Racemic mefloquinium chlorodifluoroacetate: crystal structure and Hirshfeld surface analysis

The l-shaped cation in the title salt arises from a nearly orthogonal disposition of the piperidin-1-ium ring with respect to the piperidin-1-ium group. Supramolecular chains arise in the crystal as a result of O—H⋯O and N—H⋯O hydrogen bonding.


Chemical context
Practical interest in compounds related to the title salt relates to the biological activity of Mefloquine ([2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol). This arises when the racemic compound is reacted with HCl: the resulting salt, [(R*,S*)-(2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxymethyl)piperidin-1-ium chloride is an anti-malarial drug, being effective against the causative agent, Plasmodium falciparum (Maguire et al., 2006). Subsequently, diverse pharmaceutical potential has been disclosed, namely, as antibacterial (Mao et al., 2007), anti-mycobacterial (Gonçalves et al., 2012) and as anti-cancer agents (Rodrigues et al., 2014). With the preceding facts in mind, it is not surprising that crystallography has played a key role in establishing the molecular structures of this class of compound. Of particular crystallographic interest has been the characterization of a pair of kryptoracemates of mefloquinium salts in recent years . The phenomenon of kryptoracemic behaviour has been reviewed in the last decade for both organic and coordination compounds (Fá biá n & Brock, 2010; Bernal & Watkins, 2015). ISSN 2056-9890 Briefly, for a material to be classified as kryptoracemic, it must satisfy the following crystallographic criteria: the space group must be one of the 65 Sohncke space groups, i.e. lacking an inversion centre, rotatory inversion axis, glide plane or a mirror plane, and Z 0 would usually be greater than 1 (unless the molecule lies on a rotation axis). In a continuation of structural studies of Mefloquine derivatives (Wardell et al., 2011;Wardell, Jotani et al., 2016), herein the crystal and molecular structures of the title salt, (I), isolated from the 1:1 crystallization of racemic Mefloquine and chlorodifluoroacetic acid are described along with an analysis of its calculated Hirshfeld surface.

Structural commentary
The ions comprising the asymmetric unit of (I) are shown in Fig. 1. The illustrated cation has two chiral centres, namely R at C12 and S at C13, i.e. it is the [(+)-erythro-mefloquinium] isomer. However, it should be noted that the centrosymmetric unit cell has equal numbers of the other S-,R-enantiomer, indicating that no resolution occurred during the crystallization experiment as has been observed in some of the earlier studies (see Chemical context). The pattern of hydrogen-bonding interactions involving the ammonium-N-H H atoms (see Supramolecular features) provides confirmation of protonation at the N2 atom during crystallization and, therefore, the formation of a piperidin-1-ium cation. At the same time, delocalization of the -electron density over the carboxylate residue is confirmed by the equivalence of the C18-O2, O3 bond lengths, i.e. 2 Â 1.238 (3) Å .
The quinolinyl residue is not strictly planar with the r.m.s. deviation for the ten fitted non-H atoms being 0.0399 Å . This is also reflected in the dihedral angle formed between the (N1,C1-C4,C9) and (C4-C9) rings of 3.95 (15) Å . This aspect of the structure notwithstanding, the hydroxyl-O and ammonium-N atoms lie to opposite sides of the plane through the quinolinyl residue. This is seen in the value of the C2-C3-C12-O1 torsion angle of À20.3 (3) cf. with that of 177.79 (18) for C3-C12-C13-N2. The latter angle indicates the piperidin-1-ium residue is almost perpendicular to the quinolinyl residue with the methylene-C17 group orientated towards the fused-ring system as seen in the gauche C3-C12-C13-C17 torsion angle of À60.7 (3) . The observed conformation, whereby the hydroxy-O and ammonium-N atoms lie to the same side of the molecule [the O1-C12-C13-N2 torsion angle is À59.7 (2) ], is stabilized by an intramolecular, charge-assisted ammonium-N2 + -HÁ Á ÁO1(hydroxyl) hydrogen bond, Table 1. In general terms, the shape of the cation is based on the letter, L.

Supramolecular features
The presence of charge-assisted hydroxyl-O-HÁ Á ÁO À (carb-(carboxylate) and ammonium-N + -HÁ Á ÁO À (carboxylate) hydrogen bonding features prominently in the molecular packing of (I) and leads to a supramolecular chain propagating along the b-axis direction, Fig. 1a

Hirshfeld surface analysis
The Hirshfeld surface calculations for the title salt (I) were performed in accord with an earlier publication on a related salt  and satisfactorily describe the additional influence of interatomic halogen-halogen, halogenhydrogen and halogenÁ Á Á contacts upon the packing. In addition to bright-red spots on the Hirshfeld surfaces mapped over d norm in Fig. 3a and b (labelled 1-3), corresponding to intermolecular O-HÁ Á ÁO, N-HÁ Á ÁO and C-HÁ Á ÁO interactions, Table 1, the presence of tiny faint-red spots, having labels S1-S4 in Fig. 3c    Views of the Hirshfeld surface of (I) mapped over d norm in the range À0.077 to +1.575 au, highlighting: (a) and (b) intermolecular hydrogen bonds (with labels 1-3) by black-dashed lines, and (c) and (d) short interatomic HÁ Á ÁH, FÁ Á ÁH and FÁ Á ÁF contacts (with labels S1-S4) by skyblue, red and black dashed lines, respectively. Table 2 Summary of short interatomic contacts (Å ) in (I).
Contact Distance Symmetry operation Table 2; calculated in CrystalExplorer3.1 (Wolff et al., 2012)]. On the Hirshfeld surfaces mapped over electrostatic potential in Fig. 4, the donors and acceptors of intermolecular hydrogen bonds are illustrated through the appearance of blue and red regions corresponding to positive and negative electrostatic potential, respectively. The presence of intermolecular side-on Table 1, are evident from the Hirshfeld surfaces mapped with shape-index property illustrated in Fig. 5. The overall two-dimensional fingerprint plot and those delineated (McKinnon et al., 2007) into HÁ Á ÁH, OÁ Á ÁH/HÁ Á ÁO, FÁ Á ÁH/HÁ Á ÁF, FÁ Á ÁF, CÁ Á ÁF/FÁ Á ÁC, ClÁ Á ÁH/HÁ Á ÁCl and CÁ Á ÁCl/ ClÁ Á ÁC contacts are illustrated in Fig. 6; the percentage contributions from the different interatomic contacts to the Hirshfeld surface are summarized in Table 3. The formation of a salt between the piperidinium cation and carboxylate anion through the charge-assisted hydrogen bonds and the presence of a number of HÁ Á ÁCl, F and O contacts result in the relatively small, i.e. 11.9%, contribution from HÁ Á ÁH contacts to the Hirshfeld surface. Conversely, the relative high number of  Figure 4 Two views of the Hirshfeld surface of (I) mapped over the electrostatic potential in the range À0.133 to + 0.219 au. The red and blue regions represent negative and positive electrostatic potentials, respectively.

Figure 5
Two views of Hirshfeld surface of (I) mapped over the shape-index property highlighting (a) C-ClÁ Á Á and (b) C-FÁ Á Á contacts by yellow and black dotted lines, respectively
fluorine atoms lying on the surfaces of both the cation and anion, largely participating in FÁ Á ÁH contacts, gives rise to their providing the greatest contribution, i.e. 40.8%, to the surface.
In the fingerprint plot delineated into HÁ Á ÁH contacts in Fig. 6, the short interatomic HÁ Á ÁH contact involving quinoline-H7 and methylene-H15B, both derived from the cation, Table 2, is viewed as pencil-like tip at d e + d i $2.0 Å . In the fingerprint plot delineated into OÁ Á ÁH/HÁ Á ÁO contacts, the spikes associated with the N-HÁ Á ÁO hydrogen bonds and C-HÁ Á ÁO interactions are merged within the plot. The obvious feature in the plot is a pair of spikes with tips at d e + d i $1.8 Å , which correspond to the most dominant O-HÁ Á ÁO hydrogen bond; this is also responsible for most of the points concentrated in the narrower region of spikes. The influence of short interatomic halogen-hydrogen and halogen-halogen contacts in the crystal, Table 2, is observed as a pair of forceps-like tips at d e + d i $2.5 Å (FÁ Á ÁH) and 3.0 Å (ClÁ Á ÁH), and an arrowshaped tip at d e + d i $2.8 Å in the fingerprint plots delineated into FÁ Á ÁH/HÁ Á ÁF, ClÁ Á ÁH/HÁ Á ÁCl and FÁ Á ÁF contacts, respectively. The involvement of chloride and fluoride atoms in C-halogenÁ Á Á contacts, Table 1, results in the small but significant percentage contribution from CÁ Á ÁF/FÁ Á ÁC and CÁ Á ÁCl/ ClÁ Á ÁC contacts to the Hirshfeld surface, Table 3. These intermolecular contacts are also characterized as forceps-like and anchor-shaped distributions of points in the fingerprint plots delineated into the respective contacts, Fig. 6. The small percentage contribution from other remaining interatomic contacts summarized in Table 3 have negligible effect on the packing in the crystal.

Database survey
Kryptoracemic behaviour is rare and is found in only 0.1% of all organic structures (Fá biá n & Brock, 2010). This observation clearly implies that 99.9% of racemic compounds, molecules with meso symmetry and achiral molecules will crystallize about a centre of inversion. Given there are fewer than 30 structures containing Mefloquine/derivatives of Mefloquine included in the Cambridge Structural Database (Groom et al., 2016), the reporting of two kryptoracemates of mefloquinium cations in recent times  suggests a higher than anticipated propensity for this phenomenon. The two examples were isolated from attempts at chiral resolution of Mefloquine with carboxylic acids. In the first of the two reported structures, the asymmetric unit comprised a pair of pseudoenantiomeric mefloquinium cations with the charge-balance provided by chloride and 4-fluorobenzenesulfonate anions . In the second example, again two mefloquinium cations are pseudo-racemic, with the charge-balance provided by two independent 3,3,3-trifluoro-2-methoxy-2phenylpropanoate anions, i.e. (+)-PhC(CF 3 )(OMe)CO 2 À . The appearance of kryptoracemic salts of mefloquinium with non-chiral and chiral counter-ions warrants further investigation into this comparatively rare behaviour in order to reveal the reasons for such crystallization outcomes.

Computing details
Data collection: COLLECT (Hooft, 1998); cell refinement: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); data reduction: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); program(s) used to solve structure: SHELXS (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2010). 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.