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

Abstract:

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.