1-(2′-Aminophenyl)- and 1-(2′-hydroxyphenyl)-2-methyl-4-nitroimidazole: Crystallizing with two molecules in the asymmetric unit

Article abstract of DOI:10.1016/j.molstruc.2007.06.013

Two similar 4-nitroimidazole derivatives, 1-(2′-aminophenyl)-2-methyl-4-nitroimidazole, C₁₀H₉N₃O₃, and 1-(2′-hydroxyphenyl)-2-methyl-4-nitroimidazole, C₁₀H₁₀N₄O₂, crystallize with two molecules in the asymmetric unit (Z′ = 2). Packing conflicts may result from tendency towards closing hydrogen-bonded rings (dimer for amino-, and tetramer for hydroxy-derivative) and molecular stacking. These conflicts are solved in different ways in both compounds, due to the different nature of 2′-substituents, but in both cases the crystal structure involves multiple molecules in the asymmetry unit. The geometrical features of symmetry-independent molecules are similar. The nitro group is almost coplanar with the imidazole plane in amino derivative while it is significantly twisted in hydroxy-one.

Full text of DOI:10.1016/j.molstruc.2007.06.013

Available online at www.sciencedirect.com
Journal of Molecular Structure 876 (2008) 134–139
www.elsevier.com/locate/molstruc
1-(20-Aminophenyl)- and 1-(20-hydroxyphenyl)-2-methyl-4-
nitroimidazole: Crystallizing with two molecules in the asymmetric unit
a,
b
Maciej Kubicki *, Paweł Wagner
a
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
Nanomaterials Research Centre, and MacDiarmid Institute for Advanced Materials and Nanotechnology, Massey University,
Private Bag 11 222, Palmerston North, New Zealand
b
Received 25 May 2007; received in revised form 12 June 2007; accepted 13 June 2007
Available online 26 June 2007
Abstract
Two similar 4-nitroimidazole derivatives, 1-(20-aminophenyl)-2-methyl-4-nitroimidazole, C10H9N3O3, and 1-(20-hydroxyphenyl)-2-
methyl-4-nitroimidazole, C10H10N4O2, crystallize with two molecules in the asymmetric unit (Z0 = 2). Packing conflicts may result from
tendency towards closing hydrogen-bonded rings (dimer for amino-, and tetramer for hydroxy-derivative) and molecular stacking. These
conflicts are solved in different ways in both compounds, due to the different nature of 20-substituents, but in both cases the crystal struc-
ture involves multiple molecules in the asymmetry unit. The geometrical features of symmetry-independent molecules are similar. The
nitro group is almost coplanar with the imidazole plane in amino derivative while it is significantly twisted in hydroxy-one.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Crystal structure; Multiple molecules; Nitroimidazole derivatives; Hydrogen bonds; Weak intermolecular interactions
1. Introduction
The overall population of structures with Z0 > 1 in the
Cambridge Structural Database (CSD, [3]) is more or less
constant over the years (but cf. Desiraju [4] and Anderson
and Steed [5]) and is around 8.8%. Of course this propor-
tion may change depending on the class of compounds,
there are some classes for which the probability of finding
Z0 > 1 is significantly higher, for example, nucleosides and
nucleotides (20.8%) or steroids (18.8%), as listed by Steiner
[6]. The search in the November 2006 version of the CSD
(Ver. 5.28, Jan. 2007 update) gives somewhat smaller val-
ues: 19.8% for nucleosides and nucleotides and 16.4% for
steroids (with similar search conditions). It was also found
that larger probability of finding multiple molecules exists
also for monoalcohols [7] (the authors also suggested that
the same should be the case for amino group) and for sim-
ple imidazole derivatives [8].
Crystal packing is the result of the competition between
different factors connected with close packing requirements
and intermolecular interactions. Space-group symmetry
results as a compromise, sometimes hard to achieve, and
therefore more than one molecule may appear in the asym-
metric unit. The literature dealing with this subject, which
is crucial, for example, for crystal engineering or for the
crystal structure prediction; is not that extensive as might
be expected.
Historically, the statistical analysis of the presence of
multiple molecules often accompanied papers dealing with
the frequencies of different space groups (these analyses are
reviewed by Brock and Dunitz, [1]). The problem of
multiple molecules was further analyzed in detail by Steed
[2]; recently even the dedicated website was created
(http://www.dur.ac.uk/zprime).
For some time we have studied weak intermolecular
interactions in 4-nitroimidazole derivatives (e.g., [9,10]).
This relatively simple molecule provides a convenient
object for such studies: the degrees of freedom are few,
one hydrogen bond acceptor is always available, stacking
*
Corresponding author.
E-mail address: mkubicki@amu.edu.pl (M. Kubicki).
0022-2860/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2007.06.013

M. Kubicki, P. Wagner / Journal of Molecular Structure 876 (2008) 134–139
135
Table 1
Crystal data, data collection and structure refinement
Compound
Formula
1
2
C10H10N4O2
C10H9N3O3
219.20
monoclinic
P21/n
Formula weight
Crystal system
Space group
218.22
monoclinic
P21/c
˚
a (A)
11.0134(8)
10.0994(8)
18.6433(16)
97.100(7)
2057.6(3)
8
1.41
912
0.103
10.5904(8)
17.9987(14)
10.9605(9)
100.563(6)
2053.8(3)
8
1.42
912
0.108
˚
b (A)
Scheme 1.
˚
c (A)
b (ꢁ)
3
˚
V (A )
interactions are in principle possible, and by an appropri-
ate choice of substituents one can focus on certain interac-
tions. We have previously found interesting cases of Z0 = 2
connected either with the differences in conformation or in
intermolecular interactions [8].
Here, we report the crystal structures of two simple
imidazole derivatives (Scheme 1): 1-(20-aminophenyl)-2-
methyl-4-nitroimidazole (1) and 1-(20-hydroxyphenyl)-2-
methyl-4-nitroimidazole (2). These compounds belong to
a class of compounds having higher probability of crystal-
lizing with Z0 > 1, and in fact this is a case. CSD checks do
not suggest any possibility for a missing symmetry between
the independent molecules.
Z
Dx (g cmꢀ3
F(000)
l (mmꢀ1
)
)
Crystal size (mm)
H Range (ꢁ)
hkl range
0.2 · 0.2 · 0.05
4.85–26.4
ꢀ11 6 h 6 13
ꢀ12 6 k 6 11
ꢀ22 6 l2 6 3
0.15 · 0.1 · 0.1
3–25
ꢀ12 6 h 6 11
ꢀ21 6 k 6 19
ꢀ13 6 l 6 13
Reflections
Measured
11984
4156 (0.038)
2641
11002
3603 (0.042)
2398
Unique (Rint) 4414
With I > 2r(I)
Number of parameters
Weighting scheme
A
365
357
0.07
0.049
0.132
1.05
0.05
0.040
0.098
0.98
R(F) [F2 > 2r(F2)]
wR(F2) [all refl.]
Goodness of fit
2. Experimental
The title compounds were synthesized by the ANRORC
(Addition Nucleophile Ring Opening Ring Closure) reac-
tion from 1,4-dinitro-2-methylimidazole and correspond-
ing ortho-substituted aniline in methanolꢀwater medium
at room temperature with moderate yields. The syntheses
ꢀ3
˚
Max/min Dq (e A
)
0.24/ꢀ0.24
0.24/ꢀ0.35
bridge Crystallographic Data Centre, Nos. CCDC-648297
(1) and CCDC-648298 (2). Copies of this information
may be obtained free of charge from: The Director, CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK. Fax:
+44(1223)336-033, e-mail: deposit@ccdc.cam.ac.uk, or
www.ccdc.cam.ac.uk.
´
were made in similar way described before by Suwinski
´
and Salwinska [11] (Scheme 1).
Diffraction data were collected at 100(1)K by the x-scan
technique up to 2h = 60ꢁ, on a KUMA-KM4CCD diffrac-
tometer [12] with graphite-monochromatized MoKa radia-
˚
tion (k = 0.71073 A). The temperature was controlled by
3. Discussion
an Oxford Instruments Cryosystems cooling device.
Frames (532) were measured for 1 and 2 (0.75ꢁ frame
width). The data were corrected for Lorentz-polarization
effects [13]. Accurate unit-cell parameters were determined
by a least-squares fit of 2613 (1) and 2851 (2) reflections of
highest intensity, chosen from the whole experiment. The
structures were solved with SHELXS97 [14] and refined
with the full-matrix least-squares procedure on F2 by
SHELXL97 [14]. Scattering factors incorporated in SHEL-
XL97 were used. The function Rw(|Fo|2-|Fc|2)2 was mini-
3.1. Molecular geometry
Selected geometrical parameters are listed in Table 2. As
far as the bond lengths and bond angles patterns are con-
cerned, the differences between the symmetry-independent
molecules are only of statistical nature. The normal proba-
bility plots [15,16] drawn for the bond length distribution
in both cases are almost linear, the correlation coefficients
between theoretical and experimental distributions are of
ca. 0.97. Also the differences between 1 and 2 are small,
with the notable exception of intraannular bond angles in
the phenyl ring. These angles show the typical dependence
on the kind of substituent (cf. Table 2); these differences are
generally in agreement with the trends described by
Domenicano and Murray-Rust [17].
2
mized, with wꢀ1 = [r2(Fo)2 + AÆP2] (P = [Max (Fo , 0) +
2
2Fc ]/3). The final values of the factor A are listed in Table
1. All non-hydrogen atoms were refined anisotropically,
hydrogen atoms were located in subsequent difference Fou-
rier maps and their positional and isotropic displacement
parameters (one common parameter for each CH3 group)
were refined. Relevant crystal data are listed in Table 1,
together with refinement details.
As noted before [18] there is a statistically significant
difference in the C–N–O angles of nitro group typical
for 5-H imidazoles: the C4–N4–O41 (oxygen atom cis
with respect to the N3 imidazole ring nitrogen) is, on
Crystallographic data (excluding structure factors) for
the structural analysis has been deposited with the Cam-

136
M. Kubicki, P. Wagner / Journal of Molecular Structure 876 (2008) 134–139
Table 2
ecule A (100.3(2)ꢁ) while it is – by almost the same amount
– smaller than 90ꢁ in B: 78.2(2)ꢁ.
0
˚
Selected geometrical parameters (A, ꢁ) with s.u. s in parentheses (I and II
are the least-squares planes of imidazole and phenyl rings, respectively)
The twist between the rings is large (65–78ꢁ), appar-
ently in order to relieve the steric stress, while the nitro
groups are close to coplanarity with the imidazole
rings. It must be noted however, than in 2 the twist of
the nitro group is relatively large, up to 10.0(2)ꢁ (Table
2).
1A
1B
2A
2B
C4–N4–O41
C4–N4–O42
N3–C4–N4
C5–C4–N4
C11–C12–C13
C16–C11–C12
C12–C13–C14
C2–N1–C11–C12
C5–N1–C11–C12
118.9(2)
117.4(2)
120.0(2)
126.9(2)
116.3(2)
122.1(2)
121.0(2)
100.3(2)
103.3(2)
118.2(2)
118.9(2)
119.3(2)
118.0(2)
121.4(2)
126.0(2)
116.9(2)
121.8(2)
121.5(2)
78.2(2)
ꢀ107.3(2)
ꢀ100.292)
74.4(2)
117.2(2)
121.5(2)
125.6(2)
118.2(2)
120.7(2)
120.5(2)
69.6(3)
ꢀ120.0(2)
ꢀ110.1(2)
60.3(3)
117.1(2)
121.1(2)
126.4(2)
118.9(2)
121.5(2)
119.4(2)
74.5(2)
ꢀ106.9(2)
ꢀ106.8(2)
71.8(3)
3.2. Crystal packing and intermolecular interactions
In the structures of 1 and 2 relatively strong, ‘‘classical’’
hydrogen bonds are one of the primary factors in the build-
ing of crystal network. Hydrogen bond data are listed in
Table 3. In 1 there is a heteromolecular (i.e., AB, consisting
of two symmetry-independent molecules) dimer, connected
by N–HÆÆÆN (imidazole) hydrogen bonds (Fig. 1), while in 2
the O–H...N (imidazole) hydrogen bonds combine to form
C2–N1–C11–C16 ꢀ76.5(2)
C5–N1–C11–C16
N3–C4–N4–O41
N3–C4–N4–O42
I/II
103.3(2)
ꢀ3.4(3)
176.6(2)
78.62(5)
3.2(2)
1.5(3)
7.7(3)
10.6(3)
ꢀ179.3(2)
76.54(7)
3.1(3)
ꢀ173.6(2)
65.36(7)
8.6(2)
ꢀ168.7(2)
73.10(6)
10.0(2)
I/(NO2)
a
centrosymmetric heteromolecular tetramer ABAB
(Fig. 2). Using graph-set notation, [19–21], these rings
average, 1.2ꢁ larger than C4–N4–O42 (i.e., oxygen atoms
trans to N3).
can be described as R2 (14) in 1 and R4 (28) in 2. The ten-
2
4
dency towards creating such closed structures might be the
factor causing the packing conflict which, in turn, leads to
the presence of multiple molecules in the asymmetry unit.
The rings were often observed in the mono-hydroxy struc-
tures, but the factor responsible for this was connected with
a possible conflict between the tendency towards ꢁO–
HÆÆÆO–Hꢁ. or ꢁN–HÆÆÆN–Hꢁ bonding – hydroxyl and
amino groups can act almost equally well as hydrogen
bond donor and acceptor – and close packing require-
ments. In 1 and 2 the imidazole nitrogen atom acts as an
acceptor for the hydrogen bonds.
The aromatic rings are almost planar. Generally, the
imidazole rings are closer to ideal planarity (the deviations
from the least-squares plane by five ring atoms are smaller
˚
than 0.0039(11) A) than the phenyl ones, where there are
˚
surprisingly large deviations, as high as 0.0113(14) A in 1
˚
and 0.0107(14) A in 2. The conformations of molecules 1
and 2 can be described by the dihedral angles between
the benzene and nitroimidazole rings and between the imid-
azole ring and a nitro group (Table 2). In 1 the sense of
twist is opposite in symmetry-independent molecules: the
dihedral angle C2–N1–C11–C12 is larger than 90ꢁ in mol-
Table 3
˚
Hydrogen bonds and other short contacts data (A, ꢁ)
˚
˚
˚
D
H
A
D–H (A)
HÆÆÆA (A)
DÆÆÆA (A)
D–HÆÆÆA (ꢁ)
1
N12A
N12A
N12B
N12B
C14A
C14A
C14B
C21A
H12A
H12B
H12C
H12D
H14A
H14A
H14B
H21A
O42Ai
N3Bii
0.94(3)
0.93(3)
0.92(2)
0.89(3)
0.94(2)
0.94(2)
0.98(2)
0.93(3)
2.09(3)
2.27(3)
2.24(2)
2.40(3)
2.49(2)
2.60(2)
2.87(2)
2.94(3)
3.036(3)
3.166(2)
3.076(3)
3.213(3)
3.191(3)
3.412(3)
3.587(3)
3.638(3)
174(2)
162(2)
151(2)
152(2)
131.0(14)
143.9(15)
130.1(15)
133(2)
N3Aiii
O41Biv
O42B
O42Aiii
Cg1Bv
Cg2Bv
2
O12A
O12B
C16A
C5A
C13B
C21B
C15B
C14A
C5B
H12A
H12B
H16A
H5A
H13B
H21D
H15B
H14A
H5B
N3B
0.90(3)
0.90(3)
0.95(2)
1.00(2)
0.99(2)
0.95(3)
0.91(2)
0.95(2)
0.97(2)
1.86(3)
1.90(3)
2.54(2)
2.44(2)
2.47(2)
2.60(3)
2.80(2)
2.63(2)
2.92(2)
2.745(2)
2.761(2)
3.435(3)
3.443(3)
3.436(3)
3.337(3)
3.314(3)
3.270(3)
3.743(3)
167(2)
159(3)
157(2)
179(2)
162.8(15)
135(2)
117.3(14)
125.2(14)
143.5(14)
N3Avi
O42Bvii
O42Bviii
O41Avi
O42Aix
Cg2Ax
Cg2Bviii
Cg1Axi
Cg symbol describes the centroid of the appropriate ring.
i
ii
v
vi
Symmetry codes: ꢀx, 0.5 + y,1.5 ꢀ z; ꢀ1 + x,y,z; iii1 + x,y,z; ivx, ½ ꢀ y, ꢀ 0.5+z; ꢀ1 ꢀ x,1 ꢀ y,1 ꢀ z; ꢀx,1 ꢀ y,1 ꢀ z; vii0.5 ꢀ x, 0.5 + y, 0.5 ꢀ z;
viii0.5 + x, 0.5 ꢀ y,ꢀ0.5 + z; ixx,y,1 + z; x0.5 + x, 0.5 ꢀ y, 0.5 + z; ꢀ0.5 + x, 0.5 ꢀ y, 0.5 + z.
xi

M. Kubicki, P. Wagner / Journal of Molecular Structure 876 (2008) 134–139
137
Fig. 1. The hydrogen-bonded dimer of 1 [26], with the labeling scheme of one of the molecules. Ellipsoids are drawn at 50% probability level, hydrogen
bonds are shown as spheres with arbitrary radii. Hydrogen bonds are depicted as dashed lines. Symmetry code for a primed molecule: ꢀ1 + x, y, z.
Fig. 2. The hydrogen-bonded tetramer of 2 [26], with the labeling scheme of one of the molecules. Ellipsoids are drawn at 50% probability level, hydrogen
bonds are shown as spheres with arbitrary radii. Hydrogen bonds are depicted as dashed lines. Symmetry code for primed molecules: ꢀx,1ꢀy,1ꢀz.
Only few examples of similar supramolecular structures
can be found among substituted imidazoles located via
CSD searches. In the crystal structure of 2-amino-5-(4-
chlorophenyl)-1-methylimidazole [22] the asymmetric unit
contains four molecules, two of which are connected into
a pseudo-centrosymmetric heteromolecular dimer, while
two other molecules form homomolecular centrosymmetric
dimers. All these motifs are formed by N–HÆÆÆN(imidazole)
hydrogen bonds. The structure of 3-chloro-1-(4-nitro-5-
piperidinylimidazol-1-yl)propan-2-ol [23] has also Z0 = 4.
In this case these molecules are connected into two hetero-
molecular dimers by means of O–HÆÆÆN hydrogen bonds
(actually all these bonds are three-centered, with oxygen
atom from nitro group as additional acceptor). More
commonly, multiple molecules are connected in chains of
O–HÆÆÆN bonds (e.g., (6-(imidazol-1-ylmethyl)pyrid-2-
yl)methanol [24]), or in more complicated structures, that
often contain also rings, for amino-substituted imidazole
derivatives (e.g., 4-ethyl-5-(N-methyl-N-phenylamino)-
imidazole-2-carboxamide [25]).
In 1, the hydrogen-bonded rings pack in the crystals
via p–p stacking interactions, the angle between the
mean planes is 2.6(1)ꢁ. The distance between the cent-
˚
roids of imidazole rings is 3.658(2) A; and the distance
perpendicular to the planes of almost parallel rings is
˚
as short as 3.321 A. Hydrogen bonded dimers are con-

138
M. Kubicki, P. Wagner / Journal of Molecular Structure 876 (2008) 134–139
Fig. 3. The crystal packing of 1 as seen along [010] direction. Hydrogen bonds are depicted as dashed lines. [26].
nected into chains by means of homomolecular N–HÆÆÆO
(nitro) hydrogen bonds (Fig. 3). The hydrogen bond
structure can be therefore regarded as two families of
homomolecular C(9) chains, that are interwoven into
the rings described earlier. Some other short C–HÆÆÆN,
C–HÆÆÆO and C–HÆÆÆp contacts may supply further cou-
lombic stabilization in the crystal structures (Table 3),
and they take part in formation of the three-dimensional
structure.
In 2, the tetramers are connected into chains along [101]
directions by relatively short and directional C5A-H5AÆÆÆO
(nitro, B) contacts (Fig. 4). Almost equally strong C–HÆÆÆO
bonds act as secondary interactions within the dimers
(Fig. 1). Some weaker C–HÆÆÆO and C–HÆÆÆp contacts might
be found in the crystal structure (Table 3).
4. Conclusions
The main motifs in the crystal structures of two 1(20-
(hydrogen bond donor)phenyl)-2-methyl-4-nitroimidaz-
oles, where ‘‘hydrogen bond donor’’ is an amino group in
1 and hydroxyl group in 2, are closed, hydrogen-bonded
rings: dimers in case of 1, tetramers in 2. The packing con-
flict between the tendency to form such dimers and other
packing requirements can be regarded as the reason for
the presence, in both cases, two symmetry independent
Fig. 4. The crystal packing of 2, as seen along [010] direction. Hydrogen bonds are depicted as dashed lines [26].

M. Kubicki, P. Wagner / Journal of Molecular Structure 876 (2008) 134–139
139
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of the molecules is not significantly differ, one could only
realize the opposite sense of the twisting angles between
the imidazole and phenyl groups in 1. Weaker hydrogen-
bond-type interactions connect the closed structure: dimers
and tetramers into three dimensional networks.
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