Substituent effects in the Nicholas epimerization of glycosides

The Nicholas reaction is a proven and versatile tool in glycoside chemistry. Its application is less clear‐cut, if the intermediate Nicholas cation has two reactive sides that enable different reactions. Density functional theory (DFT) calculations are used to rationalize the observed difference in product yields for the Nicholas epimerization and substitution obtained from experiments with very similar glycosides. Substituents, which can increase the rigidity of the backbone, should be avoided in epimerization reactions as they can slow down reorientation of the intramolecular ion pair so that the substitution reaction dominates.