Steric effects in the uncatalyzed and DMAP-catalyzed acylation of alcohols-quantifying the window of opportunity in kinetic resolution experiments

The kinetics of the reaction of several alcohols (benzyl alcohol, ethanol, 1-phenylethanol, cyclohexanol, and 1-methyl-1-phenylethanol) with a selection of anhydrides (acetic anyhydride, propionic anhydride, isobutyric anhydride, isovaleric anhydride, and pivalic anhydride) as catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP)/triethyl amine have been studied in CH(2)Cl(2) at 20 degrees C. In all cases the reaction kinetics can be described by rate laws containing a DMAP-catalyzed term and an uncatalyzed (background) term. The rate constants for the background reaction respond sensitively to changes in the steric demand of the alcohol and the anhydride substrates, making the reaction of cyclohexanol with acetic anhydride 526 times faster than the reaction with pivalic anhydride. Steric effects are even larger for the catalyzed reaction and the reactivity difference between acetic and pivalic anhydride exceeds a factor of 8000 for the reaction of cyclohexanol. There is, however, no linear correlation between the steric effects on the catalyzed and the uncatalyzed part. As a consequence there are substrate combinations with dominating catalytic terms (such as the reaction of benzyl alcohol with isobutyric anhydride), while other substrate combinations (such as the reaction of cyclohexanol with pivalic anhydride) are characterized through a dominating background process. The implications of these findings for the kinetic resolution of alcohols are discussed.