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

Abstract 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 NH 2 or via carbonyl oxygen with OH group generated for leaving NH 3 , 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.