Anomeric amides, amides bearing two electronegative atoms at nitrogen, constitute a
new class of amides with reduced resonance and pyramidal nitrogens. N-Alkoxy-Naminoamides are known to undergo thermal rearrangements by the HERON (heteroatom
rearrangements on nitrogen) reaction. Thermal instability in several other species
including N-acyloxy-N-alkoxyamides and N,N-dialkoxyamides, had been noted.
Consequently, the thermal decomposition of N-acetoxy-N-(4-substitutedbenzyloxy)benzamides were examined by GC-MS, 1H NMR and 13C NMR. It was found
that they decompose at 90 °C in [D8]-toluene by competing homolytic and HERON
reaction pathways. Homolysis of the anomerically weakened N–OAc bond ultimately
leads to (5H)-1,4,2-dioxazole species, while the HERON reaction by acyloxyl migration
leads to anhydrides and reactive alkoxynitrene intermediates, which undergo subsequent
intra- and intermolecular reactions under reaction conditions. The thermal
decompositions of acyclic N,N-dialkoxyamides were shown to decompose exclusively
by homolysis of an N–OR bond to form N-alkoxyamidyl radicals and alkoxyl radicals,
generating a range of products. On the other hand, alicyclic N,N-dialkoxyamides, such
as N-butoxy-δ-valerolactam, were observed to be unstable, undergoing HERON
reactions at room temperature.
Limited synthetic pathways for N,N-dialkoxyamides had been reported. A new,
convenient synthesis using hypervalent iodine reagents, PIFA and PIDA, was developed
and used to synthesise a range of acyclic and cyclic N,N-dialkoxyamides. Spectroscopic
data for all synthesised species are in line with X-ray diffraction and computed structures
of acyclic species, demonstrating highly pyramidal amide nitrogens (χN ≈ 55°) and
appreciable loss of amide character.
A new, widely applicable computational method to estimate resonance energy in a range
of amides has been developed. This transamidation (TA) method, which employs readily
computed ground-state energies and isodesmic equations, measures the resonance energy
and amidicity of a range of anomeric amide systems relative to N,N-dimethylacetamide
and demonstrated the loss of stabilising amide resonance energy in the N,Nbisheteroatom-substituted species. Amidicities of anomeric amides determined by the
TA method agree with results produced using the independent COSNAR (carbonyl
substitution nitrogen atom replacement) method. Both methods show a reduction in amidicity as the electron-withdrawing strength of N-substituents increases. Parsing
computationally modelled HERON reactions with these results, the activation barriers
were partitioned into a rearrangement component, describing the physical rearrangement,
and a resonance energy component, describing the residual amide resonance, which must
be overcome. Further, it was demonstrated that as a driving force for the HERON
reaction, reduction in amide resonance, though significant in certain anomeric amides
with strongly electron-withdrawing substituents, is subordinate to a strong anomeric
interaction.
To complete the series of investigations into properties of anomeric amides, N-alkylthiylsubstituted anomeric amides, an unusual and unexplored class, were investigated
computationally. Modelling of SNO, SNN, and SNCl systems suggest that these amides
would bear similar characteristics to other anomeric amides: anomeric interactions,
longer N–C(O) bonds, and pyramidalisation of the amide nitrogen in line with electronwithdrawing capabilities of the N-substituents. Modelled HERON reactions for these
amides had high activation barriers, similar to HERON-active ONOAc systems, but, like
acyclic ONO systems, the lack of a strong anomeric interaction would realistically
prohibit the HERON reaction.