Crystal structure of 4-methyl-N-(4-methylbenzyl)benzenesulfonamide

The synthesis and crystal structure of the title aryl sulfonamide are described. In the crystal, N—H⋯O and C—H⋯π interactions link the molecules, leading to the formation of a three-dimensional network structure.


Chemical context
Sulfonamides, commonly referred to as 'sulfa drugs', are a biologically significant class of drugs. Over 70 years since its discovery, the sulfonamide moiety is frequently used in modern medicine (Zhao et al., 2016). First recognized as a class of antibiotics in the 1930s, this class of drugs is used today to treat infectious diseases such as malaria, tuberculosis, HIV, and many more by targeting the dihydropteroate synthase (DHPS) pathway (Dennis et al., 2018). Sulfonamides also exhibit remarkable antitumor, anticancer, and antithyroid activities among others (Scozzafava et al., 2003).
As therapeutic properties of sulfonamides continue to be discovered, it is important to synthesize these compounds efficiently. Sulfonamides are commonly synthesized by a mechanism analogous to the nucleophilic acyl-substitution reaction between an electrophile and a nucleophilic amine (Patel et al., 2018). A review of the literature suggests that the most efficient method for synthesizing these compounds is by the sulfonylation of amines using either sulfonyl halides or sulfonic acids as electrophiles (Yan et al., 2007;De Luca & Giacomelli, 2008). The title compound was synthesized in dichloromethane using a sulfonyl chloride, in the presence of pyridine. The main purpose of pyridine is to act as a hydrochloric acid scavenger. However, in our ongoing efforts to produce sulfonamides, we have recently discovered an environmentally benign and facile synthesis of aryl sulfonamides. This method uses aqueous potassium carbonate in tetrahydrofuran. An increased rate of reaction and yield of sulfonamide compounds produced from a wide range of amines have been observed. We report here the synthesis of the title compound (I), as well as its molecular and crystal structures.

Supramolecular features
Molecules of compound (I) exhibit both intermolecular N-HÁ Á ÁO hydrogen bonds and C-HÁ Á Á interactions in the crystal structure (Fig. 3). The intermolecular N1-H1Á Á ÁO1 hydrogen bond is of medium strength and links molecules of title compound into ribbons that run parallel to the b axis (Table 1, Fig. 4). The C9-C14 ring hosts two C-HÁ Á Á interactions that link the ribbons into an intricate three-dimensional network (  The molecular structure of the title compound using standard CPK colors, showing the atom-labeling scheme. Aniosotropic displacement ellipsoids are shown at the 40% probability level. Table 1 Hydrogen-bond geometry (Å , ).

Figure 4
Depiction of the supramolecular ribbons formed via intermolecular N-HÁ Á ÁO hydrogen bonds (purple dashed lines), as viewed down the a axis.

Synthesis and crystallization
The title compound was prepared by the dropwise addition of p-toluenesulfonyl chloride (1.00 g, 5.25 mmol) to a stirring mixture of 4-methylbenzylamine (0.75 ml, 5.90 mmol), pyridine (0.48 ml, 5.90 mmol) and 10 ml of degassed dichloromethane under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. The mixture was acidified with 5 M HCl and diluted with 15 ml of dichloromethane. The organic phase was washed with water. The aqueous layers were combined and back extracted with dichloromethane (10 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in hot ethanol and filtered. The filtrate was transferred to a scintil-lation vial and, upon standing for 24 h, crystallized to afford pale-yellow crystals that were filtered from the mother liquor (42%; m.p. 376-378 K).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms bonded to carbon atoms were placed in calculated positions and refined as riding: C-H = 0.95-1.00 Å with U iso (H) = 1.2U eq (C) for methylene groups and aromatic hydrogen atoms, and U iso (H) = 1.5U eq (C) for methyl groups. The hydrogen atom bonded to the nitrogen atom (H1) was located using electron-density difference maps. The N1-H1 bond distance was restrained using DFIX instructions in SHELXL (Sheldrick, 2015) at 0.88 Å to agree with the known value.

4-Methyl-N-(4-methylbenzyl)benzenesulfonamide
Crystal data 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.