C(α)-proton transfer from thiazolium ions: Structure-reactivity correlations and the C(α)-H p Ka of 2-(1-hydroxyethyl)thiamin

Abstract

Rate constants for C(α)-proton transfer from racemic 2-(1-hydroxyethyl)thiamin (HET), 2-(1-hydroxyethyl)oxythiamin (oxy-HET), and several 2-(1-hydroxyethyl)-3- R-4-methylthiazolium ions catalyzed by H 2O, hydroxide ion, and various oxygen-containing and amine buffers in the pH range 2–9 were determined by iodination at 25°C and ionic strength 1.0 m in H 2O. Thermodynamically unfavorable C(α)-proton transfer from HET and oxy-HET shows general-base catalysis with a Brønsted β value of ≥0.9 and primary kinetic isotope effects of ( k H k D ) obsd = 1 . These results are consistent with diffusion-controlled proton transfer to and from the C(α) position of HET in aqueous solution and a very late, enamine-like transition state for thermodynamically unfavorable C(α)-proton transfer. General base catalysis is detectable because there is a negative deviation from this correlation by hydroxide ion. Values of p K a′ = 18.4 and 19.8 for the C(α)-proton of N(1′)-protonated HET and free HET, respectively, were calculated from the rate constants for catalysis by H 2O and buffer bases. Values of k −a = 2 × 10 10 and 3 × 10 9 m −1 s −1 were assumed for diffusion-controlled protonation of the C(α)-enamine in the reverse direction by H 3O + and buffer acids, respectively. The Hammett ϱ 1 value for C(α)-proton transfer catalyzed by hydroxide ion or phosphate dianion is 22 ± 3. The absence of a positive deviation of the rate constants for catalysis by phosphate dianion when R = Me or n-Pr from the correlation defined by bulky aryl substituents is inconsistent with significant steric inhibition of resonance in the enamine which affects the rate of C(α)-proton removal or the C(α)-H p K a ∼' value. The ≤15-fold positive deviations of the rate constants for catalysis by hydroxide ion from the correlation defined by bulky aryl substituents when R = Me > Et > n-Pr > i-Bu are attributed to a substituent-dependent “hydroxide ion anomaly.” Mechanistic implications for thiamin diphosphate-dependent enzymes are discussed.