A kryptoracemic salt: 2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-ium (+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate

The l-shaped cations in the title compound are related across a non-crystallographic centre of inversion and therefore, are kryptoracemic. Supramolecular chains arise in the crystal packing as a result of O—H⋯O and N—H⋯N hydrogen bonding.

The asymmetric unit of the title salt, C 17 H 17 F 6 N 2 O + ÁC 10 H 8 F 3 O 3 À , comprises two piperidin-1-ium cations and two carboxylate anions. The cations, each having an l-shaped conformation owing to the near orthogonal relationship between the quinolinyl and piperidin-1-ium residues, are pseudo-enantiomeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxylate, methoxy and benzene groups. Arguably, the most prominent difference between the anions occurs about the C q -O m bond as seen in the C c -C q -O m -C m torsion angles of À176.1 (3) and À67.1 (4) , respectively (q = quaternary, m = methoxy and c = carboxylate). The presence of O h -HÁ Á ÁO c and N p -HÁ Á ÁO c hydrogen bonds leads to the formation of a supramolecular chain along the a axis (h = hydroxy and p = piperidin-1-ium); weak intramolecular N p -HÁ Á ÁO h hydrogen bonds are also noted. Chains are connected into a threedimensional architecture by C-HÁ Á ÁF interactions. Based on a literature survey, related molecules/cations adopt a uniform conformation in the solid state based on the letter L.

Chemical context
Biological considerations remain as the primary reason for the study of mefloquine, Scheme 1, and derivatives thereof. For example, when the racemic compound is protonated (employing HCl as the acid) at the piperdinyl-N atom, the resulting [(R*,S*)-(2-{[2,8-bis(trifluoromethyl)quinolin-4-yl]-(hydroxymethyl)piperidin-1-ium chloride salt, usually referred to as racemic erythro-mefloquine hydrochloride, is an anti-malarial drug (Maguire et al., 2006). Other biological activities have been described for these compounds, namely anti-bacterial (Mao et al., 2007), anti-mycobacterial (Gonçalves et al., 2012) and anti-cancer (Rodrigues et al., 2014). ISSN 2056-9890 It was in this context that the title salt was isolated from the attempted chiral resolution of mefloquine with the carboxylic acid, (+)-PhC(CF 3 )(OMe)CO 2 H. Resolution of racemic bases into the individual enantiomers has been traditionally achieved via salt formation with a chiral acid, since usually such salts of the different enantiomeric bases will have different properties, especially solubilities arising from differences in their crystal structures. Hence, fractional crystallization of such salts is frequently a convenient way to separate the enantiomers. Crystallography showed the triclinic P1 crystals to comprise the [(+)-erythro-mefloquinium] and [(À)-erythro-mefloquinium] cations with two independent (+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate anions providing the charge balance, Scheme 2. There is a noncrystallographic enantiomeric relationship between the cations so the sample is classified as a kryptoracemate. Surveys of this phenomenon have appeared in recent times for both organic (Fá biá n & Brock, 2010) and metal-organic (Bernal & Watkins, 2015) systems. Herein, the crystal and molecular structures of the title salt, (I), are described.

Structural commentary
In the present study, the reaction of racemic (AE)-erythromefloquine with the chiral carboxylic acid, (+)-PhC(CF 3 )(O-Me)CO 2 H, was carried out. However, as revealed by the X-ray The molecular structures of the (a) first and (b) second independent cations in (I), showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level. (c) 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.

Figure 2
The molecular structures of the (a) first and (b) second independent anions in (I), showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level. (c) An overlap diagram highlighting the differences in the conformations of the first (red) and second (blue) independent anions. The anions are overlapped so the -atoms about the chiral centre are coincident.
crystal structure determination described herein, the isolated crystalline salt contained both mefloquinium enantiomers and two independent carboxylate anions. It is noticeable that in the 1 H NMR spectrum in DMSO solution of the isolated crystals, the proton signals, H5, H6 and H7, of the quinolinyl ring are doubled, e.g. at 7.80 and 7.85 (H6), 8.36 and 8.37 (H5) and 8.85 and 8.89 (H7) p.p.m., suggesting that the quinolinyl fragments in the complex salt are experiencing two slightly different magnetic environments. This doubling is not found for racemic mefloquinium salts of non-chiral acids, such as acetic and nitrobenzoic acids. The crystallographic asymmetric unit of (I) comprises two independent mefloquinium cations, Fig. 1, and two independent carboxylate anions, Fig. 2. Confirmation of protonation and the formation of a piperidin-1-ium cation is found in the pattern of hydrogen-bonding interactions, as discussed in Supramolecular features below. On the other hand, confirmation of deprotonation of the carboxylic acid during crystallization is seen in the virtual equivalence of the C35-O3,O4 [1.231 (5)  Symmetry codes: (i) x þ 1; y; z; (ii) x; y; z þ 1; (iii) x þ 1; y; z À 1.  The N1-containing cation, Fig. 1a, with R-and S-configurations at the C12 and C13 chiral centres, respectively, is assigned as [(+)-erythro-mefloquinium], while with inverted configurations at the C29 and C30 centres, respectively, Fig. 1b, the N3-containing cation is [(À)-erythro-mefloquinium]. The cations are related by a pseudo centre of inversion and indeed the N1-containing molecule is virtually superimposable upon the mirror image of the N3-molecule, Fig. 1c, with the r.m.s. difference for bond distances and angles being 0.0082 Å and 0.550 , respectively (Spek, 2009). Differences relate to the relative orientation of the piperidin-1-ium residue. The hydroxyl-O and ammonium-N atoms lie to the same side of the cation being gauche across the methine-C-C(methine) bond with NÁ Á ÁO = 2.677 (3) Å and O1-C12-C13-N2 = À57.5 (4) for the N1-cation, with the equivalent values for the N3-cation being 2.734 (3) Å and 59.2 (3) . Despite the close separation, the O and N atoms are connected by only a weak intramolecular hydrogen bond as the relevant H atom forms a strong intermolecular hydrogen bond in each case (see below). The piperidin-1-ium residue lies almost orthogonal to the quinolinyl residue with the C2-C3-C12-C13 and C19-C20-C29-C30 torsion angles being 100.5 (4) and À105.1 (4) , respectively. Overall, the shape of each cation is based on the letter, L.
The non-crystallographic enantiomeric relationship between the cations is an example of kryptoracemic behaviour, a phenomenon known in both organic (Fá biá n & Brock, 2010) and metal-organic (Bernal & Watkins, 2015) crystals. While known, this is rare occurring in 0.1% of all possible organic structures. This is consistent with the fact that racemic compounds, achiral molecules and those with meso symmetry prefer to crystallize about a centre of inversion.
The anions in (I) have the same absolute structure but differ in terms of the relative orientations of most of the substituents, Fig. 2a, b. As illustrated in the overlap diagram, Fig. 2c, while the C*C 3 O tetrahedron is, as expected, virtually super-imposable, except for the trifluromethyl groups, the remaining substituents are orientated differently. The differences are quantified in the following terms. While to a first approximation the carboxylate and methoxy groups lie on a plane in the first anion, Fig. 2a, [the O3,O4-C35-C36-O5 torsion angles are À18.6 (5) and 162.9 (3) , respectively, and C35-C36-O5-C38 is À176.1 (3) ], in the second anion, Fig. 2b, these groups do not lie in a plane [the O6,O7-C45-C46-O8 torsion angles are À112.9 (4) and 65.1 (4) , respectively, and C45-C46-O8-C48 is À67.1 (4) ]. In addition, the benzene rings occupy different relative positions to the carboxylate groups as indicated in the C 6 /CO 2 dihedral angles of 89.1 (2) and 77.91 (17) respectively.

Supramolecular features
As expected from the chemical composition, the molecular packing is dominated by O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonding, Table 1. Each hydroxyl group forms a charge-assisted O-HÁ Á ÁO hydrogen bond with a carboxylate-O atom; the O1hydroxyl group also forms a weaker O-HÁ Á ÁO interaction with the second carboxylate group. Each of the H1N, H2N and H3N protons of the piperidin-1-ium residues is bifurcated. Two of these interactions are intramolecular N-HÁ Á ÁO h (h = hydroxyl) while the remaining N-HÁ Á ÁO interactions, including that formed by the H4N atom, have a carboxylate-O atom as the acceptor. The result of the hydrogen bonding is the formation of a supramolecular chain along the a axis, Fig. 3a. The chains associate via C-HÁ Á ÁF contacts to form the three-dimensional crystal structure, Fig. 3b; see Table 1 for parameters describing the closest C-HÁ Á ÁF contact.

Database survey
The crystallographic literature (Groom et al., 2016) Table 2 Geometric data (Å , ) for mefloquine (Mef) and mefloquinium cations (Mef + ).  geometric descriptors is given in Table 2. Owing to multiple molecules in several of the structures, i.e. two in (II) and (V), three in (VI) and (XV), four in (IV) and five in (III), a reasonable sample of structures is available for comment. The data confirm the proximity of the hydroxy-O and ammonium-N atoms in these species, and the l-shaped conformation owing to the orthogonal relationship between the quinolinyl and piperidin-1-ium residues. Despite varying compositions in (I)-(XVII), it is apparent that the molecular structures found for mefloquine/mefloquinium cations are robust. Finally, as mentioned above, the phenomenon of kryptoracemates is rare, occurring in just 0.1% of organic crystal structures (Fá biá n & Brock, 2010). In this context it might be notable that the structure of (I) is the second example of such behaviour in the structural chemistry of mefloquinium cations, complementing the recent report of (AE)-[Mef + ][O 3 OS-C 6 H 4 F-4]Cl (Jotani et al., 2016).

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.