Continuous-Flow Process for Selective Mononitration of 1-Methyl-4-(methylsulfonyl)benzene

Article abstract of DOI:10.1021/acs.oprd.5b00374

An expeditious process for selective nitration of 1-methyl-4-(methylsulfonyl)benzene in a continuous-flow reactor in 98% yield is described. The continuous-flow mononitration ran well in adiabatic condition with 80 wt% sulfuric acid, and residence time was reduced to 5 s. The short residence time can significantly reduce byproducts. Dinitration was also studied for optimization of the mononitration. The spent acid could be reused for several times after concentration in a vacuum.

Full text of DOI:10.1021/acs.oprd.5b00374

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Full Paper
Continuous-Flow Process for Selective
Mononitration of 1-Methyl-4-(methylsulfonyl)benzene
Zhiqun Yu, Pengcheng Zhou, Jiming Liu, Wenzuo Wang, Chuanming Yu, and Weike Su
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00374 • Publication Date (Web): 06 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 16
Organic Process Research & Development
1
2
3
ContinuousꢀFlow Process for Selective Mononitration of
4
5
6
7
1ꢀMethylꢀ4ꢀ(methylsulfonyl)benzene
8
9
Zhiqun Yu,1 Pengcheng Zhou,2 Jiming Liu,2 Wenzuo Wang,2 Chuanming Yu,1,2 and Weike Su1,2*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients,
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P.R. China
2. Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College
of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China
* Correspondent. Tel: (+86)57188320899. Eꢀmail: pharmlab@zjut.edu.cn.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 16
TOC GRAPHIC:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 3 of 16
Organic Process Research & Development
ABSTRACT: An expeditious process for selective nitration of 1ꢀmethylꢀ4ꢀ(methylsulfonyl)benzene via
a continuousꢀflow reactor in 98% yield was described. The continuousꢀflow mononitration ran well in
adiabatic condition with 80 wt% sulfuric acid, and residence time was brought down to 5 s. The short
residence time can significantly reduce byproducts. Dinitration was also studied for optimization of the
mononitration. The spent acid could be reused for several times after concentrated in vacuum.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEY
WORDS:
Continuousꢀflow;
Mononitration;
Adiabatic
nitration;
1ꢀMethylꢀ4ꢀ
(methylsulfonyl)benzene
INTRODUCTION
Nitroaromatic derivatives are an important class of compounds with wide applications in
pharmaceuticals, pesticides, dyes, perfumes, explosives, etc.1 For example, the title reaction product 1ꢀ
methylꢀ4ꢀ(methylsulfonyl)ꢀ2ꢀnitrobenzene is an important material for the synthesis of Mesotrione
(Figure 1), which is a herbicide used to control some grass and broadꢀleaved weeds mainly in maize
crops.2 Nitroaromatics are generally produced by nitration of aromatic derivatives. These nitration
reactions are extremely hazardous due to highly exothermic thermodynamics as well as possible
decomposition and explosion of nitro compounds.3 The heat of reaction per electrophilic substitution by
a nitronium ion is typically −100 kJ/mol, and it presents serious hazards particularly in largeꢀscale
production. In the chemical industry, to carry out the reaction in a mild way, large quantities of diluents
or solvents are used, and slow addition is taken. Hence, it requires long reaction time and large amounts
of waste solvents.4 Also, selectivity is not satisfying due to easy overꢀnitration or oxidation when
reagents and products are both exposed to the reaction conditions over a long residence time.5 Still, the
safety risk is not eliminated owing to mass and heat transfer limitations in conventional batch reactors.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 16
1
2
3
4
5
6
7
Figure 1. Structure of Mesotrione.
8
9
The great demand of nitroaromatic compounds provides enormous impetus for extensive study of
nitration reactions. Recently, one solution complementary to the conventional batch or semiꢀbatch mode
is to employ a continuous and selective nitration mode. There are a number of reports of nitration
reactions which have been performed under continuous flow conditions.4, 6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is well proved that continuousꢀflow technology offers many advantages over batch methods7,
including precise control of stoichiometry, residence time, and temperature; high reproducibility; easy
scale up; and often better reaction yields. The much higher surface area to volume ratio under flow
conditions renders highly efficient heat transfer. Furthermore, safety hazards in handling exothermic
reactions associated with explosive reagents are minimized.8 Nitration of aromatics is particularly
advantageous when carried out in continuous flow reactors. The reactor dimensions are smaller, reactant
inventory at any given time is less, diffusion is much faster, and surfaceꢀtoꢀvolume ratio is higher,
which significantly reduces the possibility of sideꢀproduct formation, and significantly improves the
safety.
Motivated by these advantages, our group has been committed to the continuousꢀflow synthesis
technology, and has reported several practical kilogramꢀscale continuousꢀflow processes9. Herein, we
have this technology applied to the mononitration of 1ꢀmethylꢀ4ꢀ(methylsulfonyl)benzene (1) in both
isothermal and adiabatic condition (Scheme 1).
Scheme 1. Mononitration of 1-Methyl-4-(methylsulfonyl)benzene
ACS Paragon Plus Environment

Page 5 of 16
Organic Process Research & Development
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
In the batch preparation10 of mononitrated product 2, mixing acid (composed of concentrated sulfuric
acid and nitric acid) was added dropwise into sulfuric acid solution of 1 at ≤ 10 oC, followed by stirring
at room temperature for several hours, then solid product was obtained by introducing the reaction
mixture into large amount of cold water. The heat of reaction had to be removed by external cooling,
thus avoiding the overꢀnitration and oxidation side reactions. In the design of continuousꢀflow process
for 2, our original objectives were to shorten the long reaction time and reduce the amount of waste.
Isothermal Nitration Process
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
From the beginning of our investigation, commercial nitric acid (98 wt% HNO3) was selected as the
nitrating agent and sulfuric acid solution of 1 was prepared in acid tank. Scheme 2 shows the
continuousꢀflow reactor experimental setup. The equipment consists of two peristaltic pumps (P1, P2,
Baoding Longer, China) loaded with tubing connected by a Tꢀmixer (SS316, 1.5 mm i.d.) that was
connected to residence loop (SS316, 3 mm i.d., 5 mm o.d.). The reacting tube was immersed in a
thermostatꢀcontrolled water bath. The flow rate of water being very high compared to the flow rate of
the reactants, which would take the reactor to near isothermal conditions. Nitric acid and sulfuric acid
solution were pumped into the reactor. After a residence time (τ) in reacting tube, reacting mixture was
introduced into dilution tank and the reaction was quenched by cold water. Solid product was
precipitated and samples were analyzed by HPLC.
Scheme 2. Schematic of Experimental Setup of Isothermal Nitration Process
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 16
The optimization of experimental parameters started from varying residence time (τ) and temperature
(T). Reaction conditions: 98% sulfuric acid, molar feed ratio of 1 : HNO3 : H2SO4 (F1 : FN : FS) was 1 :
1.2 : 2.5, flow rates of nitric acid and sulfuric acid solution were 11.2 mL/min and 60.4 mL/min,
respectively. This procedure was greatly facilitated by continuousꢀflow conditions, and a significant
number of runs were rapidly conducted in a sequential manner. For the purpose of high efficiency, we
hope to shorten the reaction time to less than one minute. Figure 2 showed the results of the influence of
temperature and residence time on nitration. As we all know, on the basis of Arrhenius equation, the
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
reaction rate increases with increasing temperature. When reaction temperature was below 45 C, no
dinitraction product was detected, and excellent selectivity (over 98%) of mononitraction product 2 was
obtained along with low conversion rate. As raised reaction temperature (higher than 55 oC), conversion
of 1 can be completed immediately, however, dinitration product 3 and oxidation product 4 (Figure 3)
emerged. When T = 75 oC, the reaction completed within 15 s and the selectivity was only 90% (about 9%
of 3, and nearly 0.5% of 4).
Figure 2. Effect of temperature and residence time on nitration when F1 : FN : FS = 1 : 1.2 : 2.5, flow
rates of nitric acid and sulfuric acid solution were 11.2 mL/min and 60.4 mL/min. Conversion was
determined by HPLC.
ACS Paragon Plus Environment

Page 7 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
Figure 3. Oxidated byꢀproduct 4.
8
9
10
11
12
13
Based on the above results, for primary purpose of reaction selectivity, we tried to change the acids
dosage at low reaction temperature. The molar feed ratio was then studied (Table 1), when flow rate of
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
nitric acid was 11.2 mL/min, and reaction temperature was about 40 C. Flow rate of sulfuric acid
solution was adjusted to adapt to the molar feed ratio, and reactor volume was not changed (10 m tube
length). Reaction was accelerated obviously when FS/F1 increased, and selectivity was still excellent
unless the ratio value reached 10 (entries 1ꢀ5, Table 1). Shortening the residence time resulted in lower
conversion (entries 2ꢀ3, Table 1). Decreasing of FN/F1 affected the conversion rate (entries 6ꢀ7, Table 1).
Due to excellent heat transfer efficiency, the reactions were run at accurate temperature, and almost no
dinitrated or oxidated side reactions occurred in such short residence times.
Table 1. Effect of molar feed ratio on nitration when T = 40 oC.
a
entry
1
2
F1 : FN : FS
1 : 1.2 : 2.0
1 : 1.2 : 2.5
τ (s)
65
60
Conv. (%)b
96
Sel. (%)b
100
100
99
3c
4
5
6
7
8
1 : 1.2 : 2.5
1 : 1.2 : 5.0
1 : 1.2 : 7.5
1 : 1.2 : 10.0
1 : 1.1 : 5.0
1 : 1.05 : 5.0
30
43
33
27
39
38
93
99
99
98
97
99
99
100
100
100
99
94
a Molar feed ratio of 1 : HNO3 : H2SO4. b Determined by HPLC. c 5 m tube length.
The success with 98 wt% nitric acid and 98 wt% sulfuric acid prompted us to study the influence of
another process parameter, i.e. LHSV (liquid hourly space velocity). Studies11 have proved that nitration
reaction was controlled by mass transfer, for an increase in LHSV could lead to an increase in Reynolds
numbers, which finally improved the mass transport on the reaction process.
When the nitration
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 16
temperature was low, the reaction rate was slow, so the reaction was controlled by reaction kinetics. But
as the temperature was raised, the reaction rate was raised as well. If the reaction rate reached to a
certain point, the reaction was instantaneous in a macroscopical way of observation, in that case, the
reaction was controlled by the mass transport. Table 2 showed the results of effect of LHSV on nitration
1
2
3
4
5
6
7
8
9
o
when F1 : FN : FS = 1 : 1.2 : 2.5 and T = 40 C. LHSV value of 240 hꢀ1 provided better result (entry 3,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2). This phenomenon validated that at low LHSV, the flow regime was laminar flow which
mixing was relative slow, so the reaction need a longer τ to complete conversion (entries 1ꢀ2, Table 2).
As LHSV raised, the Re number raised as well, and the flow regime was transited from laminar flow to
turbulent flow which improved mixing efficiency, therefore conversion can completed in a shorter τ
(entries 3ꢀ6, Table 2). But when LHSV was too high, the reaction became drastically, that may cause
some hotspots which led to dinitration, decreased selectivity (entries 5ꢀ6, Table 2). With these
continuousꢀflow reaction parameters, excellent isolated yield of 2 was achieved (ranging from 96% to
98%).
Table 2. Effect of LHSV on nitration when F1 : FN : FS = 1 : 1.2 : 2.5 and T = 40 oC.
entry
τ (s)
60
6
20
15
10
6
LHSV (hꢀ1)
60
60
180
240
360
600
Conv. (%)a
99
Sel. (%)a
1
2
3
4
5
6
99
99
99
99
98
97
86
100
100
100
99
a Determined by HPLC.
The objective of shorten reaction time was achieved. However, the amount of waste, especially
diluted sulfuric acid was still needed to be reduced. As stated in nitration mechanism, sulfuric acid is
just catalyst and dehydration agent. Theoretically, no sulfuric acid was consumed during nitration
reaction, and we aimed to establish a continuousꢀflow nitration and sulfuric acid recycled process was
possible. The key to achieve this goal was the recycling of sulfuric acid. Concentration of sulfuric acid
was then studied when fuming nitric acid was used, and flow rate of nitric acid was 44.8 mL/min. Flow
ACS Paragon Plus Environment

Page 9 of 16
Organic Process Research & Development
rate of sulfuric acid solution was adjusted to adapt to the molar feed ratio (FN/F1 = 1.2). Tube length
was adjusted to keep 240 hꢀ1 of LHSV value. Results in Table 3 reveal that decrease of concentration of
sulfuric acid lead to decrease of conversion, and increase of FS/F1 together with reaction temperature at
low concentration of sulfuric acid won’t generate more byꢀproducts. The concentration of 80 wt%
H2SO4 can keep the purposes of conversion rate and selectivity in balance (entry 5, Table 3).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Effect of concentration of sulfuric acid on nitration when LHSV = 240 hꢀ1 and FN/F1 = 1.2.
entry
H2SO4 (wt%)
FS/F1
2.5
2.5
2.5
4.5
7.5
7.5
7.5
12.5
7.5
T (oC)
40
60
60
80
80
100
80
80
Conv. (%)b
Sel. (%)a
99
1
2
3
4
5
6
7
8
9
90
90
80
80
80
80
75
75
70
86
97
32
76
99
100
77
86
28
98
99
99
99
97
100
99
80
100
a Determined by HPLC.
Study of dinitration
An extra nitration test of mononirated product 2 (Scheme 3) was systematically investigated by
varying reaction temperature, and residence time with the above optimized conditions, i.e. 80 wt%
sulfuric acid, 98 wt% nitric acid, F2 : FN : FS = 1 : 1.2 : 7.5, LHSV = 240 hꢀ1. The experiments were
conducted in the same setup as shown in Scheme 2. It was found that dinitration reaction rate was not so
fast within the first few seconds, which makes possible an adiabatic nitration process by shortening the
reaction time within 5 s (Figure 4).
Scheme 3. Nitration of 1-methyl-4-(methylsulfonyl)-2-nitrobenzene
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Study on nitration of 2 with optimized mononitration conditions.
Adiabatic Nitration Process
Bearing in mind that few byproducts generated in a very short residence time, adiabatic process was
then undertaken. Experiment setup was shown in Figure 5, nitric acid and sulfuric acid solution of 1
were pumped into the flow reactor, and outlet of the reacting tube was connected to a dilution tank.
PTFE tube was used as reacting tube and wrapped by thermal insulation cotton. Thermal conductivity of
PTFE is only 0.25 W/(m·K), and nitration reaction can be done in a few seconds with an adiabatic
o
temperature rise of excess than 60 C, so the continuousꢀflow nitration can be regarded as adiabatic
reaction. Reaction conditions were same with optimized isothermal reaction parameters, i.e. 80 wt%
sulfuric acid, 98 wt% nitric acid (44.8 mL/min), F1 : FN = 1 : 1.2. As shown in Figure 6, the results
revealed that adiabatic nitration was complete within 5 s with 99% selectivity when FS/F1 was 3.5.
Mononitration of 1 ran well at adiabatic condition (high T, short τ). The isolated yield of mononitrated
product 2 was about 98%. In addition, increase of sulfuric acid dosage lead to decrease of conversion,
and the reason may be the decrease of adiabatic temperature elevation.
ACS Paragon Plus Environment

Page 11 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Experiment setup of adiabatic nitration process.
Figure 6. Effect of FS/F1 on adiabatic nitration.
At this point, adiabatic nitration parameters can be summarized as follows: 80 wt% sulfuric acid and
98 wt% nitric acid were used, F1 : FN : FS = 1 : 1.2 : 3.5, all reagents were fed at room temperature, total
flow rate was 395.3 mL/min, residence time was 5 s, the i.d. of reacting tube was 3 mm, length of
reacting tube was 4.6 m, and isolated yield of 2 was about 98%. To underline the advantages of the
proposed flow synthesis, a comparison with the reaction performed in a batch manner was summarized
in Table 4. Continuousꢀflow synthesis reduced byproducts and saved energy consumption obviously.
Table 4 Comparison of the Batch Process with Continuous-flow Processes
operate manner
batch
isothermal
adiabatic
continuousꢀflow
continuousꢀflow
yield (%)
purity (%)
97
96
98
99
98
99
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 16
reaction time
stirred for hours after
completing the addition
of mixing acid
within 15 s
within 5 s
1
2
3
4
5
6
7
reaction temperature addition: ≤ 10 oC (need
feeding: r.t.
feeding: r.t.
reaction: adiabatic
cooling)
reaction: r.t.
reaction: 80 oC
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Recycling of spent acid
Based on the results of adiabatic nitration process, the target of establishing a recycled nitration
process was fulfilled (Figure 7). Recycling experiments were carried out under adiabatic nitration
conditions. The spent acid collected from adiabatic process consists of sulfuric acid, water, and trace of
nitric acid. Concentration of sulfuric acid in spent acid was about 40 wt%. The diluted acid was
o
condensed to 80 wt% under vacuum at about 140 C. Higher temperature, which led to carbonation of
organic solutes12, resulted in the decrease of purity. Recycled water (about 0.1 wt% of sulfuric acid) was
reused for dilution. The results were shown in Table 5. The sulfuric acid and water could be recycled
several times without obvious decrease of product quality.
Figure 7. Schematic of recycled nitration process.
Table 5. Results of recycling experiments
Recycle run
Yield of 2 (%)
Purity of 2 (%)
1
2
3
4
98
98
100
99
99
99
99
98
ACS Paragon Plus Environment

Page 13 of 16
Organic Process Research & Development
5
6
100
95
97
94
1
2
3
4
5
CONCLUSION
6
7
8
9
In summary, an expeditious and highꢀyielding process for selective mononitration of 1ꢀmethylꢀ4ꢀ
(methylsulfonyl)benzene via a continuousꢀflow reactor has been set up. The flow technology applied in
this study increases the quality of nitration product, and the adiabatic flow process reduces the amount
of sulfuric acid and saves energy consumption apparently. Using of moderate concentration of sulfuric
acid makes the recycling process easy to implement. The process is readily adapted for preparation of
analogous compounds and can easily be scaled up by increasing the reactor size or operating several
reactors with highꢀthroughput in parallel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
All chemicals were purchased from commercial sources and were used without further purification.
Melting points were determined on a Buchi 540 melting point apparatus and were uncorrected. 1H NMR
spectra was recorded on Varian 400 MHz spectrometer using tetramethylsilane (TMS) as the internal
standard. Highꢀperformance liquid chromatography (HPLC) analysis was carried out on an Agilent
1200 system equipped with a SBꢀAq 150 mm × 4.6 mm × 5 ꢁm column and detected at 216 nm, eluted
with 30 : 70 CH3CN / H2O at 1.0 mL/min.
Continuous-Flow Experimental Procedure of Adiabatic Nitration Process. As shown in Figure 5,
a mixture of 1 (340 g, 2 mol), water (158 mL), and concentrated sulfuric acid (700 g, 7 mol) was
prepared. The mixed solution and fuming nitric acid (154 g, 2.4 mol) were pumped into the reactor by
two pumps at the flow rates of 350.5 mL/min and 44.8 mL/min, respectively. The stream flowed
through the mixer with a residence time of 5 s in reacting tube which was wrapped by thermal insulation
cotton. The temperature of the reaction mixture at outlet of the reactor was raised to 100 °C immediately
while the adiabatic temperature rise was about 70 °C. Then the mixture was introduced into the dilution
tank and the reaction was quenched by cold water (900 mL). White solid was precipitated immediately.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 16
Then the mixture was cooling to room temperature. An amount of 421 g solid product was obtained
1
2
3
1
after filtration and drying in 98% yield and 99% purity: mp 117−119 °C; H NMR (400 MHz, CDCl3)
4
5
6
7
8
δ/ppm: 8.50 (s, 1H), 8.04 (d, 1H, J = 8.0 Hz), 7.06 (d, 1H, J = 8.0 Hz), 3.11 (s, 3H), 2.71 (s, 3H).
Recycling of Spent Acid. The waste acid (about 1680 g, about 40 wt% sulfuric acid) collected from
9
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
above procedure was concentrated in vacuum at 140 C until the concentration of sulfuric acid reached
80 wt%. At the same time, 830−840 g water (about 0.1 wt% sulfuric acid) was collected. Both the acid
and water were reused, and a small amount of water was added to keep the reactants ratio of first run.
The experiment was carried out under identical conditions (residence time, feeding mole ratio, and total
flow rate) and operations in first run, and resulted in a 98% yield of product 2 with 99% purity. Further
recycling experiments were run analogously.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (No. 21406203) for financial
support.
REFERENCES
(1) Olah, G. A.; Malhotra, R.; Narang, S. C. Organic Nitro Chemistry Series: Nitration Methods and
Mechanisms; VCH: New York, 1989.
(2) Brown, S. M.; Bentley, T. W.; Jones, R. O. Process for the Preparation of Acylated Cyclic 1,3ꢀ
Dicarbonyl Compounds; WO9928282, 1999ꢀ06ꢀ10.
(3) (a) Corson, B. B.; Hazen, R. K. Organic Syntheses 1943, 2, 434−436. (b) Wang, Z. C.; Xu, X. L.;
Wu, C. J.; Zhang, J. Y.; Mao, H. X. ChlorꢀAlkali Industry 2012, 48, 29−31. (c) Smith, M. B.
Organic Synthesis: 2nd ed.; McGrawꢀHill: New York, 2001, 157−164.
(4) Sharma, Y.; Joshi, R. A.; Kulkarni A. A. Org. Process Res. Dev. 2015, 19, 1138−1147.
ACS Paragon Plus Environment

Page 15 of 16
Organic Process Research & Development
(5) (a) Tingle, J. B.; Blanck, F. J. Am. Chem. Soc. 1908, 30, 1395–1412; (b) Riegel, E. R.; Post, H. W.;
Reid, E. E. J. Am. Chem. Soc. 1929, 51, 505–508; (c) Raiford, L. C.; Wickert, J. N. J. Am. Chem.
Soc. 1931, 53, 3143–3147; (d) Gigante, B.; Prazeres, A. O.; MarceloꢀCurto, M. J.; Cornelis, A.;
Laszlo, P. J. Org. Chem. 1995, 60, 3445–3447.
1
2
3
4
5
6
7
8
9
(6) (a) Burns, J. R.; Ramshaw, C. Chem. Eng. Commun. 2002, 189, 1611–1628. (b) Panke,n G.;
Schwalbe, T.; Stirner, W.; TaghaviꢀMoghadam, S.; Wille, G. Synthesis 2003, 18, 2827–2830. (c)
Ducry, L.; Roberge, D. M. Angew. Chem. Int. Ed. 2005, 44, 7972–7975. (d) Kulkarni, A. A.;
Nivangune, N. T.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Org. Process Res. Dev. 2008, 12, 995–
1000. (e) Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Org. Process Res. Dev. 2009, 13,
999–1002. (f) Gage, J. R.; Guo, X. W.; Tao, J.; Zheng, C. S. Org. Process Res. Dev. 2012, 16,
930−933. For more references on nitration in flow, see the review: (g) Kulkarni, A. A. Beilstein J.
Org. Chem. 2014, 10, 405−424.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Hessel, V. Chem. Eng. Technol. 2009, 32, 1655–1681. (b) Wahab, B.; Ellames, G.; Passey, S.;
Watts, P. Tetrahedron 2010, 66, 3861–3865. (c) Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.;
Rencurosi, A.; Vigo, D.; Rencurosi, A. Tetrahedron 2010, 66, 3242–3247. (d) Wegner, J.; Ceylan,
S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57. (e) Wiles, C.; Watts, P. Green Chem. 2012,
14, 38–54. (f) Wiles, C.; Watts, P. Green Chem. 2014, 16, 55–62.
(8) (a) Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Josh, R. R. Org. Process Res. Dev. 2009, 13, 999–
1002. (b) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009,
48, 4017–4021. (c) Yu, Z. Q.; Tong, G.; Xie, X. X.; Zhou, P. C.; Lv, Y. W.; Su, W. K. Org. Process
Res. Dev. 2015, 19, 892−896.
(9) (a) Yu, Z. Q.; Lv, Y. W.; Yu, C. M. Org. Process Res. Dev. 2012, 16, 1669−1672. (b) Yu, Z. Q.; Lv,
Y. W.; Yu, C. M.; Su, W. K. Org. Process Res. Dev. 2013, 17, 438–442.
(10) (a) Lai, H. Q.; Zhu, Y. J.; Ding, C. L.; Zhou, Y.; Li, W. M. J. Zhejiang Univ. Technol. 2007, 35,
491−493. (b) Gao, X. Y.; Gao, Z. L.; Peng, J. B. Huaxue Shiji 2010, 32, 939−940.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 16
(11) (a) Chen, Y. Z.; Su, Y. H.; Jiao, F. J.; Chen, G. W. RSC Adv. 2012, 2, 5637–5644. (b) Chen, Y.
Z.; Zhao, Y. C.; Han, M.; Ye, C. B.; Dang, M. H.; Chen, G. W. Green Chem. 2013, 15, 91−94.
(12) There was a little product in the filtrate. It could be carbonated if the temperature of
concentration was too high with concentrated sulfuric acid, and the concentrated liquid became
black. After recycling runs, the carbonated impurities might bring into the product.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment