Process Development and Scale-up of the Continuous Flow Nitration of Trifluoromethoxybenzene

Article abstract of DOI:10.1021/acs.oprd.7b00291

In this work, continuous flow nitration of trifluoromethoxybenzene (TFMB) was conducted in a microchannel reactor. The effects of process parameters, including temperature, residence time, sulfuric acid strength, flow rate, and reactor structure, were systemically investigated. It was found that the aforementioned process parameters had significant effect on TFMB conversion, while the product selectivity was merely sensitive to the reaction temperature. On the basis of the results of process parameter optimization, a scale-up strategy combining microreactor with distributed packed tubular reactor was presented. Consequently, excellent performance was achieved in the combined reactor with a kilogram-scale production.

Full text of DOI:10.1021/acs.oprd.7b00291

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Full Paper
Process development and scale-up of continuous
flow nitration of trifluoromethoxybenzene
Zhenghui Wen, Fengjun Jiao, Mei Yang, Shuainan Zhao, Feng Zhou, and Guangwen Chen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00291 • Publication Date (Web): 04 Oct 2017
Downloaded from http://pubs.acs.org on October 8, 2017
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Process development and scaleꢀup of continuous
flow nitration of trifluoromethoxybenzene
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,2
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1*
Zhenghui Wen , Fengjun Jiao , Mei Yang , Shuainan Zhao , Feng Zhou , Guangwen Chen
1
Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, Dalian 116023, China.
2
University of Chinese Academy of Sciences, Beijing 100049, China.
*
G.W. Chen. Eꢀmail: gwchen@dicp.ac.cn.
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ABSTRACT
In this work, continuous flow nitration of trifluoromethoxybenzene (TFMB) was conducted in a microchannel
reactor. The effect of process parameters, including temperature, residence time, sulfuric acid strength, flow
rate and reactor structure, were systemically investigated. It was found that the aforementioned process
parameters had significant effect on TFMB conversion, while the product selectivity was merely sensitive to
the reaction temperature. Based on the results of process parameter optimization, a scaleꢀup strategy
combining microreactor with distributed packed tubular reactor was presented. Consequently, excellent
performance was achieved in the combined reactor with a kilogramꢀscale production.
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KEYWORDS: trifluoromethoxybenzene, continuous nitration, flow chemistry, microchannel reactor, scaleꢀup
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. INTRODUCTION
Trifluoromethoxy aniline is an important intermediate involved in the synthesis of a wide range of fine
1
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chemicals, e.g. pesticides, pharmaceuticals, liquid crystal materials . It is generally produced via the nitration
of trifluoromethoxybenzene (TFMB) with mixed acid followed by reduction of nitration products. Generally,
the nitration reactions are often difficult to control due to its extremely fast rate and highly exothermic nature,
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with the reaction heat ranging from ꢀ73 to ꢀ253 kJ·mol . Due to the inefficient transport properties of stirred
batch reactors, the nitration of TFMB (Figure 1) is always operated at very low reaction temperature (263 K),
reactant concentration and adding rate of mixed acid (28 h) to achieve a mild condition and inhibit the
formation of undesired products (mꢀNB and DNB). Apparently, the nitration of TFMB in stirred batch reactor
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is a timeꢀconsuming and lowꢀefficiency process. Therefore, it is very important and urgent to develop a new
strategy based on process intensification technology to improve the productivity and process safety.
Figure 1. Nitration of TFMB with the oꢀNB and pꢀNB as the main products, mꢀNB and DNB as side products.
As a typical process intensification technology, microreactor has opened up new horizons both in
academia and industry. Owing to the characteristic dimension of subꢀmillimeter, microreactor possesses large
surfaceꢀtoꢀvolume ratio, enhanced mass and heat transfer rate, precise control over reaction parameters, high
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integration and inherent process safety , which hold great promise for very fast and highly exothermic
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7d
reactions. Microreactor has been applied to intensify nitration reaction recently. Yu et al. proposed a
continuous flow nitration process to produce 2, 5ꢀdifluoronitrobenzene, and a 98% yield with an output being
6.25 kg/h was realized. In addition, the shorter residence time (2.3 min) in microreactor meant higher
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efficiency in comparison to the batch reactor (>1 h). Brocklehurst et al. used a commercially available
continuous flow reactor to perform the challenging nitration of 2ꢀaminoꢀ4ꢀbromoꢀbenzoic acid methyl ester
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with a 84% yield and 70 g/h production rate. Noticeably, no byꢀproduct was obtained, which greatly simplified
the process of the workup. Apart from those substantial advantages presented above, with the numberingꢀup
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strategy, the small scaling effect of microreactor makes the laboratory results easier to industrialize. Gage et
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al. reported the continuous flow nitration of 5ꢀbromoꢀ2ꢀaminoꢀ4ꢀmethylpyridine from kilogram scale in the
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laboratory to 100 kg scale in the plant with a 99.7% purity and 50% yield.
In this study, we performed the continuous flow nitration of TFMB in microreactor system. Considering
that the next step of the nitration of TFMB was the reduction of the monoꢀnitration product and it was difficult
to separate isomers of trifluoromethoxybenzenaime. Therefore, the selectivity of mꢀNB and DNB should be
controlled as low as possible to cut the cost of the separation. The objective was to minimize the byproduct
selectivity (mꢀNB < 0.1%), DNB < 1.5%) without decline of the product yield, which could bring significant
economic benefits in saving costs of downstream separation and products purification. First, the effects of
process parameters on the conversion of TFMB and product selectivity were investigated in detail. The best
performance in terms of yield and selectivity was obtained by means of process optimization. Subsequently,
based on the results of process development, a scaleꢀup strategy which combined a multiꢀchannel microreactor
with a distributed packed tubular reactor was proposed and kilogramꢀscale production was achieved in the
combined reactor.
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. RESULTS AND DISCUSSION
.1 Process development
.1.1 Effect of reaction temperature
Reaction temperature plays a significant role in the process of nitration reaction. Given that aromatic
nitration reaction is a typically heterogeneous reaction, temperature influences not only the mass transfer of
organic compounds into the acid phase, but also the intrinsic reaction rate. Figure 2 shows the effect of reaction
temperature on the conversion of TFMB and product selectivities at different residence times. The main
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product is pꢀNB that counts more than 90% of the products due to the small rotation barrier of OCF group.
3
The product selectivity follows the order pꢀNB> oꢀNB> mꢀNB. With the increase of reaction temperature, the
selectivity of pꢀNB decreases while those of mꢀNB and oꢀNB increase. According to our previous research, it
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was due to that the activation energies of orthoꢀ and metaꢀnitrations are larger than that of paraꢀnitration. It is
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reasonable that attacking the orthoꢀposition and metaꢀposition of the aromatic ring by NO
are more difficult,
considering the rotational barrier in TFMB molecules. Therefore, higher temperature is propitious to promote
the orthoꢀ and metaꢀnitrations. As we all know that nitro group is a deactivating group, so it would be harder
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the DNB formation.
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T /K
Figure 2. Effect of reaction temperature on the (a) conversion of TFMB and (b, c) product selectivity.
Molar ratio of HNO to H SO (N/S) =0.2, molar ratio of HNO to TFMB (N/F) =0.86, t=5.0 s, sulfuric acid
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.1.2 Effect of residence time
Residence time is another important parameter which affects the reagent conversion and product
selectivity. Too short residence time may lead to low conversion of reagent, while a long residence time would
let reagent pointlessly flow inside the microreactor and some intermediates may convert to side product,
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decreasing selectivity of main product. Similarly, excessive nitration may occur during prolonged residence
time and produce undesired products in nitration reaction. Therefore, the residence time should be precisely
controlled to obtain the highest yield of desired product. In this section, the residence time of the experiment
was changed by varying the length of microchannel reactor. The effect of residence time was investigated
ꢀ1
ꢀ1
under the reaction conditions of N/S=0.2, N/F=0.86, T=278 K, Q =0.5 mL·min , Q =1.2 mL·min . Figure 3
or
aq
demonstrates the effect of residence time on the conversion of TFMB and product selectivity. It is observed
that a longer residence time will result in a higher conversion of TFMB, especially with mixed acid of higher
sulfuric acid strength. Nevertheless, the product selectivity nearly remains unchanged with the increasing
residence time during the experiments, which may due to the fact that the residence time is not long enough to
reflect its influence on the product selectivity.
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mꢀNB
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Residence time /s
Figure 3. Effect of residence time on the (a) conversion of TFMB and (b, c) product selectivity.
ꢀ1
ꢀ1
N/S=0.2, N/F=0.86, T=278 K, Q =0.5 mL·min , Q =1.2 mL·min
or
aq
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.1.3 Effect of sulfuric acid strength
It is widely accepted that when nitration reaction is carried out with the mixed acid, sulfuric acid acts as a
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catalyst, which protonates nitric acid and generates NO
ions. Therefore, in order to obtain the optimized
process parameters, the effect of sulfuric acid strength on the conversion of TFMB and product selectivity
should be studied in detail. As shown in Figure 4a, conversion of TFMB increases with increasing sulfuric acid
strength. Considering that nitration reactions with mixed acid generally are heterogeneous, higher sulfuric acid
+
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strength not only promotes the generation of NO
ions, but also increases the solubility and mass transfer rate
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of TFMB in acid phase. Both of these enhance the nitration rate and then result in a high conversion of
TFMB. As displayed in Figure 4b and 4c, the product selectivities are nearly not affected with the increase in
sulfuric acid strength. This is due to the fact that the reactions of paraꢀ, orthoꢀ and metaꢀnitrations are parallel
and the reaction improvements caused by increasing sulfuric acid strength are similar. Similarly, the unchanged
selectivity of DNB can also be explained by that.
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Figure 4. Effect of sulfuric acid strength on the (a) conversion of TFMB and (b, c) product selectivity. N/S=0.2,
ꢀ1
ꢀ1
t=7.5 s, T=293 K, Q =0.5 mL·min , Q =1.2 mL·min
or
aq
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.1.4 Effect of molar ratio of HNO /TFMB
3
As we all know, an appropriate molar ratio of reaction reagents can promote the conversion of reagent and
enhance the selectivity of desired product. In addition, it can also simplify the workꢀup procedure and reduce
the waste. The effect of molar ratio of HNO /TFMB on conversion of TFMB and product selectivity is
3
presented in Figure 5. As shown in Figure 5, it is found that conversion of TFMB increases with increasing
+
2
molar ratio while the product selectivities remains unchanged. This is attributed to more NO
ions generated
for nitration. As for the unchanged product selectivities, this is due to the fact that the monoꢀnitration reactions
are parallel and the reaction orders are identical. Besides, the residence times in the experiments of this section
is not long enough for the complete conversion of reactant TFMB, which decreases the occurrence of side
reaction to some extent.
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Figure 5. Effect of molar ratio of HNO /TFMB on the (a) conversion of TFMB and (b, c) product selectivity.
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ꢀ1
ꢀ1
N/S=0.2, t=7.5 s, T=293 K, Q =0.5 mL·min , Q =1.2 mL·min
or
aq
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.1.5 Effect of flow rate
The flow rate is a vital parameter in conducting nitration reaction. In this section, the length of the
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microchannel was kept constant, which meant that the residence time decreased with the increasing flow rate.
Figure 6 demonstrates the effect of flow rate on the conversion of TFMB and product selectivity. It can be seen
from Figure 6a that the conversion of TFMB decreases slightly with the increase in flow rate. On one hand, as
ꢀ
1
the flow rate increased from 1.3 to 3.2 mL·min , the residence time decreased from 8.0 to 3.2 s, which leaded
1
5
a lower conversion of TFMB. On the other hand, higher flow rate will also enhance mass transfer rate , which
benefited TFMB nitration. Evidently, increasing total flow rate exerted an opposite effect on the conversion of
TFMB. As a result, TFMB conversion was determined by the integrated outcome of these two changes. And it
also implicates that these nitration processes are still limited by mass transfer in the microchemical system. As
shown in Figure 6bꢀd, the product selectivities of monoꢀnitrations nearly remain unchanged with the increasing
flow rate, which indicates that the performance of microreactor in heat transfer is excellent. And it is obvious
in Figure 6e that the selectivity of dinitration product decreases sharply with the increase in flow rate. A faster
flow rate would result in a better mixing effect, which can make the organic compound more evenly dispersed
in the acid phase. Besides, a faster flow rate would also decrease the residence time. Therefore, a faster flow
rate could reduce the occurrence of dinitration.
80
(a)
2
74
283
93
T / K
2
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0
40
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.5
1.5
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.5
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ꢀ1
Qtotal /mL·min
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(c)
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.5
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.08
.04
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T / K
293
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.5
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Qtotal /mL·min
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ꢀ1
0.8
(e)
0
0
.6
.4
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93
T / K
2
0.2
0
.0
0
.5
1.5
Qtotal /mL·min
2.5
3.5
ꢀ
1
Figure 6. Effect of flow rate on the (a) conversion of TFMB and (b, c, d, e) product selectivity. N/S=0.25,
N/F=1.1, φ=97 wt%
2.1.6 Effect of packing microparticles
Considering that the nitration processes were limited by the mass transfer in microchannel systems, the
method of packing microparticles (micro packedꢀbed reactor) was taken up to intensify mass transfer process
between the mixed acid and compound TFMB in microchannel system. In our previous work, it was found that
better mixing and reaction performance could be obtained in the packed microchannel system because of its
7c, 16
excellent mass transfer performance.
In this section, the reaction system consisted of a microchannel
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reactor (length 0.1 m, inner diameter 0.6 mm) and a packed tubular reactor (length 0.3 m, inner diameter 6
mm). The quartz sand microparticles with an average size of 710 ꢁm were packed in the tubular reactor at a
porosity of 0.39. It is observed from Figure 7a that TFMB is totally converted at the low flow rate and then the
conversion decreases directly with the increasing flow rate. Given such low volume of microreactor system,
multiply increasing flow rates lead to a shorter residence time which is not enough for the full nitration of
TFMB. The effect of flow rate on product selectivities in packed microchannel system are presented in Figure
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7b, c, which are similar to the results mentioned in former section. What is different is that the variation of the
product selectivities in this section is larger than that of former section, which also indicates that packing
microparticles poses a challenge to the heat transfer in microchannel reactor. In order to take advantage of the
enhanced mass transfer brought by the packed microꢀparticles, several methods are set up to deal with the heat
transfer problem in packed microchannel system during the scale up experiments, such as distributing the
released heat, changing the size of packed microꢀparticles and reducing the reaction temperature.
1
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(a)
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ꢀ1
Q total /mL·min
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.10
.08
1.8
(c)
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1
0
.4
0.06
.6
0
.04
0.2
0
2
4
6
8
10
Qtotal /mL·minꢀ1
Figure 7. Effect of flow rate on the (a) conversion of TFMB and (b, c) product selectivity in packed
microchannel system. N/S=0.25, N/F=1.1, φ=97 wt%, T=273 K
2.2 Scale-up of the TFMB nitration
As stated above, a broad range of reaction parameters for trifluoromethoxybenzene nitration process were
investigated. The highest conversion (99.6%) was achieved in the microchannel coupled with packed tubular
ꢀ1
reactor system under the reaction conditions of N/S=0.25, N/F=1.1, φ=97 wt%, T=273 K, Q =0.4 mL·min
or
ꢀ1
and Q =0.9 mL·min , with the selectivity of oꢀNB, mꢀNB, pꢀNB and DNB being 7.26%, 0.08%, 90.97% and
aq
1
.04%, respectively. Encouraged by these results, the scale up of the nitration process of TFMB was further
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performed. As the conversion of TFMB could be dramatically increased by packing microparticles, the
microreactor combined with the packed tubular reactor was chosen as the basic unit for the scaling up in this
section, and several different strategies about packed tubular reactor were tested to obtain the best reaction
performance.
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Strategy A.
The tubular reactor in Entry 1 consisted of four packed tubular reactors (stainless tube, length 1×675 mm
+
3×900 mm, 12 mm o.d., 9 mm i.d.) with a porosity being 0.46. The size of the cylindrical quartz sand was 2
mm in diameter and 2 mm in length (Φ2×2). Figure 8 show the scalingꢀup experimental setup of the
continuous flow nitration process. TFMB and mixed acid were pumped with the volume flow rate of 10
ꢀ1
ꢀ1
mL·min and 24.5 mL·min , respectively. The mixture then flowed through the microreactor which was
cooled by running water. After the quick mixing in microreactor (4.7 s), the mixture was delivered into the
packed tubular reactor with a residence time being 2.8 min.
(a)
(b)
Figure 8. Schematic setup of strategy A for the scale up of the continuous flow TFMB nitration.
(a) 3D model of setup of strategy A (b) cutaway picture of packed tubular reactor (red blocks represent packed
microparticles)
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Following the workup of the mixture stream, the products were collected and analyzed by GC. As shown
in Table 1, about 89.75% of pꢀNB, 6.9% of oꢀNB, and byproducts (0.11% of mꢀNB and 3.17% of DNB) were
detected in the products. As mentioned above, the selectivities of byproducts were sensitive to temperature.
The temperature rise of the flowing stream in the first coiler was found to be evidently high due to the fast
nitration reaction in the first coiler, which was accompanied by much reaction heat. To avoid the sharp
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16
temperature rise, the reaction should proceed in a controlled manner. According to our previous work,
a
smaller size of microparticles used in the packed tubular reactor leaded a higher effective interfacial area and
better mixing efficiency. Hence, the size of the packed quartz sand in the first coiler was changed from Φ2×2
to Φ3×3, while other three coilers remained the same (Entry 2). It can be seen from Table 1 that the
selectivities of the main product increased, while the byproducts decreased. However, the selectivity of DNB
was still beyond our expectation. To further decrease the selectivity of byꢀproduct DNB, another adjustment
was adopted. The Φ3×3 quartz sand was still used to replace the Φ2×2 one (Entry 3). The selectivities of the
byproducts decreased as we expected. Unfortunately, the conversion of TFMB also decreased (95.29%), which
demonstrated that enlarging the size of the packed particles would slow down the reaction rate and further
decrease the reaction heat. The key issue was pointed out to be distributing the reaction heat and controlling
the reaction temperature without slowing down the reaction rate.
Table 1. Screen of the size of the packed particle on the scale up of the continuous flow nitration of TFMB
GC mol%
Entry
TFMB
0.06
pꢀNB
89.75
91.32
87.52
oꢀNB
6.90
6.69
6.58
mꢀNB
0.11
DNB
3.17
1.90
Conversion
99.94
a
1
b
2
0.00
0.08
0.07
100.0
c
3
4.71
1.12
95.29
a
b
Condition: All coilers were packed with the Φ2×2 cylindrical quartz sand. The first coiler was packed with
c
the Φ3×3 cylindrical quartz sand, while others remained the same. The front half of coilers were packed with
the Φ3×3 cylindrical quartz sand, while the another half remained the same.
Strategy B.
On the basis of the results of the strategy A, a new optimized strategy (Figure 9) was then proposed. Four
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tubular reactors with smaller diameter (stainless tube, 8 mm o.d., 6 mm i.d.) were used to take place the front
half of the tubular reaction system, while the other half of reactor remained the same. Distributed design of the
tubular reactors would be beneficial for the heat transfer of the reaction. And the packed Φ2×2 cylindrical
quartz sand could also ensure the relatively quick reaction rate and that product TFMB was completely
converted. As presented in Table 2, the optimal conditions were achieved by flowing TFMB and mixed acid
0
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ꢀ1
ꢀ1
(
solution of fuming nitric acid in concentrated sulfuric acid (1:4)) at the rate of 10 mL·min and 24.2 mL·min
o
(
total residence time being 2.4 min) and controlling the reaction temperature below ꢀ2 C. 91.08% of pꢀNB,
7.05% of oꢀNB, and only trace of mꢀNB (0.08%) and DNB (1.34%) was obtained, with the conversion of
TFMB being 99.6%. The results showed that the microreactor coupled with distributed packed tubular reactor
could well conduct the continuous flow nitration of TFMB with a good performance. The precise control of
temperature distribution and the efficient mixing in microreactor ensured the nitration reaction proceeded at a
fast rate and minimized the formation of the byproducts compared to that in a batch system.
Figure 9. Schematic setup of strategy B for the scale up of the continuous flow nitration of TFMB.
Table 2. Screen of the flow rate on the scale up of the continuous flow TFMB nitration
Q /
or
Q /
aq
GC mol%
Entry
ꢀ1
ꢀ1
mL·min
mL·min
20
TFMB pꢀNB oꢀNB mꢀNB DNB Conversion
1
2
3
4
8
0
91.58 6.58
91.08 7.05
88.90 6.86
83.50 6.58
0.08
0.08
0.08
0.08
1.76
1.34
1.47
1.43
100.0
99.55
97.32
91.60
10
12
15
24.2
29.5
36.5
0.45
2.68
8.40
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CONCLUSION
In summary, experiments were performed to study the effects of reaction parameters in the process
development of the continuous flow nitration of TFMB thoroughly. The conversion and selectivity of the
products were investigated by changing various parameters, including residence time, reaction temperature,
sulfuric acid strength, molar ratio, flow rate and reactor structure. The highest conversion (99.6%) of reactant
was obtained in the microchannel coupled with tubular reactor system at the condition of N/S=0.25, N/F=1.1,
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ꢀ1
ꢀ1
φ=97 wt%, T=273 K, Q =0.4 mL·min and Q =0.9 mL·min , with the selectivity of oꢀNB, mꢀNB, pꢀNB and
or
aq
DNB being 7.26%, 0.08%, 90.97% and 1.04%, respectively.
Encouraged by the labꢀscale results, the scaleꢀup of the nitration of TFMB with several strategies were
performed. A 0.99 kg/h throughput was achieved in the microreactor coupled with distributed packed tubal
reactor system，with the selectivity of main products being 98.13% and byproducts being limited below 1.42%
(0.08% of mꢀNB and 1.34% of DNB). The process is amenable for the preparation of analogous compounds
and can easily be scaledꢀup by either increasing reactor size or numbering up the reactors in parallel. Further
development of this procedure is currently ongoing in our laboratory.
EXPERIMENTAL SECTION
General
GC calibration curves were measured for trifluoromethoxybenzene (TFMB), monoꢀnitration product
(pꢀNB, mꢀNB and oꢀNB), diꢀnitration product (DNB) and nitrobenzene as external standard for quantitative
yield calculations. For the GC assay yields, area responses were normalized with respect to nitrobenzene as the
external standard and corrected for molar relative response factors. The components (retention time) observed
by GC were: TFMB (4.6 min), mꢀNB (9.9 min), pꢀNB (10.2 min), oꢀNB (10.6 min) and DNB (14.5 min). GC
analysis was performed on an Agilent 7890B with flame ionization detector using a HP1701 column (30 m ×
ꢀ1
0.32 mm × 1.0 ꢁm) and helium was the carrier gas (1 mL·min constant flow). After 1 min, the temperature
ꢀ1
was increased from 80 °C to 280 °C at a rate of 12 °C·min and kept constant at 280 °C for 10 min. The
ꢀ1
hydrogen flow rate was 30 mL·min , the front inlet temperature was 260 °C, and the detection temperature
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was 300 °C. The purity and supplier for each chemical were: trifluoromethoxybenzene (99% purity, QiꢀChem),
sulfuric acid (98 wt%, Kemiou), fuming nitric acid (98 wt%, Kemiou), sodium bicarbonate (99.5% purity,
Kemiou), sodium chloride (99.5% purity, BoDi) and ethylene glycol (99.0% purity, Sinopharm).
General laboratory process developmental procedure
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The general laboratory process developments were carried out in microchannel reactors. TFMB (7.57 M,
ꢀ
1
flow rate of 0.4ꢀ1.0 mL·min ) and a solution of fuming nitric acid in concentrated sulfuric acid (2.49ꢀ3.19 M,
ꢀ1
flow rate of 0.8ꢀ2.2 mL·min ) were delivered by two syringe pumps (TYD01ꢀ02, Lead Fluid), respectively.
The fluids reacted in capillaries with a length defined by the desired residence times and flow rates. The
reaction temperature was controlled by a thermostat (F12ꢀME Refrigerated/Heating Circulator, Julabo). The
preꢀcooling unit, micromixer, microchannel reactor and microneutralizer were all made up of stainless steel
with an inner diameter being 0.6 mm, and immerged in the thermostat to obtain a uniform reaction temperature.
ꢀ1
At the outlet, the reaction was quenched by large amount of water flow (10 mL·min ). The product was
collected into a small beaker containing ice deionized water and separated via a separatory funnel. The organic
phase was washed with saturated NaHCO solution and deionized water for several times to remove the
3
dissolved trace acid and inorganic substances, respectively. And then, the product was analyzed by GC. The
reaction conditions were optimized by changing various parameters, including the temperature, the sulfuric
acid strength, the residence time, the molar ratio of nitric acid to TFMB, flow rate and packed particles.
General scale-up process
A microreactor, consisting of four plates, 16 channels per plate with the size and total volume of
microchannels being 1 mm×0.5 mm×85 mm and 2.72 mL, was combined with a tubular packed reactor to
conduct the scaleꢀup of continuous flow nitration. The tubular packed reactor was made up by several coilers
with different length and size, and two kinds of average size of cylindrical quartz sand microꢀparticles were
used as packed particles, average diameters of which are 2 mm and 3 mm, respectively. TFMB (7.57 M, flow
ꢀ1
rate of 10ꢀ20 mL·min ) and a solution of fuming nitric acid in concentrated sulfuric acid (3.19 M, flow rate of
ꢀ1
24ꢀ39 mL·min ) were pumped into microreactor by two metering pumps (P1, P2, SSI, USA), respectively.
The temperature of the microreactor was controlled by the microchannel heat exchanger which is integrated in
the microreactor system. And then the mixed solution was introduced into the tubular packed reactor, which
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o
was put into a sink contained the cold sodium chloride solution (15%, ꢀ9 C) to maintain the reaction
temperature. At the outlet, the product was collected into product tank (3 L) containing ice deionized water and
then separated via a separatory funnel. The organic phase was washed with saturated NaHCO solution and
3
deionized water for several times. And 0.99 kg/h of desired product oꢀNB and pꢀNB were obtained as yellow
liquid with a GC purity of 7.05% and 91.08%, while the selectivity of the undesired product mꢀNB and DNB
were limited at 0.08% and 1.34%.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: gwchen@dicp.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors would like to thank Hengqiang Li and Jiansheng Chu (engineers in our research group) for their
help in the fabrication of microreactor and the building of experimental setup. We acknowledge gratefully the
financial supports for this project from National Natural Science Foundation of China (Nos. U1608221 and
U1662124) and from the CAS supports of the Youth Innovation Promotion Association CAS (No. 2017229)
and MOST innovation team in key area (No. 2016RA4053).
SUPPORTING INFORMATION
The supplementary material contains information of GC spectra for compound involved in this reaction
and pictures of different equipment used in the process. This material (.PDF) is available free of charge via the
Internet.
REFERENCES
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