Bis(mefloquinium) butanedioate ethanol monosolvate: crystal structure and Hirshfeld surface analysis

As the piperidin-1-ium group is nearly orthogonal to the quinolinyl residue in each of the two independent cations of the title salt solvate, these cations are l-shaped. Supramolecular chains arise in the crystal as a result of charge-assisted O—H⋯O and N—H⋯O hydrogen bonding.

The asymmetric unit of the centrosymmetric title salt solvate, 2C 17 H 17 F 6 N 2 O + Á-C 4 H 4 O 4 2À ÁCH 3 CH 2 OH, (systematic name: 2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-ium butanedioate ethanol monosolvate) comprises two independent cations, with almost superimposable conformations and each approximating the shape of the letter L, a butanedioate dianion with an all-trans conformation and an ethanol solvent molecule. In the crystal, supramolecular chains along the a-axis direction are sustained by chargeassisted hydroxy-O-HÁ Á ÁO(carboxylate) and ammonium-N-HÁ Á ÁO(carboxylrboxylate) hydrogen bonds. These are connected into a layer via C-FÁ Á Á(pyridyl) contacts andstacking interactions between quinolinyl-C 6 and -NC 5 rings of the independent cations of the asymmetric unit [inter-centroid separations = 3.6784 (17) and 3.6866 (17) Å ]. Layers stack along the c-axis direction with no directional interactions between them. The analysis of the calculated Hirshfeld surface reveals the significance of the fluorine atoms in surface contacts. Thus, by far the greatest contribution to the surface contacts, i.e. 41.2%, are of the type FÁ Á ÁH/HÁ Á ÁF and many of these occur in the interlayer region. However, these contacts occur at separations beyond the sum of the van der Waals radii for these atoms. It is noted that HÁ Á ÁH contacts contribute 29.8% to the overall surface, with smaller contributions from OÁ Á ÁH/ HÁ Á ÁO (14.0%) and FÁ Á ÁF (5.7%) contacts.

Chemical context
Malaria continues to be a major worldwide health issue and vast populations in tropical countries, including visitors to those regions, are susceptible to the disease, which is spread by parasites such as Plasmodium falciparum (Maguire et al., 2006). The problem is compounded by the parasites' abilities to develop resistance to drugs, such as to the once popular chloroquine (Grabias & Kumar, 2016). Mefloquine, [2,8-bis-(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol, is a drug used against malaria (Tickell-Painter et al., 2017). The molecule contains two adjacent chiral centres, i.e. one at the carbon atom carrying the hydroxy group and one at the link connecting the piperidinyl ring to the rest of the molecule. The drug is commonly marketed as Lariam, which is the hydrochloride salt, comprising (R*,S*)-(2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxymethyl)piperidin-1-ium chloride and its (S*,R*) enantiomer. While the former is effective against malaria, the latter has an affinity for the adenosine acceptors in the brain, inducing serious psychiatric and neurologic sideeffects (Nevin, 2017). Hence, experiments at resolving the enantiomers are of practical importance (Engwerda et al., 2019). Herein, as continuation of our anion-exchange experiments of the racemic salt and attendant structural studies , the crystal and molecular structures of the butanedioate salt, isolated as an ethanol monosolvate, are described along with an analysis of the calculated Hirshfeld surfaces.

Structural commentary
The asymmetric unit of the salt solvate, (I), comprises two mefloquinium cations, a butanedioate dianion and a solvent ethanol molecule; the molecular structures of the ions are shown in Fig. 1. Evidence of proton transfer during crystallization is seen in the relatively small difference in the C . . . O bond lengths of the dianion, i.e. C35-O3, O4 = 1.236 (4) and 1.285 (3) Å , and C38-O5, O6 = 1.255 (4) and 1.271 (4) Å . While normally these bond lengths might be expected to be closer to equivalent, as noted below, each of the O4 and O6 atoms participate in two strong charge-assisted hydrogen bonds, see Supramolecular features, which explains the slightly longer C . . . O bond lengths formed by these atoms. Further support for proton transfer leading to the formation of piperidin-1-ium cations is supported by the pattern of hydrogen bonding involving the ammonium-N-H hydrogen atoms, as discussed below in Supramolecular features.
The cations exhibit very similar molecular geometries, as highlighted in the overlay diagram of Fig. 2. There are two chiral centres in each cation and the illustrated cations are R at C12 and S at C13 for the N1-cation, and R at C29 and S at C30 for the N3-cation, i.e. each conforms to the [(+)-erythro-mefloquinium] isomer; space-group symmetry indicates that the unit cell contains equal numbers of both enantiomers. The r.m.s. deviation for the ten atoms comprising the N1-quinolinyl residue is 0.0254 Å [0.0256 Å for the N3-quinolinyl residue], with the hydroxy-O1 and ammonium-N2 atoms lying to either side of the plane, i.e. À0.323 (4) and 1.302 (6) Å , respectively [0.255 (4) Å for O2 and À1.348 (6) Å for N4]. The dihedral angle of 72.55 (9) [71.48 (9) ] formed between the fused ring system and the least-squares plane through the piperinium ring indicates that, to a first approximation, the molecule has the shape of the letter L. Referring to Table 1, an intramolecular charge-assisted ammonium-N + -HÁ Á Á O(hydroxy) hydrogen-bond is formed as the hydroxyl-O1 and ammonium-N2 atoms lie to the same side of the cation with An overlay diagram of the N1-(red image) and N3-containing cations. The cations have been superimposed so that the C 5 N rings of the quinolinyl residues are coincident. Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The molecular structures of the ionic components of the asymmetric unit of (I) showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level: (a) the N1-containing cation, (b) the N3-cation and (c) the butanedioate dianion.

Supramolecular features
The most prominent feature of the molecular packing is the formation of twisted supramolecular chains propagating parallel to the a-axis direction, Table 1 and Fig. 3a. Each of the cation-bound hydroxy groups forms a charge-assisted hydroxy-O-HÁ Á ÁO(carboxylate) hydrogen bond to a carboxylate-O atom, at opposite ends of the butanedioate dianion. In addition, each of the four ammonium-N-H hydrogen atoms connects to a carboxylate-O atom, each derived from a different carboxylate residue, via a charge-assisted ammonium-N-HÁ Á ÁO(carboxylate) hydrogen bond. Thus, each of the O4 and O6 atoms accept two charge-assisted hydrogen bonds. The carboxylate-O5 atom accepts a hydrogen bond from the solvent ethanol molecule, while ethanol-O7 participates in a methine-C-HÁ Á ÁO interaction, Table 1. The carboxylate-O3 atom forms only one hydrogen bond. The number and strength of hydrogen bonds formed by the carboxylate-O atoms correlates with the magnitude of the C . . . O bond lengths, e.g. the C35-O3 < C38-O5 < C38-O6 C35-O4 (see comment in Structural Commentary).

Hirshfeld surface analysis
The analysis of Hirshfeld surface calculations for (I) was performed in order to learn more about the supramolecular association, in particular, about the inter-layer connections, following established procedures (Tan et al., 2019) and employing Crystal Explorer 17 (Turner et al., 2017). Such analyses have proven useful for salts with multiple components comprising the asymmetric unit .
It is clearly evident from the numerous characteristic red spots on the Hirshfeld surfaces mapped over d norm for the constituents of (I), shown in Fig. 4, that the butanedioate dianion plays a crucial role in forming significant interactions with each of the two independent mefloquinium cations as well as with the ethanol solvent molecule. The O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds summarized in Table 1 are characterized as bright-red spots on the Hirshfeld surface mapped over d norm for the dianion, Fig. 4a    respective donors on the Hirshfeld surfaces of the ethanol molecule, Fig. 4c, and mefloquinium cations in Fig. 4d and e. The effects of the short inter-atomic contacts on the packing of (I), summarized in Table 2, are also evident as the faint-red spots near the respective atoms, Fig. 4. The blue and red regions corresponding to positive and negative potentials, respectively, around the atoms of the dianion and solvent ethanol molecule, Fig. 5, and cations, Fig. 6, on the Hirshfeld surfaces mapped over electrostatic potential also represent donors and acceptors of the respective hydrogen bonds. The additional influence of the C-FÁ Á Á contacts involving the F2 and F3 atoms interacting with the (C4-C9) and N1-pyridyl rings of the N1-quinolinyl residue are viewed as blue bumps and bright-orange concave regions, respectively, on the Views of Hirshfeld surface mapped over electrostatic potential for the: (a) and (b) dianion in the range À0.072 to +0.066 atomic units (au) and (c) ethanol molecule (À0.077 to +0.159 au). The red and blue regions represent negative and positive electrostatic potentials, respectively.

Figure 6
Views of Hirshfeld surface mapped over electrostatic potential for the: (a) O1-containing cation in the range À0.262 to +0.215 atomic units (au) and (b) O2-containing cation (À0.255 to +0.198 au). The red and blue regions represent negative and positive electrostatic potentials, respectively.

Table 2
Summary of short interatomic contacts (Å ) in (I) a .
Contact Distance Symmetry operation Hirshfeld surface mapped with the shape-index property in  Table 3. The relatively small percentage contribution from HÁ Á ÁH contacts to the Hirshfeld surface in the overall packing of (I) is due to the formation of a wide range of different intermolecular interactions between the constituent cations, dianions and solvent ethanol molecule. This is well-evidenced in the long list of contacts in Table 3. The presence of two trifluoromethyl groups in each of the independent cations results in a major contribution from fluorine atoms to the Hirshfeld surface of (I), as highlighted in Table 3. Indeed, the major contributor of contacts to the surface is of the type FÁ Á ÁH/HÁ Á ÁF, at 41.2%. Many of these occur in the inter-layer region at separations greater than the sum of the van der Waals radii.
The presence of a cone-shaped tip at d e + d i 2.2 Å in the fingerprint plot delineated into HÁ Á ÁH contacts in Fig. 9b, is an indication of the short interatomic HÁ Á ÁH contact between symmetry-related piperidinium-H34A and ethanol-H39A atoms, Table 2. The other short HÁ Á ÁH contacts summarized in Table 2 occur between the hydrogen atoms of the cations and dianion within the asymmetric unit. In the fingerprint plot delineated into OÁ Á ÁH/HÁ Á ÁO contacts, Fig. 9c, the pair of long spikes with their tips at d e + d i $1.8 Å are due to the O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds involving the carboxylate-O4 atom of the dianion whereas the points corresponding to N-HÁ Á ÁO hydrogen bonds involving the O3 and O5 atoms of the dianion and those involved in short interatomic OÁ Á ÁH contacts, Table 2, are merged within the plot. The pair of conical tips at d e + d i $2.5 Å in the fingerprint plot delineated into FÁ Á ÁH/HÁ Á ÁF contacts, Fig. 9d, represent the presence of these short contacts. The effect of intermolecular C-FÁ Á Á/Á Á ÁF-C and short interatomic CÁ Á ÁF/ FÁ Á ÁC contacts on the molecular packing, Table 3, results in a small but measurable contribution of 2.8% to the Hirshfeld surface of (I) and are viewed as the pair of forceps-like tips at d e + d i $3.1 Å in Fig. 9e

Figure 7
A view of Hirshfeld surface mapped over the shape-index property highlighting the intermolecular C-FÁ Á Á/Á Á ÁF-C contacts by blue bumps and bright-orange concave regions.

Figure 8
A view of Hirshfeld surface mapped over d norm for the O1-containing cation in the range À0.229 to + 2.242 arbitrary units highlighting the intramolecularcontacts between the (C4-C9) ring of the O1containing cation and the (C21-C26) and N3-pyridyl rings of the O2containing cation by red and black dotted lines, respectively.
$3.0 Å in Fig. 9f. Finally, the presence ofstacking interactions between the (C4-C9) ring of the O1-cation and the (C21-C26) and N3-pyridyl rings of the O2-cation are reflected in the 3.4 and 3.3% contributions from CÁ Á ÁC contacts to the Hirshfeld surfaces of the individual cations; although the contribution from these contacts to the surfaces in the overall structure of (I) is negligible as these are embedded within the asymmetric unit.

Database survey
As indicated in the Chemical context, the specific enantiomer of Lariam is important in terms of pharmacological activity. Hence, considerable investment has been made in attempting to resolve the enantiomers by salt formation. During such studies, a seemingly high propensity towards kryptoracemic behaviour has been revealed. Kryptoracemic behaviour is related to the rare phenomenon where enantiomeric molecules crystallize in one of the 65 Sohncke space groups, i.e. space groups which lack an inversion centre, a rotatory inversion axis, a glide plane or a mirror plane. In these circumstances, the enantiomeric molecules are related by noncrystallographic symmetry, e.g. a non-crystallographic centre of inversion. A review of this phenomenon has appeared for organic compounds (Fá biá n & Brock, 2010) where such behaviour is found in only 0.1% of structures. There are about 30 mefloquine/derivatives in the Cambridge Structural Database (Groom et al., 2016) and of these, there are two examples of kryptoracemates Wardell, Wardell et al., 2016). Further, in a very recent study, 34 new mefloquine salts were reported of which two were kryptoracemates (Engwerda et al., 2019). Such a high adoption of kryptoracemic behaviour by these species suggest that further, systematic structural studies are warranted.