Crystal structure, DFT study, and Hirshfeld surface analysis of ethyl 5-(3,4-dimethoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[ 3,2-A]pyrimidine-6-carboxylate

Article abstract of DOI:10.1134/S0022476615070033

The structural characterization of fused thiazolopyrimidine 1 (C₂₄H₂₄N₂O₄S) is performed using the single crystal X-ray study, the DFT calculation, and the Hirshfeld surface analysis. The molecular packing of the crystal is mainly stabilized by C-H...O and C-H...π interactions. A DFT calculated HOMO-LUMO energy gap of 3.90 eV indicates a high kinetic stability of the compound. The 3D Hirshfeld surfaces and the associated 2D fingerprint plots are investigated for short contact interactions. The relative contribution of different interactions to the Hirshfeld surface indicates that the H...H, C...H, and O...H contacts account for about 83.4% of the total Hirshfeld surface area.

Full text of DOI:10.1134/S0022476615070033

Journal of Structural Chemistry. Vol. 56, No. 7, pp. 1246-1252, 2015.
Original Russian Text © 2015 A. Shelke, N. N. Karade, P. Kr. Dutta, S. P. Bahekar, H. S. Chandak.
CRYSTAL STRUCTURE, DFT STUDY,
AND HIRSHFELD SURFACE ANALYSIS OF ETHYL
5-(3,4-DIMETHOXYPHENYL)-7-METHYL-3-PHENYL-5H-
THIAZOLO[3,2-a]PYRIMIDINE-6-CARBOXYLATE
1
A. Shelke , N. N. Karade , P. Kr. Dutta ,
1
2
UDC 541.6:547.53
3
S. P. Bahekar , and H. S. Chandak
3
The structural characterization of fused thiazolopyrimidine 1 (C H N O S) is performed using the single
24 24 2 4
crystal X-ray study, the DFT calculation, and the Hirshfeld surface analysis. The molecular packing of the
crystal is mainly stabilized by C–H…O and C–H…π interactions. A DFT calculated HOMO-LUMO
energy gap of 3.90 eV indicates a high kinetic stability of the compound. The 3D Hirshfeld surfaces and the
associated 2D fingerprint plots are investigated for short contact interactions. The relative contribution of
different interactions to the Hirshfeld surface indicates that the H…H, C…H, and O…H contacts account
for about 83.4% of the total Hirshfeld surface area.
DOI: 10.1134/S0022476615070033
Keywords: thiazolo[3,2-a]pyrimidine, single crystal X-ray diffraction (SCXRD), DFT calculation,
Hirshfeld surface analysis.
INTRODUCTION
The remarkable biological activities of fused pyrimidines which give rise to antiviral, anticancer, anti-inflammatory,
and antihypertensive actions [1, 2] continue to bring this class of heterocyclic compounds to the forefront of interest and
study. Thiazolo[3,2-a]pyrimidines are known to possess anti HSV-1 [3], anti-tumour [4], and anti-microbial activities [5] and
to be CDC25B phosphatase inhibitors [6]. They also serve as diacylglycerol (DG) kinase inhibitors, calcium antagonists,
group 2 metabotropic glutamate receptor antagonists, and HIV-1 reverse transcriptase inhibitors [7]. Furthermore, some
thiazolo[3,2-a]pyrimidines have been assigned as new acetylcholinesterase (AChE) inhibitors, especially for the treatment of
Alzheimer′s disease [8]. The molecular self-assembly through weak non-covalent forces is an important feature of
biologically active systems. Among the various non-covalent forces, the hydrogen bonding [9, 10] and C–H…π [11]
interactions have been widely utilized in directing the molecular self-assembly for the construction of various molecular
architectures.
The single crystal X-ray diffraction (SCXRD) technique is a valuable tool in the structure-based drug design
approaches during drug discovery stages [12]. However, it is to be coupled with quantum chemical calculations for the better
1
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India;
2
nnkarade@gmail.com. Department of Chemical Sciences, Indian Institute of Science, Education and Research (IISER)
3
Kolkata, Mohanpur, India. Department of Chemistry, G. S. Science, Arts and Commerce College, Khamgaon, India;
chemants@gmail.com. The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 56, No. 7,
pp. 1312-1317, November-December, 2015. Original article submitted November 18, 2014.
1246
0022-4766/15/5607-1246 © 2015 by Pleiades Publishing, Ltd.

design of physically and bio-pharmaceutically relevant crystalline materials. In the framework of the density functional
theory (DFT) approach the B3LYP hybrid functional [13] is one of the most preferred since it proved its ability of
reproducing various molecular properties. The combined use of the B3LYP functional and the standard split valence basis set
6-31G(d) is good enough for calculating the molecular geometry [14] and vibrational spectra of large and medium size
molecules [15-17]. In addition to these, the Hirshfeld surface and its 2D fingerprint plot constitute a powerful resource for
visualising, exploring, analysing, and quantifying intermolecular interactions in molecular crystals with unprecedented ease
and rapidity [18]. he use of SCXRD, a DFT study, and the Hirshfeld surface analysis in combination constitute a powerful
tool for studying different molecular interactions and predicting their electronic properties [19]. Recently, Bedi et al. utilized
these tools to study the effect of S…π and Se…π interactions on the packing pattern in the case of phenyl-capped
cyclopenta[c]chalcogeneophenes [20].
We report here the crystal structure, the DFT study, and the Hirshfeld surface analysis of ethyl 5-(3,4-
dimethoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (1).
EXPERIMENTAL AND COMPUTATIONAL METHODS
The synthesis of thiazolo[3,2-a]pyrimidine was achieved by the reaction of 4-aryl-3,4-dihydropyrimidin-2(1H)-
thione and phenyl(phenylethyny1)iodonium tosylate in K CO as a base in the THF medium (Scheme 1) [21]. The compound
2 3
was recrystallized by slow evaporation of a petroleum ether-ethyl acetate solution (3:1) yielding light yellow single crystals
suitable for X-ray diffraction.
Scheme 1. Synthesis of thiazolo[3,2-a]pyrimidines.
X-ray data were collected on a Bruker SMART diffractometer using graphite-monochromated MoK (k = 0.71073 Å)
α
radiation at 293(2) K. The structure was solved by direct methods using the SHELXS97 software [22]. All of the non-
2
hydrogen atoms were refined anisotropically by full-matrix least-squares on F using SHELXL97. All H atoms were allowed
to ride on the parent atom in the model during the refinement. An absorption correction was performed using SADABS [23].
The CIF file containing complete information on the studied structure was deposited with CCDC, deposition number 948903,
and is freely available upon request from the following web site: www.ccdc.cam.ac.uk/data_request/ci. The crystallographic
data for the titled compound are summarised in Table 1.
A density functional theory (DFT) calculation using the GAUSSIAN-09 program package [24] and employing the
hybrid [25, 26] Becke three-parameter exchange density functional with the LYP correlation functional (B3LYP) [27] and the
6-31G(d) basis set was performed on the titled molecule. Starting geometries were taken from the single crystal X-ray data.
The DFT optimised structure is compared to the single crystal X-ray structure. A comparison of the selected bond distances
and angles of 1 obtained from the crystal structure analysis and the DFT calculation is given in Table 2. Hirshfeld surface
analyses were carried out and finger print plots were plotted using CRYSTAL EXPLORER [28]. The normalized contact
distance (d ) displays a surface with a grey-white-black color scheme, where dark black spots highlight shorter contacts,
norm
white areas represent contacts around the van der Waals separation, and black regions are devoid of close contacts.
Electrostatic potentials were calculated using the TONTO [29, 30] computer program integrated to CRYSTAL EXPLORER.
Crystal geometry was used as input to TONTO.
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TABLE 1. Crystal and Experimental Data on 1 (CCDC948903)
Formula C H N O S
24 24
2
4
Formula weight
Crystal color, habit
Crystal size, mm
Crystal system
436.52
Light yellow, Block
0.42×0.21×0.20
Triclinic
Space group
P-1
Temperature, K
298
Unit cell dimension: a, b, c, Å;
α, β, γ, deg
10.480(2), 11.164(2), 11.328(2);
64.887(4), 65.187(4), 87.235(3)
3
V, Å
1075.6(3)
3
Calculated density, Mg/m
1.348
3423
No. of reflections [I > 2σ(I)]
Z
2
Absorption coefficient F(000)
θ range for data collection
Index ranges
460
2.0-26.1
–12 ≤ h ≤ 11, –13 ≤ k ≤ 13, –13 ≤ l ≤ 13
2
Refinement method
Data / restraints / parameters
Calculated weights, w
Full-matrix least-squares on F
4037 / 0 / 284
2
2
2
1/[σ (F ) + (0.0916P) + 0.427P], where P = (F + 2 )/3
2
2
F
c
0
0
2
Goodness-of-fit on F
1.12
R = 0.036, wR = 0.165
Final R indices [I ≥ 2σ(I)]
1
2
< 0.001
0.44 / –0.65
(Δ/σ)
max
3
Δρ / Δρ , e/Å
max min
TABLE 2. Selected Geometrical Parameters and DFT Calculations (Å, deg)
Bond lengths
X-ray
DFT
Bond angles
X-ray
DFT
Bond angles
X-ray
DFT
N1–C9
N1–C12
N2–C9
1.356(3)
1.487(2)
1.303(3)
1.390(3)
1.365(3)
1.498(3)
1.461(3)
1.522(3)
1.729(2)
1.742(2)
1.407(3)
1.336(3)
1.371
1.489
1.300
1.387
1.374
1.510
1.465
1.527
1.754
1.765
1.406
1.354
C9–N1–C12
C7–N1–C12
C9–N2–C10
C11–C10–N2
N2–C9–N1
118.89(17)
124.81(16)
115.74(18)
122.18(19)
128.0(2)
117.96
124.95
116.61
121.88
127.02
127.39
120.63
107.69
111.52
C11–C12–C13
N2–C9–S1
N1–C9–S1
C8–S1–C9
C9–N1–C7
C7–C8–S1
C8–C7–N1
C8–C7–C6
N1–C7–C6
113.29(16)
122.22(16)
109.80(15)
90.94(10)
114.68(17)
112.54(18)
112.04(19)
126.0(2)
114.12
122.78
110.20
90.28
N2–C10
C10–C11
C10–C24
C11–C21
C12–C11
S1–C8
114.57
112.45
112.50
125.22
122.23
C10–C11–C21
C10–C11–C12
N1–C12–C11
N1–C12–C13
128.03(19)
121.48(18)
108.01(15)
111.33(15)
121.97(18)
S1–C9
N1–C7
C7–C8
RESULTS AND DISCUSSION
Compound 1 crystallizes in the triclinic (P-1) space group with cell parameters a = 10.480(2) Å, b = 11.164(2) Å,
c = 11.328(2) Å. The molecular structure of compound 1 is built up from two fused five- and six-membered rings linked to
methyl, phenyl, and ethylcarboxylate groups as shown in Fig. 1.
3
The crystal structure shows that the fused thiazole and pyrimidine rings are nearly in the same plane except the sp
hybridized carbon atom (C12). The ring puckering parameters (Cremer and Pople, 1975) [31] for the pyrimidine ring are
q = 0.2279 Å, q = –0.0879 Å, Q = 0.2443 Å; θ = 111.09° and ϕ = 132.82°. The selected geometrical parameters are given in
2 3
Table 2.
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Fig. 1. Molecular structure of the titled
compound with displacement ellipsoids
drawn at the 50% probability level.
The molecules pack in a stacking-like mode, arranged in an alternating pattern diagonally across the ab plane of the
unit cell. The molecular packing of the crystal is mainly stabilized by C–H…O and C–H…π intermolecular interactions. The
2
distance between the sp oxygen and aromatic hydrogen atoms (C–H⋯O) is 2.658 Å (the sum of the van der Waals radii is
2.72 Å). The C–H…π distances (C–H(23B)…C(5) and C–H(23C)…C(3)) are 2.863 Å and 2.870 Å (Fig. 2).
Compound 1 was optimized at the B3LYP/6-31G(d) level. The bond lengths and bond angles of the optimized
structure of 1 are listed in Table 2. The bond distances of the optimized structure of 1 are found slightly longer than those
obtained in the single crystal X-ray structure, except N2–C9, N2–C10, and N1–C7 which are slightly shorter (≈0.01 Å). All
bond angles involving pyrimidine nitrogen atoms in the DFT optimized geometry are slightly shorter that those determined
experimentally, except C9–N2–C10. These tiny differences between the calculated and observed geometries could be
attributed to the crystal packing of the molecules in the solid state.
The calculated HOMO-LUMO gap of molecule is 3.90 eV, which shows a high kinetic stability of the structural
system. The molecular orbital pictures of HOMO and LUMO are depicted in Fig. 3. The electron density of HOMO is
located on fused thiazolopyrimidine and phenyl rings attached to the pyrimidine ring while in LUMO it is mostly located on
fused thiazolopyrimidine rings.
The calculated vibrational spectrum has no imaginary frequencies, implying that the optimised geometry is located
at the minimum point of the potential surface. Some selected experimental and calculated IR frequencies are given in Table 3.
The close resemblance in these frequencies could be interpreted as the convenience and suitability of the utilized
computational approach.
Fig. 2. Packing diagram of compound 1 showing intermolecular non-bonding interactions via C–H…O and C–H…π.
1249

TABLE 3. Selected Experimental and Calculated Vibrational Frequencies of 1
Exp. freq., Calc. freq., Exp. freq., Calc. freq.,
Assignment
Assignment
–1
–1
–1
–1
cm
cm
cm
cm
1558.46
1271.92
1365.37
1737.39
1130.49
1558
1276
1366
1740
1139
C=C str + C=N str + C–C–H bend 1092.26
1114
1572
1282
1308
1340
C–O str + C–H bend
C=C str
C–C–O bend + C–N str
C–N str
1578.55
1271.92
1313.64
1339.43
ArC–O str
C=O str
C=C str + C–H bend
C–N str
C–N str + C–H bend
The Hirshfeld surfaces of 1 are illustrated in Fig. 4 showing the surfaces that have been mapped over d . The
norm
black pointed spots are due to C–H…O interactions, white spots are due to C–H…π interactions, and other visible spots on
the surface correspond to H…H contacts. The contribution of intermolecular contacts to the Hirshfeld surfaces are H…H
(52.1%), C…H (17%), O…H (14.3%), and others (16.6%). The O…H/H…O intermolecular contacts appear as two wings in
the 2D fingerprint plots (Fig. 5). At the top left and bottom right of the fingerprint plot there are characteristic “wings” which
are identified as a result of C–H…π interactions [32, 33].
The electrostatic potential is mapped on the Hirshfeld surface using the STO-3G basis set at the Hartree-Fock theory
level over the range of 0.01 a.u. (Fig. 6). The positive electrostatic potential (black region) over the surface indicates the
hydrogen donor potential, whereas the hydrogen bond acceptors are represented by the negative electrostatic potential (grey
region) [17].
Fig. 3. Molecular orbital pictures of HOMO-LUMO.
Fig. 4. d
mapped on the
Hirshfeld surface for visualizing
the molecular intercontacts of 1.
norm
Fig. 5. Fingerprint plot of 1: full and resolved into C…H and O…H contacts showing the percentages of
contacts contributed to the total Hirshfeld surface area of the molecule.
1250

Fig. 6. Electrostatic potential mapped on the Hirshfeld surface (different
orientation) within 0.01 a.u. Black region corresponds to the positive
electrostatic potential and grey region to negative electrostatic potential.
CONCLUSIONS
To summarize, we have reported the crystal and electronic structure evaluation using the DFT and Hirshfeld surface
analyses of compound 1 (C H N O S). In this compound, the fused thiazole and pyrimidine rings are nearly in the same
24 24 2 4
3
plane, except the sp hybridized carbon atom (C12). The molecular packing of the crystal is mainly stabilized by C–H⋯O
and C–H…π interactions. The comparison of the solid state and the optimized geometries shows a few minor structural
differences and the overall conformation is the same in both cases. The DFT calculated bond lengths and harmonic vibrations
were obtained in very good agreement with the available experimental data. An examination of close intermolecular
interactions using the Hirshfeld surfaces and the associated 2D fingerprint plots revealed that the H…H, C…H, and O…H
contacts account for about 83.4% of the total Hirshfeld surface area. All these results could be useful to the chemists to study
thiazolopyrimidine and develop its new analogues as potential drugs.
We thank Dr. Sanjio Zade, IISER Kolkata for many helpful discussions and for his valuable comments on the
manuscript. N. N. Karade is thankful to the Department of Science and Technology, New Delhi, India (No. SR/S1/OC-
72/2009) for financial support. H.S. Chandak is thankful to UGC, New Delhi, India (No. F. No. 41-335/2012) for financial
support.
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