Normal acid behavior for C(α)-proton transfer from a thiazolium lon

James T. Stivers, Michael W. Washabaugh

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)369-383
Number of pages15
JournalBioorganic Chemistry
Issue number4
StatePublished - Dec 1991

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry


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