Crystal structure of benzo[h]quinoline-3-carboxamide

A benzoquinone compound was unintentionally synthesized by photocyclization and subsequent oxidation in air while attempting to transform the E isomer of a nicotinamide derivative to its Z isomer. The chemical and molecular structures of the product was established crystallographically. The surprising synthesis, chromatographic purification and comprehensive characterization of this compound including single crystal structural analysis are reported and its structure including crystal packing is discussed in detail.


Chemical context
Quinoline and benzoquinoline scaffolds are common structural motifs in artificial, as well as natural products, and many of these compounds are of enormous value for pharmacotherapy. Their multifaceted biological efficacy is outstanding and ranges from cardiovascular (Ferlin et al., 2002;Abouzid et al., 2008) and anti-inflammatory effects (Kumar et al., 2009;Hussaini, 2016) to antimicrobial (El Shehry et al., 2018), as well as anticancer activity (Abdelsalam et al., 2019;Haiba et al., 2019;Jafari et al., 2019;Musiol, 2017;Marzaro et al., 2016). In a report on 3-(tetrazol-5-yl)quinolines with antiallergic potential, benzo[h]quinoline-3-carboxamide was mentioned as a synthetic intermediate, though its biological activity was not determined in that work (Erickson et al., 1979). In our recent studies on photoswitchable sirtuin inhibitors, we obtained benzo [h]quinoline-3-carboxamide as a side product of azastilbene photoisomerization (Grathwol et al., 2019). By UV radiation, (E)-5-styrylnicotinamide was transformed to its Z isomer as envisioned, but underwent photocyclization and successive oxidation, yielding two isomeric benzoquinoline derivatives; the identity of one of these was determined to be the benzo[h]quinoline derivative and its crystal structure is reported here.

Structural commentary
The title compound, benzo[h]quinoline-3-carboxamide, crystallizes in the monoclinic space group P2 1 /c. Four molecules are present in the unit cell (Z = 4) and there is one molecule in the asymmetric unit. Benzo[h]quinoline-3-carboxamide consists of a nicotinamide unit being fused with a benzo[h]quinoline moiety, while the pyridine ring is shared between these two common structural building blocks (Fig. 1). The molecule is essentially flat, with a largest deviation from the plane through all 17 non-H atoms of 0.050 (2) Å (O1) and an r.m.s. deviation of 0.020 (2) Å . In the unit cell, the four molecules are arranged in two perfectly coplanar pairs, with a nearly perpendicular angle between the respective planes of the two pairs of 87.64 (6) (Fig. 2). A plethora of crystal structures are known for compounds with one or other of the two building blocks that make up this molecule [for the nicotinamide scaffold, ConQuest finds over 2000 hits in the Cambridge Structural Database (CSD), while for benzoquinoline, there are over 500; Groom et al., 2016]. However, the specific combination in the title compound is unprecedented. Comparing the title compound to the known structures of unsubstituted nicotinamides, its pronounced planarity is most notable. In the six published structures in the space groups P2 1 /c or P2 1 /a, the angles between the aromatic plane (here C2/C3/N2/C4/C13/C14) and the amide substituent (here O1/N1/C1) range from 22.1 to 23.3 (general CSD refcode NICOAM; Wright & King, 1954;Miwa et al., 1999;Fá biá n et al., 2011;Jarzembska et al., 2014), i.e. this angle is quite consistent. In the only distinct polymorph of a nicotinamide in the space group P2/a, four distinct molecules were refined with this angle ranging from 8.1 to 22.4 (Li et al., 2011), i.e. they are not very consistent but still considerably larger than the corresponding angle found in the title compound, which is a mere 3.3 (4) . This points toward an extension of the aromatic resonance systems to include the amide substituent. In the parent nicotinamide scaffolds, this does not occur. Similarly, the comparatively long C1 O1 distance of 1.238 (3) Å (average 1.23 Å ) and the comparatively short C1-C2 distance of 1.491 (3) Å (average 1.50 Å in other nicotinamide structures) indicate some involvement of these atoms in resonance effects. In support of this extended resonance, in the nicotinamide structures, the aromatic C-C bonds are much less diverse (range 1.38-1.39 Å , indicating very strong aromaticity in the pyridine ring) than in the structure reported here. In fact, the C-C [range 1.376 (3) The unit cell of benzo[h]quinoline-3-carboxamide in P2 1 /c, with its four molecules in a coplanar and perpendicular arrangement, viewed along the ac diagonal.

Figure 1
The molecular structure of benzo[h]quinoline-3-carboxamide. Displacement ellipsoids are shown at the 50% probability level. more similar to the two known structures of 2-unsubstituted and 3-substituted benzo[h]quinolines (refcodes JAFVEU and SUDVES), with ranges of average C-C and C-N bond lengths of 1.38-1.42 and 1.32-1.36 Å , respectively (Martínez et al., 1992;Luo et al., 2015). The benzo[h]quinoline structural motif therefore dominates the observed metrical parameters of the molecule reported here, representing a fusion between a nicotinamide and a benzo[h]quinoline, with a partial extension of the aromaticity beyond the ring system and extending towards the amide substituent.

Supramolecular features
In the crystal, the planar molecules are all arranged in planes in two distinct orientations, which are nearly perpendicular to each other [angle 87.64 (6) ]. This forms a crisscross pattern when viewed along the ac diagonal (Fig. 2). Classical inversion-related N1-H1PÁ Á ÁO1 hydrogen bonds form dimers and generate R 2 2 (8) ring motifs (Fig. 3). Each molecule forms two classical (N-HÁ Á ÁO and N-HÁ Á ÁN) and two nonclassical (C-HÁ Á ÁN and C-HÁ Á ÁO) hydrogen bonds (Table 1), and these contacts link adjacent dimers into zigzag chains along the c-axis direction (Fig. 4). The observed packing is further stabilized by off-centrestacking between the pyridine and outermost benzene rings of each of the coplanar layers [centroid-to-centroid distance = 3.610 (1) Å ] (Fig. 5). These contacts combine to stack the molecules along the b-axis direction (Fig. 6).

Figure 6
The overall packing of the title compound, viewed along the b-axis direction.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All C-bound H atoms constitute aromatic protons, which were attached in calculated positions and treated as riding with U iso (H) = 1.2U eq (C). The two amine H atoms were found and refined without any constraints or restraints.  (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: CIFTAB (Sheldrick, 2015b) and publCIF (Westrip, 2010).

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 )