Terence L. Threlfall

Over one hundred solvates of sulfathiazole

The sulfadrug sulfathiazole forms an extensive family of solvates and adducts, the crystal structures of which show a large variety of hydrogen-bonded frameworks.

Describing hydrogen-bonded structures; topology graphs, nodal symbols and connectivity tables, exemplified by five polymorphs of each of sulfathiazole and sulfapyridine

AbstractBackgroundStructural systematics is the comparison of sets of chemically related crystal structures with the aim to establish and describe relevant similarities and relationships. An important topic in this context is the comparison of hydrogen-bonded structures (HBSs) and their representation by suitable descriptors.ResultsThree different description methods for HBSs are proposed, a graphical representation, a symbolic representation and connectivity tables. The most comprehensive description is provided by a modified graph of the underlying net topology of an HBS which contains information on the multiplicity of links, the directionality and chemical connectivity of hydrogen bonds and on symmetry relations. By contrast, the alternative symbolic representation is restricted to essential properties of an HBS, i.e. its dimensionality, topology type and selected connectivity characteristics of nodes. A comparison of their connectivity tables readily identifies differences and similarities between crystal structures with respect to the intermolecular interaction modes adopted by their functional groups. The application of these methods to the known polymorphs of sulfathiazole and sulfapyridine is demonstrated and it is shown that they enable the rationalisation of previously reported and intricate relationships.ConclusionsThe proposed methods facilitate the comprehensive description of the most important relevant aspects of an HBS, including its chemical connectivity, net topology and symmetry characteristics, and they represent a new way to recognise similarities and relationships in organic crystal structures. Graphical AbstractGraphical Representation of mixing of structures StzIV and StzV to give structure StzIII.

XPac dissimilarity parameters as quantitative descriptors of isostructurality: the case of fourteen 4,5′-substituted benzenesulfonamido-2-pyridines obtained by substituent interchange involving CF3/I/Br/Cl/F/Me/H

Crystal structures of fourteen 4,5′-substituted benzenesulfonamido-2-pyridines, with tautomeric forms R1–C6H4–SO2–NC5NH4–R2 or R1–C6H4–SO2–NH–C5NH3–R2, and with R1 = CF3, I, Br, Cl, Me, F, H and R2 = CF3 or I are reported. Comparisons carried out with the program XPac show that all investigated structures display a common 3D arrangement of N–H⋯N bonded centrosymmetric dimers. This isostructural series is exceptional in its completeness and in the diversity of the substituents involved. Accordingly, the XPac dissimilarity index x, a measure of how far two structures deviate from perfect geometrical similarity, varies from 0.9 for the interchange R1 = Br → Cl to 9.5 for the simultaneous interchange of R1 = I → H and R2 = CF3 → I. XPac plots of individual dissimilarity parameters have been used to elucidate details of geometrical similarities and differences between structures. This indicated that the geometry is preserved most closely within bc-layers that are composed of 1D slipped stacks of N–H⋯N bonded dimers, with interlayer van der Waals interactions being dominated by R1⋯R2 contacts. The main mode of geometrical adjustment for the size of R1 is a parallel shift of neighbouring layers against one another in the direction perpendicular to the layer plane, whilst the relative orientations of molecules within each layer are altered to a much smaller extent, even for those structure pairs representing R1 substituents that are very different in size. This study shows that the ability of two compounds to crystallise in fundamentally the same crystal structure depends not only on how much their molecules differ in shape but also, critically, on the specific tolerance characteristics of the crystal packing arrangement concerned. As a comparison with the present study, dissimilarity indices are reported for a set of 24 isostructural 4,4′-substituted benzenesulfonamidobenzenes previously subjected to XPac analysis.

A systematic study of the crystallisation products of a series of dicarboxylic acids with imidazole derivatives

Nineteen new crystal structures are reported containing α,ω-alkanedicarboxylic acids (HOOC–(CH2)n−2–COOH, n = 0–6), maleic acid and fumaric acid with imidazole, 1-methylimidazole, 2-methylimidazole, 4-methylimidazole and 1,2-dimethylimidazole. These were characterised by single crystal X-ray diffraction at 120 K and their crystal structures are discussed together with five published structures. In all of the characterised acid–base combinations at least one of the acidic hydrogens has been transferred to the base and most have a 1 : 1 stoichiometry. Nearly two thirds of the crystal structures adopt a basic sheet topology containing hydrogen bonded anion chains linked by cations. The sheet topologies have been classified based upon the principles of a scheme proposed by MacDonald et al. (J. C. MacDonald, P. C. Dorrestein and M. M. Pilley, Cryst. Growth Des., 2001, 1, 29–38).

A new polymorph of sulfathiazole

Crystals of sulfathiazole, 4-amino-N-thiazol-2-ylidenebenzenesulfonamide, C 9 H 9 N 3 O 2 S 2 , formed from boiling water are shown to be a fifth polymorph. The crystal structure contains two independent molecules, which associate through hydrogen bonds and van der Waals interactions to produce a two-dimensional sheet structure.

Polymorph VI of sulfapyridine: interpenetrating two- and three-dimensional hydrogen-bonded nets formed from two tautomeric forms.

Polymorph VI of 4-amino-N-(2-pyridyl)benzenesulfonamide, C(11)H(11)N(3)O(2)S, is monoclinic (space group P2(1)/n). The asymmetric unit contains two different tautomeric forms. The structure displays N-H...N and N-H...O hydrogen bonding. The two independent molecules form two separate two- and three-dimensional hydrogen-bonded networks which interpenetrate. The observed patterns of hydrogen bonding are analogous to those in polymorph I of sulfathiazole.

Further errors in polymorph identification: furosemide and finasteride

Reassessment of the reported single-crystal X-ray diffraction characterization of polymorphs of furosemide and finasteride shows that, in each case, incomplete data collections have resulted in the mistaken identification of two forms that are, in fact, identical.

Co-crystallisation of organic α,ω-dicarboxylic acids with the cyclic amides 2-pyrrolidinone and 2-imidazolidinone

Crystallisation of a selection of α,ω-alkanedicarboxylic acids (HOOC–(CH2)n–COOH, n = 0–6), maleic acid, fumaric acid, L-tartaric acid and DL-tartaric acid with 2-pyrrolidinone and 2-imidazolidinone yielded 11 new mixed systems which were shown to be co-crystals by single crystal X-ray diffraction at 120(2) K. The crystal structures are stabilised predominantly by amide–acid and amide–amide N–H⋯O hydrogen bonds and acid–amide O–H⋯O hydrogen bonds, but the synthons formed are not always as expected from the hydrogen bond hierarchy described by Etters rules (M. C. Etter, J. Phys. Chem., 1991, 95, 4601–4610). In the case of the 2-imidazolidinone and alkanediacid co-crystals, alternation in supramolecular structure is observed across the series.

A perspective on the growth-only zone, the secondary nucleation threshold and crystal size distribution in solution crystallisation

The metastable zone between the solubility curve and the crystallisation curve can be divided into two regions, separated by the secondary nucleation threshold. At a supersaturation less than that of the secondary nucleation threshold seeds will grow but not proliferate. At greater supersaturations, they will proliferate. Although this concept has been known in connection with the commercial crystallisation of sucrose and of lactose for almost a century it is virtually unrecognised beyond the sugar and dairy industries. The consequences are explored of the existence of such a boundary on the crystallisation process and the influence on crystal size distribution. It is recognised that the secondary nucleation threshold is the ‘seeded metastable limit’, but there are important consequences of avoiding the latter term. Mullins ‘latent period’ is shown to be closely related to the ‘growth only’ zone within the metastable zone.

Eight isostructural 4,4'-disubstituted N-phenylbenzenesulfonamides.

The isostructural crystals of 4-cyano-N-(4-methoxyphenyl)benzenesulfonamide, C(14)H(12)N(2)O(3)S, (I), N-(4-methoxyphenyl)-4-(trifluoromethyl)benzenesulfonamide, C(14)H(12)F(3)NO(3)S, (II), 4-iodo-N-(4-methoxyphenyl)benzenesulfonamide, C(13)H(12)INO(3)S, (III), 4-bromo-N-(4-methoxyphenyl)benzenesulfonamide, C(13)H(12)BrNO(3)S, (IV), 4-chloro-N-(4-methoxyphenyl)benzenesulfonamide, C(13)H(12)ClNO(3)S, (V), 4-fluoro-N-(4-methoxyphenyl)benzenesulfonamide, C(13)H(12)FNO(3)S, (VI), N-(4-chlorophenyl)-4-methoxybenzenesulfonamide, C(13)H(12)ClNO(3)S, (VII), and 4-cyano-N-phenylbenzenesulfonamide, C(13)H(10)N(2)O(2)S, (VIII), contain infinite chains composed of N-H···O(sulfonyl) hydrogen-bonded molecules. The crystal structures of (I)-(VIII) have been compared using the XPac software and quantitative descriptors of isostructurality were generated [Gelbrich, Threlfall & Hursthouse (2012). CrystEngComm, 14, 5454-5464]. Certain isostructural relationships in this series involve molecules with substantially different spatial demands, e.g. (VI) and (VIII) are related by the simultaneous interchange of F→CN on the benzenesulfonamide ring and OMe→H on the N-phenyl ring, which indicates that the geometry of the three-dimensional crystal-packing mode of (I)-(VIII) is unusually adaptable to different molecular shapes.