Crystal structure of 4-methyl-N-propylbenzenesulfonamide

The title compound comprises two molecules in the asymmetric unit. Intermolecular C—H⋯O and N—H⋯O hydrogen bonds lead to a three-dimensional network structure.


Chemical context
Molecules containing the sulfonamide moiety are found among a variety of biologically significant compounds, and have been used to inhibit a variety of enzymes to improve or repair biological functions. Commonly referred to as 'sulfa drugs', these molecules have been in clinical use since 1968 (Connor, 1998). Since then, many sulfonamides have been recognized as effective inhibitors of the zinc enzyme carbonic anhydrase (Gul et al., 2018). Several interesting anticancer properties are exhibited upon inhibition of this enzyme (Supuran et al., 2001).
The title compound, 4-methyl-N-propylbenzenesulfonamide, is structurally similar to a variety of biologically significant compounds. In particular, tacrine-p-toluenesulfonamide derivatives containing the 4-methyl-N-propylbenzenesulfonamide moiety have proven to be effective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors (Makhaeva et al., 2019;Fig. 1). The AChE cholinesterase enzyme catalyzes the hydrolysis of acetylcholine (ACh), a neurotransmitter with the ability to coordinate neural responses in the brain (Picciotto et al., 2012). The inhibition of AChE decreases the extent of ACh hydrolysis and enhances cholinergic transmission. AChE inhibition treats the symptoms of neuron deterioration characteristic of ISSN 2056-9890 Alzheimer's disease (García-Aylló n et al., 2011). While BChE and AChE both regulate the cholinergic system, the effects of BChE are more prevalent in the blood than the nervous system (Pohanka, 2014). BChE is, however, found in the central nervous system and is involved in the formation or growth of -amyloid plaques (Kim et al., 2016). The inhibition of both AChE and BChE improves cognitive function and minimizes the accumulation of -amyloid and is a viable strategy for treating Alzheimer's disease.
A facile synthesis of sulfonamides is necessary to produce a variety of compounds with the potential to improve human health. A review of the current literature suggests that nucleophilic substitution of sulfonyl halides or sulfonic acids with an amine is an efficient method for the synthesis of sulfonamides (Mukherjee et al., 2018;De Luca & Giacomelli, 2008). The title compound was synthesized by reacting ptoluenesulfonyl chloride with propylamine in the presence of pyridine. The reaction was carried out in an inert atmosphere, using dichloromethane as the solvent. These reaction conditions resulted in a poor yield and slow reaction time. To work toward a facile synthesis of sulfonamides, a more efficient and environmentally benign method was recently developed. By substituting pyridine and dichloromethane with aqueous potassium carbonate and tetrahydrofuran, a significant increase in the yield and rate of the reaction was observed. The products formed under these reaction conditions are easily isolated upon acidification of the reaction mixture. Furthermore, the solvent combination supports a broader range of nitrogen nucleophiles. In our ongoing efforts to synthesize and characterize sulfonamide products, the synthesis and crystal structure of 4-methyl-N-propylbenzenesulfonamide is reported here.

Structural commentary
The title compound comprises two equivalents of the molecule in the asymmetric unit, as shown in Fig. 2  The structures of the two molecules in the asymmetric unit of the title compound, with the atom-labeling scheme. Displacement ellipsoids are shown at the 40% probability level using standard CPK colors.

Figure 3
Overlay plot of the two independent molecules in the title compound, with grouping of the atoms C1-S1--N1 and C1A-S1A-N1A, and the molecule oriented so as to view it down the S-N bond. Displacement ellipsoids are as in Fig. 2 118.26 (13) , with N-S-C bond angles of 106.86 (13) and 108.27 (13) . The two independent molecules differ in the orientation of the propyl chain and the H atom attached to the N atom, however, in each case with the propyl chain being gauche to a sulfonamide oxygen atom and to the toluene moiety when the molecules are viewed down the N1-S1 bond (Fig. 3). The torsion angles between the first carbon atom of the propyl chain (C8 or C8A) and the sulfonamide oxygen atom O1 or O1A are 60.5 (3) and 57.3 (2) , respectively. The groups bonded to the sulfur atom of both sulfonamide groups adopt slightly distorted tetrahedral environments with fourfold coordination 4 descriptors of 0.94 for both S1 and S1A (ideal values are 0 for squareplanar, 0.85 for trigonal pyramidal, and 1 for tetrahedral coordinations; Yang et al., 2007).

Figure 4
A diagram showing the specific hydrogen-bonding interactions (N-HÁ Á ÁO: purple dashed lines, C-HÁ Á ÁO: green dashed lines) present in the title compound, using a ball-and-stick model with standard CPK colors. Hydrogen atoms bonded to parent atoms that are not involved in a noncovalent interaction have been omitted for clarity. [Symmetry codes:

Figure 5
A packing diagram of the title compound viewed down the b axis. Intermolecular hydrogen bonds are shown with dashed lines (N-HÁ Á ÁO: purple, C-HÁ Á ÁO: green). This figure was drawn using a ball and stick model with standard CPK colors. Hydrogen atoms bonded to parent atoms that are not involved in a non-covalent interaction have been omitted for clarity.

Database survey
A search for structures containing the p-methylbenzenesulfonamide entity in the Cambridge Structural Database (CSD, Version 5.41, November, 2019; Groom et al., 2016), where the nitrogen atom bears one carbon-containing group, resulted in over 2,200 hits. A few structures with relatively simple, yet interesting, -R groups bonded to the sulfonamide nitrogen atom are BOLPOH (Germain et al., 1983), AZUQUI (Rehman et al., 2011), AYURUI and AYURUI01 Akyıldız et al., 2018), and ATOVIO (Muller et al., 2004).
In the structures of BOLPOH and AZUQUI, the -R groups are both aromatic systems with a quinoline ring and a 4-aminobenzene ring, respectively. The structures of AYURUI and AYURUI01 contain two p-methylbenzenesulfonamide groups linked via a propane chain. Lastly, the -R group in ATOVIO is a tricycloheptyl ring system.

Synthesis and crystallization
The title compound was prepared by the dropwise addition of 0.59 M aqueous potassium carbonate (10 ml, 5.90 mmol) to a stirring mixture of propylamine (0.49 ml, 5.90 mmol) and p-toluenesulfonyl chloride (1.00 g, 5.25 mmol) in 10 ml of tetrahydrofuran. The reaction mixture was stirred at room temperate 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 combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The liquid residue was triturated with diethyl ether, placed in a freezer for 48 h and, after isolation via vacuum filtration, the product was obtained as colorless crystals (59%; m.p. 335-337 K).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The crystal under investigation was twinned by inversion, with a refined Flack parameter of 0.443 (19) (Parsons et al., 2013). For this structure, hydrogen atoms bonded to carbon atoms were placed in calculated positions and refined to ride on their parent atoms: 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. Hydrogen atoms bonded to nitrogen atoms were located using electron density difference maps, and were refined freely.  program(s) used to solve structure: SHELXS (Sheldrick, 2008); program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009;Bourhis et al., 2015); software used to prepare material for publication: CrystalMaker (Palmer, 2007).

4-Methyl-N-propylbenzenesulfonamide
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.