DFT approach to reaction mechanisms through molecular complexes. The case of an organo-catalysed nucleosidation reaction

The treatment of 3,5-di-O-benzyl-α-d-xylo-furanose 1,2-thiocarbonate with O,O′-bis(trimethylsilyl)uracil (persilylated nucleobase) under organo-catalytic conditions irreversibly leads to the corresponding β-nucleoside derivative in a highly stereoselective manner. The proposed mechanism for such a reaction has been supported by density functional theory (DFT) calculations. Two different functionals (B3LYP and M05) with two different basis sets [6-31G∗ and 6-311+G(d,p)] have been applied in order to evaluate their influence on the energetics of the molecular complexes formed along the reaction coordinate, finding that the incorporation of diffuse functions for sulphur and polarisation functions for hydrogen atoms are crucial for a lower energy profile. The use of M05 also offered lower transition states and intermediates, although its influence is somewhat smaller than that observed for the change in the basis set. The mechanism has been formulated on the basis of the establishment of molecular associations of progressively higher order (namely bi-, tri-, and tetramolecular complexes) along the reaction coordinate. This approach constitutes a new methodology in the conception of chemical mechanisms and could be of general application in all-chemical reactions.