| Abstract: | Rate constants for C(α)-proton transfer from racemic 2-(1-hydroxyethyl)-3,4-dimethylthi-oazolium ion catalyzed by lyoxide ion and various oxygen-containing and amine buffers were determined by iodination at 25°C and ionic strength 1.0
in H2O. Thermodynamically unfavorable C(α)-proton transfer to oxygen-containing and amine bases shows general base catalysis with a Brønsted β value of ≥0.92 for bases of pKa′ ≤ 15; this indicates that the thermodynamically favorable protonation reaction in the reverse direction has a Brønsted α value ≤0.08, which is consistent with diffusion-controlled reprotonation of the C(α)-enamine by most acids. General base catalysis is detectable because there is an 85-fold negative deviation from the Brønsted correlation by hydroxide ion. Primary kinetic isotope effects of (kH/kD)obsd = 1.0 for thermodynamically unfavorable proton transfer to buffer bases and hydroxide ion (ΔpKa ≤ −6) and a secondary solvent isotope effect of kDO−/kHO− = 2.3 for C(α)-proton transfer are consistent with a very late, enamine-like transition state and rate-limiting diffusional separation of buffer acids from the C(α)-enamine in the rate-limiting step, as expected for a “normal” acid. The second-order rate constants for catalysis by buffer bases were used to calculate a pKa′ of 21.8 for the C(α)-proton assuming a rate constant of 3 × 109
−1 s−1 for the diffusion-controlled reprotonation of the C(α)-enamine by buffer acids in the reverse direction. It is concluded (i) that C(α)-proton removal occurs at the maximum possible rate for a given equilibrium constant, and (ii) that C(α)-enamines can have a significant lifetime in aqueous solution and on thiamin diphosphate-dependent enzymes. |
