Study the solvation effect on 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile derivatives by TD- DFT calculations and molecular dynamics simulations

Article abstract of DOI:10.1016/j.molstruc.2019.127056

The electronic structure of 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2-mercapto-6-phenylpyridine-3-carbonitrile) and its some derivatives have been studied both theoretically and experimentally. The choice of these compounds was motivated by their biological importance and relevance. The corresponding proposed structures of all studied derivatives in this work were confirmed by FT-IR spectrophotometer, ¹HNMR spectra and XRD patterns. The Density Functional Theory (DFT) has been used to investigate the effect of substituents with different strengths of all studied compounds on the geometry structures, natural bond orbital (NBO) properties, electrostatic potential (ESP) and the global properties such as (the chemical hardness (η), global softness (S), and electronegativity (χ) by analysis of the charge distribution and extent of charge transfer in the molecule in the gas phase. Non-linear optical properties (NLO) such as (static dipole moment (μ), polarizability (α), anisotropy polarizability (Δα), first order hyperpolarizability (β) and mean second order hyperpolarizability (γ)) also, were computed by DFT in the gas and solvent (benzene and ethanol) phases. The effect of the different substitutions and solvent polarity on the NLO properties were also investigated to show their ability to be used as NLO compounds. We find that all studied compounds exhibited higher NLO properties compared to urea (reference materials) in the gas phase and showed higher NLO properties in ethanol than in the benzene phase. The effect of solvent polarity on the electronic absorption spectra of the studied molecules was measured experimentally and calculated theoretically at the Time-Dependent Density Functional Theory (TD-DFT) level of theory. The interactions of different solvents (ethanol and benzene) with studied compounds were also studied by molecular dynamics (MD) simulations. The radial distribution functions (RDFs) and coordination numbers (CNs) of all studied compounds in the different solvent are computed. The diffusion coefficient (D) also was calculated to investigate the influence of substitutions on the mobility of the studied compounds in the surrounding solvent.

Full text of DOI:10.1016/j.molstruc.2019.127056

Journal Pre-proof
Study the solvation effect on 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
derivatives by TD- DFT calculations and molecular dynamics simulations
Mahmoud K. Abdel-Latif, H.R. Abd El-Mageed, Hussein S. Mohamed, F.M. Mustafa
PII:
S0022-2860(19)31156-1
DOI:
https://doi.org/10.1016/j.molstruc.2019.127056
MOLSTR 127056
Reference:
To appear in: Journal of Molecular Structure
Received Date: 23 July 2019
Revised Date: 9 September 2019
Accepted Date: 9 September 2019
Please cite this article as: M.K. Abdel-Latif, H.R. Abd El-Mageed, H.S. Mohamed, F.M. Mustafa, Study
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calculations and molecular dynamics simulations, Journal of Molecular Structure (2019), doi: https://
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MD
TD-DFT

Study the solvation effect on 6-phenyl-2-thioxo-1,2-dihydropyridine-
3-carbonitrile Derivatives by TD- DFT calculations and molecular
dynamics simulations
Mahmoud K. Abdel-Latif*a, H.R. Abd El-Mageedb,Hussein S.
Mohamedcand F. M. Mustafaa.
aChemistry Department, Faculty of Science, Beni-Suef university, Beni-Suef City, Egypt.
bMicro-analysis and environmental research and community services center, Faculty of
Science, Beni-Suef university, Beni-Suef City, Egypt.
cResearch Institute of Medicinal and Aromatic Plants (RIMAP), Beni-Suef university,
Beni-Suef City, Egypt.
*Corresponding author mahmoud.abdellatif@science.bsu.edu.eg (Tel.:+201156634469)
Abstract
The electronic structure of 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2-
mercapto-6-phenylpyridine-3-carbonitrile) and its some derivatives have been studied
both theoretically and experimentally. The choice of these compounds was motivated by
their biological importance and relevance. The corresponding proposed structures of all
1
studied derivatives in this work were confirmed by FT-IR spectrophotometer, HNMR
spectra and XRD patterns. The Density Functional Theory (DFT) has been used to
investigate the effect of substituents with different strengths of all studied compounds on
the geometry structures, natural bond orbital (NBO) properties, electrostatic potential
(ESP) and the global properties such as (the chemical hardness (η), global softness (S),
and electronegativity (χ) by analysis of the charge distribution and extent of charge
transfer in the molecule in the gas phase. Non-linear optical properties (NLO) such as
(static dipole moment (ꢀ), polarizability (α), anisotropy polarizability (ꢁα), first order
hyperpolarizability (β) and mean second order hyperpolarizability (γ)) also, were
computed by DFT in the gas and solvent (benzene and ethanol) phases. The effect of the
different substitutions and solvent polarity on the NLO properties were also investigated
to show their ability to be used as NLO compounds. We find that all studied compounds
exhibited higher NLO properties compared to urea (reference materials) in the gas phase
and showed higher NLO properties in ethanol than in the benzene phase. The effect of
solvent polarity on the electronic absorption spectra of the studied molecules was
measured experimentally and calculated theoretically at the Time-Dependent Density
Functional Theory (TD-DFT) level of theory. The interactions of different solvents
(ethanol and benzene) with studied compounds were also studied by molecular dynamics
(MD) simulations. The radial distribution functions (RDFs) and coordination numbers
(CNs) of all studied compounds in the different solvent are computed. The diffusion

coefficient (D) also was calculated to investigate the influence of substitutions on the
mobility of the studied compounds in the surrounding solvent.
Key words: 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile, TD-DFT, MD
simulations, NLO, Diffusion coefficient
Introduction
In the last decades, pyridine-2-thiol derivatives are employed in various biological
applications such as anti-inflammatory, anti-tumor, ant mycobacterial, antifungal and
antiviral activities [1–3]. The cytotoxicity of pyridine derivatives against several human
cancer cell lines was reported [4-6]. Pyridin-2-thione derivatives represent useful
synthetic intermediates for the synthesis of biologically active deazafolates ring systems,
pyrimidine nucleosides, which reported to be significantly active both in vitro and vivo
[7] and inhibitor of dihydrofolatereductase [8]. Furthermore, pyrimidine nucleosides are
currently used dye to their cytotoxicity against various tumors as potentially as
methotrexate [9,10] and the most effective antimetabolites currently employed in the
treatment of different solid tumors [11]. Synthesis and anti-tumor activities of some new
pyridines and pyrazolo [1, 5-a] pyrimidines were discussed [12]. The molecular structure
of 3-(2-Mercaptopyridine)phthalonitrile was studied by computational and experimental
approaches, the electronic absorption spectra, nonlinear optical properties, molecular
electrostatic potential, and thermodynamic properties also were studied and reported [13].
Theoretical density functional and ab initio computational study of vertical ionization
potentials, dipole moments and 13C and 14NNMR shifts of the 2-mercaptopyridine system
was studied and reported [14].The solvent effects on the tautomerism and electronic
absorption spectra of 3-Hydroxy-2-mercaptopyridine and 2,3-Dihydroxypyridine was
studied [15]. The gas phase and solvent dependent preference of the tautomerization
between 2-pyridinethiol and 2-pyridinethione had been assessed using variable
temperature Fourier transform infrared (FTIR) experiments, and DFT computations [16].
Because of their wide range of biological activities and scientific relevance, 2-mercapto-
6-phenylpyridine-3-carbonitrile and its derivatives are currently represented the subject
of various investigations to explore a wide range of biological applications. Also, there is
no any theoretical and computational study on these compounds under considerations.
That’s why, the aim of the present work is to facilitate these biological investigations via
the compilation of various physical electronic and structural parameters which would
certainly underlie their biological activity using density functional theory. In addition to
the NLO parameters and the solvent effect on them are also investigated in this work. The
corresponding proposed structures of all studied compounds in this work are confirmed
1
by FT-IR spectrophotometer, HNMR spectra and XRD patterns as shown in the
experimental part. Electronic absorption spectra of all studied compounds were computed

by TD-DFT method in Benzene and Ethanol solvents in addition to the gas phase.
Molecular dynamical simulations is a strong tool to investigate the types of interaction
between 2-thioxo-1,2-dihydropyridine-3-carbonitrile compound and the solvents as done
by M.E. Salem et al [17]. Computational pharmacokinetic characterization of drug-
likeness has been done for Ethyl pyridine substituted 3-cyanothiopheneo complexes using
molecular dynamic simulation on the basis of an average root mean square deviation
(RMSD) and radial distribution function (RDF) [18]. So, in this study we have used the
MD simulations to gain more insight into the stability of these compounds in different
solvents (ethanol and benzene) and their binding ways with the solvents using (RMSD)
and (RDF).
2. Experimental Part
Scheme (1)
2.1 Instrumentation
All melting points are uncorrected. IR spectra were obtained (KBr disk) by using a Perkin
1
Elmer 11650 FT-IR spectrophotometer. HNMR spectra were recorded in CDCl3 on a
Varian mercury VXR-300 (300 MHz for 1H and 75 MHz for 13C). X-ray diffraction
(XRD) patterns of the studied compounds were characterized with the help of
Pananlytical Empryan Xray diffractometer 202 964 (the Netherlands). The scan range

was 5°–140. The electronic absorption spectra were measured on a Perkin Elmer Lambda
4B spectrophotometer using 1.0 cm fused quartz cells, where the spectrometer records
linearly the percent of transmittance over the range 200-700 nm. Analytical data were
carried out at Beni-Suef University. Polar (ethanol) and non-polar (benzene) solvents
used in the present work were obtained from Merck, AR grade and used without further
purification.
2.2 Synthesis:
Sodium 3-oxo-3-Arylpropan-1-olate (2):-
In a three necked flask containing [0.01 mol] of sodium methoxide and 20 ml ether, [0.01
mol] Actophenone derivatives 1 with [0.01 mol] ethyl formate was poured over it through
separating funnel with efficient stirring. The solid product was collected at the pump and
used directly in the reactions.
General procedure for the synthesis of compounds 3(a-d):-
A solution of (0.01 mol) sodium salt of compounds 2, (0.01 mol) 2-
Cyanoethanethioamide and piperidine acetate (1 ml) in H2O (3 ml) was heated for 15
minutes. Acetic acid (1.5 ml) was added to the hot solution. The solid product was
filtered off and recrystallized.
3a: 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile.
Red (yield 59%), m. p. 179-182oC (Acetic acid), umax / cm-1 (KBr) 3350 (NH), 2229
(CN),1617(C=N). 1HNMR (DMSO) d = 6.98-8.1 (m, 7H, aromatic protons ),d = 13.3 (s,
1H, NH pyridine),. m/z 212 (Calcd for C12H8N2S: C, 67.9; H, 3.8; N, 13.20; S, 15.1%.
Found: C, 67.6; H, 3.9; N, 13.5; S, 14.9%.
3b: 2-thioxo-6-(p-tolyl)-1,2-dihydropyridine-3-carbonitrile.
Deep red (yield 68%), m. p. 190-195oC (Acetic acid), umax / cm-1 (KBr) 3368 (NH),
1
2230 (CN),1634(C=N). HNMR (DMSO) d= 1.82 (s, 3H, CH3), d = 7.09-8.19 (m, 6H,
aromatic protons ),d = 12.6 (s, 1H, NH pyridine),. m/z 226 (Calcd for C13H10N2S: C, 69;
H, 4.45; N, 12.38; S, 14.17%. Found: C, 68.7; H, 4.49; N, 12.4; S, 14.14%.
3c: 6-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile.
Deep red (yield 63%), m. p. 210-215oC (Dioxane), umax / cm-1 (KBr) 3344 (NH), 2229
1
(CN),1642(C=N), 1165 (C-O). HNMR (DMSO) d= 3.76 (s, 3H, OCH3), d = 6.90-8.22
(m, 6H, aromatic protons ), d = 13.33 (s, 1H, NH pyridine),. m/z 242 (Calcd for

C13H10N2OS: C, 64.44; H, 4.16; N, 11.56; O, 6.6; S, 13.23%. Found: C, 64.47; H, 4.12;
N, 11.59; O, 6.63; S, 13.20%.
3d: 6-(4-chlorophenyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile.
Orange (yield 72%), m. p. 225-227oC (Dioxane), umax / cm-1 (KBr) 3315 (NH), 2223
(CN),1637(C=N). 1HNMR (DMSO) d = 7.22-8.16 (m, 6H, aromatic protons ), d = 13.20
(s, 1H, NH pyridine),. m/z 246 (Calcd for C13H10N2Cl: C, 58.42; H, 2.86; N, 11.35; S,
12.99; Cl, 14.37%. Found: C, 58.45; H, 2.83; N, 11.38; S, 12.95; Cl, 14.39%.
FTIR and 1HNMR spectra are presented in the supporting information in Figure S1 and
S2 respectively. All characteristic peaks of FTIR and 1HNMR of 3(a-d) compound are in
good agreement with the previous studies [19,20]
X-ray diffraction patterns
The XRD of all studied compounds are given in Figure 1. All studied compound have
semi-crystalline structures as shown in Figure 1. It is clear also from this Figure that, All
compound have the X-ray diffraction peaks of mercaptophenylpyridine at typical
scanning angles 2θ = 22.14, 25.18, 35.28, 38.34 [21], in addition to these peaks, there are
two peaks appear (at 2θ = 13.00 and 45.23) in compounds 3a and 3b and disappear in
compounds 3c and 3d also, in compound 3c there are an additionally peak appear at 2θ =
15.65. All characteristic peaks are appeared for all compounds but with different
intensity. Compound 3c have the highest intensity compared to other compounds. The
increasing in the intensity indicated that the enhancement in the degree of crystallinity.
The degree of crystallinity can be calculated by separating intensities due to the
amorphous and crystalline phase of the diffraction pattern. Percentage of crystallinity
(Xc, %) is measured as the ratio of the crystalline area to total area according to the
following equation [22].
ꢀ
ꢁ
Xc (%) = [ꢀ ꢃꢀ ] ꢄ ꢅꢆꢆ% (1)
ꢂ
ꢁ
Where, Ac = area of the crystalline phase and Aa = area of the amorphous phase. The
degree of crystallinity of compounds 3(a-d) are 68.44, 70.55, 75.65, and 72.52 %
respectively. All the previous data confirmed that the corresponding proposed structures,
of all studied compounds.
3- Computational details
Quantum mechanical calculations based on DFT were performed for all studies
compounds using the Gaussian 09 program [23]. The Becke’s three parameter Lee-Yang-
Parr hybrid exchange-correlation (B3LYP) functional was used throughout this work [24-

27]. Full geometry optimization was performed using 6-311++G(d,p) as a basis set to
generate the optimized structures and ground state properties of all studied compounds in
the gas phase. Frequency calculation has been done at the same level of theory for the
confirmation of the global minima. The electronic transition properties such as the
maximum excitation wavelength (λmax) and oscillator strengths (f ) were computed using
TD-DFT [28] in the gas phase and different solvents adopting SCRF method, where the
Polarizable Continuum Model (PCM) using the integral equation formalism variant
(IEFPCM) is the default SCRF method [29-33]. MD simulations were performed using
FORCITE Module, which is implemented in the Materials Studio 7 package [34] with the
Condensed-Phase Optimized Molecular Potential for Atomistic simulation studies
(COMPASS) force field [35–37]. All atoms were considered explicitly in a cubic box
under a periodic boundary condition. This box contained 200 ethanol or benzene
molecules and one unite from studied compounds. MD simulations were carried out
under isothermal–isobaric (NPT) conditions, with pressure and temperature held at 1 atm
and 300 K, respectively, by employing a Nose thermostat and Berendsen barostat. The
equations of motion were integrated with the velocity Verlet algorithm for a total
simulation time of 1 ns with a time step of 1 fs. During the simulations the non-bonded
energies were calculated using the popular Ewald summation while the COMPASS force
field was used to calculate both van der Waals and electrostatic interactions.
4- Results and Discussion
4.1 Energetic of the ground state
The full geometry optimizations of the proposed molecules were computed at the
B3LYP/ 6-311++G(d,p) are shown in Figure 2. The different basis set is used to choose
the one that reproduces values which are in the good agreement with experimental values
obtained from the X-ray structure as shown next in Table S1 (S mean supporting
information). The total energies, corresponding zero point vibrations energy (ZPVE)
corrections, thermodynamics parameters and Dipole moment (D.M) of the studied
compounds are listed in Table 1. The ZPE of the compound 3a is 0.1664 au which is
increased to 0.1985 au upon substitution of the H-atom with methoxy group as an
electron donating group. While the substitution of the H-atom with chloride group as an
electron withdrawing decreases the ZBE to 0.1567 au. This means that the electron
withdrawing groups stabilize the compounds in contrast to the electron donating groups
(take into accounts that the methoxy and Cl are near of the same molecular weight).
4.2 Global descriptors Properties
The energies of High occupied molecular orbital (HOMO), low unoccupied molecular
orbital (LUMO), energy gap (Eg) and the global properties of all studied compounds are

listed in Table 2. It is obvious that the separated phenylpridine ring is almost planar. The
ionization energy value, I (-EHOMO), calculates the donating property of the molecule.
The order of decreasing the ionization energy (increasing the oxidation power) of the
proposed molecules, is 3c > 3b > 3a > 3d as shown in Table 2. The electron affinity
value, A (-ELUMO), calculates the accepting property (reduction power) of the molecule.
Analysis of A indicates that the order of decreasing the reduction power is: 3d >3a > 3b >
3c which is the opposite of the order of oxidation power. Eg is the gap between EHOMO
and ELUMO; it measures the facile electron transition from HOMO to LUMO, this value
can be displayed as the chemical reactivity of the molecules. Eg values in Table 2 show
that the reactivity of these molecules increases in the order: 3c > 3d > 3b >3a. The dipole
moment signifies the polarizability of the molecules. The values of dipole moments
indicated that the order of the decrease the polarizability is: 3c > 3b > 3a > 3d which is of
the same order of the oxidation power (c.f. Table 2). The global properties such as the
global hardness η, electronegativity χ, electrostatic potential V and global softness S are
calculated by the thesis equations [38]:
ꢇ ꢈꢉ
η =
(2)
(3)
(4)
(5)
ꢊ
χ = ꢇ ꢃ ꢉ
ꢊ
V = ꢈ(ꢇ ꢃ ꢉ)
ꢊ
ꢅ
S = ꢊꢋ
For any two molecules, the electron will be partially transferred from one the molecule
which has low χ to that of high χ. The results show that the orders of decreasing χ
(increasing charge transfer within the molecules) are: 3d >3a > 3b > 3c. The small η
values for the studied compounds indicated that the ability of charge transfer inside the
molecule. Therefore, the order of increasing of η is 3c > 3d > 3b >3a. There is a
relationship between η and Eg as shown in Table 2. In which, the higher η values, the
harder is the molecule and vice versa. The occupied and unoccupied molecular orbitals
for the studied compounds are shown in Figure 3.
4.2. NBO analysis (used in the spectra part)
Natural atomic charge distributions based on Natural population analysis (NPA) was
performed on the global minimum structure of compound 3a in the gas phase. The atomic
charge distributions of all atoms in this compound are shown in Figure S3. The NBO’s
second-order perturbation theory and its second-order perturbation stabilization energy
E
(2) analysis describe the interaction between the idealized Lewis structure and the empty
non-Lewis orbital as well as. The intramolecular, intermolecular bonding and bond
interaction can be investigated by NBO analysis [39]. The larger value of E(2) value,
indicated that more intensive in the interaction between electron donors and electron
acceptors (more donating tendency from electron donors to electron acceptors). The

hyper conjugative interaction energy was derived from the second-order perturbation
theory. For each donor NBO (i) and acceptor NBO (j), the stabilization energy E(2)
associated with delocalization is estimated from the following equation [40]:
E (2) = ∆Eij = qi F (i, j) 2 / (εi- εj)
(6)
Where qi is the donor orbital occupancy, εj and εi the diagonal elements and F (i,j) is the
off diagonal NBO Fock matrix element. The calculated charge transfer energy E(2)
between the donor-acceptor orbital’s of the studied compounds computed at B3LYP/6-
311++G (d,p) level theory are summarized in Table 3, we find that the charges are
transferred from ꢌ (BD) to ꢌ* (BD)* orbitals with high stabilization energy E(2) in the
most interaction.
4.3. NLO properties
Recently, NLO materials are at the forefront of current research due to their importance
in providing the key functions of frequency shifting, optical modulation, optical
switching, optical logic, and optical memory. So, we can use NLO materials in a large
number of application such as modern communication technology, data storage, optical
signal processing, and optical interconnections [41-44]. In this study, we computed NLO
properties such as the total static dipole moment (µ), linear polarizability (α), first
hyperpolarizability tensor components (β) and mean second order hyperpolarizability (γ)
of the molecules of the all studied compounds in gas, ethanol and benzene phases at
B3LYP/6-311++G(d,p) level theory as shown in Tables S2-S4, respectively. All
equations used in the calculations of NLO properties of the studied compound are listed
in supporting information equations 7-11. Urea is one of the prototypical molecules used
in the study of the NLO properties of molecular systems. Therefore it was used
frequently as a threshold value for comparative purposes [45]. In this work, we chose as
reference material because there were no experimental values of the NLO properties of
the studied compounds. The magnitude of β is one of the key factors in the NLO system.
The analysis of β computed theoretically for the studied compounds show that of the
compound 3a (X=H) is 3 times higher than that of urea, while those of the derivatives;
X=CH3, OCH3, and Cl are 4, 6, 3 higher than the reference Urea respectively in the gas
phase as shown in Table S2. We also find that β and γ of these compounds increasing in
ethanol phase as shown in Table S3 are larger than that in benzene as shown in Table S4.
Therefore, the studied compounds are considered as effective candidates for NLO
materials.
4.5 Electronic absorption spectra

The electronic absorption spectra of 2-mercapto-6-phenylpyridine-3-carbonitrile
compound 3a and its derivatives 3b, 3c, 3d studied in this work depend on the type and
extent of interaction between different moieties. Two possible types of interaction
between subsystems can exist, as shown in scheme 2. For example, (i) no interaction
between phenylpyridine and the terminal phenyl group Ph-X (ii) full conjugation between
the two subsystems Ph-X and phenylpyridine.
4.5.1 Electronic absorption spectra of 3a.
The results of the experimental and theoretical electronic absorption spectra of compound
3a in ethanol and benzene are presented in Figure 4. The experimental spectrum in both
solvents is composed of two spectral bands in the range 200-500 nm. In benzene, the
experimental UV spectrum shows two intense bands at 269.0 nm and 306.0 nm.
Increasing solvent polarity from benzene to ethanol results in a blue shift of the two
bands, where the first band is shifted to 245.0 nm and the second band is shifted to 281.0
nm, respectively. Furthermore, increasing solvent polarity causes a marked decrease in
the intensity of the two bands going from Benzene to Ethanol. TD/B3LYP/6-
311++G(d,p) level theory calculation is valuable for the analysis of the experimental UV
Spectra of compound 3a in different solvents. The theoretical calculations are in good
agreement with the experimental calculations. Since increasing the solvent polarity from
Benzene to Ethanol has the same trend of decreasing of the intensity. In addition to the
blue shift which noticed experimentally by increasing the solvent polarity. The
theoretically calculated spectra showed a λmax of 326.87 nm for the first band in
Ethanol, and for the first band 329.43 (S1) in Benzene, and as shown in Table 5. The two
observed spectral bands are assigned as (π-π*) transitions, as reflected from the values of
molar absorptivity (ε = 5000-30000). Predicting and assigning the origin of the
experimental spectrum of compound 3a, requires the calculations of the theoretical gas
phase transitions of the various subsystems a, b, c, and d using TD-B3LYP/6-
311++G(d,p) level of theory, which are presented in Figure 5. Three strong transitions are
computed at 292.0, 261.0, and 239.0 nm for subsystem a; three transitions are computed
at 274.0, 260.0, and 245.0 nm for subsystem b; three transitions are computed at 308.0,
285.0, and 254.0 nm for subsystem c; three transitions are computed at 298.0, 292.0, and
282.0 nm for d; three transitions are computed at 326.0, 292.0, and 284.0 nm for
compound 3a. The correlation of the theoretical transitions of Table 4 between the
various subsystems shows that the transition at 292.0 nm of subsystem d correlates with
the transition at 292.0 nm of compound 3a. Moreover, the transition at 282.0 nm of
subsystem d correlates with that at 284.0 nm of compound 3a. It is clear that from this
division, the pyridine rings with the CN and SH groups contribute the most of the two
spectral bands of the gas phase of compound 3a. This is confirmed by the charge density
of HOMO of compound 3a, where the charge density is localized on this moiety. The

delocalization of the charge density of the HOMO over the whole molecule of
compounds 3b, 3c, and 3d is increased upon substitution in the para position of the
phenyl ring.
4.5.2 Electronic absorption spectra of 3b.
Compound 3b results by inserting CH3 group in the position X in Ph-X of compound 3a.
The experimental and theoretical electronic absorption spectra of compound 3b in
benzene and ethanol are combined and shown in Figure 6 and Table 6. In benzene, the
experimental spectrum is composed of two bands, at 338.0 nm and 307.0 nm. Increasing
solvent polarity from Benzene to Ethanol results in a blue shift of the two bands, where
the first band is shifted to 336.0 nm and the second band is shifted to 305.0 nm,
respectively. Furthermore, increasing solvent polarity causes a marked decrease in the
intensity of both bands. The two observed bands are assigned as (π-π*) transitions, based
on the values of molar absorptive (ε = 5000-30.000). The interpretation of the
experimentally observed UV Spectra of compound 3b in Benzene and Ethanol requires
the theoretical calculations of the vertical transitions using TD/ B3LYP/6-311++G(d,p)
level theory. Recorded theoretical spectra are in agreement with the experiment since the
blue shift and the decreasing intensity are observed with increasing the solvent polarity.
TD/DFT showed the λmax of 332.45 nm (S1) and 301.79 nm (S2) with respect to Benzene
and 330.49 nm (S1) and 300.39 nm (S2) in Ethanol.
4.5.3 Electronic absorption spectra of 3c.
Compound 3c results by inserting OCH3 group in the position X of compound 3a. The
experimental and theoretical electronic absorption spectra of compound 3c in Benzene
and Ethanol are shown in Figure 7 and Table 7. The experimental spectrum in Benzene is
composed of two bands at 348.0 nm and 277.0 nm. The change of solvent polarity from
Benzene to Ethanol results in a small red shift by 1 nm of the first band, where the second
band is blue shifted by 1 nm. Additionally, increasing solvent polarity causes a marked
decrease in the intensity of the two bands. The values of molar absorptivity (ε = 5000-
30000) indicate that the two observed bands have π-π* character. The theoretical vertical
transitions using TD/ B3LYP/6-311++G(d,p) level theory is valuable for the analysis of
the experimental UV Spectra of 3 which gives values for λmax of 346.03 nm (S1) for the
first band in Benzene , and for the first band 345.15 (S1) in Ethanol , and as shown in
Table 6.
4.5.4 Electronic absorption spectra of 3d.

Compound 3d results by inserting Cl group in the position X of compound 3a. The
experimental and theoretical electronic absorption spectra of compound 3d in Benzene
and Ethanol are shown in Figure 8 and Table 8. The experimental spectrum in Benzene is
composed of three bands. The experimental UV spectrum in benzene shows two intense
bands at 284.0 nm and 310.0 nm. Increasing solvent polarity from benzene to ethanol
results in a blue shift of the two bands, where the first band is shifted to 270.0 nm and the
second band is shifted to 298.0 nm, respectively. These transitions are assigned to π-π*
transition as indicated by the molar absorptivity values (ε=5000-30000). The theoretical
electronic absorption spectra using TD/ B3LYP/6-311++G(d,p) level theory is valuable
for the analysis of the experimental UV Spectra of compound 3d. The calculated spectra
showed a blue shift by switching the solvent from Benzene to Ethanol. In benzene, the
values of λmax is at 340.22 nm for (S1) and 278.2 nm for (S2), while the λmax is at 334.44
for (S1) and 270.31 nm for (S2) in Ethanol as shown in Table 8.
4.6 Molecular Electrostatic potential (MEP)
The MEP is related to the electronic density and is a very useful descriptor in determining
the sites for electrophilic and nucleophilic reactions as well as hydrogen bonding
interactions. To predict reactive sites for electrophilic and nucleophilic attack for the
studied compounds, the MEP at the B3LYP/6-311++G(d,p) level of theory was
calculated. The negative (red and yellow) regions of the MEP are related to electrophilic
reactivity and the positive (blue) regions are related to nucleophilic reactivity, as
indiicated in Figure 9. It is clear that from Figure 9, the MEP of compound 3a displayed
all atoms with positive electron densities (sites for nucleophilic attack) except the
nitrogen atom in (CN) group which showed a negative electron density (sites for
electrophilic attack). For compound 3b, all atoms have a positive electron densities
except the nitrogen atom in (CN) group has a negative electron density and the sulfur
atom in (SH) group displayed an intermediate negative electron density. Compound 3c,
showed all atoms with a positive electron densities except the nitrogen and the oxygen
atoms in (CN) and (OCH3) groups respectively where they showed negative electron
density while the sulfur atom in (SH) group displayed an intermediate negative electron
density. In the compound 3d all atoms displayed with a positive electron densities but the
nitrogen atom in (CN) group displayed with a negative electron density. The sulfur atom
in (SH) group and the chloride atom displayed with an intermediate negative electron
density. The MEP map displayed that the negative potential sites were on electronegative
atoms (N, O and S) and the positive potential sites were around the hydrogen atoms.
These sites give information and some light on the regions that the compound can have
intermolecular interactions with others.
4.7 MD simulations

To get more insight on the interaction between the studied compounds and different
solvent such as ethanol and benzene. MD simulations can be used to calculate diffusion
coefficient and study the hydrogen bonds (HBs) forming between the studied compounds
and different solvents. Figures S4 and S5 show MD snapshots of all studied compounds
in ethanol and benzene respectively. All snapshots were taken at 1nm (all snapshots are
taken within 3Å from the studied compounds) in which the green dashed line showed
HBs formation between studied compounds and solvents. It has been found that from
Figures S4 and S5 all studied compounds formed hydrogen bond with ethanol through S,
N and H atoms (studied compounds). The HBs formation between all studied compounds
+ ethanol and all studied compounds + benzene can be explored by the radial distribution
functions (RDFs) and coordination numbers (CNs). The RDF is the probability of finding
particle “B” within the range (r+dr) around particle A, and expressed as gAB(r). The CN
is obtained by integrating the gAB(r) [46]. The RDFs for HB sites of the parent and the
methoxy compounds with the oxygen (O) or hydrogen (H) atoms of ethanol and with
hydrogen (H) atoms of benzene molecules are plotted in Figure 10, together with the
corresponding coordination numbers (CNs).
4.7.1 RDFs and CNs of all compounds in ethanol and benzene
4.7.1.1. Compound 3a
The RDF of the hydrogen atoms of the SH group of the parent with O atom of ethanol as
shown in Figure 10 (1a), HS(parent)······O(ethanol), has an intense peak at 2.4 Å which is
related to the HBs formation; since it is within the HB distance (2.5 Å). The S and N
atoms of the parent compound formed also HBs with the hydrogen atoms of ethanol
S(parent)······H(ethanol) and N(parent)······H(ethanol) have intensive peaks at 1.8 and 2.4 Å
respectively and the intensity of the former peak is greater than the later one as shown in
Figure 10 (1b and 1c), indicating that the HB of the former is stronger than the later one.
The S and N atoms of the parent compound also formed HBs with the hydrogen atoms of
benzene S(parent)······H(benzene) and N(parent)······H(benzene) have intensive peaks at 2.4 and
1.5 Å respectively and intensity of the later peak is greater than the former as shown in
Figure 10 (1d and 1f), indicating the HB of the later is stronger than the former one, in
addition to four peaks with small intensity are found at former due to nonbonding
interactions. Parent compound strongly formed HBs with ethanol and benzene especially
in S(parent)······H(ethanol) and N(parent)······H(benzene) according to RDFs and CNs.
4.7.1.2. Compound 3b
The RDF of the hydrogen atoms of the SH group of CH3 with O atom of ethanol shown
in Figure S6 (2a). The HS(CH3)······O(ethanol), has an intense peak at 2.5 Å which is related
to the HBs formation. The S and N atoms of the CH3 compound formed also HBs with
the hydrogen atoms of ethanol S(CH3)······H(ethanol) and N(CH3)······H(ethanol) and they have
intensive peaks at 1.7 and 1.2 Å respectively. The intensity of the later peak is greater

than the former as shown in Figure S6 (2b and 2c), indicating that the HB of the later is
stronger than the former one. In addition, the former one has five peaks with low
intensity due to nonbonding interactions. The S and N atoms of the parent compound
formed also HBs with the hydrogen atoms of benzene S(CH3)······H(benzene) and
N(CH3)······H(benzene) have intensive peaks at 2.3 and 1.4 Å respectively and intensity of the
later peak is greater than the former as shown in Figure S6 (2d and 2f), indicating the HB
of the later is stronger than the former one. CH3 compound strongly formed HBs with
ethanol and benzene especially at N(CH3)······H(ethanol) and N(CH3)······H(benzene) centers
according to RDFs and CNs parameters.
4.7.1.3. Compound 3c
The RDF of the hydrogen atoms of the SH group of OCH3 compound with O atom of
ethanol as shown in Figure S7 (3a), HS(OCH3)······O(ethanol), has an intense peak at 2.3 Å
which is related to the HBs formation. The S and N atoms of the parent compound
formed also HBs with the hydrogen atoms of ethanol S(OCH3)······H(ethanol) and
N(OCH3)······H(ethanol) with the same intensive peaks at 1.7 as shown in Figure S7 (3b and
3c). The HB of the former one is stronger than the later one. The S and N atoms of the
OCH3 compound formed also HBs with the hydrogen atoms of benzene
S(OCH3)······H(benzene) and N(OCH3)······H(benzene). These HBs have intensive peaks at 2.45
for the S atom and 1.6 Å for the N atom and intensity of the later peak is greater than the
former one as shown in Figure S7 (3d and 3f), indicating that the HB of the N atom is
stronger than the S Atom, in addition to two peaks with small intensity are found at
former due to nonbonding interactions. Also oxygen atom in OCH3 group
O(OCH3)······H(ethanol) formed HB with the hydrogen atoms of ethanol with highly intensive
peak at 1.15 Å in addition to four peaks with low intensity due to nonbonding interactions
as shown in Figure S7 (3g). So, OCH3 compound strongly formed HBs with ethanol and
benzene especially at S and O centers according to RDFs and CNs.
4.7.1.4. Compound 3d
The RDF of the hydrogen atoms of the SH group of Cl compound with O atom of ethanol
shown in Figure S8 (4a), HS(Cl)······O(ethanol), has an intense peak at 2.3 Å which is related
to the HBs formation. The S and N atoms of the Cl compound formed also HBs with the
hydrogen atoms of ethanol S(Cl)······H(ethanol) and N(Cl)······H(ethanol) with intensive peaks
at 1.6 and 1.5 Å respectively and the later peak is more intense than the former one as
shown in Figure S8 (4b and 4c), indicating the strength HB formation of the later than the
former one. Also the later one has additionally five peaks with low intensity due to
nonbonding interactions. The S and N atoms of the Cl compound have also HBs peaks
formation with the hydrogen atoms of benzene S(Cl)······H(benzene) and N(Cl)······H(benzene)
at 2.4 and 1.5 Å respectively. And the intensity of the later peak is greater than the former

as shown in Figure S8 (4d and 4f), indicating the HB of the later is stronger than the
former one. Cl compound strongly formed HBs with ethanol and benzene especially in at
the N center (N(Cl)······H(ethanol) and N(Cl)······H(benzene)) according to RDFs and CNs
.
4.7.2 Diffusion coefficient (D)
The diffusion coefficient D is related to the slope of the mean square displacement of
solvent molecules and can be calculated by the Einstein relation equation. When the
solute molecules move faster in the solution the solute-solvent collisions increase and
more thermal energy are generated, and as a result the diffusion coefficient increase. This
indicated that solute which has lower value of D interact with solvent stronger than that
has higher value of D [47]. Diffusion coefficient of all studied compounds in both ethanol
and benzene are calculated by MD simulation and summarized in Table 9. The values of
Diffusion coefficient of OCH3 compound are the lowest values which indicated that the
interaction between this compound and these solvent are the strongest with respect to the
rest of compounds. Also the RDFs and the CNs calculations confirmed that this
interaction is the strongest more HBs are formed. So, we can say that OCH3 and CH3
substitutions enhanced the interaction of Thiol with ethanol and benzene but Cl
decreasing this interaction according to the diffusion coefficient values, RDFs and CNs.
Conclusion
The corresponding proposed structures of all studied derivatives in this work are
1
confirmed by FT-IR spectrophotometer, HNMR spectra and XRD patterns. Electronic
structure and geometry optimization of 2-mercapto-6-phenylpyridine-3-carbonitrile
compound 3a and some of its derivatives 3b-3d, are investigated theoretically at
B3LYP/6-311++G(d,p) level theory. All the studied compounds are found to be planar.
The ground state properties of compounds 3(a-d) show that compound 3c has the lowest
EHOMO, ELUMO, and ∆E indicating highest reactivity. The Compound 3c is found to have
the highest polarity, as shown from the computed dipole moment. The polarizability and
hyperpolarizabilities parameters indicated that compounds under investigation are
excellent candidates for NLO materials comparing the urea compound. Electronic
absorption spectra are investigated experimentally in Benzene and Ethanol; and
theoretically in gas phase at the TD-B3LYP/6-311++G(d,p) level of theory. Compounds
3b, 3c exhibit 2 bands each in the accessible vis-UV range investigated, while
compounds 3a and 3d exhibit 3 bands each in both solvents. The band maxima (λmax) and
intensities of the spectra are found to have solvent dependence. The overall trend is the
blue shift upon increasing the solvent polarity. It is noticed that decreasing of the band
intensities going from Benzene as non-polar solvent to Ethanol as polar solvent.
Theoretical calculations of the vertical excitations at the TD-B3LYP/6-311++G(d,p) level

theory reproduced the experimental spectra, indicating a good agreement between theory
and experiment. Molecular dynamic simulations based on the RDFs, CNs and D
parameters showed and confirmed that compounds 3b and 3c exhibits stronger
interactions and formed many HBs with ethanol and benzene than compound 3a and 3d.
Also, MD simulations confirmed that, the methoxy (OCH3) compound (3c) has the
stormiest interactions with the used solvents due to many hydrogen bonding formations.

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Table 1: The energetics, thermodynamics parameters, zero point energy corrections and
dipole moment of the studied compounds, calculated at B3LYP/6-311++G(d,p) level.
G.S. Properties
E0(au)
1
2
3
4
-969.94886
-608642.91
-2546115.8
0.166380
-1009.2771
-633321.4
-2649352.5
0.193445
0.208747
0.150374
-1009.08368
-1009.06838
-1009.12675
5.198
-1084.507
-680528.15
-2846830.9
0.198508
0.213643
0.154760
-1084.30850
-1084.29243
-1084.35225
5.426
-1429.5713
-897056
E0 (Kcal/mol)
E0 (KJ/mol)
EZPE (au)
-3752624.7
0.156683
0.170366
0.171311
-1429.41463
-1429.40000
-1429.45680
2.991
0.178802
Hcorr(au)
0.126450
Gcorr(au)
-969.782480
-969.769115
-969.822410
4.414
E0 + EZPE (au)
E0 + Hcorr (au)
E0 + Gcorr(au)
Dipole Moment (D)

Table 2: Energies in (a.u.) of molecular orbitals, energy gap Eg (eV) and global properties
for the studied compounds using B3LYP/6-31++G (d,p).
Orbitals
1
2
3
4
a
-0.24917
6.777
-0.24393
6.635
-0.2337
6.357
-0.2515
6.841
EHOMO
I,eV
-0.26956
-0.26339
-0.25649
-o.26976
EHOMO-1
b
-0.09189
2.499
-0.08906
2.422
-0.08593
2.336
-0.0977
2.657
E LUMO
A, eV
E LUMO+1
Eg, eV
χ,eV
-0.05882
4.28
-0.05662
4.21
-0.05511
4.02
-0.06430
4.18
4.638
4.529
4.357
4.749
-4.638
2.139
-4.529
2.107
-4.357
2.011
-4.749
2.092
V,eV
ɳ,eV
S,eV-1
0.2338
0.2373
0.2486
0.2390
aI.E. = - EHOMO b E. A. = - ELUMO

Table 3: Second Order Perturbation energy (E2), analysis of Fock matrix of compound 1 at B3LYP/6-311++G(d,p).
Donor
ED (i) (e)
1.69282
1.6655
Acceptor
ED (i) (e)
0.46182
0.41488
0.46182
0.0858
E(2) (kcal/mol)
31.11
E(j)-E(i) (a.u)
0.3
F(i,j)c (a.u)
0.089
0.081
0.06
BD*( 2) C 4 - C 5
BD*( 2) C 1 - N 6
BD*( 2) C 4 - C 5
BD*( 3) C 22 - N 23
BD*( 2) C 1 - N 6
BD*( 2) C 10 - C 12
BD*( 2) C 14 - C 16
BD*( 2) C 9 - C 11
BD*( 2) C 14 - C 16
BD*( 2) C 9 - C 11
BD*( 2) C 10 - C 12
BD ( 2) C 1 - N 6
BD ( 2) C 2 - C 3
BD ( 2) C 2 - C 3
BD ( 2) C 4 - C 5
BD ( 2) C 9 - C 11
BD ( 2) C 9 - C 11
BD ( 2) C 9 - C 11
BD ( 2) C 10 - C 12
BD ( 2) C 10 - C 12
BD ( 2) C 14 - C 16
BD ( 2) C 14 - C 16
28.86
0.27
1.6655
15.84
0.26
1.61538
1.63638
1.63638
1.63638
1.65248
1.65248
1.64749
1.64749
18.52
0.38
0.081
0.062
0.067
0.067
0.067
0.069
0.07
0.41488
0.29651
0.32885
0.3772
18.71
0.25
18.96
0.29
19.65
0.28
19.94
0.28
0.32885
0.3772
21.31
0.28
21.32
0.28
0.29651
18.46
0.29
0.066

Table 4: Theoretical gas phase transitions of the various subsystems 1a-d, using TD-
B3LYP/6-311++G(d,p).
Single point vertical excitation
1a
1b
1c
1d
Compound 1
292
261
239
274
260
245
308
285
254
298
292
282
326
292
284
S1
S2
S3

Table 5: Experimental and theoretical UV spectra of compound 1, calculated at TD-B3LYP/6-311++G(d,p).
Theoretical
Experimental
E. state
Gas phase
Coeff.
Ethanol
Benzene
Coeff.
Ethanol
Benzene
λ max,
nm
λ max,
nm
Config.
f
λ nm Config.
Coeff.
F
λ nm
Config.
F
λ nm
S1
S2
54 -> 56
55 -> 56
0.2085
0.6526
0.192 326.5 54 -> 56
55 -> 56
0.1461 0.352 326.9
0.6728
54 -> 56
55 -> 56
0.14483
0.67511
0.347 329.4
281
306
55 -> 57
0.1281
55 -> 57
0.1109
55 -> 57
0.1089
52 -> 56
0.3750
0.141 292.2 52 -> 56
0.1891 0.217 293.4
52 -> 56
53 -> 56
54 -> 56
55 -> 56
0.21648
-0.14523
0.62199
-0.14245
0.268 294.9
53 -> 56 -0.2727
54 -> 56 0.4875
55 -> 56 -0.1533
53 -> 56 -0.1520
54 -> 56
0.6262
55 -> 56 -0.1423
55 -> 57 0.1253
0.204 284.1 52 -> 56 -0.1318 0.222 286.3
55 -> 57
52 -> 56
0.1040
0.5326
55 -> 57
0.11855
S3
52 -> 56
53 -> 56
54 -> 56
-0.28867
0.58465
0.21849
0.218 286.8
53 -> 56 -0.1192
54 -> 56 -0.3964
53 -> 56
54 -> 56
0.6464
0.1770
55 -> 56
0.1594
55 -> 56 -0.1088
55 -> 57 -0.1127

Table 6: Experimental and theoretical UV spectra of compound 2, calculated at TD-B3LYP/6-311++G(d,p).
Theoretical
Experimental
E.
Gas phase
Ethanol
Coeff.
Benzene
Coeff.
Ethanol Benzene
State
λ max,
nm
λ max,
nm
Config.
Coeff.
f
λ nm
Config.
F
λ nm
Config.
f
λ nm
58 -> 60 0.2331
59 -> 60 0.6445
59 -> 61 -0.1358
56 -> 60 0.1334
57 -> 60 0.1236
58 -> 60 0.6087
59 -> 60 -0.2500
59 -> 61 -0.1571
56 -> 60 0.4687
57 -> 60 0.4718
58 -> 60 -0.1779
0.298
327.5
58 -> 60
59 -> 60
59 -> 61
58 -> 60
59 -> 60
59 -> 61
-0.1386 0.557 330.5
0.6786
58 -> 60
59 -> 60
59 -> 61
58 -> 60
59 -> 60
59 -> 61
0.1425
0.6781
-0.1069
0.6553
-0.1642
-0.1606
0.541 332.5
336
338
S1
S2
0.1066
0.347
0.064
297.6
287.7
0.6523 0.261 300.4
0.1621
0.315 301.8
305
307
-0.1770
56 -> 60
57 -> 60
59 -> 62
0.1596 0.051 289.6
0.6575
56 -> 60
57 -> 60
58 -> 60
0.2634
0.6220
-0.1030
0.054 289.5
S3
0.1374
59 -> 62
-0.1272

Table 7: Experimental and theoretical UV spectra of 3, calculated at TD-B3LYP/6-311++G(d,p).
Theoretical
Experimental
E. state
Gas phase
coefficie
nt
Ethanol
coeffici
Benzene
coefficie
Ethanol Benzene
λ
λ
λ max,
nm
λ max,
nm
config
f
config
f
config
f
λ nm
nm
nm
nt
62 -> 64
63 -> 64
63 -> 65
62 -> 64
63 -> 64
63 -> 65
61 -> 64
62 -> 64
63 -> 65
0.1445
0.6737
-0.1249
0.6279
-0.1840
-0.2414
0.2089
0.2576
0.6026
0.58 335 63 -> 64 0.6965
0.8
345 63 -> 64
0.1919
0.82
346
349
348
S1
S2
S3
0.13 310 62 -> 64 0.6256
63 -> 65 0.2952
0.05
0.03
310 62 -> 64 0.63761
63 -> 65 -0.2677
0.07
0.04
312
291
0.02 289 61 -> 64 -0.2118
62 -> 64 -0.2941
290 61 -> 64
62 -> 64
0.1919
0.2705
0.6100
63 -> 65 0.5916
63 -> 65

Table 8: Experimental and theoretical UV spectra of compound 4, calculated at TD-B3LYP/6-311++G(d,p).
Theoretical
Experimental
Ethanol Benzene
E. states
S1
Gas phase
Ethanol
Coeff.
0.418 331.4 62 -> 64 0.1615 0.459 334.44 62 -> 64 0.1585 0.466 340.2
Benzene
λ max,
nm
λ max,
nm
config
Coeff.
f
λ nm Config.
f
λ nm
Config.
Coeff.
f
λ nm
62 -> 64
63 -> 64
0.2376
0.6451
298
310
63 -> 64 0.6740
63 -> 65 0.1032
63 -> 64 0.6752
63 -> 65 0.1020
63 -> 65
-0.1248
60 -> 64
62 -> 64
63 -> 64
0.1164
0.6269
-0.2557
0.27
272.4 62 -> 64 0.6599 0.406 272.31 62 -> 64 0.6630 0.433 278.2
270
284
S2
S3
63 -> 64 -0.1806
63 -> 65 0.1249
63 -> 64 -0.1768
63 -> 65 0.1164
63 -> 65
-0.1218
60 -> 64
61 -> 64
0.6395
0.2527
0.029 245.5 60 -> 64 0.6098 0.024 245.64 60 -> 64 0.6329 0.022 252.5
61 -> 64 0.3231 61 -> 64 0.2834
62 -> 64
-0.1292

Table 9: Diffusion coefficient of all studied compounds in ethanol and benzene
obtained from MD simulation.
Diffusion coefficient (cm2/s)
Ethanol
3.84x 10-5
4.79 x 10-5
6.32 x 10-5
4.12 x 10-5
Benzene
4.23 x 10-5
4.98 x 10-5
5.06 x 10-5
4.43 x 10-5
Parent
CH3
OCH3
Cl
Scheme 2: The two possible types of interaction between subsystems.