Crystal structure, Hirshfeld surface analysis and contact enrichment ratios of 1-(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-2-(1,3-dithiolan-2-ylidene)ethanone monohydrate

The synthesis of a hybrid molecule is reported. The crystal structure of the monohydrate was investigated using Hirshfeld surface analysis and enrichment contact ratios. Hydrogen bonds induced by guest water molecules are the main driving force in crystal packing formation.

Crystal structure, Hirshfeld surface analysis and contact enrichment ratios of 1-(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-2-(1,3-dithiolan-2-ylidene)ethanone monohydrate In the title hydrated hybrid compound C 14 H 14 N 2 OS 2 ÁH 2 O, the planar imidazo[1,2-a]pyridine ring system is linked to the 1,3-dithiolane moiety by an enone bridge. The atoms of the C-C bond in the 1,3-dithiolane ring are disordered over two positions with occupancies of 0.579 (14) and 0.421 (14) and both disordered rings adopt a half-chair conformation. The oxygen atom of the enone bridge is involved in a weak intramolecular C-HÁ Á ÁO hydrogen bond, which generates an S(6) graph-set motif. In the crystal, the hybrid molecules are associated in R 2 2 (14) dimeric units by weak C-HÁ Á ÁO interactions. O-HÁ Á ÁO hydrogen bonds link the water molecules, forming infinite self-assembled chains along the b-axis direction to which the dimers are connected via O-HÁ Á ÁN hydrogen bonding. Analysis of intermolecular contacts using Hirshfeld surface analysis and contact enrichment ratio descriptors indicate that hydrogen bonds induced by water molecules are the main driving force in the crystal packing formation.

Chemical context
The imidazo[1,2-a]pyridine ring system was described for the first time in 1925 (Chichibabin, 1925). Compounds with the imidazo[1,2-a]pyridine scaffold exhibit a plethora of biological activities, including acting as receptor ligands, anti-infectious agents, enzyme inhibitors etc. as well as being potential nitrogen heterobicycle therapeutic agents, as described by recent studies (Goel et al., 2016;Deep et al., 2017;Kuthyala et al., 2018). On the other hand, compounds containing the 1,3-dithiolan-2-ylidene moiety have been found to exhibit valuable pharmacological activities, including use as potent broad-spectrum fungicides (Tanaka et al., 1976, Wang et al., 1994, antitumor agents (Huang et al., 2009), potent cephalosporinase inhibitors (Ohya et al., 1982) and anti-HIV agents (Nguyen-Ba et al., 1999;Besra et al., 2005). In light of the above, we have incorporated into our research into the design of new potentially bioactive compounds the currently attractive molecular hybridization strategy, which consists of the combination of at least two pharmacophoric moieties of different bioactive substances to produce a new hybrid compound that is medically more effective than its individual components (Viegas-Junior et al. 2007;Meunier, 2008). Yang et al. (2012) have shown that this approach is an effective way to develop novel and potent drugs for different targets.
Herein we report the synthesis, crystal and molecular structure of the title compound, an hybrid compound containing both imidazo[1,2-a]pyridine and 1,3-dithiolane scaffolds. Moreover, since this compound crystallizes as a hydrate, the presence of water molecules in the crystal structure is likely to alter its thermodynamic activity, which would impact its pharmacodynamic properties such as bioavailability and product performance (Khankari & Grant, 1995). From a crystallographic point of view, the intrusion of water molecules into a solid state modifies the network of intermolecular interactions between host molecules by incorporating additional bonds between the organic host molecules and water molecules on the one hand, and between water molecules on the other. To gain a better insight into the cohesive forces between host molecules and intrusive water molecules, and to highlight favored contacts likely to be the crystal driving force, an analysis of intermolecular interactions was carried out using contact enrichment ratios , a descriptor obtained from Hirshfeld surface analysis (Spackman & McKinnon, 2002), which allows an in-depth analysis of the atom-atom contacts in molecular crystals, providing key information on their distribution and is a powerful tool for understanding the most important forces in intermolecular interactions (Jelsch & Bibila Mayaya Bisseyou, 2017). Fig. 1 shows the asymmetric unit of the title compound, which crystallizes as monohydrate in the orthorhombic space group I4 1 cd. The hybrid molecule consists of imidazo[1,2-a]pyridine and 1,3-dithiolane scaffolds linked by an -CO-CH enone bridge. The imidazo[1,2-a]pyridine ring system is essentially planar with a maximum deviation of 0.008 (1) Å for atom N1. Its geometrical parameters are similar to those found for 1-(2methylimidazo[1,2-a]pyridin-3-yl)-3,3-bis(methylsulfanyl)prop-2-enone (Bibila Mayaya Bisseyou et al., 2009), as illustrated by the overlay of the structures shown in Fig. 2. In the 1,3-dithiolane moiety, the C11 and C12 atoms of the C-C bond of the ring exhibit occupational disorder over two positions, with relative occupancies of 0.579 (14) and 0.421 (14) for the major and minor components, respectively. This disorder in the 1,3-dithiolane skeleton is not uncommon and has been observed previously (Yang et al., 2007;Liu et al., 2008). Conformational analysis of the five-membered rings based on puckering parameters reveals a half-chair form for both disorder components [Q(2) = 0.419 (7)/0.443 (9) Å , '(2) = 303.2 (9)/128.9 (11) for the major and minor components, respectively]. The oxygen atom of the linker moiety is involved in a weak intramolecular C6-H6Á Á ÁO1 hydrogen bond (Table 1), which generates an S(6) graph-set motif.

Hirshfeld surface analysis
The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) and two-dimensional fingerprint plots (McKinnon et al., 2007) were generated using CrystalExplorer (Turner et al., 2017). The Hirshfeld surface (HS) mapped over d norm in the range À0.5072 to 1.2974 a.u. and shape-index (range À1.0 to 1.0 a.u.) are displayed in Figs A view along b axis showing hydrogen-bonded self-assembled chain of water molecules with the hydrogen bonds between the water and host molecules shown as dashed lines. For clarity, the atoms in the host molecules not involved in hydrogen bonds have been omitted.

Figure 5
A view along the c axis of the crystal packing, showing the stacking of the host molecules, with hydrogen bonds between water molecules, and between water molecules and host molecules (dashed lines). For clarity, weak hydrogen contacts and some H atoms not involved in hydrogen bonding have been omitted.

Figure 3
A partial packing diagram for the title compound showing the R 2 2 (14) graph-set motif generated by weak C-HÁ Á ÁO hydrogen bonds plotted as dashed lines. H atoms not involved in the hydrogen bonding have been omitted for clarity.

Figure 6
The three-dimensional Hirshfeld surface representation of the title compound plotted over d norm in the range À0.5086 to 1.2492 a.u. molecule. The CÁ Á ÁC contacts, with a V-shaped distribution of points, contribute 5.7%.
In order to detect favoured contacts and highlight the crystal driving force, enrichment ratios were computed with MoProViewer (Guillot et al., 2014). The enrichment ratio E XY of a chemical element pair (X, Y) is defined as the ratio between the proportion of actual crystal contacts between the different chemical species (X, Y) and the theoretical proportion of random equiprobable contacts . The asymmetric unit of the title compound is composed of two entities and in order to analyse all contacts present in the crystal, the host molecule and a neighboring water molecule not in contact each other were selected in order to obtain the integral Hirshfeld surfaces of each entity for the computation of the enrichment ratios. In addition, the hydrophobic Hc atoms bound to carbon were distinguished from the more polar Ho water hydrogen atoms and oxygen atoms were also differentiated (O = ketone oxygen atom and OW = water oxygen atom). The results obtained are summarized in Table 2. The hydrophobic Hc atoms, which constitute the largest part of the Hirshfeld surface, exhibit HcÁ Á ÁHc self-contacts with an enrichment ratio equal to 1.0. The hydrophobic CÁ Á ÁHc interactions are unprivileged with E CHc = 0.76 and correspond to weak C-HÁ Á ÁC interactions. These interactions are underrepresented because competition with the SÁ Á ÁHc, OWÁ Á ÁHc and weak OÁ Á ÁHc hydrogen bonds, the first two of which appear favoured with enrichment values of 1.35 and 1.14, respectively, and the last slightly under-represented with an enrichment ratio of 0.98. The CÁ Á ÁC contacts are privileged and display an enrichment value of 1.85, which highlight molecules stacking one on top of the other as shown in Fig. 5. This type of stacking interaction is generally favoured in heterocyclic compounds because of the favourable electrostatic complementary orientations of molecules in the crystal packing. This result is in agreement to the findings reported by Jelsch et al. (2014). These stacking interactions induce NÁ Á ÁS, OÁ Á ÁC and SÁ Á ÁC contacts displaying enrichment ratios of 1.58, 2.08 and 1.33, respectively. The NÁ Á ÁHo and OWÁ Á ÁHo polar contacts with the highest enrichment ratios of 5.03 and 5.19, respectively, are the most favoured contacts. These contacts correspond to the strong O2W-H2WÁ Á ÁN1 and O2W-H1WÁ Á ÁO2W hydrogen bonds (Table 1) observed in the Table 2 Intermolecular contacts and enrichment ratios (%) on the Hirshfeld surface by atom type.
The top part of the table gives the surface contribution S X of each chemical type X to the Hirshfeld surface. The next part shows the percentage contributions C XY of the actual contact types to the surface and the lower part of the table shows the E XY enrichment contact ratios. E XY ratios larger than unity are enriched contacts and those lower than unity are impoverished.   The three-dimensional Hirshfeld surface mapped over shape-index. crystal structure. Although crystallization is the result of concerted actions of all of the different interactions present within the crystal, the high enrichment value of the NÁ Á ÁHo and OWÁ Á ÁHo polar contacts reveal that these intermolecular interactions are the main driving force in the crystal packing formation of the title compound.
After stirring for 30 min. at 273 K, the mixture was stirred at ambient temperature for 4 h. The solution was then cooled at 273 K and 1,2-dichloro ethane (2.5 molar equivalents, 15.5 mmol) was added dropwise. The resulting mixture was then stirred for 24 h and then poured into 50 ml of ice-cold water. The precipitate was filtered and recrystallized from a mixture of water-dioxane (2:1) to obtain brown single crystals of the title compound suitable for X-ray diffraction analysis (yield 76%; m.p. 453 K).

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.