The present study reveals an unexpected anomaly observed in the acid-catalyzed hydrolysis of the 5,6-O-isopropylidene group in 3-O-protected D-gluco- and D-allofuranose derivatives. Although the removal of the 5,6-O-isopropylidene protecting group is typically rapid and quantitative under acidic conditions, an unexpected inhibition of this reaction is observed for the two C3-epimers, 3-O-imidazole sulfonyl moiety. X-ray data show a two-faced imidazole ring orientation in the crystal, while solution state NOE data reveal a critical interaction type between the isopropylidene and the imidazole rings. Advanced conformational searches coupled with ab initio molecular modeling illuminate and explain the NMR and kinetic data and lay the groundwork for the most plausible mechanism of this unprecedented inhibition. These results provide valuable insights into the cross-coupling of carbohydrate O-protecting groups and shed light on how specific ring orientations and steric effects can trigger the inhibition of an otherwise easily feasible reaction, such as an acid-catalyzed hydrolysis.