The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide

The quinoline moiety of the title quinoline carboxamide derivative is not planar as a result of a slight puckering of the pyridine ring. The secondary amine has a slightly pyramidal geometry.


Chemical context
Quinoline (1-aza-naphthalene or benzo[b]pyridine) is a natural heterocyclic building block often used as a template for derivatization and generation of drug-like libraries for the discovery of novel bioactive ligands (Mugnaini et al., 2009;Musiol, 2017). Quinoline-based compounds are well known for their antimalarial activity (Antony & Parija, 2016), although a large spectrum of other biological activities, such as anticancer, antimicrobial, anti-inflammatory, antioxidant, antihypertensive and against neurodegenerative diseases, have also been ascribed to these types of heterocyclic compounds (Nainwal et al., 2019).

Structural commentary
An ellipsoid plot for compound 1 is shown in Fig. 1. The quinoline ring system is not planar, with atoms C2 and C4 deviating from the mean plane of the quinoline ring by À0.110 (3) and 0.125 (3) Å , respectively, and C6 lying À0.100 (3) Å below the mean plane. The pyridine ring is slightly puckered with a screw-boat conformation, Q = 0.087 (3)Å , = 106 (2) and ' = 25 (2) . The mean plane of this ring makes a dihedral angle of 7.49 (13) with the mean plane of the benzene ring of the quinoline moiety. The angles between the mean planes of the quinoline ring and the benzene rings with pivot atoms C321 and C411 are 28.99 (11) and 59.16 (11) respectively. The dihedral angle between the mean plane of these benzene rings is 64.71 (14) .
The amide group attached to C3 is coplanar with the quinoline ring system. The C-N rotamer of the amide has an anti conformation placing the quinoline ring trans in relation to the ring with pivot atom C321. The amide group atoms are essentially coplanar with the quinoline ring with deviations of À0.034 (3), (C31), À0.009 (2) (O31), 0.009 (2), (N32) and 0.145 (3) Å (C321). The geometric arrangement of the amide permits the formation of an intramolecular hydrogen bond between the amine hydrogen atom and the carboxyl group of the amide, N41-H41Á Á ÁO31; geometric parameters are given in Table 1. A further intramolecular hydrogen bond, C326-H326Á Á ÁO31, occurs.
The secondary amine has a slightly pyramidal geometry, certainly not planar. The angles C411-N41-C4, C41-N41-H41 and C411-N41-H41 are 125.7 (2), 112 (2) and 115 (2) , respectively, the sum of which (352.7 ) is less than 360 ; in addition, atom H41 lies 0.41 (3) Å out of the C4/N41/C411 mean plane, confirming the sp 3 hybridization of N41. An inspection of the amine bond lengths shows that there is a slight asymmetry of the electronic distribution around it: C4-N41 = 1.364 (3) Å while N41-C411 = 1.437 (4) Å , suggesting there is higher density between the nitrogen and the carbon atom of the quinoline ring system. However, these bonds and angles are typical for a C quinoline -NH-C-R group, see the Database Survey below. As a consequence of the screw-boat pucker of the pyridine ring, the C4-N41 bond is displaced from the pyridine mean plane with a deviation of 0.159 (2) Å for N41; atom C411 is displaced by 0.965 (3) Å and consequently, the N41-C411 bond lies further from the mean plane.

Figure 1
A view of the asymmetric unit of 1 with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A view of the N32-H32Á Á ÁN1 C6 chain running along the a axis with the supplementary C2-H2Á Á ÁN1 bond. Hydrogen atoms not involved in the hydrogen bonding are omitted for clarity.
H416Á Á ÁO31 and C418-H41BÁ Á ÁO31, both involve atom O31 as an acceptor and link the chains described above to form a sheet which extends along the b-axis direction.

Hirshfeld surface analysis and lattice energies
Hirshfeld surfaces (McKinnon et al., 2004) and two-dimensional fingerprint (FP) plots provide complementary information concerning the intermolecular interactions discussed above. The analyses were generated using Crystal Explorer 3.1 (Wolff et al., 2012). The lattice energies for 1 were analysed after performing calculations as implemented in the PIXEL program (Gavezzotti, 2003(Gavezzotti, , 2008. The total stabilization energy of the crystal packing, E tot is À207.0 kJ mol À1 , distributed as Coulombic, (E coul = À112.9 kJ mol À1 ), polarization (E pol = À52.8 kJ mol À1 ), dispersion (E disp = À251.6 kJ mol À1 ) and repulsion (E rep = 210.4 kJ mol À1 ). The dispersive energy contributes the most to the total stabilization energy of the lattice, in addition to the C-HÁ Á ÁO hydrogen bonds, and to the C-HÁ Á Á interaction. The stabilization energy comes from six sub-structural motifs made by the molecule pairs I to VI that are shown in Figs. 3 to 8, together with the symmetry codes as well as the respective energies. They contribute a total energy of À369.4 kJ mol À1 for the lattice, half of it, À184.7 kJ mol À1 attributed to the (x, y, z) molecule. That energy corresponds approximately to 88% of the total stabilization energy of the network. Molecule pairs Ia/Ib: x À 1, y, z (top) and x + 1, y, z (bottom). Values of energies by pair: E tot = À55.9 kJ mol À1 , E coul = À21.4 kJ mol À1 , E pol = À10.0 kJ mol À1 , E disp = À79.5 kJ mol À1 and E rep = 55.0 kJ mol À1 . Interaction energies were calculated using PIXEL3.1 (Gavezzotti, 2003(Gavezzotti, , 2008 based on densities computed with G09 using the mp2/6-31** level of theory.
Apart from the intramolecular hydrogen bond with N41, the carboxyl oxygen atom O31 involves its lone pairs in another two intermolecular C-HÁ Á ÁO interactions, O31Á Á ÁH416-C416 and O31Á Á ÁH41B-C418. The first inter-action creates chains running along the a-axis direction that are further stabilized by C-HÁ Á Á interactions (C326-H326Á Á ÁCg pyridine ), as can be identified by the red spots in the Hirshfeld Surface (McKinnon et al., 2004) for the molecule, Fig. 9, and they form two molecule pairs, identified as substructures Ia/Ib in Fig. 3. Each of those pairs contribute À55.9 kJ mol À1 to the stabilization of the lattice, mainly dispersion energy. The second interaction, O31Á Á ÁH41B-C418, makes another two molecule pairs, IIIa/IIIb, Fig. 5. In this substructure the Coulombic energy is higher than the dispersive energy, which is indicative of the minor importance of the interactions involving the aromatic rings. These hydrogen bonds can also be identified as red spots in the HS, Fig. 9.

Figure 9
Several faces of the HS plotted over d norm for 1 showing the red spots that indicate close contacts between atoms, which are identified in the figures.
Apart from the sub-structural motifs described, there are two extra molecule pairs, identified as Va/Vb and VIa/VIb, which are also illustrated in Figs. 7 and 8: the two molecules involved are at x, y, z (green-coloured molecule) and Àx + 3 2 , Ày + 1, z À 1 2 /Àx + 3 2 , Ày + 1, z + 1 2 (black-coloured molecule) for Va/Vb and x À 3 2 , Ày + 3 2 , Àz + 1/x À 3 2 , Ày + 3 2 , Àz + 1 for VIa/VIb. Although these molecules do not exhibit atomÁ Á Áatom close contacts, each pair provides a significant contribution to the overall lattice stabilization energy of À14.5 and À11.3 kJ mol À1 , respectively for V and VI. The grey molecules drawn in this figure indicate a possible pathway for electronic delocalization within the network of molecules.  Boyd et al., 1992} with an amino group attached to C4 and a nitro group attached to C3. In both of these compounds, there is no puckering of the pyridine ring and the quinoline ring system is essentially planar. In both cases, a hydrogen atom forms an intramolecular hydrogen bond between an amino hydrogen and the carbonyl oxygen in both independent molecules of the asymmetric unit (SEZJIR) or between the amino hydrogen and a nitro group oxygen atom (PABPUD). In both structures, the C(pyridine)Á Á ÁN(amino) distances are significantly shorter than those in 1, viz. 1.325 and 1.335 Å for the two molecules in the asymmetric unit of SEZJIR and 1.320 Å in PABPUD. The corresponding value in 1 is 1.364 (3) Å .

Database survey
A survey of quinoline compounds, with an R factor of 10% or less with a C quinoline -NH-C aryl/sp 3 unit attached to C4 of the quinoline moiety gave 56 hits for 63 individual molecules, including 1. The C quinoline -N distances lie in the range 1.319 to 1.438 Å with an average value of 1.360 Å .
The situation is more complex for the N-C aryl/sp 3 bond and for the C quinoline -N-C aryl/sp 3 angle. A scatterplot of these revealed two populations, one in which the N atom is attached to a benzene ring and the other in which the connection is to an sp 3 carbon. UNIKUZ [6-(t-butylsulfonyl)-N-(5-fluoro-1Hindazol-3-yl)quinolin-4-amine methanol solvate; Haile et al., 2016) is included in the first group. The C aryl -N distances lie in the range 1.396 to 1.438 Å with an average value of 1.418 Å and an average C quinoline -N-C aryl/sp 3 angle of 126.105 . In the second case, the C aryl/sp 3-N distances lie in the range 1.439 to 1.478 Å with an average value of 1.458 Å , with an average C quinoline -N-C aryl/sp 3 angle of 123.98 .

Synthesis and crystallization
The title quinolone derivative 1 was synthesized by a one-pot reaction between 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 3,4-dimethylaniline in the presence of POCl 3 following a procedure described previously (Cagide et al., 2015). The title compound was obtained in 70% yield and characterized by NMR. It was re-crystallized from dichloromethane to yield crystals suitable for X-ray diffraction, m.p. 489-493 K.
NMR data were acquired on a Bruker AMX 400 spectrometer, recorded at room temperature in 5 mm outer-diameter tubes. The samples were prepared in deuterated dimethylsulfoxide (DMSO) with tetramethylsilane (TMS) as internal reference. Chemical shifts are expressed as (ppm) values relative to TMS; coupling constants (J) are given in Hz. Atoms are labelled with their numerical designation as per

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The H atoms were included in idealized positions and treated as riding atoms: C-H = 0.95-0.98 Å with U iso (H) = 1.2U eq (C) or 1.5U eq (C) for methyl H atoms. Those attached to N and C2 [C-H = 0.96 (3) Å ] were refined. The latter was refined since it is involved in a short contact with H32, which is attached to N32. Although in the riding model for H2 the H-atom position is within the highest contour on the difference map, it is not at the centre. In the refined model it is. The HÁ Á ÁH distances are 1.87 and 1.93 Å for the riding and refined models, respectively. The angles around C2 are N1-C2-C3 = 125.9 (3) and 125.9 (3); N-C2-H2 = 117 and 111.9 (17) and C3-C2-H2 = 117 and 122.2 (17) for riding and refined H atoms, respectively. In the case of H32, the N32-H32 distance changes from 0.89 (3) to 0.90 (4) Å and the angle C31-N32-H32 changes from 120 (2) to 119 (2) for riding to refined, respectively, which are really insignificant shifts. Hence, in this case the short contact does induce a shift in the angular position of H2 from its calculated position.

4-(3,4-Dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide
Crystal data 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.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )