The crystal structures, Hirshfeld surface analyses and energy frameworks of 8-{1-[3-(cyclopent-1-en-1-yl)benzyl]piperidin-4-yl}-2-methoxyquinoline and 8-{4-[3-(cyclopent-1-en-1-yl)benzyl]piperazin-1-yl}-2-methoxyquinoline

The title compounds, 8-{1-[3-(cyclopent-1-en-1-yl)benzyl]piperidin-4-yl}-2-methoxyquinoline and 8-{4-[3-(cyclopent-1-en-1-yl)benzyl]piperazin-1-yl}-2-methoxyquinoline differ only in the nature of the central six-membered ring: piperidine in the first and piperazine in the second. They are isoelectronic (CH cf. N) and isotypic. The major contribution to the intermolecular interactions in the crystals is from dispersion forces (E dis), reflecting the absence of classical hydrogen bonds.


Chemical context
Compounds combining dopamine D 2 receptor blockade with serotonin 5-HT 1A receptor activation rather than antagonism for the treatment of Schizophrenia have been developed by a number of researchers (Newman-Tancredi et al., 2007;Jones & McCreary, 2008). One such drug, Adoprazine (c) , was found to combine both dopamine D 2 antagonist (blockade) and serotonin 5-HT 1A agonist (activation) properties (Feenstra et al., 2001(Feenstra et al., , 2006. A similar compound structurally, Bifeprunox (c) , is a partial agonist at dopamine D 2 receptors in vitro, and shows serotonin 5-HT 1A agonist properties (Newman-Tancredi et al., 2005;Cosi et al., 2006). Unfortunately, development of Adoprazine (c) was stopped at the Phase II clinical trials for insufficient therapeutical efficacy, and the FDA refused a licence for Bifeprunox (c) for the same reason.

Structural commentary
The molecular structures of compounds I and II are shown in Figs. 1 and 2, respectively. They have very similar conformations, as illustrated by the view of their structural overlap, shown in Fig. 3. Both compounds crystallize in the triclinic space group P1 with very similar unit-cell parameters in spite of replacing the piperidine ring in I with a piperazine ring in II; they are isotypic and isoelectronic (CH cf. N). Both molecules have a curved shape, and the piperidine ring (C = N2/C10-C14) in I and the piperazine ring (C 0 = N2/N3/C10-C13) in II have chair conformations.

Figure 1
A view of the molecular structure of I, with atom labelling. The displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A view of the molecular structure of II, with atom labelling. The displacement ellipsoids are drawn at the 50% probability level. tively. In the cyclopentene rings, the double bonds C22 C26 in I and C21 C25 in II are 1.381 (2) and 1.365 (4) Å , respectively, while bonds C22-C23 and C21-C22 are 1.450 (2) and 1.457 (4) Å , respectively. These values fall within the limits of those observed for the structures of 40 compounds in the Cambridge Structural Database (CSD, Version 5.42, last update February 2021; Groom et al., 2016), viz. C C varies from ca 1.268 to 1.417 Å , while the adjacent substituted C-C bond varies from ca 1.391 to 1.534 Å (see supporting information file S1).

Supramolecular features
In the crystals of I and II, molecules are linked by C-HÁ Á Á interactions (Tables 1 and 2, respectively). In I, a single C-HÁ Á Á interaction links the molecules, forming chains propagating along the b-axis direction (Fig. 5). In II, two C-HÁ Á Á interactions link the molecules, forming ribbons propagating along the b-axis direction (Fig. 6). There are no other significant directional inter-atomic contacts present in either crystal structure.
In the crystal of III, molecules are linked by C-HÁ Á ÁO hydrogen bonds, forming chains along the [100] direction. The chains are linked by two C-HÁ Á Á interactions, forming slabs lying parallel to the ab plane (supporting information file S2; Table S1 and Fig. S2). Here too, there are no other significant directional inter-atomic contacts present in the crystal structure.

Hirshfeld surface analysis and two-dimensional fingerprint plots
The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009)     A view along the a axis of the crystal packing of II. The C-HÁ Á Á interactions are shown as dashed lines (see Table 2). Only the H atoms involved in these interactions have been included. Table 1 Hydrogen-bond geometry (Å , ) for I.
CgB is the centroid of ring C4-C9.

Figure 5
A view along the a axis of the crystal packing of I. The C-HÁ Á Á interactions are shown as dashed lines (see Table 1). Only the H atoms involved in these interactions have been included.
CgB is the centroid of ring C4-C9. ( McKinnon et al., 2007) were performed with Crystal-Explorer17 (Turner et al., 2017) following the protocol of Tiekink and collaborators (Tan et al., 2019). The Hirshfeld surfaces are colour-mapped with the normalized contact distance, d norm , varying from red (distances shorter than the sum of the van der Waals radii) through white to blue (distances longer than the sum of the van der Waals radii). The Hirshfeld surfaces (HS) of I, II and III mapped over d norm are given in Fig. 7. The most significant short contacts in the crystal structures of all three compounds are given in Table 3. It is evident from the small red spots in Fig. 7a and b that there are only weak contacts present in the crystals of compounds I and II. The slightly larger red spots in Fig. 7c concern the C ar -HÁ Á ÁO methoxy hydrogen bonds in the crystal structure of III (supporting information Table S2).
The percentage contributions of inter-atomic contacts to the HS for all three compounds are compared in Table 4. The two-dimensional fingerprint plots for compounds I, II and III are shown in Fig. 8. They reveal, as expected in the absence of classical hydrogen bonds, that the principal contributions to the overall HS surface involve HÁ Á ÁH contacts at 67.5, 65.9 and 58.2%, respectively.
The second most important contribution to the HS is from the CÁ Á ÁH/HÁ Á ÁC contacts at 25.2, 25.8 and 33.6%, for I, II and III, respectively, which are related to the presence of C-HÁ Á Á interactions (see Tables 1, 2 and S1). These are followed by OÁ Á ÁH/HÁ Á ÁO contacts at 4.5% for each compound. These two contributions are particularly significant for III, as indicated by the pair of sharp spikes for the delineated CÁ Á ÁH/ HÁ Á ÁC and OÁ Á ÁH/HÁ Á ÁO contacts shown in Fig. 8c.
The fact that compounds I and II are isoelectronic and isotypic is reflected in their almost identical Hirshfeld surfaces ( Fig. 7a and b), contributions of the inter-atomic contacts to the HS (Table 4), fingerprint plots ( Fig. 8a and b), and energy frameworks ( Fig. 9a and b).

Figure 7
The Hirshfeld surfaces of compounds (a) I, (b) II and (c) III, mapped over d norm in the colour ranges of À0.1177 to 1.5125, À0.2113 to 1.3756 and À0.1475 to 1.8614 au., respectively.
dispersion forces (E dis ) and the total energy diagrams (E tot ), are shown in Fig. 9. The energies were obtained by using the wave function at the HF/3-2IG level of theory. The cylindrical radii are proportional to the relative strength of the corres-ponding energies (Turner et al., 2017;Tan et al., 2019). They have been adjusted to the same scale factor of 80 with a cut-off value of 5 kJ mol À1 within a radius of 6 Å of a central reference molecule. It can be seen that for all three compounds, the major contribution to the intermolecular interactions is from dispersion forces (E dis ), reflecting the absence of classical hydrogen bonds in the crystals. The colour-coded interaction mappings within a radius of 6 Å of a central reference molecule for all three compounds are given in the supporting information file S3. Full details of the various contributions to the total energy (E tot ) are also included there.

Database survey
A search of the Cambridge Structural Database (CSD, Version 5.42, last update February 2021; Groom et al., 2016) for 2-methoxyquinolines gave 53 hits. In the majority of cases, the methoxy group (atoms C ar -O-C) lies close to the mean plane of the quinoline ring, with dihedral angles varying from 0 to ca 8.51 . In compounds I, II and III the same dihedral angles are 7.24 (16), 7.1 (2) and 1.98 (19)

Figure 9
The energy frameworks calculated for (a) I and (b) II, both viewed along the b axis direction, and (c) III, viewed along the a-axis direction, showing the electrostatic potential forces (E ele ), the dispersion forces (E dis ) and the total energy diagrams (E tot ).

Synthesis and crystallization
The synthesis of compounds I, II and III have been reported [I (Ullah & Al-Shaheri, 2012), compound 3e in that paper; II and III (Ullah, 2012), compounds 3e and 3a, respectively, in that paper]. Colourless crystals of I and II were obtained by slow evaporation of solutions in dichloromethane and methanol; ratios (8:3) and (8.5:1.5), respectively.

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.