Synthesis, structural and molecular characterization of 2,2-diphenyl-2H,3H,5H,6H,7H-imidazo[2,1-b][1,3]thiazin-3-one

Article abstract of DOI:10.1016/j.molstruc.2019.07.081

The thiohydantoin scaffold is of substantial importance and it is commonly used in drug discovery. Herein, a novel thiohydantoin-based compound, namely 2,2-diphenyl-2H,3H,5H,6H, 7H-imidazo[2,1-b][1,3]thiazin-3-one (PIT) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction (XRD) studies. Hirshfeld surface analysis and quantum chemical calculations were performed using density functional theory (DFT) at the B3LYP/6-311++G (d,p) level. Hirshfeld surface analysis (d_norm surface and two-dimensional fingerprint plots) revealed the nature of intermolecular interactions. The most important contributions for the crystal packing are from H?H (49.4%), H?C/C?H (26.6%), H?S/S?H (9.1%) and H?O/O?H (7.1%) interactions. The optimized structural parameters calculated using DFT correlated well with those determined by the XRD method. The molecular reactivity of the synthesized compound was further explored using HOMO-LUMO, molecular electrostatic potential (MEP), Mulliken atomic charges (MAC), natural atomic charges (NAC) and condensed descriptors (Fukui functions and the dual descriptor). Natural bond orbital (NBO) analysis was carried out to elucidate the intramolecular, hybridization and delocalization of electron density within the studied molecule.

Full text of DOI:10.1016/j.molstruc.2019.07.081

Accepted Manuscript
Synthesis, structural and molecular characterization of 2,2-diphenyl-2H,3H,5H,6H,7H-
imidazo[2,1-b][1,3]thiazin-3-one
Walid Guerrab, Ill-Min Chung, Sevgi Kansiz, Joel T. Mague, Necmi Dege, Jamal
Taoufik, Rachid Salghi, Ismat H. Ali, Mohammad I. Khan, Hassane Lgaz, Youssef
Ramli
PII:
S0022-2860(19)30925-1
DOI:
https://doi.org/10.1016/j.molstruc.2019.07.081
MOLSTR 26834
Reference:
To appear in: Journal of Molecular Structure
Received Date: 11 December 2018
Revised Date: 25 June 2019
Accepted Date: 20 July 2019
Please cite this article as: W. Guerrab, I.-M. Chung, S. Kansiz, J.T. Mague, N. Dege, J. Taoufik, R.
Salghi, I.H. Ali, M.I. Khan, H. Lgaz, Y. Ramli, Synthesis, structural and molecular characterization of 2,2-
diphenyl-2H,3H,5H,6H,7H-imidazo[2,1-b][1,3]thiazin-3-one, Journal of Molecular Structure (2019), doi:
https://doi.org/10.1016/j.molstruc.2019.07.081.
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Synthesis, structural and molecular characterization of 2,2-diphenyl-2H,3H,5H,6H,7H-
imidazo[2,1-b][1,3]thiazin-3-one
Walid Guerrab1,a, Ill-Min Chung2,a, Sevgi Kansiz3, Joel T. Mague4, Necmi Dege3, Jamal
Taoufik1, Rachid Salghi5, Ismat H. Ali6, Mohammad I. Khan7, Hassane Lgaz2* and
Youssef Ramli1*
1Laboratory of Medicinal Chemistry, Drug Sciences Research Center, Faculty of Medicine
and Pharmacy, Mohammed V University, Rabat, Morocco.
2Department of Crop Science, College of Sanghur Life Science, Konkuk University, Seoul
05029, South Korea.
3Ondokuz Mayıs University, Faculty of Arts and Sciences, Department of Physics, 55139,
Kurupelit, Samsun, Turkey.
4Department of Chemistry, Tulane University, New Orleans, LA 70118, USA.
5Laboratory of Applied Chemistry and Environment, ENSA, University Ibn Zohr, PO Box
1136, Agadir, Morocco.
6Department of Chemistry, College of Science, King Khalid University, P. O. Box 9004,
Postal Code 61413, Abha, Kingdom of Saudi Arabia.
7Chemical Engineering Department, College of Engineering, King Khalid University, Abha,
Kingdom of Saudi Arabia.
*Corresponding authors:
Youssef Ramli
Email: y.ramli@um5s.net.ma
Hassane Lgaz
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Email: hlgaz@konkuk.ac.kr
a Have equal contribution in this work
Abstract
The thiohydantoin scaffold is of substantial importance and it is commonly used in drug
discovery. Herein, a novel thiohydantoin-based compound, namely 2,2-diphenyl-
2H,3H,5H,6H, 7H-imidazo[2,1-b][1,3]thiazin-3-one (PIT) was synthesized and its crystal
structure was determined by single-crystal X-ray diffraction (XRD) studies. Hirshfeld surface
analysis and quantum chemical calculations were performed using density functional theory
(DFT) at the B3LYP/6-311++G (d,p) level. Hirshfeld surface analysis (dnorm surface and two-
dimensional fingerprint plots) revealed the nature of intermolecular interactions. The most
important contributions for the crystal packing are from HꢀꢀꢀH (49.4%), HꢀꢀꢀC/CꢀꢀꢀH (26.6%),
HꢀꢀꢀS/SꢀꢀꢀH (9.1%) and HꢀꢀꢀO/OꢀꢀꢀH (7.1%) interactions. The optimized structural parameters
calculated using DFT correlated well with those determined by the XRD method. The
molecular reactivity of the synthesized compound was further explored using HOMO-LUMO,
molecular electrostatic potential (MEP), Mulliken atomic charges (MAC), natural atomic
charges (NAC) and condensed descriptors (Fukui functions and the dual descriptor). Natural
bond orbital (NBO) analysis was carried out to elucidate the intramolecular, hybridization and
delocalization of electron density within the studied molecule.
Keywords: Thiohydantoin; Hirshfeld surface; DFT; XRD; NBO; Fukui function.
1. Introduction
Thiohydantoins and hydantoins are often found in natural products [1]. They are one of the
attractive natural-product scaffolds that is commonly used in drug discovery [1,2].
Compounds containing this scaffold exhibit remarkable pharmacological activities including
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antimicrobial, anticarcinogenic, anti-inflammatories, antibacterial, anti-androgen, and anti-
diabetic [1–6]. The diversity in the reported biological activities of hydantoin derivatives
prevalently, makes them an important target. For example, phenytoin and nilutamide are one
of the hydantoin derivatives that are used to treat convulsant and prostate cancer, respectively
[7,8]. A recent study concerning thiohydantoin derivatives has concluded that these
heterocycles are promising compounds as inhibitors of NADPH oxidase (NOX) 1 and/or 4
[9]. The synthetic (Z)-5-(4-(ethylthio)benzylidene)-hydantoin is a novel anti-metastatic
defined as a potential anticancer agent [10]. According to another recent study, 5-
chloroarylidene-2-amino substituted derivatives of hydantoin were found to exhibit an
antimycobacterial effect [11]. In addition to biological and pharmaceutical activities,
hydantoin derivatives also possess anticorrosion characteristics. Olasunkanmi et al. have
reported the synthesis of some hydantoin derivatives and tested them as corrosion inhibitors
for mild steel in 0.5 M HCl. The results indicated that all the synthesized hydantoin
derivatives showed good corrosion inhibition properties [12].
As a continuation of our efforts to discover and develop novel promising heterocyclic
compounds [13–16], a new compound, namely, 2,2-diphenyl-2H,3H,5H,6H, 7H-imidazo[2,1-
b][1,3]thiazin-3-one (PIT) has been synthesized and reported. The unique structural diversity
and potential biological and anticorrosion activities of these compounds has been the driving
force for further exploitation and perusals.
We report here, for the first time, the synthesis, single crystal X-ray diffraction, Hirshfeld
surface analysis and theoretical investigations of the PIT in details. Geometrical parameters,
molecular electrostatic potential (MEP), HOMO and LUMO analysis, Mulliken atomic
charges, natural bond orbital (NBO) analysis and global reactivity parameters of the titled
compound were performed by the B3LYP/6-311++G (d,p) level. Local reactivity descriptors
(LRD), i.e. condensed Fukui functions and the dual descriptor were calculated and reported.
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2. Experimental section
2.1. Synthesis of 2,2-diphenyl-2H,3H,5H,6H, 7H-imidazo[2,1-b][1,3]thiazin-3-one
All chemicals used are analytical grade, purchased from commercial suppliers (Sigma-
Aldrich, Merck) and used without further purification. At first, we synthesized 5,5-diphenyl-
2-thioxoimidazolidin-4-one by direct condensation of benzyl with thiourea (Scheme 1).
Scheme 1. 5,5-diphenyl-2-thioxoimidazolidin-4-one synthesis scheme.
In order to obtain bicyclic heterocycles which cleave thiophenytoin, alkylation reaction was
carried out under phase transfer catalysis conditions using bi-brominated alkylating agents
(Scheme 2). The product obtained was characterized by the single crystal X-ray diffraction
(Figure S1, supplementary material). The FT-IR spectra for PIT in the solid phase have been
measured. Spectra of experimental frequencies are shown in Figure S2 (supplementary
material).
Scheme 2. The synthesis scheme of 2,2-diphenyl-2H,3H,5H,6H, 7H-imidazo[2,1-
b][1,3]thiazin-3-one (PIT).
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2.2. Single crystal XRD studies
The X-ray intensity data for the compound was collected at 150 K using a Bruker D8
VENTURE PHOTON 100 CMOS diffractometer with CuKα radiation (λꢁ=ꢁ1.54178ꢁÅ)
equipped with an X-ray generator operating at 50ꢁkV and 1.0ꢁmA. A hemisphere of data was
collected with the APEX3 software and processed using SAINT. The crystal structure was
solved by direct methods using SHELXT [17] and refined in the spherical-atom
approximation (based on F2) by using SHELXL [18]. Crystal and refinement details are
presented in Table 1. The largest residual peak (0.74 e−/Å3) in the final difference map
appears in the vicinity of C3 but when assigned to hydrogen, gives an unreasonable geometry
about C3 and a refined Uiso for that hydrogen which is negative. It is suspected that this peak
represents an alternate location of S1 as part of a minor "whole molecule" disorder. However,
there is insufficient information from the difference map to adequately define a location for a
second orientation of the molecule. Since this peak interfered with independent refinement of
hydrogen atoms on C3, these H atoms were included as riding contributions in idealized
positions.
2.3. Hirshfeld surface analysis
The Crystal Explorer program [19] was utilized to analyze the Hirshfeld surface. For
specifying the diverse intermolecular interactions in C18H16N2OS compound, Hirshfeld
surfaces and related 2D fingerprint plots were obtained. A 2D fingerprint graph informs a
summary of the intermolecular contacts in the crystal. The Hirshfeld surface and fingerprint
plot are unique for a certain crystal structure. Also, with using the same program, electrostatic
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potential surfaces were calculated by the Hartree–Fock level of theory at STO-3G basis set.
Hirshfeld surface analysis, fingerprint graphs and electrostatic potentials surface analysis were
utilized to analyze the contribution of contacts containing the atoms of C18H16N2OS molecule.
2.4. Quantum chemical calculations
Quantum chemical calculations for the studied compound are carried out in the gas phase
using the DFT method with the B3LYP hybrid functional and a 6-311G++ (d,p) basis set
[20,21] using Gaussian 09 software [22]. The manipulation of input files and the visualization
of results were performed using GaussView molecular visualization program [23]. All DFT
calculations used Gaussian09 default convergence criteria for SCF calculation and geometry
optimization. Frontier orbital energies such as HOMO orbitals and LUMO orbitals and
derived reactivity descriptors were determined and discussed. Mulliken atomic charges
(MAC), Molecular electrostatic potential (MEP) analysis and natural population analysis
(NPA) of atomic charge were employed to probe and understand the active site of the PIT.
Additionally, in order to provide more information about intra- and intermolecular
interactions the Natural Bond Orbital (NBO) analysis was also carried out using Gaussian
NBO Version 3.1 as implemented in Gaussian software. Condensed Fukui functions for
nucleophilic, electrophilic and radical attack and the dual descriptor were calculated with the
aid of the Material studio software using the GGA functional[24] and the DNP basis set [25].
3. Results and discussions
3.1. Structural analysis
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In the investigated molecule, the C7···C12 and C13···C18 benzene rings are inclined to the
plane of the imidazole ring by 63.94 (5) and 49.21 (8) °, respectively. A Cremer-Pople
puckering analysis [26] of the conformation of the thiazine ring gave the parameters Q =
0.533 (2) Å, θ = 50.6 (2)° and φ = 109.6 (3)°. In the crystal, C5—H5B···N2 hydrogen
bonds and C16—H16···Cg3 (Cg3 is the centroid of the C7···C12 ring) interactions form
chains extending along the a-axis direction (Figure S3(A) , supplementary material) and Table
2). The chains pack with no unusually short contacts between them (Figure S3(B) ,
supplementary material). A search of the Cambridge Crystallographic Database found only
two reports of structures containing the same bicyclic ring system as reported here. One is a
nearly 40 year old room temperature structure of the present compound [27] in which the su's
on the derived geometrical parameters are noticeably larger than in the present low
temperature structure. The second is one containing the =CH-CH=Ch-Ph substituent in place
of the 2 phenyl groups [28]. In both cases, the 5-membered ring is essentially planar as found
here and the 6-membered ring adopts an "envelope" conformation.
3.2. Hirshfeld surface analysis
Figure S4 (supplementary material) illustrates Hirshfeld surfaces of C18H16N2OS with mapped
dnorm, di and de. The red spots over Hirshfeld surface point out the inter-contacts included in
hydrogen bonds [29]. The surfaces of 3D dnorm plotted over a fixed color scale of -0.158 (red)
to 1.197 (blue) Å with a standard (high) surface resolution. In Figure S5, (supplementary
material), the red circular collapsing on the dnorm surface of C18H16N2OS structure represents
the C—HꢀꢀꢀN intermolecular interactions.
The 2D fingerprint of the total of the contacts conducing to the Hirshfeld surface is illustrated
in Figure S6 (supplementary material). Figure S7 (supplementary material) (HꢀꢀꢀH) graph
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illustrates the 2D fingerprint of the (di, de) points related with H atoms. It is pointed out an
end point that points to the origin and fits to di = de = 1.08 Å, which represents the existence
of the HꢀꢀꢀH contacts in C18H16N2OS molecule (49.4%). In Figure S7, two symmetrical wings
on the left and right sides (26.6%) are shown on the graph of HꢀꢀꢀC/CꢀꢀꢀH interactions. For the
interactions in between the O and H atoms, Figure S7 illustrates a distinctive feature by the
spikes in the donor and acceptor sites of the fingerprint graph with de + di ≈ 2.5 Å.
Furthermore, there are HꢀꢀꢀS/SꢀꢀꢀH (9.1%) and HꢀꢀꢀN/NꢀꢀꢀH (5%) contacts.
Figure S8 (supplementary material) illustrates the view of the electrostatic potential surface
that plotted over three-dimensional Hirshfeld surface of C18H16N2OS utilizing Hartree–Fock
level of theory with STO-3G basis set in the range -0.107 to 0.047 a.u.. In Figure S8, the blue
and red regions over the atoms associated with positive (hydrogen-bond donors) and negative
(hydrogen-bond acceptors) molecular electrostatic potentials are represented as the donors
and acceptors, respectively. These hydrogen-bond donors and acceptors are related with the
C—HꢀꢀꢀN and C—Hꢀꢀꢀπ interactions.
3.3. Quantum chemical calculations
3.3.1. Optimized structure
The optimized molecular structure of PIT was obtained after a full geometrical optimization
by DFT calculation. The full geometry optimization by the B3LYP functional of the PIT is
shown in Figure 1. TableꢁS1 summarizes the experimental and theoretical geometrical
parameters (bond lengths, bond angles, and torsion angles) and the corresponding correlation
coefficients of the title compound. From the calculated values and correlation coefficients, it
can be seen that there are only minor deviations between the theoretical and experimental
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geometrical parameters. Such deviations can be ascribed to the differences in the molecular
environment [30]. The experimental XRD analysis were carried out in the crystalline phase
whereas the theoretical calculation was carried out in the gas phase. The S1-C5 has the
highest experimental (1.824) and theoretical (1.845) bond lengths. The C-C bond length in the
two benzene rings vary from 1.385 Å and 1.401 Å by the DFT calculations and are in good
correlation with experimental values.
3.3.2. HOMO-LUMO profile and global reactivity descriptors
Frontier orbitals of the highest occupied molecular orbital (HOMO) and the lowest
unoccupied molecular orbitals (LUMO) of the PIT compound obtained by the B3LYP
functional are given in Figure 2. The highest occupied molecular orbital that accommodates
electrons with the greatest energy determines the tendency of a molecule to release an
electron whereas the lowest unoccupied molecular orbital characterizes the ability of a
molecule to accept an electron [31–33]. Interestingly, the results in Figure 2 showed that the
HOMO (at -6.538 eV) and the LUMO (at -1.009 eV) of our compound are distributed over
the entire molecular structure. The well-distributed electron density of HOMO and LUMO
orbitals could reinforce the interactive ability of the title compound. On the other hand, the
comparison between HOMO and LUMO values of our compound and other molecules from
the same class indicates that PIT has more tendency to donate electron compared to its
electron-accepting ability [34,35].
The frontier orbital energy gap (5.528 eV) between HOMO and LUMO orbitals is a very
useful parameter for physicists and chemists [36,37]. The value of this parameter gives an
estimation of the kinetic stability and the chemical reactivity of a set of similar molecules
[33,36]. Decreasing of the energy gap leads to an increase in the reactivity of a molecule. A
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molecule with a low energy gap is more polarizable and is generally associated with low
kinetic stability. When comparing the energy gap of the present compound with those from
similar molecules [34,38], we find that the PIT compound has a higher energy gap, hence, the
molecule has higher stability and therefore is less reactive. However, these comparisons could
not give satisfying information about the reactivity of the present compound since there are
significant differences in the level of the molecular structure.
Within the framework of Koopmans' theorem [39], chemical reactivity descriptors using the
following equations [40,41]:
EA= −ELUMO
IP = −EHOMO
The electron affinity (EA)
The ionization potential (IP)
(1)
(2)
IP + EA
Absolute electronegativity (
χ
) and chemical potential (ꢀ)
χ
= −
µ
=
(3)
2
IP − EA
Absolute hardness (
η
)
η
=
(4)
2
1
σ =
Softness (
σ)
(5)
η
The calculated chemical potential value for PIT was found to be –3.773 eV while the
chemical hardness and softness were found to be 2.764 eV and 0.361 eV-1 respectively. The
electrophilicity index introduced by Parr et al[42] combines softness and chemical potential
and it is a comprehensive measure of electrophilicity. According to eq. (6), the electrophilicity
index was found to be 19.683 eV. The nucleophilicity can also be calculated as the
ε
multiplicative inverse of the electrophilicity. The nucleophilicity ( ) is given by the Eq. 7:
µ2
(6)
ω =
ε =
2η
1
(7)
ω
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The nucleophilicity index of the PIT compound was found to be 0.050 eV-1. The
electrophilicity parameter denotes the electron-accepting capability of a molecule. Whereas,
nucleophilicity represents the tendency to donate or share electrons with a chemical specie
[43]. Recently, Hemapriya et al.[44] reported some quantum chemical parameters of a thiazin-
3-one derivative. Their results showed that the investigated thiazin-3-one derivative had an
electrophilicity index of 15.688 eV and a nucleophilicity index of 0.063 eV-1. Based on these
results, we can conclude that PIT has a high electrophilicity (19.683 eV) and a low
nucleophilicity (0.050 eV-1), thus confirming its electrophilic behaviour. Table S2 reports all
quantum chemical parameters derived from DFT calculations.
3.3.4. MEP, Mulliken and Natural atomic charges
In this section of the investigation, three types of analysis were carried out to evaluate the
most active sites of the compound. These are molecular electrostatic maps, Mulliken atomic
charges (MAC) and natural atomic charges (NAC). The molecular electrostatic potential
represented in Figure 3, is an important property that can be successfully used to explain the
electrostatic interactions. As known, the red-brown colors represent electron rich regions
(related to electrophilic reactivity) whereas the blue color represents the most positive
electrostatic potential (preferred for nucleophilic attack), and green color represents the region
of neutral potential [33,45]. A visual inspection of Figure 3 suggests that the negative region
is mainly around the C=O group and nitrogen atoms (dark red) which could be easily
attributed to the lone pairs of electrons on these atoms[30]. These sites are electron-rich and
hence could be good reactive atomic sites. Positive regions are mainly distributed around
some hydrogen atoms (dark blue).
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The reactive sites of the PIT compound were also investigated by determining Mulliken and
natural atomic charges. Atomic charges reported in Table S3 were computed using DFT at the
B3LYP/6-311++G(d,p) basis set. The Mulliken charge distribution shows that except N3, N4,
C5, C11 and C17, all atoms have negative charges. The same results can be observed in NAC
which show that all atoms have negative charges except C5, C6 and C10. From Mulliken and
natural charge analysis, it is evident that the title compound has large total negative charges (-
6.347 and -4.755) from MAC and NAC respectively. These results indicate that PIT is a
highly active compound, and this activity can be sourced from the widely dispersed negative
charge.
3.3.5. Fukui functions
Fukui function gives us information about which atoms in a molecule could donate or accept
electrons [46,47]. These atomic sites are interpreted as being more susceptible to undergo a
nucleophilic or an electrophilic attack, respectively. The Fukui functions were proposed as
follows [48]:
fk+ =qk (N+1)−qk (N)
(8)
fk- =qk (N)−qk (N −1)
(9)
1
f 0 = q (N +1)−q (N −1)
[
]
(10)
k
k
k
2
where qk is the electronic population of an atomic site within a molecule in its neutral (N),
anionic (N+1) or cationic (N-1) state [49].
The condensed Fukui function indices are a commonly used tool for predicting and
interpreting local reactivity of molecules [50]. Important reactive sites can be identified by
tracking the electron density changes when the number of the electron is modified [33]. The
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f +
index of nucleophilic attack ( ) indicates the tendency of an atomic site to accept an
electron whereas its ability to lose an electron is determined by the index of electrophilic
f −
attack ( ) [51]. The most reactive sites are those having the greater nucleophilic and/or
electrophilic indexes [51]. However, in some cases, it may be difficult to distinguish these two
kinds of reactivity in the same atomic site. To get around this problem, scientists have
developed and implemented a new factor called the dual descriptor. The dual descriptor
introduced by Morell et al. [52] and it is given by:
∆f (k) = fk+ − fk−
(11)
The atomic sites with a higher nucleophilic tendency are those having positive dual descriptor
value while those having negative dual descriptor value are the most electrophilic sites. In this
study, the dual descriptor of all atomic sites was calculated and listed along with the Fukui
function indices as shown in Table S4. The most reactive sites for radical attack, governed by
f °
the values of will be S1, O2 and N4 atoms. Atoms S1, N4 and O2, C6 are, respectively, the
most nucleophilic and electrophilic reactive sites demonstrated by their higher dual descriptor
values. Heteroatoms showed significantly more intense reactivity than other atomic sites,
suggesting their higher interactive ability.
3.3.6. Natural bond orbital (NBO) analysis
The NBO calculations were performed to understand the various interactions between the
Lewis type (bonding or lone pair) filled and non-Lewis type (antibonding or Rydgberg)
virtual orbital spaces [30,36]. The second order perturbation energy obtained from NBO
analysis provides information about the strength of the interaction between donor and
acceptor orbitals, as well as the interacting stabilization energy. The stabilization energy
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(E(2)) determine the hyper conjugative interactions and charge transfers [30]. A larger
stabilization energy value indicates a more intensive interaction [36,47]. The stabilization
energy E(2) associated with i
→ j delocalization between each donor NBO (i) and acceptor
NBO (j); is estimated by the following equation:
2
F2
i F j
ij
E(2)=−q
=−q
i
(12)
i ∆E
εj −ε
i
where Fij is the off-diagonal NBO Fock matrix constituent,
elements, qi is the donor orbital occupancy.
εj, and εi are the diagonal
Table 3 lists some of the significant electron donor–acceptor interactions and their energies.
The LP(1)N3 BD*(2)O2 C6 interaction has the strongest second order perturbation energy
(E(2)) value of 53.00 kcal/mol. Some of the significant interactions with their stabilization
energy values include BD(2)C11 C16 BD*(2)C12 C13 with 19.54 kcal/mol and
C15 with 20.16 kcal/mol; BD(1)C12 C13 BD*(2)C11 C16 and
C15 with 20.59 and 20.64 kcal/mol respectively. The
C18 with 20.17 kcal/mol; BD(1)C21 C22 BD*(2)C17 C18 and
C20 with 20.54 and 20.57 kcal/mol respectively. Also,
BD*(1)N3 C6 with 28.07
C10 with 42.20 kcal/mol. These higher values of
→
−
−
→
−
BD(2)C11
BD(1)C12
BD(1)C19
BD(1)C21
−
−
−
−
C16
C13
C20
C22
→
→
→
→
BD*(2)C14
BD*(2)C14
BD*(2)C17
BD*(2)C19
−
−
−
−
−
→
−
−
→
−
LP(1)S1
→
BD*(2)N4
−
C10 with 25.26 kcal/mol; LP(1)O2
BD*(2)N4
→
−
kcal/mol, and LP(1)N3
→
−
stabilization energy account for the presence of strong electron delocalization from donor to
acceptor orbitals.
4. Conclusions
In the present work, the titled compound (PIT) was successfully synthesized and characterized
by single-crystal X-ray diffraction method. The DFT calculated geometric parameters (bond
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lengths, torsion angles, and bond angles) were determined and compared with those from
XRD method, from which a good correlation was found. X-ray diffraction results indicated
that the PIT compound belongs to orthorhombic system, P212121 space group. Hirshfeld
surface analysis has been used to explore the intermolecular interactions. The results indicate
that H⋯H, HꢀꢀꢀC/CꢀꢀꢀH, HꢀꢀꢀS/SꢀꢀꢀH and HꢀꢀꢀO/OꢀꢀꢀH contacts can account for 49.4, 26.6, 9.1
and 7.1% respectively of the total Hirshfeld surface area. NBO calculations were performed to
investigate the different intra and intermolecular bonding and interaction among bonds
occurring in the studied molecule. Quantum chemical calculations including HOMO-LUMO
orbitals, Mulliken and Natural population charges, MEP and local reactivity descriptors
indicate that the titled compound has highly reactive sites with heteroatoms showed
significantly more intense reactivity than other atomic sites.
Supplementary material
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 1904429 for this compound. Copies of the data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK. Fax:
+44 1223 336033: or e-mail: deposit@ccdc.cam.ac.uk.
Conflicts of interest: The authors declare that they have no conflict of interests.
Acknowledgements
The authors extend their appreciation to the Deanship of Scientific Research at King Khalid
University for funding this work through research groups program under grant number
15

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R.G.P.1/136/40. The authors are grateful to the National School of Applied Science, Ibn Zohr
University Agadir, Morocco, for the provision of computational facilities. JTM thanks Tulane
University for support of the Tulane Crystallography Laboratory.
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Figure captions:
Figure 1. Optimized molecular structure of PIT obtained by DFT.
Figure 2. Frontier molecular orbitals (HOMO-LUMO) of PIT.
Figure 3. The molecular electrostatic potential map of PIT.
20

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Figure 1.
21

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Figure 2.
22

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Figure 3.
23

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Tables:
Table 1: Crystal data and structure refinement parameter for the synthesized compound.
Chemical formula
Formula weight
Temperature (K)
Crystal system, space group
Unit cell dimensions
a, b, c (Å)
C18H16N2OS
308.39
100
Orthorhombic, P212121
8.4053 (4), 11.5648 (5), 15.2907 (7)
V (Å3)
1486.34 (12)
4
Z
Radiation type
µ (mm−1)
Mo Kα
0.22
Crystal size (mm)
Data collection
Diffractometer
0.42 × 0.25 × 0.24
Bruker Smart APEX CCD
diffractometer
Absorption correction
Multi-scan
SADABS[53]
Tmin, Tmax
0.84, 0.95
No. of measured, independent and
29252, 4235, 3935
observed [I > 2
σ(I)] reflections
Rint
0.035
0.707
(sin
Refinement
R[F2 > 2 (F2)], wR(F2), S
θ/λ
)max (Å−1)
σ
0.040, 0.108, 1.07
No. of reflections
No. of parameters
H-atom treatment
4235
255
H atoms treated by a mixture of independent and
constrained refinement
ꢂρmax, ꢂρmin (e Å−3)
0.74, −0.19
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Table 2: Hydrogen-bond geometry (Å, °)
D—H···A
C5—H5B···N2i
C16—
D—H
0.91 (3)
0.93 (3)
H···A
2.56 (3)
2.90 (3)
D···A
3.342 (3)
3.696 (3)
D—H···A
145 (2)
144 (2)
H16···Cg3ii
Symmetry codes: (i) x−1/2, −y+3/2, −z+1; (ii) x+1, y, z.
25

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Table 3. Second order perturbation theory analysis of Fock matrix in NBO basis for PIT.
Donor (i)
Ed/e(a)
Acceptor (j)
Ed/e(a)
ꢁ ꢃꢁ
ꢃ
ꢁ ꢃꢁ ꢃ
ꢂ ꢌ
ꢃ
ꢂ
ꢄ
ꢁ ꢃ
ꢁ
ꢃꢁꢍ
ꢀ
ꢀ ꢊ − ꢀꢁꢋꢃ
ꢀ ꢋ, ꢊ
(a.u)
(a.u)
0.64
0.29
0.28
1.08
1.27
1.27
1.14
0.28
0.28
1.28
1.14
1.28
1.16
0.29
0.29
1.09
1.27
1.28
1.14
1.15
0.58
0.64
0.28
0.29
1.28
1.16
1.28
1.14
0.29
0.29
1.09
1.27
1.27
1.14
0.29
0.28
1.09
1.10
1.09
1.09
19.80
15.10
0.26
0.63
1.64
1.03
2.10
0.69
0.61
1.74
1.72
0.28
ꢁꢅꢆ/ꢇꢈꢉꢃ
24. BD ( 2) C 11 - C 16
1.66676
/568. BD*( 1) C 5 - C 17
/581. BD*( 2) C 12 - C 13
/586. BD*( 2) C 14 - C 15
/567. BD*( 1) C 5 - C 11
/577. BD*( 1) C 11 - C 12
/583. BD*( 1) C 13 - C 14
/587. BD*( 1) C 14 - H 31
/579. BD*( 2) C 11 - C 16
/586. BD*( 2) C 14 - C 15
/583. BD*( 1) C 13 - C 14
/584. BD*( 1) C 13 - H 30
/588. BD*( 1) C 15 - C 16
/590. BD*( 1) C 16 - H 33
/579. BD*( 2) C 11 - C 16
/581. BD*( 2) C 12 - C 13
/568. BD*( 1) C 5 - C 17
/593. BD*( 1) C 17 - C 22
/594. BD*( 1) C 18 - C 19
/598. BD*( 1) C 19 - H 35
/604. BD*( 1) C 22 - H 38
/566. BD*( 1) C 5 - C 6
/567. BD*( 1) C 5 - C 11
/597. BD*( 2) C 19 - C 20
/602. BD*( 2) C 21 - C 22
/594. BD*( 1) C 18 - C 19
/595. BD*( 1) C 18 - H 34
/599. BD*( 1) C 20 - C 21
/603. BD*( 1) C 21 - H 37
/592. BD*( 2) C 17 - C 18
/602. BD*( 2) C 21 - C 22
/568. BD*( 1) C 5 - C 17
/593. BD*( 1) C 17 - C 22
/599. BD*( 1) C 20 - C 21
/600. BD*( 1) C 20 - H 36
/592. BD*( 2) C 17 - C 18
/597. BD*( 2) C 19 - C 20
/593. BD*( 1) C 17 - C 22
/596. BD*( 1) C 19 - C 20
/591. BD*( 1) C 17 - C 18
/599. BD*( 1) C 20 - C 21
/171. RY*( 1) C 6
0.08920
0.30998
0.32725
0.04121
0.02383
0.01654
0.01388
0.34559
0.32725
0.01654
0.01381
0.01610
0.01650
0.34559
0.30998
0.04312
0.02315
0.01581
0.01384
0.01436
0.08920
0.04121
0.32930
0.31424
0.01581
0.01525
0.01640
0.01364
0.34500
0.31424
0.04312
0.02315
0.01640
0.01387
0.34500
0.32930
0.02315
0.01647
0.02384
0.01640
0.01778
0.01088
0.28979
0.02404
0.01778
0.08920
0.00720
0.09070
0.08920
0.00545
0.00243
0.24818
2.85
0.041
0.067
0.068
0.057
0.061
0.053
0.047
0.068
0.068
0.053
0.047
0.053
0.046
0.068
0.067
0.043
0.061
0.057
0.044
0.047
0.039
0.038
0.067
0.068
0.053
0.047
0.053
0.047
0.068
0.067
0.058
0.061
0.053
0.046
0.069
0.068
0.059
0.056
0.064
0.057
0.334
0.219
0.075
0.051
0.149
0.050
0.067
0.126
0.102
0.061
0.062
0.113
19.54
20.16
3.67
3.62
2.75
25. BD ( 1) C 12 - C 13
30. BD ( 1) C 14 - C 15
36. BD ( 1) C 17 - C 18
1.97680
1.97964
1.97189
2.38
20.59
20.64
2.72
2.46
2.74
2.32
19.96
19.46
2.12
3.72
3.16
2.13
2.44
2.95
2.47
20.12
19.98
2.75
2.37
2.71
41. BD ( 1) C 19 - C 20
1.97947
1.97676
2.46
20.17
19.62
3.80
3.64
2.74
46. BD ( 1) C 21 - C 22
2.36
20.54
20.57
3.98
3.61
4.70
3.68
7.01
3.98
25.26
4.80
16.98
2.91
2.46
28.07
21.00
2.18
48. BD ( 1) C 21 - H 37
49. BD ( 1) C 22 - H 38
1.98025
1.97781
55. CR ( 1) O 2
57. CR ( 1) N 4
77. LP ( 2) S 1
1.99974
1.99931
1.82849
/239. RY*( 1) C 10
/565. BD*( 2) N 4 - C 10
/575. BD*( 1) C 9 - H 27
/171. RY*( 1) C 6
/566. BD*( 1) C 5 - C 6
/172. RY*( 2) C 6
/560. BD*( 1) N 3 - C 6
/566. BD*( 1) C 5 - C 6
/173. RY*( 3) C 6
78. LP ( 1) O 2
1.97644
80. LP ( 1) N 3
1.63264
/242. RY*( 4) C 10
/559. BD*( 2) O 2 - C 6
2.30
53.00
26

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/565. BD*( 2) N 4 - C 10
/570. BD*( 1) C 7 - H 23
/239. RY*( 1) C 10
0.28979
0.02218
0.01088
0.06452
42.20
6.75
6.12
0.28
0.65
1.38
0.76
0.099
0.065
0.084
0.082
81. LP ( 1) N 4
1.90991
/562. BD*( 1) N 3 - C 10
10.84
Numbering is according to Fig. S1.
(a) The electron density of donor and acceptor of NBO orbitals.
(b) The energy of hyper conjugative interactions (stabilization energy).
(c) Energy difference between donor and acceptor i and j NBO orbitals.
(d) The Fock matrix element between i and j NBO orbitals.
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•
2,2-diphenyl-2H,3H,5H,6H, 7H-imidazo[2,1-b][1,3]thiazin-3-one has been synthesized
and characterized by XRD.
•
•
•
DFT and NBO analysis have been carried out.
The XRD values were compared with the theoretical data.
Hirshfeld surface analysis of crystal structure was studied.