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

James Stivers, Michael W. Washabaugh

Research output: Contribution to journalArticle

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 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
Volume19
Issue number4
DOIs
StatePublished - 1991

Fingerprint

Proton transfer
Protons
Buffers
Acids
Catalysis
Rate constants
Isotopes
Amines
Ions
Oxygen
Thiamine Pyrophosphate
Protonation
Equilibrium constants
Ionic strength
Halogenation
Osmolar Concentration
Kinetics
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery

Cite this

Normal acid behavior for C(α)-proton transfer from a thiazolium lon. / Stivers, James; Washabaugh, Michael W.

In: Bioorganic Chemistry, Vol. 19, No. 4, 1991, p. 369-383.

Research output: Contribution to journalArticle

Stivers, James ; Washabaugh, Michael W. / Normal acid behavior for C(α)-proton transfer from a thiazolium lon. In: Bioorganic Chemistry. 1991 ; Vol. 19, No. 4. pp. 369-383.
@article{9a6e6270ec7a468fa581654353742c54,
title = "Normal acid behavior for C(α)-proton transfer from a thiazolium lon",
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 m in H2O. Thermodynamically unfavorable C(α)-proton transfer to oxygen-containing and amine bases shows general base catalysis with a Br{\o}nsted β value of ≥0.92 for bases of pKa′ ≤ 15; this indicates that the thermodynamically favorable protonation reaction in the reverse direction has a Br{\o}nsted 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 Br{\o}nsted 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.",
author = "James Stivers and Washabaugh, {Michael W.}",
year = "1991",
doi = "10.1016/0045-2068(91)90020-P",
language = "English (US)",
volume = "19",
pages = "369--383",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Normal acid behavior for C(α)-proton transfer from a thiazolium lon

AU - Stivers, James

AU - Washabaugh, Michael W.

PY - 1991

Y1 - 1991

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.

UR - http://www.scopus.com/inward/record.url?scp=0008307403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0008307403&partnerID=8YFLogxK

U2 - 10.1016/0045-2068(91)90020-P

DO - 10.1016/0045-2068(91)90020-P

M3 - Article

AN - SCOPUS:0008307403

VL - 19

SP - 369

EP - 383

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

IS - 4

ER -