Continuous and green microflow synthesis of azobenzene compounds catalyzed by consecutively prepared tetrahedron CuBr

Article abstract of DOI:10.1016/j.dyepig.2019.108071

An environmentally friendly and cross-selective process intensification for the continuous synthesis of symmetric aromatic azo compounds by using self-made cuprous bromide as the catalyst under mild conditions in the microreactor was developed. A novel tetrahedron cuprous bromide catalyst which shows outstanding catalytic activity and satisfactory stability has been synthesized in continuous flow microreactor. The online immobilization of self-made cuprous bromide on the catalyst bed achieved oxidative coupling of aromatic amines (oxygen as oxidant) and high-performance gas–liquid–solid three-phase reaction, which strongly limited the possibility of undesired reaction pathways, improving product selectivity and reducing waste generation. Meanwhile, the yield of azo-coupling reaction was up to 98% under optimized condition. As compared with earlier traditional method (diazotization reaction) for synthesizing azobenzene, the designed micro-flow process displays signi?cant advances in terms of selectivity, waste emissions, sustainability and productivity. The combination of online immobilization of self-made cuprous bromide and precise and safe control through the microreactor provides a green solution for the industrial production of valuable aromatic azo compounds.

Full text of DOI:10.1016/j.dyepig.2019.108071

Dyes and Pigments xxx (xxxx) xxx
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: http://www.elsevier.com/locate/dyepig
Continuous and green microflow synthesis of azobenzene compounds
catalyzed by consecutively prepared tetrahedron CuBr
a
,
1
a,
1
a
a
a
a,**
Hong Qin , Chengkou Liu , Niuniu Lv , Wei He , Jingjing Meng , Zheng Fang
Kai Guo
,
a,b,*
a
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No. 30 Puzhu South Road, Nanjing, China
State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
An environmentally friendly and cross-selective process intensification for the continuous synthesis of symmetric
aromatic azo compounds by using self-made cuprous bromide as the catalyst under mild conditions in the
microreactor was developed. A novel tetrahedron cuprous bromide catalyst which shows outstanding catalytic
activity and satisfactory stability has been synthesized in continuous flow microreactor. The online immobili-
zation of self-made cuprous bromide on the catalyst bed achieved oxidative coupling of aromatic amines (oxygen
as oxidant) and high-performance gas–liquid–solid three-phase reaction, which strongly limited the possibility of
undesired reaction pathways, improving product selectivity and reducing waste generation. Meanwhile, the yield
of azo-coupling reaction was up to 98% under optimized condition. As compared with earlier traditional method
Aromatic azo compounds
Cuprous bromide
Oxidative homocoupling
Microreactor
(
diazotization reaction) for synthesizing azobenzene, the designed micro-flow process displays significant ad-
vances in terms of selectivity, waste emissions, sustainability and productivity. The combination of online
immobilization of self-made cuprous bromide and precise and safe control through the microreactor provides a
green solution for the industrial production of valuable aromatic azo compounds.
1
. Introduction
desired azobenzene involve the oxidation of hydrazine, the coupling of
diazonium salts with activated aromatics (azo coupling), the coupling of
Azo dye is
a
kind of synthetic dye containing azo group
primary arylamines with nitroso compounds (Mills reaction) and the
reductive coupling of aromatic nitro derivatives [9,10]. However, the
conventional methods have several drawbacks, such as the use of strong
and toxic oxidants or harsh reaction conditions (high pressure, high
temperature), which often lead to byproduct formation and low total
yields [11,12]. In 2008, Corma and co-workers [13] made a break-
through when they developed Au/TiO2-mediated synthesis of aromatic
azo compounds from the corresponding aniline derivatives. In the
following years, many important attempts were made to synthesis azo
derivatives in good yields through utilizing precious metals (Au, Pt, or
Pd), high pressure, and base additives [14–17]. It is reported that
copper-catalyzed homodimerization processes of aromatic amines using
air [18–20] as the co-oxidantcan make these conventional processes
more facile and avoid the use of heavy-metal salts. However, the in-
compatibility of functional groups and low yields of desired products are
–
–
(
Ar–N
N–Ar). Aromatic azo compounds are important fine chemical
raw materials and have countless applications, not merely in the
chemical industry, but also in medicinal chemistry (as prodrugs, drug-
coating materials and diagnostic probe) [1–4], biotechnology (artifi-
cial muscle, molecular machines, bistable memory devices, etc.), and the
field of renewable resources. In the dye industry [5], azobenzene dye is
one of the major chemical dyes used in textile industries for dying fibre
and fabric materials. It accounts for more than 70% of all kinds of dyes.
Moreover, there has been a rapid growth in interest in their applications
as photoresponsive materials in areas of photochemical molecular
switches, liquid crystals, chemosensors and molecular shuttles, owing to
their intrinsic ability of photochemical cis/trans-isomerization [6–8].
In terms of the preparation, a myriad of synthetic methods are
available nowadays. Prevailing classical routes for the formation of
*
Corresponding author. College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No. 30 Puzhu South Road, Nanjing, China.
** Corresponding author.
E-mail addresses: fzcpu@163.com (Z. Fang), guok@njtech.edu.cn (K. Guo).
1
These authors contributed to the work equally.
https://doi.org/10.1016/j.dyepig.2019.108071
Received 8 October 2019; Received in revised form 9 November 2019; Accepted 22 November 2019
Available online 27 November 2019
0
143-7208/© 2019 Published by Elsevier Ltd.
Please cite this article as: Hong Qin, Dyes and Pigments, https://doi.org/10.1016/j.dyepig.2019.108071

H. Qin et al.
Dyes and Pigments xxx (xxxx) xxx
still inevitable [21]. Furthermore, the synthesis of azobenzene using
copper bromide in traditional batch reactor still brings the reactivity
issues and several environmental pollution problems, such as necessi-
tating long reaction times, special reaction conditions, low yield of
target product and sedimentation and accumulation of catalyst [22].
With regard to the above-mentioned limits of azobenzene formed,
gas-liquid-solid microreactors appear to be a reasonable strategy for the
production of valuable aromatic azo compounds.
pump) into a valve assisted micromixer simultaneously. One was the
mixed solution of copper sulfate and potassium bromide, the other was
the reducing agent. Then the reduction reaction was occurred in a
microreactor (PTEF tube). After centrifugation, white precipitates were
washed with water and ethanol. Subsequently, the precipitates were
dried under vacuum at room temperature for 12 h.
2
.2. Typical procedure for synthesis of the azobenzenes in batch mode
In recent years, there is a broad range of research for which
continuous flow microreactors can be used, including catalysis [23],
nanoparticle synthesis [24–26], sensors, electrochemistry [27] and
polymerization [28]. Compared with conventional batch reactors,
microreactors have helped to minimize reagent consumption and energy
waste by increasing the atom efficiency of reaction due to their small
dimensions, which in most cases do not exceed 1 mm in at least one
dimension. The small volume of microreactors makes it possible to safe
handling of even hazardous, unstable intermediates or highly
exothermic reactions while facilitating fast and easy parameter
screening [29–31]. Because of this, the application of microreactor
technology in the synthesis of azo dye is a green chemical process.
Moreover, the contained environment and the ease of pressurizing in
continuous flow reactors providing novel process windows, an increased
parameter space for chemical synthesis and process intensification.
Thus, integration of process intensification in flow system and higher
synthesis efficiency in microreactor would eliminate the main drawback
of traditional way to achieve azobenzene, resulting in an efficient and
sustainable production.
The oxidative coupling reaction of aniline was chosen as the model
reaction in order to test the catalytic activity of homemade cuprous
bromide (Scheme 1). The process was described as follows. In a 25 mL
tube, corresponding cuprous bromide (specified amount), toluene (8
mL), aniline (0.1863 g, 2 mmol) and pyridine (0.0142 g, 0.18 mmol) was
added under O
2
atmosphere. The tube was sealed and the reaction
�
mixture was heated at a 60 C in appropriate time. Then samples were
analyzed using HPLC after centrifugation.
2
.3. General procedure for synthesis of the azobenzenes in a new micro-
flow system
In order to achieve the continuous synthesis of azobenzene de-
rivatives, a simple gas-liquid-solid three-phases flow reactor was
assembled (Fig. 1). The online prepared catalyst could be automatically
filled and washed in packed column through the control of valves.
Initially, when the valve A and D were turned on and the others were
turned off, the cuprous bromide was filled in the column. When the
column was filled, the valve B and D were turned on and the others were
turned off, the column was washed by distilled water in the syringe.
Then the valve B was closed and valve C was opened, alternating with
ethanol. When the washing was finished, the valve D was turned off and
valve E was turned on. Then, the two flows were injected into the tube-
in-tube flow reactor AF-2400 at set flow rate. One was aniline (1.863 g,
In recent years, our research group have made some achievements in
the field of microfluidics. In our previous study [32,33], three kinds of
co-doped TiO
2
α
2 3 3
, -Fe O and CaCO nanoparticles were synthesized by
using a continuous precipitation method in a novel micro-flow system
and were first employed in a packed bed flow reactor. Motivated by the
remarkable progress of heterogeneous catalysis in micro-flow systems,
we exploited the benefits of continuous-flow processing for the
CuBr-mediated oxidative homocoupling of arylamines to facilitate the
time-, cost-, and atom-effective synthesis of valuable symmetric aro-
matic azo compounds. The use of flow microreactor can realize the
application of gas-liquid-solid heterogeneous reaction and give higher
yields of aromatic azobenzene. Additionally, increased reaction rate,
reduction of side products and improved product purity could be ob-
tained in the compared with conventional method for synthesizing azo
compounds. During the research, a new type of tetrahedron cuprous
bromide which has not been reported was also conducted, providing a
higher yield. Besides, the online prepared cuprous bromide could be
automatically filled, washed and applied to the next oxidative coupling
reaction without further purification through the control of valves in
continuous flow reactor.
2
0 mmol) and pyridine (1.582, 20 mmol) solution (40 mL) dissolved
with toluene, the other was O . The flow rate of oxygen was controlled
2
by a mass-flow controller, the liquid was injected by pump (Vapourtec
Ltd). Liquid inlet was connected to a standard ¼-28 UNF, gas inlet was
connected to a 10–32 UNF [32]. In the tube-in-tube flow reactor, O
liquid were respectively flowing from the inner tube and the annular
channel. O was dispersed into the liquid through the micropores in the
2
and
2
membrane [34, 35]. Subsequently, the mixture was injected into the
fixed bed flow reactor which was filled with cuprous bromide. The
temperature of the flow reactor was adjusted through air heating (R4
reactor heater from Vapourtec Ltd). At set time intervals, the reaction
mixture was analyzed using HPLC after centrifugation. The reaction
yield was good as the inner diameter of capillary column within 4 mm.
The volume of the packed column was calculated by injecting a dye
solution through the column at a set flow rate, and the time showed that
the column volume was 1.2 mL.
2
. Experimental section
All the reagents used in this study were commercially available.
3
. Results and discussion
Standard analytical reagents were purchased from Sinopharm Chemical
Reagent Co., Ltd. Cuprous bromide was obtained from Meryer
3
3
.1. Synthesis and characterization of cuprous bromide
(
Shanghai) Chemical Technology Co., Ltd. The quantitative analysis was
1
conducted on a liquid chromatograph system (Agilent 1260). H NMR
spectra were recorded on a Bruker-400 (400 MHz). The XRD patterns
were obtained on a Bruker D8 ADVANCE X-ray diffractometer with Cu
.1.1. Optimization of the reaction conditions
The conditions of preparing cuprous bromide were simply optimized
in micro-flow system. Initially, the effect of reaction time was investi-
gated. Fig. 2 showed that particle obtained at 3 min had the better
K radiation at 40 kV and 40 mA. The catalyst was characterized by an S-
α
3
400 N scanning electron microscope (SEM).
2
.1. General synthesis of cuprous bromide in continuous flow reactor
Cuprous bromide was prepared in a continuous flow reactor by the
reduction reaction of soluble divalent copper salt, reducing agent (hy-
droxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine)
and potassium bromide. Two feeds were pumped (LEaD FLUID syringe
Scheme 1. Model Reaction of research catalytic activity.
2

H. Qin et al.
Dyes and Pigments xxx (xxxx) xxx
Fig. 1. A continuous flow system for synthesis of the azobenzenes.
dispersion and uniformity compared with at 1min. Meanwhile, cuprous
bromide with the yield of 80% was obtained at 3 min, while the reaction
time was 1 min, the yield was 60%. It might be attributed to the reason
that shorter retention time lead to incomplete reduction reactions. The
effect of tube diameter was investigated in Fig. 3. It showed that tetra-
hedron b (Fig. 3) was slightly broken than a (Fig. 3). The cause of this
phenomenon might be that small diameter was not beneficial to crystal
cuprous bromide was slightly higher than commercially available
cuprous bromide. Obviously, the catalytic rate of self-made cuprous
bromide was more significantly increased compared to commercially
available cuprous bromide and the yield up to 98% of target product was
obtained by using homemade cuprous bromide at 10 h. However, when
used commercially available cuprous bromide, a yield of 70% could be
obtained. The cause for this phenomenon might be that self-made
catalyst had relatively higher specific surface area and better disper-
sion compared with the commercially available catalyst, just as the
morphologies revealed in Fig. 6.
formation. The tetrahedron cuprous bromide particles with 5–10
μ
m
could be obtained. Thus, the tube diameter (1 mm) and reaction time in
3
min might be the most efficient condition.
3
.1.2. Characterization of cuprous bromide
3.2. Synthesis of azobenzene derivatives using self-made CuBr in micro-
flow system
Fig. 4 showed the XRD patterns of the as-prepared CuBr by three
different reducing agents in micro-flow system. The results were
consistent with the data revealed in the standard card (JCPDS,
3.2.1. Optimization of the reaction conditions
0
6–0292), which demonstrated that cuprous bromide could be obtained
On the basis of the pioneering study, we investigated the effect of
oxygen flow rate, aniline flow rate, temperature and the equivalent of
pyridine. As shown in Table 1, when oxygen flow rate varied from 4 mL
by those reducing agents. The morphologies of both homemade CuBr
and commercially available CuBr were observed using a SEM. Fig. 5
illustrated that self-made CuBr (a, b) has good particle dispersion
compared with commercially available CuBr. Moreover, the shape of
CuBr prepared by hydroxylamine hydrochloride or hydroxylamine sul-
fate reductant was tetrahedron, which was different from the commer-
cially available CuBr. Due to self-made CuBr prepared by hydroxylamine
hydrochloride reducing agents has the most excellent particle size uni-
formity and dispersion than the two other reducing agents, so the hy-
droxylamine hydrochloride be chosen to apply in next experiment.
À 1
À 1
min to 10 mL min , the yield of azobenzene was increased from 40%
to 70%. The maximum yield was obtained when oxygen flow rate was
À 1
10 mL min . However, the yield was sharply decreased to 55% when
flow rate increasing. This phenomenon might be attributed to two main
causes. One was the incomplete reaction resulted by small flow rate, the
other was the short residence time in the fixed bed flow reactor under
excessive velocity. Next, there had little effect on the yield when
changed the flow rate of aniline. The cause might be that gas flow rate
was much larger than the liquid flow rate, leading to the residence time
in the column could be negligible when slightly changed the flow rate of
aniline. Nevertheless, the column pressure increased and column
blockage might be occurred when aniline flow rate was too high. The
effect of temperature on oxidation coupling reaction was investigated by
3
.1.3. Comparison of commercially available cuprous bromide and self-
made cuprous bromide
The catalytic activity of homemade cuprous bromide was compared
with commercially available cuprous bromide by varying the reaction
time in the range from 1 h to 20 h. As shown in Fig. 6, at the same
amounts of catalyst, the final yield of azobenzene catalyzed by self-made
�
�
varying the temperature in the range from 50 C to 110 C. Distinctly,
when other conditions are the same, the higher the temperature, the
Fig. 2. The SEM images of CuBr prepared in different reaction time.
3

H. Qin et al.
Dyes and Pigments xxx (xxxx) xxx
Fig. 3. The SEM images of CuBr prepared in different tube diameter.
above method, the residence time was obtained with 5 min. Therefore,
À 1
À 1
1
0 mL min of the oxygen flow rate, 0.16 mL min of aniline flow rate,
�
1
equivalent of pyridine, reaction temperature at 110 C and reaction
time in 5 min were chosen as the optimal reaction condition.
3
.2.2. Comparison of batch reactor and microreactor using self-made
cuprous bromide
As shown in Fig. 6, the reaction time of typical procedure for syn-
thesis of the azobenzenes in batch mode was nearly 8 h. Compared with
conventional batch reactor, microreactor mentioned above have helped
Fig. 4. The XRD patterns of CuBr prepared by different reducing agents.
�
higher the yield. While the temperature increased to 110 C, the yield
reached maximum and the conversion rate of aniline achieved nearly
1
00%. As shown in Table 1, the optimal amount of pyridine was 1 equiv.
When the amounts of pyridine raised from 0.4 equiv. to 1 equiv, the
yield of azobenzene increased from 47% to 98%. To determine the
residence time on the column, a solution of dye and oxygen were
pumped through the fixed bed flow reactor at the optimal flow rate, the
time that solution of dye through the column was registered. By the
Fig. 6. Investigate the catalytic activity of self-made cuprous bromide.
Reaction conditions: aniline (0.1863 g, 2 mmol), pyridine (0.0142 g, 0.18
mmol), CuBr (0.0086 g,0.06 mmol), toluene (8 mL), specified reaction time,
stirring speed 500 rpm at 60 �C under O . The yield of azobenzene calculate
2
from HPLC.
Fig. 5. The SEM images of CuBr prepared by different reducing agents.
Reaction conditions: solution A: 0.1 M of reductant in H
min at room temperature; (a) NH OH⋅H
O⋅HCl (b) NH
2
O, solution B: 0.2 M of CuSO
4
⋅5H
2 2
O and 0.2 M of KBr in H O, tube diameter was 1 mm, reaction time was 3
2
2
2
SO
4
2
(c) NH OH (d) commercially available CuBr.
4

H. Qin et al.
Dyes and Pigments xxx (xxxx) xxx
Table 1
Optimization of aniline and oxygen flow rate for the continuous synthesis of azobenzene derivatives.
�
Entry
Aniline flow rate (mL/min)
Oxygen flow rate (mL/min)
Temperature （ C）
Pyridine (equivalent)
residence time (min)
Yield (%,3a)
1
2
3
4
5
6
7
8
9
0.16
0.16
0.16
0.16
0.12
0.2
4
90
1
1.25
1.25
1.25
1.25
1.67
1
55
68
61
68
40
70
40
48
70
81
98
47
80
8
90
1
10
14
10
10
10
10
10
10
10
10
10
90
1
90
1
90
1
90
1
0.16
0.16
0.16
0.16
0.16
0.16
0.16
50
1
1.25
1.25
1.25
1.25
1.25
1.25
1.25
70
1
90
1
1
1
1
1
0
1
2
3
100
110
110
110
1
1
0.4
0.8
Reaction condition: aniline (1.863 g, 20 mmol) and pyridine were dissolved in toluene (40 mL), specified aniline and oxygen flow rate. The yield of azobenzene
calculate from HPLC.
to minify reaction time to minute level due to their small dimensions.
Table 2
Process intensification could be realized in a continuous flow system
whose feature size was several micrometers to a few millimeters. The
Scope of aniline.
Entry
1
Amine
Product
Yield (%)
98
small volume of microreactor makes it possible to safe handling of even
hazardous, unstable intermediates or highly exothermic reactions while
facilitating fast and easy parameter screening due to real-time online
reaction. Moreover, in a limited space, the catalyst was fully utilized,
thereby improving the reaction efficiency and productivity. Increased
reaction rate, reduction of side products and improved product purity
could be obtained in the microreactor compared with conventional
batch mode.
2
3
97
97
4
5
94
95
3
.3. Substrate scope for the aromatic amine in gas-liquid-solid three-phase
microreactor
Under the above optimized conditions, the substrate scope of the
oxidative coupling reaction was studied (Table 2). The reaction showed
great tolerance with anilines with electron-donating substituent such as
methoxy-, methyl-groups at the para position (Table 2, Entries 1–3).
Moreover, the effect of electron-donating groups at the different posi-
tions on the phenyl ring could be ignored (Table 2, Entries 3–5). The
yields were significantly decreased when anilines have electron-
withdrawing substituents (Table 2, Entries 6–8). Multisubstituted ani-
lines can be easily converted into the corresponding azo compound in
excellent yield (Table 2, Entry 9) and not be affected by the tremendous
steric hindrance. However, anilines with nitro-substituted was failed to
give the desired product (Table 2, Entry 10). The result might be
attributed to the weak nucleophiles and instability of the amine radical
cation resulted in the few conversions.
6
7
8
9
79
72
65
92
0
1
0
4
. Conclusion
Reaction condition: 1 equiv. of aniline (c ¼ 0.5 M) and 1 equiv. of pyridine in
�
À 1
toluene at 110 C, aniline flow rate was 0.16 mL min , oxygen flow rate was 10
In conclusion, a green and novel continuous-flow methodology was
À 1
mL min . The yield of azobenzene calculate from HPLC.
developed for the synthesis of valuable azo compounds. During the
research, we were surprised to find a new type of tetrahedron cuprous
bromide and we demonstrated the feasibility and superiority of the self-
made cuprous bromide. CuBr microparticles prepared just before use
were automatically filled into a fixed bed flow reactor for the oxidative
homocoupling of aniline derivatives, which strongly limited the possi-
bility of undesired reaction pathways, improving product selectivity and
reducing waste generation. Oxygen as the terminal oxidant, the absence
of precious metals, self-made CuBr with better uniformity and contin-
uous flow system make our catalytic protocol greener than other re-
ported systems. The proposed strategy in this study provided a green and
effective route for preparation of valuable aromatic azo compounds and
reported a new type of cuprous bromide, which may offer new appli-
cations in the fields of heterogeneous catalytic reactions. Further in-
vestigations to apply this continuous-flow strategy, symmetric
azobenzene compound and new type of cuprous bromide are ongoing in
our laboratory.
Notes
The authors declare no competing financial interest.
Declaration of competing interest
There are no conflicts of interest in this work.
5

H. Qin et al.
Dyes and Pigments xxx (xxxx) xxx
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