HERON reactions of anomeric amides: understanding the driving force

Calculations show that anomeric amides, amides bearing two electronegative atoms at the amide nitrogen, are unusual in structure and reactivity. They have much reduced amide resonance and also undergo the HERON reaction where anomeric destabilisation results in migration of one substituent from nitrogen to the carbonyl and formation of a resonance-stabilised nitrene. B3LYP/6-31G(d) calculations demonstrate how resonance and HERON reactivity are affected by bisalkoxyl substitution and aminoalkoxyl substitution at nitrogen. Because transition state structures for model reactions of N,N-dimethoxyacetamide and N-methoxy-N-dimethylaminoacetamide demonstrate complete loss of amide resonance, the overall barriers to their HERON reactions can be partitioned into a resonance (RE) and a rearrangement component (E-rearr). REs for both amides have been calculated by isodesmic methods (carbonyl substitution nitrogen atom replacement and a calibrated transamidation method), and the reduction in total electronegativity at the amide nitrogen in N-methoxy-N-dimethylaminoacetamide results in an increase in amide resonance of about 4kcalmol(-1) relative to N,N-dimethoxyacetamide (RE of 8.6kcalmol(-1)). However, there is a large decrease in E-rearr by some 20kcalmol(-1) to 10kcalmol(-1). Changes in these energies are rationalised on the basis of an increase in amide nitrogen lone pair energy, which increases resonance, and a higher energy substituent nitrogen lone pair enhancing the n(N)?sigma*(NO) anomeric effect and the ease of rearrangement. Intramolecular HERON reactions in twisted 1-aza-2-adamantanones, with no amide resonance, support the above variations in the rearrangement components to the activation barriers. On the strength of these findings, hydroxamic esters with only one oxygen at nitrogen will not undergo HERON reactions. Copyright (c) 2014 John Wiley & Sons, Ltd.