Synthesis, Spectroscopic Characterization, and Crystal Structure Analysis of rac-2-thiohydantoin-methionine

Article abstract of DOI:10.1080/15421406.2014.991116

In this work, we present the synthesis, FT-IR and NMR spectroscopic characterization, and X-ray single-crystal structural study of the heterocyclic compound rac-2-thiohydantoin-methionine, C₆H₁₀N₂OS₂, also known as rac-5-(2-methylthio-ethyl)-2-tioxo-imidazolidin-4-one. This material crystallize in the triclinic system, space group P-1 (N°2), Z = 4, with two independent molecules in the asymmetric unit. In the supramolecular structure, the molecules are linked by N-H...O and N-H...S hydrogen bonds forming infinite bi-dimensional chains along the [100] direction, with graph-set motif R²₂(8) and C²₂(9).

Full text of DOI:10.1080/15421406.2014.991116

Molecular Crystals and Liquid Crystals
ISSN: 1542-1406 (Print) 1563-5287 (Online) Journal homepage: http://www.tandfonline.com/loi/gmcl20
Synthesis, Spectroscopic Characterization, and
Crystal Structure Analysis of rac-2-thiohydantoin-
methionine
Gerzon E. Delgado, Manuel O. Hernández, Asiloé J. Mora, Ali Bahsas, Robert
Lobaton & Teresa González
To cite this article: Gerzon E. Delgado, Manuel O. Hernández, Asiloé J. Mora, Ali Bahsas, Robert
Lobaton & Teresa González (2015) Synthesis, Spectroscopic Characterization, and Crystal
Structure Analysis of rac-2-thiohydantoin-methionine, Molecular Crystals and Liquid Crystals,
616:1, 187-194, DOI: 10.1080/15421406.2014.991116
To link to this article: http://dx.doi.org/10.1080/15421406.2014.991116
Published online: 25 Sep 2015.
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Date: 26 September 2015, At: 07:10

Mol. Cryst. Liq. Cryst., Vol. 616: pp. 187–194, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2014.991116
Synthesis, Spectroscopic Characterization, and
Crystal Structure Analysis of
rac-2-thiohydantoin-methionine
1
GERZON E. DELGADO,1,∗ MANUEL O. HERNANDEZ,
´
1
2
3
´
ASILOE J. MORA, ALI BAHSAS, ROBERT LOBATON,
4
´
AND TERESA GONZALEZ
1Laboratorio de Cristalograf´ıa, Departamento de Qu´ımica, Facultad de Ciencias,
Universidad de Los Andes, Me´rida, Venezuela
2Laboratorio de Resonancia Magne´tica Nuclear, Departamento de Qu´ımica,
Facultad de Ciencias, Universidad de Los Andes, Me´rida, Venezuela
3Laboratorio de Ana´lisis Farmace´utico, Departamento de Ana´lisis y Control,
Facultad de Farmacia y Bioana´lisis, Universidad de Los Andes, Me´rida,
Venezuela
4Centro de Qu´ımica, Instituto Venezolano de Investigaciones, Cient´ıficas,
Caracas, Venezuela
In this work, we present the synthesis, FT-IR and NMR spectroscopic characteriza-
tion, and X-ray single-crystal structural study of the heterocyclic compound rac-2-
thiohydantoin-methionine, C6H10N2OS2, also known as rac-5-(2-methylthio-ethyl)-2-
tioxo-imidazolidin-4-one. This material crystallize in the triclinic system, space group
P-1 (N◦2), Z = 4, with two independent molecules in the asymmetric unit. In the
supramolecular structure, the molecules are linked by N–H···O and N–H···S hydrogen
bonds forming infinite bi-dimensional chains along the [100] direction, with graph-set
motif R2 (8) and C2 (9).
2
2
Keywords Hydrogen bonds; supramolecular chemistry; thiohydantoin; X-ray diffrac-
tion crystal structure
1. Introduction
The focus of supramolecular chemistry is the identification and study of synthons that
can control the molecular assemble and thus lead to controlled supramolecular crystal
architectures [1]. In molecular crystal, the combination of noncovalent interactions, such
as hydrogen bonds, provides a powerful way for generating supramolecular architectures
from simple building blocks [2]. Thiohydantoins and hydantoins, five-member heterocyclic
systems with a very reactive nucleus, represent significant building blocks for combinatorial
∗Address correspondence to Gerzon E. Delgado, Laboratorio de Cristalograf´ıa,
Departamento de Qu´ımica, Facultad de Ciencias, Universidad de Los Andes, Me´rida, Venezuela.
E-mail: gerzon@ula.ve
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/gmcl.
187

188
G. E. Delgado et al.
chemistry libraries [3]. The hydantoin heterocycle is present in a wide range of biologically
active compounds including therapeutic drugs for the treatment of seizures and antitumor
compounds [4–6]. Thiohydantoins, have also been used as anti-convulsant agents and
are present in fungicides, herbicides, and natural products [7, 8]. Recently, there has been
interest in the search of new synthetic routes for the preparation of these types of compounds,
via solution or solid state reactions [9–11]. In our laboratory, we are interested in the
study of thiohydantoin natural α-amino acids derivative compounds [12–17], therefore we
report here the synthesis, spectroscopic characterization and crystal structure of a new
2-thiohydantoin derivative. The analysis of the hydrogen bond patterns is also discussed.
2. Experimental
2.1. Synthesis
l-methionine (3.0 mmol) and NH4SCN (3.0 mmol) were dissolved in a mixture of acetic
anhydride (9 mL) and acetic acid (2 mL). This solution was warmed, with agitation, to
100◦C over a period of 30 min, and then cooled in ice/water and stored in a freezer overnight.
The resulting white solid was collected by filtration and washed with cold water. Crystals
of (I) suitable for single-crystal X-ray diffraction were obtained by slow evaporation of a
1:1 ethanol-methanol solution. Yield 42%, mp 149–150◦C. This experimental procedure
corresponds with a modified and improved methodology previously reported [10, 12] (see
Scheme 1).
2.2. FT-IR and NMR Spectroscopic Characterization
The FT-IR absorption spectrum was obtained as KBr pellet using a Perkin-Elmer 1600
1
spectrometer. H and 13C NMR spectra were determined on a Bruker Avance 400 model
spectrometer, using DMSO-d6 as solvent.
Figure 1. X-ray powder diffraction data for (I). The powder pattern was refined without structural
model to confirm the unit cell parameters.

Synthesis, Spectroscopic Characterization, and Crystal Structure Analysis
189
Table 1. Crystal data, data collection, and structure refinement
CCDC
997752
Chemical formula
C6H10N2OS2
190.30
Formula weight
Crystal system
Space group
a(Å)
Triclinic
P-1 (N◦2)
8.653(2)
9.790(2)
11.013(3)
84.53(2)
83.97(2)
75.61(2)
896.4(4)
4
b(Å)
c(Å)
α (◦)
β (◦)
γ (◦)
V(Å3)
Z
dx (g cm−3
F(000)
)
1.410
400
0.54
μ (mm−1
)
Crystal size (mm)
0.50 × 0.30 × 0.20
θ range (◦)
1.9-27.9
hkl range
Reflections
−10, 10; −12, 12; −12, 12
Unique
3381
Rint
0.031
With I > 2σ(I)
Refinement method
Number of parameters
R(F2) [I > 2σ(I)]
wR(F2) [I > 2σ(I)]
Goodness of fit on F2
1539
Full-matrix least-squares on F2
201
0.059
0.145
1.00
0.38/−0.36
Max/min ꢀρ (e Å−3
)
FT-IR (ν cm−1): 1175 (t, C = S), 1410 (t, C-N), 1542 (t, N-H), 1739 (t, C = O), 2900
(t, C-H), 3152 (t, N-H).
1H-NMR (400 MHz): δ 11.69 (s, 1H, N3H3), 10.08 (s, 1H, N1H1), 4.27 (t, 1H, C5H5),
2.52 (t, 2H, C7H7), 2.01 (s, 3H, C8H8), 1.90 (m, 1H, C6H6A), 1.80 (m, C6H6A).
13C-NMR (100 MHz): δ 182.5 (C2), 176.3 (C4), 59.5 (C5), 30.2 (C6), 28.6 (C7), 14.4
(C8).
2.3. X-Ray Powder Diffraction
The X-ray powder diffraction pattern of (I) was collected at room temperature in a Phillips
PW-1250 goniometer using monocromatized CuKα radiation. A small quantity of com-
pound was ground mechanically in an agate mortar and pestle and mounted on a flat holder
covered with a thin layer of grease. The sample was scanned from 5–65◦ 2θ, with a step
size of 0.02◦ and counting time of 10s. Silicon was used as an external standard. X-ray
powder pattern of hydantoin compound is shown in Fig. 1. The 20 first measured reflections

190
G. E. Delgado et al.
Figure 2. Asymmetric unit of 2-thiohydantoin-methionine (I) with anisotropic ellipsoid represen-
tations, together with atom labeling scheme. The ellipsoids are drawn at 50% probability level.
Hydrogen atoms are depicted as spheres with arbitrary radii.
were completely indexed using the program Dicvol04 [18], which gave a unique solution
in a triclinic cell with parameters a = 8.654(2) Å, b = 9.790(2) Å, c = 11.0145(2) Å, α =
84.55(1)◦, β = 83.99(1)◦, γ = 75.61(2)◦ with figures of merit M20 = 56.3 [19] and F20
=
121.5 (0.0046, 36) [20]. In order to confirm the unit cell parameters, a Le Bail refinement
Table 2. Selected geometrical parameters (Å, ◦)
Molecule 1
Molecule 2
S21-C21
S31-C71
S31-C81
O41-C41
N11-C21
N31-C21
N31-C41
S2-C2
S3-C7
S3-C8
O4-C4
N1-C2
N3-C2
N3-C4
1.657(5)
1.816(5)
1.785(7)
1.224(6)
1.348(6)
1.366(7)
1.357(6)
1.668(5)
1.771(6)
1.780(7)
1.212(7)
1.313(6)
1.391(6)
1.364(7)
S2-C2-N3
S2-C2-N1
N1-C2-N3
O4-C4-N3
C5-N1-C2-S2
C4-N3-C2-S2
126.4(4)
127.1(4)
106.5(4)
S21-C21-N31
S21-C21-N11
N11-C21-N31
O41-C41-N31
C51-N11-C21-S21
C41-N31-C21-S21
121.2(3)
130.5(4)
108.3(4)
128.4(5)
179.1(4)
−177.6(4)
124.9(5)
−179.2(4)
−177.3(4)

Synthesis, Spectroscopic Characterization, and Crystal Structure Analysis
191
Figure 3. A portion of the crystal packing of (I) showing the hydrogen bonds pattern. Intermolecular
hydrogen bonds, N–H···S and N–N–H···O are indicated by dashed lines.
[21] was carried out using the Fullprof program [22]. The Fig. 1 shows a very good fit
between the observed and calculated patterns.
2.4. X-Ray Data Collection and Structure Determination
Single crystal data were collected at room temperature in a Rigaku AFC7S diffractometer
coupled with a CCD area detector using graphite monocromated MoKα radiation (λ =
0.71073 Å). The trail unit cell parameters were found by indexing of reflections from the first
Table 3. Hydrogen bonds geometry (Å, ◦). (D-donor; A-acceptor; H-hydrogen)
D–H···A
D—H
H···A
D···A
D–H···A
N3–H3···O4(i)
0.860
0.860
0.970
0.960
1.990
2.520
2.480
2.700
2.837(5)
3.378(4)
2.854(5)
3.341(5)
168.0
176.0
166.0
177.0
N1–H1···S21(ii)
N31–H31···O41(i)
N11–HH11···S2(ii)
Symmetry codes: (i) −x, 1−y, 2−z., (ii) 1−x, 1−y, 2−z

192
G. E. Delgado et al.
Figure 4. A packing view of (I) in the ca plane, showing the infinite bi-dimensional chains along
the [100] direction. H atoms not involved in hydrogen bonding have been omitted for clarity.
20 frames and refined along with diffractometer constants to give the final cell parameters
using the program CrystalClear [23]. Integration, scaling correction, and data reduction
were accomplished using CrystalStructure [23]. Absorption corrections were performed
using the multi-scan method. The structure was solved using the program SHELXS [24]
and refined by the full-matrix least-squares methods in SHELXL [24]. The nonhydrogen
atoms were modeled anisotropically. All H atoms were placed at calculated positions and
treated using the riding model, with C-H distances of 0.97–0.98 A, and N-H distances of
0.86 A. The Uiso(H) parameters were fixed at 1.2Ueq (C, N) and 1.5Ueq (methyl carbon).
Molecular diagrams were generated using Diamond [25]. All geometrical calculations were
done using the program Platon [26]. Experimental details of the X-ray analysis are provided
in Table 1.
3. Results and Discussion
Spectroscopic studies confirm the molecular skeleton of rac-2-thiohydantoin-methionine.
From the X-ray results, the title compound (I) crystallizes in the centro-symmetric space
group P-1 with two independent molecules in the asymmetric unit. In this case, l-methionine
suffered an amino acid racemization produced by the use of acetic acid and the high temper-
ature in the synthesis [27]. Figure 2 shows the atom labeling and molecular conformation of
rac-2-thiohydantoin-methionine. Selected geometrical parameters are presented in Table 2.
All bond distances and angles are normal [28] and are in agreement with the average values
found in 43 entries with thiohydantoin ring fragments, found in the Cambridge Structural
Database (CSD, version 5.35, Feb 2014) [28] with N1 and N3 unsubstituted and sp3 hy-
bridization at C5. For instance, the S1-C2 average distance value 1.663(5) Å in the two

Synthesis, Spectroscopic Characterization, and Crystal Structure Analysis
193
Scheme 1. Synthesis of rac-2-thiohydantoin-methionine (I) from L-methionine.
molecules, agree with the average value of 1.646 Å found in the 43 fragments, with minimal
and maximum reported values of 1.519 and 1.696 Å, respectively. The thiohydantoin rings
are essentially planar with a maximum deviations of −0.030(8) Å in C4 and +0.025(6)
Å in C5 for molecule 1, and −0.014(6) Å in C41 and +0.010(5) Å in C51 for molecule
2. The S2-C2-N1 average bond angle 128.8(4)◦ for the two molecules is greater than S2-
C2-N3, 123.8(4)◦. This difference is also observed in all 43 fragments with average values
of 127.7◦ and 125.2◦, respectively. The dihedral angle between the thiohydantoin ring and
the plane formed by the alkyl chains is 66.51(1)◦ and 65.47(1)◦ for the molecules 1 and 2,
respectively.
The supramolecular structure and crystal packing of (I) are stabilized by N–H···O
and N–H···S hydrogen bonds, as depicted in Fig. 3. The geometrical parameters of these
hydrogen bonds are summarized in Table 3.
The N3–H3···O4 and N31–H31···O41 (1−x, 1−y, 2−z) hydrogen bonds generates
centro-symmetric rings parallel to the ca plane, described by the graph-set R2 (8) [29,30].
2
This motif constituted a typical amide–amide hydrogen bond joining pairs of molecules,
and is also observed in other thiohydantoins21. These dimers are parallel linked through
the N1–H1···S21 and N11–H31···S2 (−x, 1−y, 2−z) hydrogen bonds to form a second
centro-symmetric ring motif R2 (8) type. The joining together of these rings produces
2
C2 (9) chains, in alternated (R) and (S) molecules, which run along the [100] direction.
2
The combination of these interactions produces chains parallel to the ca plane in a bi-
dimensional hydrogen bond network scheme (Fig. 4).
4. Conclusions
The title compound was synthesized and characterized by spectroscopy and X-ray diffrac-
tion techniques. In the supramolecular structure of rac-2-thiohydantoin-methionine, the
molecules are linked by N–H···O and N–H···S hydrogen bonds forming a bi-dimensional
network.
Supplementary Materials
Crystallographic data for the structure reported here have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC-997752). These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (+44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
Funding
This work was supported by CDCHT-ULA (grant C-1853-13-08-A) and FONACIT (grant
LAB-97000821).

194
G. E. Delgado et al.
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