Preorganized Hydrogen Bond Donor Catalysts: Acidities and Reactivities

Measured DMSO pKa values for a series of rigid tricyclic adamantane-like triols containing 0-3 trifluoromethyl groups (i.e., 3(0)-3(3)) are reported. The three compounds with CF3 substituents are similar or more acidic than acetic acid (pKa = 13.5 (3(1)), 9.5 (3(2)), 7.3 (3(3)) vs 12.6 (HOAc)), and the resulting hydrogen bond network enables a remote γ-trifluoromethyl group to enhance the acidity as well as one located at the α-position. Catalytic abilities of 3(0)-3(3) were also examined. In a nonpolar environment a rate enhancement of up to 100-fold over flexible acyclic analogs was observed presumably due to an entropic advantage of the locked-in structure. Gas-phase acidities are found to correlate with the catalytic activity better than DMSO pKa values and appear to be a better measure of acidities in low dielectric constant media. These trends are reduced or reversed in polar solvents highlighting the importance of the reaction environment.