molecules Review Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides Stephen A. Glover * and Adam A. Rosser Department of Chemistry, School of Science and Technology, University of New England, Armidale, NSW 2351, Australia;
[email protected] * Correspondence:
[email protected] Received: 6 October 2018; Accepted: 24 October 2018; Published: 31 October 2018 Abstract: This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain configurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangement On Nitrogen) reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond, to generate acyl derivatives and heteroatom-substituted nitrenes. In other cases the anomeric effect facilitates SN1 and SN2 reactivity at the amide nitrogen. Keywords: amide resonance; anomeric effect; HERON reaction; pyramidal amides; physical organic chemistry; reaction mechanism 1. Introduction Amides are prevalent in a range of molecules such as peptides, proteins, lactams, and many synthetic polymers [1]. Generically, they are composed of both a carbonyl and an amino functional group, joined by a single bond between the carbon and nitrogen. The contemporary understanding of the resonance interaction between the nitrogen and the carbonyl in amides is that of an interaction between the lowest unoccupied molecular orbital (LUMO) of the carbonyl, π*C=O, and the highest occupied molecular orbital (HOMO) of the amide nitrogen (N2pz) (Figure1).