Invariant and Variable Supramolecular Self-Assembly in 6-Substituted Uracil Derivatives: Insights from X-ray Structures and Quantum Chemical Study

Article abstract of DOI:10.1021/acs.cgd.0c01583

In this study, three new 6-(arylthio)uracil derivatives, namely, 6-(phenylthio)pyrimidine-2,4(1H,3H)-dione (1), C10H8N2O2S; 6-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (2), C11H10N2O2S; and 6-(3,5-dimethylphenylthio)pyrimidine-2,4(1H,3H)-dione (3), C12H12N2O2S, have been synthesized. Single-crystal structures of these compounds reveal an invariant molecular tape contains alternate R22(8) synthons formed by N-H···O hydrogen bonds in 1 and 3. This alternate hydrogen-bonded pattern disappeared in 2; instead, a new synthon is generated. The lattice energy calculation suggests that the methyl-substituted derivatives (2 and 3) have high stabilization energy than compound 1. The electrostatic potential map reveals the difference in the accepting tendency of the carbonyl oxygen. The Hirshfeld surface and 2D-fingerprint plots analyses demonstrate that the major intermolecular interactions come from H···O contacts in 1, and these contacts were reduced due to the presence of methyl substitutions in 2 and 3. This reduction is compensated by the increase of the same amount of H···H contacts in these structures. Further, the PIXEL energy and DFT calculations at the M06-2X-D3/cc-pVTZ level of theory were used to characterize the dimeric topology formed in structures of 1-3. The intermolecular interaction energies of dimers calculated by the PIXEL method were compared with the B97D3/def2-TZVP level of approximation. Although these molecules' crystal packing is somewhat different, the energy frameworks show similarities on the respective crystal structure's shortest axis. Furthermore, the nature and strength of various noncovalent interactions such as N-H···O, C-H···O/S/π, π···π, and a chalcogen bond of type C-S···O═C were evaluated using the Bader's quantum theory of atoms-in-molecules framework.

Full text of DOI:10.1021/acs.cgd.0c01583

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Article
Invariant and Variable Supramolecular Self-Assembly in
6‑Substituted Uracil Derivatives: Insights from X‑ray Structures and
Quantum Chemical Study
Lamya H. Al-Wahaibi, Sai Ramya Sree Bysani, Samar S. Tawfik, Mohammed S. M. Abdelbaky,
Santiago Garcia-Granda, Ali A. El-Emam, M. Judith Percino, and Subbiah Thamotharan*
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ABSTRACT: In this study, three new 6-(arylthio)uracil derivatives,
namely, 6-(phenylthio)pyrimidine-2,4(1H,3H)-dione (1),
C10H8N2O2S; 6-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (2),
C11H10N2O2S; and 6-(3,5-dimethylphenylthio)pyrimidine-2,4-
(1H,3H)-dione (3), C12H12N2O2S, have been synthesized. Single-
crystal structures of these compounds reveal an invariant molecular
tape contains alternate R22(8) synthons formed by N−H···O
hydrogen bonds in 1 and 3. This alternate hydrogen-bonded
pattern disappeared in 2; instead, a new synthon is generated. The
lattice energy calculation suggests that the methyl-substituted
derivatives (2 and 3) have high stabilization energy than compound
1. The electrostatic potential map reveals the difference in the
accepting tendency of the carbonyl oxygen. The Hirshfeld surface and 2D-fingerprint plots analyses demonstrate that the major
intermolecular interactions come from H···O contacts in 1, and these contacts were reduced due to the presence of methyl
substitutions in 2 and 3. This reduction is compensated by the increase of the same amount of H···H contacts in these structures.
Further, the PIXEL energy and DFT calculations at the M06-2X-D3/cc-pVTZ level of theory were used to characterize the dimeric
topology formed in structures of 1−3. The intermolecular interaction energies of dimers calculated by the PIXEL method were
compared with the B97D3/def2-TZVP level of approximation. Although these molecules’ crystal packing is somewhat different, the
energy frameworks show similarities on the respective crystal structure’s shortest axis. Furthermore, the nature and strength of
various noncovalent interactions such as N−H···O, C−H···O/S/π, π···π, and a chalcogen bond of type C−S···OC were evaluated
using the Bader’s quantum theory of atoms-in-molecules framework.
crystal structures of uracil nucleobase co-crystallized with
2,3,5,6-tetrafluoroterephthalic acid20 and melamine21 have
been reported. In the former cocrystal complex, the alternate
R22(8) synthons are generated by two different donors (NH
groups) and acceptors (CO groups), and the phthalic acid
moiety does not affect the self-assembly of uracil and NH
donors and CO acceptors fully engaged in generating the
alternate R22(8) synthons. In the latter cocrystal complex,
donors and acceptors sites of the uracil molecule fully
participate in the hydrogen bonding interaction with a
melamine ligand.
INTRODUCTION
■
Pyrimidine is an integral part of DNA, and RNA imparts
various chemotherapeutic properties, mainly as non-nucleoside
anticancer,1−6 and antiviral7−11 agents. Pyrimidine-2,4-
(1H,3H)-dione (uracil) and 5-methylpyrimidine-2,4(1H,3H)-
dione (thymine) represent the core pharmacophore of several
chemotherapeutic agents. 6-(Arylthio)-5-substituted uracils
and their derivatives were discovered early as the first
chemotherapeutic agents against human immunodeficiency
virus type 1 (HIV-1) acting by inhibition of reverse
transcriptase.12−17
The pyrimidine core acts as a vital scaffold to study
molecular recognition via cocrystal formation and metal
coordination. The Cambridge Structural Database (CSD
version 5.42, November 2020)18 search yielded five hits for
the unsubstituted uracil used as a template, and these hits
include two metal complexes (with Hg and Ni), two cocrystals,
and uracil. In the uracil structure,19 a cyclic (8) N−H···O
hydrogen-bonded synthon is formed, and adjacent synthons
are interconnected by another N−H···O hydrogen bond. The
Received: November 23, 2020
Revised: April 23, 2021
Published: May 3, 2021
https://doi.org/10.1021/acs.cgd.0c01583
Cryst. Growth Des. 2021, 21, 3234−3250
© 2021 American Chemical Society
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Scheme 1. Different Types of Supramolecular Synthons (S1−S6) Are Observed in Title 6-Substituted Uracil Derivatives
In general, one of the carbonyl oxygens of the uracil moiety
has been involved in the metal coordination.22−24 Specifically,
in the mercury(II) chloride complexed with uracil, two NH
groups and a CO group have engaged in the N−H···O
hydrogen bonds which generate a molecular tape comprising
alternate R22(8) synthons, and the remaining CO group has
been involved in the metal coordination with the mercury.25 In
contrast, the NH and CO groups are engaged in hydrogen
bonding interactions with a bis(dithioureto) ligand in the
Ni(II)-uracil complex.26
A CSD search was also performed to find all crystal
structures with 6-substituted uracil, yielding 156 hits (with 3D
coordinates), including polymorphs, solvates, cocrystals, and
metal complexes. These hits decrease to 107 hits when only
organics-related molecules were considered. We found 46 hits
with the following conditions, (i) 3D-coordinates determined,
(ii) only nondisordered, (iii) no errors, (iv) not polymeric, (v)
no ions, (vi) only single-crystal structure, and (vii) only
organics. These 46 hits were used for a comparative purpose to
identify the common and variant supramolecular synthons. For
instance, Gerhardt and Egert explored the hydrogen-bond
based synthons in the cocrystals of 6-chlorouracil and 6-chloro-
3-methyluracil with several triazine and pyrimidine deriva-
tives.27 In this work, the authors found that the primary
framework was formed by R22(8) synthons of either pure N−
H···N type or mixed patterns. The intermolecular C−H···O
and halogen bonds also played significant roles in the
stabilization of cocrystal structures.
synthons observed in the present work are shown in Scheme 1,
and these motifs are formed by N−H···O hydrogen bonds
using different donor (amine) and acceptors (carbonyl) at
various sites. Further, we compared these motifs with other 6-
substituted uracil derivatives reported in the literature.
EXPERIMENTAL SECTION
■
Synthesis and Crystallization. The key intermediate 6-
chlorouracil C was prepared from barbituric acid A via reaction
with phosphorus oxychloride and N,N-dimethylaniline to yield 2,4,6-
trichloropyrimidine B, which was subsequently hydrolyzed with
aqueous sodium hydroxide to yield the target intermediate C.31 6-
Chlorouracil C was then reacted with thiophenol, p-thiocresol, and
3,5-dimethylthiophenol by heating in pyridine to yield the
corresponding 6-(arylthio)uracils 1, 2, and 3, respectively (Scheme
2).32−34 Pure single crystals were obtained by gradual cooling of an
ethanolic solution.
6-(Phenylthio)pyrimidine-2,4(1H,3H)-dione (1).
32
Colorless
prism crystals; Mp 274−275 °C, Mol. formula (Mol. wt.):
C10H8N2O2S (220.25).
6-(p-Tolylthio)pyrimidine-2,4(1H,3H)-dione (2).
33
Colorless
prism crystals; Mp 251−253 °C, Mol. formula (Mol. wt.):
C11H10N2O2S (234.27).
6-(3,5-Dimethylphenylthio)pyrimidine-2,4(1H,3H)-dione (3).
34
Colorless prism crystals; Mp 256−258 °C, Mol. formula (Mol. wt.):
C12H12N2O2S (248.30).
Single-Crystal X-ray Diffraction. X-ray intensity data were
collected at room temperature for crystals of 1−3 on an Xcalibur,
Ruby, Gemini diffractometer using a single wavelength X-ray source
(Cu Kα radiation: λ = 1.54184 Å). Pre-experiment, data collection,
data reduction, and analytical absorption correction35 were performed
with the program suite CrysAlisPro (ver. 1.171.37.35, Oxford
Diffraction, 2014). The structure was solved with the SIR-2011
structure solution program,36 and the structural refinement was
performed with the SHELXL 2018/3 program package.37 The amine
H atoms were located from difference Fourier maps, and their
positions and individual isotropic displacement parameters were
refined freely. The remaining H atoms were placed in idealized
positions (C−H = 0.93 Å) and were constrained to ride on their
parent atoms, with Uiso(H) = 1.2Ueq(C). The methyl H atoms were
constrained to an ideal geometry with C−H = 0.96 Å and Uiso(H) =
1.5Ueq(C), but were allowed to rotate freely about the C−C bond.
In the present investigation, we prepared three 6-(arylthio)-
uracil derivatives, and structures were determined using the X-
ray diffraction technique to study the occurrence of different
hydrogen-bonded synthons utilized to build self-assembly and
learn how methyl substituents influence the crystal packing.
Different theoretical tools such as Hirshfeld surface,28 PIXEL
energy,29 and Bader’s quantum theory of atoms-in-molecules
(QTAIM)30 approaches were employed to delineate the
energetics of various homo-dimers and noncovalent inter-
actions present in them. Different types of supramolecular
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generated with the B3LYP/6-31G(d,p) level of theory using the
CrystalExplorer program. For all these calculations, H atoms positions
were moved to their typical neutron diffraction values (C−H = 1.083
Å and N−H = 1.009 Å).44
Scheme 2. Synthetic Pathway for Compounds 1−3
PIXEL Energy Analysis and Pairwise Interaction. The lattice
energies for crystal structures and the intermolecular interaction
energies for various dimers in these structures were calculated using
the CLP program package.29,45−47 For these energy calculations, the
electron density of molecules 1−3 was obtained at the MP2/6-31G**
level of theory using the Gaussian 09 program.48 Further,
intermolecular interaction energies (Etot) of molecular dimers
calculated by the PIXEL method were compared with those of
interaction energies (ΔEcp) obtained at the B97D3/def2-TZVP level
of approximation.49−51 The basis set superposition error (BSSE) for
the ΔEcp values was corrected using the counterpoise method.52
Molecular Electrostatic Potential Surface (MESP). The
molecular electrostatic potential surface was generated for molecules
1−3 at their crystal structure geometries with normalized H atoms
using the WFA-SAS suite.53 A single point energy calculation was
performed using the Gaussian 09 program with the M06-2X
functional54 and cc-pVTZ basis set55 to generate wave functions,
and cube files and these two files were used as input for the MESP.
Topological Analysis of Electron Density. To assess the nature
and strength of intermolecular interactions observed in dimers of
structures 1−3, we performed the topological analysis with the
AIMALL package.56 The wave functions were generated for these
dimers at the M06-2X-D3/cc-pVTZ level of theory, where D3 is
Grimme’s empirical dispersion correction.57 Different topological
parameters such as ρ(r), ▽2ρ(r), V(r), G(r), and H(r) were obtained
for intermolecular interactions at their bond critical points (BCPs).
Further, the strength of intermolecular interactions was assessed using
the EML empirical scheme.58 The first four criteria of Koch and
The program PLATON was used for structural analysis,38 and crystal
packing and dimeric motifs were drawn using the program
MERCURY.39
Hirshfeld Surface Analysis and Energy Frameworks.
Intermolecular interactions observed in 1−3 were analyzed using
Hirshfeld surface40 and 2D-fingerprint plots41 with CrystalExplorer-
17.5.42 The energy frameworks43 for the crystal structures 1−3 were
Table 1. Crystal Data and Refinement Parameters for Compounds 1−3
1
2
3
crystal data
chemical formula
Mr
C10H8N2O2S
220.24
C11H10N2O2S
234.27
C12H12N2O2S
248.30
crystal system, space group
temperature (K)
a, b, c (Å)
monoclinic, P21/n
293 (2)
7.0390 (8), 7.6087 (8),
19.527 (2)
monoclinic, P21/n
298 (2)
12.4441 (2), 7.1991 (2),
13.2218 (3)
monoclinic, P21/n
298 (2)
7.2204 (6), 20.1062 (7),
8.2242 (3)
α, β, γ (deg)
V (Å3)
Z
90, 99.888 (12), 90
1030.3 (2)
4
90, 115.995 (3), 90
1064.66 (5)
4
90, 96.699 (3), 90
1185.8 (7)
4
radiation type
Cu Kα (γ = 1.54184)
2.65
1.420
μ (mm−1
)
2.60
2.37
ρCalc (g cm−3
)
1.462
0.19 × 0.11× 0.10
1.391
0.12 × 0.11 × 0.09
crystal size (mm3)
data collection
0.10 × 0.09 × 0.07
diffractometer
Xcalibur, Ruby, Gemini diffractometer
absorption correction
multiscan
Tmin, Tmax
0.805, 0.850
0.672, 0.797
0.771, 0.839
no. of measured, independent, and observed [I < 2σ(I)]
reflections
5603, 2030, 1049
15810, 2191, 1841
11554, 2408, 1839
Rint
0.066
0.628
0.044
0.628
0.048
0.628
(sin θ/λ)max (Å−1
refinement
)
R[F2 < 2σ(F2)], wR(F2), S
no. of reflections
0.058, 0.136, 1.03
2030
145
0.034, 0.094, 1.02
2191
155
0.041, 0.109, 1.02
2408
164
no. of parameters
H atom treatment
Δρmax, Δρmin (e Å−3
H atoms treated by a mixture of independent and constrained refinement
)
0.20, −0.19
0.26, −0.21
0.20, −0.22
CCDC no.
2044774
2044775
2044776
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Figure 1. Atomic displacement plots have been drawn at the 40% probability level for compounds (a) 1, (b) 2, and (c) 3 and (d) structural overlay
of compounds 1 (green), 2 (red), and 3 (violet).
Figure 2. Molecular electrostatic potentials for structures (a) 1, (b) 2, and (c) 3. The electron density surface drawn at 0.001 au contour. Color
scales (in kcal mol−1): red: > 20; yellow: 20 to 0, 0 to −20; and blue: > −20. The most positive (Vs,max) and negative (Vs,min) ESP values are
indicated.
Popelier59 were used to characterize the hydrogen bonding
interactions as described in our earlier work.60,61
(Vs,max). The donating strength varies ∼15 kcal mol−1 between
these two donors. However, the acceptor atoms show different
behavior as revealed by the negative electrostatic potential
(Vs,min) values, and atom O4 has more negative electrostatic
potential than the O2 atom. The strength of the acceptor
atoms varies ∼4 kcal mol−1 between these two acceptors. As
shown in Figure 2, this trend is similar in all three structures.
The phenyl rings protons show positive electrostatic potentials
and are likely to participate in the noncovalent interactions
with the available acceptor sites.
Hirshfeld Surface Analysis and 2D-Fingerprint (2D-
FP) Plots. The intermolecular interactions were analyzed
qualitatively using the Hirshfeld surface (HS) analysis. The
2D-fingerprint plots demonstrate the effect of mono- and di-
methyl substituents. The intense red spots on the HS indicate
the short intermolecular contacts, which are less than the sum
of the vdW radii of interacting atoms (Figure 3). In 1, two N−
H···O type hydrogen bonds (N1−H1···O2 and N3−H3···O4)
and one C−H···O type (C10−H10···O4) interaction have
intense red areas. In the p-methyl derivative (compound 2),
only two N1−H1···O2 and N3−H3···O4 hydrogen bonds
display intense red spots. Further, an intermolecular C−H···S
(involving H11 and S1 atoms) interaction shows pale red
RESULTS AND DISCUSSION
■
In this work, we explored the influence of the arylthio scaffold
on the crystal packing and supramolecular topology in newly
synthesized 6-(arylthio)uracil derivatives. Table 1 provides
crystal data and refinement parameters for compounds 1−3.
The unsubstituted (compound 1), mono-methyl (com-
pound 2), and di-methyl (compound 3) substituted uracil
derivatives crystallize in the monoclinic system with the
centrosymmetric space group P21/n. The ORTEP plots for
these three compounds are shown in Figure 1. As shown in
Figure 1d, compound 3 shows more phenyl ring rotation than
structures 1 and 2 concerning the uracil ring’s mean plane. The
uracil and phenyl ring orientation is an almost right angle
(86.69° in 1 and 87.15° in 2). However, the corresponding
angle is 70.91° in 3.
The molecular electrostatic potential surface map reveals the
complementary sites to predict the noncovalent interactions.
The proton bound to the N1 atom has more donating
tendencies than the proton bound to the N3 atom, as can be
concluded from the positive electrostatic potential value
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Figure 3. Hirshfeld surface shows short inter-contact in structure 1 (a), structure 2 (b), and structure 3 (c). The right columns correspond to shape
index plots for structures 1−3.
Figure 4. 2D-fingerprint plots show the percentage contribution of the different combinations of inter-contacts to the total Hirshfeld surface area.
spots, suggesting the weak nature of this interaction compared
to N−H···O hydrogen bonds. In the di-methyl substituted
derivative (compound 3), two N1−H1···O2 and N3−H3···O4
hydrogen bonds as observed in 1 and one C−H···O type
interaction (involving one of the methyl groups as a donor)
show bright red spots. The 2D-fingerprint plots for structures
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Table 2. Intermolecular Interaction Energies (in kcal mol−1) for Dimers of Crystals 1−3 Obtained by the PIXEL and DFT
Methods
DFT (B97D3/
def2-TZVP)
PIXEL (MP2/6-31G**)
a
important
interactions
geometry H···A (Å),
motif
CD
symmetry
∠D-H···A (deg)
ECoul
Epol
Edisp
Erep
Etot
ΔEcp
compound 1
M1
8.216 −x + 2, −y + 1,
−z + 1
N1−H1···O2
1.79, 172
−25.5
−9.8
−6.1
24.6
−16.8
−16.9
M2
M3
9.105 −x + 1, −y, −z + 1
N3−H3···O4
Cg1···Cg1
C8−H8···O2
C11−H11···S1
1.84, 171
3.635 (4)
2.63, 136
2.98, 111
−19.5
−4.3
−7.6
−1.3
−5.1
−9.1
19.0
5.4
−13.0
−9.3
−12.2
−12.6
5.153 −x + 1, −y + 1,
−z + 1
M4
M5
6.022 −x + 3/2, y − 1/2,
−z + 3/2
−2.2
−3.3
−1.2
−1.6
−8.1
−5.5
5.8
4.9
−5.7
−5.5
−7.5
−5.7
8.274 −x + 1/2, y − 1/2,
C10−H10···O4
2.31, 170
−z + 3/2
compound 2
M1
9.477 −x + 1, −y − 1,
N3−H3···O4
1.82, 173
−20.5
−4.8
−8.7
−1.6
−5.2
21.1
6.4
−13.3
−10.0
−12.1
−13.4
−z + 1
M2
5.627 −x + 1, −y, −z + 1
Cg1···Cg1
3.523 (1)
−10.1
C8−H8···O2
N1−H1···O2
C7−S1···O2
C11−H11···S1
C12−H12···Cg2
C8−H8···O4
2.72, 132
1.85, 166
3.294 (1), 171.29 (1)
2.82, 132
2.83, 120
M3
M4
M5
9.296 −x + 1/2, y + 1/2,
−z + 1/2
−10.2
−2.2
−4.3
−1.4
−0.6
−8.9
−3.6
−9.4
−2.3
−5.8
9.8
6.4
−8.3
−6.6
−7.9
−8.9
6.386 −x + 3/2, y − 1/2,
−z + 1/2
7.199 x, y − 1, z
2.56, 138
−1.2
1.5
−2.7
−3.5
compound 3
M1
9.377 −x + 1, −y + 1,
N1−H1···O2
1.84, 168
−21.7
19.1
−17.2
−15.7
−z + 2
M2
M3
9.693 −x, −y + 1, −z + 1
N3−H3···O4
Cg1···Cg1
C8−H8···O2
C13−H13B···O2
C14−H14B···O4
C13−H13A···Cg2
C10−H10···Cg1
1.80, 171
3.773 (1)
2.66, 148
2.71, 149
2.34, 139
2.70, 169
2.90, 142
−21.7
−4.5
−9.6
−1.8
−5.3
−10.9
23.1
7.1
−13.5
−10.1
−12.2
−13.1
5.755 −x + 1, −y + 1,
−z + 1
M4
M5
6.767 x − 1/2, −y + 3/2,
z − 1/2
−3.6
−1.3
−1.9
−0.8
−7.9
−7.8
7.0
4.1
−6.5
−5.8
−8.0
−7.7
7.260 x − 1/2, −y + 3/2,
z + 1/2
a
Neutron values are given for all D−H···A interactions. CD: centroid-to-centroid distance of the molecular pair. Cg1 and Cg2 are the centroids of
the pyrimidine and phenyl rings, respectively. All the energy values are expressed in kcal mol−1.
1−3 show differences to reveal the effect of methyl
substituents.
located around 3.0 Å in 1, indicating such interactions are less
likely to form, while the corresponding distance is below 3.0 Å,
suggesting such interactions are likely to form in 2 and 3. The
contribution of intermolecular H···S contacts to the respective
crystal packing does not change much due to mono- and di-
methyl substituents. However, the shortest di+de distance for
this contact is at 2.8 Å in 1, and this distance is shorter than the
sum of the vdW radii of H and S atoms, inferring to form this
interaction in the crystal structure. In the other two
compounds, the corresponding distance is located beyond
3.0 Å, suggesting the weak nature of this interaction. Another
common feature observed is blue and red triangles (shape
index diagram) over the uracil ring in all three structures. This
feature indicates π-stacking interaction is formed between
adjacent uracil rings with contribution ranges from 1.7% to
4.9% to the total HS area. The remaining possible inter-
contacts contribute less than 3.7% to the crystal packing, and
their role is not significant to the crystal packing (Figures S1−
S3). It is interesting to note that the relative contribution of
the S···O contact is about 1.5% to the total HS area in 1, and
the tip distance is less than the sum of the vdW radii of S and
O atoms (3.32 Å). In 2 and 3, it contributes about 1.2 and 1.0,
respectively, and the shortest distance of the S···O contact
scatters beyond 3.32 Å.
The full 2D-FP plots show distinct overall distribution
patterns for inter-contacts observed in the crystal structures of
1−3, and the decomposed 2D-FP plots reveal similarities and
differences in the normalized distances (dnorm) for different
inter-contacts (Figure 4). From this figure, we can see that the
H···O, H···H, and H··· C contacts contribute relatively higher
compared to other interactions to the crystal packing of 1−3
(Figure 4). Specifically, the contribution of H···H contacts is
increased (5.5−8.6%) due to the presence of methyl
substituents in 2 and 3 when compared to compound 1. The
shortest H···H contact distance (di+de) is located beyond 2.4 Å
in 2 and 3, whereas the corresponding distance is around 2.3 Å
in 1. It is important to note that the contribution of H···O
contacts which primarily represent N−H···O and C−H···O
interactions is slightly increased (6.1−6.5%) in 1 compared to
compounds 2 and 3. In all three compounds, the double spikes
tip distance (di+de) is located around 1.8 Å. The
intermolecular H···C contacts which represent C−H···π
interactions do not change much due to the additional methyl
substituent in 3 (20.3%) compared to 2 (20.1%). However, the
contribution of the corresponding contacts is slightly reduced
(17.7%) in 1. The shortest di+de distance for H···C contacts is
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Figure 5. (a) One of the recurrent supramolecular chains mediated by N−H···O hydrogen bonds in uracils and two different modes of adjacent M3
motifs connectivity, (b) the supramolecular chain generated by alternate M2 (N−H···O) and M3 (C−H···O and π···π interactions) motifs, and (c)
the supramolecular chain generated by alternate M4 (C−H···S) and M3 motifs, and (d) self-assembly of 1 forming hexameric supramolecular
closed loops via N−H···O (motif M1) and C−H···O (motif M5) interactions.
Molecular Dimers in the Crystal Structure of 1. The
crystal structure of 1 can be described as a columnar packing in
which the N−H···O hydrogen bonded chain runs parallel to
the crystallographic b axis. In the crystal structure of 1, five
molecular dimers (motifs: M1−M5) were identified from the
PIXEL energy analysis. The intermolecular interaction energies
for these dimers are ranging from −16.8 to −5.5 kcal mol−1.
These dimers are stabilized by two highly directional N−H···O
hydrogen bonds in addition to C−H···O, π-stacking, and a
weak C−H···S interactions.
We have also computed the interaction energies for these
dimers by the B97D3/def-TZVP level of approximation. As
summarized in Table 2, the interaction energies (Etot and
ΔEcp) calculated by two different methods for dimers M1, M2,
and M5 are comparable, whereas the corresponding energies
for dimers M3 and M4 are underestimated by the PIXEL
method that could be due to the dispersion energy and the
type of intermolecular interactions present in them.
The first two strong dimers are formed by N−H···O
hydrogen bonds in which amine and carbonyl groups of the
uracil ring have participated in the hydrogen bonds. Each of
these hydrogen bonds (M1: N1−H1···O2 and M2: N3−H3···
O4) generates an R22(8) synthon (see Scheme 1, synthons S1
and S2). These cyclic hydrogen-bonded synthons are
interlinked alternately to form a molecular tape (Scheme 1,
synthon S3; and Figure 5a). The former molecular dimer M1
stabilizes with the N1−H1···O2 hydrogen bond, which is
relatively stronger than the latter dimer M2. It should be noted
that the S3 type molecular tape is one of the recurrent synthon
topologies observed in some of the 6-substituted uracil
compounds (CSD refcodes: XOJFAE, UPAWIT, IYAQOP02,
GEDYAR, HIMMUM, IYAQOP03, OROTAC01, and CEW-
VOP03).62−66 The 6-n-propyl-2-uracil (csd refocde: PELJIA)
produces the S3 type synthon but utilizes a different
combination of donors and acceptors of the uracil moiety.67
In 6-substituted uracil-cocrystal complexes, the orotic-
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Figure 6. (a) Crystal packing of 2 projected onto the ab plane, (b) the central structural motif stabilized by C−H···O and π-stacking interactions,
(c) adjacent central motifs interlinked by motif M1, and (d) combination of motifs M3 and M5 generates a novel supramolecular arrangement.
melamine·H2O68 and 6-substituted uracil-tetrafluorotereph-
thalic acid20 complexes exhibit the S3 type synthon, and co-
formers do not affect one of the recurring S3 synthons. In the
other cocrystal complexes, mostly the S1 type synthon was
formed. The donor and acceptor groups have been involved in
the S2 synthon primarily engaged with the hydrogen bonding
interaction with the coformers, which affects the formation of
the S3 type synthon. However, only the S1 type synthon was
observed in some of the 6-substituted uracil-cocrystal
complexes.69,70
illustrated in Figure 5c, the adjacent M1 motifs are bridged by
four M5 motifs and collectively form a supramolecular closed-
loop (loop 1) in which six molecules of 1 are involved in it.
The adjacent hexameric loops (loop 1 and loop 2) are further
interconnected by a single M5 motif in the solid state.
Molecular Dimers in the Crystal Structure of 2. In
compound 2, the presence of a methyl substituent at the para
position generates similar crystal packing compared to
compound 1. However, differences in the stability of the
dimers formed by N−H···O hydrogen bonds were observed in
these two structures. As observed in 1, the crystal structure of 2
also contains five energetically significant dimers (M1−M5;
Table 2), as revealed by the PIXEL energy analysis. These
dimers are stabilized by different types of intermolecular
interactions such as N−H···O, C−H···O, C−H···π, C−H···S,
π···π interactions and a chalcogen bond (C−S···O). The
intermolecular interaction energies (Etot) for these dimers
range from −13.3 to −2.7 kcal mol−1.
As shown in Figure 6a,b, the central structural motif (motif
M2; Etot: −10.0 kcal mol−1) is mediated by the π-stacking
interaction, and this motif is also additionally stabilized by an
intermolecular C−H···O interaction (involving H8 and O2
atoms). The π-stacking interaction is of a face-to-face manner
formed between adjacent uracil rings with the centroid-to-
centroid separation of 3.523 (1) Å and the slippage parameter
of 0.701 Å. In the crystalline state, the central structural motifs
generate columnar packing along the ab plane (Figure 6a). The
motifs M2 in compound 2 and M3 in compound 1 are
structurally equivalent with respect to the way of dimerization,
Motif M3 (Etot: −9.5 kcal mol−1) in 1 stabilizes by an
intermolecular C−H···O interaction involving one of the
carbonyl oxygens (O2) and one of the protons of the phenyl
ring (H8), and additional stabilization comes from the face-to-
face π-stacking interaction formed between adjacent uracil
rings with the centroid-to-centroid distance of 3.635 (4) Å and
the slippage parameter of 0.682 Å.
Motif M4 (Etot: −5.7 kcal mol−1) in 1 is formed by a weak
intermolecular C−H···S (involving H11 and S1 atoms). It is
interesting to note that the adjacent M3 motifs are interlinked
by two different motifs, as shown in Figure 5b,c. On the one
hand, the motif M4 interconnects the adjacent M3 motifs, and
these two motifs cooperatively generate a supramolecular
chain, as shown in Figure 5b. The adjacent M3 dimers are
interconnected by the motif M2, as shown in Figure 5c.
The least stable molecular pair (motif M5; Etot: −5.5 kcal
mol−1) stabilizes by a short and directional intermolecular C−
H···O (involving H10 and O4 atoms) interaction, and this
interaction interlinks the neighboring molecules into a C(10)
chain which runs parallel to the crystallographic b axis. As
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Figure 7. (a) Structural overlay of dimers formed by N1−H1···O2 hydrogen bond and atoms labeled used for structural superimposition, (b) motif
M4 in the crystal structure of 2 produces a chain, and (c) the neighboring central structural motifs of 2 are connected by motif M4.
and the strength of the M2 dimer is slightly stronger than the
corresponding dimer in 1, as evident from the value of ΔEcp.
Unlike in compound 1, compound 2 did not produce
alternate R22(8) synthons generated by two different N−H···O
hydrogen bonds. However, one of the N−H···O hydrogen
bonds (involving H3 and O4 atoms) makes an R22(8) synthon
(S2 type, Scheme 1), and the strength of the dimer stabilized
by the N−H···O hydrogen bond (motif M2 in 1 and 3 and
motif M1 in 2) is comparable in all three structures reported in
this work. The strong M1 dimer in 2 links the adjacent central
structural motif formed by the M2 motif (Figure 6c).
Nevertheless, the function of the N1−H1···O2 hydrogen
bond (M3, Etot: −8.3 kcal mol−1) in 2 is entirely different
compared to the other two structures. Motif M3 in 2 also
stabilizes by a short and highly directional C−S···O type
chalcogen bond. The N−H···O hydrogen bond and a C−S···O
chalcogen bond cooperatively generate an R12(5) motif
extending along the crystallographic b axis (Figure 6d).
Further, motif M5 stabilizes with an intermolecular C−H···O
interaction (involving H8 and O4 atoms; Etot: −2.7 kcal
mol−1), and the supramolecular chain formed by motif M3 is
further stabilized by the motif M5 (Figure 6d).
produces a helical chain of a C(5) graph-set motif that runs
parallel to the crystallographic b axis (Figure 7b). Further
stabilization comes from an intermolecular C−H···π (involving
H12 and centroid of the phenyl ring) interaction for the M4
motif. The motif M4 helps to interlink the adjacent central
structural motif M2 (Figure 7c).
It should be noted that three different types of supra-
molecular motifs (S4−S6 types, Scheme 1) are observed in this
structure which are different from structures 1 and 3. None of
these motifs (S1−S6) is found in the structures of 6-(p-
hydroxyphenylazo)uracil (CSD refcode: HPHAUR10),71 6-
((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)pyrimidine-
2,4(1H,3H)-dione (CSD refcode: KAKSEW),72 and 6-((3,4-
bis((t-butyl(dimethyl)silyl)oxy)pyrrolidin-1-yl)methyl)-
pyrimidine-2,4(1H,3H)-dione (CSD refcode: PURGAM).73 In
trans-6-acetamidouracil (CSD refcode: MECXAV), the
synthon is very similar to S5 type and utilizing the amine at
the 3rd position and carbonyl at the 4th position.74 In the
unsubstituted uracil structure (csd refocode: URACIL), the
supramolecular synthon is very similar to S4 type and adjacent
rings are interconnected using the N1−H1···O4C4 bond.19
In the di-methyl 6-uracilmethylphosphonate (CSD refcode:
XOJDUW), the synthon observed was very similar to S5 type
but utilizing the N3−H3···O4C4 bond.62 The S1 or S2 type
synthons were observed in 6-uracilmethylphosphonic acid
(CSD refcode: BOXWOA),75 6-(chloromethyl)pyrimidine-
2,4(1H,3H)-dione (CSD refcode: SODLIJ),76 6-chlorouracil
(CSD refcode: SOZFEV),77 6-iodouracil (CSD refcode:
SOZFIZ),77 6-uradinyl-4,4,5,5-tetramethyl-4,5-dihydro-1H-
imidazole-1-oxyl (CSD refcode: VAMXUD),78 and 6-({bis-
[(pyridin-2-yl)methyl]amino}methyl)pyrimidine-2,4(1H,3H)-
dione (CSD refcode: XOZWIV).79
To explain why a cyclic R22(8) synthon formed by the N1−
H1···O2 hydrogen bond did not form in compound 2, we
compared the M3 dimer of 2 with that of M1 dimers of 1 and
3 through structural superimposition. We used H1, N1, C2,
and O2 atoms of one of the dimer molecules for structural
superimposition to visualize the second molecule’s relative
orientation in the dimer. As shown in Figure 7a, the dimer M1
of compounds 1 and 3 superimposed very well, and inversion-
related molecules form the M2 dimer in these two compounds.
In compound 2, the glide-related molecules generate the dimer
M3 and break the cyclic dimer with the R22(8) synthon.
Motif M4 (Etot: −6.6 kcal mol−1 and the dispersion energy
contributes about 72% toward stabilization) stabilizes with an
intermolecular C−H···S (involving H11 and S1 atoms) which
Molecular Dimers in the Crystal Structure of 3.
Molecules of 3 are packed in a columnar manner with a
herringbone-like architecture in the solid state. It also shows a
resemblance in the molecular arrangement with that of 1 and
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Figure 8. Supramolecular motifs observed in the crystal structure of 3. (a) A molecular tape formed by alternate M1 and M2 motifs, (b) the central
structural motif in 3, (c) supramolecular chain generated by alternate M1 and M3 motifs, (d) a chain stabilized by motif M4, and (e) a chain is
formed by the motif M5.
2. The synthons S1, S2, and S3 types are observed in 3 (Figure
8a). As observed in 1, there are five dimeric pairs (M1−M5)
identified from the PIXEL energy analysis. The intermolecular
interaction energies for these pairs are ranging from −17.2 to
−5.8 kcal mol−1. The intermolecular N−H···O, C−H···O, C−
H···π, and π···π interactions are involved in the stabilization of
different dimers in the crystal structure of 3. Unlike in
compounds 1 and 2, the intermolecular C−H···S and C−S···O
chalcogen bonding interactions do not occur in 3. As observed
in 1, the first two strong dimers stabilize by intermolecular N−
H···O (motif M1: N1−H1···O2 and motif M2: N3−H3···O4)
hydrogen bonds utilizing amine H and carbonyl oxygen atoms.
These two hydrogen bonds generate a molecular tape
comprising synthons S1, S2, and S3 (Figure 8a).
The binding energy (ΔEcp) value for the N3−H3···O4
hydrogen-bonded dimer is comparable in all three structures.
The N1−H1···O2 hydrogen bonds form a centrosymmetric
cyclic dimer in 1 and 3, and this cyclic dimer is slightly more
stable (by 1.2 kcal mol−1) in 1 than in 3. Since the N1−H1···
O2 hydrogen bond does not form a cyclic dimer in 2, the
stability of this dimer is weaker as expected.
also note that the occurrence of additional C13−H13B···O2
interactions in M3 does not add more stability compared to
the other two structures. As mentioned earlier, the adjacent
M3 motifs in 1 are interconnected in two different ways (via
M2 or M4 motifs) to generate chains (Figure 5b,c). Similarly,
the adjacent M3 motifs are noncovalently linked via the M1
motif (Figure 8c), and a chain formed by alternate M3 and M1
motifs in 3 is very similar to 1. However, compound 1 uses the
N3−H3···O4 hydrogen bond, whereas compound 3 uses the
N1−H1···O2 hydrogen bond for linkage.
Motif M4 (Etot: −6.5 kcal mol−1) is stabilized by an
intermolecular C−H···O interaction (involving H14A and
O4). This interaction links the molecules of 3 into a C(10)
chain that runs parallel to the crystallographic a axis (Figure
8d). It is important to emphasize that this 1D chain is further
supported by an intermolecular C−H···π interaction (involving
H13C and centroid of the phenyl ring). The least stable
dimeric motif (M5; Etot: −5.8 kcal mol−1) in this structure is
stabilized by an intermolecular C−H···π interaction (involving
H10 and centroid of the uracil ring), and this intermolecular
interaction interconnects the molecules of 3 into a chain as
depicted in Figure 8e.
Motif M3 (Etot: −10.1 kcal mol−1) is stabilized by a three-
centered intermolecular C−H···O (involving H8 and O2;
H13A and O2 atoms) in which one of the carbonyl oxygens
acts as an acceptor for two different C−H···O interactions
(Figure 8b). This molecular pair is further stabilized by a face-
to-face π-stacking interaction between adjacent uracil rings
with a slippage distance of 1.168 Å. It should be noted that the
dimer M3 is similar to that of dimers M3 in 1 and M2 in 2, and
one of the methyl protons (H13B atom) has additionally been
involved in the intermolecular C−H···O interaction in 3. We
Common Packing Features. In 1−3, the gross molecular
packing shows invariant structural features (N−H···O hydro-
gen bonded molecular tape) in the crystalline state (Figure 9).
However, there are differences noted, especially for compound
3. This compound packed in a columnar manner with a
herringbone feature when projected onto the crystallographic a
axis, and the other two compounds display a columnar packing.
However, the relative geometric conformation and positions of
molecules in the solid state show invariant and variable
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Figure 9. Crystal packing of (a) 1, (b) 2, and (c) 3. The H atoms have been omitted for clarity.
isostructurality. The XPac program identifies the dimension-
ality of the similarity between these structures. The result
suggests that crystals 1 and 2 show a 2D supramolecular
construct (SC; the layer of molecules match) among these
three molecules (Figure S4, Supporting Information). Crystals
1 and 2 also share 0D SC (dimer with N3−H3···O4 hydrogen
bond) with the closely related structure 6-((4-methylphenyl)-
sulfanyl)-5-propylpyrimidine-2,4(1H,3H)-dione.80
packing in terms of energy components associated with
molecular pairs.
Figure 10 shows the energy frameworks for crystal structures
1−3. The topology of the electrostatic energy frameworks for
the crystal 1 is a zigzag chain (viewed down a axis) formed by
two intermolecular N−H···O hydrogen bonds generating a
molecular tape along the crystallographic b axis. The alternate
cylindrical tubes diameter is varied due to the dimer strength
of these hydrogen bonds (N3−H3···O4: stronger, and N1−
H1···O1: weaker). The dispersion energy and the net
interaction energy frameworks show a fused hexagonal
topology and crystal packing of 1 predominantly driven by
electrostatic energy components. The topology of the energy
frameworks for crystal 2 projected down the b axis is very
similar to that of crystal 1. The larger cylindrical tubes in the
zigzag chain correspond to the N3−H3···O4 hydrogen bond,
and smaller tubes represent the N1−H1···O2 hydrogen bond.
These two hydrogen bonds generate a synthon S5 (Scheme 1).
In 3, the electrostatic component forms zigzag chains which
run parallel to the crystallographic c axis comprising alternate
small and larger cylindrical tubes. The relatively larger and
smaller tubes correspond to intermolecular N1−H1···O2 and
N3−H3···O4 hydrogen bonds, respectively. Although solid-
state packing of these molecules is somewhat different, the
energy frameworks show similarities on the respective crystal
structure’s shortest axis (ca. 7.0 Å). The common energy
frameworks suggest that all these three crystals have similar
mechanical properties.
Lattice Energies and Energy Frameworks. The total
lattice energies (Etot) for crystals 1−3 were calculated using the
PIXELC code. Table 3 summarizes various energy components
Table 3. Lattice Energies (in kcal mol−1) for Crystals 1−3
compound
ECoul
Epol
Edisp
Erep
Etot
1
2
3
−31.0
−28.8
−30.5
−11.6
−12.0
−12.4
−28.9
−34.3
−34.5
36.2
36.7
38.9
−35.3
−38.3
−38.5
such as Coulombic (ECoul), polarization (Epol), dispersion
(Edisp), and repulsion (Erep) terms. This table shows that the
electrostatic energy component (ECoul + Epol) contributes more
than 50% toward stabilizing molecular pairs in all three crystal
structures. The electrostatic energy contribution is about 60%
in 1, yet a very similar electrostatic contribution (54−55%) in
2 and 3. A slight variation in the Coulombic, polarization, and
dispersion energy terms makes variations in the total
stabilization energy. The stabilization energy is lower in the
case of crystal structure 1 (−71.5 kcal mol−1) than crystal
structures 2 (−75.1 kcal mol−1) and 3 (−77.4 kcal mol−1).
Energy framework analysis helped to visualize the crystal
Evaluation of Intermolecular Interactions. To assess
the strength and nature of noncovalent interactions in 1−3, we
computed topological properties for dimers observed in these
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Figure 10. Energy frameworks for crystal structures 1 (a), 2 (b), and 3 (c). Electrostatic (red), dispersion (green), and net interaction (blue)
energies are shown as cylindrical tubes.
a
Table 4. Characteristics of the (3,−1) BCPs Correspond to the Intermolecular Interactions in Various Dimers of 1
−V(r)
G(r)
interaction
M1
Rij (Å)
ρ(r) (e/Å3)
▽2ρ(r) (e/Å5)
V(r)
G(r)
H(r)
|
|
De
N1−H1···O2
M2
N3−H3···O4
M3
C8−H8···O2
M4
C11−H11···S1
M5
1.814
1.868
2.658
3.089
2.328
0.245
0.211
0.047
0.047
0.084
2.702
2.501
0.557
0.559
1.110
−91.8
−74.6
−9.8
82.7
71.3
12.5
12.1
25.1
−9.1
−3.2
2.7
1.11
11.0
8.9
1.2
1.1
2.4
1.05
0.78
0.74
0.79
−8.9
3.2
C10−H10···O4
−19.9
5.2
a
The values of V(r), G(r), and H(r) are given in kJ mol−1 bohr−3, and De = −0.5 × V(r) in kcal mol−1.
structures. Tables 4−6 present the selected topological
properties for these interactions at their (3,−1) bond critical
points (BCPs) in structures 1−3. Figures S5−S7 illustrate the
molecular graphs of dimers in these structures showing
different types of noncovalent interactions.
hydrogen bonds are classified as intermediate bonding between
closed and shared-shell interactions (|−V(r) | > 1, H(r) < 0, and
G(r)
▽2ρ(r) > 0). Figure 11a,b shows the uninterrupted region of
total electronic energy density (H(r)) for these two N−H···O
hydrogen bonds at their BCPs. It is to be noted that the
remaining interactions in 1 are of closed-shell interactions (|
Gatti described the assignment of purely closed-shell and
shared-shell interactions, i.e., covalent interactions and transit
−V(r) | < 1, H(r) > 0, and ▽2ρ(r) > 0). The KP-4 rule is
region of increasing covalency based on the ratio of |−V(r)
|
G(r)
G(r)
employed to differentiate between hydrogen bond and van der
Waals interactions. In this structure, the intermolecular C−H···
S interaction in M4 shows van der Waals character, and the
remaining interactions show hydrogen bonding character.
Though the De value of the C−H···S interaction is comparable
with one of the C−H···O interactions (M3), the former
value, the sign of the total electronic energy density H(r), and
the positive value of Laplacian of electron density.81 In 1, the
intermolecular N−H···O, C−H···O, and C−H···S interactions
are involved in the stabilization of the dimers in the crystal
structure. The dissociation energies (De) for these interactions
are ranging from 11.0 to 1.1 kcal mol−1. Both N−H···O
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a
Table 5. Characteristics of the (3,−1) BCPs Correspond to the Intermolecular Interactions in Various Dimers of 2
−V(r)
G(r)
interaction
Rij (Å)
ρ(r) (e/Å3)
▽2ρ(r) (e/Å5)
V(r)
G(r)
H(r)
|
|
De
M1
N3−H3···O4
M2
C8−H8···O2
M3
1.846
2.750
0.225
0.040
2.551
0.467
−81.2
−8.2
75.4
10.5
−5.9
1.08
9.7
1.0
2.3
0.79
N1−H1···O2
C7−S1···O2
M4
1.876
3.307
0.199
0.041
2.546
0.590
−70.8
−9.2
70.1
12.6
−0.7
3.4
1.01
0.73
8.5
1.1
C11−H11···S1
C12−H12···C9(π)
M5
2.851
3.047
0.050
0.036
0.614
0.407
−10.4
−6.3
13.6
8.7
3.2
2.4
0.77
0.73
1.3
0.8
C8−H8···O4
2.595
0.045
0.613
−9.9
13.3
3.4
0.74
1.2
a
The values of V(r), G(r), and H(r) are given in kJ mol−1 bohr−3, and De = −0.5 × V(r) in kcal mol−1.
a
Table 6. Characteristics of the (3,−1) BCPs Correspond to the Intermolecular Interactions in Various Dimers of 3
−V(r)
G(r)
interaction
Rij (Å)
ρ(r) (e/Å3)
▽2ρ(r) (e/Å5)
V(r)
G(r)
H(r)
|
|
De
M1
N1−H1···O2
M2
N3−H3···O4
M3
1.867
1.824
0.208
0.236
2.554
2.670
−74.1
−87.1
71.8
79.9
−2.3
−7.2
1.03
8.9
1.09
10.4
C8−H8···O2
C13−H13A···O2
M4
2.685
2.736
0.045
0.034
0.538
0.438
−9.8
−7.3
12.2
9.6
2.5
2.3
0.80
0.76
1.2
0.9
C14−H14A···O4
C13−H13C···C12(π)
M5
2.367
3.356
0.080
0.048
1.115
0.550
−18.7
−9.2
24.5
12.1
5.8
2.9
0.76
0.76
2.2
1.1
C10−H10···C5(π)
3.005
0.036
0.371
−6.0
8.1
2.0
0.75
0.7
a
The values of V(r), G(r), and H(r) are given in kJ mol−1 bohr−3, and De = −0.5 × V(r) in kcal mol−1.
interaction is of van der Waals in nature. It is important to note
that the N1−H1···O2 hydrogen bond is stronger by 2.1 kcal
mol−1 compared to the N3−H3···O4 hydrogen bond.
hydrogen bond strengths in structures 1 and 3 form S1, S2,
and S3 synthons. The distribution of total electronic energy
density (H(r)) shows an uninterrupted region for both N−H···
O hydrogen bonds at their BCPs (Figure 11e,f). The
remaining noncovalent interactions observed in this structure
are closed-shell in nature.
In 2, the intermolecular N−H···O, C−H···O, C−H···S, C−
H···π, and a chalcogen bond of type C−S···O have participated
in the stabilization of the crystal structure. The De values for
these interactions range from 9.7 to 0.8 kcal mol−1. The nature
of both N−H···O hydrogen bonds (transit region of increasing
covalency) is similar to that of structure 1, though one of the
hydrogen bonds does not take part in a cyclic dimer (Figure
11c,d). However, a slight variation in the strength of these
hydrogen bonds is noted. The strength of the N−H···O
hydrogen bond in a cyclic dimer is slightly more potent than a
noncyclic dimer. The KP-4 rule reveals that one of the C−H···
O interactions (motif M5) shows hydrogen bonding character
in addition to N−H···O hydrogen bonds. It also reveals that
the intermolecular C8−H8···O2 (M2), C11−H11···S1 (M4),
and C12−H12···C9(0) (M4) interactions display van der
Waals character rather than hydrogen bonding character. We
also note that the strength of C−H···O, C−H···O interactions
and a chalcogen bond (C−S···O) is comparable.
CONCLUSIONS
■
In summary, three (arylthio)uracil derivatives have been
synthesized, and their crystal structures were determined.
The energetics of dimers was explained with PIXEL energy
analysis and the DFT method (B97D3/def2-TZVP). Further,
intermolecular interactions present in these dimers were
explored using the Hirshfeld surface and QTAIM approaches.
Crystal packing analysis revealed that the un-methylated (1)
and mono-methylated (2) crystals showed similar 2D supra-
molecular constructs in the solid state. The di-methylated
compound (3) displayed a columnar packing with a
herringbone-like supramolecular architecture, which was differ-
ent from structures of 1 and 2. The intense red spots observed
for N−H···O hydrogen bonds on the Hirshfeld surface
indicated their important role in the stabilization of the
recurrent supramolecular topology. Though the crystal packing
of 1 and 3 was different, an invariant molecular tape formed by
alternate R22(8) synthons stabilized by N−H···O hydrogen
bonds was present. The methyl substituents reduced the
contribution of H···O interactions as evident from the
Hirshfeld surface and 2D-fingerprint plots. However, there
In 3, the intermolecular N−H···O, C−H···O, and C−H···π
interactions are involved in the stabilization of the crystal
structure. The dissociation energies for these interactions are
ranging from 10.4 to 0.7 kcal mol−1. Both N−H···O hydrogen
bonds in this structure display intermediate bonding character
between shared and closed-shell interactions based on Gatti’s
assignment (Figure 11e,f). However, slight variation in these
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Figure 11. Distribution of total electronic energy density, H(r), showing the formation of two strong N−H···O hydrogen bonds in the structure of
1 (a, b), the structure of 2 (c, d), and the structure of 3 (e, f). All N−H···O hydrogen bonds show uninterrupted regions at their BCPs.
was no substantial change in the relative contribution of H···
C/S contacts. The molecular electrostatic potential revealed
differences in the donating and accepting tendencies of amine
and carbonyl groups of the pyrimidine ring. The most positive
and negative electrostatic potentials were comparable in all
three structures. However, the corresponding values were
slightly lower in magnitude in 3, and this difference could lead
to different crystal packing utilizing available donor and
acceptors sites. The QTAIM analysis suggested that the
intermolecular N1−H1···O2 and N3−H3···O4 hydrogen
bonds had intermediate bonding character between shared
and closed-shell interaction in all three structures. The other
intermolecular interactions belonged to closed-shell interac-
tions, as concluded by the topological analysis. This study
identified the recurrent motifs (S1, S2, S3, and S5) found in 6-
substituted uracil compounds and helps to design novel
compounds.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Subbiah Thamotharan − Biomolecular Crystallography
Laboratory, Department of Bioinformatics, School of
Chemical and Biotechnology, SASTRA Deemed University,
Thanjavur 613 401, India; orcid.org/0000-0003-2758-
6649; Email: thamu@scbt.sastra.edu
Authors
Lamya H. Al-Wahaibi − Department of Chemistry, College of
Sciences, Princess Nourah bint Abdulrahman University,
Riyadh 11671, Saudi Arabia
Sai Ramya Sree Bysani − Biomolecular Crystallography
Laboratory, Department of Bioinformatics, School of
Chemical and Biotechnology, SASTRA Deemed University,
Thanjavur 613 401, India
Samar S. Tawfik − Department of Pharmaceutical Organic
Chemistry, Faculty of Pharmacy, Mansoura University,
Mansoura 35516, Egypt
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01583.
Mohammed S. M. Abdelbaky − Department of Physical and
Analytical Chemistry, Faculty of Chemistry, Oviedo
University-CINN, Oviedo 33006, Spain; orcid.org/0000-
0001-8395-8705
Santiago Garcia-Granda − Department of Physical and
Analytical Chemistry, Faculty of Chemistry, Oviedo
University-CINN, Oviedo 33006, Spain
Ali A. El-Emam − Department of Medicinal Chemistry,
Faculty of Pharmacy, Mansoura University, Mansoura
35516, Egypt
2D-fingerprint plots for different atom···atom contacts,
2D-supramolecular construct observed in 1 and 2, and
the molecular graphs showing intermolecular interac-
tions in 1−3 (PDF)
Accession Codes
CCDC 2044774−2044776 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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Integrase Inhibitor for the Treatment of HIV Infection. Expert Opin.
Invest. Drugs 2008, 17, 97−103.
M. Judith Percino − Unidad de Polímeros y Electrónica
Orgánica, Instituto de Ciencias, Benemérita Universidad
Autónoma de Puebla, San Pedro Zacachimalpa, Puebla
C.P.72960, México; orcid.org/0000-0003-1610-7155
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Complete contact information is available at:
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(12) Tanaka, H.; Baba, M.; Ubasawa, M.; Takashima, H.; Sekiya, K.;
Nitta, I.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T.
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Notes
The authors declare no competing financial interest.
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Pannecouque, C. Non-Nucleoside HIV-1 Reverse Transcriptase
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ACKNOWLEDGMENTS
■
This research was funded by the Deanship of Scientific
Research at Princess Nourah bint Abdulrahman University
through the Fast-track Research Funding Program. S.T. and
M.J.P. thank the LNS for computational resources.
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