Experimental and theoretical spectroscopic studies, HOMO-LUMO, NBO analyses and thione-thiol tautomerism of a new hybrid of 1,3,4-oxadiazole-thione with quinazolin-4-one

Article abstract of DOI:10.1016/j.saa.2015.01.061

Abstract The hybrid 3-(4-chlorophenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methylthio]quinazolin-4(3H)-one has been synthesized and characterized using elemental analysis, FTIR and NMR spectroscopy. The thione-thiol tautomeric equilibria has bee

Full text of DOI:10.1016/j.saa.2015.01.061

Accepted Manuscript
Experimental and theoretical spectroscopic studies, HOMO–LUMO, NBO anal-
yses and thione-thiol tautomerism of a new hybrid of 1,3,4-oxadiazole-thione
with quinazolin-4-one
Saied M. Soliman, Mohamed Hagar, Farahate Ibid, El Sayed H. El Ashry
PII:
S1386-1425(15)00082-7
http://dx.doi.org/10.1016/j.saa.2015.01.061
SAA 13229
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomo-
lecular Spectroscopy
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Received Date:
Revised Date:
Accepted Date:
8 September 2014
4 November 2014
25 January 2015
Please cite this article as: S.M. Soliman, M. Hagar, F. Ibid, E.S.H. El Ashry, Experimental and theoretical
spectroscopic studies, HOMO–LUMO, NBO analyses and thione-thiol tautomerism of a new hybrid of 1,3,4-
oxadiazole-thione with quinazolin-4-one, Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy (2015), doi: http://dx.doi.org/10.1016/j.saa.2015.01.061
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Experimental and Theoretical Spectroscopic Studies, HOMO–LUMO, NBO
Analyses and Thione-Thiol Tautomerism of a New Hybrid of 1,3,4-Oxadiazole-
thione with Quinazolin-4-one
Saied M. Solimana, Mohamed Hagar,b, Farahate Ibida, El Sayed H. El Ashrya*
a. Chemistry Department, Faculty of Science, Alexandria University, Alexandria
21321, Egypt.
b. Chemistry Department, Faculty of Science, Taibah University, Yanbu Branch,
Yanbu, KSA.
Abstract
The
hybrid
3-(4-chlorophenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-
yl)methylthio]quinazolin-4(3H)-one has been synthesized and characterized using
elemental analysis, FTIR and NMR spectroscopy. The thione-thiol tautomeric
equibria has been studied using both DFT/B3LYP and HF methods at different basis
sets. The results of calculations showed predominance of the thione form. The
molecular structure and vibrational spectra of the stable tautomer are predicted using
the same level of theory. The complete assignments of the vibrational modes were
performed on the basis of potential energy distribution (PED). The 6-311++G(d,p)
gave the best results compared to the experimental data. The chemical shift values of
the two tautomers are calculated using GIAO method. The NH proton of the thione
tautomer have chemical shift value closer to the experimental data compared to the
SH proton of the thiol one. The electronic transitions are predicted using the TD-DFT
calculations at B3LYP/6-311++G(d,p) level of theory. The calculated polarizability
and first hyperpolarizability showed that the studied compound has better NLO
properties than urea. The Molecular Electrostatic Potential (MEP) analysis reveals the
sites for electrophilic and nucleophilic attack in the molecule. NBO analysis is carried
out to investigate the stabilization energy of various intramolecular charge transfer
interactions within the studied molecule.
Key words: Oxadiazole - Quinazoline - Tautomerism - thione – NBO - NMR
Corresponding Author: E. S. H. El Ashry, Tel: +201227430924, e-mail:
eelashry60@hotmail.com

Introduction
The quinazoline skeleton [1] is of a great importance to chemists as well as biologists
as it is available in a large variety of naturally occurring compounds. It is also found
in clinically useful molecules having diverse biological activities [2] such as antiviral,
antimalarial, anticonvulsant, antibacterial, diuretic, hypnotic, hypoglycaemic,
antitumoral and antihypertensive. It has been reported that substitution of different
heterocyclic moieties at 2 or 3 position of quinazolinone nucleus modulates the anti-
inflammatory activity. A large numbers of azetidinones, [3,4] thiazolidinones [5, 6]
and oxadiazoles [7-9] were reported to possess anti-inflammatory activity.
Also, the biological activity of compound strongly depends on acid-base interactions
which is an addition to behavior associated with its permeability through cell
membranes and its spatial structure [10]. The geometric structure is important for
determining many factors that could affect its biological activity such as atomic
charge density, dipole moment, polarizability and the ability to interact with
biomolecules through coordinative or hydrogen bonds as well as dipole-dipole
interactions [11,12].
On other hand, the spectroscopic investigations using infrared, electronic and NMR
spectroscopy are considered as the most important tools to study the molecular
structure of organic compounds. From this point of view, the aim of this study is to
fully determine the molecular structure, IR spectra, NMR chemical shifts, absorption
wavelengths, excitation energies and dipole moment as well as nonlinear optical
properties of newly prepared quinazoline-oxadiazolyl derivative. The titled compound
has the two possible tautomers shown in Fig. 1a. The relative stability of the thiol
(T1) and thione (T2) tautomers was reported. For computations, we have carried out
HF and DFT calculations. Detailed interpretations of the vibrational spectra of our
compound have been made based on the calculated potential energy distribution
(PED).
2. Experimental
2.1. General
Melting points were determined on a meltemp apparatus and are uncorrected. IR
spectra were recorded with a Tensor 37 Bruker infrared spectrophotometer as
potassium bromide pellets and frequencies were reported in cm-1.1H NMR and 13C
NMR spectra were determined with a JEOL spectrometer at 600 MHz. The chemical
shifts are expressed in the δ scale using tetramethylsilane as a reference. TLC were

performed on Merck Kiesel gel; 60-F254 plates, and the spots were detected by UV
light absorption.
2.2. 3-(4-chlorophenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methylthio]
quinazolin-4(3H)-one
The starting material 2-(ethoxycarbonylmethyl)thio-3-(4-chlorophenyl)-4-oxo-3H-
quinazoline was prepared according to the reported method [13]. The treatment of this
ester with hydrazine hydrate afforded the corresponding hydrazide 1 [14]. To a
solution of 1 (0.5 g, 1.4 mmol) in ethanol (15 mL) was added a solution of potassium
hydroxide (0.08 g, 1.4 mmol) in water (2 mL) and carbon disulphide (0.4 mL) as
shown in Fig. 1. The solution was heated under reflux for 4 hr. The solvent was
evaporated and the residue was dissolved in water, filtered and acidified with dilute
hydrochloric acid. The precipitate was filtered off, washed with water, and
recrystallized from ethanol to give dark yellow crystals; yield: 27 %; mp 135-137 °C,
Rf 0.50 (1:1 EtOAc- petrolum ether).
IR (KBr, in cm-1): 3462 (NH), 3088-3041 (CH, aromatic), 2922 (CH alkane), 1656
(CO).
1H NMR (DMSO-d6): δ 4.54 (s, 2H, H35, H36), 7.51 (ddd, J= 1.2, 8.2, 8.0 Hz, 1H,
H27), 7.56-7.58 (m, 3H, H31, H33, H29), 7.68 (dd, J= 3.0, 9.5 Hz, 2H, H32, H34),
8.09 (dd, J=1.2, 8.0 Hz, 1H, H28), 8.86 (ddd, J= 1.2, 8.0, 8.2 Hz, 1H, H30), 13.1 (s,
1H, oxadiaz-H). 13C NMR: δ 26.3 (C25), 120.1(C5), 126.5 (C1), 127.0 (C3), 127.1
(C6), 130.2 (C13), 132.0 (C15), 134.8 (C11), 135.5 (C14), 135.6 (C2), 147.3 (C4),
155.2 (C19), 161.0 (C10), 161.1 (C8), 178.3 (C21).
1H NMR (CDCl3): δ 4.44 (s, 2H, H35, H36), 7.31 (d, 2H, J= 7.3 Hz, H31), 7.47 (dd,
1H, J= 6.7, 7.2 Hz, H27), 7.55 (d, 2H, J= 7.3 Hz, H32), 7.65 (d, 1H, J= 7.3 Hz, H29),
7.79 (dd, 1H, J= 7.2, 7.3, Hz, H28), 8.25 (d, 1H, J= 7.2 Hz, H30), 11.1 (s, 1H,
13
oxadiaz-H). C NMR: δ 26.1 (C25), 119.8 (C5), 126.5 (C1), 126.8 (C3), 127.4 (C6),
130.3 (C13), 130.6 (C12), 133.4 (C11), 135.2 (C14), 135.5 (C2), 147.2 (C4), 153.6
(C19), 160.4 (C10), 161.6 (C8), 178.6 (C21).
1H NMR (CD3CN-d3): δ 4.47 (s, 2H, H35, H36), 7.44 (d, 2H, J= 8.7 Hz, H32, H34),
7.50 (dd, 1H, J= 7.3, 8.0 Hz, H27), 7.62-7.64 (m, 3H, H31, H33, H29), 7.84 (dd, 1H,
J= 7.3, 8.0, Hz, H28), 8.17 (d, 1H, J= 7.9 Hz, H30) 10.33 (s, 1H, oxadiaz-H).

3. Computational details
The quantum chemical calculations have been performed at HF and DFT (B3LYP)
methods to predict the relative stability of the two possible tautomers of the titled
compound using Gaussian 03 package [15]. The basis sets used are 6-31G(d,p), 6-
311G(d,p) and 6-311++G(d,p). The optimized structural parameters have been used to
calculate the vibrational frequencies at the different levels of theories. The
calculations converged to the optimized geometries having true energy minima, as
revealed by the lack of imaginary frequencies in the vibrational mode calculations.
The assignments of the calculated normal modes have been made using PED analysis.
The PEDs are computed using VEDA program [16]. The chemical shift values of the
suggested tautomers are calculated using GIAO method to simulate the
experimentally measured NMR spectra. Also, the electronic spectra were calculated
using TD-DFT method to predict the excitation energies of the most stable tautomer.
4. Results and discussion
4.1. Tautomerism and thermodynamic Properties
The tautomerism of organic compounds has been subjected to extensive theoretical
studies using various quantum-chemical approaches [17]. Oxadiazole thione ring can
exist in two possible tautomeric forms; thiol and thione tautomers. A schematic
representation of the two possible tautomers is shown in Fig. 1a. In the present paper,
a combined experimental and theoretical spectral studies were used to show which
tautomer could exist. From this point of view, we used quantum chemical calculations
to predict the most stable tautomer of the studied molecule in the framework of both
the HF and DFT methods using different basis sets. Table S1 (Supplementary
materials) presents the theoretically computed corrected total energy (Ecorr), Gibbs
free energies (G), entropies (S) and enthalpies (H) of the studied tautomers using HF
and DFT methods. It is found that; thione tautomer (T2) is the most stable form. The
calculated relative energy (∆E) and relative Gibbs free energy (∆G) of T2 with
respect to T1 are presented in the same table. The energy differences (∆E) between
these two tautomers are predicted to be in the range of 8.30-9.37 kcal/mol and 6.34-
7.62 kcal/mol using DFT and HF methods, respectively. The tautomeric equilibrium
constants (k) between them were calculated using the equation K = e-(∆G/RT) where the
gas constant (R) is 2x10-3 kcal/mol.k and the temperature (T) is 298.15 k. The values
of the equilibrium constant (k) for this tautomeric equilibria are used to calculate the

mole fractions of individual tautomers. The mole fractions of the tautomer T1 is
almost null. So, the studied molecule exists only as thione tautomer (T2).
4.2. Molecular geometry and structural properties
The molecular structure and atom numbering of the stable tautomer (T2) are shown in
Fig. 2. The optimized geometrical parameters (bond lengths and angles as well as
dihedral angles) of the most stable tautomer obtained by HF and DFT/B3LYP
methods with different basis sets are presented in Table S2 (Supplementary
materials). The results are compared with the experimental X-Ray structure of the
structurally related compound [18]. From Table S2, it is found that the bond lengths
and bond angles calculated by DFT/B3LYP and HF methods are consistent with
experimental values. The maximum deviations of the calculated bond distance and
bond angle values from the experimental data are 0.032 Å and 3.061°, respectively,
using DFT method while, 0.035 Å and 3.045° using HF method, respectively. The
changes of the bond distance and bond angles due to changing the basis set do not
exceed 0.005 Å and 0.547°, respectively. The calculated bond distances are found to
have higher values in case of HF calculations with respect to B3LYP computations
except C19‒C25 and C21‒S24. On other hand, some of the B3LYP calculated bond
angles are overestimated while the others are underestimated compared to the HF
method.
The values of the calculated dihedral angles (see Table S2) indicate that, the
quinazoline, phenyl and the oxadiazole are planar rings. Also the N7‒C8‒S16‒C25
and N9‒C8‒S16‒C25 dihedral angles are -175.468 and 5.449° respectively indicating
that, the C‒S bond is slightly twisted from the quinazoline ring plane. On other hand,
the plane passing through the oxadiazol ring makes an angle of 81.12° with the
quinazoline ring plane. The angle between the quinazoline ring plane and p-
chlorophenyl ring is 87.98°. Consequently, oxadiazole and p-chlorophenyl rings are
almost perpendicular to the quinazoline ring (see Fig. 2). Furthermore, the
calculations showed the presence of intramolecular hydrogen bonding interaction
between H35 and N7 atoms. The calculated N…H intramolecular distance is 2.177Å
and the C‒H…N angle is 118.914°.
4.3. Natural Atomic Charges
The charge distribution on the molecule has an important effect on the vibrational
spectra, dipole moment, polarizability, electronic structure, and more properties of
molecular systems. The NPA charge distribution of T2 was calculated by HF and

B3LYP methods. From the NPA charge values listed in Table S3 (Supplementary
Materials), we can observe the electropositive nature of all hydrogen atoms. The
highest electropositive hydrogen is the amino group hydrogen (H37). On other hand,
all the carbon atoms are electronegative except C4, C8, C10, C11, C19 and C21 as
these atomic sites are bonded to strong electronegative atoms such as oxygen or
nitrogen. The C8, C10, C19 and C21 atoms have higher positive charge density than
the others because these carbon atoms are located between two strong electronegative
atoms instead of one in the others. Of the C-atoms, the C25 and C10 have the
minimum and maximum charge density, respectively. The highest electronegative
atomic site in the molecule is O17. Furthermore, the charge densities at H35 and H36
atomic sites are 0.2864 and 0.2488, respectively using B3LYP/6-311++G(d,p). The
higher NPA charge at the former compared to the latter is attributed to the presence of
the weak non-conventional C‒H35…N interaction.
4.4. Molecular electrostatic potential
Molecular electrostatic potential (MEP) is a useful quantities to illustrate the charge
distributions on molecule and used to visualize variably charged regions. Since the
charge distributions can give information about how the molecule interact with
another one so, MEP is widely used as a reactivity map for determining sites of
electrophilic and nucleophilic attack as well as in studies of biological recognition and
hydrogen-bonding interactions [19‒22]. To predict the reactive sites of electrophilic
and nucleophilic attack for the investigated molecule, the MEP at the B3LYP/6-
311++G(d,p) optimized geometry was calculated and shown in Fig. 3. Potential
decreases in the order blue ˃ green ˃ yellow ˃ orange ˃ red. The negative (red)
regions of the MEP are related to electrophilic reactivity, and the positive (blue)
regions are related to nucleophilic reactivity. The MEP map shows that the region of
maximum negative electrostatic potential is located around O17 with MEP value
around -0.0497 a.u while the most positive region is localized on H37 with a value of
+0.0669 a.u. So, it is expected that the most preferred region for electrophilic and
nucleophilic attack is that around O17 and H37, respectively. These sites give
information about the region from where the compound can make intermolecular
interactions.
4.5. Vibrational analysis and theoretical prediction of spectra
The experimental and theoretical vibrational spectra of the studied compound
are shown in Fig. 4. The calculated wave numbers along with their relative intensities

using HF and DFT methods at different basis sets and their assignment based on
potential energy distribution (PED) are summarized in Tables S4 (Supplementary
materials) and 1. The disagreements between the calculated and observed vibrational
wavenumbers are attributed to neglecting the anharmonicity present in real system.
Furthermore, the experiments were performed for solid samples while calculations
were made for a free molecule in gas phase. The optimal scaling factors [23] are
calculated at DFT and HF methods using different basis sets and their average values
are presented in the same table. Generally, the DFT method gave better quantitative
prediction for infrared vibrations than the HF one [24]. Since, the use of the more
sophisticated basis set 6-311G++(d,p) gave better agreement with the experimental
data than either the 6-31g(d,p) or 6-311G(d,p) so, PED discussion are described
based on the B3LYP/6-311G++(d,p) results.
4.5.1. N–H vibrations
The stretching of the amino group of the secondary amines appeared around 3500–
3000 cm−1 in the IR absorption spectra [25]. The band appeared experimentally at
3462 cm−1 is due to N–H stretching vibration which is calculated at 3672 cm−1 using
the B3LYP/6-311G++(d,p) method. Also the N‒H bending of secondary amines
appeared in the range of 1580-1490 cm−1. In the present work, this bending vibration
is calculated at 1491 cm−1. Other contributions to the NH bending vibrations are
predicted at lower frequency (modes 31, 32 and 38). It is noted that these N‒H
bending modes are almost masked by the aromatic ring vibrations [25].
4.5.2. C–H vibrations
The studied compound has three ring systems, the 1,4-disubstituted benzene (R1), the
quinazoline (R2) and the oxadiazole (R3) rings. The aromatic C–H ring stretching
vibrations are normally found between 3100 and 3000 cm-1 [26]. In the present work,
the eight C–H stretching modes are observed in the range of 3088-3041 cm-1, for
which the calculated wavenumbers are in the range of 3209-3171 cm-1 using
B3LYP/6-311++G(d,p) level. The visual inspection of these modes using Gaussview
software showed the four C–H stretching modes of the p-substituted benzene (R1) at
3209, 3207, 3192 and 3191 cm-1 while the four C–H stretching vibrations of the
quinazoline ring (R2) are predicted at 3203, 3197, 3186 and 3171 cm-1. The
symmetric υ(C–H) modes are calculated at 3209, 3207, 3203 and 3197 cm-1 while the
asymmetric C-H stretching vibrations are predicted at 3192, 3191, 3186 and 3171 cm-

1. The aliphatic C–H stretching vibrations usually appear at lower frequency than the
aromatic stretching modes. The aliphatic C‒H stretching vibrations are observed
experimentally at 2922 cm-1. The asymmetric and symmetric C‒H stretching
vibrations of the methylene group are predicted using PED analysis at 3146 and 3058
cm-1, respectively. The asymmetric vibration occurs at higher frequency and lower
intensity than the symmetric one.
Also, the DFT calculations predicted the in-plane C–H bending vibrations in the
range of 1590-1101 cm-1 (except modes 21, 22, 25, 26, 29-32, 35-39) while the out of
plane C–H deformations are predicted in the range of 1033-801cm-1 (except modes
52, 53, 56, 57) and at lower frequencies of 708, 519 and 423 cm-1. The out-of-plane
C-H bending were used to differentiate between the position of the substituents in the
disubstituted benzene (ortho, meta and para). The para disubstituted benzene
derivatives are characterized by out-of-plane C-H bending mode in the range of 860-
800 cm-1. In the present work, these bands are observed in the range of 801-845 cm-1.
The bending vibrations of the aliphatic CH2 group such as scissoring, wagging and
twisting modes are predicted at 1489, 1270 and 1207 and 1155 cm-1, respectively. All
C–H vibrations are in good agreement with the experimental data.
4.5.3. C–O and C‒S vibrations
The υ(C=O) band is observed experimentally at 1656 cm-1 while calculated at 1754
cm-1 using the B3LYP/6-311++G(d,p) method. It is known that the C‒O stretching
vibrations occur at lower frequency than the υ(C=O). The PED analysis predicted
contribution to the υ(C‒O) vibration at 1358 cm-1. Also, the C=S and C‒S bonds
showed lower absorption frequency as compared to C=O and C‒O bonds,
respectively, due to the decreased force constant and increase in reduced mass when
oxygen atom replaced with sulphur. The C=S stretching vibration (1277 cm-1) is
predicted at lower frequency than υ(C=O). Also, the C‒S stretching vibrations (743
and 659 cm-1) are predicted at lower frequency than υ(C‒O).
4.5.4. C–N and C‒C vibrations
The ring C=N and C=C stretching vibrations occur in the region of 1600-1500 cm-1
[26] and 1625-1400 cm-1 [27], respectively. Almost the C=N and C=C stretching
vibrations are found overlapped in the same region and difficult to be assigned. These
stretching vibrations are observed at 1612 cm-1. The present DFT calculations
predicted the C=N stretching vibrations at 1657 and 1590 cm-1, respectively, while the
C=C stretching vibrations in the range of 1657-1615 cm-1. The υ(C=N) modes

calculated at 1657 and 1590 cm-1 are due to the C19=N23 (R3) and C8=N7 (R2)
stretching vibrations, respectively. It is well known that, the C‒N stretching vibrations
are usually occur at lower frequency (1300-1200 cm-1) than the C=N stretching
vibrations [28]. The C‒N stretching vibrations are predicted at 1358, 1310, 1277 and
1217 cm-1(exp. 1302 and 1209 cm-1).
4.5.5. Other vibrations
The C–Cl stretching band is normally expected around 750–580 cm−1 [29]. Two
contributions to the stretching vibrations of the C‒Cl bond are predicted at 615 and
449 cm-1. The υ(N‒N) of the oxadiazole ring is predicted using the B3LYP/6-
311++G(d,p) method at 1067 cm-1 while experimentally observed at 1064 cm-1.
4.6. Electronic spectra and HOMO–LUMO analysis
The molecular orbital (MO) calculations indicated that the title compound has 103
occupied molecular orbitals (MOs). The highest one in energy is called the highest
occupied molecular orbital (HOMO) while LUMO refers to the lowest unoccupied
molecular orbital (LUMO). The energy values of the HOMO and LUMO levels
indicate the reactivity of molecule as donor and acceptor of electrons, respectively.
Also, HOMO and LUMO energies are considered as important parameters in
determining molecular properties [30]. The difference in energy between HOMO and
LUMO is called the excitation energy which indicates the chemical reactivity of the
molecule towards electron transport and recently used to establish the bioactivity from
intramolecular charge transfer [31,32]. The EHOMO, ELUMO and ∆E are calculated to be
-6.5300, -1.8044 and 4.7256 eV, respectively.
In order to get the accurate description of the electronic transitions, the first 20 spin
allowed singlet-singlet excitations were calculated using the TD-DFT method. Of
these transitions, only those of the highest oscillator strength are discussed. The
results are shown in Table S5 (Supplementary materials) which represents the
calculated λmax values with their major contributions of molecular orbitals to the
predicted electronic transitions. The highest wavelength band is calculated at 294.9nm
which corresponds to the transition from the HOMO and HOMO-2 to LUMO. The
frontier molecular orbital (FMO) plot drawn by DFT-B3LYP method using 6-
311++G(d,p) basis set is shown in Fig. 5. It can be seen that the electron densities of
the ground state MOs are mainly localized on the π-system and the lone pair of S-
atoms so; the electronic transition from the ground state to the excited state is
predicted to be mixed π-π* and n-π* transitions.

4.7. NMR
The isotropic magnetic shielding (IMS) values calculated using the GIAO approach at
1
the 6-311++G(d,p) level are used to predict the 13C and H chemical shifts (δcalc) for
the studied tautomers and the results are compared with the experimental NMR data
(δexp) as shown in Table 2. The calculated chemical shift values are in good agreement
with the experimental data except H37. This large difference between the calculated
and experimental chemical shift value for H37 is attributed to the high polarity of the
N‒H bond. In solution, this group undergoes strong solute-solvent interactions
especially with polar solvents such as DMSO which is not the case in the gas phase.
Moreover, the chemical shift of the H37 in the less polar CDCl3 solvent is found
closer to the calculated value than that in DMSO. This indicate that, the deviation of
the calculated chemical shift value for the H37 proton from the experimental data is
mainly attributed to the medium effect. Moreover, correlation graphs between the
calculated and experimental 1H-NMR chemical shifts for the T2 tautomer is shown in
Fig. S1 (Supplementary Material). It can be seen that H35 proton deviate significantly
from the straight line relation obtained which is probably due to the intramolecular
C‒H35…N interaction. Such interaction is not important in presence of solvent as the
intermolecular solute-solvent interactions become more important in solution. From
1
this point of view, omitting this point from the correlation gave the H-NMR
correlation graphs shown in Fig. S2 (Supplementary Material). The correlation
coefficient for the T2 (R2=0.974) tautomer is better than the T1 (R2=0.940). Also, the
correlation graphs between the calculated and experimental 13C-NMR chemical shifts
for the studied tautomers are shown in Fig. S3 (Supplementary Material). The
correlation equations are
y = 1.315x - 2.622
y = 0.799x + 1.609
y = 0.994x - 6.205
y = 0.973x - 4.250
R² = 0.940
R² = 0.975
R² = 0.970
R² = 0.987
T1 (1H-NMR)
T2 (1H-NMR)
T1 (13C -NMR)
T2 (13C -NMR)
The correlation coefficients are better for the T2 tautomer than the T1 one.
4.8. NLO properties
The development of materials with large nonlinear optical (NLO) properties has been
of great interest in past few decades. These materials find numerous device
applications, from lasers to optical switches and electronics [33]. So far, the organic
π-conjugated molecules have been considered mostly for this purpose because of their

easy functionalization to fine tune the desired properties and the ease of fabrication
and integration into devices [34-36]. NLO is very important in areas such as
telecommunications, optical interconnections and signal processing [37, 38].
The components of the dipole moments µ (Debye), static polarizability components α
(a.u.), the average polarizability (or linear polarizability) α0 (Å3), and the first
hyperpolarizability components β (a.u.), the first hyperpolarizability β0 (×10−31 cm5
esu−1) of the studied compound are given in Table 3. The µ, α0 and β0 are calculated to
be 5.066 Debye, 39.39Å3 and 11.52×10−31 cm5 esu−1, respectively. These are
important parameters in discussions of the NLO of a molecule. The α0 and β0 values
of the title compound are about 8 and 9 times, respectively greater than those of urea
(α0=4.28 Å3, β0=1.52×10−31 cm5.esu−1) which is considered as important molecule
used in the comparative purposes of the NLO properties of molecular systems. Also,
the NLO properties of a molecule are related to the energy gap between HOMO and
LUMO. The B3LYP/6-311++G(d,p) calculated energy gap is 4.7256 eV which is
lower than urea (∆E= 6.7063 eV). Thus, the studied compound can be regarded as a
good applicant for NLO materials.
4.9. Natural Bond Orbital Analysis
Natural Bond Orbital (NBO) analysis presents an efficient method for studying
interesting features of molecular structure. It gives a strong insight in the intra and
intermolecular bonding and interaction among bonds. Also, it provides a convenient
basis for investigating charge transfer in molecular system [39]. Table S6
(Supplementary materials) gives the occupancy of electrons and p-character in the
significant NBOs [40]. For C–H bonds, all the hydrogen atoms have almost 0% of p-
character. On contrary, 100% p-character was observed in both the atoms in π-
bonding of the C–C, C–N and C–O bonds. It is noted that, the LP of N9 and N22
atoms having 100% p-character while the LP of N7 and N23 has 72.97 and 59.91 %
p-character. Also, LP(1) of Cl26, S24, S16, O17 and O20 have 17.34, 18.55, 29.96,
41.07 and 60.92 % p-character, respectively, while almost 100% p-character was
observed in the LP(2) of these atoms as well as LP(3) of Cl26. The coefficients
C8(0.61)‒N9(0.79) and C19(0.56)‒O20(0.83) are called polarization coefficients. The
magnitude of these coefficients shows the importance of the two hybrids in the
formation of the bond. It is clear that, both nitrogen and oxygen have larger
percentage of NBO and give the larger polarization coefficients than carbon because
these atoms have the higher electronegativity.

Another useful aspect of NBO method is that it gives information about interactions
in both filled and virtual orbital spaces that could enhance the analysis of intra and
intermolecular interactions. Delocalization of the electron density between occupied
NBO (bond (or) lone pair) and the unoccupied NBO corresponding to a stabilizing
donor–acceptor interactions. The energy of this interaction can be estimated by the
second order perturbation theory [41]. Table 4 lists the calculated second order
interaction energies (E(2)) between the donor–acceptor orbital’s in the titled molecule.
The larger the E(2) value, the intensive is the interaction between electron donors and
electron acceptors, i.e., the greater the extent of conjugation of the system.
The delocalization of electrons due to LP(1)N9→BD*(2)N7‒C8, LP(1)N9→
BD*(2)C10‒O17 and LP(1)N22→ BD*(1)C21‒S24 having the highest
intramolecular charge transfer interaction (ICT) energies (E(2)) of 53.25, 43.28 and
71.58 kcal/mol respectively. Moreover, the interactions BD(2)C‒C→BD*(2)C‒C,
BD(2)C‒C→ BD*(2)N‒C, BD(2)N‒C→ BD*(2)C‒C and BD(2)C‒C→BD*(2)C‒O
are responsible for conjugation of the ring π-bonds indicate strong π-electron
delocalization within ring leading to a maximum stabilization of energy upto 25.17
kcal/mol. The movement of π-electron cloud from donor to acceptor i.e.
intramolecular charge transfer can make the molecule more polarized and the ICT
must be responsible for the NLO properties of molecule. Therefore, the titled
compound may be used for nonlinear optical materials application in future.
Furthermore, the small interaction energy (E(2)=3.21 kcal/mol) due to the ICT
between LP(1)N7 and BD*(1)C25‒H35 indicates the presence of weak C‒H…N
intramolecular H-bonding interaction.
Conclusion
A quinazoline containing mercapto-oxadiazole is synthesized and characterized by a
combined experimental and theoretical quantum chemical calculations. The DFT and
HF methods using different basis sets predicted the higher stability of thione
tautomer. The calculated NMR chemical shifts using GIAO method correlated well
with the experimental data for thione tautomer T2 than thiol one (T1). The optimized
molecular structure and spectral properties of the stable tautomer have been
calculated. The theoretical vibrational spectra calculated using the 6-311G++(d,p)
basis set gave better agreement with the experimental data than the other basis sets.
The assignments of all the fundamental vibrational modes of the title compound were

made based on the results of the PED calculations. The calculated electronic spectra
using TD-DFT predicted the longest wavelength band at 294.9nm which corresponds
to the transition from the HOMO and HOMO-2 to LUMO. The dipole moments,
linear polarizability and the first hyperpolarizability β0 predicted that the studied
compound has higher NLO than urea. Various intramolecular interactions that is
responsible for the stabilization of the molecule was revealed by natural bond orbital
analysis. The presence of C‒H…N intramolecular H-bonding interaction is confirmed
using the second order perturbation theory. The NPA analysis reveals the charge
distribution among the atoms. The MEP analysis showed that O17 and H37 are the
most preferred sites for electrophilic and nucleophilic attack, respectively.

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Cl
O
N
Cl
O
N
CS2 ,KOH
EtOH
N
N
N
NH
S
NHNH2
S
O
S
O
2
1
Fig. 1 The synthesis of the target compound 2.
Fig. 1a.The structure of the two possible tautomers of compound 2.

Fig. 2 The optimized molecular geometry and atom numbering scheme of the
thione tautomer of compound 2.

Fig. 3 Molecular Electrostatic potentials (MEP) mapped on the electron density
surface calculated by the DFT/B3LYP method.

Fig. 4 The experimental (upper) and calculated (lower) vibrational spectra of
compound 2.

Fig. 5 The ground state isodensity surface plots for the molecular orbitals (MOs)
contributed in the electronic transitions of the most stable tautomer (T2) using
B3LYP/6-311++G(d,p) method.

Table 1 The Calculated vibrational frequencies (υ) in cm-1 and vibrational intensities
(A) in kmmol-1 for the studied compound using B3LYP method.
6-31g(d,p)
A
139.5
0.1
1.3
10.4
7.4
1.3
3.1
11.8
4.6
9.1
44.4
325.0 0.9251
41.8
22.8
107.1
6-311g(d,p)
A
6-311g++(d,p)
A
No.
Exp.
Approximate assignment
S.F
0.9378
0.9561
S.F
0.9422
0.9615
S.F
0.9429
0.9624
υ
υ
υ
1
2
3
4
5
6
7
8
3692
3230
3228
3223
3217
3213
3211
3205
3190
3165
3071
1790
1670
1663
1650
1631
1630
1609
1532
1514
1504
1502
1453
1440
1376
1362
1346
1335
1323
1317
1286
1279
1276
1240
1229
1219
1199
1178
1165
1136
1131
1108
1088
1079
1049
1032
1004
990
3675
3212
3210
3204
3199
3195
3193
3187
3172
3150
3065
1772
1661
1650
1636
1619
1619
1594
1521
1503
1494
1492
1441
1431
1359
1353
1335
1323
1315
1312
1279
1278
1273
1232
1219
1217
1195
1171
1159
1132
1127
1101
1082
1069
1044
1033
1011
989
143.1
0.1
1.1
10.5
6.6
1.2
3.0
10.7
4.2
7.2
33.0
356.4 0.9347
49.5
19.3
126.9
249.4
0.8
284.3
102.4
206.6
361.6
2.1
35.7
6.0
29.2
69.7
99.6
0.2
3672
3209
3207
3203
3197
3192
3191
3186
3171
3146
3058
1754
1657
1647
1634
1616
1615
1590
1519
1501
1491
1489
1447
1429
1358
1347
1331
1320
1314
1310
1277
1270
1269
1230
1217
1207
1194
1171
1155
1132
1126
1101
1082
1067
1043
1033
1004
986
144.8
0.0
0.7
9.5
5.3
0.6
3.1
8.1
3.7
3462 100υNH
3088 95υCH
97υCH
3065 90υCH
86υCH
0.9509
0.9464
0.9566
0.9517
0.9569
0.9528
3041 90υCH
89υCH
83υCH
96υCH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
8.9
(15υC25H35+84υC25H36
)
)
assym
0.9515
0.9533
46.9
403.7
47.9
26.0
109.6
2.8
238.0
319.9
101.5
181.0
389.9
5.5
27.9
5.2
26.4
79.4
103.2
0.1
0.9557
2922 (15υC25H36+84υC25H35
0.9444 1656
sym
80υC=O+10δCNC
72υC=N+11υCC
51υCC
28υCC
48υCC+10δCNN
259.4
1.6
277.0
95.3
173.8
374.2
3.4
30.9
5.1
33.4
60.3
108.5
3.4
0.9892
0.9653
0.9931
0.9958
0.9740
0.9998
0.9984
0.9767
1.0010
1612 48υCC
1553 33υC=NCC+15δCCC+15δHCC
1521 61δHCC
37δHCC+10δCCC
53δHNN
0.9816
0.9733
0.9876
0.9882
0.9795
0.9937
0.9897
0.9810
0.9985
1474 49δHCH+42τHCSC
41υCC+10δHCC
1402 60υCC+10δHCC
10υC-N+17υC-O+22υCC+14δCCN
1345 48υCC+12δCNC
37υCC+11δHCC
10υCC+81δHCC
82υCC
0.2
5.3
5.0
29.6
103.8
44.5
45.8
9.1
111.5
29.4
4.4
0.9888
30.7
106.1
19.8
96.6
2.4
119.8
28.3
5.3
0.9927
31.6
103.6
114.4
13.5
3.0
125.6
28.8
5.6
0.9936
1302 41υC-N
13υC-N+25υC=S+30δHNN
30δHNN+30δHCH+14τHCSC
1267 17δCCC+17δHCC
46δHCC
1209 25υC-N+13δHCS
14δHCH+21δHCS
0.9931
0.9835
0.9858
0.9805
0.9953
0.9917
0.9890
0.9850
0.9981
0.9936
0.9901
0.9889
1182 56δHCS
1.7
2.7
3.2
52δHNN+13δHCS+10τHCSC
1142 17υCC+45δHCH
29υCC+65δHCC
11υCC+11δCCC+20δHCC
1090 23υCC+13δHCC
21υCC+10υCN
129.2
15.5
5.0
85.5
13.8
74.0
15.0
35.8
0.0
127.7
18.4
5.0
90.5
19.9
70.1
20.7
37.6
0.0
3.2
1.2
1.7
24.0
10.0
137.7
9.8
2.1
4.3
128.1
17.9
5.8
88.1
21.6
63.4
20.8
34.5
0.1
3.4
1.2
0.3
29.0
5.5
149.1
8.6
0.9
4.5
4.7
0.3
38.6
1.3
57.1
11.0
8.8
0.9835
0.9857
0.9841
0.9901
0.9953
0.9835
0.9903
0.9969
0.9840
1064 54υNN
77δCCC
1016 71τHCCC
31δOCN+25τHCCC
16δOCN+42τHCCC
42τHCCC+10τCCCC
40τHCCC
3.3
0.9
981
973
968
964
960
900
897
880
849
834
821
799
786
766
750
746
988
979
974
961
951
901
901
877
848
832
818
815
789
768
750
745
985
980
972
959
946
899
889
876
847
830
818
801
782
765
749
743
31.0
2.4
109.6
11.0
9.4
0.8
3.6
3.0
0.1
35.7
2.6
42.4
12.7
7.2
6.4
6.0
13.4
4.2
13.9
13τHCCC
0.9831
0.9864
0.9885
948 32δOCN +22δCNN
14δCNN
54τHCCC
0.9854
0.9952
0.9880
0.9773
0.9817
0.9966
0.9911
0.9739
0.9942
0.9971
0.9916
0.9827
884 15δCCC+11τHCCC
21τHCSC
845 32τHCCC
3.7
0.0
84τHCCC
37.2
0.5
53.4
10.1
7.9
7.5
3.3
18.4
6.1
14.4
811 12τHCCC
62τHCCC
768 28τCCCC+37τONCC (OUT)
27υCC+14δCNN+11δOCN+10τOCNN
13δCCC
737 34υC-S+10τOCNN+17τCONC(OUT)
60τCCCC
695 11τHCCC+48τCCCC+28τCONC(OUT)
22τCNNC+52τSNOC(OUT)
15τCNCN+25τNNSC(OUT)
0.9886
0.9870
0.9892
0.9787
8.0
4.8
16.6
10.4
14.8
0.9925
0.9823
719
704
670
662
727
710
670
664
725
708
665
663

69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
658
649
641
616
604
541
539
527
519
502
470
450
423
423
414
371
368
360
306
298
293
286
238
198
191
161
146
126
120
106
74
3.3
6.6
0.4
3.4
5.2
9.0
3.1
16.8
25.8
79.5
0.2
16.5
0.0
0.1
8.5
20.4
2.7
1.9
1.4
3.9
0.8
0.1
2.2
2.6
0.4
0.1
0.8
1.7
2.6
0.9
0.2
0.2
0.6
1.4
0.1
0.5
0.7
0.9871
661
649
642
615
605
541
539
527
521
510
471
449
424
423
414
370
368
361
307
298
291
286
239
196
191
160
145
126
120
105
74
6.3
7.0
0.7
2.9
4.9
8.9
4.0
23.7
34.4
69.5
0.5
17.6
0.2
0.1
8.4
17.1
4.6
3.8
1.7
2.9
0.5
0.0
2.4
2.3
0.5
0.4
1.0
1.7
2.1
0.9
0.2
0.1
0.4
1.0
1.0
0.5
0.6
0.9839
659
648
641
615
604
540
537
527
519
493
468
449
423
421
414
372
368
359
305
293
288
285
238
195
191
158
145
126
120
104
73
3.8
3.3
0.6
2.2
5.3
8.1
2.8
11.5
28.8
72.2
0.7
17.8
0.0
0.3
6.0
14.3
9.0
2.0
1.2
3.6
0.5
0.1
2.5
2.2
0.6
0.3
0.7
1.5
2.4
1.1
0.2
0.2
0.0
1.2
0.9
0.5
0.6
0.9858
650 26υC-S+21τOCNN
30δCCC
13δOCC+14δCCC
10υCCl
601 10δCCC+27δCNC
49τCCCC
535 13υCN+13δCCC
65δCNN
514 11τHCCC+37τCCCC+16τClCCC
68τHNCC+10τSNOC(OUT)
22δCCN+12τCCNC+12τCCCC
447 37υCCl
0.9952
0.9920
0.9911
0.9940
0.9919
0.9875
0.9945
0.9970
0.9897
0.9926
0.9953
0.9951
33τHCCC+55τCCCC
22δCCN+26τCCCC
27δCCC+28δSCO
10υCN+12δOCC+11δSCO
23τClCCC(out)
12υCN+33δNCS
33τCCCN+11τCCCC
16δSCCO+14δCSC
74δClCC
10δOCC+10τCCCN
16υCN
32δCSC+25τCNNC+12τSNOC(out)
15δCCN+22δCSC
10τCCCC+43τCCNC
147τCNCN+10τCNCS+10τCCCN(out)
12τCCCC+12τCNCN+13τClCCC(out)
38τCCCN(out)
38τCCCN(out)+32τCONC(out)
19τCCCN+13τNCSC+21τSCCO
53τCCNC+11τCNCS+10τCSCC
26τCCNC+23τCNCS+14τSCCO
37τSCCO
14τCNCS+40τCSCC
15τSCCO
38τCCCC
100
101
102
103
104
105
Av.
S.F
44
34
33
26
15
11
43
36
31
30
16
12
44
38
33
32
14
10
0.9783
0.9814
0.9840

Table 2 A comparison of calculated chemical shifts δ(ppm) using GIAO method with
experimental values in DMSO and CDCl3 of the studied compound.
δcalc (ppm)
Atom
δexp.(ppm)DMSO
δexp.(ppm)CDCl3
NH tautomer SH tautomer
C1
C2
C3
C4
C5
C6
C8
131.8
141.5
132.3
154.2
126.1
134.5
165.1
167.2
142.8
139.0
135.7
153.5
139.4
136.4
169.1
187.8
33.2
7.6
7.9
7.9
8.6
7.4
7.6
7.4
7.7
5.7
126.0
135.6
127.0
147.3
120.1
127.1
161.1
161.0
134.8
132.0
130.2
135.5
132.0
130.2
155.2
178.3
26.3
7.51
8.09
7.58
8.86
7.56
7.68
7.56
7.68
126.5
135.5
126.8
147.2
119.8
127.4
161.6
160.4
133.4
130.6
130.3
135.2
130.6
130.3
153.3
178.6
26.1
7.47
7.79
7.65
8.25
7.31
7.55
7.31
7.55
131.7
141.3
132.5
154.5
126.4
134.5
166.2
167.0
142.6
138.9
135.7
154.0
139.4
136.2
173.7
171.3
33.2
7.62
7.94
7.87
8.63
7.33
7.61
7.34
7.63
C10
C11
C12
C13
C14
C15
C18
C19
C21
C25
H27
H28
H29
H30
H31
H32
H33
H34
H35
H36
H37
4.54
4.54
13.1
4.44
4.44
11.1
5.6
3.9
4.8
3.6
8.2

Table 3 The dipole moments components μ(D), static polarizability components
(a.u.), the average polarizability α0 (Å3) and the first hyperpolarizability components β
(a.u.) and the first hyperpolarizability β0(×10−31 cm5 esu−1) of T2.
μx
μy
βxyy
βyyy
βxxz
βxyz
βyyz
βxzz
βyzz
βzzz
βxyy
βyyy
βx
1.0826
-0.3000
-4.9401
5.0662
94.8318
-122.5307
-52.9993
192.6732
-107.0218
33.3502
μz
μtot
αxx
αxy
αyy
αxz
αyz
αzz
α0
304.0894
34.9806
277.3650
3.3166
59.2135
-3.5027
13.0512
41.9132
-61.1724
215.9849
39.3894
1469.1743
4440.8551
11876.7916
11.5220
βy
βz
β0

Table 4 The second order perturbation energies E(2) (kcal/mol) of the most important
charge transfer interactions (donor–acceptor) in the studied compound using
B3LYP/6-311++G(d,p) method.
E(2)a
kcal/mol
20.37
17.59
16.77
21.2
19.46
14.82
11.32
25.71
16.27
19.09
21.28
20.37
18.48
20.27
22.13
8.05
15.18
3.21
53.25
43.28
4.12
23.91
17.24
31.78
4.5
35.26
38.41
23.00
71.58
8.76
E(j)-E(i)b
a.u.
F(i,j)c
a.u.
Donor NBO (i)
Acceptor NBO (j)
BD(2)C1-C6
BD(2)C1-C6
BD(2)C2-C3
BD*(2)C2-C3
BD*(2)C4-C5
BD*(2)C1-C6
BD*(2)C4-C5
BD*(2)C1-C6
BD*(2)C2-C3
BD*(2)N7-C8
BD*(2)C10-O17
BD*(2)C4-C5
BD*(2)C13-C14
BD*(2)C15-C18
BD*(2)C11-C12
BD*(2)C15-C18
BD*(2)C11-C12
BD*(2)C13-C14
BD*(1)C4-C5
BD*(1)C8-N9
BD*(1)C25-H35
BD*(2)N7-C8
0.29
0.28
0.29
0.28
0.29
0.29
0.25
0.27
0.37
0.28
0.29
0.29
0.3
0.28
0.27
0.91
0.76
0.74
0.27
0.29
1.25
0.25
0.71
0.62
1.16
0.34
0.29
0.28
0.23
0.76
0.87
0.97
1.12
0.47
0.62
0.88
0.32
0.069
0.064
0.063
0.071
0.07
BD(2)C4-C5
0.06
0.048
0.076
0.075
0.066
0.071
0.07
0.067
0.067
0.07
0.078
0.097
0.045
0.108
0.102
0.064
0.072
0.101
0.126
0.065
0.099
0.098
0.074
0.116
0.073
0.069
0.055
0.069
0.088
0.078
0.054
0.063
BD(2)N7-C8
BD(2)C11-C12
BD(2)C13-C14
BD(2)C15-C18
LP(1)N7
LP(1)N9
BD*(2)C10-O17
BD*(1) N7-C8
BD*(2)N7-C8
LP (1)S16
LP(2)S16
LP(2)O17
BD*(1)C5-C10
BD*(1)N9-C10
BD*(1)C19 -N23
BD*(2)C19-N23
BD*(1)C21-S24
BD*(2)C19-N23
BD*(1)C21-S24
BD*(1)C19-O20
BD*(1)C21-N22
BD*(1)O20-C21
BD*(1)C21-N22
BD*(1)O20-C21
BD*(1)C21-N22
BD*(1)C13-C 14
BD*(2)C13-C14
LP (1)O20
LP(2)O20
LP(1)N22
LP(1)N23
LP(1)S 24
LP(2)S24
6.80
3.69
5.16
20.17
11.94
4.2
LP (2)Cl 26
LP(3)Cl26
12.89
a E(2) means energy of hyperconjucative interactions.
b Energy difference between donor and acceptor i and j NBO orbitals.
c F(i, j) is the Fock matrix element between i and j NBO orbitals.

Highlights
 Synthesis and spectral characterization of new oxadiazole derivative are presented
 The compound exists as thione-(T2) tautomer rather than thiol-(T1) one.
 The calculated NMR spectra of T2 correlated well with the experimental data than T1
 The NBO analysis is used to explain the intramolecular charge transfer interactions

Graphical Abstract
Experimental and Theoretical Spectroscopic Studies, HOMO–LUMO, NBO
Analyses and Thione-Thiol Tautomerism of a New Hybrid of 1,3,4-Oxadiazole-
thione with Quinazolin-4-one
Saied M. Soliman, Mohamed Hagar, Farahate Ibid, El Sayed H. El Ashry*
Optimized molecular structure and molecular electrostatic potential (MEP) calculated
at B3LYP/6-311G++(d,p) method of hybrid 3-(4-chlorophenyl)-2-[(5-thioxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl)methylthio]quinazolin-4(3H)-one 2