2-((3-(4-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide

Abstract

In this work, a novel compound N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin has been synthesized. The molecular structure of the compound was determined using various spectroscopic techniques and confirmed by a single-crystal X-ray diffraction analysis. In the single crystal, C–H…O hydrogen bonds between neighboring molecules form chains along the a-axis direction. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H…H (35.7%), H…O/O…H (33.7%), and H…C/C…H (13%) interactions. The optimized structure calculated using density functional theory at the B3LYP/6–311 G(d,p) level is compared with the experimentally determined structure in the solid state. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy gap is 4.9266 eV.

1. Introduction

Heterocyclic rings containing nitrogen with an oxygen atom are considered one of the best combinations in medicinal chemistry due to their diverse biological activities [1]. Isoxazoline is a five-membered heterocyclic azole ring used as a versatile structural motif and an important intermediate [2,3] to access hydroxy ketones [4,5], amino alcohols [6], and isoxazolidines [7], which are used in natural products and compounds of great importance in the synthesis of various pharmacologically active heterocycles. In addition, isoxazoline derivatives have attracted much attention due to their various pharmacological activities such as antimicrobial [8], anticancer [9], antidiabetic [10], anti-inflammatory [11,12,13], antistress [14], antibacterial [15,16], anti-Alzheimer [17], analgesic [18], insecticidal [19,20], and acaricidal activities [21]. Besides its biological significance, isoxazolines play an important role in coordination chemistry as ligands in the synthesis of metal complexes with broad biological applications [22,23,24].

A number of methods for preparing isoxazolines have been described [3]. The most common and practical method is the 1,3-dipolar cycloaddition of alkynes with nitrile oxides [25]. Recently, our research group developed the synthesis of a new series of isoxazoline derivatives using a simple and environmentally friendly regioselective protocol and ultrasound as a green source of activation [26,27,28,29].

Theoretical calculations, besides measuring the activity of molecules, give important information about many properties of molecules [30]. With the developing technology, theoretical calculations have become faster and more reliable [31]. Owing to the wide range of applications mentioned above, the title compound N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin was synthesized and characterized spectroscopically. The three-dimensional structure was determined by single-crystal X-ray diffraction analysis. The intermolecular interactions and the hydrogen bonds were studied by Hirshfeld surface analysis and supplemented by density functional theory (DFT) calculations to find out the optimized molecular structural parameters of the compound, HOMO-LUMO energies, and thermodynamic parameters. In the study, the chemical properties of the molecules were investigated using Gaussian calculations, in B3LYP methods with the 6-311 g(d,p) basis set.

2. Results

2.1. Synthesis

The reaction of equimolar equivalents of N-allyl saccharin (1) (dipolarophile) and nitrile oxide generated in situ from 4-methoxybenzaldoxime (2) in the presence of KI/oxone as the catalyst in water and ultrasound as a green source of activation at 25 °C gave N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin (3) in 80% yield (Scheme 1) [28]. The structure of compound (3) was determined using NMR spectroscopy (See Section 3.2. for details) and confirmed by single-crystal X-ray diffraction.

The structure of synthesized compound 3 is fully characterized by IR, ¹H, ¹³C NMR, and LCMS spectra, and confirmed by single-crystal X-ray diffraction (See Supplementary Materials section). In the NMR spectrum of N-(3-(4-methoxyphenyl) isoxazolin-5-yl), 3 methylsaccharin showed a singlet on average at δ = 3.81 ppm identified as the methoxyl group, two doublets of doublet at 3.34 and 3.57 ppm for the two CH₂-isoxazolinic protons, and two other doublets of doublet at 3.86 and 3.98 for the N–CH₂ protons. This compound also showed a multiplet centered at 5.06 ppm for the H-isoxazolinic proton; thus, the presence of the signals between 7.02 and 8.34 ppm is attributable to the different aromatic protons. The ¹³C NMR spectrum of 3 exhibited characteristic signals at 41.13 ppm (N–CH₂), 37.72 ppm (CH_2isoxazoline), 76.47 ppm (CH_isoxazoline), 54.77 ppm (OMe), 158.34 ppm (C=O) and 113.71 ppm, 120.96 ppm, 121.08 ppm, 124.70 ppm, 125.64 ppm, 127.73 ppm, 134.80 ppm, 135.42 ppm, 136.15 ppm, 155.62 ppm, and 160.20 ppm, attributable to aromatic carbons (Figure 1). The structure of 3 was further confirmed by IR and mass spectrometry.

2.2. Crystal Structure Determination

The crystal was kept at 293(2) K during data collection. Using Olex2 [32], the structure was solved with the SHELXT [33] structure solution program using Intrinsic Phasing and refined with the SHELXL [34] refinement package using least-squares minimization. The N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin crystallizes in the triclinic space group P-1 with one molecule in the asymmetric unit (Figure 2). The molecule is not planar, as indicated by the torsion angles N2–C13–C14–O15 [−55.1(2)°] and C3–N2–C13–C14 [93.9(2)°]. The best plane through the isoxazoline ring (O15/N16/C17/C18/C14; r.m.s. deviation = 0.076 Å) makes a dihedral angle of 27.88(9)° with the best plane through the benzoisothiazole ring (C3-C9/S1/N2; r.m.s. deviation = 0.009 Å).

The intramolecular hydrogen bond C14–H14…O11 is shown as a red dashed line. The isoxazoline ring is slightly puckered (envelope conformation with C14 as flap, puckering parameters Q(2) = 0.171(2) Å, φ(2) = 325.2(7)°). Furthermore, an intramolecular hydrogen bond C14–H14…O11 is present (H14…O11 = 2.596 Å).

The crystal packing is characterized by C—H…O and π…π interactions (Figure 3). Chains of molecules running in the c-axis direction are formed by C8–H8…O25i hydrogen bonds between neighboring molecules (C8–H8 = 0.93 Å, H18… O25i = 2.52 Å, C8…O25i = 3.407(3) Å, C8—H8…O25ⁱ = 138°; symmetry code: (i) −1 + x, y, 1 + z). Parallel chains interact mainly through π…π interactions between neighboring phenyl rings (Cg1…Cg1ⁱⁱ = 3.921 Å, Cg1…Cg2ⁱⁱⁱ = 3.981 Å; Cg1 and Cg2 are the centroids of rings C4-C9 and C19-C24, respectively; symmetry codes: (ii) 1 − x, 1 − y, 2 − z, (iii) 1 − x, 1 − y, 1 − z) resulting in the three-dimensional structure. The crystal packing contains no voids.

The CrystalExplorer program [35] was used to investigate and visualize the intermolecular interactions of N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin. The Hirshfeld surface plotted over d_norm in the range −0.1656 to 1.2318 a.u. is shown in Figure 4. The red spots are close contacts with a negative d_norm value and represent C—H…O interactions. The white regions representing contacts equal to the van der Waals separation and a d_norm value of zero are indicative of the H…H interactions.

The three-dimensional d_norm surfaces of the crystal structure illustrate the presence of several bright red spots, which correspond to the hydrogen bonding interactions, as shown in Figure 5.

The overall two-dimensional fingerprint plot [36] is shown in Figure 6a, while those delineated into H…H, H…O/O…H, H…C/C…H, C…C, H…N/N…H, C…O/O…C, O…O, and C…N/N…C contacts are illustrated in (Figure 6b–g), respectively, together with their relative contributions to the Hirshfeld surface (HS). The most important interaction is H…H, contributing 35.7% to the overall crystal packing, which is reflected in Figure 6b as widely scattered points of high density due to the large hydrogen content of the molecule, with a tip at d_e = d_i = 1.15 Å. In the presence of O–H interactions, the pair of characteristic wings in the fingerprint plot delineated into H…O/O…H contacts (33.7% contribution to the HS) (Figure 6c) has tips at d_e + d_i = 2.41 Å. The pair of scattered points of spikes in the fingerprint plot delineated into C…H/H…C (Figure 6d) (13%) have tips at d_e + d_i = 2.95 Å. The C…C contacts (Figure 6e) (7.3%) have tips at d_e + d_i = 3.49 Å. The N…H/H…N contacts (Figure 6f) contribute 6.2% to the HS and appear as a pair of scattered points of spikes with tips at d_e + d_i = 2.63 Å. The C…O/O…C contacts (Figure 6g) contribute 2.7% to the HS and appear as a pair of scattered points of spikes with tips at d_e + d_i = 3.32 Å. The O…O contacts (Figure 6h) contribute 0.8% to the HS and appear as a pair of scattered points of spikes with a tip at d_e + d_i = 3.43 Å. Finally, the N…C/C…N contacts (Figure 6i) make only a 0.4% contribution to the HS and have a low-density distribution of points.

2.3. Density Functional Theory Calculations

The structure in the gas phase of N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin was optimized by means of density functional theory. The density functional theory calculation was performed by the hybrid B3LYP method and the 6–311 G (d,p) basis set, which is based on Becke’s model [37] and considers a mixture of the exact (Hartree–Fock) and density functional theory exchange utilizing the B3 functional, together with the LYP correlation functional [38]. After obtaining the converged geometry, the harmonic vibrational frequencies were calculated at the same theoretical level to confirm that the number of imaginary frequencies is zero for the stationary point. Both the geometry optimization and harmonic vibrational frequency analysis of the title compound were performed with the GAUSSIAN 09 program [39]. As a result of these calculations, many quantum chemical parameters have been found. Each parameter describes a different chemical property of molecules [40]. The obtained results were given comparatively, and the optimized structure is shown in Figure 7. There are some differences between experimental and computed results due to the phase difference (experimental results in solid and theoretical ones in the gas phase). In this context, we have not found the critical point to confirm the suggestions concerning the intramolecular hydrogen bond C14–H14…O11. Despite this, fairly consistent results were obtained. The theoretical and experimental results related to bond lengths and angles are summarized in Table 1. Calculated numerical values for the title compound, including electronegativity (χ), hardness (η), ionization potential (I), dipole moment (μ), electron affinity (A), electrophilicity (ω), and softness (σ), are collated in Table 2. Among the calculated parameters of the molecules, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) parameters are more important than the others [41,42]. The electron transition from the HOMO to the LUMO energy level is shown in Figure 8. The green and brown regions of the figure represent molecular orbitals with completely opposite phases. The positive phase of the molecule is shown in green color and the negative phase in brown color.The HOMO and LUMO are localized in the plane extending over the whole N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin system. The energy band gap [ΔE = ELUMO − EHOMO] of the molecule is 4.9266 eV, and the frontier molecular orbital energies, EHOMO and ELUMO, are −5.8170 and −0.8904 eV, respectively.

3. Experimental Section

3.1. Materials and Methods

¹H and ¹³C-NMR spectra were recorded in dry deuterated solvent DMSO on a Bruker (Billerica, MA, USA) AC 400 (400 and 101 MHz, respectively). Mass spectral analyses (ESI-MS) were recorded on an Agilent Technologies 1260 Infinity II LC/MSD (Santa Clara, CA, USA), and the samples were diluted in acetonitrile. Analytical thin-layer chromatography (TLC) was performed on precoated silica gel plates (Merck 60 GF254) and visualization was performed using a UV lamp (254 and 360 nm). The ultrasound-assisted reactions were performed in a Vibra-Cell™ Model 75022 Ultrasonic Processor(Sonics & Materials Inc., Newtown, CT, USA) with Titanium alloy Ti-6Al-4 V probe (20 kHz, 130 W) with 4 mm tip diameter; the reaction was performed using 60% Pmax. Using a 10–50 mL pear-shaped flask, the sonotrode was immersed in the solution for maximum energy. Melting points were determined on a Munz Köfler Bench System.

3.2. Synthesis of Compound 3

In a pear-shaped flask, N-allyl saccharin 1 (1 mmol), 4-methoxybenzaldoxime (1 mmol) 2, KI (20 mol%), and oxone (2 mmol) were added in water (10 mL) and ultrasonicated at 25 °C using the ultrasonic probe for 20 min. The completion of the reaction was monitored by TLC. The mixture was extracted with ethyl acetate (3 × 15 mL), then dried over Na₂SO₄ and concentrated in vacuum. The residue was purified by recrystallization in EtOH to afford the pure N-(3-(4-Methoxyphenyl) isoxazolin-5-yl) methylsaccharin 3.

Beige crystal, yield 80%, mp 158–160 °C (EtOH), TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.19; FTIR (ATR, cm⁻¹): 1721 (C=O), 1620 (C=N); ¹H NMR (400 MHz, DMSO) δ 8.34 (d, J = 7.6 Hz, 1H, H_Ar), 8.14 (d, J = 6.8 Hz, 1H, H_Ar), 8.08 (td, J = 7.6, 1.3 Hz, 1H, H_Ar), 8.03 (td, J = 7.5, 1.1 Hz, 1H, H_Ar), 7.61 (d, J = 8.8 Hz, 2H, H_Ar), 7.02 (d, J = 8.9 Hz, 2H, H_Ar), 5.11–5.02 (m, 1H, C5H _isoxazoline), 3.98 (dd, J = 15.1, 7.3 Hz, 1H, N–CH), 3.86 (dd, J = 15.1, 5.1 Hz, 1H, N–CH), 3.81 (s, 3H, OCH3), 3.57 (dd, J = 17.2, 10.5 Hz, 1H, C4H_isoxazoline), 3.34 (dd, J = 17.2, 6.5 Hz, 1H, C4H _isoxazoline). ¹³C NMR (101 MHz, DMSO) δ 160.2 (Cq-O-), 158.3 (C=O), 155.6, 136.2, 135.4, 134.8, 127.7 (2C), 125.6, 124.7, 121.0, 120.9, 113.7 (2C), 76.4 (CH _isoxazoline), 54.7 (O–Me), 41.1 (N–CH₂), 37.7 (CH_{2 isoxazoline}); MS (ESI+): m/z = 373.1 [M + H]⁺.

3.3. X-ray Data of Crystal Structure

Crystal data, data collection, and structure details refinement are given in Table 3. C-bound H atoms were positioned geometrically (C–H = 0.93–0.97 Å) and included as riding contributions with U_iso(H) = 1.2U_eq(C) (1.5 for methyl groups). At the end of the refinement, the final difference Fourier map showed no residual peaks of chemical significance.

4. Conclusions

The N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin crystallizes in the triclinic space group P-1 with one molecule in the asymmetric unit. The isoxazoline moiety is inclined to the saccharinic ring at a dihedral angle of 27.88(9)°. In the crystal, C–H…O hydrogen bonds between neighboring molecules form chains along the a-axis direction. According to Hirshfeld surface analysis, the most significant contributions to crystal packing come from H…H (35.7%), H…O/O…H (33.7%), and H…C/C…H (13%) interactions. The optimized structure calculated using density functional theory at the B3LYP/6–311 G(d,p) level is compared to the solid-state structure determined experimentally. The calculated energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) is 4.9266 eV.

Author Contributions

Conceptualization, K.B. and A.E.M.; methodology, K.B., H.T. and A.E.M.; A.E.M. designed the experiments, performed syntheses; X-ray crystallography experiment and structural comparisons were performed by L.V.M.; the Hirshfeld surface analysis and spectroscopic studies were done by K.C.; the paper was written by K.B., H.T. and K.C. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

The X-ray data were deposited at CCDC, as stated above, and all spectroscopic data are in the Supplementary Materials.

Acknowledgments

This work is supported by UM5R and UM6P. The authors would like to acknowledge the UATRS-CNRST Morocco.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures, Scheme and Tables

Scheme 1. Synthesis of 3.

Figure 1. Characteristic 1H, 13C NMR of 3.

Figure 2. The ORTEP diagram of compound 3 with the atom labeling scheme and 30% probability ellipsoids.

Figure 3. Partial crystal packing of N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin showing C–H…O (red dashed lines) and π…π interactions (gray dashed lines).

Figure 4. View of the three-dimensional Hirshfeld surface face 1 (a) and 2 (b) of the title compound, plotted on dnorm in the range of −0.1656 to 1.2318 a.u.

Figure 5. The main non-covalent interactions in the crystal packing.

Figure 6. Two-dimensional fingerprint plots for the title compound, showing (a) all interactions, and delineated into (b) H…H, (c) H…O/O…H, (d) C…H/H…C, (e) C…C, (f) N…H/H…N, (g) C…O/O…C, (h) O…O and (i) N…C/C…N interactions. The di and de values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface.

Figure 7. The optimized structure of title compound.

Figure 8. The energy band gap of N-(3-(4-methoxyphenyl)isoxazolin-5-yl)methylsaccharin.

Table 1

Comparison (X-ray and density functional theory) of selected bond lengths and angles (Å, °).

	X-ray	B3LYP/6–311G (d,p)
S1-N2	1.6641 (16)	1.7163
S1-C9	1.7466 (19)	1.7875
S1-O10	1.4213 (17)	1.458
O15-N16	1.419 (2)	1.4091
S1-O11	1.4297 (16)	1.4589
N16-C17	1.284 (2)	1.2895
N2-C3	1.392 (2)	1.3936
N2-C13	1.463 (2)	1.4941
C3-O12	1.206 (2)	1.2083
C22-O25	1.365 (2)	1.3591
O25-C26	1.423 (3)	1.4225
N2-S1-C9	93.00 (8)	91.7503
O10-S1-N2	110.43 (10)	109.2283
O10-S1-C9	112.43 (10)	112.4224
O10-S1-O11	116.94 (10)	118.6032
O11-S1-C9	111.96 (9)	111.2453
C3-N2-S1	115.20 (13)	114.946
C3-N2-C13	123.60 (16)	122.8963
C13-N2-S1	120.90 (13)	121.519
N2-C3-C4	108.62 (16)	109.0882
O12-C3-N2	123.96 (19)	124.7446
O12-C3-C4	127.42 (18)	126.1588
C4-C9-S1	109.89 (14)	110.0374
C8-C9-S1	127.24 (15)	127.1339
N16-O15-C14	108.53 (14)	109.5655
C17-N16-O15	109.10 (17)	108.6161
N16-C17-C18	114.05 (18)	113.1977
N16-C17-C19	121.97 (18)	121.5156
O25-C22-C21	124.07 (18)	124.6663
O25-C22-C23	116.09 (17)	115.8642
C22-O25-C26	117.92 (16)	118.7364

Table 2

Calculated energies.

Molecular Energy	Compound
Total Energy TE (eV)	−42,964.3286
EHOMO (eV)	−4.7108
ELUMO (eV)	−2.2485
Gap, ΔE (eV)	2.4623
Dipole moment, µ (Debye)	3.5690
Ionization potential, I (eV)	4.7108
Electron affinity, A	2.2485
Electronegativity, χ	3.4797
Hardness, η	1.2312
Electrophilicity, index ω	4.9173
Softness, σ	0.8122
Fraction of electron transferred, ΔN	1.4296

Table 3

Experimental details.

Crystal Data
Empirical formula	C18H16N2O5S
Formula weight	372.39
Temperature/K	293(2)
Crystal system, Space group	Triclinic, P-1
a, b, c (Å)	7.3921(3), 8.5605(3), 13.6058(4)
α, β, γ (°)	76.768(3), 86.131(3), 84.776(3)
Volume (Å3)	833.67(5)
Z	2
ρcalc (g/cm3)	1.483
μ/mm−1	0.228
F(000)	388.0
Crystal size (mm3)	0.3 × 0.3 × 0.25
Radiation	Mo Kα (λ = 0.71073 Å)
2Θ range for data collection/°	4.904 to 52.734
Index ranges	−9 ≤ h ≤ 9, −10 ≤ k ≤ 10, −16 ≤ l ≤ 16
Reflections collected	11964
Independent reflections	3407 (Rint = 0.0202, Rsigma = 0.0226)
Data/restraints/parameters	3407/0/236
Goodness-of-fit on F2	1.028
Final R indexes (I ≥ 2σ (I))	R1 = 0.0404, wR2 = 0.0987
Final R indexes (all data)	R1 = 0.0519, wR2 = 0.1061
Largest diff. peak/hole/e Å−3	0.28/−0.33

Supplementary Materials

The following supporting information, containing ¹H NMR, ¹³C NMR, and mass spectra of the synthesized compound 3 can be downloaded online.

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