Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-8-(4-chlorophenyl)-4-cyano-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}-N-(4-chlorophenyl)acetamide

The cyclohexene ring of the tetrahydroisoquinoline unit is non-planar. The two 4-chlorophenyl groups extend away from one side of this unit while the hydroxyl and acetyl groups extend away from the opposite side. An intramolecular O—H⋯O hydrogen bond fixes the rotational orientation of the acetyl group. In the crystal, N—H⋯O hydrogen bonds form chains of molecules extending along the c-axis direction. Inversion-related chains pack to form layers parallel to the bc plane.

In the title molecule, C 28 H 25 Cl 2 N 3 O 3 S, the heterocyclic portion of the tetrahydroisoquinoline unit is planar while the cyclohexene ring adopts a twist-boat conformation. The two 4-chlorophenyl groups extend away from one side of this unit while the hydroxyl and acetyl groups extend away from the opposite side and form an intramolecular O-HÁ Á ÁO hydrogen bond. The crystal packing consists of layers parallel to the bc plane. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from HÁ Á ÁH (37.3%), ClÁ Á ÁH/HÁ Á ÁCl (17.6%), OÁ Á ÁH/ HÁ Á ÁO (11.1%), CÁ Á ÁH/HÁ Á ÁC (10.9%) and NÁ Á ÁH/HÁ Á ÁN (9.7%) interactions.

Chemical context
The tetrahydroisoquinoline motif is present in a variety of natural products, including cactus alkaloids (peyoruvic acid; Chrzanowska et al., 1987) and mammalian alkaloids (salsoline carboxylic acid; Czarnocki et al., 1992). Biological tests indicate that tetrahydroisoquinolines can act as bronchodilators (Houston & Rodger, 1974) and anticonvulsants (Ohkubo et al., 1996;Thompson et al., 1990) and they have also shown anti-hypoxic activity (Gill et al., 1991). Based on these findings and following our interest in this area, we herein report the synthesis and crystal structure of the title compound. ISSN 2056-9890

Structural commentary
The overall conformation of the title molecule, Fig. 1, resembles that of a chair with the tetrahydroisoquinoline core forming the seat, the hydroxyl and acetyl oxygen atoms forming stubby legs and the 4-chlorophenyl group and the amide group forming the back. The N1/C5-C9 ring is essentially planar (r.m.s. deviation = 0.041 Å ) with the largest deviation of 0.059 (1) Å being for atom C9. A puckering analysis (Cremer & Pople, 1975) of the C1-C5/C9 ring yielded the following parameters: Q T = 0.5230 (13) Å , = 54.39 (14) and ' = 96.94 (17) . The conformation of this ring approximates a twist-boat conformation. The best planes through the C10-C15 and C23-C28 rings are inclined to the N1/C5-C9 plane by 76.05 (6) and 74.04 (6) , respectively. The acetyl group on C2 is in an equatorial position while the hydroxyl group on C3 is axial and these are syn to one another. The C10-C15 ring attached to C1 is close to equatorial and anti with respect to both other substituents (Table 1, Fig. 1). The O2-H2A hydroxyl group is favorably oriented for forming an intramolecular hydrogen bond with O1 ( Fig. 1). This was not seen for some related molecules where a stronger intermolecular interaction is favored for these O atoms (Al-Taifi et al., 2021).

Figure 2
A portion of one chain viewed along the a-axis direction with the intermolecular N-HÁ Á ÁO hydrogen bonds depicted by dashed lines.

Figure 3
Packing viewed along the b-axis direction with N-HÁ Á ÁO hydrogen bonds depicted by dashed lines.

Figure 1
The title molecule with the labeling scheme and 50% probability ellipsoids. The intramolecular O-HÁ Á ÁO hydrogen bond is depicted by a dashed line.
in Table 2. The O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds are clearly shown by the dark-red circles (Tables 1 and 2; Fig. 4).  Fig. 5f). The other contacts are negligible with individual contributions of less than 2.9% and are given in Table 3.
In the crystal of NAQRIJ, dimers form through complementary sets of inversion-related O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds. These are connected into zigzag chains along the c-axis direction by pairwise C-HÁ Á ÁN interactions that also form inversion dimers. In the crystal of KUGLIK, the heterocyclic amines are alternately connected to the hydrogen-bonding system along the c axis, which leads to the formation of syndiotactic polymer chains in this direction. The hydrogen-bonding network of the water molecules forms a water plane along the b and c axes with different ring systems (only counting the oxygen atoms) and graph-set motifs of the hydrogen-bonding network. In the crystal of DUSVIZ, molecules are linked via C-HÁ Á ÁO hydrogen bonds. For the major disorder component, these form C(11) chains that propagate parallel to the a axis. In the crystal of AKIVUO, a layer structure with the layers parallel to (101) is generated by O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds. In the crystal of ULUTAZ, molecules are linked via N-HÁ Á ÁO and C-HÁ Á ÁN hydrogen bonds, forming a three-dimensional network. Furthermore, the crystal packing is dominated by C-HÁ Á Á bonds with a strong interaction involving the phenyl H atoms. In the crystal of CARCOQ, molecules are linked by O-HÁ Á ÁO hydrogen bonds, forming chains propagating along the a-axis direction. The chains are linked by C-HÁ Á ÁF hydrogen bonds, forming layers lying parallel to the ab plane. In the crystal of POPYEB, molecules are packed in a herringbone manner parallel to (103) and (103) via weak C-HÁ Á ÁO and C-HÁ Á Á(ring) interactions. In the crystal structure of ENOCIU, various C-HÁ Á Á and C-HÁ Á ÁO interactions link the molecules. In the crystal of NIWPAL, the molecules are linked by N-HÁ Á ÁO intermolecular hydrogen bonds involving the sulfonamide function to form an infinite two-dimensional network parallel to the (001) plane.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. All C-bound H atoms were placed in geometrically idealized positions (C-H = 0.95-1.00 Å ) while those attached to O and to N were placed in locations derived from a difference map, refined for a few cycles to ensure that reasonable displacement parameters could be achieved, and then their coordinates were adjusted to give O-H = 0.87 and N-H = 0.91 Å . All H atoms were included as riding contributions with isotropic displacement parameters 1.2-1.5 times those of the parent atoms. program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/1 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg & Putz, 2012); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Special details
Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, colllected at φ = 0.00, 90.00 and 180.00° and 2 sets of 800 frames, each of width 0.45° in φ, collected at ω = -30.00 and 210.00°. The scan time was 20 sec/frame. 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. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. H-atoms attached to carbon were placed in calculated positions (C-H = 0.95 -1.00 Å) while those attached to nitrogen and to oxygen were placed in locations derived from a difference map and their coordinates adjusted to give N -H = 0.91 and O-H = 0.87 %A. All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.