Structural Comparison of Three N-(4-Methoxyphenyl)-Nitrobenzenesulfonamide Derivatives

Abstract

The series of all three N-(4-methoxyphenyl)-nitrobenzenesulfonamides has been synthesized and their crystal structures analyzed. The bond lengths and angles are all very similar, only the C-S-N-C torsion angles are significantly different in the three molecules, leading to different orientations of the phenyl rings in the molecules. All three molecules exhibit N–H^…O hydrogen bonds with the sulfonamide group; however, in only two of the three is the acceptor an oxygen atom on the sulfonamide group. In the third, the acceptor oxygen is the methoxy oxygen atom. Compound A forms an infinite three-dimensional network, compound B exhibits ladder-shaped sheets, and C shows infinite sheets that are fairly planar. Overall, the differences in overall intermolecular interactions appear to be driven by packing rather than by the overall shapes of the molecules themselves.

1. Introduction

Sulfonamides were first recognized as potential drugs in the early 1930s when Gerhard Domagk tested Prontosil, a sulfonamide azo dye, as a treatment for bacterial infections [1]. Domagk received the 1939 Nobel prize in Medicine for his discovery. While sulfonamide drugs were once among the most common, today there are only about 40 FDA approved sulfonamide drugs [2]. Recently, however, attention has turned back to sulfonamides as drug candidates due to their many favorable characteristics, including biocompatibility [3] and ease of synthesis [4]. Currently, several sulfonamides are being studied as anti-cancer agents [5,6]. A recent study identified several sulfonamide molecules that act as inhibitors of Lemur tyrosine kinase 3, several at sub-micromolar concentrations [7]. Lemur tyrosine kinase 3 has been shown to promote tumor development by numerous pathways [8]. Additionally, sulfonamides have also been shown to exhibit carbonic anhydrase inhibition [9,10], insecticidal activity [11], antibacterial activity [12], antiviral activity [13], and anti-leishmanial activity [14], as well as other biological activities [15]. Le Questel and co-workers reported several easily synthesized 3-pyridylsulfonamide compounds that showed promise as cockroach cholinergic synaptic transmission activators [11]. Potential sulfonamide targets were identified via high-throughput virtual screening and were further evaluated in silico to determine specific target molecules to be synthesized and tested. Mohamed-Ezzat and Elgemeie have also reported a novel class of sulfonamides, some of which showed promising activity versus coronavirus 229E and NCI 60 cancer cells [13].

Sulfonamides are also useful reagents for organic synthesis. Several nickel catalysts have been reported for the formation of C–N bonds via cross-coupling. You and Li reported nickel(0) catalysts for the efficient conversion of arylsulfonamides to diarylsulfonamides [16]. Xue and coworkers recently investigated nickel(II) catalyzed photochemical synthesis of aryl- and diarylsulfonamides via sulfamidation of aryl chlorides [17]. DeRatt’s group used sulfonamides for the synthesis of benzomorpholines via tandem amination oxitane ring opening using palladium catalysts [18]. Several groups have also used transition metal catalysts for the N-alkylation of sulfonamides using alcohols. Li and coworkers used ruthenium(II) arene complexes for the selective N-alkylation of benzensulfonamides [19], while Anandaraj and Ramesh used palladium(II) pincer complexes for similar reactions [20]. Yu et al. also recently reported the synthesis of 1-(phenylsulfonyl)-1H-benzimidazoles from 2-nitrobenzenesulfonamides via tandem reactions [21].

In the solid state, sulfonamides typically primarily exhibit two hydrogen-bonding patterns, either C(4) N–H^…O–S chains or $R_2^2\left(8\right)$ dimers via adjacent N–H^…O–S hydrogen bonds (Figure 1) [22]. The importance of hydrogen bonding in sulfonamide crystals has long been understood [23]. In 2009, Perlovich et al. investigated the thermodynamic and structural aspects of 10 sulfonamide molecules [24]. More recently, Bolla and Nangia explored synthon hierarchy in sulfonamide cocrystals [25], and Gonnade and co-workers investigated the π–π of several sulfonamide and sulfoester derivatives [26]. Given the prevalence of the sulfonamides in bioactive molecules, an understanding of their hydrogen bonding interactions in the solid state is important.

Our group is interested in the intermolecular interactions of small molecules with strong hydrogen bonding groups [27,28] and has recently been studying the structure–property relationships in sulfonamides [14,29]. As an extension of those studies, here, we report a comparison and analysis of the crystal structures of all three isomers of N-(4-methoxyphenyl)-nitrobenzenesulfonamide. By systematically varying the structure of only one end of the sulfonamide molecules, we hope to observe changes in the intermolecular interactions, including hydrogen bonds, to allow us to predict the interactions in other sulfonamide molecules.

2. Materials and Methods

2.1. General Experimental Section

Starting materials were obtained from commercial sources (Sigma-Aldrich, Acros, or Alfa Aesar) and were at least 97% purity. All melting points were collected on an SRS Digimelt (Sunnyvale, CA, USA) and are uncorrected.

2.2. Synthesis and Crystallization

The synthesis of N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide, A, is given as an example. 4-Nitrobenzenesulfonyl chloride (10.00 mmol, 2.2166 g) and p-anisidine (10.00 mmol, 1.2320 g) were added to a 250 mL Erlenmeyer flask containing 50 mL deionized water and 10 mL 1 M Na₂CO₃. The mixture was stirred on a stir plate for approximately 4 days. The product was collected by suction filtration and washed with deionized water and isopropanol. The product was dried in oven at low heat, and the dry product weighed. Yield: 2.6466 g (85.84%). M.P.: 182–183 °C. X-ray quality crystals were grown by solvent diffusion of heptane into an acetone solution of A.

N-(4-methoxyphenyl)-3-nitrobenzenesulfonamide, B, was prepared from 3-nitrobenzenesulfonyl chloride (10.01 mmol, 2.2188 g) and p-anisidine (10.04 mmol, 1.2366 g). Yield: 2.4580 g (79.65%). M.P.: 133–134 °C. X-ray quality crystals were grown by solvent diffusion of hexane into an acetone solution of B.

N-(4-methoxyphenyl)-2-nitrobenzenesulfonamide, C, was prepared from 2-nitrobenzenesulfonyl chloride (10.00 mmol, 2.2170 g) and p-anisidine (10.06 mmol, 1.2392 g). Yield: 0.5498 g (17.83%). M.P.: 85–86 °C. X-ray quality crystals were grown by solvent diffusion of hexane into a 1,2-dichloroethane solution of C.

2.3. Data Collection and Refinement

Data were collected on a Bruker APEX II diffractometer equipped with a CCD detector at 100(2) K using MoKα radiation (λ = 0.71073 Å). The data were processed and corrected for absorption using the Bruker (Madison, WI, USA) SAINT+ software package [30]. Structures were solved by direct methods using SHELXS-2017, and the data were refined using SHELXL-2017 [31]. All non-H atoms were refined anisotropically. Hydrogen atoms attached to carbon were assigned positions based on the geometries of their attached carbons. Hydrogen atoms bonded to oxygen and nitrogen were assigned positions based on the Fourier difference map. See

Table 1. Data collection parameters.

Compound	A (p-NO2)	B (m-NO2)	C (o-NO2)
CCDC Deposit No.	2467049	2467050	2467051
Chemical formula	C13H12N2O5S	C13H12N2O5S	C13H12N2O5S
Mr	308.31	308.31	308.31
Crystal system, space group	Monoclinic, Cc	Monoclinic, P21/c	Monoclinic, P21/c
Temperature (K)	100 (2)	100 (2)	100 (2)
a, b, c (Å)	5.1710 (4)	20.5686 (7)	12.0195 (7)
	12.9028 (10)	5.1731 (2)	7.2684 (4)
	19.7324 (15)	13.0803 (5)	15.0297 (8)
β (°)	94.420 (4)	107.7598 (16)	91.529 (3)
V (Å3)	1312.64 (8)	1325.46 (9)	1312.27 (13)
Z	4	4	4
Radiation type	Mo Kα	Mo Kα	Mo Kα
μ (mm−1)	0.271	0.269	0.271
Crystal size (mm)	0.28 × 0.20 × 0.13	0.39 × 0.32 × 0.20	0.31 × 0.18 × 0.10
Diffractometer	Bruker APEX-II CCD
Absorption correction	Multi-scan SADABS
Tmin, Tmax	0.70, 0.75	0.90, 0.95	0.92, 0.97
No. measured, independent, and observed [I > 2σ(I)] reflections	17529, 2667, 2661	36710, 2815, 2749	38370, 2880, 2687
Rint	0.020	0.017	0.024
(sin θ/λ)max (Å−1)	0.625	0.633	0.641
R[F2 > 2σ(F2)], wR(F2), S	0.0291, 0.0874, 1.173	0.0277, 0.0750, 1.052	0.0277, 0.0729, 1.065
No. of reflections	2667	2815	2880
No. of parameters	194	194	194
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δrmax, Δrmin (e Å−3)	0.50, −0.32	0.48, −0.45	0.41, −0.41

Computer programs: Bruker APEX2 [25], Bruker SAINT [25], SHELXS97 [26], and SHELXL97 [26].

for final refinement parameters. Figures were made using ORTEP3 [32], Mercury [33], and CrystalExplorer [34].

3. Results and Discussion

3.1. Synthesis

The sulfonamides were all prepared by stirring solutions of p-anisidine and X-nitrobenzenesulfonyl chloride in aqueous sodium carbonate at room temperature. The products were collected via suction filtration. All products matched previous reports of the compounds in the literature [35,36].

3.2. Crystal Structures

Figure 2 shows the ORTEP diagrams of compounds A, B, and C. All three show bond distances and angles in the range of other N-(4-methoxyphenyl)-sulfonamides [37] (

Table 2. Selected bond distances (Å).

Bond	A (p-NO2)	B (m-NO2)	C (o-NO2)
S1–C1	1.770 (3)	1.7664 (12)	1.7871 (12)
S1–N1	1.646 (3)	1.6450 (10)	1.6426 (11)
N1–C7	1.450 (4)	1.4415 (14)	1.4467 (15)

and

Table 3. Selected bond and torsion angles (°).

Bond	A (p-NO2)	B (m-NO2)	C (o-NO2)
C1–S1–N1	105.43 (15)	105.00 (5)	104.97 (5)
S1–N1–C7	116.9 (2)	119.00 (8)	115.49 (8)
O1–S1–O2	120.45 (14)	120.66 (5)	118.98 (6)
C1–S1–N1–C7	–58.6 (3)	66.56 (3)	41.78 (10)

), and all three have very similar overall structures. A search of the Cambridge Structural Database (CSD) for N-(4-methoxyphenyl)-sulfonamides resulted in 23 structures. The average bond lengths [S–C: 1.766 (9) Å; S–N: 1.633 (9) Å; N=C: 1.441 (6) Å] are all very similar to the distances in A, B, and C. Examining the bond angles, the C1–S1–N1 angles in all three are smaller than the CSD average of 107.4 (13)°. In fact, all three are smaller than the smallest C–S–N angle in the previous 23 structures, which is 105.8 (2)° for entry CEDCIZ, N-(4-methoxyphenyl)-4-iodobenzenesulfonamide [38]. The S1–N1–C7 angles for A and B fall within the range of the 23 (116.812–120.376°), while for C, the angle is now the smallest reported for all N-(4-methoxyphenyl)-sulfonamides, at 115.49 (8)°. The CSD search found a range of 117.903–120.532° for the O–S–O angle. Of the three molecules reported in this study, C falls well within the range at 118.98 (6)°, A is near the maximum at 120.45 (14)°, and C is now the largest O–S–O angle at 120.66 (5)°, though not by a significant amount.

Hydrogen bonding interactions for all three molecules are given in

Table 4. Hydrogen bonding geometry (Å, °) for A.

D–H…A	D–H	H…A	D…A	D–H…A
C5–H5…O1 i	0.95	2.43	3.144 (4)	132
C2–H2…O4 ii	0.95	2.52	3.294 (4)	139
C11–H11…O3 iii	0.95	2.50	3.414 (4)	161
N1–H1…O2 iv	0.89 (6)	2.25 (6)	3.089 (4)	156 (5)
C13–H13A…O4 v	0.98	2.56	3.352 (5)	138

Symmetry codes: (i) x + ½, y − ½, z; (ii) x − ½, y + ½, z; (iii) x + 1, − y, z − ½; (iv) x − 1, y, z; (v) x + ½, − y − ½, z − ½.

,

Table 5. Hydrogen bonding geometry (Å, °) for B.

D–H…A	D–H	H…A	D…A	D–H…A
C13–H13A…O5 i	0.98	2.60	34703 (15)	148
C4–H4…O4 ii	0.95	2.42	3.2965 (16)	153
N1–H1…O2 iii	0.856 (18)	2.176 (19)	3.0127 (14)	165.5 (16)

Symmetry codes: − y + 1, − z + 1; (ii) − x, − y + 2, − z; (iii) x, y + 1, z.

and

Table 6. Hydrogen bonding geometry (Å, °) for C.

D–H…A	D–H	H…A	D…A	D–H…A
N1–H1…O5 i	0.826 (19)	2.281 (19)	3.0534 (14)	155.8 (16)
N1–H1…O3	0.826 (19)	2.524 (18)	3.0612 (14)	123.8 (15)
C13–H13A…O2 ii	0.98	2.47	3.2891 (16)	141

Symmetry codes: (i) x, y − 1, z; (ii) x, − y + 3/2, z + ½.

. There are only two bond angles that are significantly different in any of the three molecules. First is the S1–N1–C7 angle, which is largest in B [119.00 (8)°] and smallest in C [115.9 (8)°], with A [116.9 (2)°] in between the other two. The other is the O1–S1–O2 angle, which is smaller in C [118.98 (6)°] than in A [120.45 (14)°] or B [120.66 (5)°], which are very similar. Additionally, the C1–S1–N1–C7 torsion angle is quite different in all three, giving rise to different relative orientations for the phenyl rings in the three molecules. Figure 3a shows an overlay, prepared using Mercury, of molecules A, B, and C using C7, C9, C11, and O5 as the anchoring atoms, looking down the N1–C7 bond [33]. With all three methoxy groups oriented the same direction, you can see the effect of the different C1–S1–N1–C7 torsion angles for the three molecules. Figure 3b shows an alternative overlay of the three molecules along the N1–C7 bond, anchored using S1, N1, and H1. In this orientation, the negative torsion angle of A, −58.6 (3)°, is compared to the positive torsion angles of B, +66.56 (3)°, and C, +41.78 (10)°. All three torsion angles fall within the range of the other N-(4-methoxyphenyl)-sulfonamides [37] in the CSD search, where the 23 molecules ranged from −68.704° to +71.3°.

The third difference in the molecules is the angle between the planes formed by the C1–C6 ring and the nitro group (N2, O3, O4). In molecules A [8.1 (5)°] and B [7.83 (19)°], they are nearly coplanar, while in C [47.35 (7)°], the nitro is twisted away from the benzene ring due to steric interference from the sulfonamide group.

Compound A exhibits several intermolecular contacts in the crystal structure (Figure 4). First is the formation of C(4) chains (Figure 4a) along the a-axis via N1–H1^…O2 hydrogen bonds (pink). The chains are linked together into a three-dimensional network via $R_2^2\left(10\right)$ rings involving C–H^…O interactions between the C5 on the nitrobenzene ring and sulfonamide oxygen O1 (orange) and C2 with the nitro oxygen O4 (green). Additionally, there is a C11–H11^…O3 interaction (purple), generating C(12) chains, as well as a C11–H13A^…O4 interactions (blue), yielding C(15) chains. Alternatively, the two chain interactions combine to form large $R_4^4\left(30\right)$ rings, which are assembled via the previously described $R_2^2\left(10\right)$ rings into a three-dimensional structure (Figure 4d). Compound A also exhibits an S=O^…N_nitro contact, where the O^…N distance is 2.991 (4) Å, which is 0.169 Å shorter than the sum of their van der Waals radii [39] (Figure 4b).

Figure 5 shows the intermolecular contacts in Compound B. Molecules of B form C(4) chains along the b-axis via N1–H1^…O2 hydrogen bonds (pink). The chains are linked together by $R_2^2\left(10\right)$ C4–H4^…O4 interactions (green), forming one-dimensional ladders running along the b-axis. The combination of the chains gives rise to $R_4^4\left(30\right)$ rings. Combined with C13–H13A^…O5 interactions (orange), they make up the rungs of a Stairway to Heaven (Figure 5b). Compound B also exhibits a nitro O^…N contact, with a distance of 2.883(2) Å, which is 0.277Å less than the sum of the van der Waals radii of nitrogen and oxygen [39] (Figure 5c). These O^…N contacts connect the stairways together, extending the structure into a three-dimensional network.

Molecule C has the only intramolecular hydrogen bonding interaction. The intermolecular interactions for compound C are shown in Figure 6. C also forms chains along the b-axis via N–H^…O (Figure 6c) hydrogen bonds (pink). However, the acceptor oxygen is the methoxy oxygen of the neighboring molecule, not a nitro or sulfonamide oxygen, resulting in C(7) chains. This is likely due to the nitro group not being coplanar to the attached benzene ring. The chains are linked together into two-dimensional sheets via C13–H13^…O2 interactions (orange) (Figure 6c). Additionally, there are nitro–nitro interactions between molecules with an N2^…O4 distance of 2.857 (1) Å, approximately 0.303Å shorter than the van der Waals sum [39], forming $R_2^2\left(4\right)$ dimers (Figure 6c).

Examining the melting points of the three molecules, A has the highest of the three, 182–183°. Compound A has traditional, strong, and directional N–H^…O sulfonamide C(4) hydrogen bonds along with an S=O^…N_nitro contact and four C–H^…O contacts, more than either B or C, resulting in a rigid three-dimensional network (Figure 4d). Compound B has the next highest melting point of the three, 133–134 °C. While B also contains strong, directional N–H^…O sulfonamide C(4) hydrogen bonds, there are only two C–H^…O contacts, along with the nitro O^…N contact. The stairway sheets are only connected by these O^…N contacts and, along with the fewer C–H^…O contacts, result in a lower melting point. Of the three, C has the lowest melting point, 85–86 °C. While C also has an N–H^…O hydrogen bond, the acceptor is the methoxy oxygen, which is expected to have a smaller negative charge than the sulfonamide oxygens, resulting in a weaker hydrogen bond interaction compared to A and B. The two-dimensional sheets of C are held together by relatively weak, by comparison, π–π contacts, resulting overall in a lower melting point than either A or B.

3.3. Hirshfeld Analysis

Examination of the Hirshfeld surface plots for the molecules (Figure 7) reveals several similarities. Looking at the surfaces, molecules A and C are more compact than B. All three show short contacts, as indicated by the red regions of the Hirshfeld surfaces. Of note, the short contacts on the surface are mostly between hydrogen and oxygen atoms, although the Hirshfeld surfaces are helpful for finding non-hydrogen bonding interactions. In molecule A, the S=O^…N_nitro contact is evident (O1^…N2); in B, nitro O3^…N2 contact is evident; in C, the nitro-nitro contact is indicated by two neighboring red spots on the Hirshfeld surface.

For all three structures, the most prevalent contacts are H^…O, followed by H^…H and H^…C. The only other contacts to make up more than 5% in any of the structures are C^…O contacts, which represent 5.7% in A, 8.9% in B, and 4.7% in C. Looking at the fingerprint plots for A (Figure 8), the contacts are relatively compact. The H^…O contacts show the typical hydrogen-bonding “fangs”, while the H^…H are generally distributed throughout the plot, with a sharp point between the hydrogen-bonding fangs corresponding to the shortest contact between H2 and H5 of neighboring molecules. The H^…C interactions are generally longer than the other hydrogen contacts. In molecule B (Figure 9), the H^…O plot shows the typical fangs, while the H^…H contacts culminate in a much broader peak. The H^…C contacts show wings on the outer edges of the plot, as well as some shorter H^…C contacts compared to A and C, indicating shorter and stronger interactions. The fingerprint plots for molecule C (Figure 10) also show the H^…O fangs as well as the H^…H point between the fangs, indicating the shortest H^…H contact between H8 and H13A. The major difference between C and the other two molecules is seen in the H^…C contacts, which are more spread out.

Of the three structures, only C shows any π^…π contacts, which can be seen in looking at the percentage of C^…C contacts in each molecule (3.3% in C, 0% in A, 0.3% in B). The π^…π contact can also be seen in the shape index plot for C (Figure 11), indicated by the adjacent diamond shapes on the surface of the methoxy phenyl ring. The Cg^…Cg distance between the two methoxyphenyl rings is 3.7351 (7) Å.

As can be seen in Figure 7, all three molecules have a relatively compact overall shape in the crystal structures. While molecule B appears less compact than A or C, the molecular volumes of the molecules calculated using MoloVol [40] are very similar: 265.1 ų for A, 264.8 ų for B, and 265.7 ų for C. Since all three molecules have Z = 4, their unit cell volumes are also very similar (Table 1). While the C1–S1–N1–C7 torsion angles (Table 3) are all very different, the angle between the two aromatic rings is similar in all three molecules: 30.51 (14)° in A, 41.05 (5)° in B, and 41.06 (5)° in C. Focusing on the sulfonamide nitrogen atom in the structures, it is only slightly pyramidalized. The displacement of the N1 atom from the plane defined by S1–H1–C7 is remarkably similar in all three and quite small: 0.32 (3) Å for A, 0.323 (8) Å for B, and 0.325 (9) for C. The one significant difference in B compared to A and C is the S1–N1–C7 angle, which is larger in B, leading to a less compact overall structure.

4. Conclusions

In an effort to understand the effects of substitution geometry on the crystal structures of sulfonamide derivatives, the single crystal X-ray structures of all three geometric isomers of N-(4-methoxyphenyl)-X-nitrobenzenesulfonamide were determined, and their intermolecular interactions investigated. Despite the similar structures of all three molecules, they all feature quite different interactions in the crystalline state. In molecules A and B, the sulfonamide hydrogen forms C(4) hydrogen bonds with sulfonamide oxygens. However, in molecule C, there is an intramolecular N–H^…O hydrogen bond, and the intermolecular hydrogen bond acceptor is the methoxy oxygen, forming C(7) chains. Overall, it appears the position of the nitro group on the sulfonamide benzene ring has significant effects on the interactions between molecules in the crystals. The position of the nitro group leads to different packing between the molecules, resulting in the different orientations of the aromatic rings relative to each other in the three molecules, which are manifested in the different torsion angles seen. These orientations lead to the variation in the intermolecular interactions and three-dimensional packing of the molecules. The structures of the three molecules in this study did not reveal any obvious patterns in the intermolecular interactions within the series. Therefore, further studies are underway to better understand the factors that influence the hydrogen bonding and packing patterns of diarylsulfonamide and related molecules.