Synthesis of 4-amino-4′-nitrodiphenyl sulfide

Article abstract of DOI:10.1023/A:1026340413270

The possibility of preparing 4-amino-4′-nitrodiphenyl sulfide by reaction of chlorobenzene with sodium sulfide in a two-phase system composed of water and organic solvent in the presence of a phase-transfer catalyst under continuous hydroacoustic treatment was examined.

Full text of DOI:10.1023/A:1026340413270

Russian Journal of Applied Chemistry, Vol. 76, No. 6, 2003, pp. 953 957. Translated from Zhurnal Prikladnoi Khimii, Vol. 76, No. 6, 2003,
pp. 982 986.
Original Russian Text Copyright
2003 by Pilyugin.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of 4-Amino-4 -nitrodiphenyl Sulfide
V. S. Pilyugin
Research and Technological Institute of Herbicides and Plant Growth Regulators, Academy of Sciences
of Bashkortostan Republic, Ufa, Bashkortostan, Russia
Received January 9, 2003
Abstract The possibility of preparing 4-amino-4 -nitrodiphenyl sulfide by reaction of chlorobenzene with
sodium sulfide in a two-phase system composed of water and organic solvent in the presence of a phase-trans-
fer catalyst under continuous hydroacoustic treatment was examined.
4
-Amino-4 -nitrodiphenyl sulfide I is an intermedi-
Hodson and Wilson [11] prepared diphenyl sulfide
I as follows. A solution of II in absolute ethanol is
heated almost to reflux, and an aqueous solution of
sodium sulfide is added in small portions. The re-
sulting mixture is refluxed with stirring for 10 h.
Yield of I is about 20% (mp 138 142 C).
ate in production of 3,4,4 -triaminodiphenyl sulfide,
the synthetic precursor of antihelminth agents of the
(6)-(4 -aminophenylthio)-2-aminobenzimidazole seri-
5
es [1].
Thioethers (sulfides) are prepared by condensation
of alkyl halides or nitro-substituted aryl halides with
sodium sulfide [2 4].
According to Radulova and Tapalova’s procedure
[12], a mixture of II with water and sodium sulfide is
heated, an additional portion of II is added, and, after
prolonged heating, toluene is added; the yield of I is
about 68% (mp 143 144 C).
Synthesis of thioethers by reaction of thiocyanates
with alcohols under heating in the presence of stoi-
chiometric amounts of alkali or alkaline-earth metal
hydroxides or alcoholates or those of tertiary amines
is described in a patent [5].
Zasosov and Gal’chenko prepared sulfide I by
adding a portion of II to a boiling aqueous solution of
sodium sulfide. After stirring for a certain time, the
next portion of II is added, and the mixture is re-
fluxed with stirring. Then an additional small amount
of aqueous sodium sulfide solution is introduced,
and the mixture is refluxed with stirring. The re-
sulting mixture is steam-distilled to remove un-
changed II; yield of I 77 80% (mp 145 147 C, from
toluene).
Dialkyl sulfides can also be prepared by reaction of
alkyl chlorides with an aqueous or aqueous-alcoholic
solution of alkali metal sulfide in an autoclave at high
pressure [6]; diaryl sulfides are synthesized by reac-
tion of appropriate nitrochlorobenzenes in dimethyl-
formamide (DMF) with an aqueous solution of sodi-
um sulfide in the presence of finely divided sulfur [7]
or in refluxing alcohol with fine powder of a prelim-
inarily fused mixture of sodium sulfide and sulfur [8].
Raiziss et al. [14] refluxed a mixture of Na S,
2
water, and a part of the required amount of II, after
which they added the remaining part of II, with the
refluxing continued. The resulting mixture was steam-
distilled; yield of I 80% (mp 141 413 C, from eth-
anol).
There are numerous procedures for reducing nitro
compounds to the corresponding amines [9]; in some
cases, it is possible to selectively reduce one of the
nitro groups of polynitro compounds with a calculated
amount of sodium (or ammnonium) sulfide (or hydro-
sulfide) [9].
Aminonitrodiphenyl sulfides can also be prepared
by reaction of alkaline solutions of substituted amino-
thiophenols with alcoholic solutions of halonitroben-
senes [15 20].
A procedure has been developed for preparing 4,4 -
diaminodiphenyl sulfide I by reaction of 4-nitrochloro-
benzene II with sodium sulfide in DMF, followed by
reduction of the resulting 4,4 -dinitrodiphenyl sulfide
with iron powder in aqueous alcohol in the presence
of ammonium chloride under heating [10].
All the above procedures for preparing sulfides I
are time- and labor-consuming; the yield and quality
of the target product are poor. The procedures involve
1
070-4272/03/7606-0953 $25.00 2003 MAIK Nauka/Interperiodica

954
PILYUGIN
Table 1. Variation with time of the concentrations of
p-nitrochlorobenzene II, c , and p-chloroaniline V, c ,
in the organic phase in the course of synthesis of I
Sulfide I is formed by the reaction of IV with
the remaining part of II:
II
V
II + IV
O N
2
S
NH2 (2)
Sampling time
cII
cV
NaCl
(
from the reaction start)
I
,
h
M
An impurity of p-chloroaniline V is formed by re-
duction of the nitro group via a series of intermedi-
ates:
0
0
1
1
2
2
3
3
4
5
6
7
8
3.16
2.10
1.66
1.56
1.50
1.50
1.46
1.06
0.67
0.42
0.23
0.08
0.01
.5*
.0
.5
0.10
0.12
0.11
0.12
0.11
0.12
0.12
0.12
0.12
0.12
0.12
0.12
*
*
Na2S
II
Cl
N O
Cl
.0
.5
.0
.5
.0
.0
.0
.0
.0
Na2S
Na2S
Cl
NHOH
NH2 (3)
V
An impurity of 4,4 -dinitrodiphenyl sulfide VI is
formed by the reaction of III with II:
*
*
Completion of loading Na S.
2
Addition of PEG-400.
II + III
O N
2
S
NO2 (4)
*
NaCl
VI
numerous auxiliary operations or require difficultly
available chemicals. Therefore, none of these proce-
dures has been introduced on the commercial or semi-
commercial scale.
Thiophenolate III and products of its sequential
reduction to IV are water-soluble and, when formed,
pass to the aqueous phase. The compounds mainly
occurring in the organic phase are sulfide I, chloro-
nitrobenzene II, chloroaniline V, and also dinitrodi-
phenyl sulfide VI formed in small amounts.
In this study, we developed an improved procedure
for preparing sulfide I, based on the reaction of ni-
trochlorobenzene II with sodium sulfide in a two-
phase system constituted by water and organic solvent
The optimal parameters of sulfide I preparation
temperature, reaction time before adding phase-trans-
fer catalyst, water : organic solvent and II : Na S ra-
tios) are those at which, before adding the phase-trans-
fer catalyst, the amount of V is the smallest, com-
pound VI is virtually absent, approximately half of
II is converted to salt IV and passes to the aqueous
phase, and the other half remains in the organic phase
(
(chlorobenzene, toluene, chloroform, etc.) under heat-
ing in the presence of a phase-transfer catalyst (PTC:
quaternary alkylammonium salts, polyethylene glycol
PEG-400, etc.), with simultaneous hydroacoustic treat-
ment of the reaction mixture.
2
Reaction of II with sodium sulfide involves a num-
ber of steps: formation of sodium 4-nitrothiophenolate
III and its successive reduction with sodium sulfide to
the nitroso, hydroxylamino, and finally, amino deriv-
atives. Sodium 4-aminothiophenolate IV mainly ac-
cumulates in the aqueous phase.
(Table 1).
When a phase-transfer catalyst (PEG-400 etc.) is
added at this instant of time to the reaction mixture
and the mixture is subjected to intense hydroacoustic
treat ment, the transfer of salt IV from the aqueous to
organic phase and its reaction with chloronitrobenzene
II in the organic phase to form sulfide I, also dissolv-
ing in the organic phase, are sharply accelerated. In
most cases, in synthesis of I, chlorobenzene (Table 2)
or toluene (Table 3) is used as organic solvent.
O N
2
Cl + Na2S
O N
2
SNa
NaCl
II
III
Na2S
Na2S
ON
SNa
HONH
SNa
SNa
The advantage of chlorobenzene is that, in contrast
to toluene, this solvent (and solution of I in it) can
be subsequently used for preparing 4-amino-3,4 -di-
nitrodiphenyl sulfide. Furthermore, as follows from
Na2S
H N
2
(1)
IV
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 6 2003

SYNTHESIS OF 4-AMINO-4 -NITRODIPHENYL SULFIDE
955
Table 2. Synthesis of sulfide I in chlorobenzene under various conditions and at various reactant ratios (phase-transfer
catalyst PEG-400,* reaction time before adding PEG-400 1 h )
**
II : Na S
Water chlo-
robenzene
volume ratio
II : chloro-
benzene
weight ratio
Amount of
PEG-400 rela- T, C
tive to II, %
(h) after
adding
PEG-400
Yield
Content
2
molar
ratio
of crude
of I in crude
product, % product, wt %
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
Water
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.00
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.69
1.00 : 0.46
1.00 : 0.23
1.00 : 0.93
1.00 : 1.38
1.00 : 0.48
1.00 : 0.69
1.00 : 1.01
1.00 : 1.37
1.00 : 0.29
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.56
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
1.00 : 0.50
3.125
3.125
3.125
3.125
3.125
No
3.125
3.125
2.50
98
95
6
7
6
7
7
8
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
7
6
6
6
6
6
7
5
6
6
6
6
8
9
93
93
93
70
76
52
75
90
92
90
91
93
79
92
81
93
92
91
77
71
92
92
92
78
93
95
93
82
94
87
92
81
92
84
93
92
91
90
94
72
85
74
86
91
93
91
95
93
94
93
93
93
93
93
91
94
93
93
92
88
92
68
93
85
71
78
93
78
93
85
93
93
104
90
100
102
98
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.00 : 1.00
3.00 : 1.00
6.00 : 1.00
1.50 : 1.00
1.00 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.50 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
2.79 : 1.00
a
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.74
.00 : 1.40
.00 : 1.03
.00 : 2.00
.00 : 2.50
.00 : 1.74
.00 : 1.74
b
c
d
98
102
100
98
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
2.500
2.000
1.000
0.520
4.000
5.200
2.600
2.600
2.600
2.600
2.600
2.600
2.600
2.600
2.600
2.600
100
100
100
100
102
100
102
102
100
102
100
100
100
100
100
102
102
102
102
102
102
102
102
102
102
e
f
*
a
Specific features of particular experiments: a mixture of water, chlorobenzene, and sodium sulfide was charged, after which
b
c
d
compound II was added; Katamin AB used instead of PEG-400; Tetraethylammonium iodide used instead of PEG-400; tol-
uene used instead of chlorobenzene.
*
*
e
f
Unless otherwise indicated ( , 2 h; , 0.67 h).
Table 3. Synthesis of sulfide I in toluene (molar ratio II : Na S = 1.0 : 1.7, volume ratio water : toluene = 2.5 : 1.0,
2
weight ratio II : toluene = 1.17 : 1.00, phase-transfer catalyst PEG-400)
Amount of PEG-400
relative to II,
%
Reaction time after completion of adding Na S, h
Yield of crude
Content of I in
crude product,
wt %
2
product,
%
before adding PEG-400
after adding PEG-400
3
3
2
1
4
3
3
.00
.12
.15
.50
.00
.12
.12
1.00
1.00
1.00
1.50
1.50
1.5
6
6
7
7
6
6
7
91
90
89
90
89
89
90
90
91
90
90
90
90
90
1.0
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 6 2003

956
PILYUGIN
Tables 2 and 3, chlorobenzene, compared to toluene,
ensures higher yield and quality of I.
5
m). The products were analyzed and identified
using water acetonitrile (20 : 80 to 30 : 70 by vol-
ume) eluent and diphenyl as internal reference.
Laboratory experiments on development of a pro-
cedure for preparing I (Table 2) show that the best
synthesis conditions are as follows. Temperature
A glass reactor equipped with a reflux condenser
was charged with the required amounts of water and
organic solvent (chlorobenzene, toluene, chloroform,
etc.), after which crystalline chloronitrobenzene II
was added. The mixture was vigorously stirred with
a hydroacoustic device mounted on the reactor lid and
heated to 65 70 C; in so doing, chloronitrobenzene II
gradually dissolved in the organic phase. Then crys-
talline Na S 9H O (or its aqueous solution prepared
in advance) was added in small portions so as to keep
the reaction temperature within 80 85 C. When solid
sodium sulfide was added, the temperature first no-
ticeably decreased owing to endothermic dissolution
schedule: 80 85 C in the stage of adding Na S, keep-
2
ing for 0.5 h at 80 85 C after adding the whole
amount of Na S; heating to 96 102 C for 0.5 1.0 h
2
before adding phase-transfer catalyst (PEG-400); addi-
tion of PEG-400 and subsequent reaction at 96
1
2
02 C. Ratios: water : chlorobenzene (by volume)
.5 : 1.0, chlorobenzene : II (by weight) 1.00 : 1.17,
2
2
II : Na S (molar) 1.0 : 1.7, and II : PEG-400 (by
2
weight) 1.000 : (0.014 0.017). Under these optimal
conditions, sulfide I is prepared relatively simply in
a yield of no less than 92%, with the main substance
content of no less than 93 wt %. The process was de-
veloped on a semicommercial scale (160-l reactor with
immersed device for hydroacoustic treatment [21]).
of Na S and then sharply increased owing to fast exo-
thermic reaction (with the Na S solution prepared in
advance, the temperature variations are weaker).
2
2
Therefore, Na S should be added carefully, since
overheating of the reaction mixture (above 80 85 C)
causes side reactions.
2
EXPERIMENTAL
The reaction mixtures and crude products in the
stage of preparation of I were analyzed qualitatively
by TLC and quantitatively by HPLC, and identified
After adding the whole amount of Na S, the mix-
ture was vigorously stirred at 80 85 C with a built-in
device for hydroacoustic treatment for an additional
2
by IR and 13C NMR spectroscopy.
3
0 min, after which it was heated to 96 102 C and
The IR spectra were recorded with a Jasco 810-IR
stirred at this temperature for 0.5 1 h. Then, a phase-
transfer catalyst (PEG-400 or quaternary alkylammo-
nium salt) was added in the amount of 1 4% relative
to the charged chloronitrobenzene II, and the mixture
was vigorously stirred at 96 102 C with the hydro-
acoustic treatment for 6 7 h.
spectrometer in the 4000 400 cm 1 range using CCl
4
1
3
solutions or mulls in mineral oil. The C NMR spec-
tra were measured on a Bruker CXP-100 spectrometer
at a working frequency of 22.63 MHz under condi-
tions of total proton decoupling or without it; solvent
DMSO, internal reference HMDS. The signal assign-
ment was based on the chemical shifts, coupling con-
stants, multiplicities, and relative intensities; data for
related model compounds and results of calculation
of magnetic shielding in an aromatic ring were also
taken into account.
After reaction completion and phase separation, the
lower aqueous salt solution was separated and dis-
carded, and the organic layer was washed with hot
water with vigorous stirring to remove the inorganic
salts and organic intermediates more completely.
After phase separation, the lower organic layer (a so-
lution of crude sulfide in chlorobenzene, toluene, or
chloroform) was poured into a crystallizer and cooled
to 0 C. The precipitated crystals of I were filtered off,
washed with water, and dried at 60 70 C.
The TLC analysis was performed on Silufol plates;
the development involved reduction with an SnCl2
solution, diazotization of the resulting anilines, and
azo coupling with 1-naphthol; eluent C H : C H OH,
6
6
2
5
1
0 : 1 by volume.
Quantitative HPLC analysis was performed with
CONCLUSION
an Altex model 330 liquid isocratic chromatograph
equipped with a model 110 pump, a model 153 detec-
tor, model 210 20- l loop dosing units, and 30-, 50-,
and 100- l SNR Hamilton microsyringes. Separation
and analysis of a mixture of nitrobenzene II, sulfide I,
dinitro sulfide VI, and chloroaniline V were per-
formed on a stainless steel column (25 cm 4.6 mm
i.d.) packed with Ultraspher ODS phase (grain size
The reaction of 4-nitrochlorobenzene with sodium
sulfide in a two-phase system constituted by water
and organic solvent (chlorobenzene, toluene, chloro-
form, etc.) in the presence of a phase-transfer catalyst
(PEG-400, quaternary alkylammonium salts, etc.) ad-
ded after a definite period of time, under vigorous
hydroacoustic treatment and at temperature maintained
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 6 2003

SYNTHESIS OF 4-AMINO-4 -NITRODIPHENYL SULFIDE
957
in the ranges 80 85 (addition of Na S, before adding
9. Fieser, L.F. and Fieser, M., Advanced Organic Chem-
istry, New York: Reinhold, 1962.
10. USSR Inventor’s Certificate, no. 491624.
2
phase-transfer catalyst) and 96 102 C (phase-trans-
fer step), gives 4-amino-4 -dinitrodiphenyl sulfide in
a yield of no less than 92%, with the main substance
content of no less than 93%.
11. Hodson, H.H. and Wilson, J., J. Chem. Soc., 1912,
vol. 101, no. 9, pp. 1693 1696.
1
1
2. Radulova, S. and Tapalova, E., Vet. Mid. Nauki (So-
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3. Zasosov, V.A. and Gal’chenko, M.I., Zh. Prikl. Khim.,
ACKNOWLEDGMENTS
The study was supported by the Russian Founda-
tion for Basic Research (project no. 02-03-97911).
1946, vol. 19, nos. 5 6, pp. 580 584.
14. Raiziss, G.W., Clemence, L.W., Sevarac, M., and
Maetsch, J.C., J. Am. Chem. Soc., 1939, vol. 61,
no. 12, pp. 2763 2768.
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 6 2003