Abstract
Rate constants in the pH range 3-9 for formation of the enethiolate product upon hydrolysis of N(1′)-unprotonated ("free") thiamin (1a), N(1′)-nethylthiamin (3), oxythiamine (4), and several 3-substituted-4-methylthiazolium ions in oxygen-containing and amine buffers have been determined by irreversible iodination of the enethiolate at 25°C and ionic strength 1.0 M in aqueous solution. General acid catalysis of the ring opening of 1a has a Brønsted α value of 0.57 and a solvent deuterium isotope effect of ( k H 2O / k D 2O ) BL + = 5.0 for catalysis by acetic acid. The Hammett ρ I value for catalysis by water or phosphate monoanion of the ring-opening reaction of 3-R-4-methylthiazolium ions is 12 ± 1 for substituents on the nitrogen atom of the thiazolium ring that cannot function as intramolecular catalysts. There is a 200- or 600-fold positive deviation of the rate constant for catalysis by water or phosphate monoanion, respectively, of the ring-opening reaction of 1a from the corresponding Hammett correlation which is absent when the N(3)-aminopyrimidinyl substituent is modified to make it unreactive as an intramolecular catalyst in 3 or 4. On the basis of an estimated "effective molarity" of ≥700 M for intramolecular catalysis of the ring-opening reaction by the exocyclic 4′-amino group, it is concluded that the N(3)-aminopyrimidinyl substituent of 1a provides significant intramolecular nucleophilic catalysis of nonenzymatic enethiolate formation in neutral aqueous solution. The general acid-catalyzed reaction of 1a is formulated as concerted general acid catalysis of departure of the enethiol from the neutral tricyclic amine addition campound (T N) derived from addition of the 4′-amino group to the C(2) position of the thiazolium ion. The water-catalyzed reaction of 1a is formulated as unassisted expulsion of the enethiolate from T N.
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