The reverse anomeric effect in N-pyranosylimidazolides: A molecular orbital study

Stewart S.C. Chan, Walter A. Szarek, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


The reverse anomeric effect was defined by Lemieux to describe the observation of an equatorial preference for quaternary ammonium substituents at the anomeric position of a pyranoid ring. This is contrary to the predictions of the generalized anomeric effect. Subsequent redefinitions have extended the effect, but recently the very existence of the reverse anomeric effect has been questioned. Whereas previous computational studies have focussed on -NHR 2+ substituents, this paper uses AM1 and ab initio calculations (up to MP2/6-31G*/RHF/6-31G*) on N- pyranosylimidazolides and a truncated model system to ascertain the existence, generality and cause of the reverse anomeric effect. Torsional energy profiles, natural bond orbital (NBO) analysis and electrostatic and solvation interactions have been calculated for isomers of three methoxy-methylimidazolides [CH 3OCH2lm: unsubstituted (3), 2-fluoro (4) and 2-methyl (5) imidazoles]. The axial imidazolides are dominated by two large counteracting contributions: stabilizing anomeric hyperconjugation and destabilizing 1,3-diaxial steric effects. Comparable hyperconjugative and steric effects are greatly diminished in the equatorial 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 pronounced in the equatorial conformers. Imidazolides 3 and 4 show a shift in equilibrium on protonation towards the equatorial conformation compatible 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 diminished or disappear on moving to more polar solvents. The data for imidazolide 3 are compatible with experimental data, but these calculations suggest that the reverse anomeric effect is not a general phenomenon even for quaternary ammonium substituents at an anomeric centre. The causes of the reverse anomeric effects observed in both 3 and 4 are stabilizing electrostatic interactions in the protonated equatorial conformers.

Original languageEnglish (US)
Pages (from-to)45-60
Number of pages16
JournalJournal of the Chemical Society, Perkin Transactions 2
Issue number1
StatePublished - 1995
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry


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