Crystal structure of N,N-diisopropyl-4-methylbenzenesulfonamide

The synthesis and crystal structure of a diisopropyl-substituted p-tolunesulfonamide is discussed. This structure features C—H⋯O hydrogen bonds (both intra- and intermolecular) and intermolecular C—H⋯π interactions.

The synthesis of the title compound, C 13 H 21 NO 2 S, is reported here along with its crystal structure. This compound crystallizes with two molecules in the asymmetric unit. The sulfonamide functional group of this structure features S O bond lengths ranging from 1.433 (3) to 1.439 (3) Å , S-C bond lengths of 1.777 (3) and 1.773 (4) Å , and S-N bond lengths of 1.622 (3) and 1.624 (3) Å . When viewing the molecules down the S-N bond, the isopropyl groups are gauche to the aromatic ring. On each molecule, two methyl hydrogen atoms of one isopropyl group are engaged in intramolecular C-HÁ Á ÁO hydrogen bonds with a nearby sulfonamide oxygen atom. Intermolecular C-HÁ Á ÁO hydrogen bonds and C-HÁ Á Á interactions link molecules of the title compound in the solid state.

Chemical context
Sulfonamides are biologically significant compounds that were first introduced as potent antibacterial agents (Chohan et al., 2005). Since then, sulfonamides have been reported to exhibit a variety of therapeutic properties. These properties include the inhibition of hepatitis C virus (HCV). First discovered in 1989, HCV is a liver disease that is responsible for the majority of liver-related deaths (Chen & Morgan, 2006;Morozov & Lagaye, 2018). According to data published in 2016, approximately 69.6 million individuals are affected by HCV (Hill et al., 2017).
Advances in HCV treatment have brought about a variety of novel HCV inhibitors that contain the sulfonamide moiety (Johansson et al., 2003;Gopalsamy et al., 2006). The pan genotypic NS5A inhibitor, Daclatasvir, and the NS3/4A protease inhibitor, Simeprevir, are examples of sulfonamide drugs approved for the treatment of HCV (Zeuzem et al., 2016). Arylsulfonamides, similar in structure to the title compound, were discovered as potent hepatitis C virus (HCV) 1b replicon inhibitors that target the HCV NS4B protein ( Fig. 1; Zhang et al., 2013). The HCV NS4B protein is a key component for the replication of HCV RNA (Blight, 2011). It is necessary to synthesize a variety of potential inhibitors to work towards the treatment of HCV.
Producing biologically significant sulfonamide compounds is highly dependent on a facile synthetic method. A review of the current literature suggests a viable route of synthesis is the reaction between an electrophilic sulfonyl chloride and nucleophilic amine (Almarhoon et al., 2019). Another notable method for synthesizing sulfonamide compounds is the reaction between an N-silylamine and a sulfonyl chloride (Naredla & Klumpp, 2013). The title compound was synthesized by an analogous nucleophilic acyl substitution reaction between p-toluenesulfonyl chloride and diisopropylamine in the presence of pyridine. The use of p-toluenesulfonyl chloride as an electrophile is a good starting point in synthesizing arylsulfonamides due to its availability and low cost. Herein, we report the synthesis and crystal structure of N,N-diisopropyl-4-methylbenzenesulfonamide. The crystal structure of the title compound was obtained via single crystal X-ray diffraction.

Structural commentary
The title compound crystallizes in the monoclinic space group Pc, with two equivalents of the molecule in the asymmetric unit. The structure was solved with a Flack parameter of 0.002 (14) (Parsons et al., 2013). The atom labeling scheme is shown in Fig. 2. The molecules boast S O bond lengths ranging from 1.433 (3) to 1.439 (3) Å , S-N bond lengths of 1.622 (3) and 1.624 (3) Å , and S-C bond lengths of 1.777 (3) and 1.773 (4) Å . These values lie in the expected ranges for an aromatic sulfonamide group. The O-S-O bond angles for each molecule are 119.35 (16) and 119.54 (16) . When the molecules are viewed down the S-N bond, both have adopted a similar conformation with the isopropyl groups being gauche to the aromatic ring. In each molecule, the methine carbon atom of one of the isopropyl groups is nearly coplanar with a sulfonamide oxygen with O1-S1-N1-C8 and O1A-S1A-N1A-C8A torsion angles of 17.1 (3) and 15.7 (3) , respectively. We attribute this relatively small torsion angle to the presence of intramolecular C-HÁ Á ÁO interactions, which are described in more detail below. The torsion angles (O2-S1-N1-C11 and O2A-S1A-N1A-C11A) between the methine carbon atom of the other isopropyl group and the other sulfonamide oxygen are 46.7 (3) and 46.8 (3) , respectively. Both sulfur atoms adopt a slightly distorted tetrahedral geometry with 4 descriptors for fourfold coordination of 0.94 for both S1 and S1A (where 0 = square planar, 0.85 = trigonal pyramidal, and 1 = tetrahedral; Yang et al., 2007). Finally, there are two intramolecular C-HÁ Á ÁO hydrogen bonds present between one sulfonamide oxygen atom and the methyl hydrogen atoms of an adjacent isopropyl group (Sutor, 1958(Sutor, , 1962(Sutor, , 1963Steiner, 1996). While these interactions could be simply due to sterics since the D-HÁ Á ÁA angles are around 120 (see below), we describe them here as potential C-HÁ Á ÁO hydrogen bonds. Specifically, O1 interacts with C9(H9A) and C10(H10B), while the equivalent atom O1a interacts with C9A(H9AC) and C10A(H10F). These interactions have DÁ Á ÁA distances ranging from 3.039 (5) to 3.157 (5) Å and D-HÁ Á ÁA angles ranging from 117 to 121 (Table 1, Fig. 3).

Supramolecular features
Molecules of the title compound are held together in the solid state by intermolecular C-HÁ Á Á interactions and C-HÁ Á ÁO hydrogen bonds (Fig. 3). The C-HÁ Á Á interactions have CÁ Á Ácentroid distances of 3.515 (4) and 3.548 (4) Å , with C-HÁÁcentroid angles of 120 and 121 . The intermolecular C-HÁ Á ÁO hydrogen bond is present between C8(H8) and O2 i [symmetry code: (i) x, À1 + y, z] with a DÁ Á ÁA distance of 3.465 (4) Å and a D-HÁ Á ÁA angle of 150.8 (Table 1) The molecular structure of the title compound, with the atom labeling scheme for both crystallographically unique molecules. Displacement ellipsoids are shown at the 40% probability level using standard CPK colors, and all hydrogen atoms have been omitted for clarity. Table 1 Hydrogen-bond geometry (Å , ).

D-HÁ
supramolecular interactions form ribbons that run parallel to the b-axis direction (Fig. 4).  (Zhou & Zheng, 2007) and CEMFUX (Zhou et al., 2012). In the structure of RUGQEQ, the sulfonamide nitrogen atom bears a benzyl and a cyclohexyl group, while in CIQGOZ the -R groups are methyl and phenyl. For the structure CEMFUX, two sulfonamide nitrogen atoms are linked via an ethylene chain, and the other -R group is a substituted propyl ester.

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 diisopropylamine (0.83 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. After acidification with 5 M HCl and dilution with 15 mL of dichloromethane, the organic layer was washed with water and brine. The aqueous layers were back extracted with 10 mL of dichloromethane. The combined organic layers were then dried over anhydrous sodium sulfate and evaporated to Supramolecular ribbons of the title compound assembled via intermolecular C-HÁ Á Á interactions and C-HÁ Á ÁO hydrogen bonds, as viewed down the c axis using a ball-and-stick model with standard CPK colors. The non-covalent interactions are depicted with dashed lines (C-HÁ Á Á: green; C-HÁ Á ÁO hydrogen bonds: purple), and the unit cell is drawn with orange. Only hydrogen atoms involved in a non-covalent interaction are shown for clarity.

Figure 3
Non-covalent interactions present in the title compound, using a ball and stick model with standard CPK colors. C-HÁ Á Á interactions are drawn with green, dashed lines and C-HÁ Á ÁO hydrogen bonds are drawn with purple, dashed lines. Symmetry codes: (i) À1 + x, Ày, À 1 2 + z; (ii) 1 + x, 1 À y, 1 2 + z; (iii) x, À1 + y, z.  (14) dryness. The resulting solid was dissolved in hot ethanol and filtered. The filtrate was placed in a freezer for two days and the product was isolated via vacuum filtration to give colorless crystals (13%; m.p. 362-365 K).

N,N-Diisopropyl-4-methylbenzenesulfonamide
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.