TY - JOUR
T1 - C(α)-proton transfer from thiazolium ions
T2 - Structure-reactivity correlations and the C(α)-H pKa of 2-(1-hydroxyethyl)thiamin
AU - Stivers, James T.
AU - Washabaugh, Michael W.
N1 - Funding Information:
i This research was supported in part by grants from the National Institutes of Health (GM 42878). the American Cancer Society (JFRA-213). and a Biomedical Research Support Grant to The Johns Hopkins University (2S07RR05445). Support was provided for J.T.S. by a National Institutes of Health Training Grant (5T32ES07141). ? To whom correspondence should be addressed. 3 Abbreviations used: HET, 2-( I-hydroxyethyl)thiamin; HETDP, 2-(1-hydroxyethyl)thiamin diphosphate; oxy-HET, 2(1-hydroxyethyl)oxythiamin; TDP, thiamin diphosphate, Tris. 2-amino-2-(hydroxymethyl)-1,3-propanediol; PDC, pyruvate decarboxylase; MET, 2-(1-methoxyethyl)-3,Cdimethylthi-azolium ion; Me,SO. dimethyl sulfoxide.
PY - 1992/6
Y1 - 1992/6
N2 - 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 H2O, 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 H2O. 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 ( kH kD)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 pKa′ = 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 H2O and buffer bases. Values of k-a = 2 × 1010 and 3 × 109 m-1 s-1 were assumed for diffusion-controlled protonation of the C(α)-enamine in the reverse direction by H3O+ and buffer acids, respectively. The Hammett ρ{variant}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 pKa∼' 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.
AB - 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 H2O, 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 H2O. 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 ( kH kD)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 pKa′ = 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 H2O and buffer bases. Values of k-a = 2 × 1010 and 3 × 109 m-1 s-1 were assumed for diffusion-controlled protonation of the C(α)-enamine in the reverse direction by H3O+ and buffer acids, respectively. The Hammett ρ{variant}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 pKa∼' 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.
UR - https://www.scopus.com/pages/publications/0002077809
UR - https://www.scopus.com/pages/publications/0002077809#tab=citedBy
U2 - 10.1016/0045-2068(92)90036-3
DO - 10.1016/0045-2068(92)90036-3
M3 - Article
AN - SCOPUS:0002077809
SN - 0045-2068
VL - 20
SP - 155
EP - 172
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
IS - 2
ER -