A Facile and Eco-Friendly Method for the Synthesis of Sulfonamide and Sulfonate Carboxylic Acid Derivatives — X-ray Structure , Hirshfeld Analysis and Spectroscopic Characterizations

The search for a simple and efficient method for the synthesis of sulfonamide and sulfonate derivatives under mild and eco-friendly conditions is of continuing interest. Sulfonyl chlorides are still the best choice as starting materials for the preparation of target products. Here, we report a simple, efficient and eco-friendly method for the synthesis of sulfonamide and sulfonate carboxylic acid derivatives under green conditions using water and sodium carbonate as HCl scavengers to produce the products with high yields and purities. Two derivatives, 4-(tosyloxy)benzoic acid (5a) and 4-((4-methylphenyl)sulfonamido)benzoic acid (5b), were reacted with 2-morpholinoethan-1-amine under green conditions, where OxymaPure/diisopropylcarbodiimide (DIC) was used as a coupling reagent and 2-MeTHF as a solvent to give the target product with high yield and purity. nuclear magnetic resonance (NMR) and elemental analysis confirmed the structures of all obtained products. X-ray crystallography confirmed the structures of products 4b, 4c and 7a. The molecular packing of the three compounds (4b, 4c and 7a) was analyzed using Hirshfeld topology analysis. Mainly, H . . . O hydrogen bonding interactions dominated the packing. These methods of preparation and coupling merit further attention for the development of new derivatives that might have significant biological applications.


Introduction
Since the commercialization of Prontosil [1] as a drug in 1935, intense surveys have been made and a huge number of sulfonamide derivatives and their biological applications have been reported [2][3][4][5][6][7][8][9][10][11].Several methods for the synthesis of sulfonamide from different substrates have been reported, for example, using sulfonyl chloride and amines [12,13] using a chlorinating agent with the corresponding sulfurated starting materials [14][15][16][17] or using non-conventional methods such as transition metals [18] or Grignard reagents [19].In addition, all the reported methods use organic solvents such as dichloromethane and/or toxic activating agents such as thionyl chloride for the synthesis of sulfonamides.Furthermore, multi-step synthesis methods that are time-consuming for purifications are usually needed [20].
Searching for a simple and efficient method for the synthesis of novel sulfonamides under mild conditions is of ongoing concern [21,22].The use of sulfonyl chlorides and amines as starting materials still is the method of choice [23], where organic solvents and organic amine bases are used to scavenge the HCl generated from the reaction [24,25].An elevated temperature is required in some cases, especially for the less reactive amines.Other protocol is the modified Schotten-Baumann conditions [26], where a two-phase system of organic solvents and basic aqueous solution (Na 2 CO 3 or NaOH) is used [27].Due to the hydrolysis of sulfonyl chloride under these conditions, excess reagent must be used to ensure a complete reaction.Furthermore, the isolation and purification of the sulfonamide is not always straightforward.Recently, water has been used as a green solvent for several chemical reactions because of safety and environmental concerns [28,29].
Herein, we report a facile, environmentally benign method for sulfonamide amino acid and sulfonate acid synthesis at room temperature using water in the presence of Na 2 CO 3 as HCl scavengers following the reported literature [30].The desired sulfonamide and sulfonate carboxylic acid derivatives are easily isolated in excellent yields and purities.
In addition, here, we report the coupling reaction of sulfonamide and sulfonate carboxylic acid derivatives with amine under eco-friendly conditions using our previously reported method [31][32][33][34].This method for the synthesis of sulfonamide and sulfonate carboxylic acid derivatives eliminates the use of expensive toxic organic solvents and organic bases.In addition, isolation and purification of the products only involves filtration and no waste, which makes it ideal for green chemistry.The structures of two sulfonamides, carboxylic acid and one of the coupled products were confirmed by X-ray single crystal structure measurements.

X-ray Measurements
Single crystals for compounds 4b, 4c and 7a were obtained by slow evaporation from their solvent of crystallization (ethylacetate-n-hexane; 4:6) at room temperature.The crystallographic measurements of 4b, 4c and 7a were collected on a Bruker D8 Quest diffractometer with graphite monochromated Mo-Kα radiation at λ = 0.71073 Å and 293 (2) K using a photon detector.Cell refinement and data reduction were carried out using SAINT [35], and a multi-scan absorption correction was made using SADABS [36].All calculations were performed using the SHELXTL program package [37,38].The crystal data and structure refinement details are listed in Table 1.The CIF files with the Cambridge Crystallographic Data Center CCDC numbers 1524756 (4b), 1524754 (4c) and 1524879 (7a) contain the supplementary crystallographic data for the measured compounds.This can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/ cif.In addition, Crystal Explorer 3.1 program [39] was used to quantitatively analyze the different intermolecular interactions in the studied compounds [40].

General Method for Synthesis of Sulfonamide Carboxylic Acid 4a-c and 5a-c
p-Toluenesulfonyl chloride (12 mmol) was added over a period of time of 15 min to an aqueous mixture of amino acid or hydroxyl acid (10 mmol) and Na 2 CO 3 (12 mmol) in water (50 mL) at 0 • C.After complete addition, the reaction mixture was stirred for a further 4-6 h at room temperature and then acidified at 0 • C with 10% HCl.The precipitate was collected by filtration, washed with water, dried, and then recrystallized from ethylacetate-n-hexane to produce the target product.

General Method for Preparation of 7a-b
Carboxylic acid 5a or 5b (2 mmol) was mixed with OxymaPure (2 mmol) in 2-MeTHF (10 mL) at 0 • C followed by the addition of diisopropylcarbodiimide (DIC, 2 mmol) dropwise under stirring.The reaction mixture was preactivated for 10 min at 0 • C, and then 2-morpholinoethan-1-amine 6 (2 mmol) was added dropwise, and stirring was maintained for 1 h at the same temperature and then at room temperature for 24 h.The solvent was removed, and the crude product was dissolved in ethylacetate and washed with 1 N hydrochloric acid (2 × 10 mL), saturated solution of sodium carbonate (2 × 10 mL) and sodium chloride solution (10 mL) and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure to produce the target product, which then recrystallized from ethylacetate-n-hexane to produce the target products 7a and b with excellent yield and purity.

Chemistry
Sulfonyl chlorides are still the best choice as starting materials for the preparation of sulfonamide derivatives.A typical method involves dropwise addition of tosyl chloride 1 (1.2 equiv.)into an aqueous solution of amino acid 2a-c, 3b-c or p-hydroxybenzoic acid 3a in the presence of Na 2 CO 3 (1.2equiv.)as HCl scavengers [30].The desired products 4a-c and 5a-c were easily isolated by normal acidification with 10% HCl with excellent yields and purities as observed by spectral data (Figures S1-S6, Supplementary Materials) and single crystal X-ray diffraction (Scheme 1).Recently, 2-methyltetrahydrofuran (2-MeTHF) was reported as one of the greenest solvents for peptide synthesis [31][32][33][34].In addition; OxymaPure was reported to be a safe and reactive additive compared to other additives used in coupling reactions [45].Accordingly, we used the reported method DIC-OxymaPure [45] to couple the sulfonamide and sulfonate carboxylic acid derivatives 5a-b with 2-morpholinoethan-1-amine 6.
The reaction mixture of carboxylic acid 5a or 5b, OxymaPure and DIC in 2-MeTHF was preactivated for 10 min at 0 • C, followed by the addition of amine 6 at the same temperature, and then the reaction mixture was left at room temperature for 24 h to produce target product 7a or 7b (Scheme 2) with excellent yields and purities.Scheme 2. Reaction of sulfonamide and sulfonate with amine using OxymaPure/DIC.

X-ray Structure Determination
The structures of two sulfonamide amino acids (4b and 4c) and one of the synthesized sulfonate carboxylic acid derivative (7a) were confirmed using single crystal X-ray diffraction.The structure features of these compounds are presented and the crystal details as well as the refinements results are listed in Table 1.More information can be obtained from the crystallographic information files (CCDC number: 1524756, 1524754 and 1524879 for compounds 4b, 4c and 7a, respectively).
The molecular structure showing the thermal ellipsoids and atom numbering of 4b is shown in Figure 1.The structure crystallized in the triclinic crystal system and P-1 point group with Z = 2 and the asymmetric unit of this compound comprises one molecule.A list of the geometric parameters (bond distances and angles) is shown in Table 2.The packing of 4b molecules occurs via alternative N-H . . .O and O-H . . .O hydrogen bridges (data shown in Table 3).Dimers of 4b form by two similar N-H . . .O hydrogen bonds that occur between the NH groups as a hydrogen donor with one of the sulfonate oxygen atoms in another molecule as a hydrogen acceptor.These dimeric units are interconnected via the COOH ends by strong O-H . . .O hydrogen bridges leading to the formation of the one-dimensional hydrogen bridges shown in Figure 2.      The molecular structure of 4c is shown in Figure 3.The structure crystallized in the monoclinic crystal system and P2 1 /c point group with Z = 4 and the asymmetric unit of this compound comprises one of its molecular formula.A list of the geometric parameters (bond distances and angles) is shown in Table 4. Similar to that in 4b, the molecular packing of 4c molecules occurs via alternative N-H . . .O and O-H . . .O hydrogen bridges (Table 3).The only notable difference is that the hydrogen bonds are slightly shorter than those in 4b (Table 3 and Figure 2).The molecular structure showing thermal ellipsoids and atom numbering of 7a is shown in Figure 4.The structure crystallized in the monoclinic crystal system and P2 1 /c point group with Z = 4 and the asymmetric unit of this compound comprises one of its molecular formulae.A list of the geometric parameters (bond distances and angles) is shown in Table 5.This compound contains two aromatic rings where the angle between the planes passing through them is 46.0 • , while the aliphatic morpholine ring shows the typically known chair form in the structure of 7a.If a plane is drawn passing through the base of this chair, one could note that this plane and the central phenyl ring mean plane make an angle of 83.7 • , indicating that both rings are nearly perpendicular.The packing of this compound is dominated mainly by strong N-H . . .O hydrogen bridges between the amide N-H and the carbonyl oxygen atom.In addition, the packed molecules are held together by weak C-H . . .O interactions between H9A from one of the phenyl moieties and the sulfonate O(2) atom.The hydrogen bond parameters are listed in Table 3, and presentation of the one-dimensional hydrogen bond network of 7a is shown above in Figure 2.

Hirshfeld Analysis
In order to quantify the most important intermolecular interactions in the studied compounds, we performed a Hirshfeld topology analysis (Figure 5).The intense red spots in the d norm maps of the studied crystals indicate the presence of significantly short intermolecular contacts compared to the van der Waal sum of the two elements sharing this interaction.These red spots appeared as sharp spikes in the corresponding fingerprint plots and were found to be related to the polar O . . .

Conclusions
The reaction of sulfonyl chlorides with amino acids or p-hydroxybenzoic acid in water with sodium carbonate as an HCl scavenger (green conditions) produced products with high yields and purities.NMR and elemental analysis confirmed the structures of the prepared compounds.The structures of 4b and 4c were also confirmed by X-ray crystallography.The use of OxymaPure/DIC with 2-MeTHF as a solvent (eco-friendly condition) produced the target products with high yield and purity as confirmed by NMR and elemental analysis.Crystallographic measurements confirmed the structure of one product from the synthesized compounds.Using Hirshfeld topology analysis, the packing of the studied compounds was controlled by strong O . . .H hydrogen bonds (27.1-38.5%)

Scheme 1 .
Scheme 1. Synthesis of sulfonamide amino acid and sulfonate derivatives.

Figure 1 .
Figure 1.Atom numbering and thermal ellipsoids at a 30% probability level for 4b.

Figure 3 .
Figure 3. Atom numbering and thermal ellipsoids at a 30% probability level for 4c.
H hydrogen bonding interactions (region a).The other less important intermolecular interactions appeared as faded red spots in the d norm map, and the broad peaks in the fingerprint plots are due to the hydrophobic C . . .H and H . . .H interactions (regions b and c).Full quantitative determination of all possible intermolecular contacts is graphically presented in Figure 6.It is clear that the H . . .H, O . . .H and C . . .H contacts showed the highest contributions among the intermolecular interactions which reveals the importance of these contacts in the molecular packing of the studied compounds.

Figure 5 .
Figure 5.The d norm surfaces (upper) and fingerprint plots (lower) of the studied compounds.The Sharpe spikes refer to the strong O . . .H hydrogen bonding interactions (a), while the broad peaks refer to the weak hydrophobic C . . .H (b) and H . . .H (c) contacts.

Figure 6 .
Figure 6.Quantification of the intermolecular interactions in the studied compounds.

Table 1 .
Crystal data and structure refinement for the studied complexes.

Table 3 .
Hydrogen bonds [Å and • ] of the studied compounds.