Close insight into the nature of intermolecular interactions in dihydropyrimidine-2(1H)-thione derivatives

Article abstract of DOI:10.1039/c6ce02619b

The crystal structures of four 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione derivatives [R = 2-chloro (1), 2,3-di-chloro (2), 2,4-di-methyl (3), and 4-methoxy (4)] were determined and analysis of their molecular conformations was carried out. A comparative study of the intermolecular interactions—including eight closely related structures from CSD—was performed and the degree of isostructurality was quantified. The intermolecular interactions were characterized in terms of the periodic system electron density and the topological analysis highlighted the role of N-H?S=C hydrogen bonds in the stabilization of the different supramolecular architectures. PIXEL lattice energy calculations revealed that the dispersion component was the major contributor, together with the important role of the Coulombic term to the total energy. The interaction energies for molecular pairs involving N-H?S=C hydrogen bonds indicated a dominant contribution to packing stabilization coming from the Coulombic components. Hirshfeld surfaces and fingerprint plots allowed us to visualize different intermolecular contacts and their relative contributions to the total surface for each compound. Analysis of the electrostatic potentials (ESP) correlated well with the computed energies, thus characterizing the strengths of the different interactions.

Full text of DOI:10.1039/c6ce02619b

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Floerke, A. Fantoni, A. Khurshid, H. Pérez and M. F. F. Erben, CrystEngComm, 2017, DOI:
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A Close Insight into the Nature of Intermolecular InteractioDnOsI: 1i0n.1039/C6CE02619B
Dihydropyrimidine-2(1H)-thione Derivatives †
Aamer Saeed,a,* Ulrich Flörke,b Adolfo Fantoni,c Asma Khurshid,a Hiram Pérez,d,*
Mauricio F. Erbene,*
a Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
b Department of Chemistry, University of Paderborn, 33098 Paderborn, Germany.
c
Instituto de Física La Plata, Departamento de Física, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata, 49 y 115, La Plata, Buenos Aires, República Argentina.
d
Departamento de Química Inorgánica, Facultad de Química, Universidad de la Habana,
Habana 10400, Cuba.
e
CEQUINOR (UNLP, CONICET-CCT La Plata), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, C.C. 962 (1900). La Plata, República
Argentina.
†
Electronic supplementary information (ESI) available: Ring puckering parameters and
endocyclic torsion angles for compounds 1-4 are given in Tables S1 and S2, respectively.
Topological and geometrical parameters for the main intermolecular interactions of compounds
1-4 are shown in Tables S3-S6, respectively. Interaction energies for molecular pairs involving
H…H contacts and electrostatic potentials in 1–4 and related compounds are shown in Table S7
and S8, respectively. Overlay diagram for independent molecules of compound 1 is shown in
Figure S1. Packing diagrams, as well as intermolecular energies for the respective molecular
pairs for compounds 1-4 are given in Figures S2-S5, respectively. Hirshfeld surfaces of
compound 1 is shown in Figure S6. Figure S7 shows the relative contributions of
intermolecular contacts to the Hirshfeld surface area and full 2D fingerprint plots are displayed
in Figure S8. Hirshfeld surface mapped with electrostatic potentials (ESP) and 3D-deformation
density maps for compounds 1-4 are shown in Figures S9-S12, respectively.
*Corresponding authors:
(AS) E-mail: aamersaeed@yahoo.com, Tel: +92-51-9064-2128; Fax: +92-51-9064-2241.
(HP) E-mail: hperez@quimica.uh.cu, Tel: 53-78703922; Fax: 53-78783641.
(MFE) E-mail: erben@quimica.unlp.edu.ar, Tel/Fax: +54-211-425-9485.
1

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DOI: 10.1039/C6CE02619B
Abstract
The crystal structures of four 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione
derivatives [R = 2-chloro (1), 2,3-di-chloro (2), 2,4-di-methyl (3), and 4-methoxy (4)] have
been determined and an analysis of their molecular conformations was carried out. A
comparative study of intermolecular interactions -including eight closely related structures
from CSD- was performed and the degree of isostructurality was quantified. Intermolecular
interactions have been characterized in the periodic system electron density and the topological
analysis highlights the role of N–H···S=C hydrogen bonds in the stabilization of different
supramolecular architectures. PIXEL lattice energy calculations revealed that the dispersion
component is the major contribution, with an important role of the coulombic term to the total
energy. Interaction energies for molecular pairs involving strong N–H···S=C hydrogen bonds
indicate a dominant contribution to packing stabilization coming from coulombic components.
Hirshfeld surfaces and fingerprint plots allowed us to visualize different intermolecular
contacts and its relative contributions to total surface in each compound. The analysis of
electrostatic potentials (ESP) correlates well with the computed energies characterizing the
strength of different interactions.
Keywords: dihydropyrimidine, crystal structure, Pixel energy, Hirshfeld surfaces, electrostatic
potential, deformation density.
2

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DOI: 10.1039/C6CE02619B
Introduction
Non-covalent interactions play an essential role in supramolecular chemistry, molecular
biology and crystal engineering.1 It is well known that strong hydrogen bonds have been
preferably used as tools for the design of materials with specific desirable properties.2 In
absence of strong hydrogen bonds however, other kind of non-covalent interactions can be
dominant and therefore responsible for crystal stability. The hydrogen bond do not represent an
exclusively electrostatic interaction but a complex combination of at least four components
such as electrostatic (acid/base), polarization (hard/soft), van der Waals (dispersion/repulsion),
and covalent (charge transfer). The electrostatic nature is clearly dominant in strong hydrogen
bonds, particularly if donor and acceptor atoms are very electronegative, but the proportion of
electrostatic character can vary, even in the case of weaker interactions. In this direction, the
study of non-covalent interactions in sulfur-containing compounds is attracting continuous
attention in crystal engineering,3 mainly because of the high polarizabilitity of the electron
density at the sulfur atom.. Thus, the versatility of the thioamide [–C(S)NH2],4, 5 triazole-
thione6, 7 and thiosemicarbazone8 functional groups as a key moiety for crystal engineering has
recently been recognized.
Dihydropyrimidine-2-thiones are heterocyclic compounds having a pyrimidine ring
system.9, 10 This class of compounds are usually obtained by variations of well known three-
component reaction early reported by Pietro Biginelli.11, 12 In recent years, a considerable
increased interest has been directed at the role and effect of dihydropyrimidine-2-thiones in a
variety of biological activities.13, 14
In this work, the crystal structures of four novel 1-(R-phenyl)-4,4,6-trimethyl-3,4-
dihydropyrimidine-2(1H)-thione derivatives [see Scheme 1, R = 2-chloro (1), 2,3-dichloro (2),
2,4-dimethyl (3) and 4-methoxy (4)], have been determined using single-crystal X-ray analysis.
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Scheme 1. General structure of 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-
DOI: 10.1039/C6CE02619B
thiones.
R
N
S
NH
The aims of this article are (1) to analyze the conformational stability of the 3,4-
dihydropyrimidine-2(1H)-thione moiety by varying the phenyl substitution at the 1- position,
and (2) to determine the intermolecular interactions governing the crystal structure of the 3,4-
dihydropyrimidine-2(1H)-thione and how conserved are these interactions upon substitution.
To pursuing these goals, a molecular conformation analysis and a detailed characterization of
intermolecular contacts were carried out for these four compounds as well as for eight other
closely related structures found in CSD. Also, a comprehensive analysis of intermolecular
interaction has been performed by applying a battery of complementary tools, including: (1) the
topology of the electron density obtained from a periodic quantum calculation was analyzed
within the context of the Bader’s theory of atoms in molecules (AIM)15 to characterize the
intermolecular interactions, (2) lattice energies and intermolecular interaction energies
associated to different molecular pairs have been calculated in order to determine the energy
components contributing to crystal stabilization,16, 17 (3) Hirshfeld surface based tools, such as
dnorm, shape index and curvedness surface properties,18, 19 have been used for exploration of the
packing modes and visualization of intermolecular interactions, (4) quantitative pictures of
intermolecular contacts, including the relative percentage of each type of interaction have been
obtained from fingerprint plots and their decompositions,20, 21 and (5) the intermolecular
interactions have been analyzed in terms of a combined quantitative study based on
electrostatic potential (ESP) and 3D deformation density maps.22
4

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DOI: 10.1039/C6CE02619B
2- Experimental
2.1- Preparation of 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione
derivatives. In an attempt to obtain the corresponding acyl thiourea derivative, Yamin et al.23,
24
isolated 1-phenyl-4,4,6-trimethyl-3,4-dihydropyrimidine-2-(1H)thione from the reaction
between cinnamoyl isothiocyanate and aniline in acetone. We demonstrated that 1-aryl-4,4,6-
trimethyl-3,4-dihydropyrimidine-2-(1H)thiones are in fact formed by the reaction of aniline,
KSCN and 4-methylpent-3-en-2-one, an aldol condensation product of acetone formed in situ
from acetone used as solvent.9, 10,25 Following this general method, suitable substituted anilines
(1.0 mmol) were added portion wise to a stirred suspension of potassium thiocyanate (1.0
mmol) in 4-methylpent-3-en-2-one (1.20 mmol) at room temperature. The reaction mixture was
heated at 50-60 ºC for 3-5 hours and the progress was followed by TLC. On completion, the
reaction mixture was cooled to room temperature and poured into ice-water. The precipitated
compounds were recrystallized from ethanol to afford the purified dihydropyrimidine-2-thiones
(1-4) in good to excellent yields (Scheme 2).
NH2
N
NH
O
H
R
KSCN
R
S
1-4
R= 2-Cl (1), 2,3-Cl2 (2), 2,4-(CH3) (3), 4-MeO (4)
Scheme 2. Green synthesis of 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-
thiones 1-4.
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1-(2-Chlorophenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione
(D1O)I.: 10.103W9/Ch6CitEe02619B
crystalline solid; Yield; 92%, Rf: 0.31; m.p: 123-124°C; IR (neat): 3390 (NH), 3029 (=C-H
stretch), 1645 (CS-NH), 1576 (C=C), 1297 (C-N): 1H-NMR (CDCl3, 300 MHz): δ 7.88 (s, 1H,
N-H), 7.22-6.45 (m, 5H, Ar-H), 4.25 (s, 1H, Csp2-H), 1.41 (s, 3H, Csp2-CH3) 1.28 (s, 3H,
CH3), 1.24 (s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz): δ 187.5 (CSNH), 138.1 (-C=C-), 137.3,
135.2, 134.7, 131.7, 130.4, 129.8, 110.6 (-H-C=C-), 57.4 ((CH3)2-C-), 34.2 ((CH3)2-), 33.4 (-C-
CH3). Elemental analysis C13H15ClN2S: calc (%): C 58.97, H 5.23, Cl 13.26, N 10.54, S 12.01;
found (%): C 58.94, H 5.27, Cl 13.28, N 10.53, S 12.00.
1-(2,3-Di-chlorophenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione (2). Brown
crystalline solid; Yield; 81%, Rf: 0.33; m.p: 130-131°C; IR (neat): 3401 (NH), 3087 (=C-H
1
stretch), 1694 (CS-NH), 1598 (C=C), 1307 (C-N): H-NMR ((CD3)2CO, 300 MHz): δ 7.99 (s,
1H, N-H), 7.64-7.29 (m, 5H, Ar-H), 5.04 (q, 1H, J= 1.2 Hz, Csp2-H), 1.52 (d, 3H, J=1.2 Hz,
Csp2-CH3) 1.44-1.41 (s, 6H, 2×CH3); 13C-NMR ((CD3)2CO, 75 MHz): δ 183.1 (CSNH), 137.5
(-C=C-), 137.1, 135.9, 132.8, 128.5, 128.1, 127.6, 107.9 (-H-C=C-), 57.1 ((CH3)2-C-), 33.6
(CH3)2-), 32.7 (-C-CH3). GC-MS: 300 (M+), 285, 265 (100 %), 249, 226, 185. Elemental
analysis C13H14Cl2N2S: calc (%): C 51.95, H 4.56, Cl 23.50, N 9.33, S 10.65; found (%): C
51.98, H 4.53, Cl 23.54, N 9.31, S 10.63.
1-(2,4-Dimethylphenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione (3). White
crystalline solid; Yield; 85%, Rf: 0.32; m.p: 150-151°C; IR (neat): 3320 (NH), 3082 (=C-H
1
stretch), 1697 (CS-NH), 1535 (C=C), 1290 (C-N): H-NMR ((CD3)2CO, 300MHz): δ 7.72 (s,
1H, N-H), 7.08-6.89 (m, 3H, Ar-H), 4.97 (q, 1H, J=1.2 Hz, Csp2-H), 2.31 (s, 3H, Ar-CH3), 2.17
(s, 3H, Ar-CH3), 1.44 (d, 3H, J= 1.2 Hz, Csp2-CH3), 1.39 (6H, 2×CH3); 13C-NMR ((CD3)2CO,
75 MHz): δ 177.2 (CSNH), 138.1 (-C=C-), 137.5, 136.5, 131.8, 130.8, 129.9, 128.8, 109.2 (-H-
C=C-), 51.8 ((CH3)2-), 30.8 ((CH3)2-C-), 20.2 (-C-CH3), 19.6 (2×Ar-CH3): GC-MS: 260 (M+),
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245 (100%), 179, 163, 79. Elemental analysis C15H20N2S: calc (%): C 69.14, H 7.79, N 10.72,
DOI: 10.1039/C6CE02619B
S 12.35; found (%): C 69.17, H 7.75, N 10.71, S 12.37.
1-(4-Methoxyphenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione
(4).
Red
crystalline solid; Yield; 87%, Rf: 0.47; m.p: 163-164°C; IR (neat): 3355 (NH), 3045 (=C-H
1
stretch), 1700 (CS-NH), 1585 (C=C), 1301 (C-N): H-NMR (CDCl3, 300MHz): δ 7.81 (s, 1H,
N-H), 7.65-6.17 (m, 5H, Ar-H), 4.61 (s, 1H, Csp2-H), 3.71 (s, 3H, Ar-OCH3), 1.64 (s, 3H,
Csp2-CH3) 1.24 (s, 3H, CH3), 1.21 (s, 3H, CH3); 13C-NMR (CDCl3, 75MHz): δ 186.5 (CSNH),
137.9 (-C=C-), 134.7, 126.3, 121.9, 120.2, 111.2 (-H-C=C-), 57.9 ((CH3)2-C-), 54.6 (Ar-
OCH3), 33.8 ((CH3)2-), 32.4 (-C-CH3). LC-MS (m/z) %: [M+H]+ 263.6 (100%). Elemental
analysis C14H18N2OS: calc (%): C 64.05, H 6.96, N 10.64, O 6.15, S 12.21; found (%): C 64.03,
H 6.93, N 10.66, O 6.16, S 12.20.
Instrumentation. Melting points were determined using a Gallenkamp melting point apparatus
(MP-D) and are uncorrected. Infrared spectra were recorded using a Shimadzu IR 460 as KBr
1
pellets. H-NMR spectra were obtained using a Bruker 300 NMR MHz spectrometer in
13
deuterated solvents using TMS as an internal reference. CNMR spectra were obtained by (75
MHz) NMR spectrometer in deuterated solvents. MS were recorded using an EI source (70 eV)
on Agilent technologies 6890N (GC) and an inert mass selective detector 5973 mass
spectrometer. Gaseous helium was used as mobile phase with the pressure in the column head
equal to 100 kPa. The column used was a 19091J-433 HP-5 of 30 m x 0.32 mm x 0.25 mm film
thickness. Approximately 1 µL volume of the compounds dissolved in CHCl3 or acetone were
chromatographed under the following conditions: the injection temperature was 200 ºC, the
initial column temperature (70 ºC) was held for 2 min, then increased to 200 ºC at 10 ºC/min
and held for 4 min after elevated to 250 ºC at 10 ºC/min and held for 2 min more. In the
spectrometer the source was kept at 200 ºC. Thin layer chromatography (TLC) was conducted
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on 0.25 mm silica gel plates (60 F254, Merck). Elemental analyses were conducted using
DOI: 10.1039/C6CE02619B
CHNS 932 LECO instrument.
X-ray data collection and structure refinement. The crystal and refinement data for
compounds 1-4 are listed in Table 1. Data were collected at 130(2) K on a Bruker AXS
SMART APEX diffractometer using MoK radiation. Structure solved by direct methods and
full-matrix least-squares refinement on F2 by using SHELX.26 All non-hydrogen atoms were
refined anisotropically, and all H atoms were derived from difference maps, then placed at
idealized positions and then refined using the riding model. Methyl-H atoms were allowed to
rotate but not to tip. The ring puckering parameters and geometric parameters of -stacking
were calculated with PLATON for Windows Taskbar v1.17.27 Molecular structures were
plotted using Olex2,28 and the packing diagrams were generated using MERCURY.29
Full crystallographic data have been deposited with the Cambridge Crystallographic
Data Centre (CCDC-1504146, 1504147, 1504148, 1504149 for 1-4, respectively). Enquiries for
data can be directed to: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
UK, CB2 1EZ or (e-mail) deposit@ccdc.cam.ac.uk or (fax) +44 (0) 1223 336033.
Table 1. Crystal data and structure refinement for compounds 1-4.
(1)
(2)
(3)
(4)
Empirical formula
Formula weight
Temperature / K
Crystalsystem
C13H15ClN2S
266.78
130(2)
monoclinic
P21/c
C13H14Cl2N2S
301.22
130(2)
monoclinic
P21/c
C15H20N2S
260.39
130(2)
monoclinic
P21/n
C14H18N2OS
262.36
130(2)
triclinic
P-1
Spacegroup
Unit cell dimensions
a =14.214(2)Å
b =9.8017(14) Å
c =19.392(3)Å
a =12.072(4)Å
b =7.010(2)Å
c =17.035(5)Å
a =12.228(3)Å
b =8.896(2)Å
c =14.798(4)Å
a =8.729(3)Å
b =9.683(3)Å
c =10.503(4)Å
= 64.578(5)o
= 78.685(6)o
=63.892(6)o
719.9(4)
2
= 95.548(4)o
= 101.402(7)o
= 113.166(6)o
Volume / Å3
Z
2689.0(7)
8
1413.2(7)
4
1480.1(6)
4
ρcalc. / mg mm‐3
μ / mm‐1
F(000)
1.318
0.419
1120
1.416
0.520
624
1.169
0.204
560
1.210
0.216
280
8

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Crystal size / mm3
Theta range for data collection 1.44 to 27.87°
0.32 x 0.16 x 0.12
0.23 x 0.11 x 0.04 0.38 x 0.06 x 0.03 0.48 x 0.21 x 0.04
View Article Online
1.72 to 27.88°
-15 ≤ h ≤ 15
-9 ≤ k ≤ 9
1.84 to 27.88°
-15 ≤ h ≤ 16
-11 ≤ k ≤ 11
-19 ≤ l ≤ 18
13456
2.1D5OtoI: 1207.1.01309°/C6CE02619B
-11 ≤ h ≤ 8
-12 ≤ k ≤ 11
-13 ≤ l ≤ 13
5079
Index ranges
-18 ≤ h ≤ 18
-12 ≤ k ≤ 12
-25 ≤ l ≤ 25
24935
-22 ≤ l ≤ 21
12844
Reflections collected
Independent reflections
6406 [R(int) =
0.057]
3377 [R(int) =
0.089]
3524 [R(int) =
0.100]
3133 [R(int) =
0.067]
Data/restraints/parameters
Goodness-of-fit on F2
6406/0/309
0.934
3377/0/164
1.008
3524/0/168
0.765
3133/0/167
0.824
Final R indexes [I >2σ (I)]
R1 = 0.0499
wR2 = 0.1064
R1 = 0.0537
wR2 = 0.1075
0.563 / -0.371
R1 = 0.0544
wR2 = 0.0865
0.376 / -0.327
R1 = 0.0522
wR2 = 0.0852
0.241 / -0.268
Largest diff. peak/hole / e Å-3 0.569/ -0.379
Topological analysis. Periodic calculations were performed at the B3LYP/6-31G(d,p) level
with Crystal14 code.30 Using the experimental estimations as the starting point, the coordinates
of the hydrogen atoms in the crystal were optimized to minimize the B3LYP/6-31G** crystal
energy with heavy atom coordinates and cell parameters fixed at their experimental values. The
topology of the resulting electron density was then analyzed using the TOPOND14 code.31,32
For consistency with the periodic results, molecular and supramolecular electron densities were
also analyzed with TOPOND98 from calculations performed with Crystal98 using geometry
optimized with Crystal09.
Lattice and interaction energies. Lattice energy and intermolecular interaction energies for
specific molecular pairs were calculated using the CLP (Coulomb–London–Pauli) approach
implemented in the PIXEL program package.33, 34
Hirshfeld surface calculations. Hirshfeld surfaces and their associated two-dimensional
fingerprint plots35-38 were plotted using CrystalExplorer3.0 software.39 The dnorm (normalized
contact distance) surface and the breakdown of two-dimensional fingerprint plots were used for
decoding and quantifying intermolecular interactions in the crystal lattice. The fingerprint plots
can be decomposed to highlight particular atom pair close contacts,40 which overlap in the full
fingerprint. The dnorm is a symmetric function of distances to the surface from nuclei inside and
outside the Hirshfeld surface (di and de, respectively), relative to their respective van der Waals
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radii. 3D dnorm surfaces were mapped over a fixed color scale of -0.135 au (red)D–OI0: 1.04.160039/ÅC6CaEu02619B
(blue). The 2D fingerprint plots were displayed by using the translated 0.6–2.6 Å range, and
including reciprocal contacts. Electrostatic potentials on 0.008 e/au3 isosurfaces were calculated
at the HF/6-31G* level by using Tonto program41 integrated into CrystalExplorer. 3D-
deformation densities were plotted over the electron density isosurface (0.008 e/au3), charge
depleted (CD) and charge concentrated (CC) regions were colored in red and blue, respectively.
The similarity/dissimilarity between the structures was evaluated using XPac2.0,42
which allows identify and compare ‘‘supramolecular constructs’’ (SC) for pair of structures
with the same space group and similar cell dimensions. The SC are sub-components of
complete crystal structures of 0D, 1D (row of molecules match), 2D (layer of molecules match)
and 3D similarity (isostructural systems). Furthermore, the XPac method establishes the
dissimilarity index 'x' and the stretch parameter D as a measure of how far two crystal
structures differ from perfect geometrical similarity.
3. Results
3.1-Conformational Analysis
Molecular structures for compounds 1-4 are shown in Figures 1. In compound 1 there are
two independent molecules (A and B) in the asymmetric unit. An overlay diagram of the
molecules shows that the molecule A is virtually super-imposable upon the molecule B (Figure
S1, ESI), and the r.m.s deviations with and without inversion are 1.712 and 0.54 Å,
respectively, matching all non-H atoms. The major difference between the matched molecules
is found in the twist of the axial-CH3 with respect to C-Cl group, C107-C101…C114-Cl1 and
C207-C201…C214-Cl2 pseudo-torsion angles being -172.8(2) and -3.4(2)o for molecules A and
B, respectively. These results indicate that the axial-CH3 and C-Cl groups lie on opposite sides
of the heterocyclic plane in molecule A, and on the same side in molecule B.
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DOI: 10.1039/C6CE02619B
Figure 1. Views of the molecular structures of compounds 1-4 (two independent molecules, A
and B, for compound 1). Displacement ellipsoids are drawn at the 50% probability level.
Atoms numbering are given and H-atoms are omitted for clarity.
In all structures rings are twisted each other around the N2-C(Ph) bond. The mean planes
of the heterocyclic rings through four coplanar atoms make dihedral angles of 87.0(1)
(average), 85.4(1), 87.7(1) and 83.6(1)° with the benzene ring for compounds 1-4, respectively,
44
as found in other families of 3,4-dihydropyrimidine-2(1H)-thione/one derivatives.43,
However, the benzene ring is equatorial in structures 1-4, and axial in the referred
compounds,43, 44 leading to extended and folded molecular conformations, respectively.
The ring puckering parameters45 and the endocyclic torsion angles for the pyrimidine ring
are shown in Tables S1 and S2 (ESI).
3.2-Crystal structures: a topological description
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A brief description of crystal structures of compounds 1-4 based on the main close shell
DOI: 10.1039/C6CE02619B
interactions characterized from an AIM topological analysis of the corresponding electron
densities follows. The strategy consists in associating substructures of growing dimensionality
with interactions of decreasing strength, using at this respect the criterion based on the values at
the critical point of the electron density and the positive curvature of the Laplacian.46
The basic structural block in compound 1 is set up from two molecules that are linked
through two N–H∙∙∙S interactions (I and II in Table S3, ESI, and Figure 2), these being the most
relevant from the topological view point. The computed H···S distances and N–H···S angles
are 2.42/2.60 Å and 161/146º, for the two molecules (A/B) within the asymmetric unit,
respectively (see Table S3), in qualitative good agreement with the experimental data
(2.54/2.71 Å and 162/147º). Molecules in the pair are also linked each other by a Hme∙∙∙S
interaction (VII). Connections between pairs through four S∙∙∙HR interactions (III, IV, VI, and
VIII) give rise to infinite chains along a axis direction (see Figure 2). Cl∙∙∙Hme interactions (V)
acting between chains in two different directions complete the main three dimensional
interaction network.
Figure 2. (a) Chain of pseudo-centrosymmetric pairs of molecules along a axis direction; (b)
consecutive shackles of three chains in the crystal structure of compound 1.
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a
IV
I
III
VIII
VI
II
(a)
V
V
(b)
In compound 2 molecules are linked through one N–HS, two HRS and one HmeS
interactions (I, II, III and IV in Table S4, ESI, and Figure 3) giving rise to infinite chains along
b axis direction. Chains linked each other through pairs of HmeS interactions (VI in Table S3,
ESI, and Figure 3) form layers parallel to (1 0 0). The main three dimensional interaction
network is completed by Cl2Cl2 interactions (V) connecting layers each other (see Figure 3).
The computed dCl···Cl distance 3.38 Å, in perfect agreement with the experimental value.
Figure 3. (a) b axis direction view of a chain; (b) b axis direction view of two layers of
compound 2.
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DOI: 10.1039/C6CE02619B
III
I
II
IV
b
VI
(1 0 0)
a
c
V
The basic structural blocks of compounds 3 are centrosymmetric molecular pairs whose
molecules are linked through a pair of rather strong N–H∙∙∙S interactions, geometrically
characterized by dH···S and D–H∙∙∙S of 2.37 Å and 164º, respectively (I in Table S5 ESI, and
Figure 4). Molecules in a pair are also linked each other by a pair of Hme∙∙∙S interactions (IV).
Connections between molecular pairs through pairs of S∙∙∙HR interactions (II) give rise to
infinite chains along [1 1 1] (see Figure 4). On the other hand, a second set of S∙∙∙HR
interactions (III) link centrosymmetric pairs in infinite chains along b axis direction.
Combination of the two chain kinds originates layers parallel to (2 0 2)
.
Figure 4. (a) View along a direction perpendicular to (2 0 2) of infinite chains along [1 1 1]
and along b axis; (b) Layer view along b axis direction for compound 3.
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DOI: 10.1039/C6CE02619B
b
III
II
[1 1 1]
I
IV
(2 0 2)
c
a
For compound 4, the basic substructures are also the centrosymmetric molecular pairs
whose molecules are linked through a pair of NH∙∙∙S interactions (computed dH···S and D–H∙∙∙S
values are 2.42Å and 159º, respectively, see I in Table S6, ESI, and Figure 5). Connections
between such molecular pairs through pairs of O∙∙∙Hme interactions (II) give rise to infinite
chains along a axis direction (see Figure 5). Pairs of S∙∙∙HR interactions (III) link chains each
other originating layers parallel to (0 0 1). Connection between neighbor layers through O∙∙∙Hme
interactions (IV) completes the main three dimensional interaction network.
Figure 5. (a) Infinite chain along a axis direction; (b) layer view along a axis direction of
compound 4.
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DOI: 10.1039/C6CE02619B
II
I
a
b
c
IV
{0,0,1}
III
3.3- Structural motifs and interaction energies
For each crystal under consideration lattice energy and intermolecular interaction
energies for specific molecular pairs were calculated using the CLP (Coulomb–London–Pauli)
approach which enables partitioning of the total energy into their coulombic, polarization,
dispersion and repulsion contributions. These results are summarized in Table 2.
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Table 2. Lattice energies (kJ mol−1) partitioned into coulombic (Ecoul), polarization (Epol),
View Article Online
DOI: 10.1039/C6CE02619B
dispersion (Edisp) and repulsion (Erep) components for 1–4 and related compounds.
Compound
Ecoul
Epol
Edisp
Erep ETOT
-75.6 -38.2 -148.6 124.7 -137.7
-71.1 -38.9 -161.3 121.8 -149.4
-72.2 -40.6 -138.2 115.3 -135.7
-86.4 -41.4 -143.8 123.1 -148.4
-82.1 -40.5 -151.8 130.3 -144.2
-74.8 -40.6 -154.1 122.8 -146.7
1
2
3
4
IJUGEA
DUNZIW
EVEWIM
VAGSUR
IMARIY
PUJYID
-66.3 -32.7 -119.0
91.7 -126.2
-68.9 -37.7 -127.3 102.2 -131.8
-74.3 -41.8 -133.1 116.0 -133.1
-66.7 -35.5 -141.5 110.7 -133.0
FAXVOQ-I -69.9 -35.5 -130.8 105.0 -131.3
FAXVOQ-II -65.3 -29.8 -132.2 97.5 -129.8
Detailed diagrams of crystal packing for structures 1-4 are shown in Figures S2-S5 (ESI)
respectively, and the geometry of relevant intermolecular hydrogen bonds is listed in Table 3
(Column 4) following the distance criteria47 for crystal packing analysis of supramolecular
motif. In order to compare the packing modes of 1-4 with similar structures, a search of the
crystal structural database (CSD,48 ConQuest 1.1949) for 4,4,6-trimethyl-3,4-
dihydropyrimidine-2(1H)-thione moiety was undertaken, yielding eight hits: two structures
correspond to the meta (IJUGEA)50, 51 and para (DUNZIW)9 isomers of compound 1. Other
two related structures contain mono-substituents fluorine (EVEWIM)52 and bromine
(VAGSUR)53 on the phenyl ring, while two structures are the ortho-methyl (IMARIY)25 and
meta–methyl isomers (PUJYID).10 The unsubstituted compound is present as orthorhombic
(FAXVOQ-I)23 and triclinic (FAXVOQ-II)24 polymorphs. Relevant data for these structures are
also included in Table 3.
Table 3. Interaction energies (ETOT) partitioned into coulombic, polarization, dispersion and
repulsion contributions (kJ mol−1) for various molecular pairs in 1–4 and related compounds.
Compound
Symmetry
Involved
d(H· ··
A),
Centroid
Ecoul
Epol
Edisp
Erep
ETOT
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Interactions
N11-H1A· ··S2,
N21-H2A· ··S1
C110-H11A· ··S1
C207-H20G· ··Cl1
Cg· ··Cg
N1-H1A· ··S1,
C9-H9A· ··S1
C6-H6C· ··Cl1
Cl1· ··C12
distance
7.534
D—H· ··A
DOI: 10.1039/C6CE02619B
x,½-y,-½+z
2.539(1), 162
2.707(1), 147
2.901(1), 168
2.788(1), 172
4.104(1)a
-66.5
-38.4 -38.1
74.8 -68.2
1
2
-x,1-y,1-z
x,-1+y,z
-x,2-y,1-z
-x,-½+y,½-z
5.774
8.532
7.746
7.135
-28.4
-6.2
-25.0
-45.0
-17.6 -44.4
-3.2 -20.4
-9.5 -38.0
-25.5 -40.7
42.6 -47.8
14.0 -15.9
29.5 -43.0
50.2 -61.0
2.65(2), 163
2.931(1), 161
3.179(1), 128
3.985(1)b
1-x,½+y,½-z
1-x,-½+y,½-z
1-x,1-y,-z
1-x,2-y,2-z
-½+x,1.5-y,-½+z
-x,2-y,-z
1-x,1-y,-z
-1+x,y,z
2-x,-y,1-z
2-x,2-y,1-z
1-x,2-y,-z
1-x,y,½-z
6.841
6.841
11.536
7.781
7.606
8.154
6.043
8.729
12.869
7.944
5.773
8.299
11.476
7.628
8.814
7.920
7.501
6.689
7.347
7.586
7.528
-5.0
-5.0
-2.8
-2.5 -32.7
-2.5 -32.7
14.8 -25.4
14.8 -25.4
9.1 -4.1
Cl2· ··Cl2
3.381(2)c
-1.6
-8.8
N1-H1A· ··S1
C5-H5A· ··S1
N2-H2· ··S1
2.48 (2), 164
2.989(1), 128
2.529(1), 160
2.929(1), 154
2.47(1), 154
2.671(2), 130
2.583(1), 162
3.021(1), 120
2.59(3), 169
3.049(1), 158
2.571(1), 162
2.649(2), 153
2.426(3), 170
2.981(3), 127
3.072(2), 123
2.54(3), 169
2.938(1), 130
2.621(1),151
2.596(1), 163
2.608(1), 158
2.636(1), 167
2.968(1), 155
2.707(1), 148
2.921(1), 166
-80.7
-14.1
-79.1
-28.1
-15.0
-6.7
-73.6
-27.6
-68.4
-3.0
-69.8
-8.5
-75.4
-13.3
-3.6
-52.2 -40.1
-8.0 -28.4
-47.0 -39.5
-14.4 -40.4
-5.7 -24.8
-2.5 -10.8
-43.2 -38.1
-14.1 -46.9
-45.0 -37.5
-1.8 -12.7
-41.2 -36.5
-2.6 -15.1
-48.7 -38.5
-7.2 -27.1
-1.7 -24.2
-52.8 -39.6
-8.3 -27.5
-40.2 -37.1
94.3 -78.7
22.4 -28.2
87.5 -78.0
34.5 -48.5
17.7 -27.8
8.7 -11.2
81.3 -73.6
41.6 -47.0
79.9 -71.0
7.5 -10.0
77.4 -70.0
7.5 -18.7
87.4 -75.1
20.6 -27.1
11.2 -18.3
94.6 -78.1
24.5 -26.8
72.5 -66.2
3
4
C3-H3A· ··S1
C12
-H12A· ··O1
C7 H7B· ··O1
-
N1-H1A· ··S1
C9-H9· ··Cl1
N3-H1· ··S1
C15-H15· ··Cl1
N1-H1A· ··S1
C3-H3A· ··F1
N2-H1· ··S1
C5-H8· ··S1
C7-H11· ··Br1
N2-H2· ··S1
C9-H9A· ··S1
N1-H1N· ··S2,
N3-H3N· ··S1
N2-H2A· ··S2,
N4-H4A· ··S1
C12-H12A· ··S1
N2-H2A· ··S1
C13-H13A· ··S1
IJUGEA
DUNZIW
EVEWIM
VAGSUR
1.5-x,1.5-y,2-z
1-x,-y,1-z
-1+x,y,z
-x,-y,-z
x,½-y,½+z
1-x,½+y,½-z
1-x,1-y,-z
½+x,½-y,½+z
x,y,z
-80.4
-15.6
-61.4
IMARIY
PUJYID
x,y,z
7.292
-66.5
-38.9 -35.5
69.1 -71.7
FAXVOQ-I
-½+x,y,½-z
1-x,1-y,2-z
x,-1+y,z
5.063
7.256
8.649
-22.8
-61.4
-10.2
-13.5 -52.5
-31.5 -36.6
-4.8 -17.7
43.4 -45.5
64.3 -65.2
12.7 -20.1
FAXVOQ-II
a Inter-centroid distance, Cg is the centroid of C109-C114 ring; bCl···C distance; bCl···Cl distance.
3.4- Hirshfeld surface analysis
For a better comprehension of the crystal packing for compounds 1-4, a complete
description of the main intermolecular interactions using Hirshfeld surface analysis have been
carried out. Figure 6 shows surfaces mapped over the dnorm property, in a similar orientation.
The surfaces are shown as transparent to allow visualization of the molecules. Contacts with
distances equal to the sum of the van der Waals radii are represented as white regions and the
contacts with distances shorter than and longer than van der Waals radii are shown as red and
blue colors, respectively.
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Figure 6. Views of the Hirshfeld surfaces mapped with dnorm in two orientations: front view
DOI: 10.1039/C6CE02619B
and back view (180o rotated around the vertical axis of the plot). Close contacts are labeled as
follows: (1) S···H, (2) Cl···H, (3) H···H, (4) C···H, (5) O···H, (6) C···C, and (7) Cl···Cl.
A close examination with Shape index and Curvedness, which are Hirshfeld surface
properties generally used to identify planar stacking arrangements,37 was performed. The
pattern of touching red and blue triangles on the shape index surfaces is characteristic of -
stacking.37 This type of interaction is also evident as relatively large and green flat regions
delineated by blue circles on the corresponding Curvedness surfaces.40
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The full two-dimensional fingerprint plots and decomposed fingerprint plots of the main
DOI: 10.1039/C6CE02619B
intermolecular interactions are depicted in Figure 7, and the relative contributions of individual
intermolecular interactions to the Hirshfeld surface area of structures 1-4 and full two-
dimensional fingerprint plots for eight related compounds are shown in Figures S7 and S8,
respectively (ESI). For IJUGEA, our data are in close agreement with the Hirshfeld surface
analysis recently reported by Babashkina et al.51
Figure 7. Full and decomposed 2D fingerprint plots of intermolecular contacts for 1-4.
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3.5- Electrostatic potential and 3D deformation density
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The surprising energy results about the relevance of the coulombic contributions found in
DOI: 10.1039/C6CE02619B
the studied structures prompted us to enhance the study of intermolecular interactions by
analyzing the electrostatic potential (ESP) maps.54 The ESP maps of compounds 1-4 are
presented in Figures S9a-S12a in the ESI, and the magnitudes of electrostatic potentials for all
twelve structures are given in Table S8 (ESI). In general, the ESP maps show an asymmetric
charge distribution in the molecules, generating relevant polarization effects as reflected by
high dipole moments ranging from 4.87 D for VAGSUR to 5.86 D for compound 3 (Table S8).
4-Discussion
The dihydropyrimidine-2(1H)-thione rings of the studied species adopt a puckered
conformation, and a description based on the canonical conformations for six-membered rings
is given. In structure 1 (Mol. A), the pyrimidine ring adopts an intermediate conformation
2
between a E and 2S1 screw-boat form, whereas in structures 1 (Mol. B) and 2 an E2 envelope
conformation with C101 and C1 atoms as flap atoms, respectively, is adopted. In compound 3
the heterocyclic ring adopts a conformation which is best described as an intermediate between
a 6S1 screw-boat and 6H1 half-chair form. An E4 envelope with apex at C10 atom for structure 4
is observed. The validity of these descriptions is borne out by the corresponding endocyclic
torsion angles (Table S2, ESI). The thionyl and 4-methyl groups all have equatorial
orientations, while the two 6-methyl groups present pseudo-equatorial orientations.
The similarity/dissimilarity between the twelve closely related structures was
quantitatively analyzed.55 The pair of ortho-substituted VAGSUR/IMARIY compounds
revealed the presence of 3D-SC showing a high degree of isostructurality as reflected by 'x' and
D values of 2.6 and 0.13 Å, respectively. The similarity/dissimilarity was also examined for the
pairs 3/IMARIY and 3/VAGSUR structures, which showed SC with minor but similar degree
of isostructurality, as reflected by (‘x’, D) values of (8.2, 0.49 Å) and (8.4, 0.36 Å),
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respectively. In spite of the same space group and relative similar cell dimensions for PUJYID
DOI: 10.1039/C6CE02619B
and FAXVOQ-I structures, no significant structural similarity was found in this pair of
compounds. No other pair of compounds presents isostructurality.
The topological analysis of the electron densities highlights the preponderance of N–H∙∙∙S
interactions in the stabilization of the crystal packing of the whole series of compounds here
studied. In compound 1, two N–H∙∙∙S interactions are observed for the two independent
molecules in the asymmetric unit. For compounds 3 and 4 centrosymmetric molecular pairs are
observed whose molecules are linked through such a pair of N–H∙∙∙S interactions. Furthermore,
non classical Hme∙∙∙S and S∙∙∙HR are significant contributors in the stabilization of the
dihydropyrimidine-2(1H)-thione synthon, as observed for compounds 1-4, and Cl∙∙∙Hme and
Cl···Cl are also observed for the chlorinated species 1 and 2.
Lattice energy values (Table 2) show that the dispersion energy (Edisp) is the major
contribution towards the crystal stabilization for all compounds as generally expected for
organic species, with similar percentages ranging from 53.0 % in compound 4 to 59.5 % in
compound 2. However, the coulombic component (Ecoul) is very significant for all structures
representing the second higher contributor ranging from 26.2 % (compound 2) to 31.8 %
(compound 4). A complementary description is obtained when the results of intermolecular
energy calculations for selected molecular pairs are considered, as shown in Table 3. The
occurrence of N–H···S hydrogen bonds forming
motifs is a common feature for all
structures except in compound 2 (Figures S2 and S3, ESI), generating molecular pairs with
highest energy stabilization (from -78.7 kJ/mol for compound 3 to -61.0 kJ/mol for compound
2) in comparison with molecular pairs involving other types of contacts. PIXEL energies also
reveal that the highest contribution towards the crystal stabilization in all compounds comes
from coulombic component (40.5-47.8 %) only for molecular pairs involving N–H···S
interactions, while for remaining interactions the dispersion energy is dominant.
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The four chloro-substituted compounds here analyzed (1, 2, IJUGEA and DUNZIW)
DOI: 10.1039/C6CE02619B
present the higher lattice energy values, indicating the relevant role of the chlorine atom in the
crystal stabilization of these compounds. In these molecules, weak C–H···Cl hydrogen bonds
are formed, creating dimers where the cohesive energy is ranging from -10 kJ/mol for
DUNZIW to -25.4 kJ/mol for structure 2. On the other hand, VAGSUR and IMARIY
compounds present similar dispersion (-127.3 and -133.1 kJ/mol) and total lattice energies (-
131.8 and -133.1 kJ/mol). In the case of FAXVOQ-I and FAXVOQ-II polymorphic forms, the
cohesive energy in the lattice is very similar, being the former more stable only in 1.5 kJ/mol.
This suggests that changes in the space symmetry do not alter the total lattice energy of the
unsubstituted compound.
Crystal packing of structure 1 is also characterized by the appearance of C–H···S
hydrogen bonds generating
motifs (-48.7 kJ/mol), which alternate with strong
ring patterns along the a-axis (Figure S2). In the case of structure 2, the lower coulombic
contribution of 40.5 % can be attributed to an alternated combination of N–H···S and C–H···S
hydrogen bonds forming weaker
dimers (Figure S3) in two different molecular pairs
rings
with the same pairing energy (-61.0 kJ/mol). Unlike remaining structures, the
involved in a pair molecular amounting up to 78.7 kJ/mol are interconnected by weaker C–
H···S hydrogen bonds in structure 3 (Figure S4, ESI), which are associated to a lower
intermolecular energy (-28.2 kJ/mol).
In structure 4, a
descriptor is also observed interacting through weak C–H···S
hydrogen bonds, as well as weak C–H···O hydrogen bonds due to the C7 atom in the molecule
at (x,y,z) acting as donor to the O1 atom of methoxy group in the molecule at (2-x,-y,1-z). This
interaction generates dimers (-11.2 kJ/mol) with the formation of
rings (Figure S5, ESI)
and long inter-centroid distance of 12.869 Å. Another molecular pair involves C-H···O
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hydrogen bonds with increased intermolecular energy (-27.8 kJ/mol) and shorter centroid
DOI: 10.1039/C6CE02619B
distance of 8.729 Å.
The Hirshfeld surface analysis is in sound agreement with the computed interaction
energy values. Thus, the large and red regions labeled 1 in Figure 6 are dominant in the dnorm
maps for all compounds, and represent H···S contacts attributed to N–H···S hydrogen bonds,
which form
cyclic dimers through the two larger and very close regions exhibiting
similar brightness as in structures 1, 3 and 4. In the case of structure 2, the two larger red spots
are apart to each other and exhibit different brightness, indicating the combined participation of
N–H and C–H donors where the sulfur atom acts as bifurcated acceptor. In compounds 1 and 2,
a pale blue to white spot labeled 2 on the front view of the surfaces shows Cl···H contacts
associated to weak C–H···Cl hydrogen bonds. In compound 1, distinctively to the others, a
small red region labeled 6 depicts the presence of C···C contacts indicating -stacking
interactions [characterized by Cg···Cg= 4.104(1) Å and slippage = 2.435(1) Å], providing
additional stabilization (-43.0 kJ/mol) to crystal packing (see also Figure S6).
In all structures, a significant presence of H···H, S···H and C···H contacts are found. The
H…H interactions are highlighted in the middle of scattered points in full 2D fingerprint maps,
with minimum values of (de + di) around 2.4 Å. As expected, the H···H contacts are associated
to molecular pairs with intermolecular energies (Table S7, ESI) lower than -15 kJ/mol for most
of structures, being the dispersive forces the highest contributor (56-93 %) towards the packing
stabilization, with Edisp values from -7.4 to -45.7 kJ/mol. The repulsion energy values are in the
range 3.1-27.3 kJ/mol.
The Cl···H/H···Cl interactions are present in the two chloro-substituted compounds (1-2).
In structure 1 two asymmetrical spikes appear in the fingerprint plot, which spread up to the
shorter distance of (de + di)  2.67 Å at bottom right region, and (de + di)  3.03 Å at top left
region, which indicate Cl···H/H···Cl contacts occurring between molecules A and B in the
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asymmetric unit. The fingerprint plot of 2 (de + di 3.10 Å) displays two symmetricalVieswhAartricple Online
DOI: 10.1039/C6CE02619B
spikes contributing 22.5 % to the Hirshfeld surface area. The contributions to the Hirshfeld
surface area due to Cl···H/H···Cl contacts are similar for monochloro-substituted compounds 1
(14.6 %) and IJUGEA (15.8 %, in good agreement with the value of 16.3 % reported in ref 51),
while significant Cl···C/C···Cl and Cl···Cl contacts are found for compound 2, comprising 5.1
and 3.7 %, respectively.
The molecular ESP for molecule A of structure 1 (Figure S9a, ESI) reveals a highly polar
molecule with a deep red region of strongly negative electrostatic potential (-0.082 au)
surrounding the S2 atom, and a complementary deep blue region of strongly positive
electrostatic potential (0.112 au) near the H1A hydrogen atom. These ESP values favor the
formation of strong N–H···S contacts in this structure, supported by the high intermolecular
energy value of -68.2 kJ/mol. In addition, an electronegative C–Cl group (-0.017 au on the
surface) and an electropositive C–H group (0.043 au) are responsible for the formation of
H···Cl contacts, which are electrostatically favored, and represent the weakest C207-
H20G···Cl1 hydrogen bond interaction (-15.9 kJ/mol) in the self-assembly of structure 1.
For the 2,3-di-chloro-substituted compound 2, high electropositive potential is observed
near the H-atoms involving N–H···S (0.174 au) and C–H···S (0.139 au) hydrogen bonds
(Figure S10a, ESI). These two intermolecular contacts are associated to a molecular pair with
the highest interaction energy (-61.0 kJ/mol). It is interesting to note the reduced
electronegative potentials of -0.027 and -0.022 au around the S1 atom in structure 2. This can
be explained considering that the sulfur atom participates as an acceptor in the formation of
four hydrogen bonds and the total negative charge is distributed around the periphery of the S1
atom.
The molecular ESP surface for structure 3 (Figure S11a, ESI) displays similar
electrostatic features to that in structure 1, with a deep red region of strongly electronegative
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potential (-0.086 au) surrounding the S1 atom, and a complementary deep blue area of strongly
DOI: 10.1039/C6CE02619B
electropositive potential (0.117 au) near the H1A hydrogen atom.
Like in structures 1-3, the ESP map of structure 4 (Figure S12a) shows strong N2–
H2···S1 hydrogen bonds (-78.0 kJ/mol) as result of the high electrostatic interaction (-
0.087/0.109 au) between complementary regions. Moreover, an electronegative O-atom and an
electropositive H7B hydrogen atom with lower potentials of -0.063 au and 0.018 au,
respectively, give rise to weaker C–H···O hydrogen bonds forming
motifs associated to
a molecular pair with minor interaction energy (-11.2 kJ/mol).
3D deformation density maps through the common N–H···S hydrogen bonds for
compounds 1-4 (Figures S9b-12b, ESI) and additionally the Cl···Cl halogen bond56 for
structure 2 (Figure S10b) were also calculated for a better comprehension of the attractive
nature in these interactions. It is clearly visible in all structures that the charge concentration
(CC) region around the S-atom is attracted towards the charge depleted (CD) region on the H-
atom of NH group in a neighbor molecule, confirming the formation of
cyclic dimers
through N–H···S hydrogen bonds. Finally, the map of structure 2 (Figure S10b) displays an
interaction between two CD regions representing Cl2···Cl2 halogen bond, associated with a
slightly attractive interaction (the ETOT is -4.1 kJ/mol, see Table 3). The characteristic
asphericity of the electron distribution around terminally-bonded chlorine atoms,57 reflects the
high repulsion component of the lattice energy (9.1 kJ/mol, see Table 3) for this molecular pair.
5-Conclusions
The crystal structures of four 4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione
derivatives were determined by single crystal X-ray diffraction. A complete investigation of the
crystal packing was performed, including a comparison with eight closely related structures.
Lattice energy determination indicates that the coulombic component has a relevant
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contribution (around 30 %) to the total energy for all compounds. In the saDmOeI: 10d.1i0r3e9c/Cti6oCnE0,2619B
intermolecular interaction energies of selected molecular dimers indicate maxima contribution
(40.5-47.8 %) towards the lattice stabilization coming from coulombic component. Topological
analysis and Hirshfeld surfaces give a visual three-dimensional picture of the nature of
intermolecular interactions in structures 1-4 highlighting the strongest C=S···H contacts. The
ESP and deformation density maps allowed a visual study on the electrostatic nature of
intermolecular N–H···S=C hydrogen bonds in the crystal stabilization.
The presence of halogen substituents, mainly Cl atoms, offers the possibility of
establishing further intermolecular interactions. The electrostatic potentials calculated for the
three types of hydrogen bonds observed in the crystal packing vary in the same way for both
chloro-substituted compounds, being highest for N–H···S hydrogen bond and lowest for C–
H···Cl hydrogen bond. This is a clear evidence of the relative strength of these interactions,
decreasing in the order N-H···S  C–H···S  C–H···Cl for compounds 1-4.
In summary, the nature of intermolecular interactions in crystal structures of
dihydropyrimidine derivatives was fully analyzed, and it can be useful for the prediction of
supramolecular motifs in this type of compounds. The occurrence of N–H···S=C hydrogen
bonds forming
motifs can be anticipated for the 3,4-dihydropyrimidine-2(1H)-thione
group. This interaction is governed by coulombic components with minor influence of the 1-
phenyl substitution.
Acknowledgments
ACF and MFE are members of the Carrera del Investigador of CONICET (República
Argentina). The Argentine authors thank the Consejo Nacional de Investigaciones Científicas y
Técnicas (CONICET), the ANPCYT (PICT-2130), and the Facultad de Ciencias Exactas,
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Universidad Nacional de La Plata for financial support. HP and MFE also thank DthOeI: 1P0.1r0o3g9/rCa6mCEa02619B
Redes (Ministerio de Educación, Argentina).
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