Crystallographic studies of (Z) and (E) isomers of 2-amino-5-(2-chlorobenzylidene)-1-methyl-1H-imidazol-4(5H)-one

Article abstract of DOI:10.1016/j.molstruc.2009.11.058

The X-ray structures of two geometric isomers of 5-(2-chlorobenzylidene)-creatinine (1) are reported. In the crystal of almost planar 1-(E) hydrogen bonded centrosymmetric dimmers dominate, while in the structure of 1-(Z), adopting the twisted conformatio

Full text of DOI:10.1016/j.molstruc.2009.11.058

Journal of Molecular Structure 966 (2010) 14–17
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Crystallographic studies of (Z) and (E) isomers of
2-amino-5-(2-chlorobenzylidene)-1-methyl-1H-imidazol-4(5H)-one
b
a
b,1
Janina Karolak-Wojciechowska a, ,1, Ewa Szymanska , Andrzej Fruzinski , Katarzyna Kiec-Kononowicz
*
´
´
´
a
_
´
´
Institute of General and Ecological Chemistry, Technical University of Łódz, Zeromskiego 116, 90-924 Łódz, Poland
b Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2009
Received in revised form 23 November 2009
Accepted 29 November 2009
Available online 4 December 2009
The X-ray structures of two geometric isomers of 5-(2-chlorobenzylidene)-creatinine (1) are reported. In
the crystal of almost planar 1-(E) hydrogen bonded centrosymmetric dimmers dominate, while in the
structure of 1-(Z), adopting the twisted conformation, helical chains motifs, subsequently intertwined
in braids, are preferred. Both creatinine analogs were found to crystallize in the 2-amino tautomeric form.
X-ray investigations have been supported with 1H and 13C NMR data that confirmed 2-amino form also in
DMSO solutions of (E)- and (Z)-5-(2-chlorobenzylidene)-creatinine.
Keywords:
Ó 2009 Elsevier B.V. All rights reserved.
5-Arylidene-imidazolones
5-Substituted creatinine derivatives
Hydrogen bonds patterns
1. Introduction
(1). The presence of a methyl substituent at the N1 position limits
the number of possible tautomers to two forms (Scheme 2). The
Compounds based on the imidazolidine-4-one scaffold such as
hydantoin, 2-thiohydantoin and creatinine analogs show a wide
range of biological activity including their anticonvulsant [1], anti-
arrhythmic [2], antihypertensive [3], antibacterial or fungicidal
properties [4]. Due to biological importance of this class of
compounds, their molecular structure has been intensively stud-
ied, both in solutions and in the solid state [5]. Introduction of an
arylidene fragment into position 5 of imidazolidine-4-one gener-
ates numerous structural questions concerning both stereochemis-
try and electron distribution. For each of possible geometric E/Z
isomers the equilibrium of, at least, three possible tautomeric
forms may be observed (Scheme 1). During synthetic research
(Z)-isomers were obtained predominantly among N1-unsubstitut-
ed derivatives [5–11], while in the case of N1-substituted analogs
(E)-isomers were detected as well [5–7,12,13].
The structure determination for 5-arylidene-imidazolidine-4-
one derivatives has been an object of extensive studies using both
spectral and crystallographic methods carried out also by our
group [4,10,13–16]. Structural problems reported recently due to
the potential tautomerism of some 5-arylidene-2-amino-imida-
zol-4-ones and multiplication of spectroscopic NMR signals in
solutions observed for this series [17] prompted us to perform a
synthesis of a new derivative: 5-(2-chlorobenzylidene)-creatinine
results of X-ray studies supported with the spectral data for both
geometric isomers (abbreviated as 1-(Z) and 1-(E)) are reported
in our present work.
2. Experimental
2.1. Source of the compounds
Melting points (uncorrected) were determined on Mel-Temp
melting point apparatus (Laboratory Devices Inc., USA). 1H and
13C NMR spectra of the compounds were recorded on the spec-
trometer Varian Mercury 300 MHz and 75 MHz respectively using
DMSO-d6 (dimethyl-d6-sulfoxide) with TMS as an internal stan-
dard. 2D HMBC spectra were acquired using standard pulse
sequence with 64 repetitions for each of 400 t1 increments, transfer
delay was optimized for nJ = 8 Hz.
A mixture of creatinine (1.13 g, 0.01 mol), 2-chlorobenzalde-
hyde (1.2 eq, 1.69 g, 0.012 mol) and sodium acetate (3.28 g,
0.04 mol) in acetic acid (15 mL) was refluxed for 4 h. After cooling
the yellow solid was filtrated and washed with water (30 mL) to
give the crude 1-(E). In the filtrate the precipitation was observed;
the second solid was filtrated and washed with water (30 mL) to
give the crude 1-(Z).
(E)-2-Amino-5-(2-chlorobenzylidene)-1-methyl-1H-imidazol-4(5H)-
one (1-(E)). Purified by two-time crystallization from the mixture of
acetone:methanol:acetic acid 4:8:1.Yield 37% (0.87 g), m.p. 240–
242 °C. 1H NMR (300 MHz, DMSO-d6): d [ppm] 3.17 (s, 3H, CH3), 6.20
(s, 1H, @CH), 7.23–7.27 (m, 2H, Ar), 7.41–7.44 (m, 1H, Ar), 7.90 (br.s,
* Corresponding author. Tel.: +48 604454552; fax: +48 426313128.
E-mail address: Janina.Karolak-Wojciechowska@p.lodz.pl (J. Karolak-Wojcie-
chowska).
1
Authors affiliated with COST BM0701.
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.11.058

J. Karolak-Wojciechowska et al. / Journal of Molecular Structure 966 (2010) 14–17
15
O
O
O
Ar
Ar
Ar
N
NH
NH
HN
N
HN
X
H
X
H
X
(Z)-isomer
X = O, S, NH
Ar
Ar
Ar
O
O
O
NH
NH
N
HN
N
HN
X
X H
X
H
(E)-isomer
X = O, S, NH
Scheme 1.
Ar = 2-Cl-Ph
O
Ar
Ar
O
Ar
Ar
O
4
O
5
N1 3 NH
2
N
NH
N
N
N
N
NH2
A
NH2
NH
B
NH
A
B
Scheme 2.
NH2), 8.07–8.10 (m, 1H, ArAHortho). 13C NMR (75 MHz, DMSO-d6): d
[ppm] 28.3, 107.9, 126.6, 129.1, 129.7, 132.1, 132.5, 133.1, 136.5,
167.4, 174.8.
(Z)-2-Amino-5-(2-chlorobenzylidene)-1-methyl-1H-imidazol-4(5H)-
one (1-(Z)). Purified by crystallization from the mixture of ace-
tone:methanol 1:2. Yield 33% (0.77 g), m.p. 242–243 °C. 1H NMR
(300 MHz, DMSO-d6): d [ppm] 2.82 (s, 3H, CH3), 6.39 (s, 1H, @CH),
7.33–7.37 (m, 2H, Ar), 7.38–7.43 (m, 1H, Ar), 7.49–7.52 (m, 1H, Ar),
7.95 (br.s, NH2). 13C NMR (75 MHz, DMSO-d6): d [ppm] 31.9, 104.6,
127.2, 129.6, 129.9, 132.1, 132.4, 133.7, 136.5, 170.4, 176.6.
acetone:methanol:acetic acid 4:8:1. Crystallographic data and
experimental details are presented in Table 1. The structures were
solved by direct method and refined with SHELXTL [18]. E-map
provided positions for all non-H-atoms. The full-matrix least-
squares refinement was carried out on F2’s using anisotropic tem-
perature factors for all non-H-atoms. All C-bound H-atoms were
placed in idealized locations and refined using a riding model, with
CAH = 0.93 Å and Uiso(H) = 1.2 Ueq(C). The H-atoms attached to
nitrogens were located in difference Fourier map and refined with
the restraints NAH = 0.86 Å and Uiso = 1.2 Ueq(N). The Flack param-
eter for structure 1-(Z), which equals 0.54(7), indicates raceme
twinning of the crystal.
2.2. X-ray crystal structures determination
Crystallographic data (excluding structural factors) for the struc-
ture reported in this paper have been deposited at the Cambridge
Crystallographic Data Centre and allocated with the deposition
numbers: CCDC 748629 & 748630 for compounds 1-(Z) and 1-(E),
respectively. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EW, UK (Fax:
Int code +(1223)336-033; E-mail: deposit@ccdc.cam.ac.uk).
The crystals of 1-(Z) were obtained from acetone-methanol
mixture (1:2) while 1-(E) was crystallized from the mixture of
Table 1
Crystal data and structure refinement details for 1-(Z) and 1-(E).
1-(Z)
1-(E)
Empirical formula
Formula weight
Temperature
C11H10ClN3O
235.67
293 K
C11H10ClN3O, 0.5 H2O
244.68
293 K
3. Results and discussion
Radiation
Mo(Ka) = 0.71073 Å
Crystal system
Space group
Unit cell dimensions
Orthorombic
Pna21
a = 9.3708(13)Å
b = 7.5453(10)Å
c = 30.494(4)Å
Monoclinic
C2/c
Isomer 1-(E) crystallizes in the centrosymmetric space group
(C2/c) with one main molecule and a half of water molecule as
an independent unit. Isomer 1-(Z) crystallizes in a non-centrosym-
metric orthorhombic form (Pca21) with two independent mole-
cules in a crystallographic unit. The structure motifs for both
studied objects are presented in Fig. 1, while the selected metric
parameters are gathered in Table 2. The X-ray analysis confirms
the respective E/Z configuration of both isomers as it was expected.
Thus, the torsion angle N1AC5AC6AC61 value equals almost 180o
for molecule 1-(E) while for 1-(Z) it is close to zero (Table 2). It
should be mentioned that ca. 90% of 5-benzylidene-imidazolones
deposited in CSD adopt (Z)-configuration.
a = 32.067(8)Å
b = 8.0025(19)Å
c = 8.605(2)Å
b = 90.763(7)°
2208.0(9)
8, 1.472
0.333
20.00 ꢁ 0.19 ꢁ 0.18
Volume (Å)3
2156.1(5)
8, 1.452
0.335
Z, density (g/m3)
l
(mmꢀ1
)
Crystal size (mm)
Diffractometer
Reflection collected/
unique
0.50 ꢁ 0.06 ꢁ 0.05
Bruker SMART
21839/3799
[Rint = 0.024]
3799/292
15279/1958
[Rint = 0.077]
1958/151
Data/parameters
Refinement method
R1, wR2
Full-matrix least-squares on F2
0.0340, 0.0924
ꢀ0.25, 0.32
0.54(7)
0.0469, 0.091
ꢀ0.27, 0.36
The conformations of studied molecules are significantly differ-
ent. In 1-(E), the dihedral angle between benzylidene and imidazo-
lone rings equals 7.8(1)°, which means that the molecule remains
Dq )
min and max (eÅꢀ3
Flack x

16
J. Karolak-Wojciechowska et al. / Journal of Molecular Structure 966 (2010) 14–17
Fig. 1. Structure motifs in the crystals of 1-(Z) and 1-(E) showing displacement ellipsoids drawn at the 50% probability level. The H-bonds are marked out as dotted lines.
Table 3
Table 2
H-bonds geometrical descriptions.
Selected geometrical data.
XAH. . .Y
Sym. code
Xꢂ ꢂ ꢂY (Å) Hꢂ ꢂ ꢂY (Å) XAHꢂ ꢂ ꢂY (o)
1-(E)
1-(Z)
1-(E) N7AH7a. . .N3
2ꢀx, 1ꢀy, 2ꢀz
2.897(3) 2.040
3.065(4) 2.818
2.818(3) 2.340
2.828(3) 1.980
172
141
170
167
Molecule
1
Molecule
2
N7AH7b. . .O1w 1 + x, y, z
O1wAH1w. . .O4 1ꢀx, y, 3/2ꢀz
N70AH701. . .O4
x, 1 + y, z
(a) Bond lengths (Å)
N1GAC2
N3AC2
1.362(3) 1.373(3)
1.338(3) 1.343(3)
1.314(3) 1.294(4)
1.373(3)
1.340(3)
1.329(3)
1-(Z) N70AH702. . .N30 1/2 + x, 2ꢀy, z
N7AH7a. . .O40
3.073(3) 2.220
2.855(4) 2.020
172
165
171
N7AC2
N7AH7b. . .N3
ꢀ1/2 + x, 1ꢀy, z 3.086(3) 2.230
(b) Torsion angles (°)
N1AC5AC6AC61
C5AC6AC61AC62
benzylidene/imidazolone inclination
(°)
178.6(2) ꢀ7.4(5)
ꢀ7.8(5)
141.8(3)
46.59(1)
176.2(3) 140.6(3)
7.8(1)
47.4(1)
adopt an anti position. For both geometric isomers, the X-ray anal-
ysis confirmed the same tautomeric form A, identified by the pres-
ence of two hydrogen atoms at exocyclic N7 nitrogen (Scheme 2).
The lengths of corresponding bonds in five-membered rings of
both structures are similar (within experimental error) and are in
agreement with the average values observed for imidazolones
studied in home as well as in other deposited in CSD [19].
In the crystal of 1-(E), planar molecules are joined by hydrogen
bonds of N7AH7aꢂ ꢂ ꢂN3(2ꢀx, 1ꢀy, 2ꢀz) (Fig. 2 and Table 3) and
they form bimolecular centrosymmetrical units with the graph-
set notation R22(8) [20]. These units are assembled in one layer
almost planar and a chlorine atom of the benzylidene fragment
adopts the syn position with respect to a methyl substituent at
N1. In contrast, two independent (but almost identical) molecules
of 1-(Z) have a distinctly twisted conformation due to the steric
hindrance, with dihedral angles between the planes of the two
rings reaching 47.4(1)° and 46.5(1)°, respectively. For the same
reason in both molecules of 1-(Z), chlorine and methyl substituents
Fig. 2. Packing of the molecules in the structures of 1-(Z) and 1-(E) showing hydrogen bonds as dashed lines. For 1-(Z) independent molecules are marked in different colors.
H-bonds are marked out as dotted lines.

J. Karolak-Wojciechowska et al. / Journal of Molecular Structure 966 (2010) 14–17
17
Table 4
13C chemical shifts for selected carbon atoms (assignment according to HMBC correlations).
1-(E)
1-(Z)
13C chemical shift [ppm]
Carbon
HMBC correlations with protons
13C chemical shift [ppm]
Carbon
HMBC correlations with protons
107.9
136.5
167.4
174.8
C6
C5
C2
C4
ArAHortho
CH3, CH@
CH3
104.6
136.5
170.4
176.6
C6
C5
C2
C4
ArAHortho
CH3
CH3
@CH
@CH
(Fig. 1) through subsequent H-bonds with two water molecules.
The water molecules (in special positions) are located between
layers (the distance between layers equals 3.329(3) Å) and an-
chored to four molecules of 1-(E) by two pairs of N7AH7b. . .O1w
and O1wAH1w. . .O4 hydrogen bonds (Fig. 2). The crystal structure
of 1-(Z) is much more complex and comprises two helical chains
self-assembled by additional hydrogen bonds. The helical chains
(Fig. 2) of independent molecules are formed by NAH. . .N strong
respectively, while for 2-imino form these signals appeared at
higher fields (150.5–155.9 ppm and 164.4–167.7 ppm).
4. Conclusion
Both structures presented in this paper supplemented excellently
the findings on the hydrogen bonds pattern described for (Z)-5-ary-
lidene-2-amino-imidazol-4-onein the previous paper [17]. Recently,
it was concluded that the mutual position of benzylidene and imi-
dazolone rings in the molecule is a decisive criterion for the crystals
architecture. Meanwhile, hydrogen bondedcentrosymmetricdimers
dominateinthecrystalsof1-(E)andotherplanar5-benzylidene-imi-
dazolones. On the other hand, in the structure of non-co-planar mol-
ecules (as 1-(Z)), helical chains motives, subsequently intertwined in
braids, are preferred. Crystallographic studies together with 1H and
13C NMR methods confirmed that in the solid state as well as in the
DMSO solution both geometric isomers exist as 2-amino-5-(2-chlo-
robenzylidene)-1-methyl-1H-imidazol-4(5H)-ones. The spectral
analysis performed for 1-(E) and 1-(Z) supported the signal assign-
ments adopted for other 5-arylidene-2-amino-imidazol-4-ones
[17] and helped to solve the structural problems caused by a poten-
tial tautomerism observed in this group of compounds.
hydrogen bonds down the
a axis. Therefore, the bonds of
N7AH7b. . .N3(ꢀ1/2 + x, 1ꢀy, z) and N70AH702. . .N30(1/2 + x, 2ꢀy,
z) are employed by two molecules, respectively (Table 3). The
chains of independent molecules are intertwined by hydrogen
bonds of NAH. . .O type (Fig. 1). Thus, the bonds of N7AH7a. . .O40
and N70AH701. . .O4 (x, 1 + y, z) join together four molecules and
shape a twelve-membered ring with the graph-set notation of
R44(12) [20]. It is interesting to note that in the crystal of 1-(E)
the analogous bond forms a planar and centrosymmetric dimer.
The NMR spectra of both isomers confirm the findings described
by Tan and co-workers for 1-methyl substituted 5-benzylidene-
hydantoins [6]. The most significant differences in 1H chemical
shifts can be seen for N1-methyl, vinyl and ortho-phenyl protons.
The steric crowding between the methyl group and the twisted
phenyl ring in (Z)-isomer places CH3 protons in the benzene shield-
ing region shifting their signal upfield (2.82 ppm) compared with
1-(E) (3.17 ppm). At the same time, the vinyl proton in 1-(Z),
deshielded by the anisotropic 4-carbonyl group, appears at lower
fields (6.39 ppm) relative to 1-(E) compound (6.20 ppm) in the
spectrum of 1-(Z). On the other hand, in the (E)-isomer the car-
bonyl group deshields the ortho-phenyl proton, which resonates
as a separate multiplet at lower fields (8.07–8.10 ppm) in compar-
ison with 1-(Z) (7.49–7.52 ppm).
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