Chemical Physics Letters 742 (2020) 137171

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Chemical Physics Letters

journal homepage: www.elsevier.com/locate/cplett

Research paper

Synthesis, crystal structure, spectroscopic (FT-IR, 1H and 13C NMR) and T

nonlinear optical properties of a novel potential HIV-1 protease inhibitor
A. Pekparlaka, Ö. Tamera, , S.D. Kanmazalpb, N. Berberc, M. Arsland, D. Avcıa, N. Degee,
⁎

E. Tarcanf, Y. Atalaya
a
Department of Physics, Faculty of Art and Sciences, Sakarya University, Sakarya 54147, Turkey
b
Technical Sciences, Gaziantep University, Gaziantep, Turkey
c
Department of Food Technology, Ezine Vocational School, Çanakkale 18 Mart University, Çanakakale, Turkey
d
Department of Chemistry, Faculty of Art and Sciences, Sakarya University, Sakarya 54147, Turkey
e
Department of Physics, Faculty of Art and Sciences, 19 Mayıs University, 55223, Turkey
f
Department of Physics, Faculty of Art and Sciences, Kocaeli University, 41100, Turkey

HIGHLIGHTS

• AFT-IR,
novel disulfanediylpyrimidine derivate was synthesized.
• DFT calculations1 13
UV–Vis, H and C NMR spectra were reported.
• NLO properties were
were performed.
• Molecular docking of investigated for the molecule.
• title molecule to HIV-1 Protease 1HSG receptor was performed.

ARTICLE INFO ABSTRACT

Keywords: A multicomponent reaction between ethyl 3-aminocrotonate, amonium isothiocyanates and 2,2-dichloroacetyl
Disulfanediylpyrimidine chloride gives diethyl 6,6-disulfanediylbis(2-(dichloromethyl)-4-methylpyrimidine- 5-carboxylate) compound.
IR and NMR X-ray diffraction method was used for structural characterization of the title compound. FT-IR, UV-Vis, 1H and
DFT 13
C NMR spectra have been used to make spectroscopic characterization. Density functional theory (DFT) has
NLO
been used to calculate the optimized geometry, IR, UV-Vis and NMR spectra, HOMO and LUMO energies as well
Molecular docking
as nonlinear optical (NLO) properties of the title molecule. Finally, molecular docking study was performed to
evaluate the interaction mechanism of Diethyl 6,6′-disulfanediylbis(2-(dichloromethyl)-4-methylpyrimidine-5-
carboxylate) to bind to the HIV-1 Protease 1HSG receptor.

1. Introduction
Synthesis of the pyridine ring system and its derivatives occupy an
important place in the synthetic organic chemistry because of their
interesting biological and pharmacological properties such as antic-
ancer [1], antimalaria [2] and antimicrobial activities [3,4]. Thiox-
opyrimidine is an important structural unit in several heterocyclic
compounds. Thieno [3,4] pyrimidine derivatives have very important
compounds due to the variety of biological and pharmacological
properties such as analgesics, antiinflammatory, antipyretic, anticancer,
antiviral, antidepressant, antidiabetic, antibacterial, antihistaminic,
and antihypertensive. These types of compounds have been also
evaluated as herbicides, pesticides and plant growth regulators [5]. The
most important enzyme inhibition effects of thieno compounds are the
inhibition of protein kinase [6] and dihydro- folate reductase [7].
Protein disulfide isomerase (PDI) is known as a multifunctional protein
catalyzing the formation, reduction and isomerization of disulfide
bonds. Additionally, they can also bind to polypeptide chains [8]. New
pyrimidine derivative was prepared using two-step one-pot procedure
called Multicomponent Reactions (MCR's) [9]. MCRs can clearly de-
crease the generation of chemical waste and the associated reaction
costs [10]. As known reactions such as Ugi reaction, Mannic reaction
[11,12] and Biginelli reaction [13] etc. can be given as examples for
Multi- component reactions.

⁎
Corresponding author.
E-mail address: omertamer@sakarya.edu.tr (Ö. Tamer).

https://doi.org/10.1016/j.cplett.2020.137171
Received 28 November 2019; Received in revised form 10 January 2020; Accepted 29 January 2020
Available online 30 January 2020
0009-2614/ © 2020 Elsevier B.V. All rights reserved.
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Several disulfanediylpyrimidine-contining molecules have been Table 1

synthesized and their usually crystal structures, rarely spectroscopic Crystallographic data and refinement parameters for C18H18Cl4N4O4S2.
and biological properties have been reported [14–16]. Diethyl 6,6′- Crystal data
disulfanediylbis(2-(dichloromethyl)-4-methylpyrimidine-5-carbox- Chemical formula C18H18Cl4N4O4S2
ylate), a disulfanediylpyrimidine derivate, has been synthesized for the Mr 560.28
first time, in this study. Its crystal stucture, vibrational vawenumbers, Crystal system, space group Monoclinic, P21/n
1 Temperature (K) 296
H and 13C NMR chemical shifts have been obtained by using both a, b, c (Å) 14.2440 (9), 11.4415 (5),
experimental techniques and DFT model. In order to present a deep 15.1905 (11)
understanding about the title molecule, some parameters which are the β (°) 105.679 (5)
indicators of NLO proporties such as dipole moment, polarizability and V (Å3) 2383.5 (3)
Z 4
the first-order hyperpolarizability have been investigated by DFT
Radiation type Mo Kα
model. µ (mm−1) 0.71
Crystal size (mm) 0.64 × 0.51 × 0.37
2. Methods Data collection
Diffractometer STOE IPDS 2
2.1. Experimental details Absorption correction Integration
Tmin, Tmax 0.600, 0.790
No. of measured, independent and observed 12894, 4661, 3278
2.1.1. Synthesis
[I > 2σ(I)] reflections
Ethyl 3-aminocrotonate (98%, Sigma-Aldrich, USA) (1 mmol) (1) Rint 0.076
and amonium isothiocyanates (98%, Sigma-Aldrich, USA9) (1 mmol) (sin θ/λ)max (Å−1) 0.617
(2) were stirred in THF/CH3CN (v/v = 5:5) at 50 °C temperature for 7 h Refinement
under nitrogen atmosphere (THF, ≥99.9%, Sigma-Aldrich, USA; R[F2 > 2σ(F2)], wR(F2), S 0.069, 0.202, 1.07
CH3CN, 99.8%, Sigma-Aldrich, USA). To the stirred mixture, 2,2-di- H-atom treatment H-atom parameters
chloroacetyl chloride (98%, Sigma-Aldrich, USA) (1 mmol) (3) was constrained
Δρmax, Δρmin (e Å−3) 0.77, −0.59
added. The reaction mixture was stirred for 24 h at room
temperature. At the end of the reaction, the mixture was extracted with
chloroform, and dried over MgSO4 (≥99.5%, Sigma-Aldrich, USA). The atoms of the molecule compound were fixed geometrically. The re-
product was refined by crystallization from ethanol. The single crystal finement data and selected crystallographic results for the synthesized
of the compound was grown up from ethanol-hexane as a bright yellow compound are reported in Table 1.
cubic shape. We prepared a convenient and facile multicomponent
synthesis of diethyl 6,6-disulfanediylbis(2-(dichloromethyl)-4-methyl-
pyrimidine- 5-carboxylate) (4) compound shown in Fig. 1. Yield 65%, 2.1.3. Elemental Analysis, IR, UV-Vis, 1H and 13C NMR spectra
M.p. 160–161 °C; 1H NMR (CDCl3, 300 MHz, δ, ppm)): 6.416 (s, 1H, All chemical materials and reagents were provided from commercial
CH-Cl2), 4.523 (q, 2H, CH2-O), 2.736 (s, 3H, CH3-C), 1.508 (t, 3H, CH3- suppliers. Reactions were monitored by TLC and TLC plates visualized
CH2). 13C NMR (75 MHz, CDCl3, δ, ppm): 170.3, 168.4, 166.2, 163.7, with short wave UV fluorescence (k = 254 nm). Melting points were
122.6, 70.3, 62.9, 24.6, 14.4. IR (KBr, υ, cm−1): 1718 (C=O), 1604 determined by a Yanagimoto micro-melting point apparatus (Surrey,
(C=N), 1230. Anal. Calcd. For C18H18Cl4N4O4S2: C, 38.59; H, 3.24; Cl, UK) and are uncorrected. IR spectra was acquired on a SHIMADZU
25.31, N, 10.00; O, 11.42, S, 11.45; found: C, 38.72; H, 3.42; Cl, 25.51, Prestige-21 (200 VCE) (Kyoto, Japan) spectrometer. UV-Visible spectral
N, 10.28; O, 11.62, S, 11.67 studies were conducted on Shimadzu 2600 PC spectrophotometer with
a quartz cuvette (path length, 1 cm). The absorption spectra have been
2.1.2. X-ray crystallography recorded between 600 and 200 nm. Chloroform was used as a solvent.
1
Three-dimensional X-ray data were collected on an STOE IPDS II H and 13C NMR spectra were acquired at VARIAN Infinity Plus in 300
diffractometer at low temperature for the molecule compound. The and 75 Hz (Palo Alto, California), respectively. 1H and 13C chemical
lattice parameters were determined by the least-squares methods on the shifts are referenced to the internal deuteranated solvent. The ele-
basis of all reflections with F2 > 2σ (F2). Programs SHELXS97 and mental analysis was carried out with a Leco CHNS-932 (St. Joseph,
SHELXL97 integrated into the WinGX v. 1.70.01 [17] software system Michigan) instrument.
were used to solve and refine structure. The molecular graphics
(ORTEP, packing and hydrogen bonding) were done using MERCURY 2.2. Computational details
[18] and ORTEP-3 for Windows [19]. All geometrical calculations were
carried out using the program PLATON [20]. All the non-hydrogen The ground state geometry optimization of the title compound is

Fig. 1. Synthesis of Diethyl 6,6-disulfanediylbis(2-(dichloromethyl)-4-methylpyrimidine- 5-carboxylate), C18H18Cl4N4O4S2 (4).

2
A. Pekparlak, et al.
implemented by using Density Functional Theory (DFT) method at
Gaussian 09 revision D.01 program package [21]. Then, GaussView 5
software was used to make visual the obtained result [22]. The opti-
mized molecular structure and IR spectrum for the title molecule in the
ground state (in vacuo) were computed by a hybrid DFT functional
B3LYP functional (Becke’s three parameter hybrid functional using the
LYP correlation functional) [23,24] in conjunction with 6-311+
+G(d,p) level. A exhaustive vibrational investigation is carried out on
the basis of potential energy distribution (PED) analysis via VEDA4
program [25,26]. The most powerful and effective method in studying
the molecular basis and excited state properties is time dependent
density functional theory (TD-DFT) methods [27]. TD-B3LYP level with
polarizable continuum model (PCM)[28,29] was also used to obtain
electronic absorption spectra for complex 1 and 2 in ethanol solvent.
The important contributions from molecular orbitals to the electronic
absorption bands was evaluated by using SWizard program [30]. The
molecular HOMO (Highest Occupied Molecular Orbital) and LUMO
(Lowest Unoccupied Molecular Orbital) energies were calculated by the
TD-DFT method. The first-order hyperpolarizability (β) and related
properties (αo and Δα) for the title molecule are calculated using B3LYP
method with 6-311++G(d,p) basis set [31–33]. The molecular docking
study was performed via Autodock version 4.2 software [34] along with
the graphical interface AutoDockTools (ADT) version 1.5.6 to obtain
the minimum binding energy, inhibition constant and various para-
meters of the ligand-protein docking interactions. Discover Studio Vi-
sualizer 4.0 software [35] was used to prepare ligand and target protein
as well as visualize interactions between the best conformation.
3. Results and discussion
3.1. Crystal structure and optimized geometry
The title molecule crystallizes in the monoclinic system, with a P21/
n space group. The single crystal structure and the calculated geometric
structure of the title molecule are shown in Fig. 2a, b. The calculated
optimized parameters of the molecule compound (bond lengths and
angles) by B3LYP method with 6-311++G(d,p) basis set are listed in
Table 2. These calculated theoretical parameters were compared with
the experimental parameters of the molecule. Table 3 gives the ex-
perimental hydrogen bonds involved in the investigated structure. The
molecular structure of the title molecule is composed of ethyl ester
group and dichloromethyl group attached to central methylpyrimidine
ring and these two identical fragments are linked together via group of
disulfane group (S1–S2). As in the X-ray results, distance between the
two neighbors pyrimidine rings [C10–N3(Cg(1)) and C1–N1(Cg(2))]
Fig. 2. (a) The experimental molecular structure of C18H18Cl4N4O4S2 showing the atom-numbering scheme at the 30% probability level. (b) The optimized molecular
structure of C18H18Cl4N4O4S2 obtained at B3LYP/6-311++G(d,p) level.
3
Chemical Physics Letters 742 (2020) 137171
throughout S1–S2 bond is found to be 4.721 Å and the two pyridine
moieties are in the nearly gauche position, with the dihedral angle
between the mean planes of both pyrimidine rings of 71.5°; the corre-
sponding angle is 78.13°˚ in the similar molecule [36]. Additionally, the
sum of the angles at N1, N2, and N3, N4 of the pyrimidine rings is in
accordance with sp2 hybridization. All bond distances in the pyrimidine
rings indicate partial double bond character, which suggests a deloca-
lized π-electronic system throughout the rings. The N–C bond lengths in
the pyrimidine ring observed at the range of 1.319(5)–1.347(2) Å ex-
perimentally [calculated at 1.340–1.323 Å B3LYP/6-311++G(d,p)],
and found to be comparable with those reported for similar structure
[37]. The experimental bond lengths S1–S2 [2.044 (15)Å], S1–C1
[1.785 (3) Å] and S2–C10 [1.777 (4) Å] are in a good agreement with
reported by similar 4,4′-disulfanediylbis (6-methyl-2-phenylpyr-
imidine-5-carboxylate) structure [38]. These bond lengths have been
also calculated as 2.1754, 1.7684 and 1.7777 Å, respectively. As can be
seen from Table 2, the calculated geometrical parameters are in a good
agreement with the observed X-Ray structure parameters. To make
comparison between experimental and theoretical geometrical para-
meters, the correlation graphs were presented in Fig. 3. As can be seen
from the correlation graphs, the correlation coefficient for bond lengths
and bond angles were found to be 0.991 and 0.970. In addition to Van
der Waals interactions, the molecular structure is influenced by C–H···O,
and C–H···Cl intermolecular hydrogen bonds. In the investigated crystal,
molecules are linked through intermolecular C14–H14···O1 [symmetry
code: 1-x + 1/2, y − 1/2, -z + 1/2] and C5–H5···O3 [–x + 3/2, y − 1/
2, − z + 1/2] hydrogen bonds into supramolecular chains increasing
along the (0 1 0) axis direction (Fig. 4). Other hydrogen bonds are
detailed in Table 3. According to the optimized geometrical parameters,
the optimized molecular structure of the title molecule generally sup-
ports experimental crystal molecular structure. Considering that the
experimental results belong to the solid phase and theoretical calcula-
tions belong to the gaseous phase, minor differences between the ex-
perimental and theoretical results are negligible. Correlational graphs
were drawn to show consistency between experimental and theoretical
results. Fitting value have been found as 0.991 for bond length and 0.84
for bond angles.
3.2. IR spectra
Infrared spectroscopy involves the interaction of infrared radiation
with matter and this method is used as a powerful tool to identify the
chemical systems [39,40]. The vibrational wavenumbers for the syn-
thesized compound have been calculated by using B3LYP level of
density functional theory (DFT) in cooperation with 6-311++G(d,p)
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Table 2
Comparison of experimental and theoretical bond lengths (Å) and angles (°) for C18H18Cl4N4O4S2.
Experimental Theoretical Experimental Theoretical

Bond Lengths Bond Lengths

Cl4-C14 1.750 (4) 1.7988 S1-C1 1.785 (3) 1.7684
Cl3-C14 1.750 (4) 1.7988 N1-C1 1.337 (5) 1.3348
C4-C5 – 1.5139 N2-C4 1.319 (5) 1.3236
N4-C13 1.325 (5) 1.324 N1-C4 1.321 (4) 1.3272
N3-C13 1.320 (4) 1.3277 N3-C3 1.345 (5) 1.3461
N4-C12 1.347 (5) 1.3401 C11-C12 – 1.4093
C2-C3 – 1.4118 C10-C11 – 1.4279
C1-C2 – 1.4149 C13-C14 – 1.5142
C1-N1 – 1.3382 Cl2-C5 1.758 (4) 1.7993
C3-C9 – 1.5029 Cl1-C5 1.753 (4) 1.7999
C2-C6 – 1.4921 C12-C18 – 1.5043
O1-C6 1.206 (5) 1.2088 C11-C15 – 1.4825
O4-C15 1.323 (5) 1.3434 O3-C15 1.204 (5) 1.2162
O4-C16 1.464 (6) 1.457 C15-O4 – 1.3392
C7-C8 – 1.5132 C16-O4 – 1.4572
S2-C10 1.777 (4) 1.7777 C16-C17 – 1.5138
S1-S2 2.044 (15) 2.1752

Bond Angles Bond Angles

C1-S1-S2 101.83 (13) 95.7882 N3-C10-S2 116.3 (3) 116.9286
C10-S2-S1 101.25 (12) 96.0505 N1-C1-S1 115.8 (3) 116.9286
C13-N3-C10 117.0 (3) 117.2462 N3-C13-N4 126.9 (3) 126.9214
C4-N1-C1 116.1 (3) 117.3053 N2-C4-N1 127.6 (3) 127.0995
C13-N4-C12 116.5 (3) 117.1988 O1-C6-O2 123.1 (4) 122.7503
C4-N2-C3 116.8 (3) 117.415 O3-C15-O4 124.7 (4) 123.7659

Table 3 wavenumbers due to the different phases in which the experimental

Experimental Hydrogen-bond geometries (Å, °) for C18H18Cl4N4O4S2. and theoretical methods are carried out. Additionally, it should be
D–H···A D–H H···A D···A D–H···A
noted that DFT levels gives higher wavenumbers because of negligence
of anharmonicity, incomplete inclusion of electron correlation effects
C14–H14···O1 i
0.98 2.459 3.326 147 and basis set deficiencies. Due to these well-known systematic errors,
C5–H5···O3ii 0.98 2.495 3.338 144 the obtained vibrational wavenumbers have been scaled down with
C8–H8A···Cl2iii 0.96 2.880 3.667 140
0.96 [41]. The FT-IR and calculated IR spectra have been also presented
Symmetry codes: (i) –x + 1/2, y – 1/2, −z + 1/2; (ii) −x + 3/2, y − 1/2, in Fig. 5, as compared with each other.
−z + 1/2; (iii) x − 1/2, −y + 1/2, z − 1/2.
3.2.1. C-H vibrations
basis set. After that, a detailed assignment of vibrational modes has The CH stretching vibrations are generally observed at the region of
been carried out via PED analysis. A comparison between the experi- 3000–3100 cm−1 [42]. So, the vibration bands in this region can be
mental and theoretical vibrational wavenumbers as well as the per- easily identified. In the present study, the CH stretching vibration has
centage contributions of vibration modes obtained for the title com- been observed at 3054 cm−1 and calculated at the region of
pound have been provided in Table 4. Some minor differences have 3056–2983 cm−1 using B3LYP method. It can be understood from the
been found between experimental and theoretical vibration PED contributions in Table 4, the bands calculated at 3056 and

Fig. 3. The correlation graphs between the experimental and theoretical bond lengths and angles for C18H18Cl4N4O4S2 molecule.

4
A. Pekparlak, et al.
Fig. 4. (a) Crystal-packing diagram of the molecule, C18H18Cl4N4O4S2, along a-axis. (b) In the crystal-packing diagram, hydrogen bonds are shown as dashed lines
along with C14—H14···O1 (orange) and C5—H5···O3 (green) along (0 1 0) axis. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
3052 cm−1 are purely CH stretch vibration modes with 99% PED
contribution. It is declared that the peaks originated from in plane CH
bending vibrations have been observed at 1300–1000 cm−1 region,
while those obtained from out of plane vibrations have been found at
the range of 1000–700 cm−1 [43]. In our work, in plane CH bending
vibration observed at 1406 cm−1 has been calculated at
1457–998 cm−1 region. As for the out of plane ones, these bands ob-
served at 1025–1001 cm−1 region have been computed at
1015–781 cm−1 region by using B3LYP/6-311++G(d,p) level.
3.2.2. CH2 and CH3 group vibrations
The CH3 group leads to various effects such as electronic effect,
intermolecular hydrogen bonding and Fermi resonance in molecular
systems. The presence of an oxygen atom adjacent to the CH3 group,
which indicates these properties, can change the position of CH
stretching and bending modes [44]. In aromatic compounds including
methyl group, the CH asymmetric stretching vibrations are reported
around 2980 cm−1 while the CH symmetric stretching vibrations are
reported around 2870 cm−1 [45]. The CH2 stretching vibrations are
expected in the regions 3000–2900 cm−1 [46]. In a previously reported
study, the vibration bands in the regions of 2927–2858 cm−1 and
2962–2891 cm−1 arises from the experimental and theoretical ethylene
stretching vibrations [46]. In the present study, the CH3 and CH2 group
stretching vibrations were observed at 2903 and 2973 cm−1, respec-
tively. The symmetric and symmetric C-H vibrations in ethyl and me-
thyl groups were calculated at the range of 3022–2917 cm−1 by using
B3LYP level. The PED contributions to these vibration modes were
calculated at the range of 43–100%. The CH3 and CH2 group in plane
bending vibrations were also calculated at the range of
1457–1337 cm−1 with the PED contributions of 11–78%. These bands
were observed at 1406 and 1358 cm−1 as consistent with previously
5
Chemical Physics Letters 742 (2020) 137171
reported studies [47,48]. The CH3 and CH2 out of plane bending vi-
brations observed at 1151–786 cm−1 were calculated at the range of
1129–781 cm−1.
3.2.3. Ring vibrations
In aromatic rings such as benzene, pyridine and pyrimidine, the
C=C stretching vibrations happen in the region 1625–1430 cm−1 [49].
In this study, C=C aromatic ring stretching vibrations have been ob-
served at 1604 and 1509 cm−1. These stretching vibrations have been
also calculated at 1511 and 1502 cm−1 with the PED contributions of
19%. As can be seen from Table 4, these peaks are coupled by the an-
other ring vibration (CN). As for the aromatic ring CN stretching vi-
brations, these peaks have been observed at the range of
1604–918 cm−1, and calculated at the region of 1511–962 cm−1 for the
title compound. The purest CN stretching modes have been calculated
at 1499 and 1192 cm−1 with PED contributions of 59% and 58%, re-
spectively.
3.2.4. Carbonyl vibrations
The structural unit of carbonyl is one of the most broadly worked by
infrared spectroscopy since this group has a very characteristic vibra-
tional peak defined as the stretching vibration [50]. The molecular
systems having one or more carbonyl group are generally give a peak at
a range of 1715–1680 cm−1 [51]. In our work, the vibrational band
observed at 1718 cm−1 has been assigned as the carbonyl group
stretching vibration. This peak has been also calculated at 1696 and
1655 cm−1 as mostly pure modes with the PED contributions of 88%
and 85%, respectively. Additionally, carbonyl group in plane bending
vibrations have been calculated at 827 and 824 cm−1 with the 22% and
26% PED contributions, respectively.
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Table 4 Table 4 (continued)

Comparison of the observed and calculated vibrational wavenumbers and as-
signments for C18H18Cl4N4O4S2. Assignments FT-IR (cm−1) B3LYP (cm−1)

Assignments FT-IR (cm−1) B3LYP (cm−1) ʋ ClC 26 + ω CCNC 12 + γ OCOC 10 699 699
ʋ OC 85 + ʋ ClC 36 + ω NCNC 12 + γ CCNC 12 695
ʋ CH 99 3054 3056 ʋ CC 11 + β NCN 11 + γ ClCClC 18 + β CCN 672
ʋ CH 99 3052 16
ʋ CH 76 3022 ʋ ClC 24 636 615
ʋ CH 72 3020 ʋ ClC 27 + ω CNCN 10 601 601
ʋ CH 58 3003 β CNC 10 568
ʋ CH 51 2996 ʋ CC 13 + β CCN 15 563
ʋ CH 48 2990 γ CCNC 29 562
ʋ CH 49 2986 γ CCNC 28 + γ SCNC 17 554
ʋ CH 60 2983 β CCC 11 + β CNC 17 546
ʋ CH 43 2973 2973 ʋ CC 12 + β SCN 11 + β CCN 15 527
ʋ CH 48 2972 ʋ SS 18 + β OCC 10 478
ʋ CH 98 2940 ʋ SC 19 + ʋ SS 27 + β CNC 11 451
ʋ CH 98 2937 ʋ SS 11 + ʋ SC 30 + β CNC 13 426
ʋ CH 100 2934 β OCC 10 + β CCN 17 + βCCO 15 409
ʋ CH 97 2930 β CCO 28 401
ʋ CH 99 2919
ʋ CH 99 2903 2917 ʋ, stretching; β, in plane bending; γ, out of plane bending; ω, torsion.
ʋ OC 88 1718 1696 Vibrational modes are based on potential energy distribution (PED) and only
ʋ OC 85 1655
contributions over 10% are given. Scaled wavenumbers are in unit of cm−1.
ʋ NC 15 + ʋ CC 19 1604 1511
ʋ NC 25 + ʋ CC 19 1509 1502
β CCN 15 + ʋ NC 59 1496 1499
ʋ NC 53 + β CCN 12 1484
β HCH 72 1457
β HCH 78 1440
β HCH 63 1439
β HCH 74 1428
β HCH 76 + ω HCCC 15 1423
β HCH 72 1412
β HCH 63 + ω HCCC 11 1406 1406
β HCH 32 + ω HCOC 26 1374
β HCH 44 + ω HCOC 22 1372
β HCH 29 + ʋ CC 24 1358 1363
β HCH 45 + ʋ CC 11 1362
ʋ NC 12 + ʋ CC 16 + β HCH 14 1344
β HCH 11 + ω HCOC 41 1337
ω HCOC 11 1332
ʋ CC 11 + ʋ NC 11 1314 1258
γ CClCH 11 + β HCCl 11 1251
ω HCOC 37 + β HCC 65 + β HCO 59 1246
ʋ OC 23 + ʋ CC 11 1226 1225
ʋ NC 16 + ʋ OC 11 + β CNC 21 1216
β HCCl 98 + γ CClCH 87 1212 Fig. 5. Experimental and theoretical IR spectra for C18H18Cl4N4O4S2.
γ CClCH 16 + β HCCl 19 + ʋ NC 20 1208
ʋ NC 58 1230 1192
ʋ NC 10 + β HCCl 11 + γ CClCH 10 1169 1178
γ CClCH 17 + β HCCl 15 + ʋ NC 21 1177
β HCO 33 + HCOC 13 + ω HCCO 12 1151 1129
β HCC 23 + ω HCOC 22 + ω HCCO 10 1128
ω HCCO 30 + β CCO 12 + ʋ CC 15 + ʋ OC 12 1094
ω HCCO 37 + β CCO 14 1092
ʋ OC 15 + β CCN 10 1076 1072
ʋ OC 41 1066
β HCH 26 + ω HCCC 52 1025 1015
β HCH 13 + ω HCCC 40 1001 998
ʋ CC 25 + ʋ OC 18 + ω HCCC 22 993
ʋ CC 22 + ω HCCC 22 986
ʋ OC 21 + ʋ CC 46 984
ʋ CC 28 + ʋ NC 24 964
ʋ CC 30 + ʋ NC 26 918 962
ʋ OC 15 + ʋ SC 17 + ʋ CC 11 862 860
ʋ SC 16 852
ʋ OC 19 837
ʋ OC 29 835
β OCO 22 827
β OCO 26 824 Fig. 6. The experimental and theoretical UV-Vis spectra for C18H18Cl4N4O4S2.
ω CNCN 12 + ω CCNC 16 797
ω NCNC 14 + ω CCNC 12 796
ω HCOC 32 + ω HCCO 26 786 782 3.2.5. C-S and C-Cl vibrations
ω HCOC 33 + ω HCCO 27 781 C-Cl stretching vibration is generally reported to be found at the
γ OCOC 47 761 757
range of 800–600 cm−1. The C-Cl stretching vibration has been cal-
γ OCOC 57 755
ʋ ClC 44 732
culated at 732–601 cm−1 by B3LYP/6-311++G(d,p) method. This
peak has been also observed at 699–631 cm−1 for the title compound.

6
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Table 5 same spectrum was also calculated by using TD-B3LYP/CPCM method.

Calculated total molecular energies, FMO energies, electro- The obtained experimental and theoretical spectra were presented in
negativity, hardness and softness parameters for Fig. 6 in order to provide a visual comparison between the results. TD-
C18H18Cl4N4O4S2 obtained at B3LYP/6-31++G(d,p). B3LYP/CPCM level predicts three electronic absorption bands at 391,
Parameter B3LYP/6–311++G(d,p) 348 and 329 nm. The most likely absorption band (f = 0.0464) was
calculated at 348 nm as an approximately pure transitions occurred as
EHOMO (eV) −6.5046
HOMO → LUMO + 1(98%). The other bands calculated at 391
ELUMO (eV) −2.7244
ΔE (eV) 3.7802
(f = 0.0192) and 329 (f = 0.0013) nm were mainly originated from the
I (eV) 6.5046 transitions of HOMO → LUMO(99%) and HOMO −1 → LUMO (57%),
A (eV) 2.7244 respectively.
χ (eV) 4.6145 The highest occupied molecular orbital (HOMO) and lowest un-
ɳ (eV) 1.8901
occupied molecular orbital (LUMO) energies are very significant para-
S (eV−1) 0.2645
ETOTAL (a.u) −3854.3485 meters in quantum chemistry. The HOMO energy characterizes the
electron ability. Besides that, the LUMO energy also characterizes the
ability to take an electron. The energy gap between the HOMO and
LUMO energies reflects the chemical stability of the molecular system
under the investigation [53]. The total energy, HOMO and LUMO en-
ergies, the energy gap between them, the ionization potential
(I = −EHOMO), the electron affinity (A = −ELUMO), the absolute
electronegativity (χ = (I + A)/2), the absolute hardness (ɳ = (I-A)/2)
and softness (S = 1/2ɳ) for Diethyl 6, 6′-disulfanediylbis(2-(di-
chloromethyl)-4-methylpyrimidine-5-carboxylate) have been calcu-
lated at B3LYP in conjunction with 6-311++G(d,p) basis set. All of the
obtained results are presented in Table 5. The HOMO and LUMO en-
ergies have been calculated as −6.5046 and −2.7244 eV by using
DFT/B3LYP/6-311++G(d,p) level. The energy gap between HOMO
and LUMO has been obtained as 3.7802 eV. This relatively small energy
gap demonstrates that charge transfer takes place within the in-
vestigated compound. According to Fig. 7, the electronic density in the
ground state (HOMO) is mainly located on S atoms, and rarely on ni-
trogen and oxygen atoms. But, in the first excited state (LUMO), this
density is located around the C-C, C-N bonds as well as O and Cl atoms.
This change between the ground state and the excited state is another
indicator of the charge transfer interactions. Additionally, the de-
creased value of the energy gap makes the investigated molecule more
polar, more reactive and less stable. These molecules are also called soft
molecules. The frontier molecular orbital gap assists to define the
electronegativity, chemical hardness, softness, chemical reactivity and
optical polarizability of a molecule [54]. The HOMO and LUMO energy
values can be used calculate the electronegativity, chemical hardness
and chemical softness of the molecule [55]. The χ and ɳ parameters are
Fig. 7. Frontier molecular orbital pictures and DOS spectrum for
calculated as 4.6145 and 1.8901 eV by using B3LYP/6-311++G(d,p)
C18H18Cl4N4O4S2. level. The HOMO and LUMO status of the molecule are shown in Fig. 7.
The FMO distribution was confirmed by density of states (DOS) spec-
trum performed by the GaussSum 1.0 program [56] based on the results
Literature survey revealed that the C-S stretching vibration band was
obtained from Gaussian 09 revision D.01 software, and shown in Fig. 7.
observed at the region 685–778 cm−1 with a moderate intensity in FT-
IR and calculated at the range of 673–719 cm−1 in theoretical spectrum
3.4. Electric properties
[52]. In our study, the C-S stretching vibrations has been experimen-
tally measured at 862 cm−1, and calculated at 860–426 cm−1 by
In recent years, nonlinear optical materials have been gathered
B3LYP/6-311++G(d,p) level. The PED contributions of this mode
great attention for potential applications in optoelectronics such as
were obtained at the range of 16–30%. So, it can be said that this vi-
optical communications, optical computing, optical switching and dy-
bration mode was highly coupled with some stretching and bending
namic image processing. Organic materials exhibit a range of NLO
vibrations.
properties due to their high molecular hyperpolarization properties.
NLO materials are classified in three distinct groups: multilayer semi-
3.3. UV-Vis spectrum and electronic properties conductor structures, molecular-based macroscopic assemblies, and
traditional inorganic solids. The NLO activity has been investigated on
The UV-Vis spectrum was recorded for title molecule in Chloroform various inorganic, organic and organometallic molecular systems [57].
media at the range of 200–600 nm. The compound shows peaks that are Using by DFT/B3LYP method in 6-311++G(d,p) basis set, the total
characteristic of the n → σ*, n → π* and π → π* transitions of non- static dipole moment, the mean polarizability (< α > ), the anisotropy
bonding electron pairs and pyrimidine rings. The UV spectra of the of the polarizability (< Δα > ) and the mean first-order hyperpolar-
molecule clearly exhibit a π-π* band similar to that pyrimidine double izability (< β > ) of the title compound have been computed. Then,
bonds. Conjugate bands (K band) were observed at 307, 312, and the relationship between molecular structures and nonlinear optical
315 nm. The other absorption band recorded as a relatively weak and properties (NLO) has been investigated. Gaussian 09 revision D.01
broad band was observed at 410 nm. It is thought that sulfur atoms are program present α and β components in atomic units, and therefore, the
responsible for this absorption band with the longest wavelength. The calculated values are converted into electrostatic units (α: 1

7
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Table 6 molecule compound. Experimental both 1H and 13C NMR spectra were
The total static dipole moment (µ, in Debye), the mean measured at 75 MHz on a VARIAN Infinity Plus 300 spectrometer.
polarizability (< α > , in 10−23 esu), the anisotropy of the Theoretical 1H and 13C NMR spectra were calculated of the molecule
polarizability (Δα, in 10-23 esu) and the mean first hy- compound by using B3LYP method with 6–311++G(d,p) basis set. The
perpolarizability (< β > , in 10−30 esu) for 13
C chemical shifts values for all calculations have range
C18H18Cl4N4O4S2 obtained at B3LYP/6-311++G(d,p)
~189.3–14.6 ppm at B3LYP/6-311++G(d,p) level in the average for
level.
the title molecule. The 1H chemical shifts values for all calculations
Property B3LYP/6-311++G(d,p) have range ~6.80–1.24 ppm at B3LYP/6-311++G(d,p) level in the
average for the molecule compound. When experimental and theore-
µx −6.2581
µy −1.2613 tical NMR spectra are compared, it is seen that there are small differ-
µz −0.1096 ences. The possible reason for this difference that theoretical calcula-
µ 6.4113 tions are performed for only one isolated molecule, while the
µ 2.44 [58–61] experimental technique is carried out on the crystalline structure in
<α> 5.64
<α> 22 [58–61]
solution. The signals originated from CH-Cl2 proton was observed at
Δα 1.9714 4.416 ppm and calculated at 6.65–6.80 ppm by using B3LYP level. In
<β> 2.84 this study, CH2 protons give resonance at higher value (4.523 ppm) due
<β> 8 [58–61], 0.13 [62] to the coordination to electronegative O atom. The same peaks (CH2-O)
have been calculated at the range of 4.33–4.40 ppm with B3LYP level.
CH3-C protons gives signal at more downfield region compared to those
a.u. = 0.1482 × 10−24 esu and β:1 a.u. = 8.6393 × 10−33 esu) and
for CH3-CH2 due to the excess of electron density around the first group
given in Table 6. In this paper, we have presented values of the total
(see in Table 7). As for the 13C NMR results, C1 and C10 atoms give
static dipole moment (µ), the mean polarizability (< α > ), the ani-
resonance at 170.3 ppm due to the coordination both N and S atoms.
sotropy of the polarizability (Δα) and the mean first-order hyperpo-
These signals have been calculated at 189.3–182.5 ppm by using B3LYP
larizability (< β > ) [47]. Molecular dipole moment was calculated as
level. We know that aromatic carbon atoms give resonate in the range
6.4113 Debye for B3LYP level. The anisotropy of the polarizability
of usually 100–150 ppm. In this study aromatic C atoms give peak at the
(Δα = 1.9714 × 10−23 esu), polarizability (< > = 5.64 × 10−23
range of 170.3–122.6 ppm, and these peaks have been calculated in the
esu) and the first-order hyperpolarizability (< β > = 2.84 × 10−30
region of 189.3–122.1 ppm. Some of the aromatic carbons gives re-
esu) at B3LYP/6-311++G(d,p) level for Diethyl 6, 6′-disulfanediylbis
sonance at downfield region due to having electronegative atoms
(2-(dichloromethyl)-4-methylpyrimidine-5-carboxylate) are shown in
around its environment. As in proton signals, C9 atom gives resonance
Table 6. In comparison of NLO parameters for molecular systems
at higher value than C8 atom.
without experimental measurements, p-Nitroaniline (pNA), ni-
trobenzene [58–61] and urea [62], which are the prototypical com-
3.6. Molecular electrostatic potential (MEP) surface
pounds, are used. Although the β value is 21.85 times higher than urea
(0.130 × 10−30esu) in gas phase and ethanol solvent, the β value is
The molecular electrostatic potential (MEP) surface for the title
2.82 times lower than pNA (8 × 10−30esu) in the same solvents.
molecule was obtained at the B3LYP/ 6-311++G(d,p) in the optimized
geometry and presented in Fig. 9. Molecular electrostatic potential
3.5. 1H and 13
C NMR
(MEP) is considered to be related with the electronic density at a region
and it is a very powerful descriptor for determining the possible in-
It is an effective method to combine NMR and computer simulation
teraction sites around a molecule as well as hydrogen-bonding inter-
methods in predicting and interpreting the structure of large biomole-
actions [64]. In MEP surface patterns, blue positive regions are highly
cules [63]. 1H and 13C NMR chemical shifts are calculated within GIAO
sensitive to nucleophilic attacks, while red negative regions are pre-
methods applying B3LYP/6-311++ G(d,p) level. A collation of the
ferred regions for electrophilic attack. The blue colour implies the
experimental and theoretical spectra can be very helpful in making
strongest attraction for electrons while red colour implying the stron-
correct assignments and understanding the basic chemical shift mole-
gest repulsion. The potential increases in the order red < orange <
cular structure relationship. Theoretical and experimental 1H and 13C
yellow < green < blue. The MEP value ranged from
NMR results of the molecule compound are shown in Table 7. 1H and
13
−5.106 × 10−2 a.u. to 5.106 × 10−2 a.u. According to Fig. 9, the blue
C NMR spectrum of title molecule in CDCl3 have been exhibited in
coloured positive regions is focused CH3 - CH2 protons. The green co-
Fig. 8. In Table 7, the experimental end theoretical 1H and 13C NMR
loured regions are seen around CH-Cl2 protons. It can be said that this
isotropic chemical shifts (with respect to TMS, all values in ppm) for the
region is most positive area after the blue coloured regions.

Table 7
3.7. Molecular docking
The calculated and experimental 13C and 1H isotropic NMR chemical shifts
(with respect to TMS, all values in ppm) for C18H18Cl4N4O4S2.
The title compound was selected to be docked into the active site of
Atom Experimental B3LYP/6-311++G(d,p) the HIV-1 Protease 1HSG protein, retrieved from RCSB (Research
CH-Cl2 (1H) 6.416 6.65–6.80
Collaboratory for Structural Bioinformatics) protein data bank (http://
CH2-O (2H) 4.523 4.33–4.40 www.rcsb.org/pdb/home/home.do) [65]. ADT was used to remove the
CH3-C (3H) 2.736 2.85–4.46 non-aminoacid residues, such as water molecules, ions, ligands that are
CH3-CH2 (3H) 1.508 1.24–2.38 in the complex. Polar hydrogen atoms were added to the protein,
C1-C10 170.3 189.3–182.5
atomic charges added to each atom were calculated by Kollman
C3-C12 168.4 176.6–179.7
C6-C15 166.2 171.9–170.1 method, and Lamarckian genetic algorithm (LGA) were utilized for
C4-C13 163.7 169.8–170.1 molecular docking calculations. The ligand and protein were then saved
C2-C11 122.6 122.1–124.4 in PDBQT file format. A grid box size of 80 × 80 × 80 Å3 with 0.697
C5-C14 70.3 90.7–91.4 spacing centered on 16.072, 22.321 and 3.775 was created around the
C7-C16 62.9 115.-66.7
binding site of HIV-1 Protease 1HSG protein using Autogrid. The 2D
C9-C18 24.6 28.5–26.6
C8-C17 14.4 91.8–14.6 and 3D representations for interaction of title compound taken as the
ligand with protein 1HSG are shown in Fig. 10. The amino acids in

8
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Fig. 8. (a) 1H NMR and (b) 13

C NMR spectrum of C18H18Cl4N4O4S2 in CDCl3.

active site which were PHE53, MET46 and PRO44 is also illustrated docked in the active sites of the selected protein and minimum binding
using the PyMol software [66]. The 2D representation for hydrogen energy value was examined. The 1HSG protein exhibit the minimum
bond interaction between the ligand and protein was visualized using binding energy of −3.68 kcal/mol, intermolecular energy of
Discovery studio visualizer. The title molecule acted as the ligand was −5.69 kcal/mol and inhibition constant of 2.00 mM. The PHE53,

9
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

Fig. 9. The Molecular Electrostatic Potential (MEP) surface of

C18H18Cl4N4O4S2.

MET46 and PRO44 residues form π-Sigma, π-Alkyl and Alkyl of the title
ligand with hydrogen bond length of 3.95, 4.02 and 4.03 Å shows the
existence of the ligand-protein interaction, respectively.

4. Conclusion

In this study, Diethyl 6, 6′-disulfanediylbis(2-(dichloromethyl)-4-

methylpyrimidine-5-carboxylate) molecule has been synthesized and its
crystal structure analysis has been performed X-Ray crystallography.
Then, bond length, bond angles, IR spectra, 1H and 13C chemical shifts,
electric dipole moment (µ), the polarizability (α), the hyperpolariz-
ability (β) and HOMO-LUMO energies of the molecule were calculated
using B3LYP method and 6-311++G (d,p) basis sets. All calculated
parameters of the molecule compound were compared with the ex-
perimental data. R2 value of the title molecule were found 0.991 for
bond length, 0.84 for bond angles. The energy gap between HOMO and
LUMO was found to be 3.7802 eV, demonstrating that the in-
tramolecular charge transfer occurs in the title molecule. The charge
mobility is also demonstrated by the geometric structures calculated for
HOMO and LUMO (ground and first excited electronic levels). MEP
analysis showed that the negative potential is spread over the carboxyl
group. In addition to, electric dipole moment (µ), the polarizability (α)
and the hyperpolarizability (β) were calculated at 6.4113 D,
5.64 × 10−23 esu, 2.84 × 10−30 esu, respectively. Besides, HIV-1
protease (PDB ID: 1HSG) was used as target protein for molecular
docking to explore the biological agents of the title molecule in present
study.

CRediT authorship contribution statement
A. Pekparlak: Writing - Original Draft, Investigation. Ö. Tamer:
Writing - review & editing, Methodology, Investigation. S.D.
Kanmazalp: Validation, Writing - Original Draft. N. Berber: Formal
analysis, Data curation. M. Arslan: Supervision, Formal analysis. D.
Avcı: Software, Writing - review & editing. N. Dege: Formal analysis,
Data curation. E. Tarcan: Supervision, Software. Y. Atalay:
Supervision, Software.
Declaration of Competing Interest
The authors declare that they have no known competing financial
Fig. 10. 3D and 2D molecular docked pose of C18H18Cl4N4O4S2 to receptor HIV-
1 Protease 1HSG.
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
CCDC 1582753 contains supplementary crystallographic data (ex-
cluding structure factors) for the compound reported in this article.
These data can be obtained free of charge via http://www.ccdc.ca-
m.ac.uk/deposit [or from the Cambridge Crystallographic Data Center

10
A. Pekparlak, et al. Chemical Physics Letters 742 (2020) 137171

(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223 gradients in solution by a conductor solvent model, J. Phys. Chem. A 102 (1998)
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