The Crystal Structures of Three Rhodanine-3-Carboxylic Acids

Article abstract of DOI:10.1007/s10870-016-0644-0

Abstract: The rhodanine derivatives show various pharmacological activities. Rhodanine-3-carboxylic acids can be used as the substrates in various synthesis of compounds containing rhodanine-3-carboxyalkyl moiety. In this paper new crystal structures of rhodanine-3-acetic acid and its two homologues, i.e. rhodanine-3-propionic acid and rhodanine-3-butyric acid, are reported. The relationship between the length of the alkyl chain and the geometry of these molecules was studied. The crystal network is dominated by strong hydrogen bonds O–H···O formed by the carboxyl groups. Additionally, weak C–H···O and C–H···S contacts are observed. Graphical Abstract: To study the difference in intermolecular interactions of rhodanine-3-carboxylic acid, three crystal structures were determined by X-ray diffraction method. The crystal network in all studied structures is built of homosynthons and stabilized by weak C–H···O and C–H···S contacts.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-016-0644-0

J Chem Crystallogr
DOI 10.1007/s10870-016-0644-0
ORIGINAL PAPER
The Crystal Structures of Three Rhodanine-3-Carboxylic Acids
2
1
Waldemar Tejchman1 Agnieszka Skorska-Stania Ewa Zesławska
_
•
•
´
Received: 14 October 2015 / Accepted: 24 March 2016
Ó Springer Science+Business Media New York 2016
Abstract The rhodanine derivatives show various phar-
macological activities. Rhodanine-3-carboxylic acids can
be used as the substrates in various synthesis of compounds
containing rhodanine-3-carboxyalkyl moiety. In this paper
new crystal structures of rhodanine-3-acetic acid and its
two homologues, i.e. rhodanine-3-propionic acid and rho-
danine-3-butyric acid, are reported. The relationship
between the length of the alkyl chain and the geometry of
these molecules was studied. The crystal network is dom-
inated by strong hydrogen bonds O–HÁÁÁO formed by the
carboxyl groups. Additionally, weak C–HÁÁÁO and C–HÁÁÁS
contacts are observed.
Introduction
The treatment of bacterial infections remains a challenging
therapeutic problem because of the increasing number of
multidrug-resistant bacteria. There is still a need for new
antibacterial agents, especially for those with unique
structural features that can influence by different mecha-
nisms of action.
Heterocyclic compounds have been often used in
medicinal chemistry in order to find new potential drug. In
this group of heterocycles there are molecules with a rho-
danine ring, containing the five-membered thiazolidine
with exocyclic sulfur and oxygen atoms (Scheme 1).
Rhodanine moiety is present in many molecules showing
various pharmacological activities. It was reported their
antidiabetic [1–4], antifungal [5–7], antimicrobial [8–10],
pesticidal [11] and anticancer [12] activity. Among bio-
logically active compounds there are also the 3-car-
boxyalkyl-rhodanine derivatives. One of them, epalrestat,
Graphical Abstract To study the difference in inter-
molecular interactions of rhodanine-3-carboxylic acid,
three crystal structures were determined by X-ray diffrac-
tion method. The crystal network in all studied structures is
built of homosynthons and stabilized by weak C–HÁÁÁO and
C–HÁÁÁS contacts.
has been used as the drug in the treatment of diabetic
neuropathy in Japan [13].
Keywords Rhodanine-3-acetic acid Á N-
(carboxyalkyl)rhodanine Á X-ray crystal structure Á
Intermolecular interactions Á Thiazolidine ring
In this paper, we report three new crystal structures of
rhodanine-3-carboxylic acids, namely 4-oxo-2-thioxo-3-
thiazolidineacetic acid (RA1), 4-oxo-2-thioxo-3-thiazo-
lidinepropionic acid (RA2) and 4-oxo-2-thioxo-3-thiazo-
lidinebutyric acid (RA3). These acids can be used as
substrates in various synthesis of rhodanine derivatives
[14]. Thus far, the crystal structures of these compounds
were not determined. Three crystal structure of tin
_
& Ewa Zesławska
zeslawsk@up.krakow.pl
1
Department of Chemistry, Institute of Biology, Pedagogical
´
University, Podchora˛z_ych 2, 30-084 Krakow, Poland
2
Faculty of Chemistry, Jagiellonian University, Ingardena 3,
´
30-060 Krakow, Poland
123

J Chem Crystallogr
Scheme 1 A molecular
diagram of rhodanine
refined anisotropically using weighted full-matrix least-
squares on F2, while the hydrogen atoms attached to carbon
atoms were refined isotropically in calculated positions
using riding model. Hydrogen atoms attached to oxygen
atoms were located in the difference Fourier map and refined
without any restraints. Crystal data and structure refinement
are summarized in Table 1. For molecular graphics ORTEP
[23] and MERCURY [24] programs were used.
complexes with RA1 were described earlier [15], while
there are numerous derivatives, both with carboxylate and
carboxylic acid groups deposited in the Cambridge Struc-
tural Database (CSD, ConQuest version 1.17) [16, 17];
there is one derivative of RA2 [18], and no known
derivatives for RA3.
Results and Discussion
RA1 Crystal Structure
The molecular geometry in the crystal structure of RA1
with the atom numbering is shown in Fig. 1. The bond
lengths have typical values. The thiazolidine ring is planar,
the rms deviation for the non-hydrogen atoms forming the
Experimental
The syntheses of investigated compounds were performed
using the modified methods described previously [19]. The
suitable amino acid with carbon disulphide in an alkaline
environment were used in order to obtain the salt
(Scheme 2). The salt, after treatment with chloroacetic
acid, converts to intermediate product very easily, then in
the presence of hydrochloric acid cyclizes to rhodanine-3-
carboxylic acid.
˚
plane is 0.0169 A. The carboxyl group is perpendicular to
rhodanine moiety. The angle between the planes of thia-
zolidine ring (S1, C2, N3, C4, C5) and the carboxylic
group (C7, O2, O3) is 88.9(1)°. This value is similar to
those of observed in the known crystal structures for RA1
derivatives, the range from 87.5° [25] to 79.2° [26];
whereas for the carboxylate compounds, the range of this
angle is somewhat greater, from 88.3° [25] to 70.9° [27].
The packing of the molecules in the crystal structure
can be characterized by the intermolecular interactions
listed in Table 2. As is usual for carboxylic acid com-
pounds, strong hydrogen bonding between the carboxylic
acid groups of two adjacent molecules leads to the for-
mation of H-bonded dimers with graph-set motif R22(8)
(Fig. 2) [28]. The dimers are joined to each other by weak
C–HÁÁÁO and C–HÁÁÁS interactions (Table 2). The thiazo-
lidine rings build the layers almost parallel to (010) plane
directing carboxyl groups between the layers. The bond
angle between the plane of rhodanine ring and the plane
(010) is 20°.
All obtained compounds were characterized by their
melting points (Boethius apparatus), 145–147, 156–158
and 116–118 °C for RA1, RA2 and RA3, respectively. The
values were in agreement with early published for these
compounds [20, 21].
The crystals of all the reported acids suitable for X-ray
analysis were obtained from propyl acetate by slow evapo-
ration of the solvent at 20 °C. All diffraction data were
collected at 120 K using a SuperNova diffractometer with
˚
Mo (0.71069 A) Ka radiation source. The phase problems
were solved by direct methods with SHELXS for all three
compounds and the final refinements were performed by
SHELXL program [22]. All the non-hydrogen atoms were
Scheme 2 Synthesis of the
rhodanine-3-carboxylic acids:
RA1 (n = 1), RA2 (n = 2) and
RA3 (n = 3)
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J Chem Crystallogr
Table 1 Crystal and structure refinement data for RA1, RA2 and RA3
Identification code
RA1
RA2
RA3
Empirical formula
Formula weight
Temperature (K)
C5 H5 N O3 S2
191.22
C6 H7 N O3 S2
205.25
C7 H9 N O3 S2
219.27
120
120
120
˚
Wavelength (A)
0.71073
0.71073
0.71073
ꢀ
Triclinic/P1
Crystal system/space group
Unit cell dimensions
Orthorhombic/Pbcn
a = 22.2310 (6)
b = 7.0835 (2)
c = 10.4821 (3)
1650.65 (8)
Monoclinic/P21/n
a = 5.1549 (2) a = 90
b = 31.979 (2) b = 97.670 (3)
c = 5.5708 (2) c = 90
910.12 (6)
a = 6.9906 (4) a = 90.460 (5)
b = 7.3159 (4) b = 93.863 (5)
c = 7.4597 (5) c = 90.020 (5)
380.63 (4)
˚
a, b, c (A)
a, b, c (°)
3
˚
Volume (A )
Z, Calculated density (Mg/m3)
2, 1.668
8, 1.652
4, 1.600
Absorption coefficient (mm-1
F(000)
)
0.652
0.608
0.557
196
848
456
Crystal size (mm)
Colour of compound
0.67 9 0.35 9 0.01
Orange
0.87 9 0.35 9 0.25
Orange
0.62 9 0.50 9 0.31
Orange
Theta range for data collection (°)
Reflections collected/unique
Reflections [I [ 2r(I)]
3.867–27.996
3.018–28.647
20517/2057 [RINT = 0.0429]
1811
3.745–29.291
41322/2419 [RINT = 0.1292]
2153
5105/1745 [RINT = 0.0309]
1507
Data/restraints/parameters
Goodness-of-fit on F2
1745/0/105
2057/0/113
2419/0/122
1.069
1.081
1.126
Final R indices [I [ 2r(I)]
Largest diff. peak and hole (e/A )
R1 = 0.0288, wR2 = 0.0635
0.340 and -0.270
R1 = 0.0268, wR2 = 0.0641
0.332 and -0.320
R1 = 0.0428, wR2 = 0.0949
0.395 and -0.332
3
˚
RA2 Crystal Structure
The molecular geometry in the crystal structure of RA2 is
given in Fig. 3. The thiazolidine ring is planar, the rms devi-
ation for the non-hydrogen atoms forming the plane is
˚
0.0180 A. The carboxyl group has another orientation to rho-
danine moiety in comparison to RA1. The angle between the
planes of the thiazolidine ring (S1, C2, N3, C4, C5) and the
carboxylic group (C8, O2, O3) is 55.8(1)°. This value differs
from one of the derivative with the same 3-N-carboxyethyl
substituent [18], in which this interplanar angle is 81.2°.
In the crystal lattice the expected intermolecular
hydrogen bonds O–HÁÁÁO are observed, which parameters
are listed in Table 3. This type of interactions leads to the
formation of dimers similar to RA1 crystal structure. The
characteristic rings R22(8) are arranged above each other
Fig. 1 Atom numbering schemes of RA1. Displacement ellipsoids
are drawn at the 50 % probability level
Table 2 Intermolecular
interaction for RA1
˚
˚
HÁÁÁA (A)
DÁÁÁA (A)
D–H–A (°)
Symmetry code
O3–H3ÁÁÁO2
C5–H5AÁÁÁS2
C5–H5BÁÁÁS2
C6–H6BÁÁÁO1
1.84 (3)
2.93
2.677 (2)
3.861 (2)
3.619 (2)
3.327 (2)
175 (2)
161
-x ? 2, -y ? 1, -z ? 1
-x ? 1, -y ? 1, -z
-x ? 1, -y ? 2, -z
-x ? 2, -y ? 2, -z
2.99
124
2.54
139
123

J Chem Crystallogr
Fig. 3 Atom numbering
schemes of RA2. Displacement
ellipsoids are drawn at the 50 %
probability level
Fig. 2 Partial packing view
along [100] direction for RA1.
Dashed lines indicate hydrogen
bonds and weak intermolecular
interactions
Table 3 Intermolecular
interaction for RA2
˚
˚
HÁÁÁA (A)
DÁÁÁA (A)
D–H–A (°)
Symmetry code
O3–H3ÁÁÁO2
C5–H5AÁÁÁS2
C6–H6AÁÁÁO1
C6–H6BÁÁÁO1
1.79 (3)
2.96
2.636 (1)
3.620 (2)
3.234 (2)
3.480 (2)
171 (3)
126
-x, -y ? 2, -z ? 2
-x ? 1/2,-y ? 1/2, z - 1/2
x, -y ? 1, z ? 1/2
2.46
136
2.55
160
-x, y, -z ? 3/2
along [001] direction creating the channels. The neigh-
bouring channels are formed in [010] direction (Fig. 4).
The crystal structure is additionally stabilized by C–HÁÁÁO
and C–HÁÁÁS interactions (Table 3). The rhodanine rings
are oriented in two various positions forming the inter-
planar angle 83.6°.
123

J Chem Crystallogr
Fig. 4 Partial packing view along [001] direction for RA2. Dashed lines indicate hydrogen bonds
RA3 Crystal Structure
this interaction are listed in Table 4. The ribbons are sit-
uated in two various directions parallel to planes (2 15 0)
and (2 17 0) forming the interplanar angle 80.9°. In addi-
tion, the crystal structure is stabilized by weak C–HÁÁÁO
interactions between the ribbons.
The molecular geometry in the crystal structure with the
atom numbering system is presented in Fig. 5. The thia-
zolidine ring is also planar as in RA1 and RA2, the rms
deviation for the non-hydrogen atoms forming the plane is
To summarize, in all investigated compounds the
geometry of rhodanine moiety is planar. The length of the
alkyl chain does not influence on the bonds and angles
values of the rhodanine ring.
˚
0.0237 A. The carboxyl group has another orientation to
rhodanine moiety in comparison to RA1 and RA2. The
angle between the planes of the thiazolidine ring (S1, C2,
N3, C4, C5) and the carboxylic group (C9, O2, O3) is
72.5(1)°.
All three rhodanine-3-carboxylic acids form dimers, as a
result of strong O–HÁÁÁO interactions, as is usual for these
compounds. Moreover, the crystal network is stabilized by
C–HÁÁÁO and C–HÁÁÁS interactions. The arrangement of the
rhodanine ring in the crystal network is various. In RA1 the
rhodanine rings are parallel and build the layers, whereas in
other two structures the various orientations of these rings
prevent the formation of the layers by them.
The characteristic rings R22(8) created by hydroxyl
groups are also observed as in other two RA1 and RA2
crystal structures. The neighbouring dimers are connected
by C–HÁÁÁS interactions (Table 4). The arrangement of the
molecules in the crystal lattice of RA3 leads to formation
of ribbon along [001] direction, which build two butyric
carboxylic chains belonging to two molecules connected
by O–HÁÁÁO hydrogen bonds (Fig. 6). The parameters of
The presence of carboxylic group seems to be important
for biological activity of rhodanine compounds [13]. The
123

J Chem Crystallogr
Fig. 5 Atom numbering
schemes of RA3. Displacement
ellipsoids are drawn at the 50 %
probability level
Table 4 Intermolecular
interaction for RA3
˚
˚
HÁÁÁA (A)
DÁÁÁA (A)
D–H–A (°)
Symmetry code
O3–H3ÁÁÁO2
C5–H5AÁÁÁS2
C8–H8AÁÁÁO1
1.90 (3)
2.83
2.662 (2)
3.526 (2)
3.088 (2)
172 (4)
130
-x ? 3, -y, -z ? 1
x, y, z ? 1
2.53
116
x ? 1, y, z
Fig. 6 Partial packing view along [100] direction for RA3. Dashed lines indicate hydrogen bonds and weak intermolecular contacts
distance between carboxylic group and rhodanine ring
effects flexibility of the alkyl chain and indeed the mutual
arrangement of the carboxylic group. The orientation of the
carboxylic groups seems to be always nearly perpendicular
(88.9(1)° (here)–79.2° [26]) to the rhodanine ring for those
compounds containing the acetic acid/acetate groups. For
123

J Chem Crystallogr
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Supplementary data
CCDC 1430696-1430698 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
_
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Compliance with Ethical Standards
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Conflict of interest The authors declare that they have no conflict
of interest.
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