Absence of Reverse Anomeric Effect in Glycosylimidazoles

The so-called reverse anomeric effect is the preference of cationic substituents for the equatorial position on a pyranose ring, but it is not consistent with theories of molecular structure. To reinvestigate this, we have measured the N -protonation-induced shifts of the anomeric equilibrium in N -(glycopyranosyl)imidazoles and their tetra- O -acetyl derivatives 1 − 3 with high precision through an NMR titration method that is applicable to a mixture of α and β anomers. We find a ΔΔ G ° β → α that is almost always negative, corresponding to a greater preference for the axial position of a protonated imidazolyl group than of an unprotonated group. This preference counters a small steric effect, arising from hindrance to ionic solvation, that has been measured independently in N -(4- tert -butylcyclohexyl)imidazoles 4 . These results are exactly opposite to what is expected from the reverse anomeric effect. We conclude that there is no firm evidence for this effect.