The rate of acetolysis of methyl 2,3,6-tri-O-methyl-R-D-galacto-and -glucopyranosides depends strongly on the electronegativity of the C4 substituent. Thus, of the three derivatives studied (4methoxy, 4-acetoxy, and 4-acetamido-4-deoxy derivatives of D-galacto-and D-glucopyranosides), the glycopyranosides bearing the most electronegative C4 substituent (methoxy group) acetolyze at the fastest rate, whereas those having the least electronegative C4 substituent (N-acetamido group) acetolyze at the slowest rate. Furthermore, whereas the influence of the electronegativity of the C4 substituent upon the acetolysis rate in the D-gluco series is relatively moderate (k max /k min ) 2.9-3.5), this influence is very large in the D-galacto series (k max /k min ) 44.4-58.6). We propose that this observation can only be explained by the existence of an electron donation process from the axially oriented electronegative substituent at the C4 carbon atom of the galactopyranoside ring to the forming oxocarbenium ion. Such a through-space phenomenon cannot occur in the glucopyranoside series where the C4 carbon substituent is oriented equatorially. Ab initio calculations of model molecules fully support the above conclusions.