The simplest explanation is that the equatorial configuration has the dipoles involving both heteroatoms partially aligned, and therefore repelling each other. By contrast the axial configuration has these dipoles roughly opposing, thus representing a more stable and lower energy state.
In 1998, Box’s molecular modeling studies of saccharides, and analysis of crystallographic data of monosaccharides from the Cambridge Crystallographic Database, using the molecular mechanics based program STR3DI32, resulted in a refinement of this dipolar hypothesis by showing that the dipolar repulsions originally suggested, above, were reinforced by stabilizing, and significant, C-H…O hydrogen bonds involving the acetal functional group.[3] More recent MO calculations are consistent with this hypothesis.[4] This more comprehensive analysis of the origins of the anomeric effect has also resulted in a better understanding of the related, and equally puzzling, reverse anomeric effect.[5]
An alternative and widely accepted explanation is that there is a stabilizing interaction (hyperconjugation) between the unshared electron pair on the one heteroatom (the endocyclic one in a sugar ring) and the ?* orbital for the axial (exocyclic) C–X bond. When the exocyclic (in a sugar) atom bears a lone pair of electrons there should also be a similar interaction between that unshared electron pair (of this exocyclic atom) and the ?* orbital of the annular C-O bond. This second interaction, which is a strong feature of the ?-anomer (equatorial exocyclic group), should significantly attenuate the anomeric effect. However, it is well known that when the exocyclic atoms bear lone pairs of electrons, the anomeric effect is maximal.
Some authors also question the validity of this model based on results from the theory of atoms in molecules.[6]
While most studies on the anomeric effects have been theoretical in nature, the n–?* hypothesis has also been extensively criticized on the basis that the electron density redistribution in acetals proposed by this hypothesis, is not congruent with the known experimental chemistry of acetals, and, in particular, the chemistry of monosaccharides.[7] [8]