TY - JOUR
T1 - Normal acid behavior for C(α)-proton transfer from a thiazolium lon
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 (2SO7RRO5445). Support was provided for J.T.S. by a National Institutes of Health Training Grant (5T32ES07141). Preliminary results were presented in abstract form at the Symposium on Hydrogen Transfer, 199th ACS National Meeting, Boston, MA, April 23-25, 1990. 2 To whom correspondence should be addressed. 369
PY - 1991/12
Y1 - 1991/12
N2 - 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 m 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 m-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.
AB - 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 m 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 m-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.
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U2 - 10.1016/0045-2068(91)90020-P
DO - 10.1016/0045-2068(91)90020-P
M3 - Article
AN - SCOPUS:0008307403
SN - 0045-2068
VL - 19
SP - 369
EP - 383
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
IS - 4
ER -