Crystal structure and Hirshfeld surface analysis of 2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-ium 2-hydroxy-2-phenylacetate hemihydrate

The l-shaped cations in the centrosymmetric title salt are related across a non-crystallographic centre of inversion. In the crystal, hydrogen-bonded layers are linked by π–π and C—H⋯F⋯π interactions.

The asymmetric unit of the title salt, C 17 H 17 F 6 N 2 O + ÁC 8 H 7 O 3 À Á0.5H 2 O, comprises a pair of pseudo-enantiomeric (i.e. related by a non-crystallographic centre of symmetry) piperidin-1-ium cations, two carboxylate anions and a water molecule of crystallization. The cations have similar conformations approximating to a letter, L: one of them shows disorder of its -CF 3 group over two sets of sites in a 0.775 (3):0.225 (3) ratio. Distinctive conformations are found for the anions, one with the carboxylate group lying to one side of the plane through the phenyl ring and the other where the oxygen atoms lie to either side of the plane. In the latter, an intramolecular hydroxy-O-HÁ Á ÁO(carboxylate) chargeassisted hydrogen bond is found. The packing features extensive O-HÁ Á ÁO,N hydrogen bonding, often charge-assisted; C-HÁ Á Á interactions are also formed. The hydrogen bonding results in the formation of five distinctive supramolecular synthons and assembles molecules in the ac plane. The quinolinyl rings lie to either side of the layer and inter-digitate with layers on either side, are approximately parallel to the b axis and are connected by -[inter-centroid separation = 3.6904 (18) Å ] as well as C-FÁ Á Á(quinolinyl) interactions to consolidate the three-dimensional crystal. The dominance of the conventional hydrogen bonding in the molecular packing is confirmed by an analysis of the Hirshfeld surface.

Chemical context
When the racemic compound mefloquine is reacted with HCl, protonation occurs at the piperdinyl-N atom to yield the [(R*,S*)-(2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxymethyl)piperidin-1-ium chloride salt; see Scheme for the chemical diagram of the cation, also known as mefloqinium. This salt, racemic erythro-mefloquine hydrochloride, has been used as an anti-malarial drug since 1971 (Maguire et al., 2006). As an example of drug re-positioning, new biological activities have been sought for this drug and derivatives resulting in the disclosure of their potential as, for example anti-bacterial (Mao et al., 2007), anti-mycobacterial (Gonçalves et al., 2012) and anti-cancer (Rodrigues et al., 2014) agents. This interest notwithstanding, it turns out that the crystal chemistry of the cation is rich and diverse. For example, the crystal structures of salts of the cation with three isomeric n-nitrobenzoates (n = 2, 3, and 4) have been described where the supramolecular association led to chains in each case, but these were sustained by distinct hydrogen-bonded synthons (Wardell et al., 2011).
In addition, recently, two kryptoracemates have been revealed, namely in mefloqinium salts with p-fluorobenzenesulfonate (Jotani et al., 2016) and (+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanate (Wardell et al., 2016). It was in this context that the title hydrated salt, (I), was investigated: this was isolated after racemic mefloquine was reacted with a stoichiometric amount of racemic 2-hydroxy-2-phenylacetic acid. Herein, the crystal and molecular structures of the title salt, (I), are described as well as a Hirshfeld surface analysis.

Structural commentary
The asymmetric unit of (I) comprises two 2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-ium cations, two 2-hydroxy-2-phenylacetate anions and a water molecule of crystallization. The cations, Fig. 1, are pseudoenantiomeric (i.e. related by a non-crystallographic inversion centre) with the N1-cation having an S-configuration at the C12 atom and an R-configuration at C13 and therefore being assigned as the [(À)-erythro-mefloquinium] cation. The N3cation, with chirality at the C29 and C30 atoms being R and S, respectively, is assigned as [(+)-erythro-mefloquinium]. As anticipated, protonation during crystallization leads to a piperidin-1-ium cation, as confirmed by the pattern of hydrogen bonding, which is discussed below in Supramolecular features. Each cation comprises an essentially planar quinolinyl residue attached to a piperidinium residue (with a chair conformation) via a methine link. The dihedral  The molecular structures of the (a) first and (b) second independent cations in (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level. For (b), only the major component of the disordered C27-CF 3 group is shown.

Figure 2
An overlap diagram highlighting the similarity of the conformations of the first (red) and inverted second (blue) independent cations. The cations have been overlapped so the the quinolinyl rings are coincident. The molecular structures of the (a) first and (b) second independent anions in (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level.

Figure 4
An overlap diagram highlighting the differences in the conformations of the first (red) and inverted second (blue) independent anions. The anions are overlapped so the phenyl rings are coincident. Table 1 Hydrogen-bond geometry (Å , ).

Supramolecular features
In addition to considerable conventional hydrogen bonding, often charge-assisted, there are other intermolecular interactions at play in the molecular packing (Spek, 2009). The geometric parameters characterizing most of these intermolecular interactions are given in Table 1. The pattern of hydrogen bonding clearly differentiates both the cations and in the same way, the anions. Thus, the hydroxy group of the N1-cation forms a charge-assisted hydroxy-O-HÁ Á ÁO(carboxylate) interaction with an anion, while the hydroxyl group of the N3-cation forms a hydroxy-O-HÁ Á ÁO(hydroxy) link between the cations. The piperidinium-N-H 2 H atoms of the N1-cation forms charge-assisted hydrogen bonds to the water molecule of crystallization and to the O3-carboxylate atom, whereas those of the N3-cation interact with the hydroxy-O8 and carboxylate-O4 atoms. A different hydrogen-bonding pattern is also noted for the anions, already differentiated by the formation of an intramolecular hydroxy-O-HÁ Á ÁO(carboxylate) interaction in the O6-anion. The hydroxy group of the O3-anion forms a hydroxy-O-HÁ Á ÁO(carboxylate) link between the anions. Both carboxylate-O3, O4 atoms accept hydrogen bonds from piperidinium-N-H H atoms whereas the carboxylate-O5, O6 atoms form interactions with piperidinium-N-H and anionhydroxyl-H H atoms, respectively. The carboxylate-O3 and O7 atoms each form two hydrogen bonds with the additional interactions involving water-H atoms. Finally, as just mentioned, the water molecule forms two donor interactions with carboxylate-O atoms, accepts a hydrogen bond from a piperidinium-N-H H atom and also accepts a contact from a quinolinyl-C-H atom.

Hirshfeld surface analysis
Crystal Explorer (Wolff et al., 2012)   were calculated using TONTO (Spackman et al., 2008;Jayatilaka et al., 2005) integrated into Crystal Explorer; the crystal geometry was used as the input. The electrostatic potentials were mapped onto Hirshfeld surfaces using the STO-3G basis set at the Hartree-Fock level of theory. The contact distances d i and d e from the Hirshfeld surface to the nearest atom inside and outside, respectively, enables the analysis of the intermolecular interactions through the mapping of d norm . The Hirshfeld surfaces mapped over d norm for the N1cation, N3-cation and the entity comprising the two anions together with the water molecule of crystallization are illustrated in Fig. 6, and Hirshfeld surfaces mapped over electrostatic potential for the same species, in the ranges À0.25 to +0.17, À0.26 to +0.17 and À0.14 to +0.20 au, respectively, are illustrated in Fig. 7. The mapping of Hirshfeld surfaces over d norm in the range À0.5 to +1.3 au reveals potential hydrogenbond donors and acceptors as bright-red spots. The further mapping of Hirshfeld surfaces over d norm in the range À0.1 to +1.1 au results in faint-red spots on the surfaces which can satisfactorily describe the influence of other intermolecular interactions in the crystal such as C-HÁ Á ÁO, C-HÁ Á ÁF, C-HÁ Á Á, C-FÁ Á Á andstacking. The bright-red spots appearing near the donor hydroxyl-H2O, Fig. 6c, and acceptor hydroxyl-O1O atom, Fig. 6a, show the O-HÁ Á ÁO link between the two independent cations. The charge-assisted O-HÁ Á ÁO interaction between the hydroxyl-H1O and carboxylate-O4 atoms can be viewed as bright-red spots in Fig. 6a and 6f, respectively. The bright-red spots at the piperidinium-H1N and H2N atoms, Fig. 6a, and oxygen atoms   View of Hirshfeld surfaces mapped over electrostatic potential for (a) the N1-cation (b) the N3-cation and (c) the anions and water molecule. Table 2 Additional interatomic contacts (Å ) in the crystal of (I).

Parameter
Distance Symmetry operation  Table 2. The spots near the F2 and piperidinium-C17 atoms arise form intermolecular C-HÁ Á ÁF interactions, Fig. 6b and Table 2. The presence of C-FÁ Á Á interactions are evident from the diminutive-red spots near the F4 and F5 atoms of the N1-cation, and F8 of the N3-cation, Figs. 6a, 6b and 6d, and from the short interatomic CÁ Á ÁF contacts listed in Table 2. The Hirshfeld surfaces mapped with shape-index properties are illustrated in Fig. 8 and reflect these C-FÁ Á Á interactions. In addition to above, the short interatomic C48Á Á ÁF7 contact is also viewed as very faint-red spots near these atoms on the surface, Figs. 6c, 6d and 6e. The faint-red spots present near the methylene-C14-H, Fig. 6b, and anion-phenyl-C42 atoms, Fig. 6e, and short interatomic CÁ Á ÁH/HÁ Á ÁC contacts between methylene-H14A and anion atoms C37, C41 and C42, as summarized in Table 2, clearly indicate their contribution to the C-HÁ Á Á interaction described above. The presence of a C-HÁ Á ÁO interaction between piperidinium-C31-H of the N3-cation and hydroxyl-O8 of one of the anions is observed as diminutive-red spots near these atoms in Figs. 6c and 6f, and quantified in Table 2. In addition to the above intermolecular interactions related to CÁ Á ÁH/HÁ Á ÁC contacts, the short interatomic contacts between the anion-C46 and C35 atoms, Figs. 6e and 6f, and N1-cation hydrogens H6 and H15A, Figs. 6a and 6b, are also viewed as faint-red spots near these atoms. The immediate environments about the N1-and N3-cations and the anions and water molecule within the d norm -mapped Hirshfeld surface mediated by the above interactions are illustrated in Fig. 9   The combination of d i and d e in the form of two-dimensional fingerprint plots (McKinnon et al., 2007) provides a summary of the intermolecular contacts occurring in the crystal. The overall two-dimensional fingerprint plot for (I) and those delineated into HÁ Á ÁH, OÁ Á ÁH/HÁ Á ÁO, CÁ Á ÁH/HÁ Á ÁC, FÁ Á ÁH/HÁ Á ÁF, FÁ Á ÁF, CÁ Á ÁF/FÁ Á ÁC and CÁ Á ÁC contacts (McKinnon et al., 2007) are illustrated in Fig. 10a-h, respectively; their relative contributions are summarized in Table 3. The fingerprint plot delineated into HÁ Á ÁH contacts, Fig. 10b, shows that although these make the greatest contribution to the overall Hirshfeld surface, i.e. 31.2%, its comparatively low value is due to the involvement of many of the available hydrogen atoms of the various functional groups in specific intermolecular O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds. A nearly symmetric (mirror) distribution of points reflected as a

Figure 9
The immediate environments about the (a) N1-cation, (b) N3-cation and (c) anions and water molecule. The reference molecule within the Hirshfeld surfaces are mapped over d norm and highlight their participation in intermolecular interactions. saw-tooth with the tips at d e + d i $2.1 Å correspond to a short interatomic piperidinium-H1OÁ Á ÁH2O contact between hydroxyl-hydrogens of the two independent cations, Table 2; the other short interatomic HÁ Á ÁH contacts, Table 2, are associated with the points distributed in (d e , d i ) region less than the van der Waals separations, i.e. 2 Â 1.2 Å . The 19.2% contributions from OÁ Á ÁH/HÁ Á ÁO contacts to the overall surface results from intermolecular O-HÁ Á ÁO, N-HÁ Á ÁO and C-HÁ Á ÁO interactions as well as short interatomic OÁ Á ÁH/ HÁ Á ÁH contacts in the crystal, Table 2. In the fingerprint plot delineated into OÁ Á ÁH/HÁ Á ÁO contacts, Fig. 10c, a pair of long spikes having tips at d e + d i $1.7 Å and the appearance of green points aligned as a pair of streaks are due to the presence of dominant O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds.
The fingerprint plot corresponding to CÁ Á ÁH/HÁ Á ÁC contacts, Fig. 10d, show a fin-like distribution of points with the edges at d e + d i $2.6 Å resulting from the presence of C-HÁ Á Á interactions and short interatomic CÁ Á ÁH/HÁ Á ÁC contacts, as summarized in Table 2. The presence of a pair of two small peaks at d e + d i $2.7 Å and 2.8 Å in a tube-shaped distribution of points in the fingerprint plot delineated into FÁ Á ÁH/HÁ Á ÁF contacts, Fig. 10e, arise from short intermolecular FÁ Á ÁH/HÁ Á ÁF contacts, Table 2. The presence of two trifluoromethyl groups in each cation increases the percentage contribution from these contacts to the Hirshfeld surface to 23.1%, thereby contributing to the reduced relative contribution from HÁ Á ÁH contacts. In the fingerprint delineated into FÁ Á ÁF contacts, Fig. 10f, the distribution of points in a penciltip shape with the tip at d e + d i $2.8 Å represent the short interatomic FÁ Á ÁF contacts listed in Table 2. The intermolecular C-FÁ Á Á and CÁ Á ÁF interactions in the crystal are characterized by a fin-shape, at d e + d i $3.0 Å , in the fingerprint plot delineated into CÁ Á ÁF/FÁ Á ÁC contacts, Fig. 10g, and make a 4.6% contribution to the surface. A small 2.3% contribution from CÁ Á ÁC contacts to the Hirshfeld surface with the parabolic distribution of points, Fig. 10h, around the (d e , d i ) distances slightly shorter than their van der Waals radii, i.e.
2 Â 1.7 Å , indicatestacking interactions between quinolinyl rings. The presence ofstacking interactions between the symmetry-related rings is also indicated through the appearance of red and blue triangle pairs on the Hirshfeld surface mapped with shape-index property identified with arrows in the images of Fig. 11, and in the flat regions on the Hirshfeld surfaces mapped over curvedness in Fig. 12.

Database survey
Recent contributions to the structural chemistry of mefloqinium salts (Jotani et al., 2016;Wardell et al., 2016) have included tabulated summaries of related literature structures and key geometric parameters. The cations in (I) conform to expectation. Two recently determined structures are particularly noteworthy as they exhibit kryptoracemic behaviour, i.e. contain enantiomeric species that are not related by crystallographic symmetry, meaning they crystallize in one of the 65 Sohncke space groups, which lack inversion centres, rotatory inversion axes, glide planes and mirror planes. This phenomenon is rare for organic species, occurring in just 0.1% of their structures (Fá biá n & Brock, 2010). The two kryptoracemates arise for different reasons. In the first example, the orthorhombic (P2 1 2 1 2 1 ) crystals isolated from the 1:1 reaction of mefloquinium chloride and p-fluorobenzenesulfonyl chloride in the presence of NaOH ( Views of Hirshfeld surfaces mapped over the shape-index for the (a) (N1,C1-C3,C9) and (b) (C21-C26) rings, highlightingstacking.
3,3,3-trifluoro-2-methoxy-2-phenylpropanate salt (Wardell et al., 2016). The latter reason seems to apply in the case of (I) where a non-crystallographic symmetry relationship exists between the cations. However, (I) being centrosymmetric indicates that kryptoracemic-type behaviour for the mefloquinium cation is not limited to non-centrosymmetric structures.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. The H atoms were geometrically placed (C-H = 0.95-1.00 Å ) and refined as riding with U iso (H) = 1.2U eq (C). The O-and N-bound H atoms were located from difference maps but, refined with O-H = 0.84AE0.01 Å and N-H = 0.88AE0.01 Å , and with U iso (H) = 1.2U eq (N) and 1.5U eq (O). One reflection, i.e. (111), was omitted from the final refinement owing to poor agreement. The C27-CF 3 group was modelled as being disordered over two orientations with a site occupancy ratio 0.775 (3): 0.225 (3). The anisotropic displacement parameters for pairs of F atoms were constrained to be equal and restrained to be nearly isotropic. Even so, one atom in particular showed elongated displacement ellipsoids, i.e. the F8 atom, but this was not modelled further. Multiple atomic positions were not discerned for the O6-anion, Fig. 3b. Finally, the maximum and minimum residual electron density peaks of 1.75 and 0.66 eÅ À3 , respectively, were located 0.84 Å and 0.35 Å from the H44 and O7 atoms, respectively. Given the strong and directional hydrogen bonding in this region of the molecule, it is likely that the large residual is an artefact of the data.  Computer programs: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998), SHELXS97 (Sheldrick, 2008), SHELXL2014/7 (Sheldrick, 2015), ORTEP-3 for Windows (Farrugia, 2012), QMol (Gans & Shalloway, 2001), DIAMOND (Brandenburg, 2006) and publCIF (Westrip, 2010).