Influence of Halogen Substituent on the Self-Assembly and Crystal Packing of Multicomponent Crystals Formed from Ethacridine and Meta-Halobenzoic Acids

In order to determine the influence of halogen substituent on the self-assembly of the 6,9-diamino-2-ethoxyacridinium cations and 3-halobenzoate anions in the crystals formed from ethacridine and halobenzoic acids, the series of ethacridinium meta-halobenzoates dihydrates: ethacridinium 3-chlorobenzoate dihydrate (1), ethacridinium 3-bromobenzoate dihydrate (2), and ethacridinium 3-iodobenzoate dihydrate (3), were synthesized and structurally characterized. Single-crystal X-ray diffraction measurements showed that the title compounds crystallized in the monoclinic P21/c space group and are isostructural. In the crystals of title compounds, the ions and water molecules interact via N–H⋯O, O–H⋯O and C–H⋯O hydrogen bonds and π–π stacking interactions to produce blocks. The relationship between the distance X⋯O between the halogen atom (X=Cl, Br, I) of meta-halobenzoate anion and the O-atom from the ethoxy group of cation from neighbouring blocks and crystal packing is observed in the crystals of the title compounds.


Introduction
Drug products consist of pharmaceutical ingredients (APIs) and excipients that improve the physical properties of the APIs such as the solubility, stability, pharmacodynamic and pharmacokinetic properties of the product [1][2][3][4]. An example of an API is 6,9-diamino-2-ethoxyacridine (ethacridine), a component of a commonly-used drug known as acrinol (ethacridine lactate monohydrate; trade name: rivanol). Acrinol is a bacteriostatic antiseptic drug, which is usually used to treat suppurating infections and infections of the mouth and throat [5,6]. Furthermore, ethacridine lactate monohydrate is also used illegally as a highly effective abortifacient for second-trimester pregnancy termination [7].
Synthetic studies of the API derivatives provide new ways to improve their physical properties. In this regard, crystal engineering is of highly importance as it allows the precise design of compounds with desired properties. The APIs are often crystallized in a multicomponent system to explore their ability to form a variety of intermolecular interactions, such as: hydrogen bonds (O-H· · · O, N-H· · · O, C-H· · · O,C-H· · · π) [8][9][10][11][12][13][14], halogen bonds (X· · · X, X· · · O/N/S) [15][16][17][18], π-π [19][20][21], lp· · · π [22,23]. Among them, halogen bonding is a particularly interesting interaction as it is often crucial in the self-assembly and molecular recognition [24][25][26][27]. Halogen bonding is an attractive non-covalent interaction that occurs between a halogen atom and a Lewis base and its directionality and strength are often comparable to those of hydrogen bonds. The strength of such interaction increases in the order of Cl < Br < I.
Scheme 1 Chemical structures of the crystals system component reported in this paper.

Materials and Methods
All the chemicals were purchased from Sigma-Aldrich and used without further purification. Melting points were determined on a Buchi 565 capillary apparatus and were uncorrected.

Materials and Methods
All the chemicals were purchased from Sigma-Aldrich and used without further purification. Melting points were determined on a Buchi 565 capillary apparatus and were uncorrected.

X-ray Measurements and Refinements
Good-quality single-crystal specimens of 1-3 were selected for X-ray diffraction experiments at T = 295(2) K (Table 1). They were mounted with epoxy glue at the tip of glass capillaries. Diffraction data were collected on an Oxford Diffraction Gemini R ULTRA Ruby CCD diffractometer with MoKα (λ = 0.71073 Å) radiation. In all cases, the lattice parameters were obtained by least-squares fit to the optimized setting angles of the reflections collected by means of CrysAlis CCD [33]. Data were reduced using CrysAlis RED software [33] and applying multi-scan absorption corrections (empirical absorption correction using spherical harmonics, implemented in the SCALE3 ABSPACK scaling algorithm). The structural resolution procedure was carried out using the SHELX package [34]. The structures were solved with direct methods that carried out refinements by full-matrix least-squares on F 2 using the SHELXL-2017/1 program [34]. All H-atoms bound to N-atoms were located on a difference Fourier map and refined using a riding model, with N-H = 0.86 Å and U iso (H) = 1.2U eq (C). All H-atoms bound to aromatic C-atoms were placed geometrically and refined using a riding model with C-H = 0.93 Å and U iso (H) = 1.2U eq (C). All H-atoms from the methyl group were positioned geometrically and refined using a riding model, with C-H = 0.96 Å and U iso (H) = 1.5U eq (C). All H-atoms from the water molecules were positioned geometrically and refined using a riding model, with O-H = 0.85 Å and U iso (H) = 1.5U eq (O) (DFIX command). All interactions and the Kitaigorodskii type of packing index were calculated using the PLATON program [35]. The ORTEPII [36], PLUTO-78 [37] and Mercury [38] programs were used to prepare the molecular graphics.
In the packing of the crystals of title compounds, we can observe that distance between the halogen atom substituted in the meta-  (Figure 4). It is longer than the sum of the van der Waals radii of chlorine and oxygen atoms (3.27 Å) and bromine and oxygen atoms (3.37 Å); however, it is shorter than the In these blocks, we can also observe the N (6-amino) -H· · · O (carboxy) hydrogen bond between amino group substituted on the carbon atom C6 of ethacridinium moiety and the O-atom from the carboxylate group of anion ( Figure 4). The distances between donor and acceptor atoms engaged in these hydrogen bonds are similar in the crystals of compounds 1-3 (Table 2).  In the packing of the crystals of title compounds, we can observe that distance between the halogen atom substituted in the metaposition of the aromatic ring of acid and the O-atom from the ethoxy group of cation [d(X· · · O)] from neighbouring blocks decreases with decreasing electronegativity of the halogen atom, and is d(Cl29· · · O17) = 3.450(3) Å, d(Br29· · · O17) = 3.418(3) Å and d(I29· · · O17) = 3.408(3) Å (Figure 4). It is longer than the sum of the van der Waals radii of chlorine and oxygen atoms (3.27 Å) and bromine and oxygen atoms (3.37 Å); however, it is shorter than the sum of the van der Waals radii of iodine and oxygen atoms (3.50 Å). As a result, the weak X· · · O halogen bond is observed only in the crystal of compound 3. At the same time, the distance between adjacent blocks increases with decreasing d(X· · · O) distance (the distance between the closest methyl groups from neighbouring blocks (distance between C19· · · C19 atoms) is 4.43, 4.52 and 4.77 Å for compounds 1-3, respectively) ( Figure 4).
Other relationships are observed in isostructural unsolvated co-crystals formed from acridine and meta-halobenzoic acids [30]. Due to the fact that in the crystals of these complexes the solvent molecules are absent, acridine and meta-halobenzoic acids molecules are linked through O (carboxy) -H· · · N (acridine) and C (acridine) -H· · · O (carboxy) hydrogen bonds to form centrosymmetric, cyclic heterotetramers bis[· · · acridine · · · benzoic acid· · · ] [39]. The neighbouring heterotetramers are linked via π-π stacking interactions between aromatic rings of acridine moieties, and C (acridine) -H· · · O (carboxy) and C (acridine) -H· · · X hydrogen bonds and produce blocks. The geometrical parameters characterized the aforementioned interactions (including the distance between the mean planes of adjacent acridine skeletons of neighbouring heterotetramers equal to ca. 3,56 Å) are similar in all cases. However, between neighbouring blocks X· · · O contact occurs between the halogen atom and the O-atom from the carboxy group of acids, and the d(X· · · O) distance increases with the decreasing of electronegativity of the halogen atom [d(Cl· · · O) = 3.399(3) Å, d(Br· · · O) = 3.415(3) Å and d(I· · · O) = 3.468(3) Å], as does the distance between neighbouring blocks. Simultaneously, the strength of the C (acid) -H· · · X hydrogen bond decreases, which also links the neighbouring blocks and the the Kitaigorodskii type of packing index (with the percentage of filled space equal to 68.0, 67.9 and 67.4% for complexes formed from 3-chloro, 3-bromo and 3-iodobenzoic acid respectively).

Conclusions
Considering the above, we can conclude that type of halogen atom substituted in the metaposition in the benzoate ion influences the crystal packing of the title compounds. The d(X· · · O) distance between the halogen atom substituted in the metaposition of the aromatic ring of acid and the O-atom from the ethoxy group of cation from neighbouring blocks decreases with the decreasing electronegativity of the halogen atom in the order 1 > 2 > 3, as does the distance between the mean planes of adjacent acridine skeletons of neighbouring heterohexamers. At the same time, the distance between adjacent blocks increases in the order 1 < 2 < 3, which explains the decreasing of the Kitaigorodskii type of packing index of compound 3 by about 1% compared to the other compounds. The weak X· · · O halogen bond is observed only in the crystal of compound 3. This confirms the general tendency that in multicomponent crystals formed from chloro-and bromo-substituted acids, the molecules/ions of acid are hydrogen-bonded, whereas those formed from iodo-substituted acids are halogen bonded [17][18][19][20][26][27][28][29].
Future studies are expected to confirm the conclusions that can be drawn from this research. In order to determine the influence of other substituents in the benzoic acid molecule, such as -COOH, -OH, -NH 2 and -NO 2 on the self-assembly processes, we plan to obtain other multicomponent crystals formed from ethacridine and other mono-or poly-substituted benzoic acids.
The results of our research may be of practical importance from the crystal engineering point of view for the design of new pharmaceutical multicomponent crystals formed from ethacridine or other acridine derivatives.