Theoretical foundation for the presence of oxacarbenium ions in chemical glycoside synthesis.

Glycoside formation in organic synthesis is believed to occur along a reaction path involving an activated glycosyl donor with a covalent bond between the glycosyl moiety and the leaving group, followed by formation of contact ion pairs with the glycosyl moiety loosely bound to the leaving group, and eventually solvent-separated ion pairs with the glycosyl moiety and the leaving group being separated by solvent molecules. However, these ion pairs have never been experimentally observed. This study investigates the formation of the ion pairs from a covalent intermediate, 2,3,4,6-tetra-O-methyl-α-d-glucopyranosyl triflate, by means of computational chemistry. Geometry optimization of the ion pairs without solvent molecules resulted in re-formation of the covalent α- and β-triflates but was successful when four solvent (dichloromethane) molecules were taken into account. The DFT(M06-2X) computations indicated interconversion between the α- and β-covalent intermediates via the α- and β-contact ion pairs and the solvent-separated ion pairs. The calculated activation Gibbs energy of this interconversion was quite small (10.4-13.5 kcal/mol). Conformational analyses of the ion pairs indicated that the oxacarbenium ion adopts (4)H3, (2)H3/E3, (2)H3/(2)S0, E3, (2,5)B, and B2,5 pyranosyl ring conformations, with the stability of the conformers being strongly dependent on the relative location of the counteranion.