Crystal structure, Hirshfeld surface analysis and DFT study of 6-bromo-3-(5-bromohexyl)-2-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine

The 5-bromopentyl chain is oriented so that the bromine atom is ca 4.4 Å from one of the methyl C atoms of the dimethylamino group. In the crystal, two sets of inversion-related C—H⋯π(ring) interactions form stacks of molecules extending along the a-axis direction.

In the title molecule, C 20 H 24 Br 2 N 4 , the imidazopyridine moiety is not planar as indicated by the dihedral angle of 2.0 (2) between the constituent rings; the 4-dimethylaminophenyl ring is inclined to the mean plane of the imidazole ring by 27.4 (1) . In the crystal, two sets of C-HÁ Á Á(ring) interactions form stacks of molecules extending parallel to the a-axis direction. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from HÁ Á ÁH (42.2%), HÁ Á ÁC/CÁ Á ÁH (23.1%) and HÁ Á ÁBr/BrÁ Á ÁH (22.3%) interactions. The optimized structure calculated using density functional theory (DFT) at the B3LYP/ 6-311 G(d,p) level is compared with the experimentally determined structure in the solid state. The calculated HOMO-LUMO energy gap is 2.3591 eV.

Chemical context
The family of nitrogenous drugs, particularly those containing the imidazopyridine moiety, is important in medicinal chemistry because of their wide range of pharmacological activities such as anticancer, anti-inflammatory, antibacterial, antituberculosis, anti-glycation anti-analgesic and antifungal properties, and their antioxidant potential. In particular, imadazo [4,5-b]pyridine derivatives inhibit the P-glycoprotein, which could reverse the multidrug resistance of cancer cells (Bourichi et al., 2018). They are also inhibitors of type 2 diabetes because of their ability to inhibit the Baker's yeastglucosidase enzyme, and are inhibitors of one or more proteins in the treatment of disorders characterized by the activation of Wnt pathway signalling (for example: cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases and osteoarthritis), and of genetic and neurological diseases such as PAK4 kinase 4 inhibitor activated by p21 and aurora kinase inhibitors. Imadazo [4,5b]pyridine derivatives are also therapeutic agents for dysferlinopathies through phenotypic screening on patient-induced pluripotent stem cells (Takada et al., 2019).
Given the wide range of theraputic applications for such compounds, we have already reported a route for the preparation of imidazo[4,5-b]pyridine derivatives using N-alkylation reactions carried out with di-halogenated carbon ISSN 2056-9890 chains (Jabri et al., 2020); a similar approach yielded the title compound, C 20 H 24 Br 2 N 4 ,(I). Besides the synthesis, we also report the molecular and crystal structures along with a Hirshfeld surface analysis and a density functional theory (DFT) computational calculation carried out at the B3LYP/6-311 G(d,p) level.

Structural commentary
The molecular structure of (I) is depicted in Fig. 1. The imidazopyridine moiety is not planar, as indicated by the dihedral angle of 2.0 (3) between the constituent rings. The ring of the 4-dimethylaminophenyl moiety is inclined to the mean plane of the imidazole ring by 27.4 (1) . The 5-bromopentyl chain is oriented in an arc-like form around the periphery of the 4-dimethylaminophenyl moiety so that the terminal Br2 atom of the chain is only 4.36 (6) Å from one of the methyl C atoms (C20; Fig. 1).

Hirshfeld surface analysis
In order to visualize the intermolecular interactions in the crystal of the title compound, a Hirshfeld surface (HS) analysis (Hirshfeld, 1977) was carried out by using Crystal Explorer 17.5 (Turner et al., 2017). A view of the threedimensional Hirshfeld surface of (I), plotted over d norm and electrostatic potential are shown in Fig. 3a and3b. The shapeindex of the HS reveals that there are no significantinteractions in (I), as shown in Fig. 4. The overall twodimensional fingerprint plot (McKinnon et al., 2007) is shown in Fig. 5a, while those delineated into HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, HÁ Á ÁBr/BrÁ Á ÁH, HÁ Á ÁN/NÁ Á ÁH, CÁ Á ÁBr/BrÁ Á ÁC, NÁ Á ÁBr/BrÁ Á ÁN and NÁ Á ÁC/CÁ Á ÁN contacts are illustrated in Fig. 5b-h, respectively, together with their relative contributions to the Hirshfeld surface. The most important interaction is HÁ Á ÁH, contributing 42.2% to the overall crystal packing, which is reflected in Fig. 5b as widely scattered points of high density due to the large hydrogen content of the molecule, with the tip Figure 1 The asymmetric unit of the title compound with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A portion of one stack of molecules viewed along the c-axis direction with the C-HÁ Á Á(ring) interactions depicted by green dashed lines. Table 1 Hydrogen-bond geometry (Å , ).
Cg3 is the centroid of the C7-C12 phenyl ring.  Fig. 5h, make only 0.1% contribution to the HS and have a low-density distribution of points.

DFT calculations
The optimized structure of (I) in the gas phase was calculated by density functional theory (DFT) using a standard B3LYP functional and the 6-311 G(d,p) basis-set (Becke, 1993)  Hirshfeld surface of the title compound plotted over shape-index.  View of the three-dimensional Hirshfeld surface of the title compound plotted over electrostatic potential energy in the range À0.0500 to 0.0500 a.u. using the STO-3 G basis set at the Hartree-Fock level of theory.

Figure 5
The full two-dimensional fingerprint plots for the title compound 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 HOMO and LUMO are localized in the plane extending ove  (Fig. 7) and excluding metal complexes gave seven matches. Of these, two had a -CH 2 CH 2 X-(X = O, NH) chain connecting a saturated nitrogen atom [corresponding to N2 in (I)] to an ortho position of the phenyl ring and so were considered less comparable to (I) than the remainder, which can be represented by the general structure (III) (Fig. 7). For . For R = 4-ClC 6 H 4 and R" = Br there are two reports of the compound with R 0 = 1-octyl-1H-1,2,3-triazol-4-yl)methyl [XITLUK (Bourichi et al., 2019a) and XITLUK01 (Bourichi et al., 2019b)]. The dihedral angle between the plane of the 4dimethylaminophenyl group and the mean plane of the imidazopyridine unit is ca 19 in XITLUK and ca 49 in UCOXES. Of all of these related structures, (I) is the only one with the substituent on nitrogen approximately coplanar with the imidazopyridine unit. In UCOXES, this substituent is directed outward and away from the phenyl group while in all the others, it is bent back over the phenyl group. In fact, in UNUWIK there is an HÁ Á ÁH contact of 2.4 Å between the phenyl ring of the benzyl group and that attached to the imidazole ring.

Figure 6
The energy band gap of (I).

Figure 7
Structural fragments (II) and (III) used in the database search.

Table 2
Comparison of selected (X-ray and DFT) bond length and angles (Å , ).

Synthesis and crystallization
To a solution of 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-N,N-dimethylaniline (0.4 g, 1.25 mmol), 2.2 equivalents of potassium carbonate (0.38 g, 2.75 mmol) and 0.2 equivalents of tetra-n-butyl ammonium bromide (BTBA) (0.061 g, 0.187 mmol) in 40 ml of DMF were added in small portions to 1.5 equivalent of the 1,6-dibromododecanedihalogenated reagent, and the 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 subjected to separation by chromatography on a column of silica gel using a mixture of hexane/dichloromethane = 1/4 (v/ v) as the mobile phase. Brown single crystals suitable for X-ray diffraction were obtained by evaporation of a dichloromethane/hexane solution (1:4 v/v).

Special details
Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, collected 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 20 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq