X-Ray Crystallography of Tetracycline, Doxycycline and Sancycline

Abstract The molecular and crystal structures of α-6-deoxy-β-5-oxytetracycline (doxycycline) hydrochloride, of tetracycline hydrochloride and tetracycline hexahydrate were re-determined. The crystal structures of 6-deoxy-6-dimethyl-tetracycline (sancycline) hydrochloride were, for the first time, de...
Ausführliche Beschreibung

Abstract The molecular and crystal structures of α-6-deoxy-β-5-oxytetracycline (doxycycline) hydrochloride, of tetracycline hydrochloride and tetracycline hexahydrate were re-determined. The crystal structures of 6-deoxy-6-dimethyl-tetracycline (sancycline) hydrochloride were, for the first time, determined by single crystal X-ray diffraction technique. All crystals studied exhibit the orthorhombic space group P$ 2_{1} %$ 2_{1} %$ 2_{1} $ with 4 molecules per unit cell. The starting material tetracycline (TC) hydrochloride crystallizes from aqueous solution, independently of the pH of the mother liquor, as hexahydrate complex of the zwitterion with the same molecular structure (a = 9.585(3) Å, b = 12.112(3) Å, c = 21.671(6) Å). From methanolic solution, tetracycline hydrochloride crystallizes as hydrochloride (a = 11.001(3) Å, b = 12.852(4) Å, c = 15.795(3) Å). Doxycycline hydrochloride crystallizes from acidic aqueous solution as dihydrate complex (a = 11.115(4) Å, b = 12.768(4) Å, c = 16.921(5) Å). In both hydrochloride crystals, the amide group is protonated and oriented such that an intramolecular hydrogen bond is formed between the amide oxygen and O3. In the tetracycline–hexahydrate crystal, the amide group of the zwitterion is rotated by about 180° (vs the cation) with a hydrogen bond being made by one hydrogen of its amino group and $ O3^{−} $. Sancycline hydrochloride crystallized from an acidified solvent mixture (water and methanol) adopts a geometry close to that of the tetracycline cation, e.g., with a hydrogen bond between the protonated amide oxygen and O3 (a = 6.8944(4) Å, b = 16.815(2) Å, c = 18.190(2) Å). But the dimethyl ammonium group of sancycline hydrochloride is disordered with respect to its orientation. In the majority fraction (65.9 %), the proton at N4 is directed towards O3, which has a water molecule next to it. In the minority fraction (34.1 %), the proton at N4 points away from O3 and has a methanol molecule in its neighborhood. The bond length variations in ring A of all compounds studied do not reflect the location of single and double bonds in any of the classical mesomeric structures. By comparison with calculated Wiberg-bond orders we show that this apparent discrepancy is not due to the existence of different tautomers in the crystals as discussed previously but merely a consequence of the π-conjugation in one tautomer. Graphical Abstract Although the packing of the three title compounds in the respective crystals is different, the geometries of the molecular framework are nearly the same as the one shown for the sancycline cation. A comparison of experimentally determined bond lengths with calculated Wiberg-Bond orders provides evidence that only one tautomer is present in the crystal.. Ausführliche Beschreibung

Autor*in:	Heinemann, Frank W. [verfasserIn] Leypold, Clemens F. [verfasserIn] Roman, Cyprian R. [verfasserIn] Schmitt, Matthias O. [verfasserIn] Schneider, Siegfried [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2013

Schlagwörter:	Molecular and crystal structures Tetracycline Doxycycline Sancycline Wiberg-bond order

Übergeordnetes Werk:	Enthalten in: Journal of chemical crystallography - Dordrecht [u.a.] : Springer Science + Business Media B.V, 1971, 43(2013), 4 vom: 09. März, Seite 213-222
Übergeordnetes Werk:	volume:43 ; year:2013 ; number:4 ; day:09 ; month:03 ; pages:213-222

Links:	Volltext

DOI / URN:	10.1007/s10870-013-0407-0

Katalog-ID:	SPR014214997