Abstract
An interesting aspect of the ring-opening of thiamine and certain other thiazolium ions is the biphasic kinetics of the ring reclosure process. It has previously been proposed that the two amide rotamers of the ring-opened amidoenethiolates are responsible for the two kinetic processes. We have carried out Hartree-Fock and density functional theory calculations on a series of amidoenethiolates and their corresponding tetrahedral intermediates. The corrected gas phase energy difference of 14.6 kJ/mol between 1′c and 2′c supports the notion that the two rotamers can exist in solution in sufficient quantities to give rise to two kinetic processes. The major enethiolate conformer should cyclize more rapidly (after protonation) than the minor conformer in agreement with previous observations. The most stable tetrahedral intermediate has a geometry that suggests stabilization by the anomeric effect.
Highlights
Thiamine (Vitamin B1), or its pyrophosphate, has an important biochemical role as a cofactor in many enzymatic processes.[1]
The ring-closing reaction is considerably more complex; biphasic kinetics are observed.3,4a,4b,4n,4o,5 Earlier workers attributed the faster process to the formation of pseudobase4n or its N-protonated form4a,4b,5 and the slower process to its breakdown to the thiazolium ion
Amidoenethiolates a: R1 = R2 = R3 = H four stationary points could be obtained by carrying out optimizations of rotamers 1-4 restricted to planar symmetry, 1a and 2a were each found to possess one imaginary frequency at the Hartree-Fock level; they were not considered to be true minima on the potential surface
Summary
Thiamine (Vitamin B1), or its pyrophosphate, has an important biochemical role as a cofactor in many enzymatic processes.[1] Its key structural feature is a quaternary thiazolium ion, which is crucial to its catalytic functions. This ring and other thiazolium ions undergo reversible ringopening in aqueous solution.[2] This pH-dependent equilibrium (Scheme 1)[3] favours the quaternary ion (Q+) at low pH and the ring-opened enethiolate (ETh-) at high pH, with the pseudobase (To) being the logical intermediate.[2, 4] Over forty years of kinetic studies on this equilibrium have revealed the principal steps in the interconversion. Spectroscopic (UV and NMR) evidence[3] has been used to support the proposal that the two kinetic processes arise from the two amide conformers of the enethiol which show different propensity to cyclize
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