Synthesis, characterization, crystal structure and Hirshfeld surface analysis of a hexahydroquinoline derivative: tert-butyl 4-([1,1′-biphenyl]-4-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

C—H⋯O and N—H⋯O hydrogen bonds connect molecules in the crystal, generating layers parallel to the (100) plane with (6) and C(7) graph-set motifs. C—H⋯π interactions help to reinforce this layered molecular structure.

The title compound, C 29 H 33 NO 3 , crystallizes with three molecules (A, B and C) in the asymmetric unit. They differ in the twist of the phenyl and benzene rings of the 1,1 0 -biphenyl ring with respect to the plane of the 1,4-dihydropyridine ring. In all three molecules, the 1,4-dihydropyridine ring adopts a distorted boat conformation. The cyclohexene ring has an envelope conformation in molecules A and B, while it exhibits a distorted half-chair conformation for both the major and minor components in the disordered molecule C. In the crystal, molecules are linked by C-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds, forming layers parallel to (100) defining R 1 4 (6) and C(7) graph-set motifs. Additional C-HÁ Á Á interactions consolidate the layered structure. Between the layers, van der Waals interactions stabilize the packing, as revealed by Hirshfeld surface analysis. The greatest contributions to the crystal packing are from HÁ Á ÁH (69.6% in A, 69.9% in B, 70.1% in C), CÁ Á ÁH/HÁ Á ÁC (20.3% in A, 20.6% in B, 20.3% in C) and OÁ Á ÁH/HÁ Á ÁO (8.6% in A, 8.6% in B, 8.4% in C) interactions.

Chemical context
Chronic diseases are among the most common causes of death in the world, accompanied by difficulties and costs in treatment and health care. Therefore, preventing or treating chronic diseases is of paramount importance (Raghupathi & Raghupathi, 2018). Recent advances have shown that many diseases such as cancer, atherosclerosis or neurodegenerative diseases are triggered by inflammation (Furman et al., 2019). Based on these findings, regulating inflammatory mediators and pathways has been suggested as a treatment strategy (Kany et al., 2019).
Inflammatory stimuli that cause chronic inflammation initiate the production of inflammatory mediators such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-(TNF-) as a result of the activation of signaling pathways. Receptors activated by inflammatory mediators induce chronic inflammation by various signaling pathways (nuclear factor -B (NF-KB), Janus kinase (JAK), signal transducer and activator of transcription (STAT).
Inhibiting these pathways may be a promising approach for the treatment of chronic diseases associated with inflammation (Chen et al., 2018).
Nifedipine, the first drug with a 1,4-dihydropyridine (1,4-DHP) ring, was introduced as a therapeutic agent as a result of intensive studies. The success of nifedipine as an antihypertensive drug has led to further studies and the discovery of other 1,4-DHP derivatives (De Luca et al., 2019). Numerous compounds were obtained through modifications with respect to the 1,4-DHP ring. These studies also uncovered the idea of obtaining hexahydroquinoline derivatives by condensation of the 1,4-DHP scaffold with the cyclohexane ring system (Bladen et al., 2014). In recent years, it has been found that 1,4-DHP and quinoline analogs have the potential to inhibit inflammation mediators and pathways, along with various other pharmacological activities (Costa et al., 2010;Lä ngle et al., 2015;Kim et al., 2018;Ç etin et al., 2022).
In the current study, tert-butyl 4-[(1,1 0 -biphenyl)-4-yl]-2,6,6trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was obtained by condensation of the 1,4-DHP ring with a substituted cyclohexane ring using a modified Hantzsch method. The molecular structure of the compound was confirmed by spectroscopic methods such as IR, 1 H NMR, 13 C NMR, and its composition by elemental analysis. In addition, single-crystal X-ray analysis was performed to elucidate the crystal structure of the compound. Independent of the current study, biological activity studies of the title compound are ongoing.

Structural commentary
The asymmetric unit of the title compound ( Fig. 1) contains three independent molecules (denoted with suffixes A, B and Views from the same direction of the three molecules in the asymmetric unit of the title compound, with displacement ellipsoids for the non-hydrogen atoms drawn at the 30% probability level. (a) Molecule A, (b) molecule B, and (c) molecule C (only the major component of the disorder is shown).

Figure 2
Overlay image of the three independent molecules of the title compound. While the terminal phenyl rings of molecules A and B coincide well, that of molecule C is not in the same plane with them, and is approximately normal to them. Only the major component of the disorder in molecule C is shown. C). They mainly differ in the twist of the phenyl (C24-C29) and benzene (C18-C23) rings of the 1,1 0 -biphenyl ring with respect to the plane of the 1,4-dihydropyridine ring (N1/C1-C4/C9). The corresponding dihedral angles amount to 89.26 (16) and 75.83 (19) in molecule A, 88.34 (17) and 71.7 (2) in molecule B, and 89.38 (17) and 83.6 (3) in molecule C. The phenyl and benzene rings of the 1,1 0 -biphenyl ring make dihedral angles of 39.05 (19) in A, 46.9 (2) in B, and 33.5 (2) in C. Fig. 2 shows an overlay plot of molecules A, B and C, with an r.m.s. deviation of 0.725 Å . Except for the atoms of the minor part of the disordered molecule C and the phenyl ring of the biphenyl group, the other atoms of molecule C and all atoms of molecules A and B are quite compatible and coincide with each other.
Bond lengths and angles in the three molecules of the title compound are comparable with those of closely related structures detailed in section 5 (Database survey).

Hirshfeld surface analysis
Crystal Explorer 17.5 (Spackman et al., 2021) was used to construct Hirshfeld surfaces for the three independent molecules; the disorder of molecule C was included in the calculations. The d norm mappings for molecule A were performed in the range À0.5982 to +2.4710 a.u., for molecule B in the range  Table 1 Hydrogen-bond geometry (Å , ).

Figure 3
A view of the intermolecular N-HÁ Á ÁO and C-HÁ Á ÁO interactions in the crystal structure of the title compound projected along [100]. Only the major component of the disordered molecule C is shown.

Figure 4
A general view of a part of the molecular packing formed by C-HÁ Á Á interactions in the crystal structure of the title compound. Only the major component of the disordered molecule C is shown.
À0.6131 to +2.5190 a.u., and for molecule C in the range À0.6097 to +2.4293 a.u.. On the d norm surfaces, bright-red spots show the locations of N-HÁ Á ÁO and C-HÁ Á ÁO interactions ( Fig. 5a for molecule A, Fig. 5b for molecule B, and Fig. 5c for molecule C). Fingerprint plots (Fig. 6) reveal that HÁ Á ÁH interactions make the largest contributions (69.6% for molecule A, 69.9% for molecule B, and 70.1% for molecule C) to the overall surface (Table 2). CÁ Á ÁH/HÁ Á ÁC (20.3% for A, 20.6% for B, and 20.3% for C) contacts are also significant. Table 3 lists the contributions of additional, less notable interactions. As seen in Table 3, the relevant contacts around molecules A, B, and C are quite similar.       Groom et al., 2016) for similar structures with the 1,4,5,6,7,8-hexahydroquinoline unit revealed seven closely related entries: ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7 In (I), hydrogen bonds are formed between the N-H group of one molecule and the carbonyl O atom in the cyclohexanone ring of an adjacent molecule. These hydrogen bonds link the molecules into extended chains running along [001]. In the crystal of (II), molecules are linked by N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds into layers parallel to (101). The network includes R 4 4 (30) and R 4 4 (34) graph-set motifs. In (III), an intermolecular N-HÁ Á ÁO hydrogen bond between the amine group and the carbonyl O atom of the cyclohexenone ring of a neighboring molecule links the molecules into extended chains parallel to [101]. These interactions can be described by graph-set motif C(6). In the crystal of (IV), N-HÁ Á ÁO hydrogen bonds connect the molecules into C(6) chains parallel to [010], and pairs of weak C-HÁ Á ÁO hydrogen bonds link inversion-related chains into a ladder motif through R 2 2 (18) rings. A weak intramolecular C-HÁ Á ÁO hydrogen bond is also observed. In (V), the crystal structure exhibits an intermolecular N-HÁ Á ÁO hydrogen-bonding interaction involving the carbonyl O atom of the oxocyclohexene ring, whereby the molecules are linked into C(6) chains parallel to [100]. In (VI), the frequently observed intermolecular N-HÁ Á ÁO hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighboring molecule links the molecules into extended C(6) chains parallel to [010]; there are no other significant intermolecular interactions. In the crystal of (VII), molecules are linked by pairs of N-HÁ Á ÁO hydrogen bonds, forming dimers with R 1 2 (6) ring motifs. These dimers are connected by N-HÁ Á ÁO hydrogen bonds, generating chains along [110]. A C-HÁ Á ÁO contact occurs between the independent molecules.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 4. All C-bound H atoms were positioned geometrically and allowed to ride on their parent atoms, with C-H = 0.95 Å for aryl-H atoms, C-H = 0.99 Å for methylene groups, C-H = 1.00 Å for methine groups and C-H = 0.98 Å for methyl groups, with U iso (H) = 1.5U eq (C) for methyl groups and U iso (H) = 1.2U eq (C) for other hydrogen atoms. The H atoms of the NH groups were found in a difference-Fourier map and refined freely (see Table 1).
In molecule C, except the fused carbon atoms (C4C and C9C) and the carbonyl oxygen atom (O1C) of the 6,6-dimethylcyclohex-2-en-1-one group (C4C-C5C/C5F-C6C/C6F-C7C/C7F-C8C/C8F-C9C-O1C-C16C/C16F-C17C/C17F), the other C atoms are disordered over two sets of sites with a refined occupancy ratio of 0.716 (4):0.284 (4). For the disordered components, the EADP instruction was used in the final cycles of the refinement.  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 )