Stereochemistry of intermediates in thiamine catalysis. I. Crystal structures of 2-(.alpha.-hydroxyethyl)-3,4-dimethylthiazolium bromide and DL-2-(.alpha.-hydroxyethyl)thiamine chloride hydrochloride

Abstract

The 2-(a-hydroxyethyl)-3,4-dimethylthiazolium ion is one of several models for 2-(a-hydroxyethyl)thiamine that were used in elucidating the mechanism of thiamine catalysis. The crystal structures of the title compounds were determined from X-ray diffraction data in order to (1) identify the characteristic steric features of the 2-(a-hydroxyethyl)thiazolium moiety and (2) examine the influence exerted on the thiamine structure when substituents of active intermediates are present at the C(2) position. Both structures were determined from diffractometer data using the 8-28 scan technique with Cu Ka radiation. The structures were refined by the fullmatrix least-squares method. The model compound crystalli5es in the monoclinic space group, P21/c, with unit cell parameters a = 9.771 ( 4 ) , b = 11.656 (3), c = 8.764 (2) A, p = 90.77 (4)O, and 2 = 4. The refinement of this structure converged to a conventional R factor of 0.049 over the 1439 independent observed reflections. The 2-(a-hydroxyethyl)thiamine chloride hydrochloride crystalgzes in the triclinic space group, PT, with unit cell parameters a = 12.811 (3), b = 10.749 (3), c = 7.108 (7) A, a = 108.43 (7), p = 99.05 (7), y = 96.02 (7)O, and 2 = 2. The refinement converged to a conventional R factor of 0.045 based on the 2823 observed reflections. A simple valence bond description of the resonance in the planar thiazolium ring is given which is consistent with the endocyclic bond lengths in both structures. It indicates that there is a partial positiye charge of = on the S atom. The observed intramolecular S . . .O interaction in both compounds, which is 0.4 A less than the normal van der Waals separation, provides evidence that the S bonds electrostatically with the unshared electrons on 0. The conformation of the 2-(a-hydroxyethyl) side chain appears to be strongly infiuenced by the S . e .O interaction. It is remarkably similar in the two compounds. The 0(2a)-C(2a)-C(2)-S(l) torsion angles agree to within 2.2O. The H(2)-0(2a>-C(2a)-C(2) torsion angles both deviate from 90' by less than 12' with the result that they both form a hydrogen bond which is nearly perpendicular to the plane of the thiazolium ring. The analysis of the thiamine derivative shows in addition that its conformation differs considerably from that of thiamine particularly with respect to the relative orientation of the pyrimidine and thiazolium rings. These conformational differences explain the reported shifts in the nmr spectra for these compounds in aqueous solution. On the basis of structural and spectral data, the thiamine and the 2-(a-hydroxyethyl)thiamine molecules may reasonably be expected to assume preferred conformations in aqueous solution closely resembling those in the solid state.uestions concerning details in the three-dimensional Q structure of 2-(a-hydroxyethyl)thiamine (1) have been raised in several papers dealing with the mechanism of thiamine c a t a l y s i~.~-~ In particular, the discussions on possible mechanistic roles for the 4'amino group have lead directly to specu...

Structure of thiamin dinitrate

“…The interaction between S and negative ions or electronegative atoms has been observed in a number of other thiamin structures and it has been suggested to have mechanistic importance in C(2)-substituted thiamin (Sax, Pulsinelli & Pletcher, 1974 …”

The crystal and molecular structure of thiamine iodide hydroiodide

“…Thiamine hydrochloride was the first thiamine compound whose X-ray crystal structure was solved (4). In the ensuing years, the number of reported structures of thiamine compounds has risen, but only two different conformations have been observed for these compounds (5)(6)(7)(8)(9)(10)(11)(12)(13) bThe expression for the anisotropic temperature factor is Ti = exp ( -@ i i h 2 -pz2k2 -@ 3 j l z -@j2/th…”

The crystal structure of 2,7-dimethylthiachromine-8-ethanol dihydrate

“…The angles, C(17)-O(18)-..S(1) at 85 ° and S(1)... O(18)... H(192) at 80 ° , indicate that the lone-pair electrons on O(18) are favorably disposed geometrically for coulombic interaction with sulfur and for hydrogen bonding with H(192). This S...O interaction involving O(18), the fl-hydroxy oxygen, has not been observed in any of the other thiamine structures (Kraut & Reed, 1962;Karle & Britts, 1966;Carlisle & Cook, 1969;Pletcher, Sax, Sengupta, Chu & Yoo, 1972;Sax, Pulsinelli & Pletcher, 1974) although it is a characteristic feature of the ~-hydroxy oxygen in the 2-(c¢-hydroxyethyl)thiamine derivatives (Sax, Pulsinelli & Pletcher, 1974). In thiamine compounds the torsion angle defined by S(1)-C(5)-C(16)-C(17) is characteristically observed near 90 ° which prevents any intramolecular interaction with the ring sulfur regardless of the torsion angle for C(5)-C(16)-C(17)-O(18).…”

“…The resonance in thiochrome which imparts thiazolium character to the five-membered ring results characteristically in placing approximately half of the residual po3itive charge in the ring on the sulfur (Sax, Pulsinelli & Pletcher, 1974). Indeed in many crystal structures negative ions or neighboring oxygen atoms are located closer to the thiazolium sulfur atom than would be predicted from the van der Waals separation.…”