(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl Benzene-Sulfonate

1. Introduction

Compounds bearing isoxazoline moiety are considered an significant class of nitrogen and oxygen atoms containing heterocyclic products, attracting attention from organicand 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 [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 providing easy access to a range of well-defined bioactive compounds for complete chemical, biochemical and pharmacological research [17,18]. On this account, several methods are reported for the preparation of isoxazoline systems [19,20].

However, 1,3-dipolar cycloaddition which involves alkene as dipolarophile and nitrile oxide as 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 by using of a base [22]. In this study, we 4described the preparation and structural determination of new isoxazoline-linked sul fonate compound utilizing an efficient and green protocol in water under ultrasound cav itation, which emerges as a suitable alternative to previously reported methods for the organic synthetic laboratory [23,24]

In addition to evaluating a molecule’s activity, theoretical calculations provide valuable knowledge on a variety of a molecule’s characteristics [25]. With the development of technology, calculated results have gotten more precise and faster [25]. Considering the variety of uses mentioned above, the title compound [3-(4-chlorophenyl)-4,5-dihydroisox-azol-5-yl]methyl benzenesulfonate was prepared and identified spectroscopically. The three-dimensional structure was resolute by single-crystal X-ray diffraction investigation. To determine the compound’s optimal molecular structure characteristics, HOMO-LUMO energies, and 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 6-311+ g(d,p) basis set and B3LYP techniques with Gaussian calculations.

2. Results

2.1. Synthesis

Inspired from our previous works [26,27], the one-pot synthesis of our product (5) started by the sulfonylation of equimolar equivalent of allylic alcohol (1) and benzene sulfonyl chloride (2) in water with NaOH as a base at 25 °C under sonication to give in situthe corresponding dipolarophile (3). Subsequently, in the second step, the alkene sulfonate (3) reacts 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 afford successfully the expected (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl benzenesulfonate (5) as white crystals in 85% yield (Scheme 1).

The structure of isoxazoline sulfonate (5) was fully characterized by FT-IR, 1H NMR, 13C NMR and ESI+-MS spectroscopies, and confirmed by single-crystal X-ray diffraction (See Supplementary Materials (SM) section). As illustrated in Figure 1, the 1H NMR spectrum of (5) showed two doublets of doublet 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 between 7.47 and 7.88 ppm showed the signals of the different aromatic protons. The 13C NMR spectrum exhibit three blinded signals at 36.6, 71.6 and 78.5 ppm corresponding subsequently to CH₂-isoxazoline, O-CH₂ and CH-isoxazoline and signals at 156.3, 135.5, 135.3, 135.0, 130.3(2C), 129.4(2C), 128.9(2C), 128.3, 128.2(2C) attributed to all the aromatic carbons.

2.2. X-ray Analysis

X-ray intensity data were collected at 150(2) K. Using APEX4 [28], the structure was solved via Intrinsic Phasing in the SHELXT [29] structure solution program and refined using Least Squares minimization in the SHELXL [30] refinement package. With one molecule in the asymmetric unit, the [3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl]methylbenzenesulfonate crystallizes in the orthorhombic space group Pbca (Figure 2).

The molecules are linked by a small C—H···O contact (Figure 3) and by short C—H···N contacts to form a long chain along the a-axis (Figure 4). Molecules are linked in crystallographic symmetry in a unit cell by eight molecules forming four pairs by connection by short C—H···O contacts (represented by blue dotted lines). Each pair will form a long chain along the a-axis through the 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 represented by black dotted lines (with centroids shown as of pink spheres) (Figure 5 and Table 1).

These molecules form four pairs through connection by C—H···O short contacts (depicted as blue dashed lines). Each pair will form a long chain along 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 6a, the blue and red colors surface 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 de- 123 notes connections with distances equal to the sum of van der Waals radii. The most im- 124 portant red spots and the corresponding interactions are shown in Figure 7. The shape- 125 index (Figure 6b) generated in the range -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, mapped on the Hirshfeld surface throughout the range of 0.05 a.u., set at the Hartree-Fock level of theory (Figure 6c). Positive potential electrostatic (blue zone) over the surface denotes hydrogen-donor potential, whereas negative electrostatic potential (red region) denotes hydrogen-bond acceptors.

Figure 7 depicts the existence of multiple brilliant red spots on the three-dimensional d_norm surfaces of the crystal structure, which are hydrogen bonding interactions.

Figure 8a 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 Figure 8b–i, respectively, and 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 8b as 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 8c, 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 8d (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 8e (12.8%), have the tips at d_e + d_i = 2.73 Å. The N···H/H···Nconnections, Figure 8f, appear as scattered dots with spikes at d_e + d_i = 2.42 Å and contribute 6.3% to the HS. The C···C contacts, Figure 8g, are a pair of distributed spike points with tips at d_e + d_i = 3.31 Å and contribute 6.2% to the HS. The Cl···O/O···Cl connections, Figure 8h, a pair of scattered spike tips emerge with a tip at de + di = 3.42 Å and contribute 1.9% to the HS. The O···C/C···O contacts, Figure 8i, have a low point density and only contribute 0.7% of the total points to the HS.

2.3. 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 getting the converged geometry at the same theoretical level to verify that the stationary point has no imaginary frequencies. The GAUSS- 170 IAN 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]. 172 Numerous quantum chemical parameters have been discovered as a result of these stud ies. Each parameter describes a particular molecule’s chemical characteristic [38]. Table 2 provides an overview of the experimental and theoretical findings regarding angles and bond lengths. Table 3 summarizes the results for the title compound, which include hard ness (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 9 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 [ΔE = E_LUMO - E_HOMO], and the frontier 185 molecular orbital energies, E_LUMO and E_HOMO, are -1,9053 and -6,5601 eV, respectively.

3. Experimental Section

3.1. Materials and Methods

All reactions has been 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, 1H and 13C NMR spectra were run in dry deuterated dimethylsulfoxyde (DMSOd₆) on a JNM-ECZ 500 spectrometer at 500 MHz for 1H NMR and 126 MHz for 13C NMR, The samples were diluted in CH₃CN, then mass spectra (ESI+-MS) were determined on an Agilent Technologies 1260 Infinity II LC/MSD. Melting points were measured using a Köfler Bench equipment. The reactions were sonicated using a Vibra-Cell™ ultrasonic processor model 75022 with Titanium alloy Ti6Al-4 V probe (20 kHz, 130 W) and diameter of 4 mm tip; and assisted with 60% of Pmax. The sonotrode was submerged into the solution in a conical bottom flask of 25mL in order to obtain the most energy.

3.2. Preparation of Compound 5

In a conical bottom flask, allylic alcohol (1mmol) was introduced to a basic solution of sodium hydroxide (1mmol) with water (15ml) and then the benzene sulfonyl chloride (1mmol) was added dropwise. The reaction was activated by sonication for 10min at room temperature. Subsequently, after the completion of the sulfonylation reaction as monitored by TLC, the p-chlorobenzaldoxime (1.2mmol), oxone (2mmol) and sodium hydroxide (1mmol) were added to the solution mixture at the same temperature to obtain after30min of US irradiation the corresponding cycloadduct (TLC monitoring). The organic 213 layer was extracted with DCM (3 × 10 mL) and then dried over sodium sulfate, filtred and 214 concentrated in vacuum. Recrystallization was employed to purify the crude product in 215 hot ethanol and provide the desired (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl 216 benzenesulfonate in high purity.

Yield 85%, Mp 121–123°C (Ethanol), TLC (cyclohexane 90%/Ethylacetate 10%) Rf = 0.6; FT-IR (ATR, cm-1 ): 1660 (C=N), 1190 (O=S=O), 906 (N-O) ; 1H NMR (500 MHz, DMSOd₆) δ 7.88 (d, J = 7.2 Hz, 2H, Har), 7.76 (t, J = 7.5 Hz, 1H, Har), 7.64 (t, J = 7.9 Hz, 2H, Har), 7.59 (d, J = 8.6 Hz, 2H, Har), 7.47 (d, J = 8.6 Hz, 2H, Har), 4.95 – 4.89 (m, 1H, C5H-isoxazoline), 4.19 (dd, J = 11.1, 3.1 Hz, 1H, O-CH), 4.14 (dd, J = 11.1, 5.9 Hz, 1H, O-CH), 3.47 (dd, J = 17.3, 11.2 Hz, 1H, C4H-isoxazoline), 3.12 (dd, J = 17.3, 7.1 Hz, 1H, C4H-isoxazoline). 13C NMR (126 MHz, DMSO-d₆) δ 156.3, 135.5, 135.3, 135.0, 130.3(2C), 129.4(2C), 128.9(2C), 128.3, 128.2(2C), 78.5 (CH-isoxazoline), 71.6 (O-CH₂), 36.6 (CH₂-isoxazoline). MS (ESI+): m/z = 352.3 [M + H]+, 725.7 [M + Na]+.

3.3. X-ray Crystal Structure Data

Table 4 provides data collection, crystal data and refined structural informations. F2 has been improved to combat ALL reflections. The traditional R-factors based on F, are calculated with F set to zero for negative F2, and the weighted R-factor wR and goodness of fit S are based on F2. The selection of reflections for refinement is unrelated to expression at 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 determined positions (C—H = 0.95-0.99 Å) and riding 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.

Software applications: SHELXTL [28], SAINT [28], APEX4 [28], SHELXT [29], SHELXL [30], DIAMOND [41].

4. Conclusions

In summary, we proposed an efficient and facile route to synthesize (3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl benzenesulfonate 5 in water using an environmentally friendly protocol involving a one-pot strategy combined with ultrasound cavitation. The desired product (5) was obtained in good yield and high purity, and its structure was determined by 1H, 13C NMR, ESI+-MS and IR spectra and confirmed by singlecrystal X-ray diffraction. The Hirshfeld surface has been used to elaborate on the research of intra- and intermolecular interactions, and a comparative theoretical analysis has also been detailed.