“…Glycosylation reactions, however, have long been depicted mostly as S N 1 reactions proceeding through intermediate oxocarbenium ions with the obligatory counterions considered as mere spectators and so typically omitted from reaction schemes. As we have discussed elsewhere, this viewpoint is no longer sustainable in the light of the current physical organic record. − , In brief, glycosyl oxocarbenium ions are highly destabilized by the presence of multiple electron-withdrawing C–O bonds to the extent that they might be considered borderline “superelectrophiles” ,,, and have yet to be observed spectroscopically, with the exception of the 2-deoxy and 2-deoxy-2-bromo pyranose series lacking the C–O bond at the 2-position even in superacid media. − On the other hand, the NMR spectra of many activated covalent glycosyl donors in solvents typically employed for glycosyl reactions have been reported in the literature, ,− with the continual addition of new examples. , Modern kinetic analyses of glycosylation reactions, including computational studies when conducted in the presence of the counterion, come down on the side of associative mechanisms. , The preponderance of evidence therefore suggests that typical homogeneous glycosylation reactions conducted in organic solution with rare exceptions − will hew to the S N 2 end of the mechanistic spectrum . On the basis of this understanding, we offer here a series of guidelines derived from first principles that are intended to help practitioners and nonpractitioners alike derive and execute O -glycosylation reactions with increased reproducibility.…”