THE REVERSE ANOMERIC EFFECT IN N-PYRANOSYLIMIDAZOLIDES - A MOLECULAR-ORBITAL STUDY

The reverse anomeric effect was defined by Lemieux to describe the obs ervation of an equatorial preference for quaternary ammonium substitue nts at the anomeric position of a pyranoid ring. This is contrary to t he predictions of the generalized anomeric effect. Subsequent redefini tions have extended the effect, but recently the very existence of the reverse anomeric effect has been questioned. Whereas previous computa tional studies have focussed on -NHR(2)(+) substituents, this paper us es AM1 and ab initio calculations (up to MP2/6-31G//RHF/6-31G*) on N- pyransoyl-imidazolides and a truncated model system to ascertain the e xistence, generality and cause of the reverse anomeric effect. Torsion al energy profiles, natural bond orbital (NBO) analysis and electrosta tic and solvation interactions have been calculated,for isomers of thr ee methoxy-methylimidazolides [CH(3)OCH(2)Im: unsubstituted (3), 2-flu oro(4) and 2-methyl (5) imidazoles]. The axial imidazolides are domina ted by two large counteracting contributions: stabilizing anomeric hyp erconjugation and destabilizing 1,3-diaxial steric effects. Comparable hyperconjugative and steric effects are greatly diminished in the equ atorial isomers. The conformational equilibria are thus very sensitive to small stabilizing electrostatic and hydrogen bonding interactions, which are evident in the protonated imidazolides and especially prono unced in the equatorial conformers. Imidazolides 3 and 4 show a shift in equilibrium on protonation towards the equatorial conformation comp atible with the presence of the reverse anomeric effect, but the same shift is not calculated for imidazolide 5. Furthermore, calculation of solvation energies suggests that any reverse anomeric effect may be d iminished or disappear an moving to more polar solvents. The data for imidazolide 3 are compatible with experimental data, but these calcula tions suggest that the reverse anomeric effect is not a general phenom enon even for quaternary ammonium substituents at an anomeric centre. The causes of the reverse anomeric effects observed in both 3 and 4 ar e stabilizing electrostatic interactions in the protonated equatorial conformers.