Retrograde aldol-type reactions involving thiamin in aqueous solution: Evidence for changes in transition-state structure

Abstract

Cleavage of racemic 2-(1-hydroxyethyl)- and 2-(1-hydroxyaryl)-3-R-4-methylthiazolium ions to the corresponding aldehyde and thiazolium ion in aqueous solution is catalyzed by oxygen-containing and amine buffer bases at 40°C and ionic strength 1.0 m (KCl). The buffer base-catalyzed reactions are formulated as general acid catalysis of the departure of thiazolium ion from the alcoholate anion of the substrate (general base catalysis of thiazolium ion attack on the aldehyde in the reverse direction). Brønsted α values decrease from 0.38 to 0.21 for general acid catalysis of the cleavage of (2-1-hydroxyethyl)-R-4-methylthiazolium ions (R = C 6F 5CH 2, 4-aminopyrimidinyl, Bzl). The decrease in α with decreasing p K a of C(2)-H in the leaving thiazolium ion is described by a positive interaction coefficient p xy′ = ∂α ∂ pK lg = 0.3 ± 0.1 . Brønsted α values increase from 0.39 (R′ = Ph) to 0.48 (R′ = 4-CF 3-Ph) for the corresponding reactions with 2-(HOCH(R′))thiamin. The increase in α as the carbon electrophile becomes less stable is described by a positive interaction coefficient p xy = sol∂α ∂σ para = 0.2 ± 0.1 . These positive interaction coefficients support a nonenforced concerted reaction mechanism with an important component of proton transfer in the transition state. Mechanistic implications for thiamin diphosphate-dependent enzymes are discussed.