Experimental and computational spectroscopic studies of 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/j.molstruc.2020.127820

Some 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles (DHOZs) were synthesized, and steric and electronic effects of the substituents on the heterocyclic ring C3- and C5-positions were investigated using the NMR and UV–Vis spectroscopies, and (TD)DFT/6-311

Full text of DOI:10.1016/j.molstruc.2020.127820

Journal Pre-proof
Experimental and computational spectroscopic studies of 3,5-disubstituted 4,5-
dihydro-1,2,4-oxadiazoles
Mehrnoosh Asgari, Hamid R. Memarian, Hassan Sabzyan
PII:
S0022-2860(20)30144-7
DOI:
https://doi.org/10.1016/j.molstruc.2020.127820
MOLSTR 127820
Reference:
To appear in: Journal of Molecular Structure
Received Date: 25 November 2019
Revised Date: 28 January 2020
Accepted Date: 29 January 2020
Please cite this article as: M. Asgari, H.R. Memarian, H. Sabzyan, Experimental and computational
spectroscopic studies of 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles, Journal of Molecular Structure
(2020), doi: https://doi.org/10.1016/j.molstruc.2020.127820.
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1
Experimental and computational spectroscopic studies of
,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles
3
Mehrnoosh Asgari, Hamid R. Memarian* and Hassan Sabzyan*
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, IR, Iran
Author Contributions
-----------------------------------------
1
. HamidReza Memarian defined the concept and procedures of the project, leaded the
research group and guided the discussions, involved in the interpretation of the experimental
and computational results, structure and development of the report and revision and
finalization of the manuscript.
2
. Mehrnoosh Asgari involved in the definition and development of the project, carried out
all experiments and computations, organized the results and involved in the discussions,
prepared and developed the report, prepared the initial draft of the manuscript and its
development and finalization.
3
. Hassan Sabzyan contributed to the definition of the computational procedure,
interpretation and validation of the spectroscopic and computational results, comparative
analysis of the experimental and computational results, and involved in the discussions and in
the development, revision and finalization of the manuscript.

Graphical abstract
Experimental and computational spectroscopic studies of 3,5-disubstituted 4,5-dihydro-1,2,4-
oxadiazoles, Mehrnoosh Asgari, Hamid R. Memarian, Hassan Sabzyan

1
Experimental and computational spectroscopic studies of
,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles
3
Mehrnoosh Asgari, Hamid R. Memarian* and Hassan Sabzyan*
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, IR, Iran
ABSTRACT
Some 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles (DHOZs) were synthesized, and steric
and electronic effects of the substituents on the heterocyclic ring C3- and C5-positions were
investigated using the NMR and UV-Vis spectroscopies, and (TD)DFT/6-311++G(d,p)
computations. The NMR and UV-Vis spectroscopic characteristics of the synthesized
compounds could be explained in terms of the π‐ and σ‐electronic effects of the C3- and C5-
aryl substitutions on the heterocyclic ring, respectively. Computational NMR chemical shifts
and spin-spin coupling constants of the C5‒H and N4‒H protons display a Karplus
correlation with corresponding H‒C5‒N4‒H dihedral angle. The experimental and
1
computational H NMR chemical shifts of the C5‒H proton show very good compatibility.
Conformational analysis on the o-nitro and o-methoxyphenyl C5-substituted DHOZs showed
intramolecular interactions affecting their structural and spectroscopic features.
Keywords: Dihydrooxadiazoles, Substituent effects, Spectroscopic studies, (TD)DFT/6-
3
11++G(d,p), Conformational analysis.

2
1
. Introduction
The 4,5-dihydro-1,2,4-oxadiazoles (DHOZs) and their oxidized forms 1,2,4-oxadiazoles
are an important class of heterocyclic compounds due to their pharmaceutical applications
Scheme 1). It has been known that the type and nature of substituents have different effects
(
on their pharmaceutical activities [1-4]. 5-Propyl-3-(m-toluyl)-4,5-dihydro-1,2,4-oxadiazole,
with the structure presented in Scheme 1, has shown much better antimicrobial activity
compared to the DHOZs having a p-methoxyphenyl group at the 3-position of the
heterocyclic ring [5]. The 3-(2-furanyl) substituted 1,2,4-oxadiazoles have shown optimal
treatment of diabetes [6]. So far a limited number of computational [7, 8] and experimental
[
8-10] works are devoted to the study of the effects of substituents on the structure, orbital
energies, and spectroscopic behavior of these compounds. Preparative electrochemical
oxidation of various 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles carried out under
constant current condition, has shown no clear substituent effect on the yield of the
corresponding oxadiazole products [11]. Various synthetic methods have been introduced and
applied for the preparation of dihydrooxadiazoles using glacial acetic acid, amberlite IRP-64
and piperidine as catalysts [10, 12, 13].
˂
Scheme 1 ˃
Our research interest concerns investigation of the steric and electronic effects of the
substituents attached to various heterocyclic compounds on their rate of thermal [14, 15],
microwave and photochemical oxidation [16-18], spectroscopic characteristics and
electrochemical behavior [19-22]. Recently, we have reported the results of experimental and
1
computational investigations of these effects on the UV-Vis and H NMR spectra of 3- or 5-
aryl substituted 1-phenyl-2-pyrazolines [23]. In continuation to these studies, in the present
work, we have been interested in the synthesis of various 3,5-disubstituted 4,5-dihydro-1,2,4-
oxadiazoles in order to study the effects of different electron-donor and electron-acceptor

3
substitutions at the 3- or 5-positions of the heterocyclic ring on their spectroscopic properties.
In addition to the experimental study, DFT computations are carried out to support the
obtained experimental results.
2
. Experimental and computational methods
2
.1. Chemicals and instruments
Chemicals used for the synthesis of oxadiazoles in this research were purchased from
Across, Sigma and Merck companies. Among a variety of synthetic methods examined, the
title compounds were synthesized by adoption of a reported procedure [10], in which
amidoximes are cyclo-condensed with various aldehydes in the presence of an acid catalyst.
This procedure consists of two steps; first, the arylamidoximes of our interest were prepared
by the reaction of the corresponding arylnitriles with hydroxylamine in ethanol solution, and
then, the isolated compounds were reacted under mild conditions with various aldehydes to
yield 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles. Interestingly, the first attempt towards
the synthesis of the title compounds via cyclo-condensation of the aromatic aldehydes and
amidoximes was reported to be unsuccessful, except for o-hydroxybenzaldehyde which
yields the expected product only with benzamidoxime after several weeks of standing [24].
To a solution of arylamidoxime (1 eq) in 5 ml of glacial acetic acid, 1.2 eq of the aldehyde
derivative was added. For maximum conversion, the mixture was stirred at room temperature
for appropriate periods of time (given in Table 1) to obtain the desired 3,5-disubstituted 4,5-
dihydro-1,2,4-oxadiazoles (Scheme 2). The reaction mixture was poured into cold water and
the precipitate was recrystallized from n-hexane/ethyl acetate (or otherwise mentioned)
purified by column chromatography using silica gel 60 (0.063-0.200 mm) and n-hexane/ethyl
acetate (20:1) as eluent.

4
The synthesized compounds were characterized by measuring their uncorrected melting
points using open glass capillary on a Stuart Scientific SMP2 apparatus. Infrared spectra were
1
13
obtained on a Jasco FT/IR-6300 spectrometer using KBr disc. The H and C NMR spectra
were recorded on Bruker Avance III 400 spectrometer at room temperature, using CDC1 or
3
1
DMSO-d6 as solvent. The H NMR spectral data, including chemical shifts, [multiplicity,
number of protons, coupling constants J (Hz), and assignments] are reported in the Appendix.
The UV spectra (in chloroform) were recorded on a Cary 500 Scan (Varian) spectrometer.
2
.2. Computational method
Geometry optimization of the 4,5-dihydro-1,2,4-oxadiazoles were carried out using
density functional theory (DFT) B3LYP method with 6-311++G(d,p) basis set, in the
1
conductor-like polarizable continuum model (CPCM) of chloroform solvent. The H NMR
spectra of these optimized structures were calculated using the gauge-invariant atomic
orbitals (GIAO) method. G09 program was used for all computations [25]. The UV-Vis
spectra of dihydrooxadiazoles (in the CPCM model of chloroform as solvent) were calculated
using time-dependent density functional theory (TD-DFT) TD-B3LYP/ 6-311++G(d,p)
computations considering 10 excited states.
3
. Results and discussion
The reaction times and yields at the maximum progression obtained for the synthesis of
dihydrooxadiazoles (Scheme 2) are reported in Table 1. These experimental results indicate
that aliphatic aldehydes are more reactive in the cyclo-condensation reaction than aromatic
aldehydes. Electron-withdrawing substituents in the aromatic aldehydes accelerate the
condensation reaction compared to the electron-donating substituents. The results indicate
also that 4-nitrophenylamidoxime reacts better than 4-methoxyphenylamidoxime in the
condensation reaction. Attempts to synthesize more dihydrooxadiazoles by condensation of

5
4
-methoxyphenylamidoxime with some other aldehydes (Table S1 of the Supporting
Information) were unsuccessful.
˂
Scheme 2 ˃
Table 1 ˃
˂
1
13
The IR, H NMR, C NMR and UV-Vis spectroscopic data gave useful information for
the structural assignment of the 4,5-dihydro-1,2,4-oxadiazoles products:
ꢀ
The IR spectra show the N4‒H and C3=N2 stretching bands of the heterocyclic ring
-1
-1
around 3200 cm and 1600 cm , respectively.
1
ꢀ
In the H NMR spectra, besides the characteristic signals of the protons of the
heterocyclic ring substitutions, the resonance signals of the N4‒H and C5‒H protons appear
mostly as broad singlet and doublet, respectively. Due to the attachment of the C5-atom to
the electronegative O1- and N4-atoms, the C5‒H proton is more deshielded and its signal
appears at lower fields compared to that of the N4‒H proton. Such assignment is supported
by H/D exchange due to treatment of the NMR sample with D O for compound 4, as
2
representative (Fig. 1).
1
3
3
ꢀ
In the C NMR spectra, the attachment of the sp hybridized C5-atom to the
electronegative O1- and N4-atoms in the heterocyclic ring results in the appearance of the
1
3
13
corresponding C NMR signal around 90 ppm. Also, the C signal of the C3=N2 double
bond of the heterocyclic ring appears around 160 ppm.
˂
Figure 1 ˃
The electronic nature of the substitutions attached to the C3- and C5-atoms of the
heterocyclic ring affects the spectroscopic characteristics, especially NMR signals of the N4‒
H and C5‒H protons, of the 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles (introduced in
Table 1). The electronic effects of the substituted aryl group on the electron density of the
heterocyclic ring can be induced either through the C5‒Caryl σ-bond or through the π

6
conjugation of the C3-aryl group with the C3=N2 double bond. Therefore, the substituted
3
aryl ring attached to the sp hybridized C5-atom of the heterocyclic ring is considered as a σ-
donor or σ-acceptor group, and the substituted aryl ring at the C3-position of the heterocyclic
2
ring is considered as a π-donor or π-acceptor group due to the attachment to the sp
hybridized C3-atom of the C3=N2 double bond. Possible co-planarity of the substituted C3-
aryl ring with the C3=N2 double bond of the heterocyclic ring, and also the co-planarity of
the additional substituent with the C3-aryl ring are important factors determining the extent
of the π-electron donor/acceptor ability of the C3-aryl ring. On the other hand, the steric
hindrance, electronic nature and the position of the additional substituent on the C5-aryl ring
can influence its σ-donor/acceptor ability. The methoxy group (CH O‒) on each position of
3
the C5-aryl ring (as in 5, 6 and 7) behaves as electron withdrawing inductive group due to its
electronegative oxygen atom. While, possible co-planar orientation of this group, especially
at the ortho- and para-positions, with the C5-aryl ring (5 and 7) allow delocalization of its
oxygen lone pair towards the Caryl ring directly attached to the C5-position of the heterocyclic
ring. As a balance of negative inductive (‒I) and positive resonance (+M) effects of the
methoxy group, assigned as σ-donor group, increases the electron density of the heterocyclic
ring through the σ-bond (C5‒C ). In contrast to the σ-donating methoxy substituent, the
aryl
nitro group (NO ), possessing electron-withdrawing character, at each position of the C5-aryl
2
ring induces a σ-acceptor character (‒I) to this aryl ring. In case of bonding of this group
specifically to the ortho- and para-positions (2 and 4) of the C5-aryl ring, this group is
oriented co-planar and allows delocalization of the aromatic π electrons towards the NO2
group, which causes a decrease of the electron density on the C -atom linked to the C5-
aryl
atom of the heterocyclic ring. Consequently, the electron density of the heterocyclic ring can
be decreased due to both negative inductive (‒I) and negative resonance (‒M) effects of the
NO group via the C5‒C σ-bond.
2
aryl

7
3
.1. NMR studies
Reaction of the arylamidoxime with the aldehyde molecule results in the occurrence of a
stereocenter on the C5-atom of 4,5-dihydro-1,2,4-oxadiazoles (1-28). The proton attached to
this stereocenter (i.e. C5‒H) and its vicinal proton N4‒H is influenced by the type of the C5-
aryl/alkyl substitutions, and to a lesser extent by the type of the C3-aryl substitution (Table
1
). Specifically, the position of the additional substitution on the C5-aryl ring affects the
chemical environment of these protons. The chemical shifts and the corresponding coupling
constants of these protons along with those of the CH O protons, where present, are
measured for this series of dihydrooxadiazoles (1-28) and listed in Table 2.
Table 2 ˃
‒
3
˂
1
In order to investigate the substitution effects on the experimental H NMR chemical
shifts of the 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles (DHOZs), computations at
B3LYP/6-311++G(d,p) level of theory are also carried out to calculate the GIAO NMR
chemical shifts and J-coupling constants which are reported in Table 3. For this purpose,
compound 3,5-diphenyl-4,5-dihydro-1,2,4-oxadiazole (1) serves as the reference or the parent
compound.
1
Comparative analysis of the experimental H NMR data presented in Table 2 indicates
that in the C3-phenyl substituted DHOZs, the presence of the nitro group at the 2-, 3- and 4-
(i.e. ortho-, meta- and para-) positions of the C5-aryl ring (in 2, 3 and 4), increases the
chemical shift of the C5‒H proton compared to that in the parent molecule 1 due to the σ-
acceptor nature of nitro-substituted C5-aryl ring. This increase for the 2-NO group (in 2),
2
from 6.55 ppm (in 1) to 7.15 ppm (in 2), is more significant due to the remarkable
intramolecular electrostatic interaction between one of the oxygen atoms of this group and
the C5‒H hydrogen atom, with a distance of 2.3755 Å (based on the computational optimized
structure, discussed later). For the same reason (the N4‒H˙˙˙˙˙˙O‒N=O hydrogen-bond with a

8
distance of 2.4143 Å), the chemical shift of the N4‒H proton in 2 also increases to 5.58 ppm
(from 4.92 ppm in 1). These simultaneous intramolecular electrostatic interactions of the NO2
oxygen atom with both C5‒H and N4‒H hydrogen atoms is explained by the imposed 26.5º
deviation of the 2-NO group from co-planarity with the C5-aryl ring, shown in Fig. 2 (left)
2
in the DFT optimized structure, as compared to the co-planar orientation of the 3-NO and 4-
2
NO groups in 3 and 4.
2
˂
Figure 2 ˃
1
A comparison of the experimental H NMR chemical shift of the C5‒H proton in the C5-
methoxyphenyl substituted derivatives (5, 6 and 7) with those of the reference compound 1
shows the weak σ-electron donating character of this substituted C5-aryl ring. DFT optimized
geometry of compound 5, having ortho-methoxyphenyl substitution at the C5-position of the
heterocyclic ring, illustrated in Fig. 2 (right), indicates almost co-planar orientation of the 2-
methoxy group with the C5-aryl ring, with a dihedral angle of 2.3°. This geometry would
explain the electron-donating resonance effect of the oxygen atom of the methoxy group by
delocalization of its lone pairs towards the C5-aryl ring, and consequently, an up-field shift of
both C5‒H and N4‒H protons should be expected. Surprisingly, in contrast to this suggestion,
1
the significant down-field shifts of the H NMR signals of the C5‒H and N4‒H protons from
6
.55 and 4.92 ppm (in 1) to 6.86 and 5.07 ppm (in 5) are observed. These can be attributed to
the simultaneous intramolecular electrostatic interactions of the oxygen atom of the ortho-
OCH group with the hydrogen atoms of the polarized C5‒H and N4‒H bonds, respectively
3
with the distances of 2.6984 and 2.4798 Å.
Separating the phenyl group at the C5-position of the parent compound 1 by one and two
CH moieties in the series of C3-phenyl substituted DHOZs (as C H CH ‒ in 8 and
2
6
5
2
C H CH CH ‒ in 9), decreases the electron-withdrawing effect of this phenyl ring.
6
5
2
2
Consequently, the up-field shift of the C5‒H proton is observed. Using the C=C double bond

9
for this separation (as styryl, C H CH=CH‒, in 10) partially allows back the conjugative
6
5
electron-pulling effect of the phenyl ring, and therefore, a down-field shift of this proton
compared to that in 9 having a C H CH CH ‒ substitution) is observed. In addition,
(
6
5
2
2
introducing a 1-methylstyryl group (C H CH=C(CH )‒ in compound 11, instead of
6
5
3
unsubstituted styryl group in 10) decreases the electron-pulling effect of the phenyl ring due
to non-planar orientation of the phenyl ring with respect to the C=C double bond, caused by
the steric hindrance of the methyl group in its (unavoidable) cis-position. These electron-
pulling effects are illustrated in Scheme 3.
˂
Scheme 3 ˃
The most up-field shift of the C5‒H proton is observed for compound 12 due to electron
donating inductive effect of its isopropyl group at the C5-position of the heterocyclic ring.
The electronic effect of the C5-substitution on the chemical shift of the N4‒H proton in
compounds 11 and 12 is observed differently for which we could not find any justification.
1
Analysis of the experimental H NMR data (Table 2) in the C3-(4-nitrophenyl and 4-
methoxyphenyl) substituted DHOZs (13-24 and 25-28) indicates that the π-
accepting/donating substituents at the C3-position along with the σ-accepting/donating
properties of the C5-substitutions can influence the electron population of the heterocyclic
ring depending on the electronic behavior of the C3-aryl substitutions. Therefore, variations
of the chemical shifts of the two characteristic protons of the heterocyclic ring in this series of
DHOZs appear differently. The 4-nitro substituted C3-aryl ring (in compounds 13-24), acting
as a π-acceptor substitution, causes a down-field shift of the C5‒H proton NMR resonance
compared to their corresponding derivatives with the C3-phenyl ring (1-12). It worth noting
that the electronic effects of the 4-NO (para-nitro) substituted C3-aryl ring on the extent of
2
the variation of the chemical shift of the N4‒H proton in compounds 15, 16, 18, 23 and 24 is
different from that expected by comparison with those of the corresponding compounds 3, 4,

10
6
, 11 and 12, for which no clear explanation could be found. The nitro group at the 2-, 3- and
-positions of the C5-aryl ring in C3-para-nitrophenyl substituted derivatives (14, 15 and 16,
4
respectively) acts cooperatively with this substitution to decrease the electron density over the
heterocyclic ring and subsequently to increase the chemical shifts of the C5‒H and N4‒H
protons compared to those in 1. An analysis of the NMR data reported in Table 2 for these
compounds (14, 15 and 16, all having 4-nitrophenyl substitution at the C3-position) shows
that the most down-field resonances of the C5‒H and N4‒H protons (7.24 and 5.65 ppm,
respectively) belong to compound 14, having 2-nitrophenyl substitution at the C5-position.
This is due to the simultaneous electrostatic interactions of the oxygen atom of the nitro
group with both C5‒H and N4‒H protons as discussed before. Among the DHOZs having 2-,
3
- and 4-methoxyphenyl substituted at the C5-position (17, 18 and 19, respectively), the
highest chemical shift of the C5‒H and N4‒H protons belong to compound 17. This is, again,
due to the simultaneous electrostatic interactions of the oxygen atom of the methoxy group
1
with both C5‒H and N4‒H protons. A comparative analysis of the H NMR data presented in
Table 2 indicates that evidently the trends observed for the variations of chemical shifts of the
considered protons of the two sets of DHOZs, i.e. the C5-alkyl substituted DHOZs among the
C3-phenyl substituted DHOZs as in 8, 9, 10 and the 3-(4-nitrophenyl) substituted DHOZs as
in 20, 21, 22, are correspondingly similar, and also the electronic effect of the C5-substitution
on the chemical shift of the N4‒H proton in compounds 23 and 24 is observed differently.
1
The H NMR data of compounds 25, 26 and 27 with the 4-methoxyphenyl substitution at
the C3-position, having respectively the nitro group at the 2-, 3- and 4-positions of the C5-
aryl ring, shows that compound 25 has the most down-field C5‒H and N4‒H protons
(respectively with 7.14 ppm and 5.69 ppm) due to the intramolecular electrostatic interaction
of its 2-NO group with these protons, which is already discussed above.
2

11
Effects of the electron-donating and electron-withdrawing substitutions at the C3- and C5-
positions can be competitive in which the electron-acceptor substitutions can affect the
chemical shifts of the considered hydrogen atoms much stronger than the electron-donor
substitutions at either C3- or C5-positions. In other words, despite the π-electronic properties
of the para-methoxy substituted C3-aryl ring, the C5‒H proton of compound 27 experiences
slightly larger down field shift (6.65 ppm) than that in compound 19 (6.60 ppm) with the π-
acceptor group at the C3-position of the heterocyclic ring (Scheme 4). As an experimental
evidence of these substitution effects, one can mention the red shift of the UV absorption
13
maximum wavelength of compound 19 compared to compound 27. The experimental C
NMR chemical shifts of the C5-atom (Table S2) show no clear and general correlation with
the steric and electronic effects of the substituents, or with the computed atomic charges and
hybridization of the C5-atom bonds. According to the computational results, formally
3
expected sp hybridized C5-atom varies depending on the electronic nature of the attached
O1-, N4-, Calkyl/aryl- and H5-atoms. These results indicate that contribution of the C5-atom in
4
the bond with the electronegative O1- and N4-atoms is around sp (that means, the bonding
3
electrons are more polarized towards the oxygen atom) and sp , respectively, which result in
the polarization of the C5‒O1 and C5‒N4 bonding electrons due to electron-pulling natures
of these atoms. Therefore, the lack of correlation, mentioned above, denotes multiple and
complex effects of the substituents on the electronic environment of this carbon atom.
However, for selected groups of compounds, some trends are detectable which are reported in
the description of Table S2 of the Supporting Information.
˂
Scheme 4 ˃
1
As can be seen in Table 2, while the H NMR chemical shifts of the characteristic protons
of this series of compounds are affected by the steric, structure and electronic natures of the
C3- or C5-aryl rings due to the type and positions of their additional substituents, variations

12
in the J-coupling constant values are relatively small, in the range of 2.7-5.0 Hz. To interpret
these experimental observations, density functional theory (DFT) B3LYP method with 6-
3
11++(d,p) basis set is used to optimize structures and calculate characteristics of these
1
dihydrooxadiazoles. Results of these calculations including dihedral angles and H NMR
chemical shifts and J-coupling constants are summarized in Table 3.
2
Comparative analysis shows very good agreement (with R = 0.9563) between these
1
computational H NMR chemical shifts of the C5‒H proton and their corresponding
1
experimental values (Fig. 3). The larger deviations of the calculated H NMR chemical shifts
for the N4–H proton from the perfect compatibility (the ideal δcomp = δexp line) can be
attributed to the stronger hydrogen bonding and electrostatic interactions of the N4–H proton
with the chemical (solvation) environment, not considered in the computations with the
CPCM model solvent. These hydrogen bonding and electrostatic interactions usually shift
downfield the N4–H proton signal, as is evident from Fig. 3.
˂
Figure 3 ˃
The calculated J-coupling constants for the vicinal protons of the H‒N4‒C5‒H moiety in
this series of DHOZs show a Karplus-type correlation with the optimized values of the
2
dihedral angle H‒N4‒C5‒H obeying the correlation function J = 5 Cos [a (θ+θₒ)] with a =
2
.2 and θₒ = 32, as shown in Fig. 4. The difference between this correlation function and the
common Karplus correlation function, i.e. J = A Cos [a θ], is due to the complexity of the
contributions of the lone pairs of the heterocyclic ring oxygen and nitrogen atoms to the
through-bond interactions of the two hydrogen atoms. On the other hand, contributions of the
intramolecular electrostatic interactions of the oxygen atoms of the 2-nitro group on the C5-
aryl ring with both C5‒H and N4‒H protons adds to this complexity.
˂
Figure 4 ˃
Table 3 ˃
˂

13
The dihedral angle H–N4–C5–H defining configuration of the N4–H and C5–H vicinal
protons and thus determining their NMR J-coupling constant is influenced by the type and
position of the nitro and methoxy substituents and also by the orientation of the C5-aryl ring
towards the heterocyclic ring in this series of dihydrooxadiazoles. When the nitro and
methoxy substitutions are located at the 2-position (i.e. ortho position) of this C5-aryl ring, as
in 2 and 5 derivatives respectively, their orientations become more important.
Conformational analysis on the orientation of the C5-aryl ring denoted as N4‒C5‒C12‒C17
dihedral angle (ϕ) is investigated for compounds 2 and 5, each starting from two different
initial (optimized) orientations in which the substitutions at the 2-position of the C5-aryl ring
are oriented towards either the O1- or N4-atoms, labeled by open circles in Figs. 5 and 6. In
the 2-nitro (2-methoxy) substituted compound 2 (5), these two starting conformations
correspond to the trans (cis) or cis (trans) configurations for the pair of the N4–H and C5–H
vicinal protons. Results of these conformational analysis, presented in Figs. 5 and 6, show
that the conformations in which the 2-nitro or 2-methoxy groups are oriented towards the N4-
atom (2g and 5c) are more stable than those orientated towards the O1-atom (i.e. the 2b and
5
b). This can be attributed to the stronger steric hindrance between the 2-substitution with the
lone pair electrons of the O1-atom, and partially the intramolecular electrostatic interaction
shown by dotted lines in Fig. 7) between the oxygen atom(s) of these 2-substitutions and the
(
N4–H and C5–H protons. In the most stable conformers of these compounds labeled as 2g
and 5c, the H–N4–C5–H vicinal protons adopt nearly cis and trans configurations,
respectively. It should be noted here that, interestingly, for both compounds 2 and 5, the two
potential energy diagrams obtained by starting from different initial geometries (i.e.
substitution is oriented towards the O1- and N4-atoms) are not identical, showing different
electronic and nuclear structures at each point of the dihedral angle θ. This difference arises
from the fact that in these compounds, there exist two more conformational degrees of

14
freedom, corresponding to the inter-ring (C3-aryl and heterocyclic rings) orientation and the
relative orientation of the 2-nitro or 2-methoxy group with respect to the plane of the C5-aryl
ring. Effects of these degrees of freedom, which are calculated and analyzed in detail in Fig.
S1 of the Supporting Information, are more pronounced for the 2-nitro substitution at some
ranges of the dihedral angle (compare Figs. 5 and 6). The same conformation analysis,
described above, is carried out for compound 2, but starting from opposite configurations of
the H–N4–C5–H dihedral (i.e. cis for 2b and trans for 2g) and the results are presented in
Fig. 5 by dotted curves. It can be seen in Fig. 5 that the cis ↔ trans switching of this
compound has no significant effect on its potential energy profiles.
˂
˂
˂
Figure 5 ˃
Figure 6 ˃
Figure 7 ˃
Temperature-dependent dynamic NMR experiment (Fig. 8), carried out on compound 4, at
different temperatures (295, 304 and 313 K), showed no detectable tautomerism
(prototropism) in this compound, which has been previously observed experimentally and
expected theoretically in the heterocyclic ring compounds containing the H‒N4‒C3=N2
moiety [26]. The more shielded N4‒H proton observed at high temperatures can be attributed
to the weak solute-solvent and solute-solute interactions.
˂
Figure 8 ˃
By considering the tautomeric equilibrium between both imine-C and imine-O tautomer, it
has been found computationally that compared to the imine-O tautomer, the imine-C
tautomer would be 20.5 kJ/mol unstable, due to the increased repulsion between the lone
pairs on the N2- and the neighboring O1-atoms (Fig. 9).
˂
Figure 9 ˃
3
.2. UV-Vis study

15
The UV-Vis absorption spectra obtained for the C3- and/or C5-aryl substituted
dihydrooxadiazoles 1-28 in chloroform solution explain the electronic nature (i.e. σ/π-
electron donating/accepting abilities) of the substitutions on their energy spacing of the
ground (HOMOs) and excited (LUMOs) states. The UV-Vis spectra obtained for these
dihydrooxadiazoles are reported in the Supporting Information. Characteristics of these
spectra are extracted and collected in Table 4. Analysis of these data shows that, in these
compounds, co-planar configurations of the substituted C3-aryl ring and the C3=N2 double
bond of the heterocyclic ring allows more effective π-conjugation in the molecular system,
thus, resulting in bathochromic shift of their UV-Vis absorption by decreasing the HOMOs-
LUMOs gaps. A selected set of UV-Vis spectra are presented in Fig. 10 which are discussed
below.
˂
Table 4 ˃
Analysis of the UV-Vis spectra of the C5-nitrophenyl substituted dihydrooxadiazoles 2-4
indicates hypsochromic shift with respect to that of the parent compound 1(Fig. 10a), which
can be attributed to the σ-accepting effect of the nitrophenyl substitution. Co-planar
orientation of the 4-NO group with the C5-aryl ring in compound 4 allows a more effective
2
resonance in these two groups (compared to those in other compounds 1-3), which is
displayed as the hyperchromic effect on its UV-Vis peaks. The same effect could also be
expected for compound 2, with 2-NO group substitution, if this nitro group would be co-
2
planar with the C5-aryl ring. The lack of such hyperchromic effect for compound 2 is, thus,
due to the non-co-planar orientation of the 2-NO group with the C5-aryl ring resulted from
2
its steric hindrance (see Fig. 7, and its discussion in the previous section).
The UV-Vis spectra of the C5-methoxyphenyl substituted oxadiazoles 5-7 show much
smaller hypsochromic shift (as compared to what observed for 2-4) with no hyperchromic
effect which is due to partial cancellation of the opposite π-electron-donating and σ-electron-

16
accepting effects of the methoxy group on the C5-aryl ring which results in a net weak σ-
donating effect of the C5-methoxyphenyl substitution (Fig. 10b).
˂
Figure 10 ˃
Interestingly, the UV-Vis spectrum of compound 13 containing electron-withdrawing
para-nitro group on the C3-aryl ring shows a strong bathochromic shift (referenced to that of
compound 1) opposite to what observed for compound 4 with C5-para-nitrophenyl
substitution (Fig. 10c). This bathochromic shift is attributed to the conjugative delocalization
of the lone pair electrons of the O1-atom towards the electron-acceptor nitro group (Scheme
5
).
˂
Scheme 5 ˃
Comparison of the UV-Vis spectra of the compound series 13, 16 and 19, all having C3-
para-nitrophenyl substitution, but respectively with C5-phenyl, C5-para-nitrophenyl, and
C5-para-methoxyphenyl substitutions, shows the small opposite effects of the latter two
(para-nitro and para-methoxy) substitutions on the HOMOs-LUMOs energy spacings of this
series of dihydrooxadiazole (Fig. 10d).
The experimental and TD-B3LYP/6-311++(d,p) computational UV spectra of 1, 4 and 13
are compared in Fig. 10c. It can be seen from this Figure that the experimental and
computational spectra have similar structures with comparable intensities, but different
numerical values for the maximum absorption wavelengths (energies). These differences can
be attributed generally to the solute-solvent interactions not considered in our computations
which are carried out in the presence of the CPCM model of the chloroform solvent (i.e.
without explicit solvent molecules), and the inherent inaccuracies arising from
approximations used in these TD-DFT computations. The computational results (absorption
wavelengths λmax, excitation energies, micro transitions and their probabilities, and the
frontier orbitals involved in these transitions) obtained for compounds 1, 4 and 13 are

17
summarized in Table 5 and shown pictorially in Fig. 11. As can be seen from this Figure, the
UV-Vis transitions observed experimentally in this series of compounds are of π → π*
character. Based on the computational results, it can be deduced that the absorption peak
appearing at λmax = 282 nm in the experimental UV-Vis spectrum of compound 1 has a major
(
90%) contribution from the HOMO → LUMO transition. The corresponding peak for
compound 4, appearing at λmax = 264 nm, is contributed mainly (85%) from the HOMO-
→ LUMO transition. The 18 nm hypsochromic shift from 1 to 4 is due to the presence of
4
the nitro-substitution on the C5-aryl ring in 4, which is observed also in the experimental
spectra and discussed above.
Comparative analysis of the λmax values obtained for compounds 1, 4 and 13 (reported in
Table 6) indicates good agreement between the experimental and computational results
obtained for compounds 1 and 4. While, for compound 13, the two sets of experimental and
computational λmax values are significantly different. This exceptional spectral behavior of
compound 13 can be explained considering more effective electrostatic interaction with
solvent due to its larger electric dipole moment (7.3374 D), compared to those of compounds
1
and 4 (5.2914 D and 6.5242 D, respectively), arising from electron-withdrawing nature of
its para-nitro substituent on the C3-aryl ring (Scheme 5).
Figure 11 ˃
˂
˂
Table 5 ˃
Table 6 ˃
˂
4
. Conclusion
A series of 4,5-dihyro-1,2,4-oxadiazole derivatives (DHOZs) are synthesized efficiently
starting from their corresponding aldehydes and arylamidoximes in order to elucidate the
electronic and steric effects of the electron-donating and electron-withdrawing substituents at
1
the C3- and C5-positions of the heterocyclic ring on the H-NMR and UV-Vis spectroscopic

18
characteristics. Results of (TD)DFT computations at the B3LYP/6-311++G(d,p) level of
theory are employed to reveal details of these effects. Comparative study shows good
1
agreement between the experimental H NMR chemical shifts (C5‒H) with the computational
1
GIAO H NMR chemical shifts. Furthermore, good agreement is observed between the
3
computational H‒N4‒C5‒H J proton coupling constants and the optimized H‒N4‒C5‒H
HH
dihedral angles in showing a Karplus-type correlation. The 4-nitro substituted C3-aryl ring
(13-24) has a dominant contribution to the spectral characteristics by increasing maximum
absorption wavelengths of these compounds. Interestingly, the nitro group at both ortho- and
para-positions of the C5-aryl ring (in compounds 2 and 4) is expected to act as σ-acceptor
substituent to induce a hypsochromic shift in their maximum absorption wavelengths. Co-
planar orientation of the para-nitro group with the C5-aryl ring in compound 4 causes a
hyperchromic effect in its UV-spectrum. While, the lack of such hyperchromic effect in
compound 2 can be attributed to the non-co-planar orientation of the ortho-nitro group with
the C5-aryl ring. Computational conformational analysis of the H–N4–C5–H dihedral angle
carried out for selected DHOZs in which the nitro and methoxy substitutions are located at
the ortho-position of the C5-aryl ring shows that these compounds are more stable when the
ortho-nitro and ortho-methoxy groups are oriented towards the N4-atom (than those
orientated towards the O1-atom) due to intramolecular electrostatic interaction of these
groups with the N4–H and C5–H hydrogen atoms in compounds 2 and 5, respectively.
Acknowledgement
We thankfully acknowledge the Research Council and Office of Graduate Studies of the
University of Isfahan for their financial support.
Appendix: The physical and spectroscopic data of the 4,5-dihydro-1,2,4-oxadiazoles studied
in this work.

19
3
,5-Diphenyl-4,5-dihydro-1,2,4-oxadiazole (1)
Column chromatography, n-hexane / ethyl acetate (20:1), m.p. 101-103 ºC. IR (KBr): ν =
-1 1
3
378, 3058, 1597, 1563, 1509, 1457, 1433, 1381, 1289, 1057, 897, 843, 759 cm . H NMR
(
400 MHz, CDCl ): δ = 4.92 (brd s, 1H, NH), 6.55 (d, J = 4.2 Hz, 1H, 5-CH), 7.41-7.50 (m,
3
1
3
6
H, aromatic H), 7.53-7.57 (m, 2H, aromatic H), 7.71-7.74 (m, 2H, aromatic H). C NMR
(
100 MHz, CDCl ): δ = 93.53 (C5), 125.34, 126.52, 126.63, 128.83, 129.76, 131.00, 139.12,
3
1
55.61 ppm (aromatic C). UV (CHCl ): λ (log ε) = 282 nm (3.84), 238 (3.93).
3 max
5
-(2-Nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (2)
M.p. 124-126 ºC. IR (KBr): ν = 3215, 3067, 1604, 1569, 1525, 1455, 1488, 1358, 1329,
-1 1
1
190, 1044, 899 cm . H NMR (400 MHz, CDCl ): δ =5.58 (brd s, 1H, NH), 7.15 (d, J = 3.4
3
Hz, 1H, 5-CH), 7.41-7.51 (m, 3H, aromatic H), 7.58 (td, J = 7.8, 1.3 Hz, 1H, aromatic H),
7
1
.69-7.71 (m, 2H, aromatic H), 7.77 (td, J = 7.7, 1.1 Hz, 1H, aromatic H), 8.11 (dd, J = 7.8,
1
3
.3 Hz, 1H, aromatic H), 8.17 (dd, J = 8.0, 1.1 Hz, 1H, aromatic H). C NMR (100 MHz,
CDCl ): δ = 89.25 (C5), 124.80, 125.04, 126.59, 128.45, 125.82, 129.81, 131.21, 134.70,
3
1
36.13, 146.89, 155.15 ppm (aromatic C). UV (CHCl ): λ
(log ε) = 264 nm (3.95), 239
3
max
(
3.90).
-(3-Nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (3)
M.p. 138-144 ºC. IR (KBr): ν = 3338, 3077, 2872, 1601, 1536, 1511, 1460, 1350, 1311,
5
-1 1
1
279, 1209, 1076, 841, 776, 695 cm . H NMR (400 MHz, CDCl ): δ = 5.51 (brd s, 1H, NH),
3
6
.67 (d, J = 3.3 Hz, 1H, 5-CH), 7.41-7.52 (m, 3H, aromatic H), 7.59 (t, J = 7.8 Hz, 1H,
aromatic H), 7.72 (d, J = 7.4 Hz, 2H, aromatic H), 7.90 (d, J = 7.4 Hz, 1H, aromatic H), 8.23
1
3
(
d, J = 7.8 Hz, 1H, aromatic H), 8.39 (s, 1H, aromatic H). C NMR (100 MHz, CDCl ): δ =
3
9
1
1.91 (C5), 121.71, 124.43, 124.70, 126.62, 128.93, 129.93, 131.36, 132.80, 141.56, 148.39,
55.81 ppm (aromatic C). UV (CHCl ): λ (log ε) = 261 nm (3.92), 236 (3.92).
3
max
5
-(4-Nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (4)

20
M.p. 182-184 ºC. IR (KBr): ν = 3195, 3067, 1601, 1567, 1516, 1467, 1348, 1317, 1290,
-1 1
1
202, 823, 763, 692 cm . H NMR (400 MHz, CDCl ): δ =5.19 (d, J = 3.8 Hz, 1H, NH), 6.68
3
(d, J = 4.4 Hz, 1H, 5-CH), 7.44-7.48 (m, 2H, aromatic H), 7.50-7.55 (m, 1H, aromatic H),
1
3
7
.73-7.77 (m, 4H, aromatic H), 8.28 (d, J = 8.8 Hz, 2H, aromatic H). C NMR (100 MHz,
CDCl ): δ = 91.76 (C5), 124.06, 124.72, 126.61, 127.60, 12897, 131.42, 145.98, 155.61 ppm
3
(
aromatic C). UV (CHCl ): λ (log ε) = 264 nm (4.21), 244 (sh, 4.03).
3 max
5
-(2-Methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (5)
M.p. 143-145 ºC. IR (KBr): ν = 3310, 3058, 2839, 1605, 1568, 1515, 1492, 1463, 1438,
-1 1
1
375, 1290, 1249, 1055, 1024, 850, 753 cm . H NMR (400 MHz, CDCl ): δ = 3.92 (s, 3H,
3
OCH ), 5.07 (brd s, 1H, NH), 6.86 (d, J = 2.7 Hz, 1H, 5-CH), 6.95 (d, J = 8.0 Hz, 1H,
3
aromatic H), 7.04 (td, J = 7.5, 0.5 Hz, 1H, aromatic H), 7.34-7.38 (m, 1H, aromatic H), 7.40-
7
.49 (m, 3H, aromatic H), 7.66 (d, J = 7.5 Hz, 1H, aromatic H), 7.70-7.73 (m, 2H, aromatic
1
3
H). C NMR (100 MHz, CDCl ): δ = 55.52 (OCH ), 88.99 (C5), 110.49, 120.92, 125.57,
3
3
1
26.43, 126.67, 127.64, 128.71, 130.18, 130.81, 155.58, 156.41 ppm (aromatic C). UV
(
CHCl ): λ (log ε) = 275 nm (3.71), 272 (sh, 3.70), 237 (3.76).
3
max
5
-(3-Methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (6)
Column chromatography, n-hexane / ethyl acetate (20:1), m.p. 83-85 ºC. IR (KBr): ν = 3373,
-1 1
3
059, 1609, 1587, 1487, 1455, 1432, 1379, 1283, 1248, 1154, 1047, 845, 787, 752 cm . H
NMR (400 MHz, CDCl ): δ = 3.84 (s, 3H, OCH ), 4.96 (d, J = 2.4 Hz, 1H, NH), 6.54 (d, J =
3
3
3
1
.8 Hz, 1H, 5-CH), 6.95-6.98 (m, 1H, aromatic H), 7.12-7.15 (m, 2H, aromatic H), 7.35 (m,
1
3
H, aromatic H), 7.42-7.52 (m, 3H, aromatic H), 7.73-7.76 (m, 2H, aromatic H). C NMR
(
100 MHz, CDCl ): δ = 55.38 (OCH ), 93.37 (C5), 111.65, 115.55, 118.83, 125.28, 126.52,
3 3
1
28.83, 129.94, 131.02, 140.67, 155.64, 160.01 ppm (aromatic C). UV (CHCl ): λ (log ε)
3 max
=
279 nm (3.78), 236 (3.88), 231 (sh, 3.85).
-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (7)
5

21
Column chromatography, n-hexane / ethyl acetate (20:1), m.p. 114-117 ºC. IR (KBr): ν =
-
3
229, 3054, 1608, 1565, 1512, 1460, 1433, 1370, 1304, 1249, 1173, 1030, 899, 816, 765 cm
1
1
.
H NMR (400 MHz, CDCl ): δ = 3.76 (s, 3H, OCH ), 4.72 (d, J = 2.4 Hz, 1H, NH), 6.46
3 3
(d, J = 3.8 Hz, 1H, 5-CH), 6.87 (d, J = 8.8 Hz, 2H, aromatic H), 7.34-7.40 (m, 3H, aromatic
1
3
H), 7.42 (d, J = 8.8 Hz, 2H, aromatic H), 7.65-7.68 (m, 2H, aromatic H). C NMR (100
MHz, CDCl ): δ = 55.39 (OCH ), 93.47 (C5), 114.17, 125.44, 126.46, 128.16, 128.83,
3
3
1
3
5
30.96, 131.13, 155.62, 160.79 ppm (aromatic C). UV (CHCl ): λ (log ε) = 288 nm (sh,
3 max
.63), 278 (3.45), 272 (3.74), 238 (4.05).
-Benzyl-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (8)
M.p. 144-147 ºC. IR (KBr): ν = 3251, 3058, 3025, 1596, 1565, 1511, 1468, 1411, 1384,
-
1 1
1
3
5
2
314, 1278, 1091, 1028, 856, 765, 695 cm . H NMR (400 MHz, CDCl ): ABX-system, δ =
3 A
.00 (JAB = 13.6 Hz, JAX = 6.8 Hz, 1H), δ = 3.19 (J = 13.6 Hz, JBX = 4.4 Hz, 1H), δ =
B
AB
x
.86-5.90 (m, 1H, 5-CH), 4.62 (brd s, 1H, NH), 7.26-7.29 (m, 3H, aromatic H), 7.33-7.38 (m,
1
3
H, aromatic H), 7.38-7.48 (m, 3H, aromatic H), 7.63-7.66 (m, 2H, aromatic H). C NMR
100 MHz, CDCl ): δ = 42.54 (C-benzyl), 93.42 (C5), 126.45, 127.07, 128.76, 128.81,
(
3
1
29.67, 130.93, 135.26, 155.63, 164.72 ppm (aromatic C). UV (CHCl ): λ (log ε) = 282
3 max
nm (3.77), 238 (3.88).
5
-Phenethyl-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (9)
M.p. 115-117 ºC. IR (KBr): ν = 3246, 3055, 3025, 2962, 2929, 2857, 1597, 1504, 1464,
-
1 1
1
2
4
433, 1402, 1302, 1101, 1028, 853, 759, 694 cm . H NMR (400 MHz, CDCl ): δ = 2.05-
3
.14 (m, 1H, CH), 2.16-2.25 (m, 1H, CH), 2.79-2.86 (m, 1H, CH ), 2.87-2.94 (m, 1H, CH ),
.49 (brd s, 1H, NH), 5.75 (dd, J = 9.5 Hz, J = 4.9 Hz, 1H, 5-CH), 7.22-7.26 (m, 3H,
aromatic H), 7.30-7.34 (m, 2H, aromatic H), 7.41-7.50 (m, 3H, aromatic H), 7.65-7.68 (m,
1
3
2
H, aromatic H) . C NMR (100 MHz, CDCl ): δ = 30.03 (CH ), 37.59 (CH ), 92.34 (C5),
3 2 2

22
1
25.55, 126.17, 126.42, 128.47, 128.60, 128.75, 130.89, 141.00, 155.88 ppm (aromatic C).
UV (CHCl ): λ (log ε) = 281 nm (3.68), 238 (3.75).
3
max
3
-Phenyl-5-styryl-4,5-dihydro-1,2,4-oxadiazole (10)
Column chromatography, n-hexane / ethyl acetate (25:1). m.p. 115-117 ºC, IR (KBr): ν =
3
7
198, 3054, 3028, 2850, 1654, 1599, 1567, 1509, 1461, 1382, 1269, 1137, 1026, 963, 651,
-1 1
49, 689 cm . H NMR (400 MHz, CDCl ): δ = 4.77 (brd s, 1H, NH), 6.22 (dd, J = 7.1 Hz, J
3
=
3.5 Hz, 1H, 5-CH), 6.38 (dd, J = 15.8 Hz, J = 7.1 Hz, 1H, CH), 6.81 (d, J = 15.8Hz, 1H,
CH), 7.30-7.39 (m, 3H, aromatic H), 7.45-7.52 (m, 5H, aromatic H), 7.72-7.74 (m, 2H,
1
3
aromatic H). C NMR (100 MHz, CDCl ): δ = 93.46 (C5), 125.38, 126.44, 127.07, 128.70,
3
1
28.80, 130.95, 135.23, 135.43, 155.90 ppm (aromatic C). UV (CHCl ): λ (log ε) = 288
3 max
nm (3.80), 278 (3.83), 246 (4.25).
(E)-3-Phenyl-5-(1-methyl-2-phenylethenyl)-4,5-dihydro-1,2,4-oxadiazole (11)
M.p. 138-140 ºC. IR (KBr): ν = 3189, 3056, 2903, 1598, 1568, 1507, 1458, 1331, 1265,
-1 1
1
187, 1051, 866, 695 cm . H NMR (400 MHz, CDCl ): δ = 2.03 (d, J= 1.3 Hz, 3H, CH ),
3 3
4
.95 (brd s, 1H, NH), 6.19 (brd s, 1H, 5-CH), 6.95 (brd s, 1H, CH), 7.37-7.41 (m, 3H,
1
aromatic H), 7.44-7.54 (m, 5H, aromatic H), 7.74-7.76 (m, 2H, aromatic H). H NMR (400
MHz, DMSO-d6): δ = 1.89 (d, J = 0.9 Hz, 3H, CH ), 6.10 (d, J = 2.0 Hz, 1H, 5-CH), 6.70 (s,
3
1
H, CH), 7.28-7.32 (m, 1H, aromatic H), 7.37-7.43 (m, 4H, aromatic H), 7.46-7.53 (m, 3H,
1
3
aromatic H), 7.71-7.74 (m, 2H, aromatic H), 7.82 (d, J = 1.7 Hz, 1H, NH). C NMR (100
MHz, DMSO-d6): δ = 11.58 (CH ), 97.49 (C5), 125.38, 126.21, 127.22, 128.38, 128.72,
3
1
28.90, 128.94, 130.59, 135.65, 136.18, 155.53 ppm (aromatic C). UV (CHCl ): λ (log ε)
3 max
=
287 nm (sh, 3.64), 244 (4.29).
5
-Isopropyl-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (12)
M.p. 96-98 ºC. IR (KBr): ν = 3193, 3064, 3036, 2964, 2928, 2869, 2831, 2776, 2723, 2689,
-1 1
1
602, 1568, 1510, 1465, 1391, 1337, 1282, 1080, 889,765 cm . H NMR (400 MHz, CDCl ):
3

23
δ = 1.05 (d, J = 3.5 Hz, 3H, CH ), 1.06 (d, J = 3.5 Hz, 3H, CH ), 1.93-2.05 (m, 1H, CH), 5.03
3
3
(
(
(
brd s, 1H, NH), 5.51 (d, J = 4.9 Hz, 1H, 5-CH), 7.41-7.51 (m, 3H, aromatic H), 7.72-7.75
1
3
m, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ = 16.37 (CH ), 16.42 (CH ), 33.72
3
3
3
CH), 97.33 (C5), 125.57, 126.49, 128.69, 130.79, 156.04 ppm (aromatic C). UV (CHCl3):
λmax (log ε) = 281 nm (3.60), 237 (3.64).
-(4-Nitrophenyl)-5-phenyl-4,5-dihydro-1,2,4-oxadiazole (13)
M.p. 163-165 ºC. IR (KBr): ν = 3189, 3086, 1602, 1577, 1522, 1461, 1347, 1305, 1105, 848,
3
-1 1
6
96 cm . H NMR (400 MHz, CDCl ): δ = 4.97 (d, J = 2.7 Hz, 1H, NH), 6.65 (d, J = 4.4 Hz,
3
1
H, 5-CH), 7.45-7.47 (m, 3H, aromatic H), 7.55-7.58 (m, 2H, aromatic H), 7.92 (d, J = 8.9
1
3
Hz, 2H, aromatic H), 8.31 (d, J = 8.9 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ =
3
9
4.36 (C5), 124.09, 126.56, 127.36, 128.99, 130.09, 131.40, 138.38, 149.08, 154.11 ppm
(
aromatic C). UV (CHCl ): λ (log ε) = 339 nm (3.92), 252 (4.21)
3
max
5
-(2-Nitrophenyl)-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (14)
M.p. 171-173 ºC. IR (KBr): ν = 3362, 3099, 2851, 1690, 1580, 1518, 1439, 1342, 1263,
-1 1
1
195, 1100, 1043, 970, 853, 738 cm . H NMR (400 MHz, CDCl ): δ = 5.65 (d, J = 3.0 Hz,
3
1
H, NH), 7.24 (d, J = 3.8 Hz, 1H, 5-CH), 7.62 (td, J = 8.0, 1.3 Hz, 1H, aromatic H), 7.80 (td,
J = 7.7, 1.1 Hz, 1H, aromatic H), 7.89 (d, J = 9.0 Hz, 2H, aromatic H), 8.08 (dd, J = 7.7, 1.3
Hz, 1H, aromatic H), 8.21 (dd, J = 8.0, 1.1 Hz, 1H, aromatic H), 8.30 (d, J = 9.0 Hz, 2H,
1
aromatic H). H NMR (400 MHz, DMSO-d6): δ = 7.28 (d, J = 2.6 Hz, 1H, 5-CH), 7.71-7.75
(m, 1H, aromatic H), 7.87-7.92 (m, 2H, aromatic H), 8.05 (d, J = 8.9 Hz, 2H, aromatic H),
8
1
1
.2 (d, J = 8.0 Hz, 1H, aromatic H), 8.38 (d, J = 8.9 Hz, 1H, aromatic H), 8.44 (d, J = 2.5 Hz,
1
3
H, NH). C NMR (100 MHz, DMSO-d6): δ = 89.36 (C5), 123.94, 124.87, 127.75, 127.81,
30.32, 130.99, 134.49, 135.24, 146.81, 148.53, 153.97 ppm (aromatic C). UV (CHCl ): λ
3
max
(log ε) = 330 nm (3.76), 257 (4.26), 244 (sh, 4.20).

24
5
-(3-Nitrophenyl)-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (15)
M.p. 161-163 ºC. IR (KBr): ν = 3175, 3092, 1581, 1516, 1455, 1344, 1294, 1092, 841, 698
-1 1
cm . H NMR (400 MHz, CDCl ): δ = 5.12 (d, J = 4.0 Hz, 1H, NH), 6.79 (d, J = 4.8 Hz, 1H,
3
5
2
1
1
-CH), 7.67 (t, J = 7.9 Hz, 1H, aromatic H), 7.93 (brd s, 1H, aromatic H), 7.96 (d, J= 8.9 Hz,
H, aromatic H), 8.31 (m, 1H, aromatic H), 8.34 (d, J = 8.9 Hz, 2H, aromatic H), 8.45 (m,
1
3
H, aromatic H). C NMR (100 MHz, CDCl ): δ = 92.61 (C5), 121.69, 124.22, 124.27,
3
24.79, 127.54, 128.63, 130.14, 130.82, 132.69, 133.62 ppm (aromatic C). UV (CHCl ): λ
3
max
(log ε) = 328 nm (3.80), 255 (4.26).
3
,5-Bis(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (16)
M.p. 179-181 ºC. IR (KBr): ν = 3307, 3108, 1602, 1571, 1518, 1416, 1345, 1277, 1084, 845,
-1 1
7
00 cm . H NMR (400 MHz, CDCl ): δ = 5.06 (d, J = 4.3 Hz, 1H, NH), 6.78 (d, J = 4.9 Hz,
3
1
H, 5-CH), 7.78 (d, J = 8.7 Hz, 2H, aromatic H), 7.96 (d, J = 8.9 Hz, 2H, aromatic H), 8.3 (d,
1
3
J = 8.7 Hz, 2H, aromatic H), 8.35 (d, J = 8.9 Hz, 2H, aromatic H). C NMR (100 MHz,
CDCl ): δ = 92.54 (C5), 124.20, 124.23, 127.52, 127.58 ppm (aromatic C). UV (CHCl ): λ
3
3
max
(log ε) = 330 nm (3.76), 259 (4.25).
5
-(2-Methoxyphenyl)-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (17)
M.p. 146-149 ºC. IR (KBr): ν = 3375, 3263, 3084, 1601, 1576, 1517, 1461, 1343, 1241,
-
1 1
1
1
7
1
105, 1021, 850, 758 cm . H NMR (400 MHz, CDCl ): δ = 3.93 (s, 3H, OCH ), 5.08 (brd s,
3 3
H, NH), 6.91 (d, J = 3.0 Hz, 1H, 5-CH), 6.97 (d, J = 8.2 Hz, 1H, aromatic H), 7.06 (t, J =
.5 Hz, 1H, aromatic H), 7.39 (td, J = 7.7, 1.6 Hz, 1H, aromatic H), 7.62 (dd, J = 7.5, 1.6 Hz,
H, aromatic H), 7.90 (d, J = 8.9 Hz, 2H, aromatic H), 8.29 (d, J = 8.9 Hz, 2H, aromatic H).
C NMR (100 MHz, CDCl ): δ = 55.60 (OCH ), 90.05 (C5), 110.66, 121.00, 123.97, 126.62,
1
3
3
3
1
27.27, 130.55, 131.70 ppm (aromatic C). UV (CHCl ): λ
(log ε) = 344 nm (3.71), 311
3
max
(sh, 3.55), 259 (4.05).
5
-(3-Methoxyphenyl)-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (18)

25
M.p. 157-160 ºC. IR (KBr): ν = 3218, 3090, 3022, 1612, 1577, 1522, 1458, 1354, 1273,
-1 1
1
032, 854, 784 cm . H NMR (400 MHz, CDCl ): δ = 3.86 (s, 3H, OCH ), 4.92 (d, J = 3.7
3 3
Hz, 1H, NH), 6.62 (d, J = 4.2 Hz, 1H, 5-CH), 6.99 (ddd, J = 8.1, 2.6, 0.8 Hz, 1H, aromatic
H), 7.10-7.11 (m, 1H, aromatic H), 7.14 (d, J = 7.8 Hz, 1H, aromatic H), 7.38 (dd, J = 8.1 Hz,
J = 7.8 Hz, 1H, aromatic H), 7.93 (d, J = 8.9 Hz, 2H, aromatic H), 8.32 (d, J = 8.9 Hz, 2H,
1
3
aromatic H). C NMR (100 MHz, CDCl ): δ = 55.41 (OCH ), 94.17 (C5), 111.81, 115.60,
3
3
1
18.67, 124.09, 127.36, 130.13, 131.37, 139.95, 149.09, 154.08, 160.11 ppm (aromatic C).
UV (CHCl ): λ (log ε) = 342 nm (3.73), 311 (sh, 3.60), 253 (4.03).
3
max
5
-(4-Methoxyphenyl)-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (19)
M.p. 147-149 ºC. IR (KBr): ν = 3244, 1611, 1573, 1515, 1457, 1348, 1244, 1172, 1105,
-
1 1
1
1
8
023, 856 cm . H NMR (400 MHz, CDCl ): δ = 3.85 (s, 3H, OCH ), 4.96 (d, J = 3.5 Hz,
3 3
H, NH), 6.60 (d, J = 4.1 Hz, 1H, 5-CH), 6.96 (d, J = 8.7 Hz, 2H, aromatic H), 7.49 (d, J =
.7 Hz, 2H, aromatic H), 7.90 (d, J = 8.9 Hz, 2H, aromatic H), 8.29 (d, J = 8.9 Hz, 2H,
1
3
aromatic H). C NMR (100 MHz, CDCl ): δ = 55.41 (OCH ), 94.36 (C5), 114.29, 124.07,
3
3
1
27.29, 128.14, 130.36, 131.50, 149.02, 154.16, 161.16 ppm (aromatic C). UV (CHCl ): λ
3 max
(
log ε) = 343 nm (3.78), 311 (sh, 3.65), 257 (sh, 4.09), 240 (4.17).
-Benzyl-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (20)
M.p. (Dec.) 165-167 ºC. IR (KBr): ν = 3262, 1602, 1575, 1515, 1461, 1351, 1105, 845, 746
5
-1 1
cm . H NMR (400 MHz, CDCl ): ABX-system, δ = 3.06 (J = 13.6 Hz, JAX = 6.6 Hz,
3
A
AB
1
1
2
4
H), δ = 3.23 (J = 13.6 Hz, JBX = 4.1 Hz, 1H), δ = 5.97-6.00 (m, 1H, 5-CH), 4.62 (brd s,
B AB x
H, NH), 7.30-7.33 (m, 3H, aromatic H), 7.36-7.40 (m, 2H, aromatic H), 7.84 (d, J= 8.9 Hz,
1
3
H, aromatic H), 8.29 (d, J= 8.9 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ =
3
2.46 (C-benzyl), 94.28 (C5), 124.01, 124.09, 124.22, 127.28, 128.44, 128.60, 128.87,

26
1
29.67, 165.40 ppm (aromatic C). UV (CHCl ): λ (log ε) = 349 nm (3.64), 311 (sh, 3.48),
3 max
2
52 (3.97).
-(4-Nitrophenyl)-5-(2-phenylethyl)-4,5-dihydro-1,2,4-oxadiazole (21)
3
M.p. 108-110 ºC. IR (KBr): ν = 3235, 3085, 3027, 2922, 2838, 2706, 1605, 1576, 1519,
-
1 1
1
2
4
456, 1393, 1348, 1312, 1107, 1036, 849, 696 cm . H NMR (400 MHz, CDCl ): δ = 2.06-
3
.17 (m, 1H, CH), 2.18-2.27 (m, 1H, CH), 2.79-2.86 (m, 1H, CH), 2.87-2.94 (m, 1H, CH),
.59 (d, J = 4.1 Hz, 1H, NH), 5.81 (dd, J = 9.8 Hz, J = 4.9 Hz, 1H, 5-CH), 7.22-7.26 (m, 3H,
aromatic H), 7.31-7.34 (m, 2H, aromatic H), 7.82 (d, J = 8.9 Hz, 2H, aromatic H), 8.27 (d, J
1
3
=
8.9 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ = 29.92 (CH ), 37.43 (C-benzyl),
3 2
9
3.36 (C5), 123.99, 126.32, 127.25, 128.43, 128.68, 131.65, 140.70, 148.97, 154.40 ppm
(
aromatic C). UV (CHCl ): λ (log ε) = 350 nm (3.71), 311 (sh, 3.53), 251 (4.03).
3
max
3
-(4-Nitrophenyl)-5-styryl-4,5-dihydro-1,2,4-oxadiazole (22)
M.p. 233-238 ºC (Dec.). IR (KBr): ν = 3147, 3088, 1647, 1578, 1526, 1466, 1347, 1136, 967,
-1 1
8
54, 747, 689 cm . H NMR (400 MHz, CDCl ): δ = 4.77 (brd s, 1H, NH), 6.31 (dd, J = 7.1
3
Hz, J = 3.9 Hz, 1H, 5-CH), 6.37 (dd, J = 15.5 Hz, J = 7.2 Hz, 1H, CH), 6.85 (d, J = 15.4 Hz,
1
2
9
H, CH), 7.32-7.40 (m, 3H, aromatic H), 7.46-7.48 (m, 2H, aromatic H), 7.91 (d, J = 8.6 Hz,
1
3
H, aromatic H), 8.32 (d, J = 8.6 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ =
3
4.37 (C5), 124.09, 124.54, 127.12, 127.28, 128.79, 129.00, 131.48, 135.10, 135.93, 149.08
ppm (aromatic C). UV (CHCl ): λ (log ε) = 344 nm (3.67), 290 (sh, 3.70), 253 (4.32).
3
max
(E)-3-(4-Nitrophenyl)-5-(1-methyl-2-phenylethenyl)-4,5-dihydro-1,2,4-oxadiazole (23)
M.p. 233-238 ºC. IR (KBr): ν = 3236, 3120, 3094, 2979, 2951, 2889, 2783, 1582, 1537,
-1 1
1
450, 1397, 1355, 1333, 1292, 1186, 1106, 1076, 1047, 1013, 911, 846, 696 cm . H NMR
(
400 MHz, CDCl ): δ = 2.03 (brd s, 3H, CH ), 4.81 (brd s, 1H, NH), 6.25 (brd s, 1H, 5-CH),
3
3
7
.72 (brd s, 1H, CH), 7.32-7.42 (m, 5H, aromatic H), 7.92 (d, J = 8.6 Hz, 2H, aromatic H),

27
1
3
8
.32 (d, J = 8.6 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ = 11.60 (CH ), 98.98
3 3
(C5), 124.11, 127.23, 127.54, 128.36, 129.11, 131.06, 131.42, 134.07, 136.09, 149.04, 154.44
ppm (aromatic C). UV (CHCl ): λ (log ε) = 350 nm (3.77), 250 (4.42).
3
max
5
-Isopropyl-3-(4-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (24)
M.p. 97-99 ºC. IR (KBr): ν = 3349, 3087, 2963, 2934, 2876, 2720, 2629, 1605, 1581, 1519,
-1 1
1
447, 1388, 1349, 1308, 1179, 1102, 1024, 853 cm . H NMR (400 MHz, CDCl ): δ = 1.03
3
(
d, J = 4.2 Hz, 3H, CH ), 1.05 (d, J = 4.2 Hz, 3H, CH ), 1.94-2.05 (m, 1H, CH), 4.71 (brd s,
3
3
1
H, NH), 5.55 (d, J = 5.0 Hz, 1H, 5-CH), 7.89 (d, J = 8.8 Hz, 2H, aromatic H), 8.28 (d, J =
13
8
.8 Hz, 2H, aromatic H). C NMR (100 MHz, CDCl ): δ = 16.29 (CH ), 16.40 (CH ), 33.71
3
3
3
(
CH), 98.22 (C5), 124.00, 127.26, 131.77, 148.95, 154.39 ppm (aromatic C). UV (CHCl3):
λmax (log ε) = 350 nm (3.57), 311 (sh, 3.33), 250 (3.90).
-(4-Methoxyphenyl)-5-(2-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (25)
M.p. 114-146 ºC. IR (KBr): ν = 3334, 3211, 3006, 2959, 1610, 1525, 1463, 1360, 1334,
3
-1 1
1
304, 1250, 1175, 1026, 835 cm . H NMR (400 MHz, CDCl ): δ = 3.86 (s, 3H, OCH ), 5.69
3 3
(brd s, 1H, NH), 6.94 (d, J = 8.9 Hz, 2H, aromatic H), 7.14 (brd s, 1H, 5-CH), 7.57 (dt, J =
8
.0, 1.4 Hz,1H, aromatic H), 7.66 (d, J = 8.9 Hz, 2H, aromatic H), 7.76 (dt, J = 7.7, 1.1 Hz,
H, aromatic H), 8.1 (dd, J = 7.8, 1.4 Hz, 1H, aromatic H), 8.16 (dd, J = 8.0, 1.1 Hz, 1H,
1
1
13
aromatic H). H NMR (400 MHz, DMSO-d6): δ = . C NMR (100 MHz, DMSO-d6): δ =
3
7
.80 (s, 3H, OCH ), 7.02 (d, J = 8.9 Hz, 2H, aromatic H), 7.10 (d, J = 2.7 Hz, 1H, 5-CH),
3
.64-7.66 (m, 1H, aromatic H), 7.68 (d, J = 8.9 Hz, 2H, aromatic H), 7.81-7.87 (m, 2H,
1
3
aromatic H), 8.01 (d, J = 2.6 Hz, 1H, NH), 8.14 (d, J = 7.9 Hz, 1H, aromatic H). C NMR
100 MHz, DMSO-d6): δ = 55.32 (OCH ), 88.12 (C5), 114.08, 117.20, 124.75, 127.76,
(
3
1
28.22, 130.08, 134.27, 135.78, 146.98, 154.73, 161.13 ppm (aromatic C). UV (CHCl ): λ
3 max
(log ε) = 268 nm (sh, 4.02), 250 (4.08).
3
-(4-Methoxyphenyl)-5-(3-nitrophenyl)-4,5-dihydro-1,2,4-oxadiazole (26)