Synthesis of some new pyrazolo[5,1-c][1,2,4]triazine derivatives and computational study

Article abstract of DOI:10.1016/j.molstruc.2020.128850

In this study, the synthesis novel of seven new pyrazolo [5,1-c][1,2,4]triazin derivative disperse dyestuffs was reported. First, 2-arylhydrazone-3-ketiminobutyronitriles were synthesized and reacted with hydrazine hydrate to afford 5-amino-4-arylazo-3-me

Full text of DOI:10.1016/j.molstruc.2020.128850

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Synthesis of some new pyrazolo[5,1-c][1,2,4]triazine derivatives and computational
study
Fati Yıldırım, Aykut Demirçalı, Aslı Öztürk Kiraz, Fikret Karcı
PII:
S0022-2860(20)31175-3
DOI:
https://doi.org/10.1016/j.molstruc.2020.128850
MOLSTR 128850
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 March 2020
Revised Date: 2 July 2020
Accepted Date: 6 July 2020
Please cite this article as: F. Yıldırım, A. Demirçalı, Aslı.Öü. Kiraz, F. Karcı, Synthesis of some new
pyrazolo[5,1-c][1,2,4]triazine derivatives and computational study, Journal of Molecular Structure (2020),
doi: https://doi.org/10.1016/j.molstruc.2020.128850.
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Graphical Abstract
Fati Yıldırım, Aykut Demirçalı, Aslı Öztürk Kiraz and Fikret Karcı
Synthesis of some new pyrazolo[5,1-c][1,2,4]triazine derivatives and computational study
N
O
C
N
N
N
X
OC2H5
N
N
H3C
O
C
NH2
N
N
CH
(4a-g)
N
N
N
N
AcOH
NaNO2 / HCl
C6H5COCH2CO2C2H5
C
O
OC2H5
X
X
NH
NH
N
N
H3C
H3C
N
O
C
N
N
(2a-g)
(3a-g)
N
X
N
N
H3C
OH
a, X: H
b, X: p-OCH3
c, X: p-Cl
d, X: p-CH3
e, X: m-OCH3
f, X: m-CH3
g, X: o-OCH3
(5a-g)

Synthesis of some new pyrazolo[5,1-c][1,2,4]triazine derivatives
and computational study
Fati Yıldırıma, Aykut Demirçalıb*, Aslı Öztürk Kirazc ,Fikret Karcıb
a. Pamukkale University , Denizli Technical Sciences Vocational School, Department of
Chemistry and Chemical Processing Technologies, Denizli, Turkey
b. Pamukkale University , Faculty of Science-Arts, Department of Chemistry,
Denizli, Turkey
c. Pamukkale University , Faculty of Science-Arts, Department of Physics
Denizli, Turkey
Abstract
In this study, the synthesis novel of seven new pyrazolo[5,1-c][1,2,4]triazin derivative
disperse dyestuffs was reported. First, 2-arylhydrazone-3-ketiminobutyronitriles were
synthesized and reacted with hydrazine hydrate to afford 5-amino-4-arylazo-3-methyl-1H-
pyrazoles. The 5-amino-4-arylazo-3-methyl-1H-pyrazoles were diazotised and coupled with
ethyl benzoylacetate to give ethyl pyrazolylazo benzoylacetate. The final product was heated in
glacial acetic acid and seven new pyrazolo[5,1-c][1,2,4]triazine dyestuffs were synthesized.
1
FT-IR, H NMR and elemental analysis techniques were used to characterize synthesized
dyestuffs. Density functional theory calculation methods were used for to determine the
molecular geometries and spectroscopic properties of the new seven dyestuffs. The acquired
results from calculations and experiments are conform each other.
Keywords: Ethyl benzoyl acetate, Azo dyestuff, Pyrazole, DFT, Electronic properties
*Corresponding author. Tel: 90 258 2963603
*E-mail address: ademircali@pau.edu.tr
fax: 90 258 2963535

1. Introduction
Pyrazoles and their substituted derivatives exhibit wide variety of biological and
pharmacological activities [1-8] and also find application in photography [9, 10] and as dyes
[11,12]. Some pyrazoles were reported to have nonnucleoside HIV-1 reverse transcriptase
inhibitory activity [3,7,8, 13-16].
Azolo annulated [1,2,4]triazines can be considered as isosteres of purine bases. Due to a
wide and profound biological activity [17-21], this family of heterocyclic compounds causes a
growing interest of researchers working in the fields of medicinal chemistry and pharmacology.
Pyrazolo[5,1-c][1,2,4]triazines are similar in structure to nucleic bases, can act as metabolites
and are useful as antiviral and antitumor agents [17]. In the literature, pyrazolotriazines have
been reported to have cytotoxicity against cancer cells [22, 23]. Berger and coworkers reported
that specific polysubstituted pyrazolo[5,1-c][1,2,4]triazines inhibit selectively B-Raf kinase
activity, and are preferred for the treatment of B-Raf kinase related disorders [24]. Therefore,
the development of new methods and the synthesis of newly fused 1,2,4-triazine derivatives is
of great importance.
Many patents and articles in the literature identify the synthesis and dyeing
characteristics of monoazo dyestuff on a heterocyclic coupling component [25-28]. There are
very few studies involving monoazo dyestuff based on the pyrazolo[5,1-c][1,2,4]triazine ring.
In connection with our interest in this class of compounds, our study group has reported the
synthesis of some pyrazolo[5,1-c][1,2,4]triazines [29-31]. In this article, we present the
synthesis of seven new monoazo dyestuff based on the pyrazolo[5,1-c] [1,2,4]triazine ring
system.
In the recent years, there has been great interest to the quantum chemical calculations
especially density functional theory (DFT) methods which use to determine the properties of
the molecular, optical and electronic structures of the small and big sized chemical molecules at

low computational time [32–35]. In this paper, as a part of continuous studies of our research
group, we synthesised new pyrazolo derivatives and characterized by elemental analyses, FT-
1
IR, H- NMR spectroscopic methods. Also, we studied on the estimated of the geometry
optimization, the vibrational frequencies, the chemical shifts and the electronic properties of
azo dyestuff because of their cytotoxic activity in medical and usage as a polyester/polyamide
dye in industrial applications.
2. Experimental
2.1. General details
The chemicals utilized in the synthesis were supplied from Aldrich and Merck
Chemical Company without any purification. Suitable spectroscopic grade solvents were used.
1
IR spectra were recorded via Perkin Elmer UATR Two (FT-IR) Spectrophotometer. H
NMR spectra were obtained on Agilent 400/55 annual refill 400 in DMSO-d6 utilizing TMS as
the internal reference and chemical shifts (δ) were reported in ppm. Melting points of dyestuffs
were determined using Electrothermal 9100 melting point apparatus and not corrected.
2.2. Synthesis of 2-arylhydrazone-3-ketiminobutyronitriles (1a-g) and 5-amino-4-arylazo-
3-methyl-1H-pyrazoles (2a-g)
1a-g and 2a-g were synthesized according to the literature [36-38]. The general route
for the synthesis of 1a-g and 2a-g is outlined in Scheme 1.
Scheme 1 here about

2.3. Synthesis of pyrazolo[5,1-c][1,2,4]triazine derivative dyestuffs (4a-g)
The synthesized 2a-g compounds (0.01 mol) were dissolved in a mixture containing
glacial CH3COOH and concentrated HCl (20 ml, ratio 1: 1), and the solution was cooled to 0-
5°C. Then NaNO2 solution (0.69 g, 0.01 mol) prepared in 10 ml of water was added dropwise
to this solution cooled at 0-5 °C with vigorous stirring for 1 h. The clear diazonium salt
solution was added dropwise to a solution of ethyl benzoyl acetate (1.92 g, 0.01 mol) prepared
in pyridine (10 mL) and cooled (0-5 °C). The pH of the coupling mixture was kept at 7-8
throughout the coupling by adding aqueous sodium acetate. Stirring was continued at 0-5 °C
for 4 hours and diluted with cold water (50 ml). The precipitated products were filtered, washed
several times with water, dried and recrystallized from DMF-H2O to give ethyl pyrazolylazo
benzoylacetate (3a). The obtained product (3a) was refluxed for 4 hours in glacial CH3COOH
(30 ml). The solvent casted out and the final product was collected by filtration and dried. It
was recrystallized from DMF-H2O (3:1) and orange crystals of the 4a dyestuff were obtained.
This procedure was also used to synthesis dyestuffs 4b-g (Scheme 2). Elemental analyzes and
melting points of the dyestuffs obtained are listed in Table 1.
Scheme 2 here about
Table 1 here about
3. Computational details
Quantum chemical calculations were performed at the B3LYP levels of theory with the
Gaussian 16, Rev. B01 package [39] and GaussView 6.0.16 [40] was used for visualization of
the structure. Geometries were optimized to the global minima at the ab initio DFT level 6-
31G(d,p) basis set. The optimized structures were used for the calculations of vibrational

frequencies, NMR chemical shift, electronic absorption spectrum and Natural Bond Orbital
(NBO) analysis. We have calculated the chemical shifts of them in the ground state to
differentiate the basis from the experimental chemical shifts and geometric parameters by using
DFT (B3LYP) method. And also, time-dependent density functional theory (TD-DFT) was
used to examine the electronic absorption spectrum. These calculations are worthy for ensuring
comprehend the chemical shifts and molecular parameters.
4. Results and Discussion
4.1. Molecular geometry
The geometric structures of the 4a-g compounds obtained from B3LYP/6-31G(d,p) methods
are represented in Figure 1 along with the atom numbering schemes. The 4a molecule has got
47 atoms and their basic vibrational modes are 138. The 4b, 4e and 4g molecules have got 51
atoms and their basic vibration modes are 147. While 4d and 4f molecules have got 50 atom
and 114 basic vibration modes, 4c molecule has got 47 atoms and 137 basic vibration modes.
The azo double bonds (N=N), the carbonyl single bond lenghts (C-O) and the carbonyl double
bond lenghts (C=O) are computed in the range of 1.304-1.267 Å, 1.338- 1.341 Å and 1.215-
1.214 Å, respectively.
Figure 1 here about
4.2. Tautomerization
1H-NMR spectra of the dyestuffs showed CH3 of ethoxy group peak at 0.99-1.00 ppm
1
and -OCH2- of ethoxy group peak at 4.17-4.18 ppm. Also, H-NMR spectra of the dyestuffs
did not show any the OH group peak. FT-IR spectra of the dyestuffs also did not show any the
OH group peak. These suggest that these dyestuffs in the 4a-g form and not in the 5a-g form.

The structures of azo dyestuffs are thought to be as shown in Scheme 2. Furthermore, it is
believed that the newly synthesized dyestuffs do not have a tautomeric structure.
4.3. Vibrational analysis
The FT –IR spectra of 4a-g dyestuffs shows aromatic C
H bands at 2996-2973 cm-1, azo (N=N) bands at 1579-1516 cm-1, carbonyl (C = O)
bands at 1728–1714 cm−1 and C O bands at 1086–1014 cm−1. As for corresponding B3LYP/6-
̶
H bands at 3097-3051 cm-1,
aliphatic C
̶
̶
31G(d,p) methods, aromatic C
̶ H bands, aliphatic C ̶ H bands, azo (N=N) bands, carbonyl (C =
O) bands and C
̶
O bands have been calculated as the values in the range of 3207-3178 cm-1,
3059-3016 cm-1, 1598-1505 cm-1, 1801-1798 cm-1 and 1058-994 cm-1, respectively.
Experimental and theoretical results are tabulated in Table 2.
Table 2 here about
The correlations values (R2) between these experimental and theoretical data for each
molecule are computed and presented in Table 2. The compound 4e has the most coherent
correlation with the value of 0.9998 and 4b compound has the least coherent correlation value
with the value of 0.9965 which can be seen in Figure 2. These correlation values indicated that
experimental and the theoretical data are very coherent each other.
Figure 2 here about
4.4. 1H NMR analysis
1H NMR spectra of 4a-g dyestuffs showed at 7.94–7.07 ppm (aromatic H), 4.18–4.17
ppm (OCH2), 2.74–2.69 ppm (pyrazole CH3) and 1.00-0.99 (ethoxy CH3), respectively. On the
other hand, the theoretical 1H NMR data (4a-g dyes) obtained from B3LYP/6-31G(d,p) method
are collected in Table 3 together with the experimental data.

Table 3 here about
As for corresponding B3LYP/6-31G(d,p) methods, aromatic H peaks, OCH2 peaks, pyrazole
CH3 peaks and ethoxy CH3 peaks have been calculated as the values of 8.84-7.17 ppm, 4.70-
4.35 ppm, 2.90-2.85 and 1.75-1.38 ppm, respectively. The compound 4a has the most coherent
correlation with the value of 0.9968 and 4g compound has the least coherent correlation value
with the value of 0.9912 which can be seen in Figure 3. These correlation values indicated that
experimental and the theoretical data are very coherent each other.
Figure 3 here about
4.5. Electronic Properties
The electronic properties of a molecule are designated with the energy of HOMO
(Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbitals)
molecular orbitals. Beside the electronic properties the chemical reactivity, stability, optical
properties and bioactivity of a molecule also determine with these parameters [41, 42]. The
difference between HOMO and LUMO orbitals indicates the chemical reactivity of a molecule.
If the difference is small the kinetic stability of a molecule is low so the intermolecular charge
transfer is very high between the electron donor and acceptor groups. When Table 4 is
examined, the lowest energy gap belongs to dyestuff 4d with 1.06 eV. On the other hand, the
largest energy gap belongs to dyestuff 4f with 3.35 eV.
Table 4 here about
In compound 4d, the -CH3 group is attached to the p-position and the compound has a more
linear structure. In compound 4f, the -CH3 group is attached to the meta position and is closer
to the azo group containing an unpaired electron pair. The binding of the CH3 group to the
phenyl ring from different corners indicates that the meta-position dye (4f) may be less reactive
due to the steric effect and the p-position dye (4d) may be more reactive due to its planar

nature. The other parameters; I (ionization potential), A (electron affinity), χ
(electronegativity), η (hardness), S (softness), ꢀ (electronic chemical potential) and ω (global
electrophilicity index) values of dyestuff 4a, 4b, 4c, 4e, 4f and 4g are nearly similar. Because
of the delocalization of the conjugated ꢀ bonds, the HOMO-LUMO orbitals are located in the
aromatic rings and azo groups, as seen Figure 4 and 5.
Figure 4 here about
Figure 5 here about
The absorption spectra were computed using the TD-DFT method in combination with the
same functional, basis set in gas phase and in chloroform. The calculated maximum absorption
wavelengths (λmax), and electronic transitions are shown in Table 5. The highest electronic
absorption bands are calculated at 531.9 nm in gas phase and 517.2 nm in chloroform by using
TD-DFT/B3LYP/6-31G(d,p) level for 4g and also they can be attributed π→π* and n→π*
transitions. They were determined that these band caused by the transitions of HOMO-1→
LUMO (78%), HOMO-1→ LUMO+1(14%), HOMO → LUMO (6%). The corresponding
peaks for compounds 4a-f in chloroform were obtained at 507.6 nm HOMO-1→ LUMO
(79%), 499.1 nm with the contribution HOMO-1→ LUMO (84%), 504.7 nm with the
contribution HOMO-1→ LUMO (86%), 505.6 nm with the contribution HOMO-1 → LUMO
(84%), 503.2 nm with the contribution HOMO-1 → LUMO (84%) and 507.2 nm with the
contribution HOMO-1 → LUMO (84%), respectively, as can be seen in Table 5. These values
are also similar with the obtained from the gas phase calculations. The contribution rate of
HOMO–LUMO orbitals are determined by using the GaussSum 2.2 program [43]
Table 5 here about
.
4.6. Natural Bond Orbital (NBO) Analysis
Additionally, the 6-31G(d,p)/B3LYP level were performed to the natural bond orbital
(NBO) calculations for the complexes 4a-g. NBO analysis provides a favorable charge transfer

or conjugation interaction in the molecular system, and also uses work on intermolecular
binding and interaction between bonds [44]. The E(2) value computed from the NBO analysis
show the energy of interaction between the electron acceptor and the electron donor and the
larger value demonstrates an intense interaction between electron donors and electron acceptors
[45].
As seen from the Table 6, the calculated E(2) values presented that the significant charge flows
generally occurred from the lone pair of the carbon atoms of the pyrazole ring (C13 or C14) to
the π* bond of (N22-N23) which have stabilization energy in the range of 331.89 -338.67
kcal/mol. Also, electron densities given in the Table 6 are another evidence of the larger
electron delocalization.
Table 6 here about
5. Conclusions
Seven new pyrazolo[5,1-c][1,2,4]triazine derived azo dyestuffs have been synthesized.
Characterization of these molecules was achieved by FT-IR and 1H NMR spectrum
1
measurements. Molecular structures of azo dyestuffs synthesized according to FT-IR and H
NMR results were found to be in 4a-g form. The structures, electronic and vibration properties
of novel azo dyestuffs examined by density functional methods. The vibration frequencies of
some of the main peaks found with the help of experimental and theoretical studies are
compatible with each other and correlation values were obtained between 0.9965 and 0.9998.
1
The H NMR data obtained by experimental and theoretical studies are also compatible with
each other and their correlation values ranged from 0.9968 to 0.9912.
Acknowledgment
This study has been supported by Pamukkale University Scientific Research Project
Coordination Unit by the project numbers: 2012BSP004, 2016 HZDP 036 and 2018FEBE002.

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Figure Captions
Figure 1: The calculated optimized structure of dyestuffs 4a-g.
Figure 2: Linear regression results obtained by theoretical and experimental infrared values of
4a-g compounds.
Figure 3: Linear regression results obtained by theoretical and experimental 1H NMR values of
4a-g compounds.
Figure 4: HOMO-LUMO orbitals diagram of the dyestuffs 4a-g.
Figure 5: Atomic composition of dyestuff 4d.
Tables
Table 1. Elemental analysis of dyestuffs 4a-g.
Table 2. FT-IR data for dyestuffs 4a-g.
Table 3. 1H NMR data for dyestuffs 4a-g.
Table 4. Electronic parameters of dyestuffs 4a-g.
Table 5. Calculated absorption wavelengths, energies and oscillator strengths of 4a-g using the
TD-DFT method at the B3LYP/6- 31G(d,p) level.
Table 6. Remarkable stabilization interactions in the 4a-g.

Figure Captions
Figure 1: The calculated optimized structure of dyestuffs 4a-g.
Figure 2: Linear regression results obtained by theoretical and experimental infrared values of
4a-g compounds.
Figure 3: Linear regression results obtained by theoretical and experimental 1H NMR values
of 4a-g compounds.
Figure 4: HOMO-LUMO orbitals diagram of the dyestuffs 4a-g.
Figure 5: Atomic composition of dyestuff 4d.
Tables
Table 1. Elemental analysis of dyestuffs 4a-g.
Table 2. FT-IR data for dyestuffs 4a-g.
Table 3. 1H NMR data for dyestuffs 4a-g.
Table 4. Electronic parameters of dyestuffs 4a-g.
.

Highlights
• Seven new azo dyestuffs have been synthesized.
• Dyestuffs have been characterized by FT-IR and 1H NMR.
• Theoretical studies have been done with DFT calculation method.
• Theoretical and experimental results are consistent.
• Natural Bond Orbital (NBO) Analysis.

Author Contribution Statement
Fati Yıldırım: Methodology, Experimental studies, Reviewing, Analysis interpretation
Aykut Demirçalı: Writing, Experimental studies, Analysis interpretation, Data Curation
Aslı Öztürk Kiraz: Theoretical studies, Data curation
Fikret Karcı: Review, Consultancy

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: