Crystal structure of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide

The X-ray crystal structure, and Hirshfeld surface analysis of a sulfonyl urea analogue, 4-bromo-N-(propylcarbamoyl)benzenesulfonamide is reported.


Chemical context
The title compound, 1, also known as bromopropamide, is a sulfonyl urea structural analogue, whose chemical structure is shown in the scheme. Compounds containing sulfonyl urea as the structural core have been used extensively for the treatment of Type II diabetes (McLamore et al., 1959), by stimulating insulin secretion from pancreatic -cells by binding to the ATP-sensitive potassium channel (Proks et al., 2002). Additionally, sulfonyl urea structural analogues have shown therapeutic action as herbicides and diuretic agents (Tanwar et al., 2017). Thus, the title compound was synthesized in order to perform biological characterization. The crystal structures of several sulfonyl urea compounds have been reported, especially molecules closely related to 1 that contain the N-carbamoylbenzenesulfonamide substructure, all of which have multiple polymorphic forms (Kimura et al., 1999;Drebushchak et al., 2006;Fedorov et al., 2017). Subtle changes to the molecule have shown drastic effects on its biological activity and also the arrangement of molecules in the crystal structure (Bieszczad et al., 2020). Thus, it is of interest to not only confirm the molecular structure of bromopropamide, but to also identify its crystal packing relative to other structural analogues.

Figure 3
The crystal packing in 4-bromo-N-propylcarbamoyl)benzenesulfonamide viewed along the b axis. Antiparallel stacking of the bromophenyl has a centroid-to-centroid distance of 4.213 Å . Displacement ellipsoids are drawn at the 30% probability level. H atoms are not shown for clarity.

Figure 1
The molecular structure of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide with atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Hirshfeld surface analysis
Hirshfeld surface analysis was carried out using Crystal-Explorer17.5 (Turner et al., 2017;Spackman et al., 2021) mapped over d norm , which was estimated by the calculations of the external and internal distances to the nearest nucleus and built over a volume of 322.24 Å 3 having an area of 304.35 Å 2 , with scaled color of À0.6347 a.u. (red) to 1.2043 a.u. (blue). The Hirshfeld surface of 1, shown in Fig. 4, displays close contacts between N1-H1Á Á ÁO3, N2-H2Á Á ÁO2, N2-H2Á Á ÁO3, and C10-H10CÁ Á ÁO1, supporting the conclusions about hydrogen-bonding interactions. Hirshfeld surfaces and their associated two-dimensional fingerprint plots were used to quantify the various intermolecular interactions. The overall two-dimensional fingerprint plot for bromopropamide ( Fig. 5a) and those delineated into major contacts: HÁ Á ÁH, OÁ Á ÁH/HÁ Á ÁO, BrÁ Á ÁH/HÁ Á ÁBr, and CÁ Á ÁH/HÁ Á ÁC are shown in Fig. 5b-e. The other contacts have lower contributions, with individual contributions <4.3% and a sum <12.8%. The HÁ Á ÁH interatomic contacts, which appear as a single spike in the center at d e = d i = 1.1 Å (Fig. 5b), generated 39.4% of the Hirshfeld surface, denoting these contacts have a significant effect on the molecular packing. The OÁ Á ÁH/HÁ Á ÁO interatomic contacts, which appear as a pair of spikes with tips at d e + d i $1.75 Å (Fig. 5c), represent 25.8% of the total surface and confirms the prominent role of multiple hydrogen bonds in the molecular arrangement within the crystal structure. BrÁ Á ÁH/ HÁ Á ÁBr and CÁ Á ÁH/HÁ Á ÁC contribute 12.2% and 9.8%, respectively, to the Hirshfeld surface. The placement of molecules in the crystal structure of the title compound results in efficient packing, as seen in the Hirshfeld surface analysis, which is further supported by the crystallographic density of Hirshfeld surface of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide mapped over d norm , displays close contacts in the crystal. The noncovalent interactions indicated by the red spots are labeled.

Figure 5
The two-dimensional fingerprint plots of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide with their relative contribution to the Hirshfeld surface. The units of d i and d e are Å .

Synthesis and crystallization
The synthesis of 4-bromo-N-(n-propylcarbamoyl)benzenesulfonamide used in situ formation of n-propylisocyanate from n-propylcarbamic chloride with direct capture by 4-bromobenzenesulfonamide in the presence of excess potassium carbonate in refluxing toluene (Fig. 6). This is a new methodology to generate sulfonyl ureas in an atom-efficient manner with identical chemical characterization to prior methods proceeding via carbamate (Marshall & Sigal, 1958) or carbonate (Tanwar et al., 2017) intermediates. A manuscript describing the optimization of this synthetic strategy is in preparation. n-Propylcarbamic chloride (labeled 2 in Fig. 6): A solution of triphosgene (2.24 g, 22.62 mMol as phosgene) in 25 mL of dichloromethane (DCM) was cooled in a 100 mL roundbottom flask. A solution of triethylamine (TEA) (5.6 mL, 40 mMol), n-propylamine (labeled 1 in Fig. 6) (1.7 mL, 20.1 mMol) and 10 mL of DCM was added to the triphosgene solution with slow dropwise addition over 15 min maintaining an internal temperature between 278 and 283 K. The cooling bath was removed following addition and the reaction was permitted to stir for an additional 2 h at 296 K. The reaction mixture was cooled in an ice/water bath and then transferred to a 125 mL separatory funnel previously cooled in ice-water. The mixture was then washed with 3 Â 5 mL portions of icecold water, 2 Â 5 mL of ice-cold 0.5 N HCl, 2 Â 5 mL portions of ice-cold brine, dried Na 2 SO 4 , decanted, and the solvent was carefully removed under reduced pressure without heating to theoretical mass. The conversion to n-propylcarbamic chloride was confirmed with IR absorbance of 1734 cm À1 and afforded 2.5 g (98% of a light yellow oil) and stored at 253 K until use.
4-Bromobenzenesulfonamide (labeled 4 in Fig. 6): Synthesized using a variation of the published procedure (Anana et al., 2006). Concentrated NH 4 OH (150 mL, 1.10 mol) was charged into a 500 mL three-neck round-bottom flask equipped with an overhead stirrer, thermowell, and condenser. The reaction was then cooled in an ice/water bath to an internal temperature of 283 K. Solid 4-bromobenzenesulfonyl chloride (49.9954 g, 0.1957 mol) was added in portions over 5 min. The ice/water bath was removed and the mixture was stirred at room temperature for 15 min and then brought to 308 K for 30 min. After this, the reaction was warmed to reflux for an additional 30 min. The reaction was followed by thin-layer chromatography (TLC) [R f = 0.69 (labeled 3 in Fig. 6), R f = 0.54 (labeled 4 in Fig. 6) 1/1 hexane/ ethyl acetate (H/EA), short wavelength ultra-violet (SWUV)]. The reaction was cooled to room temperature upon consumption of the starting material and then poured into 200 mL of ice-cold water. This heterogeneous mixture was brought to pH = 1 (pHydrion paper) with 6 N HCl. The precipitated white solid was collected on a #1 Whatman filter paper, pressed dry with a rubber dam, and dried 12 h in a drying pistol (P 2 O 5 , 150 mTorr, 383 K) to afford 43.03 g (93.5%) of a white solid. Proton identical with literature (Richardson et al., 2007), m.p. 434-438 K (m.p. lit: 435 K). 4-Bromo-N-(n-propylcarbamoyl)benzenesulfonamide (labeled 5 in Fig. 6): n-Propylcarbamic chloride (labeled 2 in Fig. 6), (2.0 g, 15.9 mMol), toluene (15 mL), K 2 CO 3 , (2.019 g, 14.6 mMol), and 4-bromobenzenesulfonamide (labeled 4 in Fig. 6), (1.4306 g, 6.06 mMol) were added to a dry 100 mL round-bottom flask fitted with a straight condenser and brought to reflux for 30 min. Upon loss of the sulfonamide (TLC: R f = 0.86, 1/1: H/EA SiO 2 , SWUV, I 2 ), the heating was stopped, the oil bath was removed, and the reaction was permitted to cool to room temperature. The resulting white suspension was cooled in an ice/water bath and brought to a pH = 1 (pHydrion paper: red) with 6 N HCl. This mixture was extracted with 3 Â 10 mL portions of EA, washed [3 Â 5 mL 1 N HCl, then 2 Â 5 mL NaCl (sat, aq.)], dried Mg 2 SO 4 , filtered under vacuum through #1 Whatman filter paper, and then the solvent was removed under reduced pressure to give 2.2 g of a white solid. This material was purified on a SiO 2 column (1/1: H/EA SiO 2 , R f = 0.66) then recrystallized from toluene to yield, after drying in a drying pistol at 383 K (P 2 O 5 , Reaction scheme for the synthesis of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide.
Crystals obtained from toluene were very small; therefore, they were dissolved in methanol to obtain a supersaturated solution (37.5 mg mL À1 ). This was placed in a 20 mL scintillation vial, which was covered with Parafilm 1 and punched with 5 pin holes to allow slow evaporation of methanol at room temperature over several days, until larger single crystals appeared.

Computing details
Data collection: SMART and SAINT (Bruker, 1998); cell refinement: SMART and SAINT (Bruker, 1998); data reduction: SMART and SAINT (Bruker, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: CrystalMaker (Palmer, 2014); software used to prepare material for publication: SHELXL2018/3 (Sheldrick, 2015). 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.