The role of substituents in the HERON reaction of anomeric amides

Anomeric amides, RCON(X)(Y), have two electronegative atoms at the amide nitrogen, a configuration that results in greatly reduced amide resonance and strongly pyramidal nitrogen atoms. This, combined with facilitation of anomeric interactions, can result in the HERON reaction, an intramolecular migration of the more electronegative atom, X, from nitrogen to the carbonyl with production of a Y-stabilised nitrene. We have modelled, at the B3LYP/6-31G(d) level, a variety of anomeric amides that undergo the HERON reaction to determine factors that underpin the process. The overriding driving force is anomeric destabilisation of the bond to the migrating group. Rotated transition states show loss of residual resonance and this is a component of the overall activation energies. However, the reduced resonance in these systems plays only a minor role. We have determined the resonance energies (RE) and HERON activation barriers (E-A) of five anomeric systems. REs for the amides have been calculated isodesmically using our calibrated trans amidation method and COSNAR calculations. Reduction of their overall E(A)s by the corresponding RE gives rearrangement energies (E-rearr.), a measure of relative impact on rearrangement of substituents on nitrogen. In CH3CON(OMe)(Y) systems producing (CH3CO2Me + NY), a loosely bound electron pair on the donor atom, Y, in n(Y)-sigma*(NOMe) anomeric interactions drives the reaction. Erearr. increases in the sequence Y = N(nitrene) < O-(oxide) << NMe2 < SMe << OMe. For the same systems, RE increases in the order Y = N < O- << OMe << NMe2 similar to SMe. Other effects such as molecular conformation, nature of the migrating group, X, and acyl substituents at the carbonyl carbon are discussed.