Crystal structures of three homologues with increasing ring size: 2-methoxy-4-(thiophen-2-yl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-methoxy-4-(thiophen-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile and 2-methoxy-4-(thiophen-2-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carbonitrile

The title compounds form a homologous but non-isotypic series with appreciable differences in molecular form. In each case, the packing is determined by two C—H⋯N hydrogen bonds.

The title compounds, C 15 H 14 N 2 OS (1a), C 16 H 16 N 2 OS (1b), and C 17 H 18 N 2 OS (1c), form a homologous series in which the size of the saturated ring increases from six-to eight-membered (with four, five and six methylene groups respectively). For 1b and 1c, the central (CH 2 ) n moieties are all displaced to the same side of their ring, and the CH 2 -CH 2 -CH 2 angles are much wider than the standard sp 3 value; a database search indicates that these are general features of such ring systems. For 1a, the thiophene ring lies with the sulfur atom on the opposite side of the C thiophene -C pyridine bond to the cyano group, in contrast to 1b and 1c. For each compound, the packing may be described in terms of two 'weak' C-HÁ Á ÁN hydrogen bonds, which link the molecules to form one-dimensional (1a, 1c) or three-dimensional (1b) assemblies.

Chemical context
Recently, we started a widespread study of pyridones and related compounds and have described the synthesis of new N-substituted amino-2-pyridones (Azzam et al., 2017a(Azzam et al., ,b, 2020a; see also Bolduc et al., 2022). The synthetic applications of unsaturated nitriles as reaction intermediates for the preparation of a wide range of heterocyclic compounds has stimulated considerable interest in our group over the last decade (Khedr et al., 2022a,b;Abdallah & Elgemeie, 2022). Since pyridines and their fused heterocycles have been shown to constitute a new class of antimetabolites (De et al., 2022), it is of interest to evaluate synthetic methods for the preparation of their analogues and demonstrate the effects of structural modifications on their biological activity (Elgemeie & Mohamed-Ezzat, 2022a,b). Many 2-methoxypyridine derivatives have previously been shown to possess antitubercular and antibacterial activities (Bodige et al., 2019).
Some time ago we reported the synthesis of the condensed 2-methoxy-4-thienyl-3-cyanopyridines (1a-c) via the reaction of cycloalkanones with 2-(2-thienylmethylene)malononitrile in refluxing methanolic sodium hydroxide (Elgemeie et al., 1991); we also presented experimental data and a proposed mechanism. In 2015, another research group repeated our reaction and synthesized 1c using LiOEt instead of NaOEt (Maharani & Kumar, 2015). Here we are able to present the molecular structures of 1a-c determined with single crystal XRD.

Structural commentary
The structure determinations confirm the nature of the products 1a-c. The three molecules, which form a homologous series with increasing ring size, are shown in Figs. 1-3. The compounds all crystallize in space group P2 1 /c (or its equivalent P2 1 /n) but none of them is isotypic to any other. Bond lengths and angles may be considered normal for these compound types. For instance: the exocyclic angles N-C-C at the ring junctions are appreciably less than 120 and the CH 2 -CH 2 -CH 2 angles of 1b and 1c are markedly wider than the standard value of 109.5 (see Tables 1-3). The overall form of the molecules, however, differs between 1a and the similar pair 1b/1c.
For convenience, the rings are designated as follows: Ring A, thiophene; ring B, pyridine-type ring; ring C, the ring containing the (CH 2 ) n moieties (as defined in the scheme, e.g. The molecule of 1b in the crystal. Ellipsoids represent 50% probability levels. The minor position [occupation factor 0.083 (3)] of the disordered thienyl group is omitted.

Figure 3
The molecule of 1c in the crystal. Ellipsoids represent 50% probability levels. The minor positions [occupation factor 0.101 (3)] of the disordered atoms C7 and C8 are omitted.

Figure 1
The molecule of 1a in the crystal. Ellipsoids represent 50% probability levels.
For 1a, ring C displays a standard half-chair conformation, with C6 and C7 lying 0.481 (2) and 0.293 (2) Å , respectively, in opposite directions out of the plane defined by C5, C4A, C8A and C8. The thiophene ring lies with the sulfur atom on the opposite side of the C4-C11 bond to the cyano group. The interplanar angle between rings A and B is 45.33 (4) .
For 1b and 1c, however, the thiophene rings are differently positioned, with the sulfur atom on the same side of the C4-C12 (1b) or C4-C13 bond (1c) as the cyano group. The respective S1Á Á ÁN2 distances are 3.676 (1) and 4.070 (1) Å , too long to be considered significant interactions, and the interplanar angles A/B are 61.40 (5) and 79.67 (4) . In the rings C, the (CH 2 ) n moieties are all displaced to the same side of ring B, in the direction opposite to the sulfur atom (Fig. 4).

Supramolecular features
None of the compounds contains a classical hydrogen-bond donor, and so the molecular packing must be interpreted in terms of other 'weak' interactions. The most obvious of these are 'weak' C-HÁ Á ÁN hydrogen bonds, mostly involving the nitrogen atom of the nitrile group; however, it is a moot point whether these represent significant interactions or simply the exposed nature of the one-coordinated nitrogen atoms. Each compound displays two such contacts.
hydrogen atom H11C should probably be regarded as a borderline case. For compound 1b, the two C-HÁ Á ÁN hydrogen bonds again both involve N2 (Table 5), but the operators are different (one inversion centre and one 2 1 screw axis). This leads to a complex three-dimensional structure, part of which is shown in Fig. 6. There is also a C-HÁ Á Á contact from H7B to the centroid of ring A (HÁ Á ÁCg = 2.93 Å , C-HÁ Á ÁCg = 170 , operator x À 1 2 , Ày + 1 2 , z + 1 2 ).
A search for the cyclohepta[b]pyridine subunit of 1b, excluding ring systems with further annelation, led to 26 hits, corresponding (excluding repeats) to 23 compounds; eleven of these involve seven-membered rings with no further substituents. The hits include the natural products rupestine B (refcode SUGSAP; Su et al., 2010) and D (refcode SUGSET; Su et al., 2010, Zhang et al., 2021. An analogous search for cycloocta [b]pyridine derivatives (corresponding to 1c) gave 19 hits for 18 unique compounds; in all cases, the eight-membered rings bear no further substituents. Both searches showed that the three or four central methylene groups always lie on the same side of the plane of the pyridine-type ring (ring B in Section 2), as observed for 1b and 1c (Fig. 4). They also confirmed the general trend to wide bond angles in the (CH 2 ) n moieties.

Synthesis and crystallization
Compounds 1a-c were prepared following our literature procedures (Elgemeie et al., 1991) and crystallized from ethanol.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 7. Methyl groups were included as idealized rigid groups allowed to rotate but not tip (C-H = 0.98 Å , H-C-H = 109.5 ). Other hydrogen atoms were included using a riding model starting from calculated positions (C-H aromatic = 0.95 Å , C-H methylene = 0.98 Å , C-H methine = 1.00 Å ). The U iso (H) values were fixed at 1.5 Â U eq of the parent carbon atoms for methyls and 1.2 Â U eq for other hydrogens.

Figure 6
Part of the three-dimensional molecular packing of compound 1b, viewed perpendicular to (110), showing the 'weak' hydrogen bonds (drawn as dashed bonds). Atom labels indicate the asymmetric unit. Two inversionsymmetric substructures are shown, each with two further molecules related by the 2 1 axis.

Figure 7
The molecular packing of compound 1c, viewed perpendicular to (101), showing the 'weak' hydrogen bonds (drawn as dashed bonds). Atom labels indicate the asymmetric unit. disordered by ca 180 rotation about the bond C4-C12. The occupation factor of the major disorder component refined to 0.917 (2). In the structure of 1c, the atoms C7 and C8 of the eightmembered ring are disordered over two positions; the relative occupation factors refined to 0.899 and 0.101 (3).
For both disordered structures, appropriate restraints (e.g. setting bond lengths and angles of the disorder components to be approximately equal, command SAME) were employed to improve stability of refinement, but the dimensions of disordered groups (especially the minor components) should be interpreted with caution.    (Siemens, 1994); software used to prepare material for publication: SHELXL2018/3 (Sheldrick, 2015b).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1 0.41901 (8) 0.65182 (10) 0.62167 (7) 0.01531 (18)   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.

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.  (4)