I. INTRODUCTION
Organic hydrochlorides, especially amines, are well-recognized products in the pharmaceutical field. Two well-known pharmaceutical hydrochloride compound examples are Ivabradine (Masciocchi et al., Reference Masciocchi, Aulisio, Bertolini, Sada, Garis and Malpezzi2013), a worldwide drug for symptomatic treatment of angina pectoris and inappropriate sinus tachycardia and Ethambutol (Hamalainen et al., Reference Hamalainen, Lehtinen and Ahlgren1985), an oral chemotherapeutic agent that is specifically effective against actively growing micro-organisms of the genus Mycobacterium, including Mycobacterium tuberculosis.
Many other pharmaceutical compounds are prepared, marketed, and administered as hydrochlorides (Lasocha et al., Reference Lasocha, Gawel and Lasocha2006). Generally, the pristine amine compounds are obtained as viscous oils with poor aqueous solubility, whereas their hydrochloride derivatives show higher water solubility, improving the dissolution rate and, consequently higher bioavailability (Chieng et al., Reference Chieng, Rades and Aaltonen2011). Also, hydrochloride products have affinity to complex metal ions and they can form salts, stabilized by strong hydrogen bonds, possessing important biological applications. For example, the tetrachloro-(bis(3,5-dimethylpyrazolyl)methane)gold(III) chloride, has been recently described as potent drug against human immunodeficiency virus – HIV, where doubly protonated pyrazolyl ligands make strong N–H···Cl hydrogen bonds, while the [AuCl4]− remains as the discrete ion (Fonteh et al., Reference Fonteh, Keter, Meyer, Guzei and Darkwa2009).
Here, we describe the crystal structures, based on the laboratory powder diffraction data, of N,N′-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium hydrochloride (1), Chart 1, and its [AuCl4]− salt, [N,N′-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium] bis[tetrachloro aurate(III)] (2). Compound (1) is a derivative of the N,N′-bis[thiophen-2-ylmethylidene]ethane-1,2-diamine Schiff base, which belongs to an another important class of organic compounds, prepared and characterized by us and others (Srimurugan et al., Reference Srimurugan, Suresh, Babu and Pati2008; Mota et al., Reference Mota, de Carvalho, Corbi, Bergamini, Formiga, Diniz, Freitas, da Silva and Cuin2012, Cuin et al., Reference Cuin, Pereira, Bortoluzzi and Massabni2013).
Together with the powder diffraction data and the pertinent crystallographic discussion, we provide hereafter some ancillary analytical results for both compounds.
II. EXPERIMENTAL
A. Materials and methods
Elemental analysis of carbon, hydrogen, and nitrogen was performed using a CHNS-O EA 1110 analyzer, CE Instruments. The reagents 2-thiophene-carboxaldehyde 98%, ethylenediamine 99%, NaBH4 96.5%, and K[AuCl4] 98% were purchased from Sigma-Aldrich and used without further purification. N,N′-bis[thiophen-2-ylmethylidene]ethane-1,2-diamine was prepared following the literature procedures (Wang et al., Reference Wang, Wang and Xiao2007).
Synthesis of (1)
Approximately 0.50 g of the Schiff base N,N′-bis[thiophen-2-ylmethylidene] ethane-1,2-diamine) were dissolved in methanol at 0 °C. About 0.31 g of NaBH4 were dissolved in 1.0 ml of H2O:MeOH (1:1) solution and added to the Schiff base solution. After 8 h under stirring, the solvent was evaporated and viscous and turbid yellow oil was obtained. The compound N,N′-bis(thiophen-2-ylmethyl)ethane-1,2-diamine was isolated in the organic phase after extraction with hexane:H2O (5:1), then hexane was evaporated, and the clear yellow oil obtained was solubilized in 20 ml of HCl 0.1 mol l−1. The volume was reduced to 5 ml under gentle heating (about 45 °C) and a colorless polycrystalline precipitate formed on standing after 24 h. The yield was 35%. Analytical data for C12H18Cl2N2S2: MW 325.3 g mol−1; %C, exp (calc): 44.1 (44.3); %H: 5.42 (5.58); %N: 8.62 (8.61). M.P. 257 °C.
Synthesis of (2)
Approximately 3.0 ml of an aqueous solution containing 190.3 mg of K[AuCl4] were previously prepared. About 162.1 mg of (1) were dissolved in 6.0 ml of water. Under stirring, both solutions were mixed and a yellow solid precipitated almost instantly. After 10 min, the light-yellow precipitate was collected by filtration and dried in a desiccator. The yield was 41%. Analytical data for C12H18Au2Cl8N2S2: MW 932.0 g mol−1, %C, exp (calc): 15.5 (15.5); %H: 2.30 (1.95); %N: 2.91 (3.01). M.P. 173 °C.
B. X-ray powder diffraction data collection and structure determination
Compound (1) showed a strong preferred orientation on what was later found to be the [100] direction. This direction is, inter alia, in agreement with the BFDH morphology computed by Mercury et al., (Reference Macrae, Bruno, Chisholm, Edgington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008) on the structural model later derived. This annoying effect was considerably reduced by mixing (1) with Cabosil®. However, the best low preferred orientation was achieved when the sample was prepared using the side-loading (Mc Murdie et al., Reference Mc Murdie, Morris, Evans, Paretzkin and Wong-Ng1986) technique. At the end, the hollow of silicon sample holder (a zero-background plate) was filled with pure (1). The powder diffraction data were collected during overnight scans in the 3°–105° (2θ) range with steps of 0.02° using a Bruker AXS D8 advance diffractometer, equipped with Ni-filtered CuKα radiation (λ = 1.5418 Å) and a Lynxeye linear position-sensitive detector. The following optics were used: primary beam Soller slits (2.3°), fixed divergence slit (0.5°), and receiving slit (8 mm). The generator was set at 40 kV and 40 mA. Standard peak search, and indexing through the single-value decomposition approach implemented in TOPAS-R (Bruker AXS, 2005) allowed detection of the approximate unit-cell parameters of (1). After the careful systematic absence analysis, the Iba2 space group was assigned and later confirmed by successful structure solution, performed by the simulated annealing technique implemented in TOPAS-R (Coelho, Reference Coelho2000). The simulated annealing procedure was performed using only the data in the 3°–50° (2θ) range, and a rigid body model for half (1) ion (described by the Z-matrix formalism) was placed close to a twofold axis (passing through a suitably constructed dummy atom, acting as a pivot), aligned with the c-axis. Its z-coordinates, rotation, and torsion angles (see Chart 1) and the xyz location of a single chloride ion were thus determined.
The same experimental conditions were used to obtain the diffractogram for (2), but in this case, powder of (2) was directly placed in hollow of the Si sample holder. As for (1), the approximate unit-cell parameters were obtained by TOPAS by standard peak search and followed by indexing. The space group of (2), P21/c, was assigned after the analysis of the systematic absences. Density considerations indicated Z = 2, forcing the organic dication to lie about an inversion center. Then, the simulated annealing was performed using the 3°–50° (2θ) data range and a rigid body model of half N,N′-bis[thiophen-2-ylmethylidene]ethane-1,2-diammonium) cation, defined by the Z-matrix formalism with free rotations and torsion angles (see Chart 1). A rigid square planar [AuCl4]− ion, defined by Cartesian coordinates, of (un)expansible, depending on the actual value of the refinable Au–Cl distance, was also included as an additional independent molecular fragment. In this case, the Au–Cl distance was defined and refined as 2.28 ± 0.02 Å.
In both cases, the final refinements were carried out by the Rietveld method, maintaining the rigid bodies introduced at the solution stage. For (1), a spherical harmonics description was used to model unavoidable texture effects and the anisotropy of peak broadening. Following the BFDH model implemented in Mercury (Mercury et al., Reference Macrae, Bruno, Chisholm, Edgington, McCabe, Pidcock, Rodriguez-Monge, Taylor, van de Streek and Wood2008), crystals of (2) are expected to be more isotropic, with slightly larger {100} crystal faces. Accordingly, the isosurface shape of the tensor computed by the spherical harmonics description appears to be elongated in [100]. Scattering factors, including resonant scattering terms, have been taken from the internal library of TOPAS. The background was modeled by a flexible Chebyshev polynomial. In (1), a single isotropic parameter was assigned, its rather large value probably compensating transparency effects for a non-infinitely thick sample (it is well known that “thermal factors” determined from powders can be in error because they act as scavengers for many instrumental and structural artifacts such as background level, knife-edge misplacement, transparency and porosity effects, disorder, and so on, Pecharsky and Zavalij, Reference Pecharsky and Zavalij2003). In (2), the (refined) isotropic a.d.p. of the heavy metal atom (B Au) was increased to B iso = B Au + 2.0 Å2 for the lighter atoms.
The final Rietveld refinement plot, the sketches of the crystal, and molecular structures for (1) are shown in Figures 1–3, while those for (2) are shown in Figures 4–6, respectively. Table I contains the relevant crystal data for (1) and (2). Tables II and III contain the relevant powder diffraction features and final fractional atomic coordinates for (1). Analogously, the pertinent values for (2) are collected in Tables IV and V.
(Color online) Rietveld Refinement plot in the range 6°–40° 2θ for (1) with the difference plot and peak markers at the bottom. Horizontal axis 2θ (°); vertical axis: counts. The inset shows the high-angle region.
(Color online) Crystal structure of (1) drawn using SCHAKAL (Keller, Reference Keller1986). The atoms of the asymmetric unit are labeled and hydrogen atoms are in light-gray color. For the sake of simplicity, the disorder of thiophenyl group was omitted (see text).
(Color online) SCHAKAL representation of the crystal packing of the (1) viewed down [010]. Color codes: C, dark-gray; H, light-gray, Cl, green; N, blue; and S, yellow.
(Color online) Rietveld refinement plot for (2) with the difference plot and peak markers at the bottom. Horizontal axis 2θ (°); vertical axis: counts. The inset shows the high-angle region.
(Color online) Crystal structure of (2) drawn by SCHAKAL. Atoms of asymmetric unity was labeled. Hydrogen atoms are in light-gray color.
(Color online) Schematic crystal packing of the (2) viewed down [001]. Color codes: C, dark-gray; H, light-gray; Au, light-yellow; Cl, green; N, blue; and S, yellow.
Sketch of N,N′-bis(thiophen-2-ylmethyl)ethane-1,2-diaminium hydrochloride (1). τ 1–τ 4 illustrate the torsion angles defining the conformation of the organic moiety within compound (1), of crystallographically imposed C2 symmetry; specifically, these torsions refer to the τ 1 (S–C3–C2–N), τ 2 (C3–C2–N–C1), τ 3 (C2–N–C1–C1′), and τ 4 (N–C1–C1′–N′) atomic sequences.
Crystallographic data of (1) and (2).
List of the observed diffraction peaks for (1).
Observed 2θ and d values have been computed after Kα 1 stripping. Accordingly, both 2θ calc and d calc values were calculated using Kα 1 (1.540 596 Å).
Fractional atomic coordinates for (1).
List of the observed diffraction peaks for (2).
Observed 2θ and d values have been computed after Kα 1 stripping. Accordingly, both 2θ calc and d calc values were calculated using Kα 1 (1.540 596 Å).
Fractional atomic coordinates for (2).
III. DISCUSSION
Crystals of (1) contain organic dications (generated by double protonation of the amino residues) surrounded by chlorine ions in an orthorhombic Iba2 ionic crystal packing. The shortest NH···Cl distance is 3.322 Å, and, together with a number of weaker ancillary CH···Cl contacts, define a pseudo-octahedron for the ClH6 “coordination” geometry. Each Cl− ion makes two strong NH···Cl contacts with distinct organic dicationic molecules, generating an infinite sequence of (NH2···μ-Cl) n formulation, in zigzagging along b.
Within the organic ligand, bisected by a crystallographic twofold axis aligned with c, the torsion angles were freed during the refinements and the final values are listed in Table VI. Significantly, it was necessary to introduce in the structural model of (1) a slightly disordered thiophene residue (in a 5:1 ratio) flipped by ca. 175° around the C2–C3 bond since without this minor disorder, some peaks in the 30°–35° 2θ range [namely, (10 0 0), (9 1 0), and (0 2 0)] were significantly underestimated. For the sake of simplicity, Figures 2 and 3, which depict the molecular conformation of the organic dication in (1) and the overall crystal packing, respectively, have been drawn by removing the minor component of the disordered heterocyclic ring from the list of atoms.
Torsion angles (°) τ 1–τ 4 for compounds (1) and (2).
τ 1–τ 4 are defined in Chart 1.
An ionic species containing square planar tetrachloroaurate(III) moieties (idealized by a D4h fragment with a refined Au–Cl distance of 2.28(4) Å, in very good agreement with what found in a complete CSD search, 2.28 ± 0.02 Å for 184 hits) and the same organic dication found in (1). The shortest Au–S distance (3.629 Å) suggests only a weak interaction between Au and S, but it is strong enough to avoid static reorientation of the thiophene ring and a possible disorder observed in (1). Again, short N···Cl contacts can be envisaged (3.13 Å), further stabilizing the crystal through directional hydrogen-bond interactions. The refined torsion angles of the organic portion, listed in Table VI, are significantly different from those observed in compound (1). While this is fairly obvious for the τ 4 torsion, which reflects the different molecular symmetry [the dications being located on a twofold axis in (1) and on an inversion center in (2), imposing crystallographic C 2 and C i symmetry, respectively], also the other torsion angles reflect the flexibility of this fragment.
IV. CONCLUSION
Compound (1) and its tetrachloroaurate(III) salt (2) were synthesized and the formula of the compounds C12H18Cl2N2S2 (1) and C12H18Au2Cl8N2S2 (2) were confirmed by elemental analysis. In the absence of crystals of suitable size and quality, amenable to conventional single-crystal characterization, the structures of both compounds were determined by the standard laboratory X-ray powder diffraction techniques. The diffraction patterns of both compounds were successfully indexed and the crystal structures were derived therefrom using state-of-the-art real-space structure solution methods: Compound (1) belongs to orthorhombic system (Iba2) with cell parameters a = 29.856(1), b = 5.1372(2), and c = 10.1635(4) Å and its crystal structure consists of organic dications linked by NH···Cl hydrogen bonds to chlorine ions embedded in a pseudo-octahedron defined by six short Cl···H contacts. Compound (2) crystallizes in monoclinic system (P21/c) with cell parameters a = 11.0829(1), b = 9.5852(1), c = 11.6054(2) Å, and β = 75.49(1)°; in this case, a weak, but non-negligible, interaction between the S and Au atoms of the [AuCl4]− complex ion (3.692 Å) avoids the disorder of thiophene group, found in (1). Once again, it has been shown that powder diffraction methods can supply relevant (otherwise inaccessible) structural information, although of lower quality than that can be obtained from single-crystal analyses (Masciocchi and Sironi, Reference Masciocchi and Sironi1997; Masciocchi et al., Reference Masciocchi, Galli and Sironi2005). Nevertheless, poor information is better than no information at all.
V. SUPPLEMENTARY MATERIAL
All crystallographic data for this paper are deposited with the Cambridge Crystallographic Data Centre (977057 and 977058). The data can be obtained free of charge at: http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (0) 1223-336033; e-mail: deposit@ccdc.cam.ac.uk].
ACKNOWLEDGMENTS
This work was generously supported by the grants from FAPEMIG (grant no. CEX-APQ-APQ-00256/11) and CNPq (grant no. 240094/2012-3). We also thank the reviewers and the editor for providing helpful suggestions.
SUPPLEMENTARY MATERIALS AND METHODS
The supplementary material refered to in this paper can be found online at journals.cambridge.org/pdj.
