Synthesis and crystal structure determination of hydantoin-l-proline

Article abstract of DOI:10.1007/s10870-012-0344-3

The title compound, hydantoin-l-proline, C₆H₈N ₂O₂, crystallize in the orthorhombic system with space group P2₁2₁2₁ (N°19), Z = 4, and unit cell parameters a = 7.136(1) A, b = 8.009(2) A, c = 11.378(2) A. The molecular structure shows a hydantoin and pyrrolidine ring coupling forming a bicyclohydantoin. The crystal packing is governed by N-H???O hydrogen bond-type intermolecular interactions, forming infinite one-dimensional chains.

Full text of DOI:10.1007/s10870-012-0344-3

J Chem Crystallogr (2012) 42:968–971
DOI 10.1007/s10870-012-0344-3
ORIGINAL PAPER
Synthesis and Crystal Structure Determination
of Hydantoin-L-Proline
Gerzon E. Delgado
Asilo e´ J. Mora
•
Luis E. Seijas
•
Received: 7 February 2012 / Accepted: 13 June 2012 / Published online: 30 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The title compound, hydantoin-L-proline, C H8
6
are used as herbicides [13] and fungicides agents [14]. For
N O , crystallize in the orthorhombic system with space
2
the other hand, the biocatalytic conversion of 5-substituted
hydantoins to amino acids has received considerable
attention recently for your potential applications in the
industrial productions of optically pure amino acids [15,
16].
2
group P2 2 2 (N°19), Z = 4, and unit cell parameters
1
1 1
˚
˚
˚
a = 7.136(1) A, b = 8.009(2) A, c = 11.378(2) A. The
molecular structure shows a hydantoin and pyrrolidine ring
coupling forming a bicyclohydantoin. The crystal packing
is governed by N–HÁÁÁO hydrogen bond-type intermolecu-
lar interactions, forming infinite one-dimensional chains.
For these reasons, there has been much interest in the
search of new synthetic routes for hydantoin via solution
[
17], or solid state reactions [18–21].
Keywords X-ray crystal structure Á Hydrogen bonding Á
In our laboratory we are interested in the study of
Hydantoin
N-carbamoyl and hydantoin natural amino acids derivative
compounds [22–26], therefore we report here the structure
of the hydantoin derivative of the natural amino acid
L-proline. The analysis of the hydrogen bond patterns is
also discussed.
Introduction
The imidazolidine-2,4-dione, or hydantoin, is a common
5
-member ring containing a reactive cyclic urea core [1, 2].
This heterocycle represents a significant molecular tem-
plate in combinatorial chemistry libraries [3–5], due prin-
cipally to the four possible points of substitutions. The
biological activities of hydantoin derivatives has been
known for a long time, and are responsible for a wide
variety of biological behavior [6], due principally to its
wide range of therapeutic properties. For instance, several
applications have been reported for hydantoins: antiar-
rhythmic and antihypertensive [7], antiviral [8], antineo-
plastic [9], antitumoral [10] and anticonvulsant agents [11].
The best known hydantoin, phenytoin, is the most widely
used antiepileptic drug [12]. In addition, these compounds
Experimental
Synthesis
The title compound was synthesized from L-proline using a
methodology previously reported [22, 23]. 500 mg
(4.3 mmol) of L-proline was dissolved in 20 mL of water
and the solution was acidified with concentrated HCl
(37 % v/v) to pH = 5. Then, 1,050 mg (12.9 mmol) of
KOCN was added to this solution. The mixture was
warmed up, with agitation, to 60 °C, during 4 h. The
resultant solution was acidified with HCl to pH = 2 and
agitated during 4 h, until the precipitation of a white solid.
The solid was filtered and washed with cool water. Col-
orless crystals of 1 suitable for X-ray diffraction analysis
were grown by slow evaporation in a 1:1 methanol–water
G. E. Delgado (&) Á L. E. Seijas Á A. J. Mora
Laboratorio de Cristalograf ´ı a, Departamento de Qu ´ı mica,
Facultad de Ciencias, Universidad de Los Andes,
M e´ rida 5101, Venezuela
-
1
solution (m.p.: 210–212 °C). FT-IR 1757.6 cm [t, C=O],
-
1708.7 cm [t, C=O]. H NMR (400 MHz, DMSO-d )
1
1
e-mail: gerzon@ula.ve
6
1
23

J Chem Crystallogr (2012) 42:968–971
969
Scheme 1 Synthesis of
hydantoin-L-proline
d = 7.27 (H3), 4.07 (t, H5), 3.43 (c, H6A), 3.02 (c, H6B),
2
.03 (q, H8A), 1.60 (q, H8B), 1.90 (m, H7A), 1.93 (H7B).
1
3
C NMR (100.6 MHz, DMSO-d ) d = 161.0 (C2), 174.5
6
(
(
C4), 64.0 (C5), 44.9 (C6), 26.7 (C8), 26.6 (C7)
Scheme 1).
X-Ray Crystallography
Colorless rectangular crystal (0.4, 0.2, 0.1 mm) was used
for data collection. Diffraction data were collected at
298(2) K by x-scan technique on a Rigaku AFC7S Mercury
Fig. 1 The molecular structure of 1, showing the atomic numbering
scheme. Displacement ellipsoids are drawn at 50 % probability level.
H atoms are shown as spheres of arbitrary radii
diffractometer [27] equipped with graphite-monochroma-
˚
tized MoKa radiation (k = 0.71073 A). The data were
corrected for Lorentz-polarization and absorption effects
[
28]. The structure was solved by direct methods using the
SHELXS97 program [29] and refined by a full-matrix least-
2
squares calculation on F using SHELXL97 [29]. In the
Table 1 Crystal data, data collection and structure refinement
absence of significant anomalous dispersion effects Friedel
pairs were merged [30]. This parameter confirms the correct
absolute structure of hydantoin-L-proline, which is known
from the starting material L-proline.
Chemical formula
Formula weight
Crystal system
Space group
6 8 2 2
C H N O
140.14
Orthorhombic
P2
1 1 1
2 2
All H atoms were placed at calculated positions and
treated using a riding model, with C–H distances 0.96–
˚
a (A)
7.136 (1)
8.009 (2)
11.378 (7)
650.3 (2)
4
˚
b (A)
˚ ˚
0.98 A and U (H) = 1.2 Ueq (C)], N–H 0.86 A and
iso
˚
c (A)
Uiso (H) = 1.2 Ueq (N)].
3
V (A )
˚
Z
-3
)
˚
Table 2 Selected geometrical parameters (A, °)
d
x
(g cm
1.431
F (000)
296
O2–C2
1.215(2)
1.352(2)
1.468(2)
1.356(2)
1.522(2)
1.529(3)
128.4(2)
110.9(1)
111.6(1)
-170.6(2)
-34.7(3)
O4–C4
1.224(2)
1.461(2)
1.408(2)
1.499(2)
1.529(3)
106.9(1)
124.7(2)
123.0(1)
111.9(1)
172.1(2)
-177.5(2)
-
1
)
l (mm
0.110
N1–C2
N1–C5
h range (°)
hkl range
3.1–28.1
-9 B h B 8
N1–C8
N3–C2
N3–C4
C4–C5
-
-
9 B k B 9
C5–C6
C6–C7
14 B l B 14
C7–C8
N1–C2–N3
N3–C2–O2
C2–N1–C8
C2–N3–C4
C4–N3–C2–O2
C2–N3–C4–O4
Reflections
Collected
N1–C2–O2
C2–N1–C5
C5–N1–C8
C5–N1–C2–O2
C8–N1–C2–O2
7,408
Unique (Rint
)
1,374(0.026)
With I [ 2r(I)
1,207
2
Refinement method
Number of parameters
Full-matrix least-squares on F
93
2
R(F ) [I [ 2r(I)]
0.0389
0.1042
1.09
wR(F2) [I [ 2r(I)]
Goodness of fit on F
˚
Table 3 Hydrogen bonds geometry (A, °)
2
-
3
D–HÁÁÁA
D–H
0.98
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
˚
Max/min Dq (e A
)
0.17/-0.13
-0.2(2)
1,374
Flack parameter
Friedel pairs
(i)
N3–H3ÁÁÁO4
i
Symmetry codes( ) -x, 1/2 ? y, 1/2 - z
1.90
2.881(2)
174
123

9
70
J Chem Crystallogr (2012) 42:968–971
Fig. 2 A portion of the crystal
packing viewed in the cb plane.
Intermolecular hydrogen bonds,
N–HÁÁÁO, are indicated by
dashed lines. H atoms not
involved in hydrogen bonding
have been omitted for clarity
Fig. 3 Packing view of 1
showing the extended chains
along the b axis and separated
3
˚
.57 A along the a direction
Crystallographic data for the structure reported here
The molecular structure shows the coupling between the
hydantoin and pyrrolidine rings forming a bicyclohydan-
toin. The hydantoin ring is essentially plane with a maxi-
have been deposited with the Cambridge Crystallographic
Data Centre (Deposition No. CCDC-835894). The data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/
perl/catreq.cgi (or from the CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK; Fax: ?44 1223 336033; e-mail:
deposit@ccdc.cam. ac.uk).
˚
mal deviations of 0.049(1) A in N1 and -0.050(4) A in
˚
C7. The pyrrolidine ring shows maximal deviations to the
˚
average plane in the atoms C3 (-0.225(3) A) and C4
˚
(0.176(3) A).
The N1–C2–O2 bond angle 128.4(2)° is slightly greater
than the N3–C2–O2 angle 124.7(2)° (Table 2). This dif-
ference is also observed in the hydantoin molecule [32] and
the others hydantoin derivative compounds found in the
Cambridge Structural Database, CSD version 5.32 updates
(Nov 2011) [33], including the same hydantoin structural
report without hydrogen atoms [34].
Results and Discussion
Figure 1 shows the molecular structure and the atom-
labeling scheme of 1 [31], and Table 1 shows the crystal-
lographic data and structure refinement parameters.
1
23

J Chem Crystallogr (2012) 42:968–971
971
The asymmetry parameter analysis of the pyrrolidine
10. Carmi C, Cavazzoni A, Zuliani V, Lodola A, Bordi F, Plazzi PV,
Alfieri RR, Petronini PG, Mor M (2006) Bioorg Med Chem Lett
ring, [DCs
max
´
= ?47.1(3)°, DCsmin = ?1.9(4)°, DC2max
´
1
1. Singh G, Driever PH, Sander JW (2005) Brain 128:7
6:4021
=
?62.0(3)°, DC2min = 16.5(3)°, DCs(C8) = 1.9(4)°, DCs
C6–N1) = 1.9(4)°], indicates that the same adopt an
envelope conformation [35].
1
(
12. Merrit HH, Putnam TJ (1938) Schweiz Arch Neurol Psychiatr
39:1003
1
1
3. Shiozaki M (2002) Carbohydr Res 337:2077
4. Marton J, Enisz J, Hosztafi S, Tim a´ r T (1993) J Agric Food Chem
The molecular structure and crystal packing of 1 are
stabilized by intermolecular N3–H3ÁÁÁO4 (-x, 1/2 ? y,
4
1:148
1
/2 - z) hydrogen bonds (Table 3), forming infinite one-
15. Wilms B, Wiese A, Syldatk C, Mattes R, Altenbuchner J (2001) J
Biotechnol 86:19
1
dimensional zigzag chains that run along [010] direction,
which can be described in graph-set notation as C(4) [36].
These chains which extend along the b axis overlap
resulting in a lamellar packing type with layers of chains
stack along the a axis direction with an average interplanar
6. Burton SG, Dorrington RA (2004) Tetrahedron Asymmetry
5:2737
7. Kleinpeter E (1997) Struct Chem 2:161
1
1
18. Ganesan A (2003) Methods Enzymol 369:415
zquez J, Royo M, Albericio F (2004) Lett Org Chem 1:224
19. Va
20. Alsina J, Scott WL, O’Donnell MJ (2005) Tetrahedron Lett
6:3131
´
˚
separation of 3.57 A (Figs. 2, 3).
4
2
2
2
2
2
2
1. Kumar V, Rana H, Sankolli R, Kaushik MP (2011) Tetrahedron
Lett 52:6148
2. Seijas LE, Delgado GE, Mora AJ, Bahsas A, Uzcategui J (2006)
Av Qu ´ı m 1:3
3. Seijas LE, Delgado GE, Mora AJ, Bahsas A, Brice n˜ o A (2007)
Acta Cryst C63:o303
4. Delgado GE, Mora AJ, Uzc a´ tegui J, Bahsas A, Brice n˜ o A (2007)
Acta Cryst C63:o448
5. Seijas LE, Mora AJ, Delgado GE, Brunelli M, Fitch AN (2010)
Powder Diffr 25:342
6. Delgado GE, Seijas LE, Mora AJ, Gonz a´ lez T, Brice n˜ o A (2012)
J Chem Crystallogr 42:388
7. Rigaku (2002) CrystalClear. Rigaku Corporation, Tokyo
8. Rigaku MSC (2004) Crystal structure. Rigaku/MSC, The
Woodlands
9. Sheldrick GM (2008) Acta Cryst A64:112
0. Flack HD (1983) Acta Cryst A39:876
Acknowledgments This work was supported by CDCHT-ULA
(
Grant C-1755-11-08-B) and FONACIT (Grant LAB-97000821). The
authors also thank to MSc. Teresa Gonz a´ lez and Dr. A. Brice n˜ o,
IVIC, Venezuela, for data collection.
References
1
. L o´ pez CA, Trigo GG (1985) Adv Heterocycl Chem 38:177
2
. Meusel M, G u¨ tschow M (2004) Org Prep Proced Int 36:391
3. Park KH, Ehrler J, Spoerri H, Kurth MJ (2001) J Comb Chem
2
2
3
:171
4
5
. Lin MJ, Sun CM (2003) Tetrahedron Lett 44:8739
. Zhang W, Lu YM, Chen CHT, Zeng L, Kassel DB (2006) J Comb
Chem 8:687
2
3
3
3
3
3
6
. Mutschler E, Derendorf H (1995) Drug actions, basic principles
and therapeutic aspects. Medpharm Scientific Publishers,
Stuttgart
1. Brandenburg K (1998) DIAMOND. Crystal Impact GbR, Bonn
2. Yu FL, Schwalbe CH, Watkin DJ (2004) Acta Cryst C60:o714
3. Allen FH (2002) Acta Cryst B58:380
7
8
. Dylag T, Zygmunt M, Maciag D, Handzlik J, Bednarski M,
Filipek B, Kiec-Kononowicz K (2004) Eur J Med Chem 39:1013
. Opacic N, Barbaric M, Zorc B, Cetina M, Nagy A, Frkovic D,
Kralj M, Pavelic K, Balzarini J, Andrei G, Snoeck R, Declercq E,
Raic-Malic S, Mintas M (2005) J Med Chem 48:475
. Lattmann E, Ayuko WO, Kinchinaton D, Langley CA, Singh H,
Karimi L, Tisdale MJ (2003) J Pharm Pharmacol 55:1259
4. Arte E, Tinant B, Declercq J, Germain G, van Meerssche M
(
1980) Bull Soc Chim Belg 89:379
3
3
5. Griffin JF, Duax W, Weeks M (1984) Atlas of steroid structure.
Plenum Publishing Corporation, New York
6. Etter MC (1990) Acc Chem Res 23:120
9
123