2-{[2,8-Bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-ium trichloroacetate: crystal structure and Hirshfeld surface analysis

The mefloquinium cation in the title salt is l-shaped as the piperidin-1-ium group is nearly orthogonal to the quinolinyl residue. Supramolecular chains arise in the crystal as a result of charge-assisted O—H⋯O and N—H⋯O hydrogen-bonding.


Chemical context
Kryptoracemic behaviour is an interesting but rare phenomenon whereby enantiomeric molecules crystallize in one of the 65 Sohncke space groups. Sohncke space groups lack an inversion centre, a rotatory inversion axis, a glide plane or a mirror plane, implying Z 0 would usually be greater than 1 (unless the molecule lies on a rotation axis) and in which enantiomeric molecules, when present, are related by a noncrystallographic symmetry, e.g. a non-crystallographic centre of inversion. Reviews of this phenomenon have appeared for organic compounds (Fá biá n & Brock, 2010) and for coordination complexes (Bernal & Watkins, 2015). For organic molecules, kryptoracemic behaviour is uncommon and is found in only 0.1% of structures (Fá biá n & Brock, 2010). It is therefore of interest that pharmacologically relevant (Gonçalves et al., 2012) mefloquine/derivatives, for which there are about 30 structures included in the Cambridge Structural Database (Groom et al., 2016), present two examples of kryptoracemates Wardell, Wardell et ISSN 2056-9890 al., 2016. In order to investigate reasons for this seemingly high propensity towards kryptoracemic behaviour in mefloquine derivatives, crystallographic studies of different mefloquinium salts have subsequently been performed  and in a continuation of these, herein the crystal and molecular structures of the title salt, (I), isolated from the 1:1 crystallization of racemic mefloquine and trichloroacetic acid are described. This is complemented by an analysis of its calculated Hirshfeld surface.

Structural commentary
The two ions comprising the asymmetric unit of salt (I) are shown in Fig. 1. The crystal of (I) is racemic. Each cation contains two chiral centres and the illustrated cation in the arbitrarily chosen asymmetric unit is S at C12 and R at C13, i.e. conforming to the [(À)-erythro-mefloquinium] isomer. That protonation from the carboxylic acid to the base occurred during co-crystallization is readily seen in the equivalence of the C18 . . . O2, O3 bond lengths, i.e. 1.238 (3) and 1.245 (3) Å , respectively. The formation of the piperidin-1-ium cation is supported by the pattern of hydrogen bonding involving the ammonium-N-H H atoms. Indeed, an intramolecular ammonium-N + -HÁ Á ÁO(hydroxy) hydrogen bond is formed ensuring the hydroxyl-O1 and ammonium-N2 atoms are orientated to the same side of the cation with the O1-C12-C13-N2 torsion angle of 58.90 (19) angle indicating a + synclinal relationship. The r.m.s. deviation for the 10 atoms comprising the quinolinyl residue is 0.0147 Å , with the hydroxy-O1 [À0.299 (3) Å ] and ammonium-N2 [1.490 (4) Å ] atoms lying to either side of the plane. The dihedral angle of 74.00 (5) formed between the fused ring system and the best plane through the piperidin-1-ium ring indicates that, overall, the molecule has the shape of the letter L. This is confirmed by the +syn-clinal C3-C12-C13-C17 torsion angle of 60.1 (2) .
In the anion, the r.m.s. deviation through the C 2 O 2 atoms is 0.0131 Å with the Cl3 atom lying to one side of the plane [deviation = 1.7153 (3)

Supramolecular features
The presence of charge-assisted hydrogen bonds between the constituent ions lead to linear, supramolecular chains along the a-axis direction in the crystal of (I), Table 1 and Fig. 2(a). The most prominent feature of the packing is the formation of centrosymmetric, eight-membered {Á Á ÁOÁ Á ÁHNH} 2 synthons, which arise as a result of ammonium-N + -HÁ Á ÁO À (carboxylate) hydrogen bonds whereby two ammonium cations bridge, via both hydrogen atoms, a pair of carboxylate-O2 atoms. The four-ion aggregates are linked into the chain via chargeassisted hydroxyl-O-HÁ Á ÁO À (carboxylate) hydrogen bonds. These lead to larger centrosymmetric agglomerates, i.e. 18membered {Á Á ÁOCOÁ Á ÁHOC 2 NH} 2 synthons. The connections between the chains are of the type C-XÁ Á Á, for X = Cl and F. The molecular structures of the two ions comprising the asymmetric unit of (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level. The dashed line signifies an N-HÁ Á ÁO hydrogen bond. Table 1 Hydrogen-bond geometry (Å , ).
Cg1 and Cg2 are the centroids of the C4-C9 and N1/C1-C4/C9 rings, respectively. Such interactions are inherently weak, providing energies of stabilization less than 4 kcal mol À1 , with those for interactions involving chloride atoms being greater than those with fluoride (Tsuzuki et al., 2016). In the crystal of (I), C-ClÁ Á Á(C 6 -quinolinyl) interactions are formed whereby the C-Cl bond is approximately parallel to the C 6 ring. Each of the fluoride atoms bound to the C10 atom participates in a C-FÁ Á Á contact as these CF 3 groups lie in regions flanked by quinolinyl residues. Two of the contacts are as for the chloride atom, i.e. side on, whereas the other is best described as an end-on C-FÁ Á Á contact as the angle subtended at the F1 atom is 170.95 (14) . The aforementioned interactions combine to form a three-dimensional architecture. A view of the unit-cell contents is shown in Fig. 2(b).

Hirshfeld surface analysis
The Hirshfeld surface calculations for the title salt (I) were performed in accord with an earlier publication on a related organic salt . This analysis provides a convenient means to describe the formation of the salt through the charge-assisted N-HÁ Á ÁO hydrogen bonds and C-HÁ Á ÁO contacts, and the influence of weak interactions involving halide substituents in the crystal. Views of the Hirshfeld surface of (I) mapped over d norm in the range À0.171 to +1.475 a.u. for the (a) cation and (b) anion, highlighting N-HÁ Á ÁO and C-HÁ Á ÁO contacts as black dashed lines. Table 2 Summary of short interatomic contacts (Å ) in (I) a .
Contact Distance Symmetry operation  surfaces mapped over d norm in Fig. 3 represent the chargeassisted N-HÁ Á ÁO hydrogen-bonds; the methylene-C13-HÁ Á ÁO3 contact, Table 2, on the Hirshfeld surface is evident as the diminutive-red spot between the respective atoms in Fig. 3 Table 3. The relatively small contribution, i.e. 12.4%, from HÁ Á ÁH contacts to the Hirshfeld surfaces of (I) is due to the presence of terminal halide substituents in both the cation and anion and their relatively high contribution to a major portion of the surface.
The intermolecular N-HÁ Á ÁO and O-HÁ Á ÁO hydrogenbonds in the packing of (I) indicate a significant contribution from OÁ Á ÁH/HÁ Á ÁO contacts to the surface and these are evident as the two pairs of superimposed long spikes with the tips at d e + d i $1.7 Å in the delineated fingerprint plot. The largest percentage contribution to the Hirshfeld surface are from FÁ Á ÁH/HÁ Á ÁF contacts, i.e. 25.4%. This is due to the presence of a number of short interatomic HÁ Á ÁF contacts,

Figure 4
Views of the Hirshfeld surface of (I) mapped over d norm in the range À0.121 to +1.475 a.u. for the (a) cation, (b) anion and (c) ion pair. The N-HÁ Á ÁO, O-HÁ Á ÁO and C-HÁ Á ÁO contacts are shown as black dashed lines. The faint-red spots near the labelled atoms in (b) and (c) indicate the short interatomic contacts (see text and Table 2).

Figure 5
A view of the Hirshfeld surface of (I) mapped over the electrostatic potential in the range À0.128 to + 0.215 a.u. The red and blue regions represent negative and positive electrostatic potentials, respectively.

Figure 6
Three views of Hirshfeld surface of (I) mapped over the shape-index property highlighting (a) C-ClÁ Á Á/Á Á ÁCl-C contacts through yellow dotted lines, (b) and (c) C-FÁ Á Á/Á Á ÁF-C contacts with through black dotted lines. The '1 0 , '2 0 and '3 0 refer to the F1-F3 atoms, respectively  Table 2. The presence of short interatomic CÁ Á ÁF/FÁ Á ÁC contacts, Table 2, and C-FÁ Á Á contacts (Table 1) involving fluoride atoms substituted at the methyl-C10 atom is evident from the forceps-like distribution of points in the fingerprint plot delineated into these contacts. The C-ClÁ Á Á contact, Table 1, involving the carboxylate-Cl3 atom, Fig. 6(a), is viewed as the spear-shaped distribution of points with the pair of adjoining tips at d e + d i $ 3.5 Å in the fingerprint plot delineated into CÁ Á ÁCl/ClÁ Á ÁC contacts. Although the interatomic ClÁ Á ÁH/ HÁ Á ÁCl and ClÁ Á ÁCl contacts make significant contributions to the Hirshfeld surface of (I), Table 3, and are reflected in the forceps-like and pencil-tip like distributions of points, respectively, in their delineated fingerprint plots, they occur at van der Waals separations. The small contribution from the other interatomic contacts to the Hirshfeld surface of (I), listed in Table 3, show negligible influence upon the packing.

Database survey
As noted in the Chemical context, there are two mefloquine derivatives that exhibit kryptoracemic behaviour with both examples being isolated after attempts at chiral resolution of racemic mefloquine with different carboxylic acids. In one example, two mefloquinium cations are related across a pseudo centre of inversion, and the charge balance is provided by two crystallographically independent 3,3,3-trifluoro-2methoxy-2-phenylpropanoate anions, i.e. (+)-PhC(CF 3 )-(OMe)CO 2 À . That it is not necessary to have chiral carboxylate anions is seen in the second example of kryptoracemic behaviour whereby, as a result of incomplete substitution of chloride by 4-fluorobenzenesulfonate during an anion exchange experiment, the asymmetric unit comprises a pair of pseudo-enantiomeric mefloquinium cations with equal numbers of chloride and 4-fluorobenzenesulfonate counter-ions .
There are a number of other structurally characterized mefloquinium salts, namely three isomeric n-nitrobenzoates , 3-amino-5-nitrobenzoate sesquihydrate (de Souza et al., 2011), hydroxy(phenyl)acetate hemihydrate  and trifluoroacetate trifluoroacetic acid hemihydrate (Low & Wardell, 2017), and all of these crystallize in centrosymmetric space groups with equal numbers of the mefloquinium enantiomers. Further studies into the interesting phenomenon of kryptoracemic behaviour in mefloquinium salts are underway.