Remarkable Reactivity Differences between Glucosides with Identical Leaving Groups

Two isomeric aryl
2-deoxy-2-fluoro-β-glucosides react with
a β-glucosidase at rates differing by 106-fold, despite
the fact that they release the same aromatic aglycone. In contrast,
the equivalent glucoside substrates react with essentially identical
rate constants. Insight into the source of these surprising rate differences
was obtained through a comprehensive study of the nonenzymatic (spontaneous)
hydrolysis of these same substrates, wherein an approximate 105-fold difference in rates was measured, clarifying that the
differences were inherent rather than being due to specific interactions
with the enzyme. The possibility that an alternate nucleophilic aryl
substitution mechanism was responsible for the rapid reaction of the
faster substrate was excluded through 18O-labeling studies.
Further exploration of the origins of these rate differences involved
analysis of X-ray crystal structures as well as quantum chemical calculations,
which surprisingly revealed that ground state destabilization and
transition state stabilizing effects contribute almost equally to
the observed reactivity differences. These studies highlight the dangers
of using simple reference equilibria such as pKa values as measures of leaving group ability.