(3-(4-Chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl Benzenesulfonate

: A novel single crystal of (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl benzenesul-fonate has been synthetized via a one-pot sequential strategy under sonication. The single crystal has been investigated using X-ray diffraction analysis. Hydrogen bonding between C–H ··· O and C–H ··· N produces a layer structure in the crystal. According to a Hirshfeld surface analysis, interactions H ··· H (28.9%), H ··· O/O ··· H (26.7%) and H ··· C/C ··· H (15.8%) make the largest contributions to crystal packing. The optimized structure and the solid-state structure that was obtained through experiments are compared using density functional theory at the B3LYP/6-311 G + (d,p) level. The computed energy difference between the lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) is 4.6548 eV.


Introduction
Compounds bearing an isoxazoline moiety are considered a significant class of nitrogen and oxygen atom-containing heterocyclic products, attracting attention from organic and medicinal chemists due to their large spectrum of biological properties such as antibacterial [1,2], antimicrobial [3], anti-inflammatory [4], anticancer [5,6], antidiabetic [7] and anti-Alzheimer effects [8].Moreover, isoxazoline derivatives are also known by their agrochemical properties as herbicidal [9], insecticidal [10][11][12] and acaricidal agents [13].On the other hand, sulfonic esters are clearly identified for their crucial role in the synthesis of organic compounds and have shown interesting pharmacological properties in the past decade [14][15][16].Accordingly, the synthesis of molecules containing both isoxazoline and sulfonate ester scaffolds provide easy access to a range of well-defined bioactive compounds for complete chemical, biochemical and pharmacological research [17,18].To this end, several methods have been reported for the preparation of isoxazoline systems [19,20].However, 1,3-dipolar cycloaddition which involves alkene as a dipolarophile and nitrile oxide as a dipole remains as one the most attractive route to prepare this aza-heterocycle [21].As for the sulfonate ester synthesis, the most common protocol for its preparation is the reaction of sulfonyl chlorides with alcohols using a base [22].In this study, we described the preparation and structural determination of a new isoxazoline-linked sulfonate compound utilizing an efficient and green protocol in water under ultrasound cavitation, which emerges as a suitable alternative to previously reported methods for organic synthesis laboratories [23,24].
In addition to evaluating a molecule's activity, theoretical calculations provide valuable knowledge on a variety of the molecule's characteristics [25].With the development of technology, the calculation of results has become more precise and faster [25].Considering the variety of uses mentioned above, the title compound [3-(4-chlorophenyl)-4,5dihydroisoxazol-5-yl]methyl benzenesulfonate was prepared and identified spectroscopically.The three-dimensional structure was resolved by single-crystal X-ray diffraction investigations.To determine the compound's optimal molecular structure characteristics, HOMO-LUMO energies, thermodynamic parameters, Hirshfeld surface analysis and density functional theory (DFT) computations were used to study the intermolecular interactions and hydrogen bonds.In this study, the chemical properties of the molecules were investigated employing a 6-311 + g(d,p) basis set and B3LYP techniques with Gaussian calculations.

Synthesis
Inspired by our previous works [26,27], the one-pot synthesis of our product (5) started with the sulfonylation of equimolar equivalents of allylic alcohol (1) and benzene sulfonyl chloride (2) in water with NaOH as a base at 25 • C under sonication to produce the corresponding dipolarophile (3) in situ.Subsequently, in the second step, the alkene sulfonate (3) reacted with p-chlorobenzaldoxime (4) via 1,3-dipolar cycloaddition using NaCl as a precatalyst generated from the first step and oxone as a terminal oxidant to successfully generate the expected (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl benzenesulfonate (5) as white crystals at a 85% yield (Scheme 1).In addition to evaluating a molecule's activity, theoretical calculations provide valuable knowledge on a variety of the molecule's characteristics [25].With the development of technology, the calculation of results has become more precise and faster [25].Considering the variety of uses mentioned above, the title compound [3-(4-chlorophenyl)-4,5dihydroisoxazol-5-yl]methyl benzenesulfonate was prepared and identified spectroscopically.The three-dimensional structure was resolved by single-crystal X-ray diffraction investigations.To determine the compound's optimal molecular structure characteristics, HOMO-LUMO energies, thermodynamic parameters, Hirshfeld surface analysis and density functional theory (DFT) computations were used to study the intermolecular interactions and hydrogen bonds.In this study, the chemical properties of the molecules were investigated employing a 6-311 + g(d,p) basis set and B3LYP techniques with Gaussian calculations.

Synthesis
Inspired by our previous works [26,27], the one-pot synthesis of our product (5) started with the sulfonylation of equimolar equivalents of allylic alcohol (1) and benzene sulfonyl chloride (2) in water with NaOH as a base at 25 °C under sonication to produce the corresponding dipolarophile (3) in situ.Subsequently, in the second step, the alkene sulfonate (3) reacted with p-chlorobenzaldoxime (4) via 1,3-dipolar cycloaddition using NaCl as a precatalyst generated from the first step and oxone as a terminal oxidant to successfully generate the expected (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl benzenesulfonate (5) as white crystals at a 85% yield (Scheme 1).The structure of isoxazoline sulfonate (5) was fully characterized by FT-IR, 1 H NMR, 13 C NMR and ESI + -MS spectroscopies, and confirmed by single-crystal X-ray diffraction (See Figure S1-S4 in Supplementary Materials (SM) section).As illustrated in Figure 1, the 1 H NMR spectrum of (5) showed two doublets of doublets at 3.47 and 3.12 ppm corresponding to the two protons of the CH2-isoxazolinic as well as two doublets of doublets at 4.14 and 4.19 ppm for the O-CH2 protons.Furthermore, we detected the presence of a multiplet centered at 4.92 ppm illustrating the H-isoxazolinic proton.Then, the region be- The structure of isoxazoline sulfonate (5) was fully characterized by FT-IR, 1 H NMR, 13 C NMR and ESI + -MS spectroscopies, and confirmed by single-crystal X-ray diffraction (See Figures S1-S4 in Supplementary Materials (SM) Section).As illustrated in Figure 1, the 1 H NMR spectrum of (5) showed two doublets of doublets at 3.47 and 3.12 ppm corresponding to the two protons of the CH 2 -isoxazolinic as well as two doublets of doublets at 4.

These molecules form four pairs through connections by C-H•••O short contacts (depicted as blue dashed lines). Each pair will form a long chain along the a-axis through C-H•••N interactions (not shown). The four long chains interact with each other through C-H•••π (ring) and C-O•••π (ring) interactions, which are depicted as black dashed lines (with centroids displayed as pink spheres).
Crystal Explorer 17.5 [31][32][33] was used to conduct a Hirshfeld surface (HS) analysis in order to see how [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methyl benzenesulfonate interacts with other molecules in the crystal.As shown in Figure 3a, the blue-and redcolored surfaces in the HS plotted over d norm denote contacts with distances that are longer (distinct contact) or shorter (in close contact), respectively, whereas the white color denotes connections with distances equal to the sum of the van der Waals radii.The most important red spots and the corresponding interactions are shown in Figure S8 (See SM).The shape-index (Figure 3b) generated in the range of −1 to 1 Å shows that there are no π-π interactions, normally indicated by adjacent blue and red triangles.The sites of intimate intermolecular contacts in the compound are clearly visible in the potential electrostatic calculated utilizing the STO-3G basis, which are mapped on the Hirshfeld surface throughout the range of 0.05 a.u. and set at the Hartree-Fock level of theory (Figure 3c).Positive potential electrostatic (blue zone) over the surface denotes hydrogen-donor potential, whereas negative electrostatic potential (red region) denotes hydrogenbond acceptors.
important red spots and the corresponding interactions are shown in Figure S8 (See SM).The shape-index (Figure 3b) generated in the range of −1 to 1 Å shows that there are no π-π interactions, normally indicated by adjacent blue and red triangles.The sites of intimate intermolecular contacts in the compound are clearly visible in the potential electrostatic calculated utilizing the STO-3G basis, which are mapped on the Hirshfeld surface throughout the range of 0.05 a.u. and set at the Hartree-Fock level of theory (Figure 3c).Positive potential electrostatic (blue zone) over the surface denotes hydrogen-donor potential, whereas negative electrostatic potential (red region) denotes hydrogen-bond acceptors.Figure S9a (See SM) displays the entire two-dimensional fingerprint pa ern [34], S9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in Figure S9b S9i, have a low point density and only contribute to 0.7% of the total points of the HS.

Theoretical Calculation Details
DFT was used to optimize the structure of [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methyl benzenesulfonate in the gas phase.The 6-311 G + (d,p) basis-set and the hybrid B3LYP method, which are built on the model of Becke [35] and take into account a combination of the exact (Hartree-Fock) and using the B3 functional DFT exchange, as well as the LYP correlation functional [36], were used to calculate the DFT.The harmonic frequen-  Figure S9a (See SM) displays the entire two-dimensional fingerprint pattern [34], S9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in Figure S9b

Theoretical Calculation Details
DFT was used to optimize the structure of [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methyl benzenesulfonate in the gas phase.The 6-311 G + (d,p) basis-set and the hybrid B3LYP method, which are built on the model of Becke [35] and take into account a combination of the exact (Hartree-Fock) and using the B3 functional DFT exchange, as well as the LYP correlation functional [36], were used to calculate the DFT.The harmonic frequencies of vibration were estimated after obtaining the converged geometry at the same theoretical level to verify that the stationary point has no imaginary frequencies.The GAUSSIAN 09 program was used to optimize the shape and analyze the harmonic vibrational frequency of [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methyl benzenesulfonate [37].Numerous quantum chemical parameters have been discovered as a result of these studies.Each parameter describes a particular molecule's chemical characteristics [38].Table S2 (See SM) provides an overview of the experimental and theoretical findings regarding angles and bond lengths.Table S3 (See SM) summarizes the results for the title compound, which include hardness (η), electronegativity (χ), ionization potential (I), electron affinity (A), dipole moment (µ), softness (σ) and electrophilicity (ω).The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) properties of the molecules are more significant than the others [39].Figure S10 (See SM) depicts the electron's change in energy level from HOMO to LUMO.The figure's brown and green areas correspond to molecular orbitals with diametrically opposed phases.The molecule's positive phase is depicted in green, and its negative phase in brown.In the plane that spans the entire [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methyl benzenesulfonate system, the LUMO and HOMO are localized.The molecule's energy band gap is 4.6548 eV [∆E = E LUMO − E HOMO ], and the frontier molecular orbital energies, E LUMO and E HOMO , are −1.9053 and −6.5601 eV, respectively.

Materials and Methods
All reactions were followed by thin-layer chromatography (precoated sheets, Silica gel 60 F254, E. Merck), and chromatograms were viewed using UV lights at 254 and 360 nm, 1 H and 13 C NMR spectra were run in dry deuterated dimethylsulfoxide (DMSO-d 6 ) on a JNM-ECZ 500 spectrometer at 500 MHz for 1 H NMR and 126 MHz for 13 C NMR.The samples were diluted in CH 3 CN, then mass spectra (ESI + -MS) were determined on an Agilent Technologies 1260 Infinity II LC/MSD.Melting points were measured using Köfler Bench equipment.The reactions were sonicated using a Vibra-Cell™ ultrasonic processor model 75,022 with a Titanium alloy Ti6Al-4 V probe (20 kHz, 130 W) with a 4 mm diameter tip, and used 60% of Pmax.The sonotrode was submerged into the solution in a conical bottom flask of 25 mL in order to obtain the most energy.

Preparation of Compound 5
In a conical bottom flask, allylic alcohol (1 mmol) was introduced to a basic solution of sodium hydroxide (1 mmol) with water (15 mL) and then benzene sulfonyl chloride (1 mmol) was added dropwise.The reaction was activated by sonication for 10 min at room temperature.Subsequently, after the completion of the sulfonylation reaction as monitored by TLC, the p-chlorobenzaldoxime (1.2 mmol), oxone (2 mmol) and sodium hydroxide (1 mmol) were added to the solution mixture at the same temperature to obtain the corresponding cycloadduct after 30 min of US irradiation (with TLC monitoring).The organic layer was extracted with DCM (3 × 10 mL) and then dried over sodium sulfate, filtered and concentrated in a vacuum.Recrystallization was employed to purify the crude product in hot ethanol and provide the desired

X-ray Crystal Structure Data
Table S4 (See SM) provides the data collection, crystal data and refined structural information.F2 has been improved to combat ALL reflections.The traditional R-factors based on F, were calculated with F set to zero for negative F2, and the weighted R-factor wR and goodness of fit S were based on F2.The selection of reflections for refinement was unrelated to expression at a threshold of F2 > 2 sigma (F2), which is utilized solely for computing R-factors (gt), etc. R-factors based on F2 will be statistically even larger than those based on F, which are statistically nearly twice as large.With the determined positions (C-H = 0.95 − 0.99 Å) and using contributions with isotropic displacement values 1.2-1.5 times that of the linked atoms, H-atoms connected to carbon were positioned in the correct positions.

Figure 2 .
Figure 2. The title molecule with labeling scheme and 50% probability ellipsoids.

Figure 2 .
Figure 2. The title molecule with labeling scheme and 50% probability ellipsoids.

Figure 2 .
Figure 2. The title molecule with labeling scheme and 50% probability ellipsoids.

Figure S8 (
Figure S8 (See SM) depicts the existence of multiple brilliant red spots on the threedimensional dnorm surfaces of the crystal structure, which are hydrogen bonding interactions.FigureS9a(See SM) displays the entire two-dimensional fingerprint pa ern[34],while those divided into H•••O/O•••H, H•••H, H•••C/C•••H, H•••Cl/Cl•••H, H•••N/N•••H, C•••C, Cl•••O/O•••Cl and O•••C/C•••O contacts are illustrated in FigureS9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in FigureS9bas widely sca ered points of high density with a tip at de = di = 1.28 Å.The tips of the pair of distinctive wings in the fingerprint plot demarcated into H•••O/O•••H interactions (26.7%), Figure S9c, are at de + di = 2.22 Å when O-H interactions are present.The tips of the two distributed points of spikes in Figure S9d (15.28%), the fingerprint plot demarcated into C•••H/H•••C, are at de + di = 2.74 Å.The Cl•••H/H•••Cl contacts, Figure S9e (12.8%), have the tips at de + di = 2.73 Å.The N•••H/H•••N connections, Figure S9f, appear as sca ered dots with spikes at de + di = 2.42 Å and contribute to 6.3% of the HS.The C•••C contacts, Figure S9g, are a pair of distributed spike points with tips at de + di = 3.31 Å and contribute to 6.2% of the HS.The Cl•••O/O•••Cl connections, Figure S9h, are a pair of sca ered spike tips that emerge with a tip at de + di = 3.42 Å and contribute to 1.9% of the HS.The O•••C/C•••O contacts, Figure S9i, have a low point density and only contribute to 0.7% of the total points of the HS.
Figure S8 (See SM) depicts the existence of multiple brilliant red spots on the threedimensional dnorm surfaces of the crystal structure, which are hydrogen bonding interactions.FigureS9a(See SM) displays the entire two-dimensional fingerprint pa ern[34],while those divided into H•••O/O•••H, H•••H, H•••C/C•••H, H•••Cl/Cl•••H, H•••N/N•••H, C•••C, Cl•••O/O•••Cl and O•••C/C•••O contacts are illustrated in FigureS9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in FigureS9bas widely sca ered points of high density with a tip at de = di = 1.28 Å.The tips of the pair of distinctive wings in the fingerprint plot demarcated into H•••O/O•••H interactions (26.7%), Figure S9c, are at de + di = 2.22 Å when O-H interactions are present.The tips of the two distributed points of spikes in Figure S9d (15.28%), the fingerprint plot demarcated into C•••H/H•••C, are at de + di = 2.74 Å.The Cl•••H/H•••Cl contacts, Figure S9e (12.8%), have the tips at de + di = 2.73 Å.The N•••H/H•••N connections, Figure S9f, appear as sca ered dots with spikes at de + di = 2.42 Å and contribute to 6.3% of the HS.The C•••C contacts, Figure S9g, are a pair of distributed spike points with tips at de + di = 3.31 Å and contribute to 6.2% of the HS.The Cl•••O/O•••Cl connections, Figure S9h, are a pair of sca ered spike tips that emerge with a tip at de + di = 3.42 Å and contribute to 1.9% of the HS.The O•••C/C•••O contacts, Figure S9i, have a low point density and only contribute to 0.7% of the total points of the HS.

Figure S8 (
Figure S8 (See SM) depicts the existence of multiple brilliant red spots on the threedimensional d norm surfaces of the crystal structure, which are hydrogen bonding interactions.FigureS9a(See SM) displays the entire two-dimensional fingerprint pattern[34],while those divided into H•••O/O•••H, H•••H, H•••C/C•••H, H•••Cl/Cl•••H, H•••N/N•••H, C•••C, Cl•••O/O•••Cl and O•••C/C•••O contacts are illustrated in FigureS9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in FigureS9bas widely scattered points of high density with a tip at d e = d i = 1.28 Å.The tips of the pair of distinctive wings in the fingerprint plot demarcated into H•••O/O•••H interactions (26.7%), Figure S9c, are at d e + d i = 2.22 Å when O-H interactions are present.The tips of the two distributed points of spikes in Figure S9d (15.28%), the fingerprint plot demarcated into C•••H/H•••C, are at d e + d i = 2.74 Å.The Cl•••H/H•••Cl contacts, Figure S9e (12.8%), have the tips at d e + d i = 2.73 Å.The N•••H/H•••N connections, Figure S9f, appear as scattered dots with spikes at d e + d i = 2.42 Å and contribute to 6.3% of the HS.The C•••C contacts, Figure S9g, are a pair of distributed spike points with tips at d e + d i = 3.31 Å and contribute to 6.2% of the HS.The Cl•••O/O•••Cl connections, Figure S9h, are a pair of scattered spike tips that emerge with a tip at de + di = 3.42 Å and contribute to 1.9% of the HS.The O•••C/C•••O contacts, Figure S9i, have a low point density and only contribute to 0.7% of the total points of the HS.
Figure S8 (See SM) depicts the existence of multiple brilliant red spots on the threedimensional d norm surfaces of the crystal structure, which are hydrogen bonding interactions.FigureS9a(See SM) displays the entire two-dimensional fingerprint pattern[34],while those divided into H•••O/O•••H, H•••H, H•••C/C•••H, H•••Cl/Cl•••H, H•••N/N•••H, C•••C, Cl•••O/O•••Cl and O•••C/C•••O contacts are illustrated in FigureS9b-i (See SM), respectively, along with their relative contributions to the Hirshfeld surface (HS).Given the high hydrogen content of the molecule and its significant contribution of 28.9% to the total crystal packing, the most significant interaction is HH, which is depicted in FigureS9bas widely scattered points of high density with a tip at d e = d i = 1.28 Å.The tips of the pair of distinctive wings in the fingerprint plot demarcated into H•••O/O•••H interactions (26.7%), Figure S9c, are at d e + d i = 2.22 Å when O-H interactions are present.The tips of the two distributed points of spikes in Figure S9d (15.28%), the fingerprint plot demarcated into C•••H/H•••C, are at d e + d i = 2.74 Å.The Cl•••H/H•••Cl contacts, Figure S9e (12.8%), have the tips at d e + d i = 2.73 Å.The N•••H/H•••N connections, Figure S9f, appear as scattered dots with spikes at d e + d i = 2.42 Å and contribute to 6.3% of the HS.The C•••C contacts, Figure S9g, are a pair of distributed spike points with tips at d e + d i = 3.31 Å and contribute to 6.2% of the HS.The Cl•••O/O•••Cl connections, Figure S9h, are a pair of scattered spike tips that emerge with a tip at de + di = 3.42 Å and contribute to 1.9% of the HS.The O•••C/C•••O contacts, Figure S9i, have a low point density and only contribute to 0.7% of the total points of the HS.