Crystal structure of 2-thiohydantoin-L-isoleucine synthesized under solvent-free conditions

Article abstract of DOI:10.1080/15421406.2014.928433

The title compound with systematic name: (S)-5-secbutyl-2-thiohydantoin, is synthesized through a solvent-free reaction, crystallizes in the non-centrosymmetric space group P2₁2₁2₁. In the crystal structure, the molecules are joined by NH?O and NH?S hydrogen bonds, forming chains C²₂(10) and macrocycles R⁵₆(26) in an infinite bi-dimensional network.

Full text of DOI:10.1080/15421406.2014.928433

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Crystal Structure of 2-Thiohydantoin-L-
Isoleucine Synthesized under Solvent-
Free Conditions
Gerzon E. Delgadoa, Luis E. Seijasb, Asiloé J. Moraa, Rafael Almeidab
& Teresa Gonzálezc
a Laboratorio de Cristalografía, Departamento de Química,
Universidad de Los Andes, Mérida, Venezuela
b Laboratorio de Procesos Dinámicos en Química, Departamento de
Química, Universidad de Los Andes, Mérida, Venezuela
c Centro de Química, Instituto Venezolano de Investigaciones,
Científicas, Caracas, Venezuela
Published online: 26 Feb 2015.
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To cite this article: Gerzon E. Delgado, Luis E. Seijas, Asiloé J. Mora, Rafael Almeida &
Teresa González (2015) Crystal Structure of 2-Thiohydantoin-L-Isoleucine Synthesized
under Solvent-Free Conditions, Molecular Crystals and Liquid Crystals, 607:1, 192-199, DOI:
10.1080/15421406.2014.928433
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Mol. Cryst. Liq. Cryst., Vol. 607: pp. 192–199, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2014.928433
Crystal Structure of 2-Thiohydantoin-L-Isoleucine
Synthesized under Solvent-Free Conditions
2
GERZON E. DELGADO,1,∗ LUIS E. SEIJAS, ASILOE J.
´
1
2
3
´
MORA, RAFAEL ALMEIDA, AND TERESA GONZALEZ
1Laboratorio de Cristalograf´ıa, Departamento de Qu´ımica, Universidad de Los
Andes, Me´rida, Venezuela
2Laboratorio de Procesos Dina´micos en Qu´ımica, Departamento de Qu´ımica,
Universidad de Los Andes, Me´rida, Venezuela
3Centro de Qu´ımica, Instituto Venezolano de Investigaciones, Cient´ıficas,
Caracas, Venezuela
The title compound with systematic name: (S)-5-secbutyl-2-thiohydantoin, is synthe-
sized through a solvent-free reaction, crystallizes in the non-centrosymmetric space
group P212121. In the crystal structure, the molecules are joined by N H···O and
N
H···S hydrogen bonds, forming chains C2 (10) and macrocycles R5 (26) in an infinite
2
6
bi-dimensional network.
Keywords Crystal structure; hydrogen bonds; thiohydantoin
1. Introduction
2-thioxoimidazolidin-4-ones, or thiohydantoins, are sulfur analogs of imidazolidine-2,4-
diones, or hydantoins, and constituted by two five-member heterocyclic system with a very
reactive nucleus, which provides four possible points of diversity [1, 2]. The biological
activities of hydantoin and 2-thiohydantoin derivatives has been known for a long time,
and are responsible for a wide variety of biological behavior, due principally to its wide
range of therapeutic properties [3]. Depending on the nature and type of substitution on
the heterocyclic ring, these compounds may display pharmaceutical and biological activity
with a variety of applications: anti-epileptic activity, anti-tumoral, and anti-inflammatory
[4], fungicidal [5], antiviral [6], herbicide [7], HIV protease inhibitor [8], hypolipidimic
agent [9], and anti-hypertensive agent [10]. 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 [11–13]. We are interested in thiohydantoin derivatives of α-amino acids
[14–18], and report here the structure of the 2-thiohydantoin derivative of L-isoleucine,
synthesized from a solvent-free reaction.
∗Address correspondence to Gerzon E. Delgado, Laboratorio de Cristalograf´ıa, Departamento
de Qu´ımica, Universidad de Los Andes, Me´rida 5101, Venezuela. Tel.: +58-274-2401372. 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.
192

Crystal Structure of 2-Thiohydantoin-L-Isoleucine
193
Scheme 1. Solvent-free synthesis of 2-thiohydantoin-L-isoleucine.
2. Experimental
2.1 Solvent-Free Synthesis
The title compound was synthesized using a solvent-free modified methodology previously
reported, which involves the direct condensation between α-amino acids and thiourea [13].
L-isoleucine and thiourea were mixed in an agate mortar in 1:3 molar ratio. The solid
mixture was placed in a reflux system and heated in an oil bath to 453 K, where thiourea
melt and amino acid was dissolved in it. Reaction was maintained for 30 min and then let
cool to room temperature. The resulting white solid was washed with cool water and filtered.
Crystal of (I) suitable for X-ray diffraction analysis were obtained by slow evaporation of
ethanol solution (Scheme 1).
Table 1. Crystal data, data collection and structure refinement
Chemical formula C7H12N2OS
CCDC
933210
Formula weight
Crystal system
Space group
172.26
Orthorhombic
P212121
Radiation (MoKα)
θ range (◦)
hkl range
λ = 0.71073 Å
1.5–28.1
−10, 13; −13, 14; −31,
31
a(Å)
b(Å)
c(Å)
V(Å3)
Z
11.279(3)
12.203(4)
26.915(7)
3704.5(2)
4
Reflections
Unique
Rint
With I > 2σ(I)
Refinement method
7150
0.112
4102
Full-matrix least-squares
on F2
dx (g cm−3
F(000)
μ(mm-1)
)
1.235
1472
0.299
Number of parameters 405
R(F2) [I > 2σ(I)]
0.1196
0.2775
wR(F2) [I > 2σ(I)]
Crystal size (mm) 0.40 × 0.30 × 0.05 Goodness of fit on F2 1.17
Max/min ꢀρ (e Å−3
)
0.30/−0.37

194
G. E. Delgado et al.
Figure 1. The molecular structure of (I), showing the atomic numbering scheme. Displacement
ellipsoids are drawn at 25% probability level. H atoms are shown as spheres of arbitrary radii.
2.2 Spectral Studies
The synthesized compound was characterized by spectroscopic data. The Fourier transform
infrared spectroscopy (FT-IR) absorption spectrum was obtained as KBr pellet using a
1
Perkin-Elmer 1600 spectrometer. H-NMR and 13C-NMR spectra were recorded on a
Bruker Avance 400 model spectrometer in DMSO-d6 solution.
FT-IR: 1174 cm−1 (t, C N), 1739 cm−1 (t, C O), 3152 cm−1 (t, N-H)].
1H-NMR (400 MHz, DMSO-d6): δ 11.60 (s, 1H, N3H3), 10.02 (s, 1H, N1H1), 4.20
(d, 1H, C5H5), 1,78 (m, 1H, C6H6), 1.16 (m, 2H, C8H8), 0.88 (t, 3H, C7H7), 0.73 (d, 3H,
C9H9).
13C-NMR (100 MHz, DMSO-d6): δ 182.71 (C2), 175.97 (C4), 64.33 (C5), 36.04 (C6),
23.50 (C8), 14.87 (C7), 13.24 (C9).

Crystal Structure of 2-Thiohydantoin-L-Isoleucine
195
Table 2. Selected geometrical parameters (Å, ◦)
Molecule 12
Molecule 21
S1-C2
O1-C4
N1-C2
N3-C2
S1-C2-N1
S1-C2-N3
C5-N1-C2-S1
C4-N3-C2-S1
C4-C5-C6-C7
C4-C5-C6-C8
Molecule 33
1.658(8)
1.224(9)
1.333(13)
1.386(9)
127.8(6)
125.2(7)
179.2(7)
−179.5(7)
−175.4(8)
57.1(10)
S2-C21
O2-C41
N11-C21
1.646(8)
1.242(8)
1.357(12)
1.378(9)
128.4(6)
125.4(7)
−174.8(6)
−179.7(7)
−178.0(7)
54.5(9)
N31-C21
S2-C21-N11
S2-C21-N31
C41-N31-C21-S2
C52-N12-C22-S3
C41-C51-C61-C71
C41-C51-C61-C81
Molecule 44
S3-C22
O3-C42
N12-C22
N32-C22
S3-C22-N12
S3-C22-N32
C52-N12-C22-S3
C42-N32-C22-S3
C42-C52-C62-C72
C42-C52-C62-C82
1.659(8)
1.242(10)
1.302(12)
1.418(9)
130.8(6)
122.0(6)
−179.7(7)
−179.8(6)
−51.6(11)
−175.5(8)
S4-C23
O4-C43
N13-C23
1.653(8)
1.223(11)
1.290(12)
1.398(10)
128.7(6)
123.8(7)
−178.0(6)
177.6(6)
−59.1(9)
175.5(7)
N33-C23
S4-C23-N13
S4-C23-N33
C53-N13-C23-S4
C43-N33-C23-S4
C43-C53-C63-C73
C43-C53-C63-C83
2.3 X-Ray Data Collection and Structure Determination
Colorless rectangular crystal (0.40 × 0.30 × 0.05 mm) was used for data collection.
Diffraction data were collected at 298(2) K by ω-scan technique on a Rigaku AFC7S
Mercury diffractometer [19] equipped with graphite monochromatized MoKα radiation
(λ = 0.71073 Å). The data were corrected for Lorentz-polarization and absorption effects
Table 3. Hydrogen bonds geometry (Å, ◦). (D-donor; A-acceptor; H-hydrogen)
D H···A
D H
H···A
D···A
D H···A
N H1···O4(i)
0.860
0.860
0.860
0.860
0.860
0.860
0.860
0.860
2.080
2.100
2.150
2.040
2.020
2.030
2.550
2.610
2.921(9)
2.948(8)
2.962(8)
2.874(9)
2.860(9)
2.860(9)
3.371(8)
3.449(8)
165.0
167.0
159.0
164.0
165.0
163.0
159.0
164.0
N13 H13···O1(i)
N1 H11···O3(ii)
N12 H12···O2(ii)
N3 H31···O1(iii)
N33 H33···O3(iv)
N32 H32···S4(i)
N3 H3···S2(ii)
1
1
1
1
Symmetry codes: (i) −2 −x, 2 −y, 1−z, (ii) 2 −x, 2 −y, 1−z, (iii) −1+x, y, z, (iv) 1+x, y, z

196
G. E. Delgado et al.
Figure 2. A partial view of the crystal packing in the ba plane, shown the four molecules in the
asymmetric unit. H atoms not involved in hydrogen bonding have been omitted for clarity.
[19]. Three standard reflections were monitored every 100 reflections (intensity decay:
none). The structure was solved by direct methods using the SHELXS program [20] and
refined by a full-matrix least-squares calculation on F2 using SHELXL [20].
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 (methyls). All geometrical calculations were done using
the program Platon [21]. Table 1 summarizes the crystal data, intensity data collection, and
refinement details for the title compound.
3. Results and Discussion
The title compound (I) crystallizes as a diasteromeric mixture in the non-centrosymmetric
space group P212121 with four molecules in the asymmetric unit, two of these molecules
have an “RS” configuration, while the other two present an “SS” configuration. Figure 1
shows the molecular structure and the atom-labeling scheme of 2-thiohydantoin-L-
isoleucine. Selected geometrical parameters are presented in Table 2. All bond distances
and angles are normal [22] and are in agreement with the average values found in 43
entries with thiohydantoin ring fragments, searched in the Cambridge Structural Database
(CSD, version 5.34, May 2013) [22] with N1 and N3 unsubstituted and sp3 hybridization
at C5. For instance, the S1-C2 average distance value 1.654(8) Å in the four 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 +0.025(8) Å in C21 and −0.026(6)

Crystal Structure of 2-Thiohydantoin-L-Isoleucine
197
Figure 3. A portion of the crystal packing viewed in the ba plane. Intermolecular hydrogen bonds,
N
H···O are indicated by dashed lines. C atoms of the aliphatic chain and H atoms not involved in
hydrogen bonding have been omitted for clarity.
Å in N11, both in molecule 1. The S1-C2-N1 average bond angle 128.9(6)◦ for the four
molecules is greater than S1-C2-N3, 124.1(7)◦. This difference is also observed in all
43 fragments with average values of 127.7◦ and 125.2◦, respectively. These distances
and bond angles also agree with those found in the crystal structures of racemic and
enantiomeric 5-isopropyl-5-methyl 2-thiohydantoin, more recently reported [23, 24].
Figure 4. A partial view of the crystal packing viewed along the [010] direction. Intermolecular
hydrogen bonds, N H···S are indicated by dashed lines. H atoms not involved in hydrogen bonding
have been omitted for clarity.

198
G. E. Delgado et al.
The molecular structure and crystal packing of (I) are stabilized by N H···O and
N H···S hydrogen bonds. Details of the hydrogen-bonding geometry are given in Table 3.
The four molecules in the asymmetric interact through three hydrogen bonds of the type
N H···O (Fig. 2). There, the oxygen of one of the molecules acts as a bifurcated hydrogen-
acceptor, forming a trimmer sub-unit, described by the graph-set D1 (3) [25, 26].
2
The molecular structure and crystal packing of the title compound are stabilized by
six intermolecular N H···O hydrogen bonds, forming infinite one-dimensional chains that
run along [010] direction, which can be described in graph-set notation as C2 (10) [25, 26]
2
(Fig. 3). Together, these hydrogen bond patterns produce a two-dimensional array parallel
to the ba plane with the formation of a 26-atom macrocycle with graph-set R5 (26) (Fig. 3).
6
This graph-set is also observed in the 2-thiohydantoin structure [27]. These sheets are
parallel linked through the N H···S hydrogen bonds to form a bi-dimensional network
(Fig. 4).
4. Conclusions
The title compound was synthesized by a solvent-free reaction of L-isoleucine and thiourea.
The structure was unambiguously assigned by X-ray diffraction studies. The FT-IR and
nuclear magnetic resonance (NMR) results were consistent with the structural results. In
the crystal structure of 2-thiohydantoin-L-isoleucine, the molecules are linked by N H···O
and N H···S hydrogen bonds, forming infinite bi-dimensional network.
Funding
This work was supported by CDCHT-ULA (grant C-1853-13-08-A) and FONACIT (grant
LAB-97000821).
Supplementary Data
Crystallographic data for the structure reported here have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC-933210). These data can be obtained free of
charge from CCDC, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44)1223336033;
E-mail: deposit@ccdc.cam.ac.uk.
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