Crystal structure, Hirshfeld surface analysis and energy framework study of 6-formyl-7,8,9,11-tetrahydro-5H-pyrido[2,1-b]quinazolin-11-one

A short [2.592 (3) Å] intramolecular N—H⋯O hydrogen bond leads to an S(6) graph-set motif. Intermolecular π–π stacking and C—O⋯π interactions dominate the crystal packing.


Chemical context
Two major aspects contribute to the interest in modified structural analogues of quinazoline alkaloids. On the one hand, they are attractive targets for the development of methods in organic synthesis; reactions sufficiently general to target a wide range of derivatives of a given lead structure should be easy to carry out and warrant high yields. On the other hand, substituted quinazolines allow the study of structure-property relationships with respect to their biological activities (Shakhidoyatov, 1988;Shakhidoyatov & Elmuradov, 2014).
Based on 1 H NMR data and quantum-chemical calculations,  confirmed that the tautomer with the intramolecular hydrogen bond represents the energetically favourable form. In order to establish the tautomeric form of (1) in the solid state, we studied its molecular and crystal structure. We also report the analysis of the Hirshfeld surface and the energy framework of crystalline (1).

Structural commentary
The asymmetric unit of the title compound contains two molecules A and B (Fig. 2). They are almost superimposable, with an r.m.s. of 0.023 Å (Spek, 2020); an overlay of A and B is depicted in the supporting information (Fig. S1). In contrast to the quinazolinone moiety, the alkyl ring is not planar. The maximum deviation from the least-squares plane through each of the molecules is encountered for the atoms C2A and C2B and amounts to 0.515 (3) and 0.521 (3) Å , respectively. The almost coplanar arrangement of the aldehyde group and the pyrimidine ring in either molecule A and B enables an intramolecular N-HÁ Á ÁO interaction (Table 1) and formation of an S(6) graph-set motif.
Molecules of (1) stack into columns parallel to [100] in an equidistant series of coplanar moieties; the independent molecules A and B segregate into different stacks (Fig. 3). The intra-stack arrangement does obviously not correspond to translation but involves the a glide plane with its mirror component along [010]. The carbonyl groups in subsequent molecules of a stack are therefore oriented alternately in the positive and negative direction of the crystallographic b axis, and the same arrangement can be expected for their dipole moments. Although no 'real' translation relates consecutive molecules along [100], the rather regular arrangement of essentially planar objects at half a lattice parameter is reflected in moderate pseudosymmetry in reciprocal space: reflection intensities I hkl are stronger for even indices h than for odd ones, with a ratio I hkl , h = 2n: I hkl , h = (2n + 1) of 1.5.
Compound (1) crystallizes in the non-centrosymmetric achiral space group Pna2 1 , and its absolute structure deserves a comment. The absolute structure is linked to the direction of the polar screw axis along [001]. In the absence of heavy atoms, resonant scattering in (1) is minor, with Friedif (Flack & Shmueli, 2007) of 28. We have recently investigated a case of similar low resonant scattering in a Sohnke group, where the absolute structure could be linked to the absolute configuration of the target molecule, and chemical and spectroscopic information could help (Wang & Englert, 2019). As might be expected, the commonly used indicators for diffraction-based assignment of the absolute structure of (1) were associated with rather large standard uncertainties: the Flack parameter (Flack, 1983) refined to 0.51 (7), and similar results were obtained for Parsons' quotient method [0.52 (5); Parsons et al., 2013] and Hooft's Bayesian analysis [0.51 (5); Hooft et al., 2010]. All of these indicators suggest that the specimen used for the diffraction experiment was a twin. Refinement converged for a volume ratio of 0.7 (2):0.3 (2) for the twin domains. The asymmetric unit of (1) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular N-HÁ Á ÁO hydrogen bond forming an S(6) ring motif is shown with dashed lines.

Hirshfeld surface analysis
In order to visualize intermolecular interactions in (1), the Hirshfeld surface (HS) (Spackman & Jayatilaka, 2009) was analysed and the associated two-dimensional fingerprint plots (McKinnon et al., 2007) calculated with Crystal Explorer 17 (Turner et al., 2017). The HS mapped with d norm is represented in Fig. 5. White surface areas indicate contacts with distances equal to the sum of van der Waals radii, whereas red and blue colours denote distances shorter (e.g. due to hydrogen bonds) or longer than the sum of the van der Waals radii, respectively.

Interaction energy calculations
Intermolecular interaction energies were calculated using the CE-HF/3-21G energy model available in Crystal Explorer 17 (Turner et al., 2017). The total intermolecular energy (E tot ) is the sum of electrostatic (E elec ), polarization (E pol ), dispersion (E dis ) and exchange-repulsion (E rep ) energies (Turner et al., 2015) with scale factors of 1.019, 0.651, 0.901 and 0.811, respectively (Mackenzie et al., 2017). According to these calculations, the major contribution of À306.5 kJ mol À1 is due to dispersion interactions (Fig. 7). The other energy components have values of À91.5 kJ mol À1 , À37.6 kJ mol À1 and 155.7 kJ mol À1 for the E elec , E pol and E rep energies, respectively. The total interaction energy resulting from these four components amounts to À267.1 kJ mol À1 .

Synthesis and crystallization
Compound (1)  Energy frameworks for the electrostatic (red, top) and dispersion (green, middle) components and the total interaction energy (blue, bottom). Cylinder radii are proportional to the corresponding energy; a scale factor of 80 and a cut-off value of 10 kJ mol À1 have been used. detailed report on the synthesis of (1) and its characterization by 1 H NMR is available in Zhurakulov et al. (2017). Crystals suitable for X-ray diffraction were obtained from a methanol solution by slow evaporation of the solvent at room temperature.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms attached to C were positioned geometrically, with C-H = 0.95 Å (for aromatic), 0.95 Å (for the aldehyde H atom), 0.99 Å (for methylene H atoms) and were refined with U iso (H) = 1.2U eq (C). The enamine H atoms H5A and H5B were refined with a common isotropic displacement parameter; N-H distances were restrained to similarity. SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020); software used to prepare material for publication: publCIF (Westrip, 2010). Extinction coefficient: 0.0008 (2) Absolute structure: Refined as an inversion twin. Absolute structure parameter: 0.3 (2) 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.