A computational study of the reaction mechanism involved in the fast cleavage of an unconstrained amide bond assisted by an amine intramolecular nucleophilic attack

In the present work, the fast amide bond cleavage of [3-((1R,5S,7s)-3-azabicyclo[3.3.1]nonane-7-carbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylic acid (bi-ATDO)], through an intramolecular nucleophilic attack of an amine group is evaluated. First, six possible peptide bond cleavage mechanisms, two of them including a water molecule, are described at the ωB97XD/6–311 + G(d,p)//MP2/6–311 + G(d,p) level of theory. The reaction consisting of an intramolecular nitrogen nucleophilic attack followed by a proton transfer and the amide bond cleavage is determined as the most favorable mechanism. The activation free energy computed for the latter is 20.5 kcal mol⁻¹, which agrees with the reported experimental result of 24.8 kcal mol⁻¹. Inclusion of a water molecule to assist the first step of the reaction results in an activation free energy increase of about 17 kcal mol⁻¹. All the steps in the most favorable mechanism are studied more in detail employing intrinsic reaction coordinate as well as the reaction force and reaction electronic flux analysis.