On the deprotonation of chlorothiazide

Abstract

Three alkali metal salt forms of the diuretic chlorothiazide (systematic name: 6-chloro-1,1-dioxo-2H-1,2,4-benzothiazine-7-sulfonamide, HCTZ) are described. When crystallized from aqueous solution, the Na and K salts, namely, poly[[μ-aqua-aqua(μ₃-6-chloro-1,1-dioxo-7-sulfamoyl-2H-1,2,4-benzothiadiazin-2-ido)sodium] hemihydrate], {[Na(C₇H₅ClN₃O₄S₂)(H₂O)₂]·0.5H₂O}_n, and poly[[diaqua(μ₅-6-chloro-1,1-dioxo-7-sulfamoyl-2H-1,2,4-benzothiadiazin-2-ido)potassium] hemihydrate], {[K(C₇H₅ClN₃O₄S₂)(H₂O)₂]·0.5H₂O}_n, are both found to have stoichiometry MCTZ·2.5H₂O, with CTZ deprotonated at a heterocyclic ring N atom. Both the stoichiometry and the deprotonation site are different to those described in previously published versions of these structures. The Cs salt form is found to be the monohydrate CsCTZ·H₂O, namely, poly[[aqua(μ₅-6-chloro-1,1-dioxo-7-sulfamoyl-2H-1,2,4-benzothiadiazin-2-ido)caesium], [Cs(C₇H₅ClN₃O₄S₂)(H₂O)]_n. As with the Na and K cognates, this structure is also deprotonated at the heterocyclic ring. NaCTZ is found to be a two-dimensional coordination polymer with bridges between Na centres formed by H₂O and SO₂ groups, and by links through the length of the coordinated CTZ anions. Water ligands in KCTZ and CsCTZ are terminal, rather than bridging between metal centres, but both compounds form structures where M-Cl interactions link two-dimensional motifs formed via M-O bonds (and in CsCTZ, M-N bonds) into three-dimensional coordination polymers.

Keywords: alkali metals; crystal structure; diuretic; pharmaceuticals; salt selection; sulfonamide.

Figure 1

Contents of the asymmetric unit of NaCTZ, expanded so as to show all metal-to-ligand coordination bonds. Note that here and elsewhere, non-H atoms are drawn as 50% probability ellipsoids and H atoms as small spheres of arbitrary size. See supporting information for full details of bonding contacts, including symmetry operations, for all structures.

Figure 2

Contents of the asymmetric unit of KCTZ, expanded so as to show all metal-to-ligand coordination bonds.

Figure 3

Contents of the asymmetric unit of CsCTZ, expanded so as to show all metal-to-ligand coordination bonds.

Figure 4

Detail of the coordination bonding in NaCTZ, showing one-dimensional chains with [NaONaO] and [NaOSO]₂ rings linked into a two-dimensional motif by CTZ anions bridging between the chains.

Figure 5

Packing structure of NaCTZ, viewed along the a axis and showing organic and inorganic layers alternating along the c direction.

Figure 6

Packing structure of KCTZ, viewed along the a axis and showing organic and inorganic layers alternating along the c direction.

Figure 7

Part of the structure of KCTZ, showing the two-dimensional coordination motif formed by Cs—O and Cs—N bonds. Cs—Cl and hy­dro­gen bonds link neighbouring motifs, along the c direction, into a three-dimensional network.