ion-dipole complex formed between hydroxide and N, N-dimethyl acetamide, of comparable stability to the tetrahedral adduct, was located on the potential energy surface. There is a considerable potential energy barrier separating the ion-dipole complex and the tetrahedral adduct in the gas phase. However, in aqueous solution, the ion-dipole complex disappears as a minimum. The calculated free energy barriers in solution at the HF/6–31+G ∗∗ level of theory are 27.7 and 7.4 kcal mol −1 for the forward and reverse reactions respectively; the corresponding experimental values, according to Guthrie's analysis, are 24.6 and 5.8 kcal mol −1. In view of the previous difficulties in reproducing experimental free energy barriers in solution for nucleophilic addition of hydroxide to formaldehyde, the present study has clearly demonstrated the potential of the ab initio self-consistent reaction field approach to study chemical reactions in solution. The effects of geometry relaxation on calculated free energy barriers have also been evaluated.