The Anomeric Effect: It's Complicated.

Abstract

The origin of the anomeric effect has been reexamined in a coordinated experimental and computational investigation. The results of these studies implicate a number of different, but correlated, interactions that in the aggregate are responsible for the anomeric effect. No single factor is uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. A CH···G nonbonded attraction between a polar axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle has been demonstrated experimentally. The hyperconjugation model involving electron transfer from a ring heteroatom to an excited state of an axial C-G bond was shown to be, at most, a minor contributor because of the very small changes in charge density at the ring heteroatom(s): the main charge transfer is from hydrogen to G in the H-C-G unit. This appears to result from lengthening the C-G bond to minimize repulsion with the ring atom lone pair(s) and the advantage of having a more positive hydrogen that leads to a stabilizing Coulombic interaction with the ring heteroatom(s). In short, the anomeric effect arises mainly from two separate CH···G nonbonded Coulombic attractions.