Combined DFT calculation, Hirshfeld surface analysis, and Energy framework study of non-covalent interactions in the crystal structure of (Z)-5-ethylidene-2-thiohydantoin determined by powder X-ray diffraction

Article abstract of DOI:10.1016/j.molstruc.2021.130361

The thiohydantoin core is used in the synthesis and development of new drugs. Furthermore, the study of these materials allows us to analyze the role that non-covalent interactions play in their supramolecular structure and how they can influence their pharmacological properties. Herein, a novel thiohydantoin compound, namely (Z)-5-ethylidene-2-thiohydantoin was synthesized and characterized by FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopy. Its crystal structure was determined and refined by powder X-ray diffraction techniques. This material crystallizes in the monoclinic system with space group P2₁/c, Z=4. The crystal packing is controlled by N–H···O, N–H···S and C–H···O hydrogen bond interactions, forming infinite two-dimensional sheets with graph-set motifs R²₂(8), R¹₂(7), and R⁶₆(26). NCI calculations, Hirshfeld surface analysis, and the Energy framework study reproduce in good agreement the crystal packing exhibited by the X-ray diffraction study.

Full text of DOI:10.1016/j.molstruc.2021.130361

Journal of Molecular Structure 1236 (2021) 130361
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Combined DFT calculation, Hirshfeld surface analysis, and Energy
framework study of non-covalent interactions in the crystal structure
of (Z)-5-ethylidene-2-thiohydantoin determined by powder X-ray
diffraction
Gerzon E. Delgadoa,b,∗, Asiloé J. Moraa, Luis E. Seijasc, Luis Rincónd, Gustavo Marroquine,
Jonathan Cisternab, Alejandro Cárdenasf, Iván Britob
a Laboratorio de Cristalografía, Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida 5101, Venezuela
b Departamento de Química, Facultad de Ciencias Básicas, Universidad de Antofagasta, Campus Coloso, Antofagasta 1240000, Chile
c Laboratorio de Procesos Dinámicos en Química, Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida 5101, Venezuela
d Grupo de Química Computacional y Teórica and Instituto de Simulación Computacional, Universidad San Francisco de Quito, Quito 170901, Ecuador
e Escuela Superior de Ingeniería Química e Industrias Extractivas, Instituto Politécnico Nacional, Zacatenco 07738, Ciudad de México, México
f Departamento de Física, Facultad de Ciencias Básicas, Universidad de Antofagasta, Campus Coloso, Antofagasta 1240000, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
The thiohydantoin core is used in the synthesis and development of new drugs. Furthermore, the study
of these materials allows us to analyze the role that non-covalent interactions play in their supramolecu-
lar structure and how they can influence their pharmacological properties. Herein, a novel thiohydan-
toin compound, namely (Z)-5-ethylidene-2-thiohydantoin was synthesized and characterized by FT-IR,
1H-NMR, and 13 C-NMR spectroscopy. Its crystal structure was determined and refined by powder X-ray
diffraction techniques. This material crystallizes in the monoclinic system with space group P21/c, Z=4.
The crystal packing is controlled by N–H···O, N–H···S and C–H···O hydrogen bond interactions, forming
infinite two-dimensional sheets with graph-set motifs R22(8), R12(7), and R66(26). NCI calculations, Hir-
shfeld surface analysis, and the Energy framework study reproduce in good agreement the crystal packing
exhibited by the X-ray diffraction study.
Received 17 January 2021
Revised 4 March 2021
Accepted 18 March 2021
Available online 26 March 2021
Keywords:
Powder X-ray diffraction
thiohydantoin
hydrogen bond patterns
NCI calculations
Hirshfeld surface analysis
Energy framework
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
Both of these heterocycles, thiohydantoins and hydantoins, are
commonly used as templates in combinatorial chemistry libraries
Thiohydantoins and hydantoins are five-member heterocyclic
compounds with a very reactive nucleus, which provides four pos-
sible points of diversity [1,2]. Due to the biological importance of
this class of compounds, there has been interested in the devel-
opment of new strategies for the synthesis of substituted hydan-
toins and thiohydantoins prepared more straightforwardly. Their
molecular and crystalline structure has been studied, in solution
and in the solid-state [3-5]. The biological activities of these mate-
rials have been known for a long time and are responsible for their
wide range of therapeutic properties [6,7]. The best-known hydan-
toin, phenytoin, is the most widely used antiepileptic drug [8,9].
In particular, in the case of thiohydantoin (2-thioxo-imidazolidin-
4-ones), the principal current interest comes from its recent appli-
cation for the treatment of prostate cancers [10,11].
[12], due to the possibility of forming simple building blocks to
generate supramolecular architectures mainly based on the diverse
and strong non-covalent interactions that can be formed. Precisely,
in biological systems constituted by amino acids and their deriva-
tives, the non-covalent interactions are key factors in their bi-
ological and chemical activity, particularly due to the formation
of hydrogen bond interactions [13]. Thiohydantoins and hydan-
toins structural motifs, therefore, are suitable to form excellent
supramolecular architectures through hydrogen bonds, which play
a key role in molecular recognition and crystal engineering [14,15].
On the other hand, single-crystal X-ray diffraction is the most
powerful technique for crystal structure determination of small
molecules. However, when the intrinsic nature of the material is
polycrystalline, or when a single crystal is not available, powder
X-ray diffraction is the crystallographic tool to be used [16].
In this work, in continuation of our ongoing interest in the
structural studies of thiohydantoin and hydantoin α-amino acid
∗
Corresponding author.
E-mail address: gerzon@ula.ve (G.E. Delgado).
https://doi.org/10.1016/j.molstruc.2021.130361
0022-2860/© 2021 Elsevier B.V. All rights reserved.

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
˚
˚
˚
a= 4.0310(5) A, b=16.087(3) A, c= 9.649(1) A, β= 95.00(1)° us-
ing the program Dicvol04 [24], with figures of merit: M20= 76.9
[25] and F20= 146.6(0.0038, 32) [26]. Evaluation of the system-
atic absences in the diffraction pattern indicated the space group
P21/c (No 14). The crystal structural solution was obtained by di-
rect methods using the program EXPO [27]. All nine non-hydrogen
atoms from the molecule were found in the E map of the best so-
lution proposed by the EXPO program. The hydrogen atoms were
placed in calculated positions. The model was refined by the Ri-
etveld method [28] using the GSAS-II program [29]. Bragg reflec-
tions were modeled using a pseudo-Voigt peak shape function [30],
and the background was fitted by the automatic interpolation of
10 points through the whole pattern. The powder pattern did not
show preferred orientation, as can be seen in the well-modeled
peaks in Fig. 2. Rotating the sample during data collection con-
siderably reduces this problem. Therefore it was not necessary to
apply this type of correction. Table 1 summarizes the crystal data,
intensity data collection, and refinement details for the title com-
pound (I). Experimental, calculated, and differences plot for the fi-
nal Rietveld refinement cycle for compound (I) are shown in Fig. 2.
Crystallographic data for the structure reported here have been
deposited with the Cambridge Crystallographic Data Centre (De-
position No. CCDC-1994886). These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data_request/cif. The Cambridge
Structural Database (CSD, version 5.42, November 2020) was used
for structure analysis [31].
Fig. 1. Synthesis of (Z)-5-ethylidene-2-thiohydantoin (I).
derivatives [17-23], we analyze a new thiohydantoin crystal, ob-
tained from natural amino acid. We analyze the molecular
a
and crystalline structure of the new compound (Z)-5-ethylidene-2-
thiohydantoin, which was obtained from conventional X-ray pow-
der diffraction data and refined by the Rietveld method. We con-
sider this a good opportunity where non-covalent interactions,
which exist within the crystal, can be discussed. The crystal three-
dimensional hydrogen-bond network is examined here using pow-
der X-ray diffraction. Furthermore, the nature of the non-covalent
interactions existing in the crystal is analyzed through several the-
oretical methods and theories as DFT solid-structure optimization
with NCI calculations, Hirshfeld surface and Energy framework
analysis, and the main geometric characteristics rendered by this
calculations were compared with those found from the crystallo-
graphic analysis.
2. Experimental Section
2.4. NCI calculations
2.1. Synthesis
The Non-Covalent-Index (NCI) is based on the analysis of the
electron density. This approach can highlight interactions on the
low density, low gradient regime, and allowed us to identify differ-
ent types of chemical interactions in terms of the electron density
and its reduced gradient of density [32,33].
All the reagents used were purchased from commercial suppli-
ers without further purification. Melting point determination was
recorded using the Barnstead 9100 Electrothermal digital melting
point apparatus. L-threonine (476.5 mg, 4.0 mmol) and NH4SCN
(304.5 mg, 4.0 mmol) were dissolved in a mixture of acetic an-
hydride (9 mL) and acetic acid (2 mL) (Fig. 1). This solution was
warmed, with agitation, to 100°C over 1 hour, and then cooled to
room temperature and stored in a freezer overnight. The resulting
brown solid was collected by filtration and washed with cold water
(m.p. 227-229°C).
The molecular crystals have different types of non-covalent in-
teractions that cannot be straightforwardly analyzed from direct
inspection of the atom’s position. The geometric characterization
constitutes the first phase in the description of non-covalent in-
teractions on the crystal structure, nevertheless, the relationship
on the kind or strength of these interactions is not free of con-
troversy [34]. So, the classification for the different types of non-
covalent interactions based on pairwise distances and van der
Waals radius could give systematics errors. Additionally, weak non-
covalent interactions, such as dispersion interactions cannot be
straightforwardly characterized by molecular orbital analysis. In
such cases, a complementary topological analysis for the derived
electron density is required. Many methods based on electron den-
sity have been proposed in recent years [35], as is the case of
the Atoms in Molecules (AIM) theory [36,37]. In this theory, topo-
logical properties of electron density ρ(r) can be employed for
the quantitative assessment of weak interactions [38-41]. Lapla-
cian of electron density can be written as the sum of contribu-
tions along the three principal axes of maximum variation, that is,
2.2. Spectroscopic characterization (FTIR, 1H-NMR, 13 C-NMR)
The FT-IR absorption spectrum was obtained as KBr pellet using
a Perkin-Elmer 1600 spectrometer. 1H and 13C NMR spectra were
determined on a Bruker Advance 400 model spectrometer, using
DMSO-d6 as solvent. FT-IR v (cm−1): 3233 and 3140 (N-H sp2),
2861 (C-H sp3), 1724 (C=O), 1673 (C=C), 1460 (C-N), 1186 (C=S).
1H-NMR (400 MHz): δ 12.06 (s, 1H, N3-H3), 11.93 (s, 1H, N1-H1),
5.73 (c, 1H, C6-H6), 1.85 (d, 3H, C7-H7. 13C-NMR (100 MHz): δ
178.0 (C2, C=S), 164.1 (C4, C=O), 131.8 (C5, C-C), 111.6 (C6, C-H),
12.5 (C7-CH3).
2.3. Powder X-ray diffraction
2
∇ (r) = λ1 + λ2 + λ3, where λi, are the eigenvalues of Hessian
Powder X-ray diffraction experiments were performed at room
temperature (295 K) using a Siemens D5005 diffractometer (40 KV,
30 mA) equipped with Ge<111> monochromated CuKα1 radiation
matrix. These eigenvalues allow the classification of critical points
according to their rank, ω, number of non-zero curvatures at the
critical point, and the sing of their algebraic sum of signs of the
Hessian eigenvalues λi, σ: (ω, σ). The bond critical point (3,-1)
(BCP) is the most important type of critical point in the charac-
terization of chemical interactions [34], there λ3 varies along the
inter-nuclear direction, whereas λ1 and λ2 vary in the plane per-
pendicular to λ3. Bonding interactions are associated with an elec-
tron density concentration in the inter-nuclear region. For cova-
˚
(λ = 1.54059 A). A small quantity of the sample was ground me-
chanically in an agate mortar and pestle. The resulting fine powder
was mounted on a flat sample holder covered with a thin layer of
petroleum jelly. The sample was spun about its normal at 15 r.p.m.
and step scanned from 5° to 60° in 2θ, with a step size of 0.02°
and counting time of 40 s. Quartz was used as an external stan-
dard.
2
lent interactions negative contributions dominate and ∇ (r) < 0,
The powder pattern revealed that the synthesized compound
(I) was a single-phase and was indexed in a monoclinic cell with
whereas for non-covalent interactions positive contributions domi-
2
nate and ∇ (r) > 0, with λ2 < 0. In the particular case of hydrogen
2

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Fig. 2. Final Rietveld refinement plot for (I). The vertical scale of the 20° and 42° portions of the profiles has been multiplied by a factor of 2 and 4, respectively.
Fig. 3. FT-IR spectra of (I).
bonds, the electron density accumulation in the interatomic region,
at BCP, is larger than the corresponding to van der Waals interac-
tions.
are localized, Pauli repulsion has little significance. In consequence
χ(r) → 0 and η(r) → 1, allowing us to highlight the regions where
electron localization occurs, which are associated with chemical in-
teractions [41]. The ELF function represents a measure of the elec-
tron localization. Within the ELF representation, it is possible to
find in a molecule two kinds of basins, core, and valence basins.
The first ones are surrounding the nuclei. The other type of basins
are characterized by the number of atomic valence shells in which
they participate, in other words by the number of core basins with
which they share a boundary, this is their synaptic order. In hy-
Another classical alternative for non-covalent interaction char-
acterization is the electron localization function (ELF) (eq 1), which
depends on the difference between the total kinetic energy and
the von Weizsäcker density functionals weighted by the Thomas-
Fermi kinetic energy density functional through the localization
index χ(r). This function yields the local excess of electron ki-
netic energy due to Pauli repulsion. In regions where electron pairs
3

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Table 1
Crystallographic data and experimental details for (I)
Chemical formula
C5H6N2OS
CCDC
1994886
Formula weight
Crystal system
Space group
142.19
Diffractometer
Siemens D5005
1.54059
5-60
˚
monoclinic
P21/c (N°14)
4.0307(3)
16.0744(9)
9.6457(8)
95.006(2)
622.6(1)
4
Radiation [A]
2θ range [°]
˚
a [A]
Step size (°)
0.02
˚
b [A]
Step time (s)
40
˚
c [A]
Structure determination
EXPO2014
Rietveld (GSAS-II)
0.040
β [°]
Refinement method
3
˚
V [A ]
Rexp
Rp
Z
0.031
−3
•
Dcal [g cm
]
1.517
Rwp
χ2
0.049
Temperature [K]
295
1.5
Rexp = 100 [(N-P+C) / ꢀw(yobs2)]1/2
Rp = 100 ꢀ|yobs - ycalc| / ꢀ|yobs
|
2
Rwp = 100 [ꢀw|yobs - ycalc
|
/ ꢀw|yobs|2]1/2
χ2 = [Rwp / Rexp
]
2
drogen bonds two valence basins appear, one disynaptic basin as-
sociated with the bond electron pair in the donating group D-H
and a monosynaptic basin associated with the acceptor lone pair.
The ELF allows us to define localization domains, which contain all
attractors bounded by an external isosurface with η(r) = f. Succes-
sive reductions of localiation domains, resulting from an increase
in the f value, will split the parent domain into several domains,
each one containing fewer attractors of the parent one. This split
occurs at turning points located in the separatrix of two basins,
originally involved in the parent domain. Ordering by increasing
the value of f has been successfully employed to evaluate the HB
strength [[40,42].
for each crystal [49]. The properties of the surface give informa-
tion about the intermolecular interactions in the crystal. Each point
on the Hirshfeld surface represents two distances: (1) the distance
from this point to the nearest external nucleus (de) and (2) the
distance to the nearest internal nucleus (di). Graphical plots of
the molecular Hirshfeld surfaces are mapped with the normalized
contact distance (dnorm), and these indicate regions of important
intermolecular interactions [50]. The value of the dnorm is repre-
sented by red, white, or blue when the intermolecular contacts
are shorter, equal, or longer to the van der Walls separation, re-
spectively. The normalized contact distance dnorm, defined in terms
of de, di, and VdW radii of the atoms, was calculated using Eq. 1,
where de and di are the distance from the Hirshfeld isosurface to
the nearest external and internal nucleus, respectively, and VdW is
the van der Waals radii of atoms taken from the literature [51].
η(r) = (1 + χ2(r))−1
(1)
di − rivdw
de − revdw
The recently non-covalent interaction (NCI) index developed by
Jhonson et al., use the reduced gradient (eq. 2) [32,33], in contrast
to AIM which reveals covalent and non-covalent interactions, NCI
identify the space regions where the non-covalent interactions take
place, with the advantage of mapping the reduced gradient isosur-
faces with a color scale based on electron density multiplied by
the design of the second eigenvalue of the Hessian, allowing the
dnorm
=
+
(3)
rivdw
revdw
The combination of de and di in the form of a 2D fingerprint
plot gives a summary of the intermolecular contacts in the crystal
[52]. The fingerprint plots enable observation of contributions from
different interaction types and it provides a valuable quantitative
analysis of the intermolecular interactions occurring in the crys-
tal structure. Moreover, quantification of energy framework ener-
gies is considered a powerful method for understanding the topol-
ogy of the overall interactions of molecules in the crystal. This
method allowed us to calculate and compare different energy com-
ponents, i.e. repulsion (Erep), electric (Eele), dispersion (Edis), polar-
ization (Epol), and total (Etot) energy based on the anisotropy of the
topology of pairwise intermolecular interaction energies.
identification of different interactions types, steric/repulsive (λ2
0), Van-der-Waals like (λ2 ≈ 0), and attractive (λ2 < 0).
>
s(r) = ∇ρ(r) / 2(3π2)1/3ρ4/3(r)
(2)
To study the non-covalent interactions experimentally observed
in the crystal structure, we used four structural models based
on the crystal structure coordinates and without further geome-
try optimizations, to represent the most important non-covalent
interactions in the crystal structure. The non-covalent interac-
tions were assessed by the analysis of the DFT-CAM-B3LYP-D3BJ/6-
311G++(d,p) [43,44] electron density ρ(r) topology employing the
Quantum Theory of Atoms in Molecule (QTAIM), the NCI-index
(reduced gradient of ρ(r)) and the Electron Localization Function
(ELF). For the QTAIM analysis, we use the AIMALL program [45],
while the NCI-index calculations were carried out with NCIPLOT
program [41] and the ELF calculations were carried out with Mul-
tiwfn program [46]. All the isosurfaces were build up with VMD
[47].
For the title compound, an analysis of the Hirshfeld surfaces
[48] was performed with the aid of CrystalExplorer17.5 software
[53]. The two-dimensional fingerprint plots were calculated for the
crystal, as were the electrostatic potentials [52]. The electrostatic
potentials were mapped on the Hirshfeld surfaces using the 6-
31G(d,p) basis set at B3LYP level of theory over a range of
0.002
au. The crystallographic information file (CIF) of (I) was used as
input for the analysis. For the generation of fingerprint plots, the
bond lengths of hydrogen atoms involved in interactions were nor-
˚
malized to standard neutron values (C-H = 1.083 A, N-H = 1.009
˚
˚
A, O-H = 0.983 A).
3. Results and Discussion
2.5. Hirshfeld surfaces
3.1. FT-IR and NMR spectroscopic characterization
Hirshfeld surfaces of molecules in a crystal structure are con-
structed based on the electron distribution, which is calculated as
the sum of spherical atom electron densities [48] and is unique
Spectroscopic studies confirm the molecular skeleton (see
Fig. 1) of (Z)-5-ethylidene-2-thiohydantoin (I). Fig. 3 shows the FT-
4

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Fig. 4. 1H-NMR spectra of (I).
Fig. 5. 13 C-NMR spectra of (I).
Table 2
IR spectra where N-H, C-H, C=O, C=C, C-N, and C=S absorption
bands in the regions of 3233 and 3140 cm−1, 2915 cm−1, 1724
cm−1, 1673 cm−1, 1460 cm−1, and 1186 cm−1, respectively were
observed.
˚
Hydrogen bonds geometry (A, °) for (I).
•••
•••
•••
•••
D–H A
D–H
A
D—H
H
A
D
A
(i)
(ii)
••
N1–H1 O4
0.860
0.860
0.960
2.000
2.550
2.400
2.854(5)
3.399(4)
3.352(5)
172
170
170
For (Z)-5-ethylidene-2-thiohydantoin (I) six signals are observed
in the 1H NMR spectra (Fig. 4) corresponding to N3-H3 in δ 12.64
(1H, s), C5-H5 in δ 4.57 (1H, d), C7-H methyl in δ 2.73 (3H, s), C8-
H8 in δ 2.43 (1H, m), C9-H methyl in δ 1.09 (3H, d) and C10-H
methyl in δ 0.77 (3H, d). The 13C NMR spectrum (Fig. 5) of (I) dis-
played eight resonances including a thiocarbonyl C2 δ 183.0, two
carbonyl group C4 δ 172.3 and C6 δ 169.7, C5 δ 66.7, C8 δ 29.0, C7
δ 27.3, C9 δ 17.4 and C10 δ 15.4. The COSY (Fig. 1S), HMBC (Fig.
••
N3–H3 S2
(iii)
••
C7–H7A O4
(i)
Symmetry codes:
(ii)
-1+x,½-y,-½+z
1-x,-y,1-z
(iii)
-1+x,½-y,-½+z
S2) and NOESY (Fig. S3) spectra confirm the Z configuration of the
present thiohydantoin (I).
5

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Table 3
Electron density topological properties in (3,-1) critical points found in structural models derived from
the crystal structure of (Z)-5-ethylidene-2-thiohydantoin.
2
Interaction
CP
ρ(r) (au)
∇ (r) (au)
λ2 (au)
H(r) (a.u)
Ellipticity
ELF∗
N1—H1…O4
N3—H3…S2
C7—H7A…O4
C6—H6…S2
S2…C7
H7B…H7C
N3…S2∗∗
N1…C4∗∗
O4…C5∗∗
C6…H7A∗∗
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
(3,-1)
0.01892
0.01380
0.01026
0.00407
0.00344
0.00307
0.00642
0.00529
0.00444
0.00291
0.09379
0.04152
0.03492
0.01056
0.01432
0.01181
0.01765
0.01812
0.01530
0.00947
-0.02365
-0.01283
-0.00961
-0.00275
-0.00122
-0.00219
-0.00250
-0.00194
-0.00119
-0.00126
0.00437
0.00173
0.00136
0.00520
0.00091
0.00074
0.00059
0.00065
0.00061
0.00050
0.013182
0.076212
0.016159
0.05188
0.03932
0.06497
0.03429
0.01918
0.00699
0.00688
0.02687
0.01469
0.01127
0.00819
0.434434
3.812222
0.415658
0.267336
0.869834
0.432932
∗
∗∗
ELF value evaluated at (3,-1) electron density CP;
CP found in stack model.
tor, with graph-set R12(7) (labeled B in Fig. 7). Moreover, these hy-
drogen bonds form a macrocycle (hexamer) with graph-set R66(26)
(labeled C in Fig. 7) with 6 molecules of (I) involved.
3.3. NCI calculations results
Trying to gain more insights into the characteristics of the non-
covalent interactions in the crystal structure of (Z)-5-ethylidene-
2-thiohydantoin (I), we performed an electron density topologi-
cal analysis. In this analysis, we could identify 10 intermolecu-
lar interactions decreasing in strength from conventional and non-
conventional hydrogen bonds to van der Waals interactions. Run-
ning along the [2 0 1] and [0 -1 0] crystallographic directions we
found a conventional N—H···O HB and N—H···S, C—H···O and C—
H···S non-conventional HB interactions. Table 3 shows the prin-
cipal electron density topological properties calculated for all the
non-covalent (3,-1) bond critical point (BCP) found in the four
structural models considered. In the first model, Fig. 8a, we could
identify the three hydrogen N1—H1···O4, C6—H6···S2, C7—H7···O4.
Fig. 6. The asymmetric unit of (I), showing the atomic numbering scheme; H atoms
are shown as spheres of arbitrary radii).
2
These HBs has a close shell bond nature, with ∇ (r) > 0 and H(r)
3.2. Crystal and molecular structure
> 0. Also from the same figure, we notice the acceptor bifurcated
HBs with O4, with angles N,C—H···O4 of 172.2° and 170.1° for the
N and C donors respectively. Fig. 8b, allows us to identify the N3—
H3···S2 contact. This interaction has around the same electron den-
sity at BCP than the C—H···O HB and the triple of the C—H···S HB.
A comparison between the topological parameters at BCP shows us
that N—H···O has 27% more electron density at BCP than N—H···S.
The ellipticity has been defined as ε = |λ1|/| λ2| - 1, where λ1
and λ2 are the negative eigenvalues of the electron density Hes-
sian at the BCP. The ellipticity at the BCP can be interpreted as a
measure in the anisotropy of the curvature in the normal direc-
tions to the bond path at the BCP. In the X—H···Y interactions we
can observe an increase in the bond anisotropy following the or-
der: N1—H1···O4 < C7—H7A···O4 < C6—H6···S2 < N3—H3···S2, the
contacts X—H···S has the higher anisotropy, this is due to the high
polarizability of the sulfur atom. Also, the title molecule (I) has
two intramolecular weak contacts, H1···H7A and H6—O4, which
are not associated with any BCP. This type of interaction is asso-
ciated with an electron density distortion due to the presence of
a second atom and corresponds to the steric clash entitled to the
Z conformation in the molecule (I). The combination and periodi-
cal replication of the dimers showed in Fig. 8a and 8b, produce a
supramolecular sheet showed in Fig. 9 in there we can observe two
additional interactions associated with BCPs S2···C7 and H7B···H7C,
(Z)-5-ethylidene-thiohydantoin (I) crystallizes in a monoclinic
cell with space group P21/c with one molecule in the asymmetric
unit. Fig. 6 shows the atom labeling and molecular conformation
of the title compound. Supplementary material contains the frac-
tional atomic coordinates and anisotropic temperature factors for
non-hydrogen atoms, atomic positions and isotropic temperature
factors for hydrogen atoms, and geometrical parameters as bond
distances, bond, and torsion angles for (I).
All bond distances and angles are normal [54] and agree with
the average values found in 33 entries with thiohydantoin ring
fragments, found in the Cambridge Structural Database (CSD, ver-
sion 5.42, November 2020) [31] with N1 and N3 unsubstituted. A
search, including sp2 hybridization at C5=C6 bond, showed 5 en-
tries: AZADOV [55], CORZIT [56], MAKQEU [57], WOSLEV [58], and
YINSUK [59]. The lengths of the C=S and C=O bonds are similar
to those found in the two 2-thiohydantoin polymorphs [60,61] and
all the entries with thiohydantoins found in CSD. The molecule is
essentially planar, except for hydrogens H7B and H7C that are out
˚
of the plane, with a maximum deviation of -0.0059 A in N3 and
˚
+0.0058 A in C2.
In the crystal structure of (I) one intermolecular hydrogen bond
interaction N1–H1···O4 (-1+x,½-y,-½+z) and two non-conventional
N3–H3··S2 (1-x,-y,1-z) and C7–H7A··O4 (-1+x,½-y,-½+z) interac-
tions are observed (Table 2). The thioamide groups are linked into
centrosymmetric dimers with graph-set motifs R22(8) [62] labeled
A in Fig. 7. These hydrogen bonds form infinite sheets in the cb
plane (Fig. 7), which are reinforced by the C–H··O interactions
forming a new ring, with the O4 atom act as bifurcated accep-
these two interactions can be considered as attractive with λ2
<
0 (see Table 3) and relative more ellipticity as X—H···Y interac-
tions, this is due to the dispersion nature of this interactions. The
stacking interactions are shown in Fig. 10. In there we can observe
that these stacking interactions are largely delocalized between the
molecules, also it is possible to observe the presence of intermolec-
6

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
2
O hydrogen bonds and the formation of R 2(8), R12(7) and R66(26)
•••
••• •••
S and C—H
Fig. 7. Packing view of (I) in the cb plane, showing the intermolecular N—H
O, N—H
rings (labeled A, B, and C, respectively). H atoms not involved in hydrogen bonds have been omitted for clarity.
•••
O4 and (b) for the dimer formed through the
S2. The isosurfaces were colored employing a color scheme for ρ sing(λ2) value been red for regions with λ2 < 0 and blue λ2 > 0 regions. The
Fig. 8. Reduced gradient of density isosurface s(r)= 0.6399, (a) for the dimer formed by the conventional HB N1—H1
∗
•••
non-conventional N3—H3
electron density critical points (3,-1) (orange) and (3,+1) (yellow) are shown.
7

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Fig. 9. Reduced gradient of density isosurface s(r)= 0.6399, for the molecular sheet formed by the combination of dimer showed in fig. 1. The isosurfaces were colored
employing a color scheme for ρ∗sing(λ2) value been red for regions with λ2 < 0 and blue λ2 > 0 regions. The electron density critical points (3,-1) (orange) and (3,+1)
(yellow) are shown.
Fig. 10. Reduced gradient of density isosurface s(r)= 0.6299, for the stacking interactions in (I). The isosurfaces were colored employing a color scheme for sing(λ2)ρ value
been red for regions with λ2 < 0 and blue λ2 > 0 regions. The electron density critical points (3,-1) (orange) and (3,+1) (yellow) are shown.
˚
ular BCPs. The delocalization of this interaction across the crystal
structure is associated with cooperative effects, however, the quan-
tification of these effects is still in intense debate [63].
cal broad wing for H···C, with de + di ~ 3.3 A, for H···N as a broad
˚
spot with de + di ~ 3.5 A, the distance is greater than the van der
˚
Walls radii of N and H atoms (de + di > 2.75 A) and, H···O as sym-
˚
metrical sharp needles with de + di ~ 1.9 A. Another type of weak
interaction is also observed in the Hirshfeld Surface analyses. For
3.4. Hirshfeld surfaces analysis
example, in this compound, the contribution of O···C and O··· N
˚
with de + di 2.4, 3.4 and, 3.4 A, respectively, could be owing to O
A Hirshfeld surface analysis was conducted to verify the con-
tributions of the different intermolecular interactions. This analysis
was used to investigate the presence of hydrogen bonds and other
weak intermolecular interactions in the crystal structure. The plots
of the Hirshfeld surface confirm the presence of the non-covalent
interaction described below (Fig. 11), in very good agreement with
the diffraction and NCI analyses.
(lone pair)···π (thiohydantoin) interaction as evidenced by the NCI
plot in Fig. 10. The oxygen interactions observed, corresponding to
oxygen atoms of the title compound with an imidazoline ring. To
the best of our knowledge, this is one of the first examples ob-
served in the literature. The presence of this type of interaction is
verified by a shape index plot in the molecule density (Fig. 11b).
On the other hand, the interatomic contacts of H···H interac-
tions, show a broad triangular spot at diagonal axes di + de~ 2.2 A
° < 2.4 A °, denoting H···H short contacts with another significant
effect on the molecular packing.
To visualize and quantify the similarities and differences in
intermolecular contacts across the crystal structure the Hirshfeld
surface analysis was made with complementary analyses such as
shape index and curvedness surface. For the title compound (I), the
weak intermolecular interactions are mainly constituted by classi-
cal hydrogen bond interactions and some other weak interactions
because of the centrosymmetric setting, the contributions are de-
picted in Fig. 11a. The reciprocal contacts appear as an asymmetri-
The energy framework analysis helped us to a better under-
standing of the packing and topology of the crystal structure and
the supramolecular rearrangement (see Fig. 12). According to the
tube direction, it can conclude that the formation of the framework
8

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
Fig. 11. Hirshfeld surface analysis and fingerprint plot (a) and, Shape index maps (b) of the title compound.
Fig. 12. Energy framework diagrams for Eele, Edis, and Etot for title compound along the [100] direction.
ergy components have values of +18.7 kJ·mol−1, -8.1 kJ·mol−1, and
-5.0 kJ·mol−1 for Erep, Eele, and Epol, respectively. Energy framework
diagrams show zig-zag ladder type and brick type topologies for
electrostatic and dispersion energies, respectively (see Fig. 12). The
small value of electrostatic energy versus dispersion energy in the
title compound is attributed to the presence of weak classical hy-
is directed by the centrosymmetric setting for the title compound.
This rearrangement allows the formation of other weak interac-
tions to stabilize the crystal packing. The results of the calculations
revealed that it exhibits dispersion interactions approximately par-
allel to the tube shape by the heterocycle in an antiparallel rear-
rangement through the b-axis with -29.9 kJ·mol−1. The other en-
9

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
drogen bond interactions. The total interaction energy that resulted
[8] H.H. Merrit, T.J. Putnam, A new series of anticonvulsant drugs tested by exper-
iments on animals, Schweiz Arch. Neurol. Psychiatr. 39 (5) (1938) 1003–1015,
doi:10.1001/archneurpsyc.1938.02270050129007.
from all four main components is - 24.3 kJ mol−1
.
[9] J.M. Keppel Hesselink, D.J. Kopsky, Phenytoin: 80 years young, from epilepsy to
breast cancer, a remarkable molecule with multiple modes of action, J. Neurol.
264 (8) (2017) 1617–1621, doi:10.1007/s00415-017-8391-5.
4. Conclusions
[10] M.E. Jung, S. Ouk, D. Yoo, C.L. Sawyers, C. Chen, C. Tran, J. Wongvipa,
Structure-Activity relationship for thiohydantoin androgen receptor antagonists
for castration-resistant prostate cancer (CRPC), J. Med. Chem. 53 (7) (2010)
2779–2796, doi:10.1021/jm901488g.
[11] J. Liu, B. Liu, Y. Jing, G. Zhao, Design, synthesis, and biological evaluation of
thiohydantoin derivatives as novel anti-prostate cancer agents, Anti-Cancer
Agent 16 (6) (2016) 740–746 https://www.ingentaconnect.com/contentone/
ben/acamc/2016/00000016/00000006/art00009.
[12] A.V. Bogolubsky, Y.S. Moroz, O. Savych, S. Pipko, A. Konovets, M.O. Platonov,
O.V. Vasylchenko, V.V. Hurmach, O.O. Grygorenko, An old story in the parallel
synthesis world: An approach to hydantoin libraries, ACS Comb. Sci. 20 (1)
(2018) 35–43, doi:10.1021/acscombsci.7b00163.
With the need to explain in detail the wide-ranging nature of
the many interactions that exist within a crystal, here we stud-
ied the non-covalent interactions in the new compound (Z)-5-
ethylidene-2-thiohydantoin (I). Its crystal structure, determined by
direct methods using conventional powder X-ray diffraction and
refined by the Rietveld method, indicates that this material crys-
tallizes in the monoclinic system, space group P21/c, with one in-
dependent molecule in the unit asymmetric. Hydrogen-bond anal-
ysis show that in the crystal structure, molecules are packed
through intermolecular N–H···O, N–H···S, and C–H···O classical hy-
drogen bond interactions, which lead to the formation of infi-
nite two-dimensional sheets in the cb plane with graph-set motifs
R22(8), R12(7), and R66(26). The experimental structure was com-
plemented with quantum chemical calculations as the NCI, Hirsh-
feld surfaces, and Energy framework study showing a good agree-
ment with available experimental data. Hirshfeld surfaces and 2D
fingerprint plots were used to clarify intermolecular interactions in
the crystal lattice of the title molecule. The three-dimensional in-
teraction energy analysis showed that the dispersion energy frame-
works Edis were slightly dominant over classical electrostatic terms
[13] A.M. Maharramov, K.T. Mahmudov, M.N. Kopylovich, A.J.L. Pombeiro, Non-co-
valent interactions in the synthesis and design of new compounds, John Wiley
& Sons, New Jersey, 2016.
[14] G.R. Desiraju, Hydrogen bridges in crystal engineering: Interactions without
borders, Acc. Chem. Res. 35 (7) (2002) 565–573, doi:10.1021/ar010054t.
[15] G. Desiraju, Crystal engineering: A brief overview, J. Chem. Sci. 122 (5) (2010)
667–675 10.1007%2Fs12039-010-0055-2.
[16] W.I.F. David, K. Shankland, Structure determination from powder diffraction
data, Acta Cryst A64 (1) (2008) 52–64, doi:10.1107/S0108767307064252.
[17] L.E. Seijas, A.J. Mora, G.E. Delgado, M. Brunelli, A.N. Fitch, Study of the con-
version of N-carbamoyl-L-proline to hydantoin-L-proline using powder syn-
chrotron X-ray diffraction, Powder Diffr 25 (4) (2010) 342–348, doi:10.1154/
1.3503660.
[18] G.E. Delgado, L.E. Seijas, A.J. Mora, Synthesis and crystal structure determina-
tion of hydantoin-L-proline, J. Chem. Cryst. 42 (9) (2012) 968–971, doi:10.1007/
s10870-012-0344-3.
Eele
.
[19] L.E. Seijas, R. Almeida, A.J. Mora, G.E. Delgado, Cooperative effects on the
formation of supramolecular synthons of thiohydantoin derivatives, J. Comp.
Meth. Sci. Eng. 14 (1) (2014) 5–16, doi:10.3233/JCM-140480.
Declaration of Competing Interest
[20] G.E. Delgado, L.E. Seijas, A.J. Mora, R. Almeida, T. González, Crystal structure of
2-thiohydantoin-L-isoleucine synthesized under solvent-free conditions, Mol.
Cryst. Liq. Cryst. 607 (1) (2015) 192–199, doi:10.1080/15421406.2014.928433.
[21] G.E. Delgado, J.A. Rodríguez, A.J. Mora, J. Bruno-Colmenárez, J. Uzcátegui,
C. Chacón, Supramolecular structure of 5-methyl-5-phenyl hydantoin and
hydrogen-bonding patterns in 5,5’-substituted hydantoins, Mol. Cryst. Liq.
Cryst. 629 (1) (2016) 96–104, doi:10.1080/15421406.2015.1107745.
[22] L.E. Fernández, G.E. Delgado, L.V. Maturano, R.M. Tótaro, E.L. Varetti, Exper-
imental and theoretical vibrational study of N-carbamoyl-L-proline, J. Mol.
Struc. 1168 (1) (2018) 84–91, doi:10.1016/j.molstruc.2018.05.006.
[23] G.E. Delgado, A.J. Mora, L.E. Seijas, R. Almeida, C. Chacón, L. Azotla-Cruz,
J. Cisterna, A. Cárdenas, I. Brito, N-acetyl-5-isopropyl-2-tioxoimidazolidin-4-
one: Synthesis, spectroscopic characterization, crystal structure, DFT calcula-
tions, Hirshfeld surface analysis and energy framework study, J. Mol. Struc.
1219 (1) (2020) 128630 (12), doi:10.1016/j.molstruc.2020.128630.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
Gerzon E. Delgado: Conceptualization, Supervision, Writing -
original draft. Asiloé J. Mora: Conceptualization, Writing - review
& editing. Luis E. Seijas: Software, Methodology. Luis Rincón: Soft-
ware, Methodology. Gustavo Marroquin: Methodology. Jonathan
Cisterna: Software, Supervision. Alejandro Cárdenas: Writing - re-
view & editing. Iván Brito: Writing - review & editing.
[24] A. Boultif, D. Löuer, Powder pattern indexing with the dichotomy method, J.
App. Cryst. 37 (5) (2004) 724–731, doi:10.1107/S0021889804014876.
[25] P.M de Wolff,
A
simplified criterion for the reliability of
a
powder pat-
1 (1) (1968) 108–113 http://doi.org/10.1107/
Acknowledgements
tern indexing, J. App. Cryst.
S002188986800508X.
This work was partially done into G.E. Delgado visit at the Uni-
versidad de Antofagasta, supported by MINEDUC-UA project, code
ANT 1856. G.E. Delgado thank to FONACIT-Venezuela (grant LAB-
97000821).
[26] GS. Smith, R.L. Snyder, A criterion for rating powder diffraction patterns and
evaluating the reliability of powder-pattern indexing, J. App. Cryst. 12 (1)
(1979) 60–65 http://doi.org/10.1107/S002188987901178X.
[27] A. Altomare, F. Ciriaco, C. Cuocci, A. Falcicchio, F. Fanell, Combined powder X-
ray diffraction data and quantum-chemical calculations in EXPO2014, Powder
Diffr 32 (S1) (2017) S123–S128, doi:10.1017/S088571561700015X.
[28] H.M. Rietveld, A profile refinement method for nuclear and magnetic struc-
tures, J. Appl. Cryst. 2 (2) (1969) 65–71, doi:10.1107/S0021889869006558.
[29] B.H. Toby, R.B. Von Dreele, GSAS-II: the genesis of a modern open-source all
purpose crystallography software package, J. Appl. Cryst. 46 (2) (2013) 544–
549, doi:10.1107/S0021889813003531.
[30] P. Thompson, D.E. Cox, J.B. Hastings, Rietveld refinement of Debye-Scherrer
synchrotron X-ray data from Al2O3, J. Appl. Cryst. 20 (2) (1987) 79–83 http:
//doi.org/10.1107/S0021889887087090.
References
[1] C. Avendaño López, G. González Trigo, The chemistry of hydantoins, Adv. Heter.
Chem. 38 (1) (1985) 177–228, doi:10.1016/S0065-2725(08)60920-4.
[2] M. Meusel, M. Gütschow, Recent developments in hydantoin chemistry.
A
review, Org. Prep. Proced. Int. 36 (5) (2004) 391–443, doi:10.1080/
00304940409356627.
[3] G.G. Muccioli, J.H. Poupaerta, J. Wouters, B. Norberg, W. Poppitzc, K.E Gerhard,
G.K. Scribad, D.M. Lamberta, A rapid and efficient microwave-assisted synthe-
sis of hydantoins and thiohydantoins, Tetrahedron 59 (8) (2003) 1301–1307,
doi:10.1016/S0040-4020(03)00033-4.
[31] C.R. Groom, I.J. Bruno, M.P. Lightfoot, S.C. Ward, The Cambridge Struc-
tural Database, Acta Cryst.
S2052520616003954.
B
72 (2) (2016) 171–179, doi:10.1107/
[32] E.R. Jhonson, S. Keinan, P. Mori-Sánchez, J. Contreras-Garcia´, A. Cohen, W. Yang,
Revealing non-covalent interactions, J. Am. Chem. Soc. 132 (18) (2010) 6498–
6506, doi:10.1021/ja100936w.
[33] J. Contreras-Garcia´, E.R. Jhonson, S. Keinan, R. Chaudret, J.P. Piquemal, D.N. Be-
ratan, W. Yang, NCIPLOT: a program for plotting noncovalent interaction re-
gions, J. Chem. Theory Comput. 7 (3) (2011) 625–632, doi:10.1021/ct100641a.
[34] B. Lakshmi, A.G. Samuelson, K.V. Jovan Jose, S.R. Gadre, E. Arunan, Is there a
hydrogen bond radius? Evidence from microwave spectroscopy, neutron scat-
tering and X-ray diffraction results, New. J. Chem. 29 (2) (2005) 371–377,
doi:10.1039/B411815D.
[4] Z.D. Wang, S.O. Sheikh, Y. Zhang,
A simple synthesis of 2-thiohydantoins,
Molecules 11 (10) (2006) 739–750, doi:10.3390/11100739.
[5] L. Konnert, E. Colacino, Recent advances in the synthesis of hydantoins: The
state of the art of a valuable scaffold, Chem. Rev. 117 (23) (2017) 13757–13809,
doi:10.1021/acs.chemrev.7b00067.
[6] S.H. Cho, S-H Kim, D. Shin, Recent applications of hydantoin and thiohy-
dantoin in medicinal chemistry, Eur. J. Med. Chem. 164 (2) (2019) 517–545,
doi:10.1016/j.ejmech.2018.12.066.
[7] L. Chen, Y. Hao, H. Song, Y. Liu, Y. Li, J. Zhang, Q. Wang, Design, synthesis, char-
acterization, and biological activities of novel spirooxindole analogues contain-
ing hydantoin, thiohydantoin, urea, and thiourea moieties, J. Agric. Food Chem.
68 (39) (2020) 10618–10625, doi:10.1021/acs.jafc.0c04488.
[35] G. Scoles (Ed.), Atomic and molecular beam methods, Oxford University Press,
New York, 1992.
10

G.E. Delgado, A.J. Mora, L.E. Seijas et al.
Journal of Molecular Structure 1236 (2021) 130361
[36] R.F.W. Bader, T.T. Nguyen-Dang, Quantum Theory of Atoms in Molecules–
Dalton Revisited, Adv. Quantum Chem. 14 (1) (1981) 63–124, doi:10.1016/
S0065-3276(08)60326-3.
[51] A. Bondi, van der Waals Volumes and Radii, J. Phys. Chem. 68 (3) (1964) 441–
451, doi:10.1021/j100785a001.
[52] MA. Spackman, J.J. McKinnon, Fingerprinting intermolecular interactions in
[37] S.J. Grabowski, Relationships between QTAIM and the decomposition of
the interaction energy-comparison of different kinds of hydrogen bond, in:
C.F. Matta, R.J. Boyd (Eds.), The quantum theory of atoms in molecules: from
solid state to DNA and drug design, Wiley, Darmstadt, 2017, doi:10.1002/
9783527610709.ch17.
molecular crystals, CrystEngComm
b203191b.
[53] M.J. Turner, J.J. McKinnon, S.K. Wolff, D.J. Grimwood, P.R. Spackman, D. Jayati-
laka, M.A. Spackman, CrystalExplorer17, University of Western Australia, 2017
http://hirshfeldsurface.net.
4 (66) (2002) 378–392, doi:10.1039/
[38] L. Rincon, R. Almeida, D. Garcia´-Aldea, H. Diez y Riega, Hydrogen bond cooper-
ativity and electron delocalization in hydrogen fluoride clusters, J. Chem. Phys.
114 (13) (2001) 5552–5562, doi:10.1063/1.1351878.
[54] F.H. Allen, O. Kennard, D.G. Watson, L. Brammer, A.G. Orpen, R. Taylor, Tables
of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond
lengths in organic compounds, J. Chem. Soc., Perkin Trans. 2 (12) (1987) S1–
S19, doi:10.1039/P298700000S1.
[55] A.M. Asiri, H.M. Faidallah, A.O. Al-Youbi, T.R. Sobahi, S.W. Ng, Z)-2-
Sulfanylidene-5-(thiophen-2-ylmethylidene) imidazolidin-4-one, Acta Cryst
E67 (9) (2011) o2429, doi:10.1107/S1600536811033034.
[39] J. Bruno-Colmenarez, R. Atencio, M. Quintero, L.E. Seijas, R. Almeida, L. Rincón,
Crystal structure analysis and topological study of non-covalent interactions in
2,2-biimidazole: salicylic acid 2:1 co-crystal, J. Chem. Cryst. 47 (4) (2017) 47–
58, doi:10.1007/s10870-017-0679-x.
[40] A.J. Mora, L.M. Belandria, G.E. Delgado, L.E. Seijas, A. Lunar, R. Almeida, Non-
covalent interactions in the multicomponent crystal of 1-aminocyclopentane
carboxylic acid, oxalic acid and water: a crystallographic and a theoretical ap-
proach, Acta Cryst. B 73 (5) (2017) 968–980, doi:10.1107/S2052520617011775.
[41] M.E. Alikhani, F. Fuster, B. Silvi, What can tell the topo- logical analysis of
ELF on hydrogen bonding? Struct. Chem. 16 (6) (2005) 203–210, doi:10.1007/
s11224-005-4451-z.
[56] W. Ksiazek, K. Kiec-Kononowicz, J. Karolak-Wojciechowska, Crystal and molec-
ular structure of 5-benzylidene-2-thiohydantoin: The S...S intermolecular in-
teractions between two C=S groups, J. Mol. Struct. 921 (1-3) (2009) 109–113,
doi:10.1016/j.molstruc.2008.12.060.
[57] J.S. Casas, A. Castineiras, N. Playa, A. Sanchez, J. Sordo, J.M. Varela,
E.M. Vazquez-Lopez, Methylmercury and dimethylthallium complexes of 5-
(4’-dimethylaminobenzylidene)-2-thiohydantoin (HDABTd). The crystal and
molecular structures of HDABTd and [TlMe2 (DABTd)(DMSO)], Polyhedron 18
(27) (1999) 3653–3659, doi:10.1016/S0277-5387(99)00298-3.
[58] M.M. Chowdhry, D.M.P. Mingos, A.J.P. White, D.J. Williams, Syntheses and char-
acterization of 5-substituted hydantoins and thiazolines-implications for crys-
tal engineering of hydrogen bonded assemblies, J. Chem. Soc., Perkin Trans. 1
(20) (2000) 3495–3504, doi:10.1039/B004312P.
[42] L.E. Seijas, L. Lunar, L. Rincón, R. Almeida, On the electron density localization
in HF cyclic clusters, J. Comput. Methods Sci. Eng. 17 (1) (2017) 5–18, doi:10.
3233/JCM-160656.
[43] T. Yanai, D. Tew, N. Handy, A new hybrid exchange-correlation functional us-
ing the Coulomb-attenuating method (CAM-B3LYP), Chem. Phys. Lett. 393 (1-3)
(2004) 51–57, doi:10.1016/j.cplett.2004.06.011.
[44] S. Grimme, S. Ehrlich, L. Goerigk, Effect of the damping function in dispersion
corrected density functional theory, J. Comp. Chem. 32 (7) (2011) 1456–1465,
doi:10.1002/jcc.21759.
[45] T.A. Keith, T.K. Gristmill, AIMAll version 19.10.12, Overland Park KS, USA, 2019.
http://aim.tkgristmill.com.
[59] S.F. Brady, J.D. Bauer, M. Clarke-Pearson, R. Daniels, Natural products from
isnA-containing biosynthetic gene clusters recovered from the genomes of cul-
tured and uncultured bacteria, J. Am. Chem. Soc. 129 (40) (2007) 12102–12103,
doi:10.1021/ja075492v.
[60] L.A. Walker, K. Folting, L.L. Merritt, The crystal structure of 2-thiohydantoin,
C3H4ON2S, Acta Cryst. B 25 (1) (1969) 88–93, doi:10.1107/S0567740869001804.
[61] T. Ogawa, H. Okumura, M. Honda, M. Suda, S. Fujinami, A. Kuwae, K. Hanal,
K.K. Kunimoto, A new polymorph of 2-thiohydantoin. 91-92. X-ray Struc Anal,
Online 25 (9) (2009) 91–92, doi:10.2116/xraystruct.25.91.
[46] L. Tian, C. Feiwu Chen, Multiwfn: A multifunctional wavefunction analyzer, J.
Comput. Chem. 33 (5) (2012) 580–592, doi:10.1002/jcc.22885.
[47] W. Humphrey, A. Dalke, K. Schulten, VMD
Molec. Graphics 14 (1) (1996) 33–38, doi:10.1016/0263-7855(96)00018-5.
[48] M.A. Spackman, P.G. Byrom, novel definition of molecule in crystal,
- Visual Molecular Dynamics, J.
A
a
a
[62] M.C. Etter, J.C. MacDonald, J. Bernstein, Graph-set analysis of hydrogen-bond
patterns in organic crystals, Acta Crystallogr B46 (2) (1990) 256–262, doi:10.
1107/S0108768189012929.
Chem. Phys. Letters 267 (3-4) (1997) 215–220, doi:10.1016/S0009-2614(97)
00100-0.
[49] J.J. McKinnon, M.A. Spackman, A.S. Mitchell, Novel tools for visualizing and ex-
ploring intermolecular interactions in molecular crystals, Acta Cryst B60 (12)
(2004) 627–668, doi:10.1107/S0108768104020300.
[63] M. Alonso, T. Woller, F.J. Martin´ -Martin´ ez, J. Contreras-Garcia´, P. Geerlings,
F. De Proft, Undertanding the fundamental role of p/p, s/s and s/p dispersion
interactions in shaping carbon-based materials, Chem. Eur. J. 20 (17) (2014)
4931–4941, doi:10.1002/chem.201400107.
[50] J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Towards quantitative analysis
of intermolecular interactions with Hirshfeld surfaces, Chem. Comm. 37 (1)
(2007) 3814–3816, doi:10.1039/B704980C.
11