Modelling the hydrolysis of succinimide: formation of aspartate and reversible isomerization of aspartic acidviasuccinimide

Abstract

In the present study, we have modelled the nucleophilic attack of water and a hydroxyl anion on the carbonyl carbon of a succinimide derivative leading to aspartate and aspartic acid. Calculations have been carried out at the B3LYP/6-31+G* level in a vacuum. The IEF–PCM methodology has been used to carry out single point calculations in solution. In neutral medium, hydrolysis is facilitated by the presence of a polar continuum, whereas in basic medium the polar environment hinders the hydrolysis of succinimide. The ΔH° and ΔS° values for the cyclization reactions of aspartic acid yielding succinimide are 29.2 kJ mol⁻¹ and 133.5 kJ mol⁻¹ K⁻¹ respectively in accordance with the experimental results on the isomerization of the Ac–Asp–Gly–NHMe dipeptide unit. In a neutral medium, the isoaspartate : aspartate is found to be 2.2 : 1 in a vacuum and 3.4 : 1 in solution, in line with the experimental findings based on the hydrolysis of a tetrapeptide (Ac–Gly–Asn–Gly–Gly–NHMe) and a hexapeptide (Val–Tyr–Pro–Asn–Gly–Ala) where this ratio was found to be 3.1 : 1.