The syntheses and crystal structures of metronidazole-derived compounds

Article abstract of DOI:10.1007/s10870-008-9343-9

Metronidazole (MET-OH), widely used as an antibacterial agent, is found to have some side effects on human bodies. Due to these disadvantages, people have been looking for its modification compounds for substituents. In this article, four MET-OH derivatives were designed, prepared, and structurally characterized by single crystal X-ray diffraction. These compounds are MET-OTs (1), MET-Br (2), MET-Cl (3), and MET-I (4). X-ray structure analyses revealed that, 1 crystallized in the monoclinic system with space group P2 ₁ /c, with a = 16.1178, b = 7.5473, c = 13.4161 A, V = 1520.3 A³, β = 111.3210^o and Z = 4. 2 crystallized in the monoclinic system with space group P2 ₁ /c, with a = 12.079, b = 11.089, c = 6.380 A, V = 847.1 A³, β = 97.57^o and Z = 4. 3 crystallized in the monoclinic system with space group P2 ₁ /c, with a = 12.098, b = 11.007, c = 6.295 A, V = 830.3 A³, β = 97.886^o and Z = 4. 4 crystallized in the triclinic system with space group P1, with a = 6.192, b = 7.740, c = 10.001 A, V = 457.9 A³, α = 89.073, β = 86.903, γ = 73.097 ^o and Z = 2. In this article, metronidazole-derived compounds were prepared and structurally characterized by single crystal X-ray diffraction [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-008-9343-9

J Chem Crystallogr (2008) 38:461–466
DOI 10.1007/s10870-008-9343-9
COMMUNICATION
The Syntheses and Crystal Structures of Metronidazole-derived
Compounds
Huan-Qiu Li Æ Zhu-Ping Xiao Æ Rui-Qin Fang Æ
Hai-Liang Zhu
Received: 31 May 2006 / Accepted: 27 March 2008 / Published online: 15 April 2008
Ó Springer Science+Business Media, LLC 2008
Abstract Metronidazole (MET-OH), widely used as an
antibacterial agent, is found to have some side effects on
human bodies. Due to these disadvantages, people have
been looking for its modification compounds for substitu-
ents. In this article, four MET-OH derivatives were
designed, prepared, and structurally characterized by single
crystal X-ray diffraction. These compounds are MET-OTs
(1), MET-Br (2), MET-Cl (3), and MET-I (4). X-ray
structure analyses revealed that, 1 crystallized in the
It is extensively used in the treatment of anaerobic infec-
tions and is under continuing investigation [1, 2]. Though
widely used as an antibacterial medicine, it also has some
side effects [3]. For example, the metabolism products of
MET-OH can combine with nerve cell RNH, which may
strengthen the excitement of the bronchus myocardial
nerve fiber controlled by the RNH, extend the capillary
vessel and increase the transparence, consequently it would
cause the nervous system, respiration system, cardiovas-
cular system, immune system(... etc. to work abnormally.
In order to overcome its disadvantages, a variety of com-
pounds related to MET-OH with less toxicity needed to be
synthesized. There is a hydroxyl group in the molecule of
MET-OH, thus there are definitely lots of modifying mea-
surements starting from this group. For example, changing the
structure to the Tinidazole (Scheme 2) can make it more
effective in the treatment of anaerobic fungus and diseases
infected by ectosarc [4, 5]. However, as it is not so easy to
change the hydroxyl directly into other functional groups, the
hydroxyl group can be designed to be remodeled to -OTs
group or halogen group firstly, consequently, the introduction
of other more complex groups would become convenient.
There some reports on the halogenations of the hydroxyl
group in the literature [6–8], but the reaction condition is
rather strict and the yield is rather low, here a more convenient
and effective way to replace the hydroxyl group is presented
and the structures of four intermediates (Scheme 3) were
determined by X-ray crystallography report.
monoclinic system with space group P21/c, with
3
˚
˚
a = 16.1178, b = 7.5473, c = 13.4161 A, V = 1520.3 A ,
b = 111.3210o and Z = 4. 2 crystallized in the monoclinic
system with space group P21/c, with a = 12.079,
3
o
˚
˚
b = 11.089, c = 6.380 A, V = 847.1 A , b = 97.57 and
Z = 4. 3 crystallized in the monoclinic system with space
˚
group P21/c, with a = 12.098, b = 11.007, c = 6.295 A,
3
o
˚
V = 830.3 A , b = 97.886 and Z = 4. 4 crystallized in
the triclinic system with space group P1, with a = 6.192,
3
˚
˚
b = 7.740, c = 10.001 A, V = 457.9 A , a = 89.073,
b = 86.903, c = 73.097o and Z = 2.
Keywords Metronidazole (MET-OH) Á Crystal structure Á
Halogenations Á 4-Methyl-benzenesufonyl chloride
Introduction
MET-OH (Scheme 1) is one of the nitroimidazole deriva-
tives that are an extremely important class of compounds.
Experimental
H.-Q. Li Á Z.-P. Xiao Á R.-Q. Fang Á H.-L. Zhu (&)
Engineering Research Center for Clean Production of Textile
Dyeing and Printing, Ministry of Education, Wuhan University
of Science and Engineering, Wuhan 430073, P. R. China
e-mail: zhuhl@nju.edu.cn
Materials and Physical Measurements
All chemicals and reagents used in current study were of
analytical grade. MET-OH was purchased from Chan Zhou
123

462
J Chem Crystallogr (2008) 38:461–466
(10 mL) was added. The reaction mixture was stirred at
0 °C for 5 h, and 30 mL of ice water was added, the layer
was separated, and the aqueous layer was extracted with
ethyl acetate (2 9 30 mL). The organic layer was com-
bined and washed with saturated NaHCO3, and dried with
anhydrous Na2SO4 for 0.5 h. Removal of the solvent gave
a slight-yellow crystal of compound 1 (5.89 g, 18.1 mmol).
CH3
N
OH
N
1
Yield: 90%; Mp: 155–157 °C; H NMR (DMSO-d6): 2.40
NO2
(s, 3H, Ar–CH3); 2.49 (s, 3H, –CH3–); 4.38 (t, J = 9.72 Hz,
2H, N–CH2–); 4.55 (t, J = 9.80 Hz, 2H, O–CH2–); 7.38
(d, J = 7.97 Hz, 2H), 7.59 (d, J = 8.30 Hz, 2H); 7.92
(s, 1H).
Scheme 1 Structure of Metronidazole
O
S
CH3
CH2CH3
Synthesis of 1-(2-bromoethyl)-2-methyl-5-nitro-1H-
imidazole (2) (Scheme 4)
N
N
O
Compound 1 (6.54 g, 20.1 mmol) was dissolved in 30 mL
of anhydrous DMF and the solution was stirred at 100 °C
for 15 min. Then NaBr (5.2 g, 50 mmol) in anhydrous
DMF (20 mL) was carefully added, after the mixed solu-
tion was stirred at 100 °C for 4 h, the mixture was cooled
to 20 °C, and the solvent was removed under reduced
pressure. The residue was suspended in EtOH (100 mL)
and filtered, the solvent was removed under reduced pres-
sure, and the residue was chromatographed. Elution with
EtOAc gave an oil which recrystallized from EtOAc/
petroleum ether (3/1) to give 1-(2-bromoethyl)-2-methyl-5-
nitro-1H-imidazole (2) (3.28 g, 14 mmol). Mp: 78.5–
NO2
Scheme 2 Structure of Tinidazole
O
H3C
N
H3C
S
O
N
O
O2N
1
CH3
N
CH3
CH3
Br
I
Cl
N
N
N
1
79.5 °C; Yield: 70%; H NMR (DMSO-d6): 2.50 (s, 3H,
–CH3–); 3.51 (t, J = 8.68 Hz, 2H, N–CH2–); 4.61
N
N
(t, J = 8.51 Hz, 2H, –CH2–); 8.05 (s, 1H).
NO2
NO2
NO2
4
2
3
Synthesis of 1- (2-chloroethyl)-2-methyl-5-nitro-1H-
imidazole (3) (Scheme 5)
Scheme 3 Structures of compounds 1–4
Dongsheng Company, Chan Zhou, P. R. China. TLC was
run on the silica gel coated aluminum sheets (silica gel 60
GF254, E. Merk, Germany) and visualized in UV light
(254 nm). All the NMR spectra were recorded on a Bruker
DRX 500 model Spectrometer in either DMSO-d6 or
CDCl3. Chemical shifts (d) for 1H-NMR spectra are
reported in parts per million to residual solvent protons.
Melting points were measured on a Boetius micro melting
point apparatus.
MET-Cl was synthesized as the literary method [9] with
slight changes. MET-OH (4.71 g, 30 mmol) was dissolved
in SOCl2 (11 mL, 0.15 mol), and the solution was stirred at
70 °C for 6 h and cooled. The solvents and excess SOCl2
were then removed under reduced pressure. Compound 3
(4.98 g, 26.3 mmol) was obtained as a yellow crystal.
Yield: 88%; Mp: 78.5–79.5 °C; 1H NMR (DMSO-d6): 2.49
(s, 3H, –CH3–); 3.69 (t, J = 9.75 Hz, 2H, N–CH2–); 4.95
(t, J = 9.88 Hz, 2H, –CH2–); 8.35 (s, 1H).
Preparations
Synthesis of 1-(2-iodo-ethyl)-2-methyl-5-nitro-1H-
imidazole (4) (Scheme 5)
Synthesis of 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester
toluene-4-sulfonate (1) (Scheme 4)
MET-I was synthesized as the literary method [10] with
slight changes. Compound 3 (10.43 g, 55.0 mmol) was
dissolved in 30 mL of anhydrous acetone; the solution
was stirred at 90 °C for 15 min. Then NaI (9.0 g,
60.0 mmol) in anhydrous acetone (20 mL) was carefully
MET-OH (3.14 g, 20 mmol) and Et3N (3.0 mL, 22 mmol)
were dissolved in CH2Cl2 (20 mL), and 4-methyl-ben-
zenesufonyl chloride (3.83 g, 20.1 mmol) in CH2Cl2
123

J Chem Crystallogr (2008) 38:461–466
463
Scheme 4 The synthetic route
of compounds 1 and 2
CH3
N
O
S
OH
H3C
O
S
O
H3C
N
N
Cl
H3C
O
N
Et3N CH2Cl2
0oC 5h 90%
O
NO2
O2N
1
CH3
Br
N
NaBr 70%
N
DMF 100oC 4h
NO2
2
Scheme 5 The synthetic route
of compounds 3 and 4
CH3
N
CH3
N
CH3
N
OH
Cl
I
N
N
N
SOCl2 6h
NaI 12h 82%
60oC 88%
acetone
NO2
NO2
NO2
4
3
added. After the mixed solution was stirred at 90 °C for
12 h, the solvents were removed and the residue recrys-
tallized from chloroform gave compound 4 (12.70 g,
45.2 mmol) as a yellow solid. Yield: 82%; Mp: 78.5–
also been carried out, the cheap sodium bromide is used as the
brominating agent in DMF in place of phosphorus tribromide
in the organic solvent, in thus condition the reaction could be
easier to handle, which also supplied a new valuable method
for the bromization.
1
79.5 °C; H NMR (DMSO-d6): 2.59 (s, 3H, –CH3–); 3.89
(t, J = 11.25 Hz, 2H, N–CH2–); 4.64 (t, J = 11.15 Hz,
As to the chlorination of the hydroxyl group, dichloro-
sulfoxide has been used as the chlorination reagent, the
reaction is homogeneous and the reaction condition is
milder in comparison to the literatures, the selectivity is
also very good. The less poisonous dichlorosulfoxide
compared to benzene is employed as the solvent and thus
the reaction proceed under a comparatively low tempera-
ture, which made the reaction more controllable and
milder.
2H, –CH2–); 7.99 (s, 1H).
Results and Discussion
Syntheses of the Four MET Derivatives
In this paper, four MET derivatives: 1, 2, 3, and 4 were
synthesized from the metronidazole. Treatment of MET-
OH with TsCl gave 1, treatment of 1 with sodium bromide
in DMF gave 2, treatment of MET with thionychloride
gave 3, treatment of 3 with sodium iododide in anhydrous
acetone gave 4.
Crystal Structures of Compounds 1–4
Diffraction intensities for complexes 1–4 were collected on
a CCD area detector diffractmeter equipped with graphite-
˚
When the hydroxyl group was changed to -OTs, the ratio of
the starting materials had great effect on the yield of the
reaction. Both triethylamine and pyridine could act as the base
in the reaction, the less poisonous triethylamine is chosen as
the base in our study. The use of equivalent of triethylamine in
the reaction is the most optimal, and dichloromethane is found
to be the best solvent for the reaction that produced the highest
yield. The bromization reaction with the intermediate 1 has
monochromated Mo Ka (k = 0.71073 A) radiation. The
intensities were collected using the 2h scan mode with
variable scan speed. Crystal data were corrected for Lor-
entz and polarization effects during data reduction using
XSCANS [11–13]. All the non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were generated
geometrically and allowed to ride on their parent carbon
atoms. Analytical expressions of neutral-atom scattering
123

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J Chem Crystallogr (2008) 38:461–466
Table 1 Crystallographic and experimental data for compounds 1–4
Compound
1
2
3
4
Formula
C13 H15 N3 O5 S
325.34
C6H8BrN3O2
234.06
C6H8ClN3O2
189.60
C6H8IN3O2
281.05
FW
Crystal shape/color
Crystal size/mm
Crystal system
Space group
Block/colorless
0.20 9 0.10 9 0.10
Monoclinic
P21/c
Prism/colorless
0.40 9 0.30 9 0.10
Monoclinic
P21/c
Prism/colorless
0.38 9 0.35 9 0.30
Monoclinic
P21/c
Prism/Pale yellow
0.40 9 0.35 9 0.35
Triclinic
P1
˚
a/A
16.1178
12.079
12.098
6.192
˚
b/A
7.5473
11.089
11.007
7.740
˚
c/A
13.4161
6.380
6.295
10.001
89.073
86.903
73.097
457.9
a/o
b/o
c /o
111.3210(10)
97.57
97.886
3
˚
V /A
1520.3
847.1
830.3
Z
4
4
4
2
T/ K
l/mm-1(Mo-Ka)
Dx/mg m-3
292
293
298
298
0.240
4.815
0.42
3.46
1.421
1.835
1.517
2.039
Reflections/parameters
F(000)
3469/201
680
1647/109
464
1895/110
1553/110
675
429
Tmax
0.9764
0.6445
0.2490
1.70/25.95
-14/14, -13/0, 0/7
1647
0.890
0.298
Tmin
h range /o
0.9536
0.850
0.265
2.71/27.50
-20/20, -9/9, -17/17
3469
1.70/28.33
-16/14, -14/14, -6/8
1895
2.04/25.00
-7/7, -7/9, -10/11
1553
Index range (h, k, l)
Reflections collected
Independent reflections
Goodness of fit on F2
R1, wR2 [I C 2r(I)]a)
1647
960
1328
1410
1.051
1.050
1.004
1.060
0.0485, 0.0598
0.0659, 0.1251
0.0503, 0.0711
0.0391, 0.0423
factors were employed, and anomalous dispersion correc-
tions were incorporated. The crystallographic data were
listed in Table 1.
Figures 1–4 gives a perspective view of the molecular
structures of 1–4 together with the atomic labeling system.
Counpound 1–3 crystallized monoclinically with space
group P21/c, while MET-I 4 crystallized in the triclinic
system with space group P1. For compound 1, the imid-
azole ring (plane I) and the benzene ring (plane II) both are
˚
well-defined planes with an average deviation of 0.0010 A
˚
for the former and 0.0051 A for the later. The dihedral
angles between the basal planes are as follows: 3.9o
between plane I and the nitro plane; 10.3o between plane I
and plane II; and 7.3o between the nitro plane and plane II.
In the molecules of compound 2–4, the imidazole ring in
each molecule is planar, with an average deviation of
Fig. 1 Molecular structure of 1. The displacement ellipsoids are
drawn at the probability level
˚
˚
0.0023 A for compound 2, 0.0016 A for compound 3 and
˚
0.0079 A for compound 4. The nitro N atom lays 0.059 A
˚
˚
˚
˚
C2) and 0.022 A (for C3) from the plane of the ring of
˚
compound 2, 0.144 (for C4) and 0.004 A (for C6) of
˚
compound 3, 0.229 (C5) and 0.027 A (C4) of compound 4,
of 2 (0.060 A for 3, 0.017 A for 4) above the plane. The
two other groups attached to the ring are located on the
opposite side of the plane, with displacements of 0.097 (for
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J Chem Crystallogr (2008) 38:461–466
465
Fig. 4 Molecular structure of 4. The displacement ellipsoids are
drawn at the probability level
o
Table 2 Selected bond lengths (A) and angles ( ) for 1–4
˚
MET-OTs (1)
C(2)–C(1)
1.357 C(1)–N(3)
1.381 C(3)–N(1)
1.348 C(5)–N(1)
1.318 C(6)–O(1)
1.407
1.353
1.469
1.462
C(1)–N(1)
C(2)–N(2)
Fig. 2 Molecular structure of 2. The displacement ellipsoids are
drawn at the probability level
C(3)–N(2)
O(1)–C(6)–C(5)–N(1)
O(4)–N(3)–C(1)–N(1)
-63.35
2.9
O(5)–N(3)–C(1)–N(1) 5.3
MET-Br (2)
C(5)–C(6)
1.368 C(4)–N(2)
1.348
1.413
1.455
1.897
C(5)–N(1)
1.355 C(6)–N(3)
1.383 C(2)–N(2)
1.327 C(1)–Br(1)
C(6)–N(2)
C(4)–N(1)
Br(1)–C(1)–C(2)–N(2)
59.2
O(1)–N(3)–C(6)–N(2) 4.8
O(2)–N(3)–C(6)–N(2) -176.1
MET-Cl (3)
C(2)–C(3)
1.366 C(1)–N(1)
1.365
1.407
1.465
1.791
C(2)–N(2)
1.343 C(3)–N(3)
1.382 C(4)–N(1)
1.339 C(5)–Cl(1)
C(3)–N(1)
C(1)–N(2)
Cl(1)–C(5)–C(4)–N(1)
60.3
O(1)–N(3)–C(3)–N(1) 4.4
O(2)–N(3)–C(3)–N(1) -175.94
Fig. 3 Molecular structure of 3. The displacement ellipsoids are
drawn at the probability level
MET-I (4)
C(2)–C(3)
1.348 C(1)–N(1)
1.358
1.414
1.516
2.163
respectively. The dihedral angle between the imidazole
ring and the nitro plane is 6.6o for 2 (6.5o for 3, 6.6o for 4).
The selected bond distances and bond angles in 1–4
given in Table 2 are discussed as below. The crystal
structures of compounds 2, 3 and 4 are quite similar, they
all consist of an imidazole ring, a nitro plane, and a halogen
atom. As shown in table 1, the bond lengths of C–X are
C(2)–N(2)
1.345 C(3)–N(3)
1.385 C(5)–N(1)
1.334 C(6)–I(1)
C(3)–N(1)
C(1)–N(2)
I(1)–C(6)–C(5)–N(1)
-179.9
O(2)–N(3)–C(3)–N(1) 8.3
O(1)–N(3)–C(3)–N(1) -171.4
˚
1.897, 1.791 and 2.163 A in 2, 3, and 4, respectively, which
˚
compound 1, the bond length of C–O is 1.462 A, which is
the shortest because the size of O atom is smaller than that
of the halogen atoms.
well correspond to the size of the halogen atom and all
conform to the normal value for the C–X bond. While for
123

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J Chem Crystallogr (2008) 38:461–466
Fig. 5 The packing structure of
compound 1 along the b-axis
showing hydrogen bonds
In the imidazole ring, the double bond lengths of C–N
˚
are 1.318, 1.327, 1.339, and 1.334 A; the double bond
the CCDC numbers are 609616 (MET-Br) & 609617
(MET-OTs).
˚
lengths of C–C are 1.357, 1.368, 1.366, and 1.348 A in 1, 2,
3, and 4, respectively, typical of double bonds. The packing
structure of compound 1 along the b-axis showing hydro-
gen bonds was listed in Fig. 5.
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123