Comment

Thio-analogues of the nucleobases play an important role in biological processes. For example, 2-thiouracil was found to be part of the anticodon of transfer RNAs. For six-membered cyclic compounds with hydrogen-bonding sites similar to 2-thiouracil, the R₂²(8) hydrogen-bonding pattern (Bernstein et al., 1995) turned out to be preferred for N-HO or N-HS interactions (Tutughamiarso & Egert, 2011). Moreover, a Cambridge Structural Database substructure search (CSD, Version 5.33, November 2011 plus four updates; Allen, 2002) revealed that for 2-thiouracil derivatives, N-HS hydrogen bonds are solely observed within R₂²(8) motifs. Prompted by these results, we decided to crystallize 6-amino-2-thiouracil, (I), in order to analyze the effect of an additional NH₂ donor group on the hydrogen-bonding pattern formed. 6-Amino-2-thiouracil shows anticorrosion and antifouling properties and can be used as an additive in marine anticorrosion paint (Tadros & Abd El Nabey, 2000). It exhibits antiviral activity (Romero et al., 1993) and is also an important precursor for the synthesis of compounds with various pharmacological properties, including anti-analgesic, anti-inflammatory (Alagarsamy et al., 2007; Youssif & Mohamed, 2008; Abu-Hashem & Youssef, 2011), antibacterial, antifungal, antitumor and diuretic activity (Mohamed et al., 2007; El-Gazzar

& Hafez, 2009). Furthermore, it is used as a precursor for the synthesis of A₃ adenosine receptor antagonists (Cosimelli et al., 2008), as well as for inhibitors of DNA III polymerase (Wright & Brown, 1976).

Crystallization experiments from different solvents yielded five new pseudopolymorphs of (I), i.e. the dimethylformamide (DMF) disolvate, (Ia), the dimethylacetamide (DMAC) monosolvate, (Ib), the dimethylacetamide sesquisolvate, (Ic), and two different 1-methylpyrrolidin-2-one (NMP) sesquisolvates, (Id) and (Ie).

Compound (Ia) crystallized in the triclinic space group P with two planar 6-amino-2-thiouracil molecules, A and B [r.m.s. deviations for all non-H atoms = 0.027 (for A) and 0.024 Å (for B)], and four DMF molecules, denoted W, X, Y, and Z, in the asymmetric unit (Fig. 1). All molecules in the asymmetric unit lie in a common plane parallel to (11) (r.m.s. deviation for all non-H atoms = 0.086 Å). The molecules of (I) are connected by N-HO hydrogen bonds (Table 2) in an R₂¹(6) pattern, forming chains running along [10] (Fig. 2). Linked by N-HO hydrogen bonds to (I), the DMF molecules are located on both sides of the chains, respectively, with molecule A connected to DMF molecules W and X and molecule B to DMF molecules Y and Z.

The DMAC solvate (Ib) crystallized in the monoclinic space group P2₁/n. The asymmetric unit consists of one 6-amino-2-thiouracil (r.m.s. deviation for all non-H atoms = 0.017 Å) and one disordered DMAC molecule. The two molecules are connected by an R₂¹(6) pattern of N-HO hydrogen bonds (Table 3) and are almost coplanar with each other (r.m.s. deviation = 0.088 Å for all non-H atoms; Fig. 3). In the crystal packing, the 6-amino-2-thiouracil molecules show R₂²(8) motifs of N-HO hydrogen-bonded homodimers. Connected by further N-HO hydrogen bonds, these dimers assemble into a three-dimensional network with adjacent dimers enclosing a dihedral angle of 48.26 (3)° (Fig. 4).

Compounds (Ic) and (Id) are isomorphous and crystallized in the orthorhombic space group Pca2₁. The asymmetric unit consists of two 6-amino-2-thiouracil molecules, A and B [r.m.s. deviations for all non-H atoms = 0.024 (for A) and 0.013 Å (for B) in (Ic), and 0.022 (for A) and 0.011 Å (for B) in (Id)], and three solvent molecules, denoted X, Y and Z (Figs. 5 and 6). DMAC molecules X and Y in (Ic), as well as NMP molecules Y and Z in (Id), are disordered over two positions. The 6-amino-2-thiouracil molecules are connected to homodimers stabilized by an R₂²(8) pattern of N-HO hydrogen bonds (Tables 4 and 5). Adjacent dimers are connected by further N-HO hydrogen bonds and enclose a dihedral angle of 47.3 (1)° in (Ic) and 50.7 (7)° in (Id). In addition, the molecules of (I) show R₂¹(6) N-HO interactions with the solvent molecules whereby molecule A is connected to X and molecule B to Z, respectively (Fig. 7). Molecule B also forms an N-HO hydrogen bond with solvent molecule Y. The crystal packing consists of zigzag-like chains of AB homodimers running along the a axis.

Pseudopolymorph (Ie) crystallized in the orthorhombic space group Pbca. The asymmetric unit consists of two 6-amino-2-thiouracil molecules, A and B [r.m.s. deviations for all non-H atoms = 0.020 (for A) and 0.011 Å (for B)], and three NMP molecules, denoted X, Y and Z (Fig. 8). The molecules of (I) form homodimers stabilized by R₂²(8) N-HO hydrogen bonds (Table 6). Adjacent dimers are connected by N-HO hydrogen bonds and enclose a dihedral angle of 51.6 (6)°. Both molecules A and B show additional R₂¹(6) N-HO interactions, with molecule A connected to molecule X and molecule B to Z, respectively (Fig. 9). Molecule B also forms one N-HO hydrogen bond with NMP molecule Y. In the crystal packing, the AB homodimers are arranged in a herringbone structure (Fig. 10).

In the structures of these five pseudopolymorphs, two different types of N-HO hydrogen-bonding patterns are observed. In all structures, R₂¹(6) motifs are present, which are either formed between two molecules of (I) in (Ia) or between one molecule of (I) and one solvent molecule in (Ib), (Ic), (Id) and (Ie). In the latter four structures, additional R₂²(8) hydrogen-bond patterns between molecules of (I) are formed. In these five structures, the S atoms do not participate in any hydrogen-bonding interactions.

The hydrogen-bonding pattern formed by (I) was compared with other 2-thiouracil derivatives retrieved from the CSD. This search yielded a total number of 39 hits, of which 29 structures contain R₂²(8) motifs. Nine of these structures show R₂²(8) motifs with two N-HO hydrogen bonds [refcodes FAJWES (Brewer et al., 1987), FICBEY (Delage, H'Naifi & Goursolle, 1986), HEPMIY (Pastor et al., 1994), MUYTIK (Ivanova & Spiteller, 2010), HAFLAC (Antoniadis et al., 2003), LACJIJ (Tashkhodzhaev et al., 2002), EBAQOP (Balas et al., 2011), and EBAQOP01 and DAYGUH (Kubicki et al., 2012)] and 11 structures contain R₂²(8) motifs characterized by two N-HS hydrogen bonds [FALWOF (Orzeszko et al., 2004), FUWBOP (Medda et al., 2009), LOFDAL (Fonar et al., 1999), MUGMIK (Matkovic-Calogovic et al., 2002), PABNAJ, PABNIR (Chierotti et al., 2010), QAYCID (Van Hecke et al., 2005), QEHSEB (Tiekink, 2001), ZZZGEO01 (Delage, H'Naifi, Goursolle & Carpy, 1986), and CALFUS and CALGAZ (Tutughamiarso & Egert, 2011)]. In nine structures, two different R₂²(8) motifs with either two N-HO or two N-HS hydrogen bonds can be observed [CASPUI (Hu et al., 2005), GEMCAC (Read et al., 1988), PABPAL (Chierotti et al., 2010), RAPNAY (Long et al., 2005), TURCIL01 (Tiekink, 1989), TURCIL02 (Munshi & Guru Row, 2006), UXIXUV (Ferreira et al., 2011), UXIXUV01 (Tutughamiarso & Egert, 2011) and LANZIL (Al-Deeb et al., 2012)].

The CSD search also yielded the crystal structure of the monohydrate of (I) [CSD refcodes AMTURM (Swaminathan & Chacko, 1978), AMTURM01 (Raper et al., 1985) and YEJKUV00 (Hützler & Bolte, 2012)], in which the molecules of (I) are connected by R₂¹(6) motifs of N-HO hydrogen bonds, building chains that are crosslinked via the water molecules, resulting in a three-dimensional network. Hydrogen bonds involving S atoms as an acceptor are only present between molecules of (I) and water (O-HS).

In summary, the additional NH₂ hydrogen-bond donor group at C6 (next to the N-H group) of 2-thiouracil seems to favour the formation of an R₂¹(6) N-HO hydrogen-bonding pattern since this motif is present in all crystal structures of (I). The S atom of (I) participates in hydrogen bonds exclusively in the presence of water which is the only incorporated solvent containing hydrogen-bond donor groups. In four pseudopolymorphs of (I), the formation of R₂²(8) dimers is observed. This is in agreement with the results of a CSD substructure search, which revealed the R₂²(8) motif to be the most frequent hydrogen-bond pattern in crystal structures of 2-thiouracil derivatives.

Experimental

Solvent evaporation experiments with the commercially available monohydrate of 6-amino-2-thiouracil under different conditions yielded compounds (Ia)-(Ie) (see Table 1). In order to optimize the crystallization process, further experiments at different temperatures and with varied crystallization rates were carried out. However, the crystal quality did not improve significantly.

All H atoms except those of the disordered solvent molecules were initially located by difference Fourier syntheses. Subsequently, all H atoms in (Ia) and (Id), the H atoms bonded to C atoms in (Ib), (Ic) and (Ie), and the H atoms of the imide groups in (Ic) and (Ie) were refined using a riding model, with methyl C-H = 0.98 Å, secondary C-H = 0.99 Å, aromatic C-H = 0.95 Å and N-H = 0.88 Å, and with U_iso(H) = 1.5U_eq(C) for methyl H atoms, 1.2U_eq(C) for secondary and aromatic H atoms, and 1.2U_eq(N). In (Ib), all H atoms bonded to N atoms were refined isotropically and the N-H bond lengths were restrained to 0.88 (2) Å. In (Ic) and (Ie), isotropic refinement of the H atoms of the amino groups resulted in isotropic displacement parameters smaller than the equivalent isotropic displacement parameters of the parent N atoms. Therefore, they were coupled to those of the N atoms, with U_iso(H) = 1.2U_eq(N), and the N-H distances were restrained to 0.88 (2) Å. For all methyl groups, except those of the disordered solvent molecules, free rotation about their local threefold axis was allowed.

The DMAC molecule in (Ib) and DMAC molecules X and Y in (Ic), respectively, show disorder over a pseudo-mirror plane along atoms O21(X/Y) and C32(X/Y) [site-occupation factor for the major occupied orientation = 0.629 (8) in (Ib), and 0.712 (11) for X and 0.630 (11) for Y in (Ic)].

In (Id), NMP molecules Y and Z show disorder over a pseudo-mirror plane, respectively [site-occupation factor for the major occupied orientation = 0.600 (14) for Y and 0.688 (11) for Z]. In molecule Y, the pseudo-mirror plane intersects the N1Y-C2Y and C4Y-C5Y bonds; thus, all atom positions are different for both orientations. In molecule Z, the pseudo-mirror plane intersects O21Z and the N1Y-C2Y and C4Y-C5Y bonds; hence, the positions of O21Z coincide in both orientations.

Similarity restraints for the 1,2 and 1,3 distances were applied for all solvent molecules in (Ib), (Id) and (Ie) and for solvent molecules X and Y in (Ic).

The isotropic restraint (ISOR; Sheldrick, 2008), similar-ADP restraint (SIMU) and rigid-bond restraint (DELU) were applied for all solvent molecules in (Ie) and for disordered DMAC molecules X and Y in (Ic). In (Id), SIMU and DELU were applied for disordered NMP molecules Y and Z.

For all pseudopolymorphs, data collection: X-AREA (Stoe & Cie, 2001); cell refinement: X-AREA; data reduction: X-AREA; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2008) and XP in SHELXTL-Plus (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

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Supplementary data for this paper are available from the IUCr electronic archives (Reference: FG3285 ). Services for accessing these data are described at the back of the journal.

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