Catalysis of the deprotonation of β-keto esters by cyclodextrins

The rates of deprotonation of several β-keto esters in basic aqueous solution are elevated by α- and β-cyclodextrin (α- and β-CD). In most cases saturation kinetics are observed that indicate fairly strong binding of the esters to the CDs (K d = 0.22-11 mM); catalytic ratios (k c /k u ) are in the range 1.9-17. For esters of the form RCO-CH 2 COOEt with both α- and β-CD the values of K d and k c /k u show little sensitivity to the acyl group, RCO (R = Me, Et, Pr, i-Pr), and for 2-carboethoxycyclopentanone, a cyclic analogue, these parameters are similar. In contrast, for R-COCH 2 CO-OR′ (R = Me or Et; R′ = Me, Et, allyl) there is a marked dependence of the parameters on the alkoxyl group, OR′. These results suggest that the β-keto esters studied bind to the CDs with their alkoxyl groups in the CD cavity and that the catalysis ensues from the complexes thus formed. Variations in two other kinetic parameters, k 2 = k c /K d (substrate selectivity) and K TS = k u /k 2 (apparent constant for dissociation of CD from the transition state) support this interpretation. Apparent second-order rate constants for the reaction of the esters with neutral CD (k 2 = k c /K d ) are 1900-360 000 M −1 s −1 (at pH ≈ 10), whereas for hydroxide ion attack on ethyl acetoacetate k OH = 5500 M −1 s −1 . Assuming the pK a s of the CDs are 12.2 and 12.3, deprotonation of the esters by the CD anions has rate constants of 10 5 to 5 × 10 7 M −1 s −1 . Thus, binding of the β-keto esters in the CD cavities, adjacent to a basic oxyanion site, enhances the reactivity of the CD anions towards these weak carbon acids by at least 2-4 orders of magnitude.