Co-crystallization of 3,5-dinitrobenzoic acid with two antipsychotic agents: a simple 1:1 salt with trihexyphenidyl and a 1:2 acid salt containing a very short O—H⋯O hydrogen bond with chlorprothixene

Co-crystallization of 3,5-dinitrobenzoic acid with trihexyphenidyl [or 1-cyclohexyl-1-phenyl-3-(piperidin-1-yl)propan-1-ol], gives a 1:1 salt (I) but chlorprothixene [or (Z)-3-(2-chloro-9H-thioxanthen-9-yl)-N,N-dimethylpropan-1-amine], gives a 1:2 acid salt (II) containing a very short O—H⋯O hydrogen bond. Multiple hydrogen bonds link the ions in (I) into a complex chain of rings and those in (II) link the ions into a sheet.

In the selected asymmetric unit of (I) (Fig. 1), the ionic components are linked by just two hydrogen bonds, one each of O-HÁ Á ÁO and N-HÁ Á ÁO types (Table 1), to form a compact unit containing an R 2 2 (10) (Etter, 1990; Etter et al.,

Figure 2
The molecular structure of compound (II) showing the atom-labelling scheme and the hydrogen bonds, drawn as dashed lines, within the selected asymmetric unit. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
The molecular structure of compound (I), showing the (S)-enantiomer of the cation, the atom-labelling scheme and the hydrogen bonds, drawn as dashed lines, within the selected asymmetric unit. Displacement ellipsoids are drawn at the 50% probability level.
1990; Bernstein et al., 1995) ring. By contrast, within the selected asymmetric unit of (II), the components are linked not only by the short O-HÁ Á ÁO hydrogen bond referred to above, but also by a three-centre N-HÁ Á Á(O) 2 hydrogen bond and a two-centre C-HÁ Á ÁO hydrogen bond (Fig. 2, Table 2). The cyclohexyl and piperidyl rings in the cation of compound (I) both adopt chair conformations with the sole C-substituent occupying an equatorial site in each case (Fig. 1). In the cation of compound (II), the dihedral angle between the two aryl rings is 41.56 (4) , indicating a butterfly conformation for the tricyclic component; the central ring adopts a boat conformation where the atoms C14A, C14B, C18A and C18B are coplanar with the atoms C19 and S10, which form the bow and stern of the boat (Fig. 3), displaced from the plane of the other four ring atoms by 0.456 (2) and 0.541 (2) Å respectively. The ring-puckering parameters calculated for the atom sequence (S10, C14A, C18B, C19, C18A, C14B) are Q = 0.5721 (12) Å , = 86.71 (13) and ' = 0.53 (14) : for an idealized boat form the puckering angles are = 90.0 and ' = 60k , where k represents an integer (Boeyens, 1978).
In the anion of (I), the nitro group containing atom N43 forms a dihedral angle of only 3.03 (3) with the adjacent ring, but the other nitro group and the carboxylate group form angles of 21.3 (2) and 20.4 (2) , respectively. Comparable differences are observed also in the anionic component of (II), where the carboxylate groups form dihedral angles with the adjacent rings of 3.6 (2) and 11.8 (2) , while the corresponding angles for the four nitro groups range from 3.5 (2) to 18.2 (2) .

Supramolecular features
In addition to the hydrogen bonds within the selected asymmetric unit of compound (I) (Fig. 1, Table 1), the resulting ion-pairs are linked by three independent C-HÁ Á ÁO hydrogen bonds, which together generate a complex chain structure (Fig. 4). The hydrogen bond involving atom C33 as the donor links inversion-related pairs of cations and anions to form a four-ion aggregate characterized by an R 4 4 (24) motif. The hydrogen bond involving atom C36 as the donor, by contrast, forms an almost planar three-centre C-HÁ Á Á(O) 2 system, again linking inversion-related ion pairs to form a complex motif in which a central R 2 2 (14) ring containing only cations is concentric with an outer R 4 4 (14) motif involving both cations and anions. The R 4 4 (24) rings are centred at ( 1 2 , n, n) and the fourteen-membered rings are centred at ( 1 2 , n + 1 2 , n + 1 2 ), where n represents an integer in each case, so forming a chain of rings running parallel to the [011] direction (Fig. 4). Chains of this type are linked by astacking interaction involving the anions at (x, y, z) and (1 À x, Ày, 1 À z). These rings are strictly parallel, with an interplanar spacing of 3.4413 (6) Å : the ring-centroid separation is 3.5231 (10)   The boat conformation of the thiopyran ring in compound (II), including all the immediate ring substituent atoms.

Figure 4
Part of the crystal structure of compound (I) showing the formation of a hydrogen-bonded chain of rings parallel to [011]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to the C atoms which are not involved in the motifs shown have been omitted. Table 1 Hydrogen-bond geometry (Å , ) for (I). Symmetry codes: (i) Àx þ 1; Ày; Àz; (ii) Àx þ 1; Ày þ 1; Àz þ 1.
a ring-centroid offset of 0.755 (2) Å (Fig. 5), and this interaction links the hydrogen-bonded chains into a sheet lying parallel to (100).
In the structure of compound (II) there are just two C-HÁ Á ÁO hydrogen bonds linking the ion-pairs (Fig. 2, Table 2) into sheets, whose formation is most easily analysed in terms of two simple-one-dimensional sub-structures (Ferguson et al., 1998a,b;Gregson et al., 2000). The hydrogen bond involving atom C14 as the donor links the ions into a C 2 2 (7) chain running parallel to the [010] direction ( Fig. 6), while that having atom C1 as the donor generates a second C 2 2 (7) chain, this time running parallel to the [001] direction (Fig. 7). The combination of chains running parallel to [010] and [001] suffices to generate a sheet lying parallel to (100). The only significantstacking interactions lie within the hydrogenbonded sheets, rather than between adjacent sheets, so that the supramolecular assembly is strictly two-dimensional.

Database survey
It is of interest briefly to note the structures of some compounds related to (I) and (II). In neutral trihexyphenidyl, there is an intramolecular O-HÁ Á ÁN hydrogen bond forming an S(6) motif, but there are no significant direction-specific interactions between the molecules (Camerman & Camerman, 1972), while in the hydrochloride salt (Maccaroni et al., 2010), a combination of O-HÁ Á ÁCl and N-HÁ Á ÁCl hydrogen bonds links the ions into C 1 2 (7) chains. By contrast, in the hydrochloride salt of procyclidine, which differs from trihexy- Part of the crystal structure of compound (I) showing thestacking overlap between the anions at (x, y, z) and (1 À x, Ày, 1 À z). For the sake of clarity, the unit-cell outline and all of the H atoms have been omitted. The atoms marked with an asterisk (*) are at the symmetry position (1 À x, Ày, 1 À z).

Figure 6
Part of the crystal structure of compound (II) showing the formation of a hydrogen-bonded C 2 2 (7) chain running parallel to the [010] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms not involved in the motif shown have been omitted. Table 2 Hydrogen-bond geometry (Å , ) for (II). Symmetry codes: (i) x; Ày þ 1 2 ; z À 1 2 ; (ii) Àx; y À 1 2 ; Àz þ 1 2 .
phenidyl only in having a pyrrolidine ring in place of the piperidine ring, a combination of O-HÁ Á ÁCl and N-HÁ Á ÁCl hydrogen bonds generates an R 1 2 (8) ring, so that the hydrogenbonded structure consists of ion pairs rather than chains (Camerman & Camerman, 1971). Neutral 3-(2-chloro-9Hthioxanthen-9-yl)-N,N-dimethylpropan-1-amine can exist in (E) and (Z) isomers, and the structures of both forms have been reported (Post et al., 1974;Sylte & Dahl, 1991). Flupenthixol (sometimes called flupentixol) is an antipsychotic agent related to chlorprothixene, but having a trifluoromethyl substituent in place of the chloro substituent and a 4(2-hydroxyethyl)piperazine substituent in place of the dimethylamino group: the structures of both the E and Z isomers have been reported (Post et al., 1975a,b), as have those of the dihydrochloride salt (Siddegowda et al., 2011) and the tartrate salt (Yamuna et al., 2014).
Very short O-HÁ Á ÁO hydrogen bonds have been reported in a number of acid salts derived from simple carboxylic acids.

Synthesis and crystallization
Samples of racemic trihexyphenidine and (Z)-chlorprothixene were gifts from RL Fine Chem Pvt. Ltd., Bengaluru, India. For the synthesis of compound (I), equimolar quantities of trihexyphenidine and 3,5-dinitrobenzoic acid (0.33 mmol of each) were dissolved in hot methanol (10 ml) and the resulting solution was stirred at 333 K for 30 min. The solution was then allowed to cool to ambient temperature, and the resulting crystalline product was collected by filtration. For the synthesis of (II), equimolar quantities of chlorprothixene and 3,5dinitrobenzoic acid (0.60 mmol of each) were dissolved in hot methanol (10 ml) and the resulting solution was stirred at 333 K for 10 min. The solution was then allowed to cool to ambient temperature, and the resulting crystalline product was collected by filtration. Use of initial molar ratios in the range 5:1 to 1:5 always yielded the same products (I) and (II). Crystals of (I) and (II) suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in methanol-dimethylsulfoxide (1:1, v/v) and N,N-dimethylformamide.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All H atoms were located in difference maps. The H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions with C-H distances 0.95 Å (aromatic), 0.98 Å (CH 3 ), 0.99 Å (CH 2 ) or 1.00 Å (aliphatic C-H) and with U iso (H) = kU eq (C), where k = 1.5 for the methyl groups, which were permitted to rotate but not to tilt, and 1.2 for all other H atoms bonded to C atoms. For atom H312 in the short O-HÁ Á ÁO hydrogen bond, the atomic coordinates and the U iso (H) value were all refined; Part of the crystal structure of compound (II) showing the formation of a hydrogen-bonded C 2 2 (7) chain running parallel to the [001] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to the C atoms which are not involved in the motif shown have been omitted.
for the remaining H atoms bonded to N or O atoms, the atomic coordinates were refined with U iso (H) = 1.2U eq (N) or 1.5U eq (O). The resulting N-H and O-H distances are given in Tables 1 and 2. For compound (II), the largest peak in the final difference map, 0.53 e Å À3 , was located near the bond C17-H17, at distances from these two atoms of 1.40 and 0.62 Å , but no plausible chemical interpretation of this seems possible. Computer programs: APEX2 (Bruker, 2014), SAINT (Bruker, 2015), SHELXS97 (Sheldrick, 2008), SHELXL2014 (Sheldrick, 2015) and PLATON (Spek, 2009 For both structures, data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2015); data reduction: SAINT (Bruker, 2015); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015) and PLATON (Spek, 2009). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.