Synthesis, experimental, theoretical characterization and biological activities of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione

Article abstract of DOI:10.1016/j.saa.2012.12.052

This work presents the characterization of 4-ethyl-5-(2-hydroxyphenyl)-2H- 1,2,4-triazole-3(4H)-thione (III) by quantum chemical calculations and spectral techniques. The molecular geometry, vibrational frequencies and gauge including atomic orbital (GIAO

Full text of DOI:10.1016/j.saa.2012.12.052

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
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Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Synthesis, experimental, theoretical characterization and biological activities of
4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione
a
b
c
Metin Koparir a, , Cahit Orek , Pelin Koparir , Kamiran Sarac
⇑
a Firat University, Faculty of Science, Department of Chemistry, 23119 Elazig, Turkey
b Department of Chemistry, Forensic Medicine Institute, TR-44000 Malatya, Turkey
c Inönü University, Faculty of Science, Department of Chemistry, 44100 Malatya, Turkey
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
"
"
"
"
4-Ethyl-5-(2-hydroxyphenyl)-2H-
1,2,4-triazole-3(4H)-thione was
prepared.
Synthesis compound was confirmed
by IR, NMR and X-ray single-crystal
diffraction.
Experimental parameters of title
compound were compared with
calculated parameters.
The title compound has been tested
in vitro for biological effects.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 October 2012
Received in revised form 10 December 2012
Accepted 14 December 2012
Available online 2 January 2013
This work presents the characterization of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione
(III) by quantum chemical calculations and spectral techniques. The molecular geometry, vibrational fre-
quencies and gauge including atomic orbital (GIAO) 1H and 13C NMR chemical shift values of III in the
ground state have been calculated using the density functional method (B3LYP) with the 6-31G(d) basis
set. The calculated results show that the optimized geometry can well reproduce the crystal structure,
and the theoretical vibrational frequencies and chemical shift values show good agreement with exper-
imental values. To determine conformational flexibility, the molecular energy profile of the title com-
pound was obtained by DFT calculations with respect to the selected torsion angle, which was varied
from ꢀ180° to +180° in steps of 10°. The energetic behavior of III in solvent media was examined using
the B3LYP method with the 6-31G(d) basis set by applying the Onsager and the polarizable continuum
model (PCM). The predicted nonlinear optical properties of III are greater than ones of urea. In addition,
DFT calculations of molecular electrostatic potentials and frontier molecular orbitals of III were carried
out at the B3LYP/6-31G(d) level of theory. The title compound was screened for antibacterial, antifungal
and antioxidant activities.
Keywords:
4-Ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-
triazole-3(4H)-thione
DFT
NMR
IR spectra
Biological effects
Ó 2012 Elsevier B.V. All rights reserved.
Introduction
including anti-inflammatory [3,4], antiviral [5], analgesic [6], anti-
microbial [7], anticonvulsant [8], anticancer [9], antioxidant [10],
1,2,4-triazole rings are typically planar 6
p
-electron aromatic
antitumoral [11] and antidepressant activity [12], the last usually
being explored by the forced-swim test [13,14]. Furthermore, some
of the complexes containing 1,2,4-triazole ligands have rather pe-
culiar structures and specific magnetic properties [15–18].
systems, featuring an extensive chemistry [1,2]. 1,2,4-triazole
and its derivatives represent one of the most biologically active
classes of compounds, possessing a wide spectrum of activities,
4,5-Substituted products containing 1,2,4-triazole ring in their
structure seem to be suitable candidates for further chemical mod-
ifications and might be of interest as pharmacologically active
⇑
Corresponding author. Tel.: +90 424 237 00 00; fax: +90 424 237 00 10.
E-mail address: mkoparir@hotmail.com (M. Koparir).
1386-1425/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.saa.2012.12.052

M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
523
compounds and useful ligands in coordination chemistry [19].
Derivatives of 4-amino-5-substituted 1,2,4-triazole were synthe-
sized by intramolecular cyclization of 1,4-disubstituted thiosemic-
arbazides [20]. In addition there are some studies on electronic
structures and thiol-thione tautomeric equilibrium of heterocyclic
thione derivatives [21–25]. Several heterocycles containing a thia-
diazole or triazole moiety have been reported; [26–30] however,
the synthesis of heterocyclic systems containing a phenol-substi-
tuted triazole ring has rarely been reported [31–33].
Density functional theory (DFT) has been one of the widely used
theories in theoretical modeling during recent years. By means of
the development of better exchange–correlation functionals, it
has become possible to calculate many molecular properties which
have accuracies that can be comparable to traditionally correlated
ab initio methods, all these could be done with more favorable
computational costs [34]. It has been figured out during the litera-
ture survey that in reproducing the experimental values in geom-
etry, dipole moment, vibrational frequency, etc. DFT has a precise
accuracy [35–39].
The aim of this study is to investigate the energetic and struc-
tural properties of the 1,2,4-triazole compound, 4-ethyl-5-(2-
hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (Fig. 1), using den-
sity functional theory calculations. In this study, the optimized
geometry, vibrational spectra and assignments, statistical ener-
getic parameters, conformational analysis and nonlinear optical
properties of III have been studied. These calculations are valuable
for providing insight into molecular properties of 1,2,4-triazole
compounds. Besides the characterization of the title compound,
the biological activities of the III, such as antibacterial, antifungal
and antioxidant activities, were investigated.
one FT-IR spectrophotometer was used in order to record FT-IR
spectra of III in 4000–400 cmꢀ1 region. Electronic spectral studies
were conducted on a Shimadzu model UV-1700 spectrophotome-
ter in the wavelength 1100–200 nm. The 1H and 13C spectra were
taken on Bruker AC-400 NMR spectrometer operating at
400 MHz for 1HA, 100 MHz for 13C NMR. Elemental analyses were
done on a LECO-CHNS-938. Compound was dissolved in DMSO-d6
and chemical shifts were referenced to TMS (1H and 13C NMR).
Starting chemicals were provided by Merck or Aldrich. The synthe-
sis reaction of III is shown in Fig. 2.
Antibacterial activity
The synthesized compound III was screened for their antibacte-
rial activity against Escherichia coli (ATTC-25922), Staphylococcus
aureus (ATTC-25923), Pseudomonas aeruginosa (ATCC-27853) and
Klebsiella pneumoniae (recultured) bacterial strains by serial plate
dilution method [40,41]. Serial dilutions of the drug in Muller–Hin-
ton broth were taken in tubes and their pH was adjusted to 5.0
using phosphate buffer. Standardized suspension of the test bacte-
rium was inoculated and incubated for 16–18 h at 37 °C. The min-
imum inhibitory concentration (MIC) was noted by observing the
lowest concentration of the drug at which there was no visible
growth. A number of antimicrobial disks are placed on the agar
for the sole purpose of producing zones of inhibition in the bacte-
rial lawn. Agar media were poured into each Petri dish. Excess of
suspension was decanted and placing in incubator at 37 °C for
1 h dried the plates. Using an agar punch, wells were made on
these seeded agar plates and minimum inhibitory concentrations
of the test compounds in DMSO were added into each labeled well.
A control was also prepared for the plates in the same way using
DMSO as solvent. The Petri dishes were prepared in triplicate
and maintained at 37 °C for 3–4 days. Antibacterial activity was
determined by measuring the diameter of inhibition zone. Activity
of each compound was compared with Ciprofloxacin as standard
[42,43]. Zone of inhibition was determined for title compound
the results are summarized in Table 1.
Experimental
Synthesis
For the synthesis of 1(2-hydroxybenzoyl)-4-ethyl thiosemicar-
bazide (II), a mixture of I (0.01 mol) and ethyl isothiocyanate
(0.01 mol) in absolute ethanol was refluxed for 8 h. The solid mate-
rial obtained on cooling was filtered, washed with diethyl ether,
dried and crystallized from ethanol–dioxane (yield 65%, m.p.
489–491 K). IR (ˆ, cmꢀ1): 3495, 3317 (NAH, OH), 1668 (C@O),
1262 (C@S). For the synthesis of III, a stirred mixture of II
(0.01 mol) and sodium hydroxide (40 mg, 0.01 mol, as a 2 N solu-
tion) was refluxed for 4 h. After cooling, the solution was acidified
with HCl (37%) and the precipitate was filtered off. The precipitate
was then crystallized from an ethanol–dioxane mixture (yield 85%,
m.p. 527–531 K). IR (ˆ, cmꢀ1):3390, 3216(NAH, OAH), 1622 (C@N),
1535, 1260, 1050, 950 (NAC@S, amide I, II, III and IV bands); 1H
NMR (400 MHz, DMSO-d6, 24ꢀC): d 1.03 (t, J = 7.02, 3H, CH3), 3.47
(q, J = 7.32, 2H, CH2), 7.82–7.14 (m, 4H, ArAH), 10.00 (s, 1H, OH),
13.80 (s, 1H, SH). Elemental analysis: C, 54.25; H, 5.05; N, 18.96.
Antifungal activity
Newly prepared compound was screened for their antifungal
activity against Aspergillus flavus [NCIM No. 524], Aspergillus fumig-
atus [NCIM No. 902], Penicillium marneffei [recultured] and Tricho-
phyton mentagrophytes [recultured] in DMSO by serial plate
dilution method [44,45]. Agar media were prepared by dissolving
peptone (1 g), D-glucose (4 g) and agar (2 g) in distilled water
(100 mL) and adjusting the pH to 5.7. Normal saline was used to
make a suspension of spore of fungal strains for lawning. A loopful
of particular fungal strain was transferred to 3 mL saline to get a
suspension of corresponding species. Agar media of 20 mL were
poured into each Petri dish. Excess of suspension was decanted
and plates were dried by placing in an incubator at 37 °C for 1 h.
Using an agar punch each labeled well were made on these seeded
agar plates and MIC of the test compounds in DMSO were added
into each labeled well. A control was also prepared for the plates
in the same way using solvent DMSO. The Petri dish were prepared
in triplicate and maintained at 37 °C for 3–4 days. Antifungal activ-
ity was determined by measuring the diameter of the inhibition
zone. Activity of each compound was compared with Ciclopiroxol-
amine as standard. Zones of inhibition were determined for title
compound the results are summarized in Table 2.
Physical measurements
Melting points were determined on a Thomas Hoover melting
point apparatus and uncorrected, but checked by differential scan-
ning calorimeter (DSC). KBr pellets on a Perkin–Elmer Spectrum
DPPH free radical scavenging activity
Free radical scavenging activity of the title compound was
determined by measuring the change in the absorbance of
Fig. 1. Chemical diagram of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-
thione.

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M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
Fig. 2. The reaction for the synthesis of title compound.
Table 1
Minimum inhibitory concentration (MIC,
l
g/mL) data of the title compound against a number of bacteria.
Compound
MIC in
lg/mL and zone of inhibition (mm)
E. coli
K. pneumoniae
P. aeruginosa
S. aureus
Title compound
Ciprofloxacin
6.25 (16–20)
6.25 (16–20)
12.50 (11–15)
6.25 (16–20)
12.50 (16–20)
6.25 (16–20)
6.25 (16–20)
1.56 (22–30)
Note: The MIC values were evaluated at concentration range, 1.56–25 lg/mL.
Table 2
Antifungal activity of title compound.
Compound
MIC in lg/mL and zone of inhibition (mm)
P. marneffei
T. mentagrophytes
A. flavus
A. fumigatus
Title compound
Ciclopiroxolamine
12.50 (11–15)
6.25 (16–20)
6.25 (16–20)
3.125 (27–33)
6.25 (16–20)
3.125 (25–30)
12.50 (11–15)
6.25 (16–20)
Note: The MIC values were evaluated at concentration range, 1.56–25 lg/mL.
DPPHÅ (1,1-diphenyl-2-picrylhydrazylradical) at 517 nm spectro-
photometrically. Stock solutions of 500 M of tested sample and
DPPHÅ were prepared in DMSO. 400 L of DPPHÅ solution was
added to sample solution at different concentrations (500, 1000,
1500, 2000 and 2500 L) and appropriately diluted with DMSO
to total volume of 4.0 mL. A 400
L from DPPHÅ stock solution
was also diluted to 4.0 mL using DMSO as solvent to make the con-
trol. The reaction mixtures were thoroughly mixed by shaking the
test tubes vigorously and incubated at 25 °C for 60 min in a water
bath in the dark. Absorbance at 517 nm was measured and the sol-
vent was corrected throughout. Ascorbic acid was used as a stan-
dard (using the reference antioxidant) for this test. The DPPH
(1,1-diphenyl-2-picrylhydrazyl) radical scavenging method was
chosen to determine the antioxidant potential of the target com-
pounds in comparison with the commercially available antioxidant
Ascorbic acid at the same concentrations. The scavenging effect
was calculated using the following equation [46]:
Computational methods
The molecular geometry was taken directly from the X-ray dif-
l
l
fraction result unrestrainedly. In the following step, the Gaussian
09W software package [47] was used to make the DFT calculations
with a hybrid functional B3LYP (Becke’s Three parameter hybrid
functional by means of the LYP correlation functional) with the
6-31G(d) basis set using the Berny method [48,49]. At the same le-
vel of the theory, the harmonic vibrational frequencies for the opti-
mized structure were assessed and the frequencies obtained scaled
by 0.9613 [50]. Gauss-View molecular visualization program was
used to carry out vibrational band assignments [51]. Conforma-
tional energies were calculated as a one-dimensional scan by vary-
l
l
ing the
u1(NlAClAC3AC4) and u2(ClAN3AC9AC10) dihedral
angles from ꢀ180° to ꢀ180° in steps of 10°, and the molecular en-
ergy profile was obtained.
On order that we can evaluate the energetic and atomic charge
behavior of III in solvent media, we performed optimization calcu-
lations in five solvent [
dichloroethane (CH2ClCH2Cl);
46.83, DMSO; = 78.36, water (H2O)]. These calculations were
e
= 4.71, chloroform (CHCl3);
e = 10.13,
A0 ꢀ As
e
= 24.85, ethanol (C2H5OH);
e =
Scavenging activity ð%Þ ¼
ꢁ 100
A0
e
made at the B3LYP/6-31G(d) level and Onsager [52] and Polariz-
able Continuum Model (PCM) [53–56] methods were used. To
investigate the reactive sites of III the molecular electrostatic
potentials were evaluated using B3LYP/6-31G(d) method. The
mean linear polarizability and mean first hyperpolarizability
where As is the absorbance of the DPPHÅ in the presence of the
tested compound and A0 is the absorbance of the DPPHÅ in the ab-
sence of the tested compound (control). The data for antioxidation
presented as means SD of three determinations.

M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
525
properties of III were obtained from molecular polarizabilities
based on theoretical calculations. In addition, frontier molecular
orbitals (FMOs) and thermodynamic parameters for the title com-
pound were performed with B3LYP/6-31G(d) the optimized
structure.
the calculated and experimental values in solid state. The orienta-
tion of the triazole ring of III proved the most notable discrepancy,
and is defined with torsion angle C2AN2AN1AC1 [ꢀ0.922(13)°],
which is calculated at ꢀ0.878 °C for B3LYP/6-31G(d) level.
The structures obtained from theoretical calculations is globally
compared through a logical method that superimposes molecular
skeleton with what obtained from X-ray diffraction, which in con-
clusion gives a RMSE of 0.403 Å for B3LYP/6-31G(d) (Fig. S2). This
magnitude of RMSE can be explained by the fact that the intermo-
lecular Coulombic interaction with the neighboring molecules are
absent in gas phase, whereas the experimental result corresponds
to interacting molecules in the crystal lattice [58].
Results and discussion
Description of the crystal structure
The crystal structure of III is monoclinic and space group P21/c,
Mw = 221.28, a = 9.7879 (8) Å, b = 7.9071 (5) Å, c = 13.8045 (10) Å,
b = 102.266 (6), and V = 1043.99(13) Å3, Dx = 1.408 g/cmꢀ3. Addi-
tional information for the structure determinations are given in
Table S1. The dihedral angle between the benzene and triazole
rings is 85.33 (6)°, indicating that these two rings are almost
orthogonal to each other. Similarly, the plane of the ethyl moiety
(N3/C9/C10) is twisted by 89.71 (8)° out of the mean plane of the
triazole ring. There is one weak intramolecular CAHꢂ ꢂ ꢂS interaction
(Fig. S1), forming a five-membered ring fused with the triazole
ring. Intermolecular N2AH2ꢂ ꢂ ꢂS1ii hydrogen bonding (Table 3) re-
sults in the formation of a dimeric structure.
IR spectroscopy
DFT/B3LYP method with 6-31G(d) basis set was used for calcu-
lating harmonic vibrational frequencies of III, and Gauss-View
molecular visualization program for the vibrational band assign-
ments. The vibrational frequencies were analyzed for facilitating
the assignment of the observed peaks and the results of our calcu-
lation for III were compared with the experimental results (Ta-
ble 5). The consistency of the experimental results with our
calculations gives good conclusions in general.
Fig. 4 shows its results. The OH group vibrations are found to be
the possibly most sensitive to environment, therefore they show
pronounced shifts in the spectra of the hydrogen-bonded species.
The optimum absorption region of non-hydrogen-bonded or a free
hydroxyl group is 3550–3700 cmꢀ1 region [59]. In case of their
presence in molecule, intra- and intermolecular hydrogen bonding
reduces OAH stretching band to 3000–3550 cmꢀ1 region [60]. The
IR spectra of III with an intense and relatively sharp band at max-
imum 3216 cmꢀ1 was assigned to the stretching vibrations of the
sub-group in the intermolecular OAHꢂ ꢂ ꢂN hydrogen bonds formed
between N1 atom and O atom of hydroxyl group. This band has
been calculated at 3606 cmꢀ1 for B3LYP level.
Intermolecular OAHꢂ ꢂ ꢂN and CAHꢂ ꢂ ꢂ
p interactions (Table 3)
link the molecules into an infinite two-dimensional network (Cg1
in Table 3 is the centroid of the triazole ring). Intermolecular weak
p–p stacking interactions between the benzene ring and its sym-
metry-related partner at (1 ꢀ x, ꢀy, ꢀz) are also observed along
the b axis, with a distance of 3.906 (2) Å between the ring centroids
and a perpendicular distance between the rings of 3.556 (2) Å.
Previously, we have reported the closely related compound 3-
(2-hydroxyphenyl)-4-phenyl-H-1,2,4-triazole-5(4H)-thione, (VIII)
[57], which differs only in the 4-position (ethyl versus phenyl).
When the bond lengths and angles of the triazole rings in (III)
and (VIII) are compared, it is seen that the values are very close
to each other. However, the C1AC3 bond length of 1.4731 (14) Å
in (III) is significantly longer than the corresponding value in (VIII),
1.458 (2) Å. This difference may be due to a shortening of the
In the literature, some NAH stretching modes observed for the
different substituent-triazole ring are 3383 cmꢀ1 [61] and
3417 cmꢀ1 [62] as experimentally. In our study, the NAH stretch-
ing mode was observed at 3390 cmꢀ1 which has a red shift and
the cause of this shift is the intermolecular N2AH2ꢂ ꢂ ꢂS1 hydrogen
bonding. The red shifting is further enhanced by the reduction in
the NAH bond order values, occurring due to donor–acceptor
interaction [63]. These differences of OAH (390 cmꢀ1) and NAH
stretching vibrations (141 cmꢀ1) occurred between the results of
the experimental and calculations are due to the consideration of
the isolated molecules (in gas phase) in the calculational method.
The aromatic CAH stretching, CAH in-plane bending and CAH
C1AC3 bond length in (III) caused by OAHꢂ ꢂ ꢂN and CAHꢂ ꢂ ꢂ
p intra-
molecular interactions.
Optimized geometry
The optimized parameters like bond lengths, bond angles, and
dihedral angles of III were taken by using the B3LYP/6-31G(d)
method. The atomic numbering design of the theoretical geometric
structure is given in Fig. 3b. The geometric parameters which
accounted with the experimental data from the study are listed
in Table 4. The slight conformational discrepancies are observed
between the X-ray structure of III and its optimized counterparts
(see Fig. S2). It is clear that the experimental results and the theo-
retical calculations are for the solid phase and for the gas phase
sequentially. The existence of a crystal field along with the
intermolecular interactions connects the molecules together,
which results with some differences in bond parameters between
out-of-plane bending vibrations appear in 2900–3150 cmꢀ1
,
1100–1500 cmꢀ1 and 700–1000 cmꢀ1 frequency ranges, respec-
tively. The CAH aromatic stretching mode was observed at
3102 cmꢀ1 experimentally, and calculated at 3049–3099 cmꢀ1 for
B3LYP. The bands at 3040 and 2983 cmꢀ1 correspond to the asym-
metric stretching CH2 and CH3 modes, respectively. The CAH in-
plane bending vibrations computed at 1445, 1386 and 1250 cmꢀ1
by B3LYP/6-31G(d) method shows excellent agreement with FT-
IR bands at 1480, 1390 and 1230 cmꢀ1. The theoretically computed
values of the angles bending vibration modes show good agree-
ment with the experimental values. The other vibrational frequen-
cies can be seen in Table 5.
Table 3
Hydrogen bonding geometry (Å, °) for the title compound.
DAHꢂ ꢂ ꢂA
DAH
Hꢂ ꢂ ꢂA
Dꢂ ꢂ ꢂA
DAHꢂ ꢂ ꢂA
C9AH9Bꢂ ꢂ ꢂS1
1.00 (2)
0.85 (2)
0.90 (2)
1.00 (2)
2.86 (2)
1.98 (2)
2.38 (2)
2.76 (2)
3.2386 (12)
2.8227 (12)
2.2789 (10)
3.4652 (13)
104 (1)
175 (2)
174 (2)
128 (1)
O1AH1ꢂ ꢂ ꢂN1(i)
N2AH2ꢂ ꢂ ꢂS1(ii)
C9AH9Bꢂ ꢂ ꢂCg1(iii)
NMR spectra
B3LYP method with 6-31G(d) basis set was used in order to
calculate GIAO 1H and 13C chemical shift values (with respect to
TMS), which then compared with the experimental 1H and 13C
Symmetry code: (i) 1 ꢀ x, 1/2 + y, 1/2 – z, (ii) 2 ꢀ x, ꢀy, 1 – z, (iii) 2 ꢀ x, 1/2 + y, 1/
2 ꢀ z.

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M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
Fig. 3. (a) Ortep-3 diagram of the title compound and (b) the theoretical geometric structure of the title compound (with B3LYP/6-31G(d) level).
Table 4
Table 5
Selected molecular structure parameters.
Comparison of the experimental and calculated vibrational frequencies (cmꢀ1).
Parameters
Experimental
B3LYP/6-31G(d)
Assignments
Experimental IR with
KBr
B3LYP/6-
31G(d)
Bond lengths (Å)
N(1)AC(1)
N(1)AN(2)
N(2)AC(2)
N(3)AC(2)
N(3)AC(1)
N(3)AC(9)
RMSEa
1.3076 (13)
1.3737 (13)
1.3376 (14)
1.3688 (13)
1.3705 (13)
1.4694 (13)
1.309
1.366
1.360
1.385
1.389
1.467
0.013
ˆ (OAH)
ˆ (NAH)
3216
3390
3102
3606
3531
3099
3087
3076
3050
ˆs Phenol (CAH)
ˆas Phenol (CAH)
ˆas Phenol (CAH)
ˆas Phenol (CAH) + ˆas ethyl
(CAH)
ˆas Phenol (CAH) + ˆas ethyl
(CAH)
3040
2983
2950
1640
3049
Bond angles (°)
C(1)AN(1)AN(2)
C(2)AN(2)AN(1)
C(2)AN(3)AC(1)
N(1)AC(1)AN(3)
N(2)AC(2)AN(3)
RMSEa
104.20 (9)
113.06 (9)
108.20 (8)
110.71 (9)
103.81 (9)
103.86
114.57
108.08
111.18
102.30
0.489
ˆas Ethyl (CAH)
ˆas Ethyl (CAH)
ˆs Ethyl (CAH)
ˆs Ethyl (CAH)
ˆ (C@C)
3021
3013
2965
2950
1606
1586
1541
1482
1463
1445
1439
1386
1353
1323
1318
1250
1190
1130
1071
1022
946
ˆ (C@C)
ˆ (C@N) + ˆ (C@C)
Dihedral angles (°)
N(3)AC(1)AC(3)AC(8)
C(1)AN(3)AC(9)AC(10)
1622
1490
83.54 (13)
88.49 (13)
118.45
110.10
a
a
(CAH) of ethyl
(CAH) of ethyl
V (CAH) of phenol
1480
a
Between the bond lengths and the bond angles computed by the theoretical
method and those obtained from X-ray diffraction.
V (CAH) +
V (CAH) +
a
x
(CAH) + V (NAH)
(CAH) + V (NAH)
1390
1340
x
(CAH) of ethyl + V (NAH)
V (CAH) of phenol + V (OAH)
d (CAH) of ethyl
V (CAH) of phenol + ˆ (CAO)
chemical shift values. Table 6 shows the results of the aforemen-
tioned calculation.
1300
1230
1150
1140
We have calculated 1H chemical shift values (with respect to
TMS) of 8.83–0.84 ppm at B3LYP/6-31G(d) level, whereas the
experimental results are observed to be 13.80–1.03 ppm. The trip-
let observed at 3.42 ppm is assigned to C(9)H2 and quartet ob-
served at 1.03 ppm is assigned to C(10)H3 that have been
calculated at 3.33–3.90 and 0.84–1.77 ppm. The aromatic protons
resonate at 7.14–7.82 ppm multiplet experimentally, that have
been calculated at 6.72–7.48 ppm. In different substituent-1,2,4-
triazole, the H chemical shift of NAH were observed to be 11.33–
13.56 ppm [64]. The NH hydrogen of the 1,2,4-triazole ring appears
at 13.80 ppm, and is determined computationally at 8.83 ppm. The
signal assigned to proton of the OH is observed at 10.00 ppm. This
was calculated 4.72 ppm at B3LYP level. In previous work, it was
observed that chemical shift of OAH and NAH protons with the va-
lue of 10.45 ppm exist in the same band but these signals have
been calculated as 5.56 and 9.64 ppm for 6-31G(d) level, respec-
tively [65]. Because the intermolecular hydrogen bonds in molecu-
lar structure of III are neglected in the calculations, we can say that
this difference between experimental and calculated chemical
shifts is due to NAHꢂ ꢂ ꢂS and OAHꢂ ꢂ ꢂN intermolecular interactions.
We have calculated 13C chemical shift values (with respect to
TMS) of 13.37–164.32 ppm with B3LYP/6-31G(d), while, the exper-
imental results were observed to be 15.10–182.33 ppm. As can be
seen from Table 6, theoretical 1H and 13C chemical shift results of
x
(CAH) of ethyl + ˆ (CANAC)
ˆ (C@S)
d (CAH) of ethyl + ˆ (NAN)
ˆ (CAC) of phenol
ˆ (CAC) of ethyl
ˆ (CAC) of ethyl + d (CAH)
d (CAH)
d (CACAC) of phenol
d (CANAC) + d (CACAC)
d (NACAS)
941
823
726
703
740
657
ˆ, Stretching;
a, scissoring; V, rocking; x, wagging; s, symmetric; as, asymmetric; b,
bending; d, of out plane bending.
the title compound are generally closer to the experimental chem-
ical shift data.
Energetics and dipole moments
Calculations were conducted in five solvents (
= 46.83, DMSO; = 24.85, C2H5OH; = 10.13, CH2ClCH2Cl;
= 4.71, CHCl3) in order to evaluate the total energy and dipole
e = 78.36, H2O;
e
e
e
e
moment behavior of III in solvent media, which was conducted
at B3LYP/6-31G(d) level using the Onsager and PCM methods.
Table S2 shows the results of the aforementioned calculation. It

M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
527
Fig. 4. (a) FT-IR spectrum of the title compound and (b) simulated B3LYP level IR spectra.
systems. The charge distributions over the atoms suggest the for-
mation of donor and acceptor pairs involving the charge transfer
in the molecule. The Mulliken atomic charges for the non-H atoms
of III calculated at the B3LYP/6-31G(d) level in gas-phase are pre-
sented in Table S3. To investigate the solvent effect for the atomic
charge distributions of III, based on the B3LYP/6-31G(d) model and
PCM method, three solvents (chloroform, ethanol and water) were
selected and calculated values were also listed in Table S3.
The Mulliken atomic charges show that the N1, N2 and N3 atoms
of triazole ring, O1 atom of hydroxyl group and S1 atom have larger
negative atomic charges in the gas phase. On the other hand, it is
found that, in solution-phase, the atomic charge values of the N1,
S1 and O1 atoms are larger than those in gas-phase and while their
atomic charge values will increase with the increase of the polarity
of the solvent, that value of N2 and N3 decrease with the increasing
polarity of the solvent. The coordination of these atoms will change
in different solvents, which may be helpful when one wishes to use
III to construct interesting metal complexes with different coordi-
nate geometries [68]. This calculated result is not only consistent
with many reported experimental values [69–71], it also supports
the original idea of our synthesis.
Table 6
Theoretical and experimental 1H and 13C isotropic chemical shifts (with respect to
TMS, all values in ppm) for the title compound.
Atom
Experimental (ppm) (DMSO- Calculated (ppm) B3LYP/6-
d6)
31G(d)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
160.13
182.33
115.45
168.1
146.20
164.32
107.43
148.92
117.88
135.51
116.01
134.77
45.04
109.52
127.56
114.40
127.63
42.71
15.10
13.37
1.03
0.84,1.61 and 1.77
3H (CH3)
3.47
3.33 and 3.90
7.14–7.82
2H (CH2)
4H
(ArACH)
6.72–7.48
1H (NH)
13.80
10.00
8.83
4.72
1H (OAH)
can be inferred from the table that an increase in the polarity of the
solvent decreases the total energy amount that III obtains, which
therefore increases the stability of III. Fig. S3 shows the energy dif-
ference between gas phase and solvent media. It can be observed in
Fig. S3 that PCM method provides more stable structure than
Onsager’s method (6.45778 kcal/mol average). On the other hand,
that trend in total energies was not observed in dipole moments.
The dipole moments calculated using the Onsager method are lar-
ger than those calculated with PCM method in various solvents,
and an increase in solvent polarity causes also an increase in the
dipole moments obtained for the two solvation methods. Solvent
effects improve the charge present delocalized in molecules, there-
fore, causes dipole moments to rise. One of the important factor in
measuring solvent effect is ground-state dipole moment; a large
ground-state dipole moment strongly increases the effects of sol-
vent polarity [66,67].
Molecular electrostatic potential
Molecular electrostatic used extensively for interpreting poten-
tials have been and predicting the reactive behavior of a wide vari-
ety of chemical system in both electrophilic and nucleophilic
reactions, the study of biological recognition processes and hydro-
gen bonding interactions [72].
V(r), at a given point r(x, y, z) in the vicinity of a molecule, is de-
fined in terms of the interaction energy between the electrical
charge generated from the molecule electrons and nuclei and posi-
tive test charge (a proton) located at r. Unlike many of the other
quantities used at present and earlier as indices of reactivity, V(r)
is a real physical property that can be determined experimentally
by diffraction or by computational methods. For the systems stud-
ied the MEP values were calculated as described previously, using
the equation [73]:
Z
ðr0Þ
X
ZA
jRA ꢀ rj
q
VðrÞ ¼
ꢀ
dr0
Atomic charge distributions in gas-phase and in solution-phase
jr0 ꢀ rj
Mulliken atomic charge calculation has an important role in the
application of quantum chemical calculation to molecular system
because of atomic charges effect dipole moment, molecular polar-
izability, electronic structure and a lot of properties of molecular
where the summation runs over all the nuclei A in the molecule and
polarization and reorganization effects are neglected. ZA is the charge
of the nucleus A, located at RA and
function of the molecule. To predict reactive sites for electrophilic
q
(r0) is the electron density

528
M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
and nucleophilic attack for the investigated molecule, molecular
electrostatic potential (MEP) was calculated at B3LYP/6-31G(d) opti-
mized geometries. Red and blue areas in the MEP map refer to the re-
gions of negative and positive potentials and correspond to the
electron-rich and electron-poor regions, respectively, whereas the
green color signifies the neutral electrostatic potential. The MEP sur-
face provides necessary information about the reactive sites.
The negative regions V(r) were related to electrophilic reactivity
and the positive ones to nucleophilic reactivity. As easily can be
seen in Fig. 5, this molecule has several possible sites for electro-
philic attack in which V(r) calculations have provided in-sights.
Negative regions in the studied molecule were found around the
O1 atom and N1 atom of triazole ring. The negative V(r) values
are ꢀ0.045 a.u. for O1 atom, which is the most negative region,
ꢀ0.038 a.u. for N1 atom which is a less negative region. However,
a maximum positive region is localized on the H atom of the hy-
droxyl group with a value of +0.080 a.u. indicating a possible site
for nucleophilic attack. According to these calculated results, the
MEP map shows that the negative potential sites are on electroneg-
ative atoms as well as the positive potential sites are around the
hydrogen atoms. These sites give information about the region
from where the compound can have intermolecular interactions.
with B3LYP method using 6-31G basis set as a function of the se-
lected degrees of torsional freedom, 1(N3AClAC3AC8) and u2-
(C10AC9AN3AC1). The respective values of the selected degrees
torsional freedom, 1(N3AClAC3AC8) and 2(C10AC9AN3AC1),
u
u
u
are in optimized geometries ꢀ118.449 and ꢀ110.102°, respectively
for B3LYP/6-31G(d).
The molecular 1-D energy profiles with respect to rotations
about the selected torsion angles are presented in Fig. 6. According
to the results, the low-energy domains for
u1(N3AClAC3AC8) are
located at ꢀ130 and +120°, with energies of ꢀ1025.356 and
ꢀ1025.355 a.u., respectively, while they are located at ꢀ80 and
+110° having energy of ꢀ1025.356 and ꢀ1025.355 a.u., respec-
tively, for
u2(C10AC9AN3AC1). Energy difference between the
most favorable and unfavorable conformers, which arises from
rotational potential barrier calculated with respect to the selected
torsion angles, were calculated as 7.185 kcal/molꢀ1 for B3LYP/6-
31G(d).
Frontier molecular orbitals
In principle, there are several ways to calculate the excitation
energies. The simplest one involves the difference between the
highest occupied molecular orbital (HOMO) and the lowest unoc-
cupied molecular orbital (LUMO) of a neutral system, which is a
key parameter in determining molecular properties [74]. More-
Conformational analysis
To define the preferential positions of phenol ring and ethyl
group, a preliminary search of low energy structures was performed
over, the Eigen values of HOMO (p donor) and LUMO (p acceptor)
and their energy gap reflect the chemical activity of the molecules.
Recently, the energy gap between HOMO and LUMO has been used
to prove the bioactivity from intramolecular charge transfer (ICT)
[75,76]. Fig. 7 shows the distributions and energy levels of the
HOMOꢀ1, HOMO, LUMO and LUMO+1 orbitals computed at the
B3LYP/6-31G(d) level for III. As seen from Fig. 7, both in the HOMO
and HOMOꢀ1, electrons are delocalized on the S1 atom and tria-
zole ring. For the LUMO and LUMO+1 electrons are mainly delocal-
ized on the triazole and phenol rings. The value of the energy
separation between the HOMO and LUMO is 4.371 eV. This large
HOMO–LUMO gap automatically means high excitation energies
for many of excited states, a good stability and a high chemical
hardness for III.
Nonlinear optical effects
NLO properties has been of great interest by the recent years.
Because some synthesized novel materials show efficient nonlinear
optical that are used telecommunication, potential applications in
Fig. 5. Molecular electrostatic potential map calculated at B3LYP/6-31G(d) level.
Fig. 6. Molecular energy profile against the selected torsional degree of freedom at B3LYP/6-31G(d) level.

M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
529
modern communication technology, optical signal processing and
data storage.
The text previously explains the way that total molecular dipole
moment (l), linear polarizability (a) and first-order hyperpolariz-
ability (b) are calculated using Gaussian output in detail [77].
DFT has been commonly used as an effective method to investigate
organic NLO materials. Literature extensively states that electric
hyperpolarizability can reliably be calculated through the B3LYP
approach reliable values in, compared to accuracies of traditional
ab initio methods. It is also reported that most computational sci-
entists are interested in this aforementioned predictive capability
of widely used B3LYP method [78,79]. In addition, this study pre-
ferred the basis set 6-31G(d) for the calculations of the hyperpolar-
izability, considering its reliability and the required computational
time [80].
The electronic dipole moment li(i = x, y, z), polarizability aij and
the first hyperpolarizability bijk of III were calculated at the B3LYP/
6-31G(d) level using Gaussian 09W program package. Urea is one
of the prototypical molecules used in the study of the NLO proper-
ties of molecular systems. Therefore it was used frequently as a
threshold value for comparative purposes. The calculated values
of atot and btot for III are, 21.264 Å3 and 5.727 ꢁ 10ꢀ30 cm5/esu,
which are greater than those of urea (the atot and btot of urea are
3.831 Å3 and 0.37 ꢁ 10ꢀ30 cm5/esu obtained by B3LYP/6-31G(d)
method). According to the magnitude of the first hyperpolarizabil-
ity, III may be a potential applicant in the development of NLO
materials.
Biological study
Antibacterial and antifungal activity
The investigation of antibacterial and antifungal screening data
revealed that the title compound showed good inhibition at 1.56–
25 mg/mL in DMSO. The screening result indicate that title com-
pound tested exhibited significant antibacterial and antifungal
activities when compared with the reference drug. The title com-
pound was found to be same potent as the reference drug, cipro-
floxacin, in case of E. coli. Structure and biological activity
relationship of title compound showed that presence of 4-hydroxy
groups attached to phenyl ring to the triazole ring of the title com-
pound is responsible for good antimicrobial activity [81]. In conclu-
sion the present study showed that the synthesized compound can
be used as template for future development through modification
and derivatization to design more potent and selective antimicro-
bial agents.
Antioxidant activity
Since the antioxidants are gaining a lot of importance as pana-
cea for a large number of life-style diseases like aging, cancer, dia-
betes, cardiovascular and other degenerative diseases, it is of
immense significance to establish some new antioxidants by a con-
venient synthetic methodology.
Fig. 7. Molecular orbital surfaces and energy levels given in parentheses for the
HOMO, HOMOꢀ1, LUMO and LUMO+1 of the title compound computed at B3LYP/6-
31G(d) level.
Although a number of methods such as ORAC, ABTS, DMPD,
FRAP, TRAP, TBA, superoxide radical scavenging, hydroxyl radical
scavenging, nitric oxide radical scavenging, xanthine oxidase, cyto-
chrome C, reducing power method, etc. available, the DPPH meth-
od is very common and proved as the best [82].
It has been reported that the antioxidant activity of the phenolic
compounds depends on their molecular structure, especially on
their hydrogen-donating ability and subsequent stabilization of
the formed phenoxy radical [83]. As shown in Table 7, the title
compound has scavenging activity between 40.9% and 88.1% with-
in the investigated concentration range. The antioxidant activity of
the title compound is obvious that the scavenging activity in-
creases with increasing sample concentration in the range tested.
This activity can be explained on the basis of their structure as
Table 7
Antioxidant scavenging activity data of the title compound on DPPHÅ free radical at
different concentrations.
Tested
compound
DPPH scavenging activity (%)
62.5 125 187.5
l
M
lM
lM
250
l
M
312.5 lM
Title
40.9 0.4 55.2 0.1 66.0 0.3 75.5 0.1 88.1 0.1
compound
Ascorbic acida
55.0 0.2 65.0 0.2 75.0 0.2 85.0 0.2 95.0 0.2
a
Ascorbic acid, was used as a standard.
these derivatives posses phenolic hydroxyls which are available
as hydrogen donors to the DPPH radical.

530
M. Koparir et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 105 (2013) 522–531
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The investigation of the present work is illuminate the spectro-
scopic properties such as molecular parameters, frequency assign-
ments and magnetic properties of title compound by using FT-IR,
1H and 13C NMR techniques and tools derived from the density
functional theory. A conformational analysis was carried out by
means of molecular dynamics simulations. Due to the lack of
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in the literature, the optimized geometric parameters (bond
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stabilized by NAHꢂ ꢂ ꢂS and OAHꢂ ꢂ ꢂN hydrogen bonds. It was noted
here that the experimental results belong to solid phase and theo-
retical calculations belong to gaseous phase. In the solid state, the
existence of the crystal field along with the intermolecular interac-
tions have connected the molecules together, which result in the
differences of bond parameters between the calculated and exper-
imental values. Despite the differences observed in the geometric
parameters, the general agreement is good and the theoretical cal-
culations support the solid-state structure. The vibrational FT-IR
spectrum of the III was recorded and computed vibrational wave-
numbers. The magnetic properties of the title molecule were ob-
served and calculated the same method. The chemical shifts
were compared with experimental data in DMSO solution, showing
a very good agreement both for 13C and 1H chemical shifts. The to-
tal energy of III decrease with the increasing polarity of the solvent
and the stability of III increase in going from the gas phase to the
solution phase. When all theoretical results scanned, they are
showing good correlation with experimental data. The antimicro-
bial activity study revealed that the title compound showed good
antibacterial and antifungal activities against pathogenic strains.
The antioxidant activity of the title compound is obvious that the
scavenging activity increases with increasing sample concentra-
tion in the range tested.
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