Methoxylation and Direct Hydrogenative Coupling of Chloronitrobenzenes in Continuous Flow

Article abstract of DOI:10.1002/cjoc.201600606

A novel continuous flow method for the methoxylation of chloronitrobenzenes was developed. The reaction went smoothly and high yields were achieved under the optimized conditions. Furthermore, up to 76% yield of azoxybenzenes were obtained from the corresponding nitrobenzenes in the presence of NaOH in continuous flow. Compared to batch conditions, the reaction time was significantly shortened, and the chemical waste was reduced obviously.

Full text of DOI:10.1002/cjoc.201600606

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DOI: 10.1002/cjoc.201600606
Methoxylation and Direct Hydrogenative Coupling of
Chloronitrobenzenes in Continuous Flow
Songjie Shi,a Li Wan,a,b Xiaoning Sun,a Jiawei Zhang,a and Kai Guo*,a,b,c
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, Jiangsu 211816,
China
b State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, Jiangsu
210009, China
c Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), 30 Puzhu South Road, Nanjing,
Jiangsu 211816, China
A novel continuous flow method for the methoxylation of chloronitrobenzenes was developed. The reaction
went smoothly and high yields were achieved under the optimized conditions. Furthermore, up to 76% yield of
azoxybenzenes were obtained from the corresponding nitrobenzenes in the presence of NaOH in continuous flow.
Compared to batch conditions, the reaction time was significantly shortened, and the chemical waste was reduced
obviously.
Keywords methoxylation, azoxybenzenes, chloronitrobenzenes, continuous flow, sodium methoxide
Introduction
electron-rich aromatic compounds, which is consider as
a typical one. However, azo synthesis is recommended
as a better method due to its versatility and high selec-
tivity by contrast.[19] The approach mostly used is direct
reductive coupling of nitroarenes because of the wide
applicability and simple one-pot procedure.[20-24]
The research of etherification is quite meaningful for
organic chemistry industry owing to the high value of
aromatic ethers, which appear widely in natural prod-
ucts and active pharmaceutical ingredients, and are also
used as base intermediates for the synthesis of valuable
compounds, such as dyes,[1-3] pharmaceuticals,[4-6] com-
ponents for color photography, etc.[7-9] The electronic
properties of aromatic compounds could be changed by
methoxy group because of its strong electronic proper-
ties, and reflected in distinctive material characteris-
tics.[10,11] Here we introduce a highly efficient method to
synthesize o-nitroanisole, which is mostly used in the
production of dyestuff and pharmaceutical intermedi-
ates.
The azo moiety (-N＝N- bond) is known as a widely
used functional group in the production of dyestuff and
pigments. As essential component in various synthetic
organic colorants up to now,[12,13] azo dyes are the most
species of synthetic dyes and widely applied in dyeing
numerous natural and synthetic fibers.[14,15] And it was
also used in plastics, pharmaceuticals and analytical
chemistry.[16-18] In such an era, information technology
develops rapidly, the synthesis of new materials is con-
sidered to have broad applications and prospects. Owing
to the wide application of azo motif and its high value
(reflected in multifarious constructions), more and more
methods for preparation of azo compounds are being
raised such as coupling reaction of diazonium salts with
Chemical production is mainly performed by using
either batch systems or continuous-flow systems. By
contrast with batch reactors, flow reactors possess more
advantages including: (1) stable heat and mixing effi-
ciency;[25] (2) convenient control of velocity of flow;[26]
(3) safety and reproducibility;[27] (4) increased pho-
ton-flux in photochemical reactions; (5) increased elec-
trode surface-to-reactor volume ratio (electrochemis-
try);[28] (6) increased solution-solid phase interactions.[29]
According to these advantages, we have reasons to be-
lieve that continuous flow systems are superior to batch
systems. And with the progress of society and the de-
velopment of technology, chemical manufacturing starts
to be in need of not only high quality of synthesis but
also environmental-friendly methods and reproducibility.
In order to meet these requirements, continuous-flow
systems are being developed rapidly in organic synthe-
sis. Therefore, we dedicated to develop a novel method
to prepare nitroanisoles and azoxybenzenes in con-
tinutous flow system.[30]
Experimental
All reagents and solvents were commercially availa-
*
E-mail: guok@njtech.edu.cn; Tel.: 0086-025-58139935
Received September 20, 2016; accepted November 17, 2016; published online XXXX, 2017.
Chin. J. Chem. 2017, XX, 1—5
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Shi et al.
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－
1
1
ble and used without any further purification. Unless
otherwise noted, all reactions were run under air and the
indicated reaction temperature was that of the oil bath.
Purification of reaction products was carried out by
flash chromatography using 100－200 mesh silica gel.
Components of chloronitrobenzenes from factory were
p-nitroanisole (45%), o-nitroanisole (34), m-nitroanisole
(21%). GC-MS spectra (EI, 70 eV) were obtained on
Micromass (GC-TOF).
831 (CAr－H) cm ; H NMR (400 MHz, CDCl3) δ:
8.16 (d, J＝8.8 Hz, 2H), 7.96 (d, J＝8.4 Hz, 2H), 7.48
(dd, J＝9.8, 2.2 Hz, 4H); 13C NMR (100 MHz, CDCl3)
δ: 150.07, 144.79, 136.78, 132.62, 128.15, 125.74,
123.63. HRMS (ESI-TOF) calcd for C12H9Cl2N2O [M＋
H]＋ 267.0086, found 267.0092.
(Z)-1,2-Bis(2-chlorophenyl)diazene oxide (4b):
Yellow powder; m.p. 108－109 ℃; IR (KBr) ν: 3010
(CAr－H), 1543 (N＝N), 1473, 1412, 1307 (C－N), 756
－
1
(CAr－H) cm ; 1H NMR (400 MHz, CDCl3) δ: 8.09 (dd,
J＝7.8, 2.0 Hz, 1H), 7.69 (dd, J＝7.8, 2.0 Hz, 1H),
7.66－7.62 (m, 1H), 7.61－7.56 (m, 1H), 7.55－7.45
(m, 3H), 7.37 (td, J＝7.8, 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 157.60, 130.77, 130.41, 130.10, 130.02,
129.40, 129.18, 127.81, 127.62, 123.40, 123.30. HRMS
(ESI-TOF) calcd for C12H9Cl2N2O [M＋H]＋ 267.0086,
found 267.0101.
Procedure for methoxylation of chloronitrobenzenes
in continuous flow
The reactants were introduced into a polytetrafluo-
roethylene (PTFE) capillary (ID＝0.5 mm) with an
inner volume of 5 mL by using syringe pump. Chloroni-
trobenzenes (10.0 mmol, 1.0 equiv.) were dissolved in
MeOH (66.6 mL) and loaded in one syringe, NaOH
(11.0 mmol, 1.1 equiv.) was dissolved in MeOH (33.3
mL) and loaded in another syringe. Those two fluids
were mixed in a PTFE T-mixer (ID＝0.5 mm) before
entering into the microreactor. A 8 bar back pressure
regulator (BPR) was set at the tail of reaction system to
inhibit gasification in the microreactor. The micro-
reactor was coiled and put into a heating cabinet at
125 ℃, so that the collection vial could be placed under
heating atmosphere. The reason for using heating
cabinet is to avoid the coagulation in the microreactor
after reaction completed. The injection rate of syringe
pump A was 0.11 mL/min, while that of syringe pump
B was 0.056 mL/min, so the flow rate in the micro-
reactor was 0.166 mL/min. The exiting reaction mixture
in the first period was discarded to ensure steady-state
data colletion. Next, the reaction mixture was collected
until at least 1.0 mmol product was gathered. The
organic mixture was analyzed by GC-MS.
(Z)-1,2-Diphenyldiazene oxide (6): Yellow powder;
m.p. 35－36 ℃; IR (KBr disc) ν: 3062 (CAr－H), 1570
(N＝N), 1479, 1423, 1310 (C－N), 756, 670 (CAr－H)
－
1
1
cm ; H NMR (400 MHz, CDCl3) δ: 8.22－7.95 (m,
4H), 7.44－7.30 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ: 159.41, 145.02, 132.67, 130.28, 128.99, 128.50,
125.40, 122.20; HRMS (ESI-TOF) calcd for C12H11N2O
[M＋H]＋ 199.0866, found 199.0873.
Results and Discussion
We started our investigation by reacting 4-chloro-
nitrobenzene and NaOH in MeOH in continuous flow.
Initially, the reaction was performed in the presence of
10 mmol (1.0 equiv.) 4-chloronitrobenzene and the ratio
of reactants was 1∶1 with NaOH. 7% yield was given
at 85 ℃ after 5 min residence time (Table 1, Entry 1).
As we increase the reaction temperature, higher yields
could be achieved and finally reached 40% at 130 ℃
(Table 1, Entries 2－6). Considering the influence of the
dosage of alkali in the reaction, we increased the load-
ing of NaOH by 0.1 equiv. each time and the results are
listed in Table 1. It did not show any obvious increasing
in yield but a little lower ones (Table 1, Entries 7, 8).
Then we investigated if lengthening the residence time
could promote the reaction and satisfactory results were
given as we lengthened the residence time. The best
result 85% yield was obtained as the residence time was
extended to 30 min when the ratio was 1∶1.1 (Table 1,
Entries 9－11). In addition, in this continuous flow, it
needs a BPR to prevent the gasification.
In Table 2 are listed the results of methoxylation for
chloronitrobenzenes from factory in continuous flow.
Considering the efficiency in industrial manufacture,
factories use the mixture of chloronitrobenzenes as raw
material. The reaction was performed by using 10 mmol
(1.0 equiv.) chloronitrobenzenes and NaOH in the ratio
of 1∶1.1. Raw material contains three substituent posi-
tions of Cl on nitrobenzene. Therefore, the products are
relative, and we named 4, 2, 3 substituent positions as a,
b, c. At the temperature of 125 ℃, after reacting for 20
Procedure for chloronitrobenzenes converted into
the corresponding azoxybenzene in continuous flow
The reactants were introduced into a PTFE capillary
(ID＝0.5 mm) with an inner volume of 5 mL by using
syringe pump. Chloronitrobenzenes (10.0 mmol, 1.0
equiv.), NaOH (11.0 mmol, 1.1 equiv.) and MeOH (4.0
mL) were mixed and loaded in one syringe. The
microreactor was coiled and put into a heating cabinet at
125 ℃, so that the collection vial could be placed under
heating atmosphere. The reason for using heating
cabinet is to avoid the coagulation in the microreactor
after reaction completed. The injection rate of syringe
pump was 1.0 mL/min. The exiting reaction mixture in
the first period was discarded to ensure steady-state data
colletion. Next, the reaction mixture was collected until
at least 1.0 mmol product was gathered. The organic
mixture was analyzed by GC-MS. The product was
1
isoalted and characterized by H NMR, 13C NMR and
HRMS.
(Z)-1,2-Bis(4-chlorophenyl)diazene oxide (4a):
Yellow powder; m.p.: 154－156 ℃; IR (KBr disc) ν:
3055 (CAr-H), 1576 (N＝N), 1483, 1424, 1323 (C－N),
2
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Methoxylation and Direct Hydrogenative Coupling of Chloronitrobenzenes in Continuous Flow
Table 1 Optimization of reaction conditions in continuous flowa
Entry
NaOH/equiv.
Temp./℃
85
Residence time/min
Yield b/%
1
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.2
1.1
1.1
1.1
5
7
2
95
5
15
27
31
37
40
40
39
48
62
85
3
105
115
125
130
125
125
125
125
125
5
4
5
5
5
6
5
7
5
8
5
9
10
20
30
10
11
a Reaction conditions: 4-chloronitrobenzene (10.0 mmol, 1.0 equiv.) in MeOH (66.6 mL) and loaded in a 100 mL syringe; NaOH was
dissolved in MeOH (33.3 mL) and loaded in a 50 mL syringe; 5.0 mL microreactor, PTFE tubing 0.5 mm inner diameter; attached to a 8
bar back pressure regulator at the end of microreactor. b Determined by the analysis of GC-MS results.
Table 2 Results of methoxylation for chloronitrobenzenes from factory in continuous flowa
Entry
Temp./℃
125
Residence time/min
Yield of 3ab/%
Yield of 3bb/%
Yield of 3cb/%
trace
1
2
3
4
20
30
30
30
70
86
81
89
62
78
73
79
125
trace
115
trace
130
trace
a Reaction conditions: chloronitrobenzenes (10.0 mmol, 1.0 equiv.) in MeOH (66.6 mL) and loaded in a 100 mL syringe; NaOH (11.0
mmol, 1.1 equiv.) was dissolved in MeOH (33.3 mL) and loaded in a 50 mL syringe; 5.0 mL microreactor, PTFE tubing 0.5 mm inner
diameter; attached to a 8 bar back pressure regulator at the end of microreactor. b Determined by the analysis of GC-MS results.
min, 70% yield p-nitroanisole (3a) and 62% yield
o-nitroanisole (3b) were given (Table 2, Entry 1). In-
creasing the residence time could benefit the reaction.
When the residence time was extended to 30 min, all
products yields were increased. If the reaction time was
kept at 30 min, raising the temperature could also be
helpful to increase the yield, and the best result was
given when the reaction temperature was increased to
130 ℃ with 89% yield for 3a and 79% yield for 3b
(Table 2, Entries 2－4). However, under this condition it
Chin. J. Chem. 2017, XX, 1—5
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Shi et al.
COMMUNICATION
could be highly possible to cause the clogging in the
microreactor, so in all, the optimum condition could be
considered at the temperature of 125 ℃ with 30 min
reaction time and 86% 3a, 78% 3b were obtained (Table
2, Entry 2). Moreover, yields of m-nitroanisole (3c)
were obtained in trace.
emission-reduction. Besides, it is generally known that
alkali is corrosive, so less reaction time could protect
instruments and prolong service life effectively. Fur-
thermore, we also tried nitrobenzene as reactant in the
same ratio with NaOH in MeOH. And fortunately 68%
yield was obtained under the optimized conditions (Fig-
ure 1).
After completion of the etherification study, we also
investigated the method for synthesizing azoxybenzenes
in continues flow. We chose chloronitrobenzenes (10.0
mmol, 1.0 equiv.) from fatory, NaOH (11.0 mmol, 1.1
equiv.) and MeOH (4.0 mL) to investigate the optimum
reaction conditions. Interestingly, when we remove BPR
from the continuous reaction system, the azo products
4a and 4b were obtained as main products. At first, the
residence time was set at 5 min, the reaction was carried
out at different temperature, and the best result was dis-
covered at 125 ℃ with 76% yield for 4a, 71% yield for
4b (Table 3, Entries 1－3). Then we kept the tempera-
ture constant, and tried to reduce the residence time and
lower yields were obtained in the reaction (Table 3, En-
tries 4, 5). Comparing with other traditional methods of
azo synthesis, continues flow system provides intensive
mixing and better reaction efficiency, and under the
premise of ensuring adequate yields, it spent much less
reaction time, which is propitious to energy-saving and
Conclusions
In summary, the method we developed can effi-
ciently complete the processes of both etherification and
diazotization in continuous flow. And this system pro-
vides shortened reaction time and economic reaction
conditions, which possesses more advantages by con-
trast with many traditional methods such as energy con-
servation. Good to excellent yields were obtained by
employing reactants in a ratio of 1∶1.1 (reactants to
NaOH). In addition, we cut down the reaction time to 30
min for etherification while 5 min for diazotization.
Compared with factory methods, it saved a great deal of
reaction time, which shortened reaction period and re-
sulted in less chemical waste. The high efficiency ex-
hibited in our method may have extensive application in
commercial production.
Table 3 Reductions of chloronitrobenzenes into the corresponding azoxybenzenes in continuous flowa
Cl
Cl
O
N
Cl
N
N
Cl
4a
4b
Cl
+
NO2
1a
NO2
1b
NO2
1c
O
Cl
+
N
NaOH in MeOH
2
Cl
Entry
Temp./℃
Residence time/min
Yield of 4ab/%
Yield of 4bb/%
1
2
3
4
5
125
115
130
125
125
5
5
5
2
3
76
62
74
71
73
71
58
72
69
70
a Reaction conditions: chloronitrobenzenes (10.0 mmol, 1.0 equiv.), NaOH (11.0 mmol, 1.1 equiv.) and MeOH (4.0 mL) were mixed and
loaded in a 50 mL syringe; 5.0 mL microreactor, PTFE tubing 0.5 mm inner diameter; attached to a 8 bar back pressure regulator at the
end of microreactor. b Determined by the analysis of GC-MS results.
Figure 1 Reductions of nitrobenzene into the corresponding azoxybenzene in continuous flow.
4
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Methoxylation and Direct Hydrogenative Coupling of Chloronitrobenzenes in Continuous Flow
Frank, G.; Müllen, K. Adv. Mater. 1993, 5, 854.
Acknowledgement
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This work was supported by the National Natural
Science Foundation of China (Nos. 21502090,
21522604), Natural Science Foundation of Jiangsu
Province (Nos. BK20150942, BK20150031) and the
National Key Basic Research Program of China (No.
2012CB725204). We also thank the financial support
from Top-notch Academic Programs Project of Jiangsu
Higher Education Institutions (TAPP).
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