Electrostatic acceleration of enolization in cationic ketones

Rate constants for the water, acetate, and hydroxide ion-catalyzed enolizations of the cationic ketones 2-acetyl-1-methylpyridinium ion (3) and 1-methyl-8-oxo-5,6,7,8-tetrahydroquinolinium ion (4) have been measured at 25 degrees C and compared with those reported for the enolization of 2-acetyl-3,4-dimethylthiazolium ion (2) (Halkides, C. J.; Frey, P. A.; Tobin, J. B. J. Am. Chem. Sec. 1993 115, 3332). For 3, k(H2O), k(OAc), and k(OH) are 1.32 +/- 0.21 s(-1), (2.82 +/- 0.95) x 10(-2) M(-1) s(-1), and 187 +/- 50 M(-1) s(-1), respectively. The corresponding values for 4 are 9.17 +/- 0.24) x 10(-2) s(-1), (4.32 +/- 0.18) x 10(-4) M(-1) s(-1) and 10.9 +/- 0.2 M(-1) s(-1), respectively. The values of pK(a) for 3 and 4 are 11.13 and 11.90, respectively, at 25 degrees C. The hydration equilibrium constant K-h for 3 is 0.084 +/- 0.004 at 25 degrees C. The correlation of hydration constants for ketones with sigma* (Greenzaid, P. Luz, Z.; Samuel, D. J. Am. Chem. Sec. 1967 89, 749) allow the hydration constants for 2 and 3 to be used in the estimation of sigma* values for the substituents. The sigma* values are 1.68 and 1.02 for 2-(N-methylthiazolium) and 2-(N-methylpyridinium), respectively. Use of the sigma* values to estimate the inductive effects of these substituents on the pK(a)s of 2 and 3 allows the inductive effects to be separated from the through-space electrostatic effects. The inductive effects re estimated to contribute 4.2- and 1.9-log units to lowering the pK(a)s of 2 and 3, respectively. From this and the measured pK(a) of 11.1 for 3, the through-space electrostatic contribution td lowering the pK(a) is 6.3-log units, or 8.6 kcal mol(-1) in free energy of enolate stabilization. Assuming the same through-space effect for 2, its pK(a) is estimated to be 8.8. Comparisons of these enolization rates and pK(a)s with those for ordinary methyl and benzyl ketones indicate that the 2-(N-methylpyridinium) substituent in 3 stabilizes the enolate by 11.2 kcal/mol in free energy, and about 8.6 kcal/mol of this can be attributed to through-space electrostatic stabilization. The through-space electrostatic component accounts for a 330-fold enhancement in k(OH) for 3 compared with a typical methyl ketone (pK(a) = 19.3 for acetone). The value of k(OH) for 2 is 1.1 x 10(6) times that for a typical methyl ketone (pK(a) = 19.3) and 70 times that for a neutral methyl ketone exhibiting the pK(a) of 8.8 estimated for 2. The through-space electrostatic effects on the enolate of 2 and the transition state for its formation account for a 2.3 x 10(4)-fold enhancement in the enolization rate. The remaining 47-fold rate-enhancement for 2 is attributed to inductive effects. The through-space electrostatic effects have important implications for enzymatic catalysis of enolization.