Specific features of nucleophilic substitution in 1-chloro-3,4- dinitrobenzene

Article abstract of DOI:10.1007/s11178-005-0043-z

Effects of the solvent, temperature, and nucleophile nature on the selectivity of nucleophilic substitution in 1-chloro-3,4-dinitrobenzene were studied, and optimal conditions were found for the synthesis and isolation of particular products.

Full text of DOI:10.1007/s11178-005-0043-z

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1473–1476. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1522–1525.
Original Russian Text Copyright © 2004 by Zotova, Kushakova, Kuznetsov, Rodin, Garabadzhiu.
Specific Features of Nucleophilic Substitution
in 1-Chloro-3,4-dinitrobenzene
N. V. Zotova, P. M. Kushakova, V. A. Kuznetsov, A. A. Rodin, and A. V. Garabadzhiu
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: gar@sitecs.spb.ru
Received March 10, 2004
Abstract—Effects of the solvent, temperature, and nucleophile nature on the selectivity of nucleophilic
substitution in 1-chloro-3,4-dinitrobenzene were studied, and optimal conditions were found for the synthesis
and isolation of particular products.
Aromatic nucleophilic substitution reactions have
been studied in sufficient detail [1]; nevertheless, these
processes still attract strong interest from the view-
points of both synthetic organic chemistry and kinetic
studies. Up to now, a great number of studies have
been reported on reactions of activated halobenzenes,
e.g., 1-chloro-2,4-dinitrobenzene, with O-, S-, and
N-nucleophiles. However, the properties of isomeric
1-chloro-3,4-dinitrobenzene remain almost unstudied.
Relevant information dates back to 1930s. 1-Chloro-
3,4-dinitrobenzene (I) is a polyfunctional substrate,
and its chemical transformations are not limited to
nucleophilic substitution of the nitro group in position
3. Each intermediate product in this process is a reac-
tive and interesting species which could give rise to
compounds belonging to various classes, including
phenol derivatives, fused systems, and heterocyclic
compounds [2, 3].
It is known [4, 5] that the solvent nature may affect
not only the rate of a reaction but also its direction
provided that several reaction centers are available.
Moreover, the conditions for isolation of final products
also depend on the solvent, although this aspect is
seldom taken into account.
We examined solvents belonging to two main
groups: aprotic (DMSO, acetone, and diethyl ether)
and protic (methanol and ethanol). Reactions of
chlorodinitrobenzene I with various aliphatic amines
were carried out at room temperature, the molar ratio
compound I–amine was 1:2, the reaction time in all
cases was 6 h, and the conversion of I was no less than
95% (Table 1). According to the data in Table 1, in
all cases the major product is that resulting from
replacement of the nitro group in position 3. It should
be noted that the solvent nature considerably affects
the ratio of the “anomalous” substitution products.
However, from the viewpoint of isolation of the target
product, the best solvent was methanol; in all experi-
ments, the product spontaneously crystallized from
the reaction mixture, and it generally required no
additional purification (it contained more than 95% of
the main substance).
O2N
Cl
Nu
Cl
NuH
O2N
O2N
I
IIa–IIt
Nu
O2N
Cl
O2N
O2N
+
+
Nu
IIIa–IIIt
IVa–IVt
The effect of temperature on the direction of
nucleophilic substitution in chlorodinitrobenzene I was
studied in methanol and ethanol at a I-to-amine molar
ratio of 1:2 and a substrate concentration of 10 wt %;
the reaction time was 10 h at 10°C, 6 h at 20°C, and 40
or 30 min in boiling methanol or ethanol, respectively
(Table 2). It was found that rise in temperature reduces
II–IV, Nu = MeNH (a), EtNH (b), t-BuCH2NH (c),
Ph(CH2)2NH (d), Me(Ph)CHNH (e), cyclopropylamino (f),
PhCH2NH (g), HO(CH2)2NH (h), HO(CH2)3NH (i),
HOCH2CH(Me)NH (j), CH2=CHCH2NH (k), 2-furylmethyl-
amino (l), 1-pyrrolidinyl (m), piperidino (n), morpholino (o),
N-methyl-1-piperazinyl (p), N-phenyl-1-piperazinyl (q),
N-benzyl-1-piperazinyl (r), 3-pyridylmethylamino (s),
azepan-1-yl (s).
1070-4280/04/4010-1473 © 2004 MAIK “Nauka/Interperiodica”

ZOTOVA et al.
1474
Table 1. Ratios of products II, III, and IV (wt. %)a in nucleophilic substitution of the nitro groups and chlorine atom in
1-chloro-3,4-dinitrobenzene (I) in different solvents
Nucleophile
Benzylamine
Ethylamine
DMSO
Acetone
70:18:12
70:25:50
69:18:13
77:18:50
70:17:13
Diethyl ether
72:16:12
67:20:13
65:20:15
78:15:70
69:16:15
Methanol
80:14:60
75:17:80
76:15:90
82:15:30
75:12:13
Ethanol
80:12:80
73:17:10
75:15:10
80:13:70
72:12:16
76:16:80
74:16:10
75:15:12
80:15:50
74:12:14
2-Aminoethanol
Piperidine
Morpholine
a
The overall amount of compounds II, III, and IV was taken as 100%.
Table 2. Ratios of products II, III, and IV (wt. %)a in nucleophilic substitution of the nitro groups and chlorine atom in
1-chloro-3,4-dinitrobenzene (I) in methanol and ethanol at different temperatures
Methanol
20°C
Ethanol
20°C
Nucleophile
10°C
64°C
10°C
78°C
82:13:50
78:11:11
80:14:60
75:12:13
75:15:10
70:15:15
80:15:50
75:15:10
80:12:80
72:12:16
72:12:16
65:15:20
Benzylamine
Morpholine
a
See footnote a to Table 1.
the selectivity of nucleophilic substitution with respect
to the 3-nitro group.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DPX-200 spectrometer from solutions in DMSO-d6;
the chemical shifts were measured relative to the
residual proton signals of the solvent. The elemental
compositions were determined from the high-resolu-
tion mass spectra which were obtained on a Varian
MAT-311A instrument (xenon, accelerating voltage
2–6 kV, current 0.1–0.5 mA, resolution 30000). The
product ratios were determined by HPLC on a Varian
9065 Polychrom chromatograph equipped with
a PUMP 9012 UV detector (λ 254 nm) and a 250×
4.6-mm column packed with Phenil reversed phase;
eluent 50% MeCN–50% 0.05 M NaClO4, flow rate
1 ml/min. The progress of reactions was monitored by
TLC on Silufol UV-254 plates using chloroform–
hexane (1:2), chloroform–methanol (9:1), or hexane–
acetone–diethyl ether (5:2:1) as eluent.
Primary aromatic and secondary alicyclic amines
readily reacted with chlorodinitrobenzene I, and the
major products were the corresponding 3-amino
derivatives II. In reactions with secondary aliphatic
amines, such as dimethylamine, diethylamine, and di-
benzylamine, we succeeded in detecting only traces of
substitution products even on heating in boiling di-
methylformamide. Anilines also failed to react with
compound I. Therefore, we examined how the degree
of branching at the α-carbon atom in aliphatic amines
affects the conversion of substrate I.
We found that the rate of the reaction of 1-chloro-
3,4-dinitrobenzene (I) with 2-phenylethylamine is
higher by a factor of ~2 than with (1-phenylethyl)-
amine. An analogous relation was observed for
3-amino- and 2-amino-1-propanols. tert-Butylamine
did not react with chlorodinitrobenzene I.
N-Methyl-5-chloro-2-nitroaniline (IIa). Methyl-
amine, 6.2 g (20 mmol), was added with stirring to
a solution of 20.2 g (10 mmol) of 1-chloro-3,4-di-
nitrobenzene (I) in 200 ml of methanol, and the mix-
ture was vigorously stirred for 3 h at room temperature
and cooled to 6–8°C. The precipitate was filtered off,
washed with methanol, and dried in air. Yield 11.2 g
Thus the direction of the reaction of 1-chloro-3,4-
dinitrobenzene (I) with primary aliphatic and alicyclic
amines depends on all the above factors, solvent and
amine nature and temperature. We succeeded in
finding optimal conditions for nucleophilic substitution
in compound I (solvent methanol, temperature 18–
20°C, reaction time 6 h), which ensured preparation in
good yields of a number of products resulting from
replacement of the 3-nitro group in the substrate.
1
(60%), mp 100–102°C. H NMR spectrum, δ, ppm:
2.96 d (3H, CH3), 6.64 d (1H, 4-H), 6.96 s (1H, 6-H),
8.05 d (1H, 3-H), 8.18 s (1H, NH). Found: M+ 186.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

SPECIFIC FEATURES OF NUCLEOPHILIC SUBSTITUTION
1475
C7H7ClN2O2. Calculated: M 186.599. Compounds IIb–
IIl were synthesized in a similar way.
(1H, NH). Found: M+ 230. C9H11ClN2O3. Calculated:
M 230.653.
2-(5-Chloro-2-nitrophenylamino)-1-propanol
(IIj). Yield 10.4 g (45%), mp 107–109°C. H NMR
N-Ethyl-5-chloro-2-nitroaniline (IIb). Yield 11.3 g
(56%), mp 76–78°C. 1H NMR spectrum, δ, ppm: 1.27 t
(3H, CH3), 3.36 m (2H, CH2N), 6.60 d (1H, 4-H),
6.96 s (1H, 6-H), 8.03 d (1H, 3-H), 8.09 s (1H, NH).
Found: M+ 201. C8H9ClN2O2. Calculated: M 200.626.
1
spectrum, δ, ppm: 1.16 d (3H, CH3), 3.26 m (2H,
CH2N), 3.90 s (1H, CHOH), 4.95 s (1H, OH), 6.62 d
(1H, 4-H), 7.05 s (1H, 6-H), 8.05 d (1H, 3-H), 8.31 s
(1H, NH). Found: M+ 230. C9H11ClN2O3. Calculated:
M 230.653.
N-(2,2-Dimethylpropyl)-5-chloro-2-nitroaniline
(IIc). Yield 15.8 g (65%), mp 96–98°C. 1H NMR spec-
trum, δ, ppm: 1.27 s [9H, (CH3)3], 3.13 d (2H, CH2N),
6.62 d (1H, 4-H), 7.08 s (1H, 6-H), 8.05 d (1H, 3-H),
8.21 s (1H, NH). Found: M+ 243. C11H15ClN2O2. Cal-
culated: M 242.707.
N-Allyl-5-chloro-2-nitroaniline (IIk). Yield 11.5 g
(54%), mp 47–49°C; published data [2]: mp 52–53°C.
1H NMR spectrum, δ, ppm: 4.04 t (2H, CH2N), 5.25 t
(2H, =CH2), 5.91 m (1H, =CH), 6.66 d (1H, 4-H),
6.93 s (1H, 6-H), 8.06 d (1H, 3-H), 8.31 s (1H, NH).
Found: M+ 212. C9H9ClN2O2. Calculated: M 212.637.
N-(2-Phenylethyl)-5-chloro-2-nitroaniline (IId).
1
Yield 12.5 g (45%), mp 60–62°C. H NMR spectrum,
N-(2-Furylmethyl)-5-chloro-2-nitroaniline (IIl).
δ, ppm: 3.02 t (2H, CH2Ph), 3.54 t (2H, CH2N),
6.59 d (1H, 4-H), 6.83 s (1H, 6-H), 7.29 m (5H, C6H5),
8.09 d (1H, 3-H), 8.40 s (1H, NH). Found: M+ 276.
C14H13ClN2O2. Calculated: M 276.725.
1
Yield 13.9 g (55%), mp 63–65°C. H NMR spectrum,
δ, ppm: 4.49 d (2H, CH2N), 6.31 d (2H, CH, furyl),
6.64 d (1H, 4-H), 6.92 s (1H, 6-H), 7.39 s (1H, CHO,
furyl), 8.11 d (1H, 3-H), 8.33 s (1H, NH). Found:
M+ 253. C11H9ClN2O3. Calculated: M 252.659.
N-(1-Phenylethyl)-5-chloro-2-nitroaniline (IIe).
1
Yield 18.8 g (68%), mp 90–92°C. H NMR spectrum,
1-(5-Chloro-2-nitrophenyl)pyrrolidine (IIm).
Pyrrolidine, 14.2 g (20 mmol), was added with stirring
to a solution of 20.2 g (10 mmol) of 1-chloro-3,4-di-
nitrobenzene (I) in 200 ml of methanol, and the mix-
ture was vigorously stirred for 5 h at room temperature
and cooled to 6–8°C. The precipitate was filtered off
and recrystallized from methanol. Yield 18.7 g (70%),
δ, ppm: 1.65 d (3H, CH3), 4.64 m (1H, CHPh),
6.56 d (1H, 4-H), 6.63 s (1H, 6-H), 7.33 m (5H, C6H5),
8.10 d (1H, 3-H), 8.45 s (1H, NH). Found: M+ 276.
C14H13ClN2O2. Calculated: M 276.725.
N-Cyclopropyl-5-chloro-2-nitroaniline (IIf).
1
Yield 12.7 g (60%), mp 78–80°C. H NMR spectrum,
1
δ, ppm: 0.66 m (2H, CH2), 0.93 m (2H, CH2), 2.55 m
(1H, CH), 6.63 d (1H, 4-H), 7.27 s (1H, 6-H), 8.07 d
(2H, 3-H, NH). Found: M+ 213. C9H9ClN2O2. Calcu-
lated: M 212.637.
mp 74–76°C. H NMR spectrum, δ, ppm: 1.98 s (4H,
CH2), 3.19 s (4H, CH2N), 6.65 d (1H, 4-H), 6.88 s (1H,
6-H), 7.68 d (1H, 3-H). Found: M+ 267. C10H11ClN2O3.
Calculated: M 266.664. Compounds IIn–IIt were syn-
thesized in a similar way.
N-Benzyl-5-chloro-2-nitroaniline (IIg). Yield 9.3 g
1
(70%), mp 88–90°C. H NMR spectrum, δ, ppm:
1-(5-Chloro-2-nitrophenyl)piperidine (IIn). Yield
1
4.65 d (2H, CH2Ph), 6.62 d (1H, 4-H), 6.81 s (1H,
6-H), 7.36 m (5H, C6H5), 8.14 d (1H, 3-H), 8.44 s
(1H, NH). Found: M+ 262. C13H11ClN2O2. Calculated:
M 262.698.
15.6 g (65%), mp 64–66°C. H NMR spectrum, δ,
ppm: 1.68 m (6H, CH2), 3.02 t (4H, CH2N), 6.87 d
(1H, 4-H), 7.04 s (1H, 6-H), 7.73 d (1H, 3-H). Found:
M+ 241. C11H13ClN2O2. Calculated: M 240.691.
2-(5-Chloro-2-nitrophenylamino)ethanol (IIh).
Yield 14.1 g (65%), mp 108–110°C. H NMR spec-
4-(5-Chloro-2-nitrophenyl)morpholine (IIo).
Yield 12.6 g (52%), mp 69–71°C. H NMR spectrum,
1
1
trum, δ, ppm: 1.81 s (1H, OH), 3.49 d (2H, CH2N),
3.93 d (2H, CH2OH), 6.62 d (1H, 4-H), 6.88 s (1H,
6-H), 8.11 d (1H, 3-H), 8.28 s (1H, NH). Found:
M+ 216. C8H9ClN2O3. Calculated: M 216.625.
δ, ppm: 3.05 t (4H, CH2N), 3.83 t (4H, 2CH2O), 6.99 d
(1H, 4-H), 7.06 s (1H, 6-H), 7.77 d (1H, 3-H). Found:
M+ 242. C10H11ClN2O3. Calculated: M 242.664.
1-(5-Chloro-2-nitrophenyl)-4-methylpiperazine
1
(IIp). Yield 11.8 g (46%), mp 73–75°C. H NMR
3-(5-Chloro-2-nitrophenylamino)-1-propanol
(IIi). Yield 12.9 g (56%), mp 75–77°C. 1H NMR spec-
trum, δ, ppm: 1.87 s (1H, OH), 1.94 m (2H, CH2),
3.43 m (2H, CH2N), 3.84 m (2H, CH2OH), 6.57 d
(1H, 4-H), 6.85 s (1H, 6-H), 8.08 d (1H, 3-H), 8.26 s
spectrum, δ, ppm: 2.34 s (3H, CH3N), 2.56 t (4H,
CH2NCH3), 3.08 t (4H, CH2N), 6.95 d (1H, 4-H),
7.05 s (1H, 6-H), 7.74 d (1H, 3-H). Found: M+ 255.
C11H14ClN3O2. Calculated: M 255.706.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

ZOTOVA et al.
1476
1-(5-Chloro-2-nitrophenyl)-4-phenylpiperazine
(IIq). Yield 15.9 g (50%), mp 125–127°C. H NMR
spectrum, δ, ppm: 3.26 t (8H, CH2N), 6.79 t (1H, Ph),
6.94 t (1H, Ph), 7.20 d (1H, 4-H), 7.22 t (1H, Ph),
7.34 s (1H, 6-H), 7.85 d (1H, 3-H). Found: M+ 318.
C16H16ClN3O2. Calculated: M 317.778.
4-(4-Chloro-2-nitrophenyl)morpholine (IIIo).
A solution of 1.92 g (1 mmol) of 1,4-dichloro-2-
nitrobenzene in 20 ml of morpholine was heated for
2 h at the boiling point. The mixture was poured under
stirring into 60 ml of cold water, and the precip-
itate was filtered off, and recrystallized from 70%
1
1
methanol. Yield 1.2 g (50%), mp 45–47°C. H NMR
1-Benzyl-4-(5-chloro-2-nitrophenyl)piperazine
spectrum, δ, ppm: 3.00 s (4H, CH2N), 3.81 s (4H,
CH2O), 7.10 d (1H, 6-H), 7.44 d (1H, 4-H), 7.79 s
(1H, 3-H). Found: M+ 242. C10H11ClN2O3. Calculated:
M 242.664.
hydrochloride (IIr). Yield 16.6 g (45%), mp 190–
1
192°C. H NMR spectrum, δ, ppm: 3.35 m (8H,
CH2N), 4.36 s (2H, CH2Ph), 7.18 d (1H, 4-H), 7.35 s
(1H, 6-H), 7.41 s (2H, Ph), 7.72 s (1H, Ph), 7.89 d
(1H, 3-H). Found: M+ 368. C17H18ClN2O3. Calculated:
M 368.266.
Compounds IIIa–IIIm and IIIq–IIIt were syn-
thesized in a similar way. Products IVa–IVt were
isolated from the reaction mixtures by column chro-
matography on silica gel (40–64 µm, Merck) using
chloroform–hexane (1:2) as eluent. Their structure
was proved by the 1H and mass spectra.
N-(3-Pyridylmethyl)-5-chloro-2-nitroaniline
1
(IIs). Yield 11.1 g (42%), mp 90–92°C. H NMR
spectrum, δ, ppm: 4.68 d (2H, CH2N), 6.64 d (1H,
4-H), 6.92 s (1H, 6-H), 7.30 t (1H, CH, pyridine),
7.74 d (1H, CH, pyridine), 8.07 d (1H, 3-H), 8.45 d
(1H, CH, pyridine), 8.59 s (1H, CH, pyridine), 8.77 s
(1H, NH). Found: M+ 264. C12H10ClN3O2. Calculated:
M 263.685.
REFERENCES
1. Trost, B., Comprehensive Organic Synthesis, New York:
Pergamon, 1991, vol. 4, p. 147.
1-(5-Chloro-2-nitrophenyl)azepane (IIt). Yield
2. Mangini, A., Gazz. Chim. Ital., 1935, vol. 65, p. 1191.
3. Mangini, A., Gazz. Chim. Ital., 1933, vol. 63, p. 612.
4. Akiyele, E.T., Onyido, I., and Hirst, J., J. Chem. Soc.,
Perkin Trans. 2, 1988, p. 1859.
5. Onioha, G.N. and Onyido, I., J. Chem. Soc., Perkin
Trans. 2, 1988, p. 971.
1
10.2 g (40%), mp 63–65°C. H NMR spectrum, δ,
ppm: 1.59 s (4H, CH2), 1.79 s (4H, CH2), 3.24 t (4H,
CH2N), 6.73 d (1H, 4-H), 7.08 s (1H, 6-H), 7.64 d
(1H, 3-H). Found: M+ 255. C12H15ClN2O2. Calculated:
M 254.718.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004