The epimerisation of 2-tetrahydropyranol catalysed by the tautomeric couples 2-pyridone/2-hydroxypyridine and formamide/formamidic acid as a model for the sugar's mutarotation: a theoretical study

Abstract

In the present computational study a complete reaction mechanism for the sugar's mutarotation promoted by tautomeric catalysts in vacuum is outlined. The rate determining step of the process consists in the breaking of the C–O bond of the sugar ring which occurs by a concerted double proton transfer between the substrate and the catalyst. After ring opening, the –CHO group of the substrate rotates around the C2–C3 bond without dissociation of the substrate–catalyst adduct. The activation energy of this step is generally less than 8–9 kcal mol−1. Alternative reaction paths which require the dissociation of the substrate–catalyst complex are less favourable for both probability and energetic reasons. When the mutarotation is catalysed by the 2-pyridone/2-hydroxypyridine (PD/HP) tautomeric couple, the process may be promoted by either PD or HP derived from the dissociation of the (PD)2, (HP)2 or PD–HP dimers. According to B3LYP and MP4 (SDQ) calculations the HP-promoted reaction path should be faster than the PD-promoted one. When the process is catalysed by the formamide/formamidic acid (F/FA) tautomeric couple, the reaction path promoted by FA, which is derived from the dissociation of the F–FA dimer, should be the most favourable, according to B3LYP, MP2 and MP4(SDQ) calculations. Solvent effects in benzene, calculated by the PCM method, did not affect to a relevant extent the mechanism outlined in vacuum. The present study suggests, differing from the hypothesis formulated in many experimental studies, that the sugar's mutarotation process is more efficiently catalysed by the less stable tautomer or catalyst dimer rather than by the more stable one of both the PD/HP and F/FA couples.