Synthesis of Some Pyrimidine, Pyrazole, and Pyridine Derivatives and Their Reactivity Descriptors

Article abstract of DOI:10.1155/2018/8795061

A series of novel pyrimidine (2, 3), pyrazole (4, 5), and pyridine (6) derivatives were synthesized using a chalcone-bearing thiophene nucleus (1). The target compounds were synthesized by reaction of compound (1) with urea, thiourea, malononitrile, hydrazine hydrate, and 2,4-dinitrophenyl hydrazine, respectively. Molecular electronic structures have been modeled within density functional theory framework (DFT). Reactivity indices and electrostatic surface potential maps (ESP maps) allow us to establish trends that enable making predictions about chemical characteristics of the newly synthesized molecules and their proton transfer tautomers. Proton transfer is generally more favored in solution than in the gas phase. In acetonitrile, keto-form tautomers and thione-form tautomers become more energetically stable than the corresponding enol or thiol tautomers due to solvent-induced enhancement in the molecular polarity identified by computed dipole moment.

Full text of DOI:10.1155/2018/8795061

Hindawi
Journal of Chemistry
Volume 2018, Article ID 8795061, 11 pages
https://doi.org/10.1155/2018/8795061
Research Article
Synthesis of Some Pyrimidine, Pyrazole, and Pyridine
Derivatives and Their Reactivity Descriptors
2
Nour E. A. Abd El-Sattar ,1 Eman H. K. Badawy,1 and M. S. A. Abdel-Mottaleb
1Department of Chemistry, Organic Labs, Faculty of Science, Ain Shams University, Abbasiya, Cairo 11566, Egypt
2Department of Chemistry, Computational Chemistry Lab, Faculty of Science, Ain Shams University, Abbasiya,
Cairo 11566, Egypt
Correspondence should be addressed to M. S. A. Abdel-Mottaleb; phochem08@photoenergy.org
Received 2 September 2018; Revised 9 October 2018; Accepted 22 October 2018; Published 13 November 2018
Academic Editor: Pedro M. Mancini
Copyright © 2018 Nour E. A. Abd El-Sattar et al. (is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A series of novel pyrimidine (2, 3), pyrazole (4, 5), and pyridine (6) derivatives were synthesized using a chalcone-bearing
thiophene nucleus (1). (e target compounds were synthesized by reaction of compound (1) with urea, thiourea, malononitrile,
hydrazine hydrate, and 2,4-dinitrophenyl hydrazine, respectively. Molecular electronic structures have been modeled within
density functional theory framework (DFT). Reactivity indices and electrostatic surface potential maps (ESP maps) allow us to
establish trends that enable making predictions about chemical characteristics of the newly synthesized molecules and their
proton transfer tautomers. Proton transfer is generally more favored in solution than in the gas phase. In acetonitrile, keto-form
tautomers and thione-form tautomers become more energetically stable than the corresponding enol or thiol tautomers due to
solvent-induced enhancement in the molecular polarity identified by computed dipole moment.
In the present work, a chalcone-bearing thiophene nu-
cleus (1) was prepared and used as a key starting material for
obtaining the desired pyrimidine, pyrazoline, and pyridine
derivatives (2–6) (Figure 1). Experimentally obtained physical
and spectroscopic properties will be presented and validated
by theoretical parameters related to the molecular reactivities
(such as, electrophilicity, nucleophilicity, chemical potential,
and hardness), which are obtained by quantum chemical
computations using DFT approximations. ESP maps of the
energetically optimized new molecules will also be reported.
(e ESP map surfaces that enable exploration of molecular
reactive sites will be discussed. Moreover, the reliably iden-
tified lowest energy tautomers will be explored in the gas
phase as well as in acetonitrile (aprotic solvent).
1. Introduction
Chalcone derivatives from natural sources or synthetic or-
igin exhibit diverse pharmacological activities, such as an-
timicrobial [1], anticancer [2], antioxidant [3], antitumor
[4], anti-inflammatory [5], and antitubercular [6].
Heterocyclic compounds particularly five- or six-
membered ring compounds have occupied the first place
among various classes of organic compounds for their
diverse biological activities. (ese compounds possess diverse
chemotherapeutic and pharmacological activities. Pyrim-
idine and their derivatives have been found to possess
a broad spectrum of biological activities such as antimi-
crobial, anti-inflammatory, analgesic, antiviral, and anti-
cancer activities [7].
Pyrazolines are well-known important nitrogen-
containing five-membered heterocyclic compounds. It is
also worthy to mention that pyrazoline derivatives have been
known to possess widespread pharmacological activities,
such as anti-inflammatory [8], anticonvulsant [9, 10], an-
timicrobial [11, 12], anticancer [13], antiviral [14], and
hypotensive [15] activities.
2. Experimental Section
2.1. Synthesis
2.1.1. General Procedure for the Preparation of Compounds
(2 and 3). A mixture of chalcone (1) (2.5 g, 10 mmol) and
different nucleophilic reagents, namely, urea and thiourea

2
Journal of Chemistry
1-(4-Nitrophenyl)-3-
(thiophen-2-yl)prop-2-en-1-
one
O
1
CH=CH-C
NO2
S
NO2
S
2
3
N
N
OH
4-(4-Nitrophenyl)-6-
(thiophen-2-yl)pyrimidine-2-
NO2
S
N
N
SH
ꢀiol
3-(4-Nitrophenyl)-5-
(thiophen-2-yl)-4,5-dihydro-
1H-pyrazole
NO2
4
5
S
N
HN
1-(2,4-Dinitrophenyl)-3-(4-
nitrophenyl)-5-(thiophen-2-
yl)-4,5-dihydro-1H-pyrazole
NO2
S
N
N
NO2
O2N
2-Amino-6-(4-nitrophenyl)-4-
(thiophen-2-yl)nicotinonitrile
6
NO2
S
N
NC
NH2
Figure 1: Optimized geometries (best view) of chalcone (1) and newly synthesized molecules (left side) as well as nomenclature (right side).
Hydrogen atoms are removed from some molecules for clarity.
(10 mmol), was dissolved in ethanolic sodium hydroxide (4 g
NaOH and 10 mL ethanol) and was stirred for about 2-3
hours with a magnetic stirrer. (is was then poured into
400 ml of cold water with continuous stirring for an hour,
and after that, we kept the mixture in a refrigerator for 24
hours. (e precipitate obtained was filtered, washed, and
recrystallized (mostly in ethanol).
4-(4-Nitrophenyl)-6-(thiophen-2-yl) pyrimidin-2-ol (2).
Yields 80%, m.p. 252–255oC, yellow powder; IR (KBr,
−1
−1
−1
]/cm ): 3434 (3877) cm
(]OH); 3096 (3242) cm

Journal of Chemistry
3
−1
−1
−1
−1
−1
(]Aromatic), 1574.59 (1629) cm (]C�C), 1652.7 cm (]C�N).
1H-NMR (300 MHz, DMSO-d6): δ ppm 8.3 (8.8) (doublet,
2H, ArH, J � 6.8 Hz), 8.2 (8.6) (doublet, 2H, ArH, J � 6.8 Hz),
7.9 (7.7) (singlet, 1H, pyrimidine), 7.8 (5.8) (singlet, 1H, OH,
D2O exchangeable), 7.1–7.7 (7.3–8) (multiplet, 3H, thiophen),
anal. calculated for C14H9N3O3S (299.30): C, 56.18; H, 3.03; N,
14.04; S, 10.71; found: C, 56.00; H, 3.01; N, 14.20; S, 10.67 [16].
4-(4-Nitrophenyl)-6-(thiophen-2-yl) pyrimidine-2-thiol
3016.2 cm (]NH2); 3106.76 cm (]Aromatic), 2197.49 cm
(]CN), 1574.59 cm−1 (]C�C), 1637.27 cm−1 (]C�N), 1346.07 cm
−1
(]C-S-C group).1H-NMR (300 MHz, DMSO-d6): δ ppm 10.1
(singlet, 1H, NH, D2O exchangeable); δ ppm 8.3 (doublet, 2H,
ArH, J � 8.2 Hz), 8.1 (doublet, 2H, ArH, J � 8.2 Hz), 8.0 (singlet,
1H, pyridine), δ ppm 7.0–7.8 (multiplet, 3H, thiophene), anal.
calculated for C16H10N4O2S (322.34): C, 59.62; H, 3.13; N,
17.38; S, 9.95; found: C, 59.32; H, 2.99; N, 17.07; S, 9.55.
−1
(3). Yields 85%, m.p. 250°C, yellow powder; IR (KBr, ]/cm ):
−1
−1
3098.08 (3237) cm (]Aromatic); 2362.37 (2797) cm (]SH),
2.2. Instrumentation. (e infrared spectra were recorded
1575.56 (1516) cm (]C�C), 1652.7 (1627) cm (]C�N). 1H-
NMR (300 MHz, DMSO-d6): δ ppm 8.3 (8.7) (doublet, 2H,
ArH, J � 7.9 Hz), 8.2 (8.5) (doublet, 2H, ArH, J � 7.9 Hz); 8.0
(7.7) (singlet, 1H, pyrimidine), 7.9–7.2 (7.9–7.3) (multiplet,
3H, thiophen); 7.2 (4.8) (singlet, 1H, SH), anal. calculated for
C14H9N3O2S2 (315.37): C, 53.32; H, 2.88; N, 13.32; S, 20.33;
found: C, 53.29; H, 2.81; N, 13.30; S, 19.98 [17].
−1
−1
using potassium bromide disks on a Pye Unicam SP-3-300
1
infrared spectrophotometer. H-NMR spectra were run at
300 MHz, on a Varian Mercury VX-300 NMR spectrometer
using TMS as an internal standard in deuterated dime-
thylsulphoxide. (e microanalytical data were measured in
the Central Lab of Cairo University, Egypt; the Ministry of
Defense Chemical Laboratories, Egypt; and the Microana-
lytical Center of Ain Shams University, Egypt. All the
chemical reactions were monitored by TLC. Melting points
measured were uncorrected.
2.1.2. General Procedure for the Preparation of Compounds (4
and 5). We dissolved a mixture of chalcone (1) (2.5 g, 10
mmol) and different nucleophilic reagents, namely, hydra-
zine hydrate and 2,4-dinitrophenyl hydrazine (10 mmol),
50 ml ethanol, and furthermore, we added a few drops of
conc. HCl. (en, the reaction mixture was refluxed for 4 hr,
and after that, we poured the mixture on crushed ice. (e
precipitate was filtered, dried, and recrystallized from eth-
anol to give compounds 4 and 5.
2.3. Computations. Computations were performed using
Gaussian 16 revision A.03 package [18] and/or Spartan’16
parallel QC program (Wavefunction, Inc., USA). Optimized
structures and spectroscopic data were obtained within DFT
by employing the widely used wB97X-D/6-31G (d,p) model.
Long-range corrected hybrid density functional, the wB97X-D
functional [19], includes empirical damped atom-atom dis-
persion corrections. wB97X-D is significantly more accurate
than the commonly used functional B3LYP. Harmonic vi-
brational frequencies of the optimized geometries were cal-
culated with the same model in order to verify that they are
true minima (with zero imaginary frequencies). Tight SCF
convergence (energy change 1.0e−08 au) and larger integration
grids are used. (e list of the convergence criteria followed is
5e−9 for RMS density change, 1e−7 for maximum density
change, 5e−7 for direct inversion in the iterative subspace
(DIIS) error convergence, and 1e−5 for orbital gradient
convergence. Finally, we used successfully a less-expensive
computational model wB97X-D/6-31G (d) without any
change in the trends obtained from the basis set 6-31G(d,p).
3-(4-Nitrophenyl)-5-(thiophen-2-yl)-4,
5-dihydro-1H-
pyrazole (4). Yields 70%, m.p. 91–92°C, yellow powder; IR
(KBr, ]/cm ): 3427.85 cm−1 (]NH); 3100.01 cm−1 (]Aromatic),
−1
−1
−1
1576.52 cm
(]C�C), 1656.6 cm
(]C�N). 1H-NMR
(300 MHz, DMSO-d6): δ ppm 8.3 (8.6) (doublet, 2H, ArH,
J � 7.6 Hz), 7.9 (7.4) (doublet, 2H, ArH, J � 7.6 Hz), 7.2–6.9
(7.2–6.9) (multiplet, 3H, thiophene), 7.1 (singlet, 1H, NH,
D2O exchangeable), 4.0 (3.2) (triplet, 1H, pyrazole), 3.4
(doublet, 2H, pyrazole), anal. calculated for C13H11N3O2S
(273.31): C, 57.13; H, 4.06; N, 15.37; S, 11.73; found: C, 57.01;
H, 3.96; N, 15.17; S, 11.51.
1-(2,4-Dinitrophenyl)-3-(4-nitrophenyl)-5-(thiophen-2-yl)-
4, 5-dihydro-1H-pyrazole (5). Yields 87%, m.p. 145–147oC,
−1
−1
brown crystal; IR (KBr, ]/cm ): 3140.51 cm
(3253)
(]C�N),
−1
−1
(]Aromatic), 1577.49 cm
(]C�C), 1627.63 cm
1239.04 cm−1 (] C–S–C group). 1H-NMR (300 MHz, DMSO-d6):
δ ppm 8.3 (8.6) (doublet, 2H, ArH, J � 6.8 Hz), 7.5 (7.4)
(doublet, 2H, ArH, J � 6.8 Hz), δ ppm 7.1 (7.2–7.5) (multiplet,
3H, thiophene), 4.0 (3.6) (triplet, 1H, pyrazole), 3.1 (doublet,
2H pyrazole), anal. calculated for C19H13N5O6S (439.40): C,
51.94; H, 2.98; N, 15.94; S, 7.30; found: C, 51.54; H, 2.68; N,
15.79; S, 7.21.
3. Results and Discussion
3.1. Synthesis and Spectroscopic Properties. New pyrimidine
derivatives are prepared by reaction of the chalcone (1) with
urea and thiourea in ethanolic sodium hydroxide to produce
4-(4-nitrophenyl)-6-(thiophen-2-yl) pyrimidin-2-ol molecule
(2) and 4-(4-nitrophenyl)-6-(thiophen-2-yl) pyrimidine-2-
thiol (3), respectively. (e structure of the products was
confirmed by IR which showed OH group stretching at 3434
2.1.3. Synthesis of 2-Amino-6-(4-nitrophenyl)-4-(thiophen-2-
yl) Nicotinonitrile (6). A mixture of compound 1 (2.5 g,
10 mmol), ammonium acetate (0.5 g), and malononitrile
(0.66 g, 10 mmol) in 30 mL ethanol was refluxed for 4 hr. (e
solvent was evaporated under reduced pressure, and the
remaining residue was poured into cold water. (e obtained
precipitate was filtered off and recrystallized from ethanol to
produce compound 6. (6) yields 90%, m.p. 110–112°C,
(calculated 3675) cm . (e 1H-NMR showed singlet of
−1
pyrimidine protons at δ 7.96 (7.5 calculated) ppm in com-
pound 2. (e IR of compound 3 confirms the presence of
−1
the SH group at 2362.37 (2689 calculated) cm , while its
1H-NMR showed the formation of pyrimidine by presence of
singlet proton at δ 8.002 (δ 7.4 calculated) ppm, as shown in
experimental (Scheme 1).
−1
yellowish brown powder; IR (KBr, ]/cm ): 3363.25,

4
Journal of Chemistry
NO2
NO2
C2H5OH/
NH2CONH2
40% NaOH
amm acetate
CH2(CN)2
S
S
N
N
N
NC
OH
NH2
2
O
6
CH=CH-C
NO2
S
1
Chalcone
NO2
NO2
C2H5OH
NH2CSNH2
S
N
N
2,4-Dinitrophenyl
hydrazine
S
40% NaOH
NO2
N
N
NO2
O2N
SH
5
3
S
N
HN
4
Scheme 1
(e IR of compound 4 showed stretching vibration of the
(eoretical reactivity indices based on the conceptual
density functional theory (DFT) have become a powerful tool
for the semiquantitative study of organic reactivity, and the
most relevant indices defined within the conceptual DFT [20]
are reviewed and discussed elsewhere [21–26]. Molecular
reactivity indices [20–26] such as chemical potential (μ),
hardness (η), and electrophilicity (ω) were computed from the
energies of frontier orbitals (graphically represented in Fig-
ure 2 and summarized in Table 1) and defined in terms of
ionization energy (I) and electron affinity (A) as follows:
−1
NH group at 3427.85 cm , and its 1H-NMR showed singlet of
1
the pyrazole protons at δ 4.061 (3.2) ppm. (e H-NMR of
compound 5 shows a singlet due to pyrazole protons at δ
5.105 ppm. Finally, reaction of chalcone (1) with malononitrile
in presence of ethanol and ammonium acetate produced the
corresponding pyridine derivatives 2-amino-6-(4-nitrophenyl)-
4-(thiophen-2-yl) nicotinonitrile (6). (e IR spectrum of
compound 6 exhibits stretching vibrations of the NH group at
−1
−1
3363.25 cm and CN group at 2197.49 cm . Unfortunately,
the computed IR spectra of these compounds in gaseous phase
were not in good agreement with the experimentally measured
IR spectra in the solid phase. It seems that the difference in the
phase has influence in these molecules, whereas the computed
(1) Chemical potential is defined as
1
2
1
2
μ ≈ − (I + A) ≈ ∈ − ∈
,
ꢀ
ꢁ
L
H
(1)
1
(using the same model) H-NMR shifts (given between pa-
rentheses in the Experimental Section 2.1.) are in a fair
agreement with experimentally measured values.
or simply μ � 0.5(LUMO + HOMO).
Chemical potential is the link between structure and
reactivity. (e greater a structure’s chemical potential, the
greater is its reactivity. (e most important factors that
contribute to the chemical potential are low-energy LUMO
indicating strong acid behavior (reactive electrophile) and
high-energy HOMO reflecting strong base behavior (re-
active nucleophile). However, the defined index of chemical
3.2. Molecular Reactivities. Chemical reactivity theory
quantifies the reactive propensity of isolated species through
the introduction of a set of reactivity indices or descriptors. Its
roots go deep into the history of chemistry, as far back as the
introduction of such fundamental concepts as acid, base,
Lewis acid, and Lewis base. It pervades almost all of chemistry.

Journal of Chemistry
5
HOMO-LOMO
Compound
1
HOMO
LOMO
2
3
4
5
6
Figure 2: HOMO-LUMO frontier orbital of the newly synthesized molecules and the starting molecule (red color represents negative phase
while the blue color points to the positive one). All molecules containing one or three nitro groups are of noticeable charge transfer character
showing larger contribution of the orbitals localized on the nitro groups in the LUMOs.
Table 1: (e structure-properties relationships in gas phase reflecting the effect of molecular structure on the associated energy and
thermodynamic parameters, which are important for molecular characterization (HOMO-LUMO values of geometry-optimized molecules
in acetonitrile (ACN) are also given).
H°
G°
S°
Gas
ACN acetonitrile
Molecule
label
Energy
Dipole
(debye) (kcal/mol) (kcal/mol) (J/mol·K)
(kcal/mol)
EHOMO (eV) ELUMO (eV) EHOMO (eV) ELUMO (eV)
1
−739848
−8.36
−1.15
−8.11
−1.15
5.97
6.35
5.96
7.10
−739716
−739755
130.73
136.44
140.30
131.58
2
−832472
−8.52
−0.94
−8.31
−0.99
−832327
−832368
3
−1035131
−8.52
−1.01
−8.33
−1.02
−1034990
−1035031
4
−762106
−7.91
−0.61
−7.80
−0.84
−761954
−761993
5
6
−1163613
−867806
−8.16
−8.4
−1.16
−0.99
−7.78
−8.17
−1.14
−1.00
9.58
3.42
−1163402
−867646
−1163457
−867690
182.46
145.88

6
Journal of Chemistry
potential takes into account the mean value of HOMO and
LUMO.
the more simple indices of chemical potential, hardness,
and nucleophilicity are more reliable than the electro-
philicity parameter, which is defined as the square of
chemical potential divided by double of the hardness
(Section 3.2).
(2) Hardness is given by
1
2
1
2
η ≈ (I − A) ≈ ∈ − ∈
,
ꢀ
ꢁ
L
H
Inspection of Table 2 reveals the reactivities of the new
molecules; molecule 4 is the most susceptible molecule to
electrophilic attack due to its large N value of 1.21 eV and
smaller ω value of 2.49 eV, whereas molecule 3 is the most
likely attacked by a nucleophile. Molecule 3 is of highest
chemical potential (�−4.77 eV), lowest nucleophilicity N
(�0.60 eV), and of considerable high electrophilicity (�3.02).
(us, molecule 3 is the most chemically reactive among the
related molecules (2, 4–6) and is seeking for electrons.
However, in presence of a solvent such as acetonitrile,
molecule 5 is of highest nucleophilic character. Nucleo-
philicity decreases in the order 5 > 4 > 1 > 6 > 2 > 3. More
will be discussed later.
(2)
or simply η � 0.5(LUMO − HOMO).
(e chemical hardness η can be thought as a resistance of
a molecule to exchange electron density with the environment.
(3) Electrophilicity. Parr (in 1999) defined the electro-
philicity index [26] ω � μ2/2η, which measures the
total ability to attract electrons. (e electrophilicity
index gives a measure of the energy stabilization of
a molecule in case it acquires an additional amount
of electron density from the environment. (e
electrophilicity index shows the tendency of an
electrophile to acquire an extra amount of electron
density, given by μ, and the resistance of a molecule
to exchange electron density with the environment,
given by η. (erefore, a good electrophile exhibits
a high absolute μ value and a low η value. (e
electrophilicity index is considered an important
facility for the study of the reactivity of organic
molecules [21].
Spartan codes enabled identification of tautomers (due
to proton transfer) through tautomer search. Each of
molecules 2 and 3 has two tautomers, whereas molecule 6
has only one tautomer. Geometry optimized (employing
wB97X-D/6-31G (d,p) model) tautomer’s information is
summarized in Table 3, and their optimized geometries are
depicted in Figure 4. It seems that the lowest energy (most
stable) tautomers are the genuine 2, 3, and 6 molecules
themselves. Proton transfer to form other tautomers (Fig-
ure 4) results in energy destabilization. Relative energy is
reported for comparing relative energy of tautomers of
individual compounds (Table 3). Largest destabilization
could be seen in case of proton transfer in tautomer 6-1.
(e reactivities of the tautomers in the gas phase are
tabulated in Table 3 and could be easily seen by inspection
of Figure 5. However, it should be mentioned that solvent
nature could be of influential effect on the stability of
a tautomer. (us, we tried geometry optimization in the
acetonitrile solvent (aprotic solvent) using the wB97X-
D/6-31G(d,p) model and CPCM solvation model [27] and
found a drastic effect on the relative stability of the tau-
tomers as can be seen from the data summarized in Table 4.
Proton transfer is generally more favored in solution
than in the gas phase. Moreover, keto-form tautomers and
thione-form tautomers become more energetically stable
than the corresponding enol (2) or thiol (3) tautomers
most probably because of the increase in conjugation.
However, although solvent induces tiny stability relative to
that of the gas phase, proton transfer in 6 is still a less-
favored process. Understanding how reactivity descriptors
of these polar molecules and their tautomers are modified
in going from the gas phase into solution can be un-
derstood with the solvent-induced increase in the dipole
moment value (Table 4) as well as thermodynamic pa-
rameters. (e more polar the molecule is the more it is
energetically stabilized as could be seen from the dipole
moment data summarized in Table 4 for the gas and
solvent phases. Furthermore, from thermodynamics point
of view (Table 5), enhancements in the computed enthalpy
and Gibbs free energy are noticed in acetonitrile. (e
values verify the conclusions drawn from Table 4.
(4) Nucleophilicity (N). Domingo and his coworkers
[21–25] suggested that a simple index chosen for
the nucleophilicity, N, based on the HOMO en-
ergy, within DFT, could be employed to explain
the reactivity of the organic material towards
electrophiles.
(e nucleophilicity index is defined as N � EHOMO(ev) +
9.12(ev), where −9.12 is the energy of the HOMO of tetra-
cyanoethylene (TCE). (us, this nucleophilicity scale is re-
ferred to TCE and taken as a reference because TCE exhibits
the lowest HOMO energy (� −9.12 eV) in a large series of
molecules investigated [22].
Inspecting molecule’s ESP surface is probably a good
start for considerations of the molecule’s reactivity since this
is where two approaching molecules would first interact. ESP
maps are depicted in Figure 3. (e results should point to the
binding sites, which are of potential influence in chemical
reactivities and medical applications.
Table 1 shows a compilation of some thermodynamic
parameters and dipole moment values reflecting molec-
ular polarities. All molecules are fairly polar and should
be soluble in polar solvents. (e computed total energy
and thermodynamic parameters reflect the stability of the
molecules. Solvent effect induced by acetonitrile (aprotic
solvent) is reflected in destabilization of HOMO. LUMO
energy levels are almost unaffected except in case of
molecule 4 where its LUMO is stabilized by about 0.23 eV.
(is is reflected in the difference in reactivity indices given
in Table 2. Nucleophilicity is markedly enhanced, while
chemical potential and hardness values are lowered in
presence of the solvent. Electrophilicity shows irregular
behavior relative to the gas phase values. It seems that

Journal of Chemistry
7
1
2
3
4
5
6
Figure 3: Solid surface (8 bands) of ESP maps and color codes. (e color code reflects electrostatic potential energy values in kJ/mol. (e
redder the area is, the higher the electron density is susceptible to electrophilic attack and the bluer the area is, the lower the electron density
is that could easily bind with a nucleophile.
Table 2: Effect of the solvent on computed reactivity indices in eV sorted according to descending nucleophilicity in the gas phase.
Gas
Acetonitrile
Molecule
μ
η
ω
N
μ
η
ω
N
4
−4.26
3.65
3.50
3.61
3.71
3.79
3.76
2.49
3.10
3.14
2.97
2.95
3.02
1.21
0.96
0.76
0.72
0.60
0.60
−4.32
3.48
3.32
3.48
3.59
3.66
3.66
2.68
3.00
3.08
2.93
2.95
2.99
1.32
1.34
1.01
0.95
0.81
0.79
5
−4.66
−4.46
1
6
2
3
−4.76
−4.63
−4.70
−4.59
−4.73
−4.77
−4.65
−4.68

8
Journal of Chemistry
Table 3: Relative energies and frontier orbital energies of the tautomers of molecules 2 (denoted as 2-1 and 2-2), 3 (3-1 and 3-2), and 6 (6-1)
in the gas phase.
Tautomer
2
Relative energy (kJ/mol)
EHOMO (eV)
ELUMO (eV)
μ
η
ω
N
Dipole (debye)
6.35
4.33
9.18
5.96
6.03
9.92
0
−8.52
−0.94
−4.73
3.79
3.68
3.72
3.755
3.185
3.265
2.95
3.34
3.1
3.02
3.33
3.19
0.6
0.48
0.6
0.6
1.33
1.29
2-1
2-2
15.1
18.07
−8.64
−1.28
−4.96
−8.52
−1.08
−4.80
3
0
−8.52
−1.01
−4.77
3-1
18.5
−7.79
−1.42
−4.61
3-2
22.1
−7.83
−1.3
−4.57
6
0
−8.4
−0.99
−1.53
−4.70
−4.50
3.705
2.97
2.97
3.41
0.72
1.65
3.42
3.81
6-1
74.69
−7.47
2
2-1
2-2
3
3-1
3-2
6
6-1
Figure 4: Optimized geometries of the tautomers of molecules 2, 3, and 6.
Reactivity indices also altered significantly. Nucleo-
stabilizing the HOMO of the thione tautomers of 3 and
on 6-1 tautomer. Chemical potential and hardness
markedly decrease except for thione tautomers of 3,
whereas it increases in acetonitrile due to influential
philicity increases for 2 and its tautomers as well as for 3
and 6 because the solvent has a noticeable effect on
HOMO stabilization. (e solvent has smaller effect on

Journal of Chemistry
9
3.6
3.4
3.2
3
–4.2
–4.4
–4.6
–4.8
–5
3.8
3.6
3.4
3.2
3
2
1.5
1
5
3
2.8
2.6
2.4
6
2
1
0.5
0
4
2.8
1
11
Molecule
Chemical potential
Nucleophilicity
Electrophilicity
Hardness
Figure 5: Quantitative structure-reactivity descriptor relationships of the synthesized molecules and its tautomers. Each of molecules 2 and
3 has two other tautomers, while molecule 6 can exist in two tautomeric shapes (Figure 4). Similar figure is obtained in the solution phase
(ACN).
Table 4: Relative energies and frontier orbital energies of the tautomers of 2 (denoted as 2-1 and 2-2), 3 (denoted as 3-1 and 3-2), and 6
(denoted as 6-1) in acetonitrile
Dipole (debye)
Tautomer
Relative energy (kJ/mol)
EHOMO (eV)
ELUMO (eV)
μ
η
ω
N
ACN
8.02
6.49
12.44
7.79
10.32
14.85
∗Gas
6.35
4.33
9.18
5.96
6.03
9.92
2
0
−8.31
−0.99
−4.65
3.66
3.6
3.68
3.655
3.375
3.43
2.95
3.03
3.09
2.99
3.18
3.15
0.81
0.85
0.67
0.79
1.11
1.04
2-1
2-2
−0.77
−8.27
−1.07
−4.67
−10.51
−8.45
−1.09
−4.77
3
0
−8.33
−1.02
−4.68
3-1
−14.22
−8.01
−1.26
−4.64
3-2
−24.61
−8.08
−1.22
−4.65
6
0
−8.17
−7.77
−1.01
−1.13
−4.59
−4.45
3.58
3.32
2.94
2.98
0.95
1.35
3.73
5.42
3.42
3.81
6-1
60.96
∗Dipole moment in the gas phase is given for quick comparison.
Table 5: (ermodynamic parameters in (kJ/mol) of the tautomers calculated using less-expensive wB97X-D/6-31G(d) computational
model.
Gas phase
Acetonitrile
Tautomer
Relative energy
H
G
Relative energy
H
G
2
0
−3482461.966
−3482630.103
0
−3482505.024
−3482677.546
2-1
2-2
16.67
19.93
−3482444.454
−3482612.486
−6.43
−3482511.089
−3482683.663
−3482441.645
−3482609.834
−16.19
−3482520.41
−3482692.826
3
0
−4330401.034
−4330574.264
0
−4330442.438
−4330620.237
3-1
26.45
−4330365.747
−4330537.638
−13.52
−4330447.715
−4330624.07
3-2
22.22
−4330369.659
−4330541.209
−23.99
−4330457.876
−4330633.889
6
0
−3630234.663
−3630415.639
0
−3630280.845
−3630217.623
−3630466.941
−3630400.936
6-1
74.94
−3630157.368
−3630335.692
61.13
destabilization of LUMO. Electrophilicity dominantly
decreases in acetonitrile.
More about the reactivities of other molecules could be
predicted by inspection of Figure 5. It is of interest to
visualize (Figure 5) the structure-properties relationship in
the gaseous phase. Systematic increase in nucleophilicity
while changing from molecule/tautomer 2-1 (of lowest
nucleophilicity index) to 6-1 (of highest nucleophilic

10
Journal of Chemistry
[3] B.-T. Kim, K.-J. O., J.-C. Chun, and K. Hwang, “Synthesis of
dihydroxylated chalcone derivatives with diverse substitution
patterns and their radical scavenging ability toward DPPH
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[4] D. Kumar, N. M. Kumar, K. Akamatsu, E. Kusaka, H. Harada,
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property) could be suggested as a measure of tuning
molecular properties. One can quickly predict any re-
activity descriptor of a molecule or a tautomer by a glimpse
of Figure 5. One can easily correlate all reactivity indices of
a molecule to each other.
4. Conclusion
We synthesized five new products of pyrimidine, pyrazole,
and pyridine derivatives using a chalcone substituted with
a thiophene nucleus. Spectroscopic data were introduced as
well as reactivity indices.
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new synthesized substituted pyrimidine, thiopyrimidine and
thiazolopyrimidine derivatives,” European Journal of Medic-
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dihydro-1H-pyrazole-1-carboxamides and their thio-
analogues of potential PGE2 inhibitory properties,” Euro-
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pp. 2172–2177, 2009.
[9] M. Yusuf and P. Jain, “Synthetic and biological studies of
pyrazolines and related heterocyclic compounds,” Arabian
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[10] A. A. Siddiqui, M. A. Rahman, M. Shaharyar, and R. Mishra,
“Synthesis and anticonvulsant activity of some substituted 3,
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vol. 44, no. 4, pp. 1396–1404, 2009.
(e wB97X-D/6-31G (d,p) model within the DFT is used
to optimize the structures and predict the structure-properties
relationships. Reactivity parameters calculated from the
frontier orbitals help in prediction of nucleophilicity, elec-
trophilicity, and hardness as well as chemical potential of the
molecules synthesized. Proton transfer from functional
groups in some molecules results in presence of several
tautomers. In the gas phase, proton transfer destabilizes the
tautomer molecules. Proton transfer is generally more favored
in solution than in the gas phase due to solvent-induced
enhancement of the molecular polarity identified by the
computed dipole moment values. In particular, keto-form
tautomers and thione-form tautomers become more ener-
getically stable than the corresponding enol (2) or thiol (3)
tautomers. However, proton transfer in 6 is still a less-favored
process since the solvent induced small increase in the dipole
moment value. Additionally, thermodynamic parameters
verify the conclusions drawn from the molecular polarity.
Computed and visualized ESP map surfaces enable ex-
ploration of molecular reactive sites.
Generally, based on the relative nucleophilicity index N,
nucleophilicity increases in the order 3 < 2 < 6 < 1 < 5 < 4 in
the gas phase, while the order in acetonitrile is slightly
different 3 < 2 < 6 < 1 < 4 < 5. Generally, all reactivity indices
computed could be easily predicted for a compound by
a glimpse of a reactivity indices-molecule graph.
Data Availability
(e data used to support the findings of this study are
available from the corresponding author upon request.
[14] M. S. Mui, B. N. Siew, A. D. Buss, S. C. Crasta, L. G. Kah, and
K. L. Sue, “Benzylidene rhodanines as novel inhibitors of
UDP-N-acetylmuramate/l-alanine ligase,” Bioorganic and
Medicinal Chemistry Letters, vol. 12, no. 4, pp. 697–699, 2012.
[15] G. Turan-zitouni, P. Chevallet, F. S. Kilic, and K. Erol,
“Synthesis of some thiazolyl-pyrazoline derivatives and pre-
liminary investigation of their hypotensive activity,” European
Journal of Medicinal Chemistry, vol. 35, pp. 635–641, 2000.
[16] V. D Joshi, M. D. Kshirsagar, and S. Singhal, “Synthesis and
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Pharmacia Sinica, vol. 3, no. 3, pp. 343–348, 2012.
[17] M. M. M. Hussain, k. Ishwar Bhat, B. C. Revanasiddappa, and
D. R. Bharathi, “Synthesis and biological evaluation of
some novel 2-mercapto pyrimidines,” International Journal of
Pharmacy and Pharmaceutical Sciences, vol. 55, pp. 471–473,
2013.
Conflicts of Interest
(e authors declare that there are no conflicts of interest in
publishing this manuscript.
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