Mechanism of Hydroxylamine Hydrochloride-Catalyzed Transamidation: Covalent Catalysis over Hydrogen Bonding

Transamidation of acetamide with primary methylamine and benzylamine for secondary amide formation has been examined at the M06-2X(SMD)/6-311++G(2df,2p)//M06-2X(SMD)/6-31+G(d) level. Two alternative mechanisms are taken into account involving non-covalent catalysis by hydrogen-bonding (Path I) and covalent catalysis via hydroxamic acid formation (Path II). In Path I, hydroxylamine hydrochloride activates acetamide through hydrogen bonding in favor of nucleophilic attack of methylamine/benzylamine, while in Path II the initial nucleophilic attack of hydroxylamine generates the intermediate hydroxamic acid for subsequent aminolysis. In Path I and Path II, N-path and O-path are considered, where proton shifts to NH2 or via carbonyl oxygen with OH group generated for leaving NH3, respectively. Our computational results manifest that Path II via O-path is more favorable with lower free energy barriers of 21.9 (ammonia-mediated), 22.7 (methylamine-mediated) and 23.0 kcal mol-1 (hydroxylamine-mediated) than Path I for methylamine as nucleophile. The ammonia-mediated Path II via O-path for benzylamine as nucleophile is still the most favorable pathway, with a free energy barrier of 22.1 kcal mol-1. The preference of Path II over Path I is rationalized by NBO analysis. Our theoretical results give useful insight to design more effective catalysts for activating the carboxamide in the future. Two alternative mechanisms are considered involving non-covalent catalysis by hydrogen-bonding (Path I) and covalent catalysis via hydroxamic acid formation (Path II) for the transamidation of acetamide and benzylamine. The ammonia-mediated Path II via O-path is the most favorable pathway, with a free energy barrier of 22.1 kcal mol-1 than Path I via N-path.image