Synthesis, structural studies and biological activities of three new 2-(pentadecylthio)-5-aryl-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.molstruc.2016.09.057

1,3,4-Oxadiazoles are important class of heterocyclic compounds, with diverse biological applications. In this study, the synthesis of three different 1,3,4-oxadiazoles bearing pentadecyl moiety is reported. All compounds were synthesized with significant (70–82%) yields, characterized by using different spectroanalytical techniques such as UV–vis., FT-IR, NMR (¹H and ¹³C), and finally structures were confirmed unequivocally by single crystal X-ray diffraction analysis. Quantum chemical studies by using GAUSSIAN software at DFT/B3LYP/6-31G (d, p) level of theory have been exercised to compare and validate the spectroscopic and X-ray results. Frontier molecular orbitals (FMOs) analysis of all compounds was performed by utilizing optimized geometries and gave the idea about kinetic stability and reactivity. Molecular electrostatic potential (MEP) analysis indicated the regions for electrophilic as well as nucleophilic attack. Compounds were also screened to check their antibacterial and antifungal potential.

Full text of DOI:10.1016/j.molstruc.2016.09.057

Accepted Manuscript
Synthesis, structural studies and biological activities of three new 2-
(pentadecylthio)-5-aryl-1,3,4-oxadiazoles
Muhammad Naeem Ahmed, Khawaja Ansar Yasin, Shahid Hameed, Khurshid Ayub,
Ihsan-ul –Haq, M. Nawaz Tahir, Tariq Mahmood
PII:
S0022-2860(16)30995-4
10.1016/j.molstruc.2016.09.057
MOLSTR 22969
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 1 July 2016
Revised Date: 9 September 2016
Accepted Date: 20 September 2016
Please cite this article as: M.N. Ahmed, K.A. Yasin, S. Hameed, K. Ayub, I.-u. –Haq, M.N. Tahir, T.
Mahmood, Synthesis, structural studies and biological activities of three new 2-(pentadecylthio)-5-
aryl-1,3,4-oxadiazoles, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.09.057.
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ACCEPTED MANUSCRIPT
Graphical Abstract
IR/NMR/CHNS/UV
Crystallography
Bioactivities
DFT studies

ACCEPTED MANUSCRIPT
Synthesis, structural studies and biological activities of three new 2-
(pentadecylthio)-5-aryl-1,3,4-oxadiazoles
a*
a
b
Muhammad Naeem Ahmed , Khawaja Ansar Yasin , Shahid Hameed , Khurshid
c
d
e
c*
Ayub , Ihsan-ul –Haq , M. Nawaz Tahir , Tariq Mahmood
a
Department of Chemistry, The University of Azad Jammu and Kashmir Muzaffarabad, 13100
Pakistan.
b
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
c
Department of Chemistry, COMSATS Institute of Information Technology, University Road,
Tobe Camp, 22060, Abbottabad, Pakistan.
d
Department of Pharmacy,Faculty of Biological Sciences, Quaid-i-Azam University,
Islamabad 45320, Pakistan.
e
Department of Physics, University of Sargodha, Sargodha, Pakistan.
*
To whom correspondence should be addressed: E-mail: mahmood@ciit.net.pk (T. M) and
aromatics790@gmail.com (M. N. A).
1

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Abstract
1
,3,4-Oxadiazoles are important class of heterocyclic compounds, with diverse biological
applications. In this study, the synthesis of three different 1,3,4-oxadiazoles bearing pentadecyl
moiety has been reported. All compounds were synthesized with significant (70-82 %) yields,
1
characterized by using different spectroanalytical techniques such as UV-vis., FT-IR, NMR ( H
1
3
and C), and finally structures were confirmed unequivocally by single crystal X-ray diffraction
analysis. Quantum chemical studies by using GAUSSIAN software at DFT/B3LYP/6-31G (d, p)
level of theory have been exercised to compare and validate the spectroscopic and X-ray results.
Frontier molecular orbitals (FMOs) analysis of all compounds was performed by utilizing
optimized geometries and gave the idea about kinetic stability and reactivity. Molecular
electrostatic potential (MEP) analysis indicated the regions for electrophilic as well as nucleophilic
attack. Compounds were also screened to check their antibacterial and antifungal potential.
Keywords: a) 1,3,4-Oxadiazole, b) Crystal Structure, c) DFT, d) Antibacterial, e) Antifungal
2

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1
. INTRODUCTION
The history of heterocyclic chemistry started in early 1800s and flourished rapidly with the aid of
organic synthesis tools. Heterocyclic compounds comprise the largest division of organic
chemistry, which show broad range of pharmacological applications. About two third of organic
compounds are heterocyclic in nature [1].
Oxadiazoles constitute an indispensable class of heterocyclic family to exhibit diverse
pharmaceutical as well as biological applications [2]. The synthesis and biological evaluation of
diverse oxadiazole derivatives have been demonstrated extensively in last two decades. The very
famous marketed antihypertensive agents (tiodazosin [3], nesapidil [4]) and antibiotics (furamizole
[
5]) have oxadiazole scaffold as major structural unit. 1,3,4-Oxadiazoles are abundantly utilized as
pharmacophores due to their tremendous metabolic profile, and ability to interact with targets
through non-covalent interactions. In mid 1960s, 2-amino-1,3,4-oxadiazoles was reported by Yale
and co-workers as muscle relaxant as well as antimitotic agents [6]. Recently, a large number of
1
,3,4-oxadiazoles have been synthesized, and examined as antibacterial [7], anti-inflammatory [8],
antimicrobial [9], anticancer [10], antidiabetic [11], fungicidal [12], herbicidal [13], analgesic
14], anticonvulsant [15], anti-HIV [16], antihypertensive [17], and antiobesity [18]. Apart from
the biological applications of 1,3,4-oxadiazoles, these are also used as useful oxidation inhibitors
19], important structural motifs in cyanine dyes [20], metal chelating agents and corrosion
[
[
inhibitors [21].
Quantum chemical methods by using density functional theory (DFT) are important aspect of
quantum chemistry, which deal with molecules on electronic level. Now a days, DFT based
methods are extensively used not only for structural investigations but also for validations of
spectroanalytical results[22–25]. Electronic and optical properties like frontier molecular orbital
3

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analysis, molecular electrostatic potential through different quantum chemical methods help to
understand the structure activity relationship of compounds [26,27]. Wide applications of 1,3,4-
oxadiazoles as important structural motifs in medicinal chemistry have gained attraction across the
globe. In continuation of our previous research regarding structure property relationship of
heterocyclic compounds [28,29], the present work describes the synthesis of of 1,3,4-oxadiazoles
bearing 15 carbon long chain. The syntheses of these compounds were targeted in order to
understand how changing the position of methyl and methoxy groups on aromatic ring influences
the biological activities of these compounds. All compounds are synthesized with impressive
yields, characterized by using different spectroanalytical techniques and finally structures were
confirmed unambiguously by single crystal X-ray diffraction analysis. The DFT calculations were
validated through comparison with data from single crystal X-ray diffraction. The electronic and
optical properties like frontier molecular orbital (FMOs) analysis, molecular electrostatic potential
(MEP) and first hyperpolarizability were also calculated by using DFT methods. All three 1,3,4-
oxadiazol derivatives compounds were also tested for antileishmanial, antibacterial and antifungal
activities and exhibited promising results.
2
. Materials and Methods
2
.1 Experimental
Different carboxylic acids and long chain alkyl halides were purchased from Sigma-Aldrich and
Fluka, used further without purification. Hydrazine hydrate and carbon disulfide were purchased
from Merck. n-Hexane, ethyl acetate, acetone, ethanol and methanol were distilled before use. The
°
reactions were performed in 100 mL 2-neck round bottom flask with a teflon stirring bar at 40 C
4

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and monitored by silica gel coated on aluminium TLC plates. Final products were purified by
flash column chromatography by eluting with suitable solvents. Melting points were monitored on
a Yanaco melting point apparatus and are reported as uncorrected. IR spectra were recorded on a
1
13
Nicolet FT-IR 5DX spectrometer under neat conditions. H and C-NMR spectra were recorded
on a 400 MHz, JEOL-ECA in deutrated chloroform with tetra methyl silane (TMS) as an internal
standard, and J values are reported in Hz. Elemental analysis was carried out by using GmbH -
vario EL III Element Analyzer.
2
.2 Synthesis
1
,3,4-oxadiazole derivatives 1, 2 and 3 were synthesized according to synthetic scheme given in
Fig. 1. Esters and carboxylic acid hydrazides were synthesized according to protocol already
reported in the literature [1,30].
2
.2.1 General Procedure for the synthesis of 1,3,4-oxadiazole derivatives (1-3)
The synthesis of final products was accomplished trough following literature [31] protocol with
slight modification.
Alkyl bromide (2.5 mmol) was added to a suspension of 5-aryl-1,3,4-oxadiazole-2-thiol (1.5
mmol), potassium carbonate (2 mmol) and acetone (20 mL) in round bottom flask. The resultant
°
mixture was stirred at 40 C for 4 h. After completion, the reaction mixture was diluted with water,
extracted with DCM and finally washed with brine. Purification of products was carried out using
flash column chromatography.
2
.2.1.1 5-(2-Methoxyphenyl)-2-(pentadecylthio)-1,3,4-oxadiazole (1)
5

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°
-1
White crystalline solid, m. p. 49-50 C, yield = 75 %, FT-IR (ATR, cm ): ν 2916, 1553, 1511,
max
1
1
2
1
2
7
471, 1431, 1249, 1123, 1035, 999, 763; H-NMR δ ppm 7.88-7.02 (m, 2H), 3.97 (s, 3H), 3.27 (t,
13
H, J = 6 Hz), 1.88-1.78 (m, 2H), 1.48-1.19 (m, 24H), 0.87 (t, 3H, J = 8Hz); C-NMR δ ppm
64.2, 164.1, 157.6, 132.8, 130.1, 120.6, 112.8, 111.8, 55.8, 32.5, 31.8, 29.6, 29.5, 29.4, 29.3,
9.0, 28.5, 22.6, 14.0. CHNS calculated for C H N O S (418.64): C, 68.86; H, 9.15; N, 6.69; S,
2
4
38
2
2
.66. Observed: C, 68.81; H, 9.13; N, 6.65; S, 7.59.
2
.2.1.2 5-(3-Methoxyphenyl)-2-(pentadecylthio)-1,3,4-oxadiazole (2)
°
-1
White solid, m.p. 61-62 C, yield = 77 %, FT-IR (ATR, cm ): ν 2818, 1618, 1560, 1492, 1473,
max
1
1
431, 1294, 1225, 1196, 1049, 717 ; H-NMR δ ppm 7.59-7.06 (m, 2H), 3.87 (s, 3H), 3.30 (t, 2H,
13
J = 6 Hz), 1.86-181(m, 2H), 1.47-1.25 ( m, 24H); C-NMR δ ppm 164.5, 164.2, 160.1, 130.1,
27.2, 113.3, 55.5, 36.5, 31.5, 30.1, 29.5, 29.3, 28.9, 28.5, 22.5, 14.0. CHNS calculated for
C H N O S (418.64): C, 68.86; H, 9.15; N, 6.69; S, 7.66. Observed: C, 68.79; H, 9.11; N, 6.64;
1
24
38
2
2
S, 7.60.
2
.2.1.3 2-(Pentadecylthio)-5-(p-tolyl)-1,3,4-oxadiazole (3)
°
-1
White crystalline solid, m.p. 71-73 C, yield = 82 %, IR (ATR, cm ): ν 2920, 1612, 1553,1475,
max
1
1
525, 1180, 1056, 831; H-NMR δ ppm 7.90-7.87 (m, 2H), 7.30-7.26 (m, 2H), 3.27 (t, 2H, J = 10
13
Hz), 2.41 (s, 3H), 1.85-1.78 (m, 2H), 1.48-1.25 (m, 24H), 0.87 (t, 3H, J = 8 Hz); C-NMR δ ppm
1
65.7, 164.1, 142.0, 129.6, 126.5, 120.9, 32.6, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 28.6, 22.6,
6

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2
1.5, 14.1. CHNS calculated for C H N OS (402.64): C, 71.59; H, 9.51; N, 6.96; S, 7.96.
2
4
38
2
Observed: C, 71.55; H, 9.50; N, 6.90; S, 7.92.
2
.3 Crystallography
Suitable crystals of oxadiazole (1-3) having proper size and shape were picked and analyzed by
single crystal X-ray diffraction analysis. Single crystal of each compound was coated with
paratone oil and mounted on a glass fiber. All the measurements were performed on Bruker Kappa
Apex-IICCD diffractometer having graphite monochromator and by using M -K radiation source.
o
α
The structures were solved by direct method and refined by using SHELXL 2013 [32] and figures
were plotted with the aid of ORTEP II [33].
The CIF files of compounds (1-3) have been assigned CCDC numbers 985700, 1473181 and
9
94383 respectively, can be obtained free of charge on application to CCDC 12 Union Road,
Cambridge CB21 EZ, UK. (Fax: (+44) 1223 336-033: data_request@ccdc.cam.ac.uk).
2
.4 Computational details
DFT investigations were performed at B3LYP/6-31G(d,p) level of theory by using Gaussian 09
suit of programs [34]. Optimized geometries visualized through Gauss View 5.0 [35]. Frequency
calculations were performed at the similar level of DFT, to confirm the optimized geometries as
true minima (no imaginary frequency was observed). Furthermore, frequency output files were
1
used for simulated vibrational analysis. Nuclear magnetic resonance ( H-NMR) chemical shifts
were computed by adopting GIAO formalism at B3LYP/6-311+G (2d, p) level of DFT and
7

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chemical shift values are referred with reference to internal standard i. e. tetramethylsilane.
Absorption spectra (UV-vis.) were simulated at TD-DFT/B3LYP/6-31G (d,p) level of theory in
gas phase and in solvent phase through (CPCM model). Total twenty states (10 singlet and 10
triplet) were calculated to measure the theoretical UV-vis. spectra. Molecular electrostatic
potential (MEP) and frontier molecular orbital (FMOs) were computed at B3LYP/6-31G (d, p)
level of DFT.
2
.5 Antibacterial assay
In vitro antibacterial potential of all compounds was evaluated by agar disc diffusion method
reported by Fatima et. al., [36]. Turbidity of 24 h bacterial cultures [(gram positive: Micrococcus
luteus ATCC-10240) and gram negative (Salmonella typhimurium ATCC-14028, Bordetella
bronchiseptica ATCC # 4617)] was adjusted by comparing with McFarland 0.5 BaSO standard.
4
A lawn of refreshed culture was made on nutrient agar plates. Sterile filter paper discs
impregnated with 5 ꢀL (10 mg/mL DMSO, 50 ꢀg/disc) of each sample were placed on the seeded
plates. Disc infused with Cefixime (20 ꢀg/disc) served as positive control while DMSO infused
disc was used as negative control. Plates were incubated at 37 °C for 24 h, after which the average
diameter of the zone of inhibition around the sample as well as control treated discs was measured
and recorded. Samples producing an inhibition zone ≥ 10 mm in diameter were considered active.
The assay was performed in triplicate.
2
.6 Antifungal assay
8

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The antifungal potential of oxadiazoles (1-3) was evaluated in triplicate by adopting agar disc
diffusion method [37]. The spores of given fungal strains [Mucor species (FCBP-0300),
Aspergillus niger (FCBP-0198) and Aspergillus flavus (FCBP-0064)] were harvested in 0.02%
tween 20 solution and their turbidity was adjusted according to McFarland 0.5 turbidity standard.
Then, 100 ꢀL of each strain was swabbed on sterile petri plates containing Sabouraud Dextrose
agar. Sterile filter paper discs impregnated with 5 ꢀL (10 mg/mL DMSO, 50 ꢀg/disc) each of
sample were placed on the seeded plates. DMSO and standard drug clotrimazole (20 ꢀg/disc) was
used as negative and positive controls, respectively. After incubation at 28 °C for 24–48 h, the
average diameter (mm) of the zone of growth inhibition around the samples as well as control
treated discs was measured. Samples producing an inhibition zone ≥ 10 mm in diameter were
considered as active.
3
. Results and discussion
All three 1,3,4-oxadiazole derivatives (1-3) have been synthesised starting from commercially
available starting materials in four steps (detailed procedures and spectroscopic data has been
given in the experimental section). After accomplishing the successful synthesis of products in
good yields, the structures were solved through different spectroanalytical tehniques such as UV-
1
13
vis., FT-IR, NMR ( H and C), and finally the structures of all compounds (1, 2 and 3) were
confirmed unequivocally by single crystal X-ray diffraction studies.
9

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3
.1 X-ray Diffraction analysis
Oxadiazole derivatives 1, 2 and 3 were crystallized as white solids. Suitable crystals were picked
and analyzed by X-ray diffraction analysis to ensure the final structures and to study their three
dimensional structural patterns. The complete X-ray and structural parameters of all compounds
are narrated in Table 1. All three molecules were crystalized with the triclinic crystal system
having P -1 space group. The molecular weights are observed 418.62 grams/mol, 418.62
grams/mol and 402.62 grams/mol for 1, 2 and 3 respectively. The Z number for all compounds is
observed same i. e. 2. The unit cell volume of all compounds (1, 2 and 3) is also same i.e.
3
3
3
1
2.7.5(2) Å , 1203.05 Å and 1200.7(3) Å . The lesser unit cell volume of compound 3 indicates
the absence of oxygen atom in it as compare to 1 and 2. Different R factors indicate how correctly
structures data sets were collected and refined to get the final structures (Table 1).
3
.2 Geometry optimization
X-ray structural parameters are reference for theoretical calculations. Any reliable theoretical
method should reproduce the experimental structure parameters with fair accuracy. Nowadays
DFT methods are powerful tools to validate the geometric parameters obtained through X-ray
diffraction studies [37]. The starting geometries were extracted from X-ray diffraction data and
optimized to energy minima by using B3LYP method of DFT with the 6-31G (d,p) basis set. The
optimized structures of 1,3,4-oxadiazoles (1, 2 and 3) are shown in Fig. 2 (overlaid with ORTEP
1
0

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plot). Table 2 and 3 contain comparative illustration of important X-ray and computed geometric
parameters (bond length and bond angles) of all three compounds. Some differences among the
experimental and simulated values are because of the experimental data collected for the sample in
the condense phase and theoretical calculations are always performed for a single molecule in gas
phase.
The calculated values of some important bond lengths such as S1-C9, S1-C10, O1-C2, O1-C1,
O2-C9, O2-C8, N1-C8, N1-N2 and N2-C9 in 1 are at 1.75, 1.84, 1.36, 1.42, 1.36, 1.37, 1.30, 1.39
and 1.29 Å respectively. The corresponding experimental bond lengths are at 1.72, 1.81, 1.35,
1
.42, 1.35, 1.36, 1.28, 1.40 and 1.28 Å, respectively, and corroborate nicely with the theoretical
values. For compound 2, the prominent bond distances showed a very tight correlation between
theory and experiment. The maximum deviation is observed in the range of 0-0.05 Å. In 2 the
theoretical values like C3-O1, C7-O1, C8-N1, C8-O2, C9-N2, C9-O2, C9-S1, C10-S1 and N1-N2
(atomic labels are accordance Fig. 2) observed at 1.36, 1.41, 1.29, 1.37, 1.29, 1.36, 1.74, 1.84 and
1
1
.39 Å, respectively, whereas their experimental counterparts appeared at 1.36, 1.42, 1.28, 1.35,
.27, 1.37, 1.71, 1.79 and 1.41 Å, respectively. Similarly, the computed and experimental bond
distances in 3 showed excellent correlation to each other. The deviation observed in the range 0.0-
.04 Å, and maximum difference observed for S1-C10 bond length is 0.04 Å (for detailed values
0
see Table 2).
From the data narrated in the Table 3, it is evident that bond angles of all these molecules seemed
to match well between theory and experiment. For compound 1, the deviation of important bond
o
angles is found in the range 0.22-1.74 . Theoretical values of bond angles C9-S1-C10, C2-O1-C1,
C9-O2-C8, C8-N1-N2, C9-N2-N1, O1-C2-C3, O1-C2-C7, N1-C8-O2, N1-C8-C7, O2-C8-C7, N2-
o
o
o
o
o
C9-O2, N2-C9-S1, O2-C9-S1 and C11-C10-S1 are 100.83 , 118.70 , 102.49 , 107.81 , 105.91 ,
1
1

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o
o
o
o
o
o
o
o
o
1
23.24 , 117.27 , 111.51 , 126.31 , 122.21 , 112.81 , 126.86 , 120.17 and 114.72 , respectively.
o
o
o
o
o
Their respective experimental values appeared at 102.57 , 118.36 , 102.71 , 106.85 , 105.62 ,
o
o
o
o
o
o
o
o
o
1
24.24 , 116.23 , 111.75 , 126.92 , 121.24 , 113.06 , 125.83 , 121.09 and 115.41 respectively.
Similarly, for 2 and 3, the X-ray and computed bond angles showed tight correlation to each other.
o
The deviation for 2 (between theory & exp.) found in the range 0.04-3.06 and maximum
difference is observed for C11-C10-S1, which is due to the flexibility of hydrocarbon side chain.
o
Similarly, for 3 the deviation in bond angles is observed in the range 0.07-1.36 and maximum
difference (almost negligible) is predicted for C11-C10-S1, again which is due to the flexibility of
hydrocarbon side chain (for detailed values see Table 3).
3
.3 Vibrational analysis
Vibrational spectroscopy is very fundamental and useful tool to assign different functional groups
38]. Quantum chemical methods have been widely used to assign the modes of vibrations
[
especially in the finger print region of IR spectrum [39]. Experimental and simulated FT-IR
spectra of oxadiazole derivatives (1, 2 and 3) are shown in Fig. 3 and Fig. S1 (supplementary
information). Prominent experimental and simulated frequencies are narrated in Table 4.
The simulated vibrations generally appear at higher value as compared to the experimental ones,
and it is due to harmonic approximation. To minimize the theoretical error, scaling factor (0.9627)
was used, which is common for 6-31G(d, p) basis set [40]. The values depicted in the Table 4
clearly indicated that a strong correlation exists among computational and experimental data.
1
2

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3
.3.1 CH and CH vibrations
2 3
All three compounds have straight chain alkyl group attached at the same position of oxadiazole
moiety. Therefore similar trend of symmetric/asymmetric stretching vibrations of CH and CH
3
2
was observed in simulated as well as experimental spectra. Prominent simulated CH and CH
3
2
-1
-1
-1
-
(
symmetric/asymmetric) vibrations of 1appeared at 2989 cm , 2962 cm , 2923 cm and 2914 cm
1
-1
,
whereas their experimental counterpart appeared at 2916 cm . In compound 2, simulated values
-
1
-1
-1
-1
of CH and CH vibrations appeared at 2989 cm , 2969 cm , 2962 cm , 2915 cm and showed
2
3
-1
nice correlation with experimental value which appeared at 2818 cm . Again, simulated and
experimental CH and CH stretching vibrations in 3, corroborate nicely to each other (Table 4).
3
2
3
.3.2 Aromatic ring vibrations
In vibrational spectrum aromatic ring vibrations (both C=C and CH) appear strongly, therefore can
be identified and correlated easily. Simulated values of aromatic C=C stretching
-1
-1
(
symmetric/asymmetric) vibrations for 1 are observed at 1595 cm and 1577 cm , for 2 are
-1
-1
-1
-1
observed at 1607 cm and 1577 cm , and for 3 are observed at 1609 cm and 1489 cm
-1
respectively. The experimental counter parts of these vibrations appeared at 1553 cm (1), 1618
-1
-1
-1
-1
cm and 1650 cm (2), 1612 cm and 1475 cm (3) respectively. Apart from stretching
vibrations, several in and out of plane aromatic CH bending vibrations are observed in all three
compounds. The prominent in and out of plane aromatic CH vibration of compound 1 are found at
-1
-1
-1
1
111 cm , 1040 cm and 746 cm in simulated spectrum, whereas experimentally these
-1
-1
-1
vibrations are depicted at 1123 cm , 1035 cm and 763 cm respectively. In compound 2,
1
3

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-1
-1
theoretical in and out of plane bending CH (aromatic) vibrations appeared at 1479 cm , 1224 cm
-1
-1
-1
and 1048 cm , whereas experimentally these values are found at 1492 cm , 1225 cm and 1049
-1
cm , respectively. The similar trend was observed for aromatic CH bending vibrations (in and out
of plane) in compound 3 and showed excellent correlation to each other.
3
.3.3 Oxadiazole ring vibrations
Oxadiazole ring is mainly composed of N-N, C=N and C-O functional groups. Experimental and
-1
-1
computed value of C=N stretching vibration in 1 appeared at 1519 cm and 1511 cm ,
respectively, and corroborate nicely to each other. Similarly in 2 and 3, C=N stretching vibration
-1
-1
are observed at 1545 cm and 1541 cm in simulated spectrum, showed excellent correlation
-1
with experimental value appeared at 1553 cm .
1
3
.4 Nuclear magnetic resonance (NMR) studies ( H)
Nuclear magnetic resonance spectroscopy is a powerful tool in structure elucidation since last two
or three decades. In these days, the quantum mechanical methods are playing active role to predict
1
and validate the experimental NMR chemical shifts. Experimental H-NMR chemical shifts of all
compounds 1, 2 and 3 were recorded in CDCl , and spectra are provided in electronic
3
supplementary information Fig. S2-S4 (supplementary information). Theoretical NMR chemical
shifts were computed with the aid of GIAO method at DFT/B3LYP/6-311+G (2d, p) level of
theory (Higher basis set works efficiently for accurate measurements of chemical shift values
1
[
41]). Theoretical and experimental H-NMR chemical shift values of all compounds are given in
1
Table 5. In experimental H-NMR spectrum of 1, the chemical shift values of aromatic protons are
1
4

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found in the range 7.88-7.02 ppm. Whereas the computed aromatic protons chemical shifts
appeared in the range 9.00-7.12 ppm. The methoxy protons attached to the aromatic ring depicted
at 3.97 ppm in experimental spectrum of 1. The simulated value of same protons in compound 1
observed at 3.99 ppm and showed an excellent correlation with the experimental value. The
experimental chemical shift values of SCH and alkyl chain CH groups in 1, are found 3.27 ppm
2
2
and 1.88-1.19 ppm respectively. The simulated chemical shifts of these protons showed excellent
correlation, and appeared at 3.11 ppm and 1.74-1.14 ppm, respectively. The terminal CH protons
3
in 1 found at 0.87 ppm and 0.95, experimentally as well as theoretically. In compound 2, on the
difference in structure is position of OCH group, rest of structure is same. The Experimental and
3
theoretical chemical shift values in compound 2 showed excellent correlation to each other (Table
5
). Similarly, in 3, methyl group is attached to the para position of phenyl ring, the experimental
chemical shift CH protons found at 0.87 ppm, corroborate nicely with theoretical value which
3
observed at 1.00 ppm.
3
.5 Frontier molecular orbitals (FMOs) analysis
The frontier molecular orbitals (FMOs) analysis is significant approach to explain the
optoelectronic properties and chemical reactivity of compounds [42]. The HOMO/LUMO
surfaces of compounds 1–3 are shown in Fig. 4 and corresponding energies along with energy
gap are listed in the Table 6. The highest and lowest HOMO-LUMO gaps are observed for
compound 2 (4.96 eV) and for 1 (4.60 eV) respectively. The isodensity in the HOMO of 1
showed a maximum spread over entire oxadiazole, benzene, methoxy group and carbons of alkyl
side chain (Fig. 4). This maximum dispersion of isodensity is indicative of higher conjugation in
1
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1
. Whereas in compound 2 and 3 dispersion of isodensity is observed only on oxadiazole,
benzene ring and groups attached to the benzene moiety. In case of LUMOs, in all compounds
the dispersion of isodensity showed almost similar trend.
3
.6 UV-Vis. spectral analysis
The absorption spectroscopy is been widely used to understand the electronic transitions as well
as optical properties of compounds [43]. The experimental UV–Vis. absorption spectra of all
compounds (1–3) were recorded within 200–600 nm range in ethanol and the combined spectra
(experimental/theoretical) along with respective λmax. values are given in Fig. 5.
The experimental UV-vis. spectrum of compound 1 revealed two absorption maxima, one at 268
nm, and second at 304 nm, which are due to π-π* transition. The computed values at 297 nm in
the gas phase and 274 nm, 303 nm in ethanol corroborate nicely with the experimental data. The
experimental UV-vis. λmax. of 2 appeared at 272 nm, and showed excellent correlation with
computed values at 274 nm, 287 nm (gas phase) and 278 nm, 294 nm (ethanol). Similarly the
computed and experimental absorption maxima’s of 3 showed very excellent correlation to each
other. The density of state (DOS) spectra of TD-DFT calculations are calculated with the
GaussSum program and are given in Fig. 6. The energy gap to promote electrons from π to π* is
observed 4.52 eV, 4.45eV and 4.32 eV for 1, 2 and 3 respectively, and is in total agreement with
the HOMO/LUMO band gap of all compounds (Table 6).
3
.7 Molecular electrostatic potential (MEP) mapping
1
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Molecular electrostatic potential mapping through quantum chemical methods is a prominent tool
to describe the structure and activity relationship, and electrophilic or nucleophilic sites within the
molecules [44]. The presence of non-covalent interactions within the molecules can be explained
with the help of ESP analysis [45].
The electrostatic potentials values are ranged from -0.06397 a.u. to 0.06397 a.u for 1, -0.0576 a.u
to 0.0576 a.u for 2 and -0.05550 a.u to 0.05550 a.u for 3 respectively. The molecular surface map
clearly indicated that the negative region in all compounds is localized over the nitrogen atoms of
oxadiazole ring, whereas the rest of rest of molecules have green shade.
3
.8 Antibacterial activity
All three oxadiazoles (1-3) were tested against both gram negative and gram positive bacterial
strains. Compounds 1 and 2 showed maximum zones of inhibition against S. typhi and B.
bronchiseptica respectively (Table 7). These results are supported by another report in which few
pyrazolyl 1,3,4-oxadiazole derivatives were moderately active against gram negative K.
pneumonia (14-21 mm zone of inhibition) [9]. Compound 1 showed maximum activity against
M. luteus (Table 7) in accordance with previous findings in which bis-1,3,4-oxadiazoles
derivatives were moderately active against gram positive S. aureus and B. subtilis.
3
.9 Antifungal activity
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Synthesized compounds were also tested against different fungal strains to determine antifungal
potential. Compound 3 was found to be active against A. flavus and Mucor Sp., whereas
compound 1 gave maximum zone of inhibition against italicize A. (Table 7). It is supported from
the literature that 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles showed mild to
significant activities against F. solani, C. lunata, A. niger ranging from 7-29 mm zones of
inhibition [9]. Clotrimazole is the imidazole derivative that possess potent antifungal activity.
Since, both compounds have similar azole moiety, thus their effects against fungal strains are also
comparable [46].
4
. Conclusions
In this study, three new 1,3,4-oxadiazole derivatives with long chain hydrocarbon, have been
successfully synthesized in good yields. Final structures were characterized by using different
1
13
spectroanalytical techniques such as FT-IR, UV-vis., H, C-NMR. Finally, the structures were
confirmed unequivocally by single crystal X-ray diffraction studies. All compounds crystalized in
mono clinic crystal system having space group P-1. DFT investigations performed at B3LYP/6-
3
1G(d,p) level of theory revealed that simulated and experimental results corroborate to each other
strongly. FMOs analysis revealed that 2 has highest HOMO-LUMO gap and is equal to 4.96 eV
whereas 1 has lowest band gap (4.60 eV). The molecular electrostatic potential investigations
showed that all three compounds are nucleophilic in nature and electronegative region is localized
over the nitrogen atoms of oxadiazole ring. All three compounds were also tested against different
antibacterial and antifungal stains. The findings suggest possible implications of oxadiazoles
derivatives (1-3) as prospective antimicrobial and antifugal agents.
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Acknowledgements
The authors are highly thankful to Higher Education Commission Pakistan (HEC) for financial
support (Grant no. 20-3013/NRPU/R&D/HEC/14/525). The authors acknowledge COMSATS
Institute of Information Technology Abbottabad for financial support as well.
Supplementary material
Cartesian co-ordinates of optimized geometries and cif files of oxatriazoles 1, 2 and 3 are provided
1
in supporting information. Theoretical FT-IR and experimental H-NMR are also pasted in
supporting information as Fig. S1-S4. Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/
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Captions
Table 1: X-ray and structural parameters of all compounds (1-3).
Table 2: Comparison of some important X-ray and simulated bond lengths (Å) of all compounds
1
, 2 and 3, (Atomic labels are with reference to Fig. 2).
Table 3: Comparison of some important X-ray and simulated bond angles ( ) of all compounds (1,
and 3, (Atomic labels are with reference to Fig. 2).
Table 4: Prominent experimental and simulated vibrational (cm ) frequencies of 1, 2 and 3.
o
2
-1
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Table 5: Comparison of experimental and simulated H-NMR of 1, 2 and 3 (ppm).
Table 6: HOMO and LUMO energies along with energy gaps of compounds 1, 2 and 3.
Table 7: Antibacterial and antifungal activity results of compounds 1, 2 and 3.
Figure 1: Synthetic scheme for the synthesis of 1,3,4-oxadiazole (1-3).
Figure 2: Combined optimized geometries (pink) and ORTEP (yellow) plots of compound 1, 2
and 3.
Figure 3: Experimental FT-IR spectra of compounds 1, 2 and 3.
Figure 4: HOMO and LUMO surfaces of compounds 1, 2 and 3.
Figure 5: Combined experimental and theoretical UV-vis. spectra of compounds 1 (balck), 2 (red)
and 3 (blue) along with respective λmax. values.
Figure 6: The DOS diagrams of TD-DFT calculations of compounds 1-3
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