Synthesis, crystal structure, DFT studies and Hirshfeld surface analysis of novel isoxazole derivatives

Article abstract of DOI:10.1016/j.molstruc.2020.129450

This article describes firstly the synthesis of a new series of isoxazole 5a-e from p-methoxythymol, extracted from Tetraclinis Articulata, as starting material involving 1,3-dipolar cycloaddition reaction and secondly a detailed study of the molecular pa

Full text of DOI:10.1016/j.molstruc.2020.129450

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Synthesis, Crystal structure, DFT studies and Hirshfeld surface
analysis of novel isoxazole derivatives
Yassine Laamari , Aziz Auhmani , Mohamed Saadi ,
Lahcen El Ammari , Mostafa Khouili , My Youssef Ait Itto ,
Abdelwahed Auhmani , El Mostafa Ketatni
PII:
S0022-2860(20)31765-8
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.129450
MOLSTR 129450
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Journal of Molecular Structure
Received date:
Revised date:
Accepted date:
14 August 2020
6 October 2020
12 October 2020
Please cite this article as: Yassine Laamari , Aziz Auhmani , Mohamed Saadi , Lahcen El Ammari ,
Mostafa Khouili , My Youssef Ait Itto , Abdelwahed Auhmani , El Mostafa Ketatni , Synthesis, Crys-
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Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.129450
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Synthesis, Crystal structure, DFT studies and Hirshfeld surface analysis of novel isoxazole derivatives
a
a,*
b
b
c
Yassine Laamari , Aziz Auhmani , Mohamed Saadi , Lahcen El Ammari , Mostafa Khouili , My
a
a
c,**
Youssef Ait Itto , Abdelwahed Auhmani , El Mostafa Ketatni
a
Laboratory of Organic Synthesis and Physico-Molecular Chemistry, Department of Chemistry, Faculty
of Sciences Semlalia, B.P. 2390, Marrakech 40001, Morocco
b
Laboratoire de Chimie Appliquée des Matériaux, Centre des Sciences des Matériaux, Faculty of
Sciences, Mohammed V University in Rabat, Avenue Ibn Batouta, BP 1014, Rabat, Morocco.
c
Laboratory of Organic and Analytical Chemistry, Sultan Moulay Slimane University, Faculty of Science
and Technology, BP 523, 23000 Beni-Mellal, Morocco
*
Correspondence e-mail: a.auhmani@uca.ac.ma, elm_ketatni@hotmail.fr,
Highlights

Novel isoxazole derivatives was synthesized using natural product as a starting material and
1
13
characterized by H and C NMR and confirmed by single crystal X-ray diffraction method.
Interactions in crystal packing were supported by Hirshfeld surface analysis.
DFT calculation have been investigated and compared with X-ray results.


Abstract
This article describes firstly the synthesis of a new series of isoxazole 5a-e from p-
methoxythymol, extracted from Tetraclinis Articulata, as starting material involving 1,3-
dipolar cycloaddition reaction and secondly a detailed study of the molecular packing and
intermolecular interactions in crystals of five related 5-((2-isopropyl-4-methoxy-5-
methylphenoxy)methyl)-3-phenylisoxazole derivatives. All compounds were synthesized and
subjected to solid state characterization by single-crystal X-ray diffraction analysis, and to
studies with the use of NMR and Hirshfeld surface analysis. All structures display
intermolecular C—H···O hydrogen bonding and C—H···π interactions, forming layers in the
crystal lattice. The crystal structures of compounds 5a; 5c and 5d are consolidated by π—π
interactions. Hirshfeld surface analysis, the dnorm surfaces, electrostatic potential and two-
dimensional fingerprint plots were examined to verify the contributions of the different
intermolecular contacts within the supramolecular structure. The most important contributions
for the crystal packing are from H···H, H···C/C···H and O···H/H···O interactions.
Additionally, DFT calculations have been used to analyze the electronic and geometric
frontier molecular orbital and Molecular Electrostatic Potential map analyses of the
compounds were produced using the optimized structures.

Keywords: Phenolic monoterpenoids, Isoxazole, 1,3-dipolar cycloaddition, Crystal structure,
Hydrogen bond, C—H...π interactions, Hirshfeld surface analysis, DFT
1
- Introduction
Due to their chemical and biological importance, heterocyclic moieties are attractive targets in
medicinal and pharmaceutical chemistry [1]. Among heterocyclic compounds, isoxazole has
proved to be the one of the most important moieties in organic synthesis. The wide range of
biological activities displayed by isoxazole compounds include cytotoxic [2, 3], antimicrobial
[
[
4], analgesic [5], antirhinovirus [6], anti-inflammatory [7], anthelmintic [8], muscle relaxant
9], hypoglycemic [10], adenosine antagonist [11], fungicidal [12, 13], herbicidal [14, 15],
nematocidal [16], insecticidal [17], antiparasitic [18]. The Modification of isoxazole structure
has offered a high degree of diversity that has proven useful for the development of new
therapeutic agents having improved potency and reduced toxicity. All above biological
activities of isoxazole derivatives aroused our attention and inspired us to prepare a new series
of isoxazole.
The p-methoxythymol is an important phenolic monoterpenoïd (PM) obtained from the
essential oil of many plants such as the genus Origanum, Thymus [19] and Satureja [20]. It
exhibits a large number of pharmacological activities including antimicrobial [21], anti-
inflammatory [22], analgesic, and antioxidant [23]. Additionally, phenolic monoterpenoïds
are generally regarded as safe (GRAS) food flavoring, which is an indication of low

mammalian toxicity starting materials [24]. Due to the aforementioned biological activities,
phenolic monoterpenoïd could be highly promising alternatives to synthetic agents for the
development of natural and nontoxic therapeutic agents [25]. At the same time, it is also
suitable as a starting molecule for the synthesis of organic and bio-organic product analog
based fine chemicals [26, 27].
Encouraged by the aforementioned facts, we envisioned that the introduction of a substituted
isoxazole pharmacophore into the parent p-methoxythymol scaffold might produce some new
compounds with multiple biological activities. In this study, we describe the design and synthesis of a
number of novel isoxazoles derivatives bearing PM.
2
- Experimental
All reagents were used as obtained from commercial sources (Aldrich and Acros). Melting
points (m.p.) was determined using a Kofler bench apparatus and are uncorrected (They are
not taken with a calibrated thermometer). Elemental analyses were taken with an Elementar
Vario EL-III Analyzer. Analytical thin-layer chromatography (TLC) was performed on
aluminum plates percolated with E. Merck silica gel 60 F254 to a thickness of 0.25 mm. IR
spectra were recorded on a Bruker Vertex 70 spectro-photometer using potassium bromide
1
1
13
discs in the frequency range 4000–400 cm- . H and C NMR spectra were recorded on a
Bruker Avance 300 (75) MHz spectrometer. Chemical shifts (δ ppm) were reported with
1
reference to SiMe ( H). All solvents were dried and distilled before use. Phenolic
4
monoterpene 2 used as a starting material for triazole hémisynthesis were isolated by column
chromatography from the dichloromethanic extract of the root part of medicinal plant
Tetraclinis articulate.
2
2
-1 Hemisynthesis
.1.1 General procedure for the extraction of paramethoxythymol 3 from Tetraclinis
articulata
Powdered wood of Tetraclinis articulata (500 g) was exhaustively extracted by maceration
with dichloromethane at room temperature for 24 h under agitation. The solvent was removed
in a rotavapor and the residue obtained (26 g) was chromatographed in a silica gel column
eluting with a solvent gradient hexane– EtOAc (9:1 v/v) affording 2.9 g of p-methoxythymol
3
, whose identification was confirmed on the basis of its spectroscopic analyses.

2
.1.2 General procedure for the synthesis of substituted benzaldoximes 2a-e
To a stirred solution of H O/Ethanol (14 ml, 1:1) substituted benzaldehyde 1a-e (14 mmol),
2
hydroxylamine hydrochloride (1.5 eq, 21 mmol) and NaOH (5.8 ml, 35 mmol, 6.0 M in H O) was
2
added. After 5 h, the reaction was quenched with 2 M HCl (10 ml), extracted with Et O (3 x 20 ml),
2
and washed with brine (50 ml). The dried (Na SO ) organic layers were concentrated in vacuo to give
2
4
crude oxime 2a-e as colorless solids.
2
.1.3 General procedure for O-propargylation of paramethoxythymol 3
To a solution of corresponding PM 3 in dry acetone, K CO (1 equiv) was added. The reaction mixture
2
3
was stirred for 30 min and propargyl bromide (1 equiv) was added drop-wise. The mixture was stirred
overnight until none of the starting materials were detected using TLC. The solution was concentrated
and solubilized in 60ml of CH Cl . The organic layer was washed with distilled water (2 x 10mL),
2
2
dried over Na SO and concentrated. The resulting crude product was purified by silica gel column
2
4
chromatography using n-hexane–ethyl acetate (95:5 v/v) as eluent.
1
-isopropyl-5-methoxy-4-methyl-2-(prop-2-yn-1-yloxy)benzene, 4.
-1
Light yellow liquid, Yield 85%; IR (KBr), max/cm : 3281 (≡C-H), 2960 (C-H), 2120 (C≡C),
1
1
5
587 (C=C), 1041 (C-O); H NMR (300 MHz, CDCl ) δ(ppm) 6.77 (s, H-6), 6.62 (s, H-3),
3
.18 (s, H-10), 3.83 (s, H-11), 3.37 (sept, J= 7.3 Hz, H-9), 2.44 (s, H-13), 2.23 (s,H-11), 1.25
13
(
d, J= 7.3 Hz, H-8); C NMR (75 MHz, CDCl ) δ(ppm) 158.9 (C ), 140.6 (C ), 135.6 (C ),
3 Ar Ar Ar
1
2
30.1 (CH ), 128.0 (C ), 114.3 (CH ), 78.0 (≡CH),76.0 (≡C-), 55.9 (OCH ), 52.6 (OCH ),
Ar Ar Ar 2 3
6.5 (CH), 22.4 (CH ), 19.3(CH ). Analysis calculated (%) for C H O : C, 77.03; H, 8.31;
3
3
14 18
2
found: C, 77.11; H, 8.26.
2
.1.4 Typical experimental procedure for the preparation of isoxazoles 5a-e
To a solution of compound alkyne (1 equiv) in dichloromethane (25ml), substituted
benzaldoximes (1.1 equiv) and sodium hypochlorite (9–12% in water) (10 ml) were added at
0
°C. Then the reaction mixture was stirred at 0°C for 2-5 h. The progress of the reaction was

monitored by TLC analysis (15% EtOAc/hexane). Then, 50 ml of water was added and the
reaction mixture was extracted with dichloromethane (3x20ml). The combined organic layer
was washed with water, followed by brine and dried over anhydrous Na SO and concentrated
2
4
in vacuo. The residue was purified by flash chromatography on silica gel using n-hexane–
ethyl acetate (92:8 v/v) as eluent.
5
-((2-isopropyl-4-methoxy-5-methylphenoxy)methyl)-3-phenylisoxazole, 5a.
-1
Colorless crystal, m.p.: 87-89 °C, Yield:70%; IR (KBr), max/cm : 2954 (C-H), 1609 (C=N),
1
1
2
2
511 (C=C), 1209,1056 (C-O); H NMR (300 MHz, CDCl ) δ(ppm) 7.88-7.85 (d, J = 6.9 Hz,
3
H,Ar-H), 7.49-7.48 (m, 3H,Ar-H), 6.80 (s, 1H), 6.79 (s, 1H), 6.66 (s, 1Hisoxazole), 5.17 (s,
H,CH ), 3.85 (s, 3H,OCH ), 3.44-3.38 (m, 1H), 2.25 (s, 1H), 1.33-1.28 (d, J= 7.2 Hz, 6H);
2
3
1
3
C NMR (75 MHz, CDCl ) δ(ppm) 169.3(C ), 162.5(C ), 152.9(C ), 148.7(C ), 136(C ),
3
Ar
Ar
Ar
Ar
Ar
1
6
30.2(CH ), 128.9(CH ), 126.9(CH ), 124.5(C ), 116.1(CH ), 109(CH ), 101(CH ),
Ar Ar Ar Ar Ar Ar Ar
3(OCH ), 55.9(OCH ), 27.1(CH), 23.1(2×CH )., 16.1(CH ). Analysis calculated (%) for
2
3
3
3
C H NO :C, 74.75; H, 6.87; N, 4.15; found: C, 74.72; H, 6.82; N, 4.06.
21
23
3
5
-((2-isopropyl-4-methoxy-5-methylphenoxy)methyl)-3-(p-tolyl)isoxazole, 5b.
-1
Colorless crystal, m.p.: 123–125°C, Yield: 74%; IR (KBr), max/cm : 2958 (C-H), 1612
1
(
C=N), 1509 (C=C), 1203,1032 (C-O); H NMR (300 MHz, CDCl ) δ(ppm) 7.78 (d, J = 8.1
3
Hz, 2H,Ar-H), 7.45 (d, J = 8.1Hz, 2H,Ar-H), 6.83 (s, 1H), 6.82 (s, 1H), 6.66 (s, 1Hisoxazole),
5
.16 (s, 2H,CH ), 3.84 (s, 3H,OCH ), 3.44 (m, 1H), 2.44 (s,3H, CH ), 2.29 (m, 1H), 1.33-1.28
2
3
3
1
3
(
d, J= 7.2 Hz, 6H); C NMR (75 MHz, CDCl ) δ(ppm) 169.1(C ), 162.4(C ),
3 Ar Ar
1
1
2
52.9(C ),148.7(C ), 140.2(C ), 136(C ), 129.6(CH ), 126.7(CH ), 126.1(C ),
Ar Ar Ar Ar Ar Ar Ar
24.5(C ), 116(CH ), 109(CH ), 101(CH ), 63(OCH ), 55.9(OCH ), 27.1(CH), 23(CH ),
Ar
Ar
Ar
Ar
2
3
3
1.4(CH ), 16.1(CH ). Analysis calculated (%) for C H NO : C, 75.19; H, 7.17; N, 3.99;
3
3
22 25
3
found: C, 75.12; H, 7.12; N, 3.95.
3
-(4-chlorophenyl)-5-((2-isopropyl-4-methoxy-5-methylphenoxy)methyl)isoxazole, 5c.
-1
Colorless crystal, m.p.: 128–130°C, Yield: 71%; IR (KBr), max/cm : 2956 (C-H), 1606
1
(
C=N), 1509 (C=C), 1205,1032 (C-O), 832 (C-Cl); H NMR (300 MHz, CDCl ) δ(ppm) 7.78
3
(d, J = 8.4 Hz, 2H,Ar-H), 7.45 (d, J = 8.4Hz, 2H,Ar-H), 6.77 (s, 1H), 6.76 (s, 1H), 6.62 (s,
1
1
1
Hisoxazole), 5.16 (s, 2H,CH ), 3.84 (s, 3H,OCH ), 3.39-3.35 (m, 1H), 2.23 (s,3H, CH ), 1.27-
2 3 3
1
3
.21 (d, J= 7.2 Hz, 6H); C NMR (75 MHz, CDCl ) δ(ppm) 169.6(C ), 161.5(C ),
3
Ar
Ar
52.9(C ), 148.6(C ), 136.1(C ), 136(CH ), 129.2(CH ), 128.1(CH ), 127.4(C ),
Ar
Ar
Ar
Ar
Ar
Ar
Ar

1
1
24.5(C ), 116(CH ), 109(CH ), 100.8(CH ), 63(OCH ), 55.9(OCH ), 27(CH), 23(CH ),
Ar Ar Ar Ar 2 3 3
6(CH ). Analysis calculated (%) for C H ClNO C, 67.83; H, 5.96; Cl, 9.53; N, 3.77,
3
21 22
3
found: C, 67.77; H, 5.91; N, 3.72.
5
-((2-isopropyl-4-methoxy-5-methylphenoxy)methyl)-3-(4-nitrophenyl)isoxazole, 5d.
-1
Yellow Color crystals, m.p.:126–128 °C, Yield: 68%; IR (KBr), max/cm : 2939 (C-H), 1600
1
(
C=N), 1517 (C=C), 1205, 1062 (C-O); H NMR (300 MHz, CDCl ) δ(ppm) 7.78 (d, J = 7.2
3
Hz, 2H,Ar-H), 7.45 (d, J = 7.2 Hz, 2H,Ar-H), 6.77 (s, 1H), 6.76 (s, 1H), 6.73 (s, 1Hisoxale),
5
7
1
1
1
6
.19 (s, 2H,CH ), 3.83 (s, 3H,OCH ), 3.38-3.34 (m, 1H), 2.21 (s,3H, CH ), 1.33-1.24 (d, J=
2
3
3
1
3
.2 Hz, 6H); C NMR (75 MHz, CDCl ) δ(ppm) 170.4(C ), 160.6(C ), 152.9(C ),
3
Ar
Ar
Ar
48.7(C ), 148.4(C ), 135.9(C ), 134.9(C ), 127.7(CH ), 124.5(C ),, 124.2(CH ),
Ar
Ar
Ar
Ar
Ar
Ar
Ar
15.9(CH ), 109(CH ), 101.1(CH ), 62.9(OCH ), 55.9(OCH ), 27(CH ), 23(CH ),
Ar
Ar
Ar
2
3
3
3
6.07(CH ). Analysis calculated (%) for C H N O C, 65.96; H, 5.80; N, 7.33; found C,
3
21 22
2
5
5.92; H, 5.75; N, 7.29.
5
-((2-isopropyl-4-methoxy-5-methylphenoxy)methyl)-3-(2-methoxyphenyl)isoxazole, 5e.
-1
Colorless crystal, m.p.: 117–119 °C; Yield: 68%; IR (KBr), max/cm : 2956 (C-H), 1603
1
(
C=N), 1507 (C=C), 1202,1033 (C-O); H NMR (300 MHz, CDCl ) δ(ppm) 7.97-7.94 (d, J =
3
7
1
1
1
1
1
.8 Hz, 2H,Ar-H), 7.45-7.42 (m, 1H,Ar-H), 7.11-7.06 (m, 2H,Ar-H), 6.89 (s, 1H), 6.82 (s,
H), 6.79 (s, 1Hisoxazole), 5.16 (s, 2H,CH ), 3.91 (s,3H,OCH ), 3.86 (s, 3H,OCH ), 3.44 (m,
2
3
3
13
H), 2.26 (s, 3H,CH ), 1.31-1.28 (d, J= 7.2 Hz, 6H); C NMR (75 MHz, CDCl ) δ(ppm)
3
3
67.7(CAr), 160(CAr), 157.2(CAr), 152.7(CAr), 148.8(CAr), 136(CAr), 131.2(CHAr),
29.4(CH ), 124.4(C ), 120.9(CH ), 117.8(C ), 116.2(CH ),111.4(CH ), 108.9(CH ),
Ar
Ar
Ar
Ar
Ar
Ar
Ar
04.7(CH ), 63.03(OCH ), 55.8(OCH ), 55.4(OCH ), 27(CH ), 22.9(CH ), 16(CH ).
Ar
2
3
3
3
3
3
Analysis calculated (%) for C H NO C, 71.91; H, 6.86; N, 3.81; found C, 71.87; H, 6.80;
2
2
25
4
N, 3.77.
2
.2 Single crystal X-ray data collection
The X-ray intensity data were collected on a Bruker D8 Venture Super DUO diffractometer
with PHOTON100 CMOS area-detector using MoKα radiation (= 0.71073Å)
monochromated by graphite at room temperature. The following software was used: Frame
integration, Bruker SAINT software package [28] and data were corrected for Lorentz-
Polarization effects and for absorption by the multi-scan semi-empirical method implanted
in SADABS [29]. The structures were solved by direct methods using SHELXT-2014/5 [30]

2
and refined (by weighted full matrix least-square on F techniques) to convergence using the
SHELXL-2018/3 program [31]. All non hydrogen atoms were refined with anisotropic
thermal parameters. The C-bound H atoms were geometrically placed (C—H = 0.93–0.98 Å)
and refined as riding with Uiso(H) = 1.2–1.5Ueq(C). Crystal data, data collection and
structure refinement details for 5a-e were summarized in Table 1. The molecular graphic were
drawn using Diamond programs [32].
2
.3 Hirshfeld surface and 2D fingerprint plots
The Hirshfeld surfaces calculated for compounds 5a-e were analyzed to clarify the nature of
the intermolecular interactions between different units in the crystal packing motif and
visualize them graphically. Thus, a Hirshfeld surface analysis [33] and the associated two-
dimensional fingerprint plots [34] were performed using CrystalExplorer17.5 [35] to figure
out the normalized contact distance (dnorm), which depends on contact distances to the closest
atoms outside (d ) and inside (d ) the surface. The molecular HS were performed using a
e
i
standard (high) surface resolution with the three-dimensional surfaces mapped.
2
.4 Quantum chemical calculations
Density functional theory (DFT) has proved to be useful for studying the electronic structures
of all molecules under investigation. The geometry optimization was performed by means of
the Gaussian 09 W program and GaussView molecular visualization software [36, 37] on a
personal computer, based on density functional theory DFT, using Beck's three parameters
hybrid functional exchanges [38], with 6-311G (d,p), 6-311++G(d,p) and 6-311++G basis
sets and Lee-Yang-Parr correlation functional (B3LYP) [39, 40]. Single crystal XRD
structural models were taken as a starting geometry. The Molecular Electrostatic Potential
(MEP) and Mulliken charges were determined to investigate the charge distribution on the all
molecules 5a-e.
3
3
. Results and discussion
.1. Synthesis
Several methods exist for the synthesis of isoxazole rings. The important and the most used
method is the [3+2] cycloaddition reaction [41]. The overall synthetic route of isoxazole
derived based paramethoxythymol is shown in Scheme 1. Our approach to synthesize the

target isoxazoles began with the O-propargylation of paramethoxythymol 3 following
previously reported procedures [42]. We first treated paramethoxythymol 3 with an excess of
propargyl bromide in the presence of potassium bicarbonate in dry acetone under magnetic
stirring for 12 hours at room temperature to give compound 4. Its structure was confirmed
according to its spectral data, where the IR spectra indicated the existence of the band at νmax
-1
1
=
3293cm that corresponded to the alkyne proton. Its H NMR spectrum showed two
singlets at 5.18 ppm attributable to the ethylenic proton and at 2.44 ppm attributable to the
1
3
terminal methylenic protons, respectively. Its C NMR spectrum confirmed the above
spectral data with the appearance of new signals at δ 56.06, 76.04 and 80.38ppm that
C
corresponded to the carbons of the propargyl bromide used.
The benzaldoxime 2a and its substitutes 2b-e were prepared via addition-elimination reactions
between aromatic aldehyde 1a-e, hydroxylamine hydrochloride and potassium hydroxide in
an ethanol/ water mixture at room temperature. The structures of compounds 2a-e were
identified by their melting points and FT-IR spectroscopy. The physical properties and FT-IR
spectroscopy were corresponding to those described in the literature [43].
In the next step, the obtained oximes 2a-e was converted to the related nitrileloxids in situ
with NaOCl. Then, reaction of nitrileoxides with propargyl compounds 3 by a [3+2]
cycloaddition reaction gave the related isoxazoles 5a-e in good yields (55–74%).
The structures of these compounds were confirmed according to their spectral data, where the
IR spectra of compounds 5a-e indicated the existence of the isoxazole C=N group at νmax
-1
1
=
1598–1610 cm . The H NMR spectra of compounds 5a–e indicated the existence of the
isoxazolic moieties by showing essentially the resonance of the protons introduced by the
1
arylnitrileloxids. The H NMR spectrum for 5b as an example, showed a singlet at δ 5.36
H
relative to the methylenic protons H and another singlet at δ 6.66 corresponding to the
1
1
H
isoxazole proton H . The same spectrum showed two doublets at δ 7.78 and 7.45ppm (J=8.1
4
'
H
Hz) attributable to the protons aromatic. The disappearance of the signal for the alkyne proton
1
3
at 2.44ppm favored the cycloaddition reaction. Further, the C NMR spectrum of this
cycloadduct 5b was also a good support for the proposed structure which exhibited
characteristic signals at δ 63.03ppm corresponding to O–CH carbon, and at δ 101.04,
C
2
C
1
62.4, and 169.1ppm relative to isoxazole carbons. Single crystal structures of 5a and 5e were
also recorded to further confirm the proposed structures.

Scheme 1. Synthetic route of isoxazole. Reagents and conditions: (i) Propargyl bromide,
K CO , Acetone, rt, 12 h; (ii) NH OH.HCl, KOH, EtOH:H O (1:1), rt, 10 h; (iii) NaOCl,
2
3
2
2
DCM 0°C, 5h.
3
.2 Crystal structure description of 5a-e
A suitable single crystals of compounds 5a-e for X-ray diffraction study was obtained by p-
methoxythymol extracted from Tetraclinic Articulata with 1,3-dipolar cycloaddition. The plot
of the crystal structures belonging to the prepared compounds is illustrated in Fig. 1. All
̅
compounds crystallize in the triclinic system, space group P ꢀEach structure contains three
essentially planar aromatic or heterocyclic rings, i.e. benzene (C1—C6), isoxazole (atoms
C3’–C5’/N1/ O1), and (C13—C18), of which the latter two are directly connected via C3’
and C13 atoms. Selected bond lengths and angles of these compounds are also given in Table
2
. Hydrogen bond distances and angles together with details of offset C—H··· and π···π
contacts for 5a-e are shown in Table 3. The molecular structures of the five compounds 5a-e
are sufficiently similar to be discussed together as they vary only in the substitution pattern on
the benzene ring of the isoxazole system. The phenyl is substituted by a single methyl, Cl and
NO group at C16 for 5b, 5c and 5d respectively, while 5e carries methoxy substituent at C18.
2
A comparison of related distances and angles within the isoxazole ring shows a good
agreement between all five structures, with a systematically C3’—N1 and C4’—C5’ bonds
lengths ranging from 1.304 to 1.316 Å and 1.332 to 1.346Å, corresponding to C=N and C=C
double bond, respectively. The N1-O1 single bond present values from 1.405 to 1.415Å. The
C5’—O1 and C4—O2 bond lengths are ranging 1.345 to 1.356 Å and 1.378-1.389 Å
2
respectively, indicating the presence of a single bond between oxygen and a sp carbon atom,

whereas the single bond lengths C11—O2 (1.396-1.427 Å) are slightly longer due to oxygen
3
and a sp carbon. Geometrical parameters are in a good agreement with those of the related
compounds containing phenyl-isoxazole [44-46]. A larger discrepancy is observed for the
dihedral angle between the isoxazole ring and the phenyl ring in the p-methoxythymolin:
6
8
4.59(8)° (5c) and 71.25(11)° (5e), this is much larger than the value of 16.04(1)° (5a),
.34(8)° (5b), 10.55(12)° (5d), 7.19(2) [43], 3.63(2) [43], 17.1(1)° [44] and 36.8(2)° [46],
while it has close that found in [45] (73.04(8)°).
It is noteworthy that the nitrogen N atom does not participation an intermolecular interaction
like in all compounds. In addition, a weak C—H··· interaction involving different donor
groups and acceptor -ring systems are present in all crystals. A reasonable separation
between aromatic rings to be considered as sensible π···π contacts is < 4.0 Å so that those
observed here in compounds 5a, 5c and 5d can be considered to be quite significant.

Table 1: Crystal Data, Summary of Intensity Data Collection, and Structure Refinement
5a
5b
5c
5d
5e
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system,
space group
C H NO
337.40
296(2)
0.71073 Å
Triclinic, Pꢁ
C H NO3
351.43
296(2)
0.71073 Å
C H ClNO3
371.84
296(2)
C H N O
382.40
296(2)
0.71073 Å
C H NO
367.43
296(2)
0.71073 Å
Triclinic, Pꢁ
21
23
3
22 25
21 22
21 22
2
5
22 25
4
0.71073 Å
Triclinic, Pꢁ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
Triclinic, Pꢁ
Triclinic, Pꢁ
a, b, c (Å)
9.4958(10),
7.8247(3),
10.4383(5),
12.4226(6)
78.202(2),
83.069(2),
77.892(2),
967.89(8)
2
8.792(4), 10.217 8.391(2),
10.4871(5),
10.5128(5),
10.7032(6)
72.751(2),
84.704(2),
63.683(2)
1009.08(9)
2
9
1
.5333(15),
0.2143(16)
(5), 11.316(5)
10.488(4),
11.224(5)
97.4752°,
94.48(2),
98.5352°
963.7(6)
2
, ,  (°)
96.630(6),
102.89(2),
103.51(2),
96.93(2),
947.3(8)
2
9
9
0.474(5),
3.885(6)
3
Volume (A )
Z
916.2(2)
2
Calculated density
1.223
1.206
1.304
1.318
1.209
3
(

g/cm )
(mm )
-1
0.081
Plate, colorless
0.080
0.222
0.095
0.083
Block, colorless
Crystal shape and
color
Block, colorless Block, colorless Plate, yellow
Crystal size (mm)
Theta range for
data collection (°)
Limiting indices
0.38x0.26x0.15 0.41×0.22×0.16 0.33×0.22×0.13 0.40x 0.27x0.13 0.36x0.26x0.11
2.770 – 26.367 2.671- 27.999 2.423- 30.508 2.467– 25.681 2.256 – 24.999
-11 h 11, -11 -10 h 10, -13 -12 h 12, -14 -10h 10, -12 -12 h 12, -12

l 12
k 11, -12 
 k 13, -16  l  k 14, -16  l k 12, -13  l
 k 12, -13 
l 13
 16
 16
13
Diffractometer
Bruker D8
VENTURE
Super DUO
Multi-scan
(SADABS,
Brucker, 2016)
0.6862-0.7462
32299, 3746,
2716
Bruker D8
VENTURE
Super DUO
Multi-scan
(SADABS,
Brucker, 2016)
0.6918-0.7462
39315, 4684,
3211
Bruker D8
VENTURE
Super DUO
Multi-scan
(SADABS,
Brucker, 2016)
0.7041-0.7465
34664, 5774,
4096
Bruker D8
VENTURE
Super DUO
Multi-scan
(SADABS,
Brucker, 2016)
0.6624-0.7462
21479, 3656,
2375
Bruker D8
VENTURE
Super DUO
Multi-scan
(SADABS,
Brucker, 2016)
0.6874-0.7465
33948, 3828,
2640
Absorption
correction
Tmin. Tmax.
No. of measured,
independent and
observed [I > 2σ(I)] [R(int) = 0.042] [R(int) = 0.039] [R(int) = 0.036] [R(int) = 0.044] [R(int) = 0.05]
reflections
Refinement method Full-matrix
Full-matrix
Full-matrix
Full-matrix
Full-matrix
least-squares on least-squares on least-squares on least-squares on least-squares on
2
2
2
2
2
F
F
F
F
F
Data / restraints /
parameters
3746/0/231
4684/ 0 / 241
5774/ 0 / 240
3371/0/258
3828/0/250
2
2
R[F > 2(F )],
0.048, 0.133,
1.03
0.049, 0.153,
1.10
0.046, 0.138,
1.03
0.060, 0.174,
1.06
0.049, 0.135,
1.02
2
wR(F ), S
H-atom treatment
H-atom
H-atom
H-atom
H-atom
H-atom
parameters
constrained
Δρmax, Δρmin (e Å ) 0.16, -0.16
parameters
constrained
0.25, -0.16
parameters
constrained
0.29, -0.29
parameters
constrained
0.17, -0.21
parameters
constrained
0.15, -0.13
−
3

Table 2: Selected experimental and calculated (italic) geometric parameters (Å, °) for
compounds 5a-e
5
a
5b
5c
5d
5e
Bond lenghts
C12—O3
1.411(2)
.418
1.376(2)
.371
1.387(2)
.382
1.410(2)
.413
1.488(2)
.492
1.336(2)
.354
1.348(2)
.346
1.414(2)
.396
1.309(2)
.315
1.422(2)
.433
1.414(2)
1.418
1.372(2)
1.371
1.383(2)
1.381
1.396(2)
1.413
1.482(2)
1.492
1.331(2)
1.354
1.345(2)
1.346
1.415(2)
1.397
1.428(2)
1.418
1.381(2)
1.371
1.390(2)
1.382
1.427(2)
1.412
1.493(2)
1.492
1.345(2)
1.355
1.355(2)
1.346
1.407(2)
1.395
1.405(4)
1.419
1.373(3)
1.370
1.386(3)
1.383
1.400(3)
1.411
1.478(3)
1.492
1.334(3)
1.355
1.346(3)
1.347
1.407(3)
1.390
1.401(3)
1.417
1.378(3)
1.372
1.378(3)
1.379
1.418(3)
1.423
1.480(3)
1.488
1.334(3)
1.356
1.347(2)
1.349
1.406(2)
1.386
1
C1—O3
1
C4—O2
1
C11—O2
C11—C5’
C5’—C4’
C5’—O1
N1—O1
1
1
1
1
1
N1—C3’
C4’—C3’
C18—O4
C19—O4
O1N—N2
O2N—N2
Cl—C16
1.303(2)
1.316
1.415(2)
1.433
1.316(2)
1.316
1.428(2)
1.432
1.304(3)
1.316
1.412(3)
1.431
1.306(2)
1.320
1.413(3)
1.431
1
1
-----
-----
-----
-----
-----
-----
-----
-----
1.360(3)
1
.365
1.420(3)
.422
-----
-----
------
-----
-----
-----
-----
1
1.228(3)
-----
-----
-----
1
.224
1.211(4)
.223
-----
1
1.746(2)
-----
1.758
Angles
C1—O3—C12
117.8(2)
117.8(2)
118.7
115.8(2)
115.6
123.8(2)
124.2
118.4(2)
118.4
123.5(2)
123.3
115.4(2)
116.0
106.0(2)
107.8
108.3(2)
117.8(2)
118.7
115.6(2)
115.4
124.2(2)
124.2
117.2(1)
118.4
123.6(2)
123.3
115.8(2)
116.0
106.9(2)
107.7
108.7(2)
118.1(2)
118.7
115.5(2)
115.4
123.9(2)
124.2
117.5(2)
118.4
123.2(2)
123.3
115.8(2)
115.9
107.4(2)
107.5
108.7(2)
118.1(2)
118.6
115.7(2)
115.5
123.6(2)
124.2
118.2(2)
118.6
123.9(2)
123.6
115.1(2)
115.8
106.6(2)
108.3
108.6(2)
1
18.7
115.3(2)
15.5
124.2(2)
24.2
116.8(2)
18.4
123.2(2)
23.2
116.2(2)
16.0
106.9(2)
07.6
108.3(2)
O3—C1—C2
O3—C1—C6
C4—O2—C11
O2—C4—C3
C5—C4—O2
O2—C11—C5’
N1—O1—C5’
1
1
1
1
1
1

1
08.9
110.7(2)
11.1
105.2(2)
03.8
105.7(2)
05.9
120.5(2)
20.4
108.9
111.5(2)
111.1
104.9(2)
103.9
105.2(2)
105.9
120.2(2)
120.5
109.0
110.7(2)
111.1
105.1(2)
103.8
105.9(1)
105.9
120.3(2)
120.3
109.1
111.52)
111.2
105.1(2)
103.7
105.2(2)
105.9
118.7(2)
120.1
109.2
110.8(2)
110.5
105.5(2)
104.2
105.7(2)
106.4
118.5(2)
119.0
N1—C3’—C4’
C5’—C4’—C3’
C3’—N1—O1
1
1
1
N1—C3’—C13
Cl1—C16—C15
Cl1—C16—C17
C18—O4—C19
O1N—N2—O2N
1
-----
-----
-----
-----
-----
119.1(2)
-----
-----
1
19.5
119.6(2)
19.5
-----
-----
-----
-----
-----
-----
1
-----
118.6(2)
119.0
-----
123.8(3)
-----
124.9
Table 3
Hydrogen bonds (Å , °), C—H…π and π…π interactions for compounds 5a-e
Cg1, Cg2 and Cg3 represent the centroids of the N1/O1/C3’-C5’, C1–C6 and C13–C18 rings,
respectively.
D—H…A
D—H H…A
D…A or
Cg…Cg
3.432(2)
3.496(2)
2.804(2)
3.533(2)
3.992(2)
3.427(2)
3.555(2)
2.767(2)
3.718(2)
3.740(2)
3.454(2)
2.856(3)
2.783(2)
3.577(2)
3.970(2)
3.811(2)
3.488(3)
2.778(3)
3.829(4)
3.960(2)
3.836(2)
3.448(3)
3.418(4)
2.741(3)
3.759(4)
D—H…A Symmetry codes
5
a
C11—H11A···O1
C16—H16···O3
C8—H8···O2
C8—H8B···Cg2
Cg3….Cg3
C11—H11A···O1
C12—H12C···O3
C8—H8···O2
C11—H11B···Cg2
C10—H10B···Cg3
C11—H11A···O3
C18—H18···N1
C8—H8···O2
C12—H12C···Cg2
Cg1···Cg3
Cg3···Cg3
C11—H11A···O1N
C8—H8···O2
C10—H10B···Cg3
Cg1···Cg2
0.97
0.93
0.98
0.93
2.62
2.59
2.35
2.66
141
165
107
150
-x, -y+1, -z+1
1+x, -1 +y, -1+z
x, y, z
1-x,1-y,1-z
2-x,-y,-z
5
b
0.97
0.96
0.98
0.97
0.96
0.97
0.93
0.98
0.96
2.62
2.68
2.32
2.91
2.88
2.60
2.55
2.33
2.74
141
152
107
142
150
146
100
108
146
2-x, 2-y, -z
-x, 2-y, 1-z
x, y, z
1 - x, 2 - y, -z
2 - x, 1 - y, - z
-x, 1-y, 1-z
x, y, z
x, y, z
1–x, 1-y, 1–z
-x,-y, 2-z
5
c
-1-x,-y, 2-z
1+x, 1+y, z
x, y, z
5
d
0.97
0.98
0.96
2.54
2.30
2.92
165
109
158
1+x, y, z
-1+x, y, z
-1-x, -y, 1-z
1-x,-y, 2-z
-1+x,1+y, 1+z
x, y, z
Cg3···Cg3
5
e
C11—H11A···O4
C16—H16···O3
C8—H8···O2
0.97
0.93
0.98
0.96
2.49
2.57
2.34
2.99
170
152
103
138
C19—H19A···Cg3
-x, 1-y, 2-z

5a
5b
5c
5d
5e
Figure 1: The structures of 5a-e showing the atom numbering with ellipsoids drawn at the
0% probability level
5
In the crystal structure of 5a, the dihedral angle between isoxazole ring and two phenyl (C1–
C6) and (C13-C18) are 16.04(1) and 11.69(1)° respectively, while that between the two
aromatic six-membered rings is 26.63(8)°. Additional intermolecular C16–H16···O3 and
C11–H11A···O1 hydrogen bonds link groups of four molecules (Fig. 2a) and generate sheets
parallel to a plane. An intermolecular C–H···π interaction between the H at C11 and the C1-
C6 aromatic ring of the neighboring molecule with H···π distance of 2.66 Å interconnects the
molecular chains together. These contacts are strongly supported by extensive π···π contacts
between the adjacent C13-C18 rings, Fig. 2b, with centroid to centroid distances Cg3···Cg3 =
3
.992(2) Å (Table 3). These combinations of dimers formation and - stacking interactions
form layers parallel to (110) (Fig. 2c).
Another significant feature of the packing in 5a is a series of strong, inversion related C–
H···π interactions and π···π contacts to generate sheets of molecules parallel to the bc plane,
Fig. 2b. The C11–H11A···O1 contacts serve to connect these sheets (Fig 2c).

H16
O3
H11A
O1
O1
H11A
O3 H16
b
a
c
Figure 2: (a) Detail of the intermolecular C–H···O hydrogen bonds (orange dashed lines), (b)
C–H···π and π···π contacts are shown as green and purple dashed lines, respectively and (c)
crystal packing for 5a viewed along the c axis.
In the title compound 5b, the dihedral angles between the isoxazole ring C3’–C5’/N1/ O1 and
two phenyl (C1–C6) and (C13-C18) are 8.34(8) and 26.27(8)° respectively while that between
the two aromatic six-membered rings is 34.59(8)°. For 5b crystal packing is again dominated
ꢄ
ꢄ
by C—H···O and C—H···π contacts. A centrosymmetric dimers ꢃ ꢅꢆꢇ formed by C11—
H11A···O1 hydrogen bond are connected to another via C—H···π (C11—H11B···Cg2)
interactions, where Cg2 is the centroid of the ring C1—C6 forming chains along a-axis (Fig.
3
b). These chains are related by C—H···π (C10—H10B···Cg3) interactions, where Cg3 is the
centroid of the ring C13—C18, forming sheets parallel to ab plane (Fig. 3c). Adjacent layers
are interconnected by hydrogen bond C12—H12C···O3 (Fig. 3d).

H11A
2
H11B
R (8)
2
H11A
2
R (8)
2
H11A
b
a
c
d
Figure 3: (a) The molecular chain generated by intermolecular C—H···π interactions, (b) C–
H···O interconnected by C–H···π interactions, (c) Overall packing for 5b viewed along the c
axis showing C–H···O and C–H···π interactions are shown as orange and green dashed lines,
respectively and (d) the molecular sheet assembled by intermolecular C—H···O and C—
H···π interactions
In crystal 5c, the dihedral angles between C3’–C5’/N1/ O1 ring and two phenyl (C1–C6) and
(C13-C18) are 64.59(8) and 10.31(8)° respectively, while that between the two aromatic six-
membered rings is 68.51(7)°. C11–H11A···O3 hydrogen bonds form inversion dimers
ꢄ
ꢄ
generating ꢃ (16). An intermolecular C–H···π interaction between the H at C12 and the C1-
C6 aromatic ring of the neighboring molecule with H···π distance of 2.74 Å connects the
adjacent dimmers forming chains along the a-axis direction. The chains are linked by slipped
parallel π···π interactions, between C3’–C5’/N1/ O1 (Cg1) and C13-C18 (Cg3) rings, with
centroid to centroid distances Cg1…Cg3 = 3.970(2) Å and Cg3···Cg3 = 3.811(2) Å (Table 3),
forming slabs parallel to the ac plane (Fig. 4).

O3
H11A
O3
H11A
Figure 4: Overall packing for 5c showing C–H···O, C–H···π and π···π interactions as dashed
lines
In the crystal of compound 5d, The dihedral angles between C3’–C5’/N1/O1 ring and two
phenyl (C1–C6) and (C13-C18) are 10.55(12) and 21.01(12)° respectively. In the crystal, the
molecules are linked together by a C—H···π -phenyl (C13-C18) interaction (Table 1), with an
H…centroid distance of 2.92 Å forming chains propagating along the a direction. The
cohesion of the crystal structure is enhanced by two π – π stacking interactions between the
rings, with centroid– centroid distances in the range 3.836(2) to 3.960(2) Å (Table 3 and Fig.
5
), so the chains are connected via C—H···O hydrogen bond to form of a supramolecular
three-dimensional structure (Fig. 5).

H10B
b
a
c
Figure 5: (a) The molecular chain generated by intermolecular C—H···O interactions, (b)
C–H···π and π···π contacts are shown as green and purple dashed lines, respectively and (c)
crystal packing for 5d viewed along the c axis
Due to the position of the methoxy group in position C18 in the 5e compound, its structure is
different from that of the other compounds, the dihedral angle between the isoxazole and the
attached ring is widely different with a value of 34.78(12)°. Moreover, the dihedral angle
between the isoxazole and the C1—C6 cycle is 71.25(11)°, while that between the two
aromatic six-membered rings is 39.72(11)°. In the crystal structure of 5e, C11—H11A···O4
ꢄ
ꢄ
hydrogen bonds form inversion dimers with ꢃ (16) ring motifs. Adjacent dimers are linked
ꢄ
ꢄ
by C16—H16···O3 contacts that combine to form ꢃ (26) rings generating corrugated chains
of molecules running approximately parallel to (011), Fig. 6a. On the other hand, the dimers
ꢄ
ꢄ
ꢃ (16) are linked by slipped parallel C—H···π (C19—H19A···Cg3) interactions, where Cg3
is the centroid of the ring C13—C18, forming chains along the b direction (Fig. 6b). The
packing crystal is shown in Fig. 6c.

O4
O3
O3
H16
H11A
a
c
b
Figure 6: (a) Crystal packing of compound 5e with indication of the hydrogen-bonding, (b)
C—H···O and (c) C—H···O and C—H··· interaction
3
.3 Frontier Molecular Orbitals (FMOs)
All molecular calculations were performed in the gas phase using Density Functional Theory
DFT) using the B3LYP/6-311g(d, p) exchange correlation functional. A comparison of bond
(
lengths and bond angles in the crystal to those from the DFT calculation is listed in Table 2,
while with B3LYP/6-311++g(d,p)/6-311++g are reported in Table S1. The differences
between calculated and experimental bond lengths and angles are within a few Angstroms and
degrees, respectively, when compared to the experimental parameters, which indicate that our
calculations are acceptable. This sensitive gap is attributed to the difference between the solid
phase and gas phase model. The DFT calculations provide some important information on the
reactivity and site selectivity of the molecular framework. The energy of the HOMO is
directly related to the ionization potential, while the energy of LUMO is related to electron
affinity and the energy gap between the HOMO and LUMO characterizes the molecular
chemical stability. The energy levels of the HOMO and LUMO for all compounds are

illustrated in Fig. 7. Red and green color distributions represent positive and negative phase in
molecular orbital wave function, respectively. The electron density of HOMO in the all
compounds is concentrated on p-methoxythymol, the isodensity in the LUMO is localized on
the R-phenylisoxazole. The energies of HOMO and LUMO, energy gap, electronegativity (),
chemical hardness (), global softness () and electrophilicity () index are calculated and
presented in Table 4. Furthermore, the high values of the electrophilicity index 6.185 eV
compared to the low values of chemical potential (4.284 eV) for 5d prove its electrophilic
character. The dipole moment (D) of compound 5d is greater than other studied compound,
therefore we can say that this compound is more reactive that other compound. On the other
side, the chemical potential of 5d (Table 4) is smaller compared to other compound; therefore
5
d behaves as an acceptor of electrons. The chemical hardness for 5d is smaller than those of
other compounds, indicating that the electrons are attracted from compound 5d. It is clear that
the value of E for the different studied molecules increases in the order 5d < 5c < 5e < 5a <
5
b; this indicates that compound 5d exhibit higher chemical reactivity attributed probably to
the presence of nitro group related to phenyl group attached to isoxazole ring.
It is noted from Table S2 and Fig. S13, the estimated values of quantum chemical parameters
from all compounds with the three basis set are having a similar trend. For example, 6-
3
11g(d,p) basis set shows the minimum dipole moment and the basis set of 6-311++g gives
maximum dipole moment value.
Table 4: HOMO–LUMO energies and values of quantum chemical parameters calculated by
B3LYP/6-311G (d,p)
property
Values
5
a
5b
5c
5d
5e
ET (eV)
-29776.600 -30846.320 -42278.312 -35340.515 -32892.405
EHOMO (eV)
ELUMO (eV)
EHOMO-1 (eV)
ELUMO+1 (eV)
-5.612
-1.269
-6.658
-0.469
4.343
6.189
2.172
0.230
3.441
2.723
-3.441
3.405
-5.591
-1.171
-6.436
-0.448
4.420
5.988
2.210
0.226
3.381
2.583
-3.381
3.145
-5.671
-1.527
-6.710
-0.829
4.144
5.881
2.072
0.241
3.599
3.122
-3.599
4.304
-5.765
-2.803
-6.934
-1.303
2.962
5.631
1.481
0.337
4.284
6.185
-4.284
6.888
-5.402
-1.213
-6.262
-0.165
4.189
6.097
2.094
0.239
3.308
2.614
-3.308
4.083
E(
(eV)
LUMO –HOMO)
E(
(eV)
LUMO+1–HOMO-1)
Global hardness ()
Softness ()
Chemical potential ()
Electrophilicity ()
Electronegativity ()
Dipole moment (D)
2
=1/2[ELUMO-EHOMO], =1/2, = -[1/2(ELUMO+EHOMO)], =  /2,  = -

Optimized structure
HOMO
LUMO
5
5
a
b
5
5
c
d
5e
Figure 7: Optimized structure and 3D plots of frontier molecular orbital of 5a-e
3
3
.4 Molecular Properties
.4.1 Mulliken population analysis
The Mulliken charge values were calculated using B3LYP functional with 6-311G(d,p), 6-
11++G(d,p) and 6-311++G basis set for the all structures. The color range in the scale of
3
positive and negative charge for Milliken atomic charges of 5a-e with 6-311g(d,p) is shown in
Fig. 8. While the Mulliken charge obtained by 311++G(d,p) and 6-311++G basis set are
reported in Table S3. The C1/C4/C11/C5’/C4’ atoms of the all molecules exhibit positive
charge while the other carbon has negative charges, the C16 atom has a positive charge when
it is attached to the nitro group. Moreover, all the hydrogen atoms have a net positive charge.
Oxygen O2 and O3 have a high negative charge value which imposes a positive charge to C4
and C1 for all compounds, respectively. The Mulliken atomic charge of all compounds shows
that the nitrogen atoms N1 has negative charge value which imposes a positive charge to a
carbon atom bonded, while the nitrogen atom N2 posses positive charge which was imposed
by oxygen atoms O1N and O2N in compound 5d.

The charge changes with basis set presumably occurs due to polarization. For example, the
charges of N1 atom are a range -0.152 to -0.161e- for B3LYP/6-311g(d,p), -0.378 to -0.487e-
for B3LYP/6-311++g(d,p) and -0.477 to -0.576e- for B3LYP/6-311++g (Table S3).
The charge of O1 is negative B3LYP with 6-311g(d,p) basis set, however in both B3LYP/6-
3
11++g and B3LYP/6-311++g(d,p) this charge is positive.
-0.387
0.202
-0.388
0.202
5b
5a
-0.390
0.201
-0.389
0.202
5d
5c
-0.375
0.220
5e
Figure 8: Mulliken atomic charge distribution of 5a-e
3
.4.2 Molecular Electrostatic Potentiel (MEP)
The electrostatic potential shows static distributions of charge on a molecule. In order to study
the site of 5a-e available for electrophilic and nuclephilic attack, the MEP is plot of
electrostatic potential mapped onto the constant electron density surface. Molecular

electrostatic potential of 5a-e using B3LYP/6-311G (d, p) optimized geometry is computed,
contour and surface map is shown in Fig. 9b. The negative electrostatic potential is indicated
by red regions, the blue region indicates the positive electrostatic potential, the yellow region
reveals the slightly rich electron and the green region shows neutral potential.
5
5
a
b
5
5
5
c
d
e
a
b
Figure 9: (a) the contour map of electrostatic potential and (b) the total electron density
mapped with electrostatic potential of 5a-e at an isosurface value of 0.020 a.u. and an
isodensity of 0.0004 a.u.

For isoxazole compounds, the total electron density surface mapped with electrostatic
potential indicates the presence of a high negative charge on N—O units of the isoxazole ring
which undergoes electrophilic reactivity. While the positive region of the MEP map over the
methoxy hydrogen atoms and all other hydrogen atoms indicates that these sites are
susceptible sites for nucleophilic attack. In addition, the region near to Cl in 5c compound is
positive due to the fact that C1 atom is surrounded by the electropositive hydrogen atoms
(H15 = 0.119e and H17 = 0.122e). MEP for 5d compound showed the presence of localized
most electronegative potential region (in red color) near the oxygen atoms of the nitro (NO2)
group in the para position of the phenyl ring. The MEP results are supported by the
electrostatic potential contour map showing the lines isosurface in where the red lines refer to
the strong electron-withdrawing atoms such as in N—O units of the isoxazole ring in all
compounds and in NO group for 5d. Analyses of the MEP surface of these compounds
2
represent the availability of electrons for possible interaction with another group of atoms.
3
.5 Hirshfeld surface analysis
The nature of intermolecular interactions in the all compounds 5a-e has been computed by
CrystalExplorer17.5, using Hirshfeld surface analysis mapped over dnorm, shape-index and
two-dimensional fingerprint plots. The red spots highlight the interatomic contacts included in
C—H···O hydrogen bonding in all compounds (Fig. 10a).
Fig. 11a shows the two-dimensional fingerprint plot for the sum of the contacts contributing
to the Hirshfeld surface represented in normal mode. The percentage contributions of the
various interatomic contacts to the Hirshfeld surfaces are summarized in Table 5. The most
important interaction is H···H contributing 47.5-61.2% to the overall all compounds to
stabilize the crystal packing, which is reflected in Fig. 11b as widely scattered points of high
density due to the large hydrogen content of the molecules with the small split tips at d  d 
e
i
1
- 1.2 Å.The presence of C—H··· interactions in the all crystals is indicated by the pair of
characteristic wings in the fingerprint plot delineated into C···H/H···C (Figs. 10c and 11c).
The C···H/H···C interactions are represented by the spikes at the bottom right and left (d + d
e
i

2.65 – 2.85Å). The percentage of C···H/H···C increases from the compound 5d (12.7%) to
5
b (21.9%) is in agreement with the substituted group. The O···H/H···O contacts (8.6 (5a)-
4.4% (5d)) (Fig. 11d) between the oxygen atoms inside the surface and the hydrogen atoms
2
outside the surface and vice versa, d + d  2.35 – 2.50Å are shown two symmetrical points
e
i
on the top, bottom left and right, which are characteristic of C—H···O hydrogen bond. Also

worth mentioning is the contribution of C···C contacts ranging from 1.0 to 5.2% in all
structures. They are shown on the fingerprint plots as areas on the diagonal at d = d ≈ 1.7–
e
i
2
.2 Å (Fig. 11f). These contacts correspond to the presence of the above mentioned π···π
stacking interactions in the crystal structures 5a, 5c and 5d. — interaction is indicated by
adjacent red and blue triangles in the shape-index map (Fig. 10b).
In 5c, the structure is further characterized by a significant proportion of H···Cl contacts,
comprising about 9.6 % of the molecular surface. The shortest H···Cl contacts are shown on
the fingerprint plots as a pair of spikes at d + d ≈ 3.0 Å (Fig. 11g).
e
i
Table 5: Percentage contributions of interatomic contacts to the Hirshfeld surface for
compounds 5a-e
Contact type 5a
5b
5c
5d
5e
H···H
59.6
61.2
21.9
9.5
50.2
16.6
9.9
9.6
4.4
3.4
1.4
1.4
1.4
0.1
0.8
-----
-----
0.7
47.5
12.7
24.4
-----
4.1
59.1
20.6
12.4
-----
5.8
C···H/H···C 21.5
O···H/H···O 8.6
Cl···H/H···Cl -----
N···H/H···N 5.3
-----
5.1
C···C
2.1
1.0
5.2
1.3
C···N/N···C
-----
-----
0.6
2.0
-----
0.7
C···O/O···C 1.6
C···Cl/Cl···C -----
2.0
-----
-----
-----
-----
0.6
-----
1.0
-----
-----
-----
-----
-----
-----
O···O
Cl···Cl
N···N
1.1
-----
-----
-----
0.4
N···O/O···N 0.3
O···Cl/Cl···O -----
0.7
-----
-----

5a
5b
5c
5d
5e
(a)
(b)
(c)
Figure 10: View of the three-dimensional Hirshfeld surface of 5a-e plotted over (a) dnorm, (b)
shape-index and (c) shape-indexed showing CH⋯ interactions through black dashed lines
5
a
5b
5c
5d
5e

(
(
(
(
(
(
(
a)
b)
c)
d)
e)
f)
All contacts
All contacts
All contacts
All contacts
All contacts
H⋯H 61.2
H⋯H 59.6
H⋯H 50.2
H⋯H 47.5
H⋯H 59.1
C⋯H/H⋯C 21.9
C⋯H/H⋯C 16.6
C⋯H/H⋯C 21.5
C⋯H/H⋯C 12.4
C⋯H/H⋯C 20.6
O⋯H/H⋯O 8.6
O⋯H/H⋯O 9.5
N⋯H/H⋯N 5.1
C⋯C 1.0
O⋯H/H⋯O 9.9
N⋯H/H⋯N 4.4
C⋯C 3.4
O⋯H/H⋯O 24.4
O⋯H/H⋯O12.4
N⋯H/H⋯N 5.3
N⋯H/H⋯N 4.1
N⋯H/H⋯N 5.8
C⋯C 2.1
C⋯C 1.3
C⋯C 5.2
g)
Cl⋯H/H⋯Cl 9.6
Figure 11: Two-dimensional fingerprint plots and relative contributions of various interactions to
the Hirshfeld surface of the compounds 5a-e corresponding to (a) All interactions, (b) H⋯H, (c)
C⋯H/H⋯C, (d) H···O/O···H (e), N⋯H/H⋯N, (f) C⋯C and Cl⋯H/H⋯Cl (5c)

Conclusion:
We have synthesized new p-methoxythymol derivatives 5a-e by simple and convenient
1
13
methodology and characterized them by IR, H, C NMR and X-ray single crystal diffraction.
Overall, we believe that the novel series of substituted isoxazole should be considered as an
important advance in medicinal and pharmaceutical chemistry. X-ray crystallographic studies
for 5a-e display intermolecular C—H···O hydrogen bonding and C—H···π interactions,
forming layers in the crystal lattice. The results of HS analysis indicate that the major
interactions were found for H···H interaction with contributions of 61.2, 59.6, 59.1, 50.2 and
4
7.5% of the total HS area in 5b, 5a, 5e, 5c and 5d products, respectively. Frontier molecular
orbital analysis and molecular electrostatic potential map of five isoxazole derivatives has
been studied using DFT calculations. The Molecular electrostatic potential analysis gives the
information about intermolecular interaction regions. The results indicate that compound 5d,
with smaller LUMO/HOMO gap, more reactive than other compounds. As a result, it is
expected that this research will be beneficial for the design, synthesis and various applications
of new isoxazole-based compounds.
Supplementary material
These data include NMR spectra for all new compounds 5a-e. CCDC 2022526, CCDC
2022527, CCDC 2022528, CCDC 2022529, CCDC 2022534 for 5a, 5b, 5c, 5d and 5e,
respectively contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam. ac.uk, or by contacting the Cambridge Crystallographic Data Centre,
1
2 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Credit authorship contribution statement
Yassine Laamari : Performing manipulations
Aziz Auhmani : Conceptualization, Supervision, Writing - review & editing

Mohamed Saadi : Methodology, Software.
Lahcen El Ammari : Methodology, Software, Investigation
Mostafa Khouili: Sample Tracking
My Youssef Ait Itto: Conceptualization, Supervision
Abdelwahed Auhmani: Product and material order tracking
El Mostafa Ketatni: Software, Validation, Writing - review
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors are greatly thankful to the University Cadi Ayyad for its support and Faculty of
Science, Mohammed V University in Rabat for the X-ray measurements.
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