Stereochemistry of the methylidene-bridged quinazoline-isoquinoline alkaloid 3-{[6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methylidene}-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-9-one methanol monosolvate

The main residue and the solvent molecule aggregate to discrete pairs via a classical O—H⋯O hydrogen bond, while non-classical C—H⋯O interactions lead to the formation of an extended network.

Over the years the synthetic interest in the quest for new isoquinoline derivatives has not declined (Bentley, 2006;Zhurakulov et al., 2013Zhurakulov et al., , 2014Zhurakulov et al., , 2015, because even minor changes in the molecular geometry may lead to improved therapeutic effects. Both moieties mentioned above, a quina-zoline and an isoquinoline, have been successfully connected by a methylidene bridge (Elmuradov et al., 1998(Elmuradov et al., , 2008Turdibayev et al., 2011;Zhurakulov et al., 2015). This coupling reaction allows two potentially bioactive components to be combined in a single molecule. In view of the high chemical and biological activity of isoquinoline and tricyclic quinazoline alkaloids, we expect that the combination of both scaffolds as in the target compound of the present study could lead to unprecedented properties.

Structural commentary
The title compound crystallizes in the monoclinic space group P2 1 /n with one molecule of the target heterocycle and one molecule of methanol in the asymmetric unit. A displacement ellipsoid plot and the numbering scheme for both molecules are provided in Fig. 2.

Figure 3
Ball and stick representation (Spek, 2020) of a hypothetical Z-configured molecule generated by 180 rotation of all atoms of the tricyclic quinazoline moiety about the C17 C18 bond; the dashed red line emphasizes the unfavourable intramolecular contact (see text). aromatic ring in the dihydroisoquinoline moiety (C4A-C8A), with out-of-plane distances of 0.082 (3) Å for C9 and 0.221 (3) Å for C10. The twist conformation of the heterocyclic ring of the dihydroisoquinoline moiety and the equatorial position of the nitrophenyl substituent observed here are similar to those in related structures (Olszak et al., 1996;Turgunov et al., 2016). C1, C4, C4A and C8A are coplanar within error, whereas C3 and N2 are on opposite sides of this plane. The nitrophenyl substituent C11-C16 and the aromatic part of the dihydroisoquinoline (C4A-C8A) form an angle of 75.70 (14) . The main motivation for our crystallographic study was to establish the configuration about the C17 C18 double bond. Intuition suggests that the E configuration should clearly be favoured, and our experiment confirms this expectation. In order to further explore the steric congestion of an alternative Z configuration, we generated such a hypothetical molecule by 180 rotation of the complete tricyclic quinazoline moiety about C17 C18. The resulting geometry is depicted in Fig. 3.
The prohibitively short intramolecular contact between N19 and C3, shown as a dashed red line, amounts to only 2.05 Å without taking the hydrogen atoms attached to C3 into account. If the two parts of the target molecule are perceived as at least moderately rigid groups, such an alternative Z configuration can safely be excluded. It is important to note, however, that this construction of a hypothetical Z-configured molecule relies on the experimentally established geometry of the semi-rigid isoquinoline and quinazoline moieties. The tricyclic quinazoline system, formed by three fused rings, shows deviations from planarity for the sp 3 carbon atoms, with maximum displacements of 0.126 (3) Å for C26 and 0.110 (3) Å for C25 on opposite sides of the mean plane.

Supramolecular features
An OÁ Á ÁH-O hydrogen bond links the co-crystallized methanol molecule to the keto group of the quinazoline moiety and gives rise to a D(2) graph-set motif (Table 1). Additional short contacts involve non-classical C-HÁ Á ÁO interactions, with HÁ Á ÁO distances ranging between 2.29 and 2.59 Å , forming a complex three-dimensional network (Table 1, Fig. 4). Stacking (Fig. 5) occurs between the pyrrole rings of neighbouring molecules about a centre of inversion [symmetry code: (i) 1 À x, 1 À y, 1 À z], with a distance between the centroids Cg1Á Á ÁCg1 i of 3.832 (2) Å and a ring slippage of 1.246 Å . Both short intermolecular contacts together lead to a supramolecular layer structure parallel to the (010) plane.

Figure 4
Crystal packing in a view along the b axis. O-HÁ Á ÁO bonds are shown as black, C-HÁ Á ÁO contacts as blue dashed lines. The dark-blue dotted line indicates a stacking interaction.

Figure 5
View approximately along the c axis, showing stacking between the pyrrole rings (dashed dark-blue lines). The O-HÁ Á ÁO hydrogen bond is shown in light blue, other hydrogen atoms have been omitted. main molecule in III, mapped with d norm and its interaction with the co-crystallized solvent molecule is represented in Fig. 6. Colours on the Hirshfeld surface encode contact distances (red -close, white -medium, blue -long) between atoms on either side of the surface. The most obvious intermolecular interaction, the classical OÁ Á ÁH-O hydrogen bond, shows up as a prominent deep-red spot on the surface, oriented towards the co-crystallized methanol molecule. The less-pronounced red features on the surface are associated with C-HÁ Á ÁO contacts. Fig. 7 shows a 2D fingerprint plot for the contacts between O and H atoms. These contacts are responsible for the short lateral 'spikes' on either side of the main diagonal of the plot.

Refinement details
Crystal data, data collection parameters and refinement results are summarized in Table 2. H atoms on C atoms were positioned geometrically and treated as riding on their parent atoms, with C-H = 0.95 (aromatic), 0.98 (methyl), 0.99 (methylene) or 1.00 Å (tertiary C atom) and were refined with U iso (H) = 1.5U eq (C) for methyl H atoms and 1.2U eq (C) otherwise. The H atom in the hydroxy group of the co-crystallized methanol was refined with a distance restraint [target distance O-H = 0.84 (2) Å ] and with U iso (H) = 1.2U eq (O).
The anisotropic displacement parameters of N1 and O3 atom were subjected to an enhanced rigid-bond restraint (Thorn et al., 2012).

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.