Crystal structure, Hirshfeld surface analysis and DFT studies of 6-bromo-3-(12-bromododecyl)-2-(4-nitrophenyl)-4H-imidazo[4,5-b]pyridine

In the title molecule, the imidazolopyridine and phenyl rings are nearly co-planar, and the 12-bromododecyl side chain is directed so as to give the complete molecule a V-shape.


Chemical context
Imidazole derivatives are a class of heterocyclic compounds exhibiting pharmacological activities across a wide range of therapeutic targets (El Kazzouli et al., 2011;Martínez-Urbina et al., 2010). Imidazopyridine derivatives are used in medicinal chemistry because of their biological and pharmacological properties, in particular as anti-inflammatory, anti-cancer, antiviral, anti-osteoporotic, anti-parasitic and antihypertensive agents. Certain compounds with an imidazopyridine skeleton are used to treat psychiatric and autoimmune disorders (Dymínska, 2015;Bababdani & Mousavi, 2013). They have also been approved as effective antifungal agents and exhibit antimicrobial activities (Devi et al., 2018), some of which can be used for the treatment of disorders characterized by activation of the Wnt signaling pathway (cancer, abnormal cell proliferation, angiogenesis, fibrous disorders, bone or cartilage and arthritis), as well as genetic and neurological diseases. On the other hand, imidazopyridine compounds, which have a specificity to GPR4 as negative allosteric modulators (Tobo et al., 2015), can also be used for the treatment of gastric and/or duodenal ulcers. Several imidazo[4,5-b]pyridine derivatives have also been ISSN 2056-9890 reported as corrosion inhibitors of steel in an acidic environment (Bouayad et al., 2018;Sikine et al., 2016;Yadav et al., 2014), and also as inhibitors of a nanomolar rhodesaine (Ehmke et al., 2013) or the Et-PKG enzyme (Cheng et al., 2010).
Following our research work directed at obtaining new heterocyclic compounds having an imidazo [4,5-b]pyridine moiety, we were interested in the condensation of imidazo [4,5b]pyridine derivatives with di-halogenated chains under phase-transfer catalysis (PTC) conditions. We report herein the synthesis and the molecular and crystal structures of the title compound (I) together with Hirshfeld surface analysis and DFT calculations for comparison with the experimentally determined molecular structure in the solid state.

Structural commentary
The molecule of (I) consists of an imidazolopyridine moiety to which a nitrophenyl group is attached to the C atom (C6) of the five-membered ring. The 12-bromododecyl side chain is attached to one of the two N atoms (N1). The imidazolopyridine moiety is planar to within 0.0208 (15) Å (r.m.s. deviation = 0.0122 Å ) with atom C3 being the most distant from the least-squares plane. The phenyl ring (C7-C12) is inclined to the above plane by only 1.6 (1) , making the two ring systems essentially planar. The C4-N1-C13-C14 torsion angle (C13 and C14 are the first two atoms of the 12bromododecyl chain) is 95.7 (2) . The C15-C22 portion of the 12-bromododecyl chain is approximately planar [maximum deviation from the least-squares plane running through the eight C atoms is 0.09 (1) Å for C20], and this plane is inclined to that of the imidazolopyridine moiety by 21.9 (8) , giving the molecule an overall V-shape (Fig. 1). The terminal C24-Br2 portion of the 12-bromododecyl chain is disordered over two resolved sites in a refined ratio of 0.902 (3):0.098 (3).

Supramolecular features
In the crystal, sloped stacks of molecules extending along the a-axis direction are formed by slippedstacking interactions between the N1/C1-C5 and C7-C12 rings, with a centroid-to-centroid distance of 3.5308 (13) Å , a dihedral angle of 1.83 (9) and a slippage of 1.192 Å . The angle between the plane defined by the relevant centroids in the stack and (001)  The asymmetric unit of (I) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. Only the major part of the disordered -CH 2 Br group is shown.

Figure 2
Detail of the intermolecular interactions viewed along the c-axis direction. The weak C-H Pyr Á Á ÁO Ntr and C-H Brmdcyl Á Á ÁO Ntr (Pyr = pyridine, Ntr = nitro and Brmdcyl = bromododecyl) hydrogen bonds and stacking interactions are depicted, respectively, by black and orange dashed lines.

DFT calculations
The optimized structure of the molecule in the gas phase was calculated via density functional theory (DFT) using the standard B3LYP functional and 6-311G(d,p) basis-set calculations (Becke, 1993) as implemented in GAUSSIAN 09 (Frisch et al., 2009). The theoretical and experimental bond lengths and angles are in good agreement (Table 2). Results for E HOMO and E LUMO energies, electronegativity (), hardness (), potential (), electrophilicity (!) and softness () are collated in Table 3. The electron transition from the HOMO to the LUMO energy level is shown in Fig. 6. The energy band gap [ÁE = E LUMO -E HOMO ] of the molecule is 1.6731 eV, and the calculated frontier molecular orbital energies, E HOMO and E LUMO , are À4.0238 and À2.3507 eV, respectively.

Database survey
The . In all of the matches where R 0 is an alkyl chain, the base of the chain is approximately perpendicular to the benzimidazole plane but not all of them have the remainder of the chain in a fully extended conformation and in no instances are structures seen in which the alkyl chains overlap. Part of the reason is that the butyl group is not long enough to counteract the packing interactions involving the benzimidazole moiety and the substituents in the 2-position. The possible exception is in DUKJAV wherestacking interactions appear to occur between the benzimidazole units and between the carbazole units. Also, all of the related molecules identified have a dihedral angle between the plane of the benzimidazole unit and the plane of the aromatic ring in the 2-position of 28-48 while in (I) the two are nearly coplanar [1.6 (1) ]. This is likely due to packing considerations.

Figure 7
Lewis structures of fragments (II) and (III) used in the database search. dibromododecane. The resulting mixture was stirred magnetically at room temperature for 48 h. After removal of the salts and evaporation of DMF under reduced pressure, the product was separated by chromatography on a column of silica gel using a mixture of hexane/dichloromethane: 1/4 (v/v) as the mobile phase. Orange single crystals suitable for X-ray diffraction were obtained by slow evaporation of the eluant.

Refinement
Crystal, data collection and refinement details are presented in Table 4. Hydrogen atoms were included as riding contributions in idealized positions with isotropic displacement parameters tied to those of the attached atoms. The terminal C24-Br2 portion of the 12-bromododecyl chain is disordered over two resolved sites in a 0.902 (3)/0.098 (3) ratio. The two components of the disorder were refined with restraints so that their bond lengths and angles are comparable.

Funding information
JTM thanks Tulane University for support of the Tulane Crystallography Laboratory. TH is grateful to Hacettepe University Scientific Research Project Unit (grant No. 013 D04 602 004).

Special details
Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, colllected at φ = 0.00, 90.00 and 180.00° and 2 sets of 800 frames, each of width 0.45° in φ, collected at ω = -30.00 and 210.00°. The scan time was 10 sec/frame. 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. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. Hatoms attached to carbon were placed in calculated positions (C-H = 0.95 -0.99 Å). All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms. Br2 is disordered over two sites in a 0.902 (3)/0.098 (32) ratio with the two components refined with restraints that they have comparable geometries.