Nucleophilic substitution reactions of 1-methyl-4,5-dinitroimidazole with aqueous ammonia or sodium azide

Article abstract of DOI:10.1007/s10593-018-2389-5

[Figure not available: see fulltext.] In this work, 5-amino-1-methyl-4-nitroimidazole was synthesized by amination reaction of 1-methyl-4,5-dinitroimidazole with aqueous ammonia in 95% yield. Meanwhile, one of its isomers, 4-amino-1-methyl-5-nitroimidazole as byproduct was obtained from the filtrate. Furthermore, nucleophilic substitution reaction of 1-methyl-4,5-dinitroimidazole with sodium azide gave 5-azido-1-methyl-4-nitroimidazole in 98% yield. The three compounds were characterized by IR, ¹H and ¹³C NMR spectra, melting points, and elemental analysis. The structure of 4-amino-1-methyl-5-nitroimidazole was further confirmed by single crystal X-ray diffraction. These reactions indicate that the nitro group at position 5 of 1-methyl-4,5-dinitroimidazole is quite unstable, as well as partial substitution of nitro group at position 4 also occured in aqueous ammonia. Only one nitro group of the two is involved in nucleophilic substitution reaction in each case.

Full text of DOI:10.1007/s10593-018-2389-5

DOI 10.1007/s10593-018-2389-5
Chemistry of Heterocyclic Compounds 2018, 54(11), 1045–1049
Nucleophilic substitution reactions of 1-methyl-4,5-dinitroimidazole
with aqueous ammonia or sodium azide
Peng-Bao Lian1, Xiao-Jie Guo2, Jian-Long Wang1,
Li-Zhen Chen1*, Fan-Fan Shen1
1 School of Chemical Engineering and Technology, North University of China,
College road on the 3rd, Taiyuan 030051, China; е-mail: chen17555@163.com
2 Shanxi DaYi Hospital (Shanxi Academy of Medical Sciences),
186 Long cheng St., Taiyuan 030032, China; е-mail: 550245264@qq.com
Submitted July 21, 2018
Accepted after revision October 9, 2018
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(11), 1045–1049
In this work, 5-amino-1-methyl-4-nitroimidazole was synthesized by amination reaction of 1-methyl-4,5-dinitroimidazole with aqueous
ammonia in 95% yield. Meanwhile, one of its isomers, 4-amino-1-methyl-5-nitroimidazole as byproduct was obtained from the filtrate.
Furthermore, nucleophilic substitution reaction of 1-methyl-4,5-dinitroimidazole with sodium azide gave 5-azido-1-methyl-4-nitroimidazole
1
in 98% yield. The three compounds were characterized by IR, H and 13C NMR spectra, melting points, and elemental analysis. The
structure of 4-amino-1-methyl-5-nitroimidazole was further confirmed by single crystal X-ray diffraction. These reactions indicate that
the nitro group at position 5 of 1-methyl-4,5-dinitroimidazole is quite unstable, as well as partial substitution of nitro group at position 4
also occured in aqueous ammonia. Only one nitro group of the two is involved in nucleophilic substitution reaction in each case.
Keywords: 4-amino-1-methyl-5-nitroimidazole, 5-amino-1-methyl-4-nitroimidazole, 5-azido-1-methyl-4-nitroimidazole, 1-methyl-
4,5-dinitroimidazole, nucleophilic substitution reaction.
Scheme 1
Nitroimidazoles are widely used as antitumor, anti-
bacterial, antifungal, antiviral drugs due to their biological
activity.1–4 Recently, polynitroimidazoles have become
object of increased interest as energetic materials. Several
nitro compounds with the imidazole moiety as the core
have been reported as insensitive energetic materials.5–12 It
has been shown (Scheme 1) that when 1-methyl-4,5-di-
nitroimidazole (4,5-MDNI) (1) reacts with hydrochloric
acid, chlorination occurs at position 5, thereby providing
5-chloro-1-methyl-4-nitroimidazole in 74% yield.13
4,5-MDNI (1) reacts with thiophenol, H2S, phenol, sodium
methylate, cyclic amine, or sodium azide, in all cases at
position 5, and affords mercaptophenyl, mercapto, phenoxy,
methoxy, cyclic amino, or azido derivatives, respectively
(Scheme 1).14–16 These reactions illustrate that the nitro
group at position 5 is labile and hence susceptible to
nucleophlic substitution reactions, whereas the nitro group
at position 4 remains unaffected.
O2N
Cl
N
N
Me
O2N
O2N
PhS
N
N
HCl
NH
N
N
X
N
PhSH
X
O2N
O2N
Me
Me
N
O2N
N3
N
Me
O2N
HS
NaN3
H2S
N
N
1
N
Me
N
PhOH
O2N
MeONa
O2N
Me
N
N
MeO
PhO
N
N
Me
Me
5-Amino-1-methyl-4-nitroimidazole (2) as an inter-
mediate compound has a wide range of applications. It not
only displays solvatochromism, but also plays an important
role as propellant with excellent detonation performance,
high melting point, and low sensitivity. Therefore, it can be
used for heat-resistant explosives. Three methods for the
preparation of 5-amino-1-methyl-4-nitroimidazole (2) have
0009-3122/18/54(11)-1045©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(11), 1045–1049
been reported (Scheme 2). In the first approach, 5-chloro-
imidazole (6) was obtained as byproduct by extracting the
filtrate with ethyl acetate. During the experiment, we found
that 5-amino-1-methyl-4-nitroimidazole (2) was soluble
only in dimethylformamide and dimethyl sulfoxide (solu-
bility 0.026 and 0.031 g/ml at 80°C, respectively) and
insoluble in ethyl acetate. However, according to literature
reports, it was extracted with ethyl acetate.19,20 When we
extracted the filtrate of the reaction mixture with ethyl
acetate, the isomeric byproduct 6 was obtained. The
structure of two compounds was confirmed by infrared
spectroscopy, nuclear magnetic resonance spectroscopy,
and elemental analysis, and the data are consistent with
those reported before.25 The structure of 4-amino-1-methyl-
5-nitroimidazole (6) was further confirmed by single
crystal diffraction analysis. The density of the electron
cloud at the position C-5 is lower than at the position C-4
of the imidazole ring of 4,5-MDNI (1), which may explain
why the nitro group is displaced more readily at C-5 than
C-4 carbon atom.15
1-methyl-4-nitroimidazole (3) was heated with 3.5%
alcoholic ammonia at 140°C.17 The second method was
amination reaction of 1-methyl-4-nitroimidazole (4) with
trimethylhydrazinium iodide,18 sulfenamide,19 or 4-amino-
1,2,3-triazole20 to give product 2 at room temperature.
Although the product obtained by the two methods had
good purity, the reaction yield was relatively low and a
long reaction time was necessary. Even more, the first
method required high temperature, and the amination
reagents of the second method were expensive. The third
method, nucleophilic substitution reaction of 4,5-MDNI (1)
with aqueous ammonia gave 5-amino-1-methyl-4-nitro-
imidazole (2) in high yield.21,22 This method also has the
advantages of low temperature, high purity, and low cost.
Scheme 2
Scheme 4
5-Azido-1-methyl-4-nitroimidazole (5) not only holds
promise as a potential melt-casting explosive,23 but also
was used as a precursor to synthetic antiparasitic drugs.16
Nucleophilic substitution reaction of 5-chloro-1-methyl-
4-nitroimidazole (3) with sodium azide to give 5-azido-
1-methyl-4-nitroimidazole (5) has been reported in two
articles (Scheme 3).23,24 The reported yield of product 5
was 68% with dimethyl sulfoxide and water as solvents at
18–20°C and 72 h reaction time.23 However, when DMF
was used as a solvent the yield of product 5 reached 99% at
20°C within 17 h.24 In the first procedure, the lower yield
could be due to the presence of water in the reaction
system. Applying another method, 4,5-MDNI (1) was
reacted with sodium azide in water to give 5-azido-
1-methyl-4-nitroimidazole (5) in 99% yield at room
temperature (Scheme 1).16
Furthermore, 4,5-MDNI (1) was subjected to reaction
with sodium azide in acetone under the ambient tempe-
rature. The reaction was very rapid and in 20 min 5-azido-
1-methyl-4-nitroimidazole (5) was isolated as a pale-yellow
solid in 98% yield (Scheme 4). When the filtrate was
extracted with an organic solvent, such as dichloromethane,
diethyl ether, ethyl acetate, or toluene, no other product
was obtained. Unlike the nucleophilic substitution reaction
with aqueous ammonia, when 4,5-MDNI (1) reacted with
sodium azide the nitro group at the position C-4 was not
replaced by an azide group, probably due to the lower
basicity of azide ion in comparison with ammonia.
Although this reaction has been performed in water,16 we
found that 4,5-MDNI (1) was not completely dissolved in
water, and we chose acetone as the solvent.
Scheme 3
The IR spectra of 5-amino-1-methyl-4-nitroimidazole
(2) (Fig. 1a) and 4-amino-1-methyl-5-nitroimidazole (6)
(Fig. 1b) show strong absorption peaks at 3444 (3456) and
1645 (1630) cm–1 (numbers in parentheses are for
compound 6), which can be assigned to the stretching and
bending vibration of the NH2 group, respectively. The
stretching vibration absorption peak of =C–H fragment in
the imidazole ring is observed at 3066 (3100) cm–1. The
bands at 1550 (1533) and 1325 (1304) cm–1 correspond to
the asymmetric and symmetric stretching vibration
movements of the C–NO2 fragment, respectively. At 1409
(1404) cm–1, there is the stretching vibration absorption
peak of C=C bond of the imidazole ring. The band at 1373
In this paper, an improved synthetic method involving
the direct amination of 4,5-MDNI (1) was used to synthe-
size 5-amino-1-methyl-4-nitroimidazole (2) with higher
yield and higher purity at room temperature (Scheme 4). At
the same time, the isomeric 4-amino-1-methyl-5-nitro-
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Chemistry of Heterocyclic Compounds 2018, 54(11), 1045–1049
Figure 2. Molecular structure of 4-amino-1-methyl-5-nitro-
imidazole (6) according to X-ray diffraction analysis.
file). The length of C–N and C–C bonds are shorter than
the standard C–N (1.48 Å) and C–C (1.54 Å) single bonds,
but longer than that of C=N (1.29 Å) and C=C (1.34 Å)
double bonds. This may be illustrated by the resonance
structure, as shown in Figure 3. This conjugative effect can
also be found in the imidazole ring of 4,5-MDNI.26
There are four different intermolecular hydrogen bonds
in each unit cell of 4-amino-1-methyl-5-nitroimidazole, and
each molecule of 4-amino-1-methyl-5-nitroimidazole (6)
contains one intramolecular hydrogen bond (Fig. 4, Table 1).
Except the hydrogen atoms of the methyl group, all atoms
of the 4-amino-1-methyl-5-nitroimidazole molecule are
coplanar, which may be due to intramolecular hydrogen
bonds and conjugation effect.
Figure 1. FT-IR spectra of a) 5-amino-1-methyl-4-nitromidazole
(2) and b) 4-amino-1-methyl-5-nitroimidazole (6).
Figure 3. Resonance structures of 4-amino-1-methyl-5-nitro-
imidazole (6).
(1452 and 1365) cm–1 can be assigned to the bending
vibration absorption of the methyl group. Finally, at 1234
(1232) cm–1 there is the stretching vibration absorption
peak of the C–NH2 bond. The differences in IR spectra of
the two isomers may be due to the effect of the different
positions of the amino and nitro substituents with respect to
the imidazole ring.
4-Amino-1-methyl-5-nitroimidazole (6) crystallizes in
the monoclinic crystal system with space group P21/c, and
each elementary cell has eight molecules that form 4 pairs
of nonequivalent molecules. The main crystallographic data
are listed in Table 1S (Supplementary information file). The
compound exhibits an unsymmetrical structure, as shown
in Figure 2. The imidazole ring is almost planar with the
dihedral angles 0.293° and 0.178° for the two molecules
(Table 2S, Supplementary information file). The nitrogen
atoms of the nitro groups and the amino groups, the
hydrogen atoms of the amino groups, the oxygen atoms of
the nitro groups, and the carbon atoms of the methyl groups
are almost coplanar with the imidazole ring; for the
respective torsion, see Table 3S (Supplementary
information file). However, the hydrogen atoms of the
methyl groups are rotated out of the plane.
The bond lengths of 4-amino-1-methyl-5-nitroimidazole
(6) are shown in Table 4S (see Supplementary information
Figure 4. 2D chain of 4-amino-1-methyl-5-nitroimidazole (6)
molecules in the elementary cell.
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Chemistry of Heterocyclic Compounds 2018, 54(11), 1045–1049
Table 1. Characteristics of hydrogen bonds in the crystal of 4-amino-1-methyl-5-nitroimidazole (6)
D–H…A
d(D−H), Å
d(H···A), Å
d(D···A), Å
Symmetry transformations
(DHA), deg
162.96
N(4)#20–H(4A)#21…N(7)#12
N(8)#8–H(8A)#9…N(3)#19
N(8)#8–H(8A)#9…N(3)#19
N(4)#20–H(4A)#21…N(7)#12
N(8)#8–H(8B)#10…O(3)#3
N(4)#20–H(4B)#22…O(2)#4
0.861
0.860
0.860
0.861
0.860
0.860
2.125
2.136
2.136
2.125
2.280
2.277
2.959
2.983
2.983
2.959
2.820
2.818
x, y, z
–x, 1 – y, –z
1 + x, y, 1 + z
1 – x, 1 – y, 1 – z
– x, 1 – y, –z
x, y, z
168.21
168.21
162.96
120.95
120.821
In summary, we have studied the nucleophilic sub-
stitution reactions of 1-methyl-4,5-dinitroimidazole with
aqueous ammonia at room temperature, which produced
5-amino-1-methyl-4-nitroimidazole and the isomeric 4-amino-
1-methyl-5-nitroimidazole as byproduct. The reaction of
1-methyl-4,5-dinitroimidazole with sodium azide in
acetone at room temperature allowed to obtain 5-azido-
1-methyl-4-nitroimidazole in high yield without side
products. The structure of products of these reactions
indicate that the nitro group at position 5 of the starting
1-methyl-4,5-dinitroimidazole is highly labile compared to
position 4.
4-Amino-1-methyl-5-nitroimidazole (6). The filtrate of
the above-mentioned reaction mixture was extracted with
ethyl acetate (5×50 ml). The extracts were combined, washed
with water, dried over MgSO4, and evaporated under
reduced pressure. Yield 0.42 g (3%). Pale-yellow powder.
Mp 153.8–155.5°C (mp 157–160°C25). IR spectrum, ν, cm–1:
3456 (–NH2), 3100 (=C–H), 1630 (–NH2), 1530 (C–NO2),
1452 (–CH3), 1404 (C=C), 1365 (–CH3), 1304 (C–NO2),
1
1232 (C–NH2). H NMR spectrum ((CD3)2CO), δ, ppm:
7.53 (1H, s, H-2); 6.74 (2H, s, NH2); 3.88 (3H, s, CH3).
13C NMR spectrum ((CD3)2CO), δ, ppm: 35.8 (CH3); 120.4
(C-5); 137.8 (C-2); 148.3 (C-4). Found, %: C 33.74; H 4.24;
N 39.37. C4H6N4O2. Calculated, %: C 33.81; H 4.26; N 39.42.
5-Azido-1-methyl-4-nitroimidazole (5). A mixture of
MDNI (1) (3.44 g, 0.02 mol), NaN3 (1.95 g, 0.03 mol), and
acetone (30 ml) was stirred at room temperature for 20 min.
Then the precipitate that formed was filtered off, washed
with water, and dried in vacuum. Yield 3.29 g (98%).
Yellow powder. Mp 108.3–110°C (mp 108–110°C16).
IR spectrum, ν, cm–1: 2143 (–N3), 1550 (C–NO2), 1428
Experimental
IR spectra were recorded in KBr pellets on a Bruker
1
Model Vertex 80 FTS spectrometer. H and 13C NMR
spectra were recorded on a Bruker Model AVANCE
spectrometer (400 and 100 MHz, respectively). The solvent
signals were used as internal reference (δ 2.50 and
39.5 ppm for 1H and 13C nuclei, respectively, in DMSO-d6;
δ 2.05 and 29.8 ppm for 1H and 13C nuclei, respectively, in
(CD3)2CO). Elemental analyses were performed on an
Elementar Vario EL elemental analyzer. Melting points were
determined using a Buchi Melting Point M-565 apparatus.
Acetone (AR, 99.5%) from XiLong Science Company
was used as the reaction solvent.
1
(–CH3), 1410 (C=C), 1382 (C–NO2). H NMR spectrum
(DMSO-d6), δ, ppm: 7.61 (1H, s, H-2); 3.48 (3H, s, CH3).
13C NMR spectrum (DMSO-d6), δ, ppm: 30.8 (CH3); 136.6
(C-2); 137.9 (C-5); 139.9 (C-4). Found, %: C 28.32; H 2.36;
N 49.89. C4H4N6O2. Calculated, %: C 28.58; H 2.40; N 49.99.
X-ray structural investigation of 4-amino-1-methyl-
5-nitroimidazole (6). Single crystals were grown from
acetone solution by solvent evaporation method at ambient
temperature. X-ray diffraction data were collected on an
Agilent Xcalibur & Gemini diffractometer equipped with
graphite monochromator; MoKα radiation (λ 0.07107 nm).
The structure was solved by the direct methods (SHELXL-97
software)29 and refined by the full-matrix-block least-
squares method on F2 with anisotropic thermal parameters
for all non-hydrogen atoms (OLEX2 software).30 The
hydrogen atoms were added according to the theoretical
models. The complete crystallographic data set was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 1851350).
4,5-MDNI (1) was prepared according to a published
procedure.27,28
Caution: 4,5-MDNI is considered as dangerous and
proper precaution should be taken in handling and storage.
5-Amino-1-methyl-4-nitroimidazole (2). 4,5-MDNI (1)
(17.2 g, 0.1 mol) was dissolved in acetone (50 ml), and 25–
28% aqueous ammonia (15 ml) was added slowly under
stirring in a water bath to avoid a rise in temperature. The
reaction mixture was stirred for 30 min at room
temperature, during which the yellow precipitate was
deposited which was filtered off and dried at 40°C. Yield
13.5 g (95%). Yellow powder. Mp 301.5–302.5°C (mp 301–
303°C13). IR spectrum, ν, cm–1: 3444 (–NH2), 3066
(=C–H), 1645 (–NH2), 1550 (C–NO2), 1409 (C=C), 1373
1
(–CH3), 1325 (C–NO2), 1234 (C–NH2). H NMR spectrum
Supplementary information file containing crystallo-
graphic data of compound 6 is available at the journal
website at http://link.springer.com/journal/10593.
(DMSO-d6), δ, ppm: 7.55 (2H, s, NH2); 7.24 (1H, s, H-2);
3.43 (3H, s, CH3). 13C NMR spectrum (DMSO-d6), δ, ppm:
30.0 (CH3); 126.7 (C-2); 133.9 (C-4); 141.6 (C-5). Found,
%: C 33.68; H 4.32; N 39.24. C4H6N4O2. Calculated, %:
C 33.81; H 4.26; N 39.42.
We thank the Center of Testing and Analysis, Beijing
University of Chemical Technology, for support.
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16. Efimov, I.; Beliaev, N.; Beryozkina, T.; Slepukhin, P.;
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