Safe, efficient and selective synthesis of dinitro herbicides via a multifunctional continuous-flow microreactor: One-step dinitration with nitric acid as agent

Article abstract of DOI:10.1039/c2gc36652e

A continuous and selective method for synthesis of dinitro herbicides through one-step dinitration approach has been successfully developed in microreactor systems. Compared to a conventional two-step batch process, reaction can be conducted without the need to separate intermediates and much less solvent or solvent-free condition has been employed.

Full text of DOI:10.1039/c2gc36652e

Green Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Safe, efficient and selective synthesis of dinitro
herbicides via a multifunctional continuous-flow
microreactor: one-step dinitration with nitric acid as
agent†
Cite this: Green Chem., 2013, 15, 91
Received 18th October 2012,
Accepted 13th November 2012
Yizheng Chen,a,b Yuchao Zhao,a Mei Han,a Chunbo Ye,a,b Minhui Danga,b and
Guangwen Chen*a
DOI: 10.1039/c2gc36652e
www.rsc.org/greenchem
A continuous and selective method for synthesis of dinitro herbi-
The broad applications of dinitroaniline herbicides provide
cides through one-step dinitration approach has been successfully enormous impetus for extensive study of nitration reactions.
developed in microreactor systems. Compared to a conventional The well-established mechanisms for nitration of reactive
two-step batch process, reaction can be conducted without the species, such as aniline and phenol compounds, include both
need to separate intermediates and much less solvent or solvent- electrophilic and charge-transfer processes.6 Recently, one
free condition has been employed.
solution complementary to the conventional batch or semi-
batch mode is to employ a continuous and selective nitration
mode. The continuous process can offer much small reaction
volume and relatively large surface-to-volume ratio; thus
process safety is improved and both temperature and residence
time can be precisely controlled, which may improve selectivity
by suppression of side reactions.7 Microreactors have been
demonstrated as an effective tool in continuous processes for
mononitration of some aromatic compounds, for instance
benzene, toluene and chlorobenzene.8 Beneficial for its charac-
teristic submillimeter dimensions, microreactors have much
short diffusion paths and large surface-to-volume ratios com-
pared with batch reactors, which are beneficial to realize excel-
lent heat and mass transfer. So far, most academic and
industrial attention has been focused on mononitration pro-
cesses, and the straightforward one-step dinitration in con-
tinuous-flow reactors has been rarely reported.
To envisage that one-step dinitration of aniline derivatives
may be carried out in a safe, efficient and selective way, a con-
tinuous-flow microreactor has been employed in this study. At
the start of our investigation, we proposed the following
criteria as the essential requirements of our microreaction
system and method: one-step dinitration in a continuous-flow
approach, precise reaction temperature control (the variation
between reaction temperature and the fluid outlet temperature
is less than 2 °C), avoidance of any pre-protection of the amino
groups of aniline derivatives, obviation of sulfuric acid (this
approach is beneficial to the downstream purification
process), residence time <10 s, minimal solvent or solvent-free
conditions, minimal HNO3 : aniline derivative molar ratio
(although nitric acid can be separated by simple phase sepa-
ration and reused after concentration). Other features include
easily assembled and less-expensive peripherals,9 and a multi-
Dinitroaniline derivatives are an important class of com-
pounds with wide applications in herbicides and pesticides.1
For example, pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-
2,6-dinitroaniline, is a widely-used selective herbicide in agri-
cultural industry.2 Dinitroaniline derivatives are generally pro-
duced by nitration of aniline derivatives. These nitration
reactions are extremely hazardous due to highly exothermic
thermodynamics as well as possible decomposition and
explosion of nitro compounds.3 The reaction heat of direct
dinitration can be twice as much as that of mononitration. In
the chemical industry, to carry out the reaction in a mild way,
a two-step process is generally conducted, in which one mono-
nitration step is followed by subsequent mononitration.4 More-
over, large quantities of solvents or diluents are used in each
nitration step since nitration reactions are usually fast for reac-
tive species such as phenol and aniline derivatives. Thus, it
requires long reaction time and large amounts of waste sol-
vents. Also, selectivity is not satisfying due to easy oxidation or
over-nitration of aniline derivatives when reagents and pro-
ducts are exposed to the reaction conditions over a long resi-
dence time, and protection of the amino group by acetylation
may be required prior to nitration.5 Still, the safety risk is not
eliminated owing to mass and heat transfer limitations in con-
ventional batch reactors.
aDalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian, 116023, China. E-mail: gwchen@dicp.ac.cn;
Fax: +86-411-84379327; Tel: +86-411-84379031
bUniversity of Chinese Academy of Sciences, Beijing, 100049, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2gc36652e
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 91–94 | 91

View Article Online
Communication
Green Chemistry
functional microreactor integrated with mixing, heat exchange out the reaction. Benefiting from the short residence time, 1e
and reaction (see ESI†). The total reaction volume of the micro- was not determined in all cases (Table 1), and the fluid outlet
reactor is ca. 0.2 ml. The heat transfer coefficient has been temperatures were almost the same as the reaction tempera-
tested in the magnitude of 10 kW m−2 K−1 and mass transfer ture, the variations of temperature were always within 2 °C. We
coefficient in the magnitude of 10 s−1 in the microreactor, observed that 85% conversion was obtained with 98% HNO3,
which are two orders larger than those in a reported conven- while only 24% conversion was achieved with 65% HNO3
tional reactor.10
(entries 1–3, Table 1). Bearing in mind that increase in sub-
N-Alkylated anilines 1–4 have been prepared prior to use strate concentration in microreactors may result in improved
(see ESI†). Dinitration of aniline 1 in a microreactor has been conversion, the concentration of aniline 1 was increased to
chosen as a model reaction. Nitric acid acts as the nitrating 80% (entries 4–6, Table 1). We found complete conversion was
agent and acid catalyst. The desired dinitrated product shown achieved with a residence time of 9 s and temperature of 60 °C
in Scheme 1 is pendimethalin (N-(1-ethylpropyl)-3,4-dimethyl- (entry 6, Table 1). However, the molar ratio of 1a : 1b in the
2,6-dinitroaniline, 1a). Another less-desired product is N- products distribution was very low, which meant that large
nitroso-pendimethalin (1b) which can be readily and quantitat- amounts of 1b were required to be converted into 1a in the
ively converted to pendimethalin 1a (see ESI†). It is a liquid– downstream process. When the concentration of nitric acid
liquid biphasic reaction in which the reaction takes place in was changed to 65%, 100% conversion and 98% selectivity
acid phase.
were obtained and the molar ratio of 1a : 1b was as high as 3.6
In the industrial batch production of pendimethalin in (entry 7, Table 1).
chlorinated solvent, the aniline solution (30 wt%) is treated
The success with 65% nitric acid and 80% aniline 1 solu-
with dilute nitric acid as the first step. After separation of the tion prompted us to study the influence of other process para-
organic phase and spent acid phase, the organic phase is meters, such as LHSV (liquid hourly space velocity),
treated with more concentrated nitric acid as the second step, temperature and initial HNO3 : aniline 1 molar ratio. Fig. 1
obtaining 89% yield of 1a and 1b with a molar ratio for 1a : 1b demonstrates that the conversion of aniline 1 first increased
of 7 : 3. The total reaction time is 4 h, and 1e is usually pro- with the increase of LHSV (600–1800 h−1), then a stable conver-
duced in a significant amount since 1b can be further con- sion of 100% could be obtained when LHSV was higher than
verted into 1e11 under long reaction time (Scheme 2).
1800 h−1 at a temperature of 60 °C. This phenomenon was a
The batch method threw some light on the development of direct evidence that the reaction was controlled by mass trans-
our one-step dinitration process. From the beginning of our fer, for an increase in LHSV could lead to an increase in Rey-
investigation, 1,2-dichloroethane was selected as solvent and nolds numbers, which finally improved the mass transport on
concentration of aniline 1 was fixed at 30 wt% in the organic the reaction process.12 This trend became less apparent when
tank. Two commercial nitric acids, 65 wt% and 98 wt% HNO3, temperature was raised to 70 °C and 80 °C, for the conversion
were prepared in the acid tank. Then the organic stream and of aniline 1 was slightly changed.
the acid stream were pumped into the microreactor to carry
Scheme 1 One-step dinitration of N-(1-ethylpropyl)-3,4-xylidine (1) in a con-
tinuous-flow microreactor system.
Scheme 2 Conventional two-step dinitration of N-(1-ethylpropyl)-3,4-xylidine
(1) in the batch system.
Table 1 Optimization of one-step dinitration of aniline 1 in a continuous-flow microreactora
Entry
T (°C)
tb (s)
LHSV (103 h−1
)
[Aniline 1] (wt%)
[HNO3] (wt%)
HNO3 : 1 (mol/mol)
Conv.c (%)
Sel.c (%)
1a : 1bd (wt/wt)
1
2
3
4
5
6
7
8
80
80
80
40
50
60
70
60
6.1
9.0
40
7.2
7.2
9.0
6.1
0.8
0.6
0.4
0.1
0.5
0.5
0.4
0.6
4.1
30
30
30
80
80
80
80
80
65
98
98
98
98
98
65
65
3.0
3.0
3.0
3.1
3.1
4.3
3.9
3.0
24
85
40
61
74
100
100
100
72
64
57
89
90
92
98
97
1.1
0.4
0.3
0.5
0.4
0.2
3.6
4.2
a See ESI. b Residence time. c Determined by HPLC. d In all cases, 1e was not determined.
92 | Green Chem., 2013, 15, 91–94
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Communication
Table 2 One-step dinitration of aniline derivatives using the continuous-flow
microreactor
Aniline
derivative
T (°C) Conc. (wt%.) ta (s) Conv.b (%) Sel.c (%)
1
60
90
80
80
80
0.8
1.3
1.5
0.9
100
100
100
90
97
98
99
99
2
3
4
100
100
80
Fig. 1 The influence of LHSV on the conversion of aniline 1 at different reac-
tion temperatures. HNO3 : aniline 1 = 3.9 (mol/mol). Concentration of HNO3,
65 wt%; concentration of aniline 1, 80 wt%.
a Residence time. b Determined by HPLC. c Determined by HPLC. The
a : b ratios for anilines 1–4 are 4.2, 1.1, 2.8 and 1.5, respectively.
that at LHSV of 800–4200 h−1 and temperature of 70 °C,
quantitative conversion was achieved at a molar ratio of 3.1 or
3.5, while <90% conversion was obtained with a low molar
ratio of 2.7.
Based on study of the process parameters, the reaction con-
ditions were finally selected as HNO3 : aniline 1 molar ratio of
3.0 (HNO3: 6.0 ml min−1, aniline solution: 7.8 ml min−1),
temperature of 60 °C and LHSV of 4100 h−1, and 100% conver-
sion and 97% were obtained (entry 8, Table 1). To test the
stability of our microreactor system under these conditions,
the flow process was run continuously for 1 h, obtaining
0.54 kg of target products of 1a and 1b in 97% yield as
expected (isolated yield). This corresponds to an output of
12.96 kg per day or 4.32 t per year (considering 8000 h running
time in a year) for the target products. Besides, the reaction
proceeded smoothly without evaporation of solvent or clogging
of channels. Scale-up can be realized13 by a factor of 100 (plate
to stack, see in ESI†), which corresponds to an output of 432 t
per year, thus approaching factory-scale. Actually, the
16-channel microreactor in this study can be considered as
16× scale-up compared with a single-channel microreactor.
Two other N-alkyl-substituted derivatives underwent com-
plete conversion and high selectivity even under solvent-free
conditions (entries 2 and 3, Table 2). The reaction temperature
Fig. 2 The influence of LHSV on the molar ratio of 1a : 1b at different reaction
temperatures. HNO3 : aniline 1 = 3.9 (mol/mol). Concentration of HNO3, 65 wt%;
concentration of aniline 1, 80 wt%.
Fig. 3 The influence of LHSV on the conversion of aniline 1 at different initial
HNO3 : aniline 1 molar ratios. T = 70 °C. Concentration of HNO3, 65 wt%; con-
centration of aniline 1, 80 wt%.
Fig. 2 shows the variation of molar ratio of 1a : 1b with for anilines 2 and 3 must be increased to 90 °C and 80 °C,
LHSV and temperature. Surprisingly, the molar ratio of 1a : 1b respectively; presumably anilines 2 and 3 are less reactive than
turned out to be 1.4–5 with 65 wt% nitric acid, whereas it was aniline 1. One sterically hindered aniline 4 was also tested and
0–0.5 with 98 wt% nitric acid in the previous study. Thus, its initial concentration was limited by its solubility in
65 wt% nitric acid was advantageous over 98 wt% nitric acid. 1,2-dichloroethane. However, its conversion was slightly
The results indicated both low temperature and low LHSV reduced (entry 4, Table 2).
were advantageous to obtain a high molar ratio of 1a : 1b.
In conclusion, one-step dinitration method has been suc-
However, low temperature or LHSV may lead to an incomplete cessfully developed in a continuous-flow microreactor system
conversion of aniline 1 as profiled in Fig. 1. Based on the total without the need for separation of intermediates. The risks
effect of reaction temperature and LHSV, temperature of 70 °C associated with highly exothermic dinitration are eliminated.
or 60 °C and LHSV > 1800 h−1 were appropriate. Further effort Pendimethalin and two other dinitro herbicides were syn-
was concentrated on studying the influence of initial molar thesized in high yields when the residence time was less than
ratio of HNO3 : aniline 1 to choose an optimal value so as to 2 seconds, and no pre-protection of the amino group is
minimize the quantities of spent acid. Fig. 3 demonstrates needed. The undesired by-product 1e has been eliminated by
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 91–94 | 93

View Article Online
Communication
Green Chemistry
virtue of short residence time. When the HNO3 concentration
is changed from 98% to 65%, the molar ratio of 1a : 1b in the
products can switch from 0.2 to 4.2, which greatly benefit
downstream processing. It is worth noting that pendimethalin
can be produced at 4.32 t per year via this microreactor, and
industrial-scale production can be realized by numbering-up
principle.
Finally, it should be emphasized that the most important
features of this method (high yield, high output, seconds-level
residence time, HNO3 as the only agent, no pre-protection of
amino group) are collectively possible only because the micro-
reactor has very effective heat and mass transfer rate and the
reaction temperature and aniline concentration have been
improved to 60–90 °C and over 80%, respectively. A batch
reactor performing one-step dinitration under identical con-
ditions would be impossible or very hazardous because of its
low heat and mass transfer ability and relatively large reaction
volume. Microreactors thus offer great opportunities for one-
step dinitration of aniline derivatives in a continuous and
selective way. Studies on one-step dinitration of more aniline
compounds and other aromatics are under way.
5 (a) J. B. Tingle and F. Blanck, J. Am. Chem. Soc., 1908, 30,
1395–1412; (b) E. R. Riegel, H. W. Post and E. E. Reid, J. Am.
Chem. Soc., 1929, 51, 505–508; (c) L. C. Raiford and
J. N. Wickert, J. Am. Chem. Soc., 1931, 53, 3143–3147;
(d) B. Gigante, A. O. Prazeres, M. J. Marcelo-Curto,
A. Cornelis and P. Laszlo, J. Org. Chem., 1995, 60, 3445–3447.
6 (a) J. Ridd, Chem. Soc. Rev., 1991, 20, 149–165;
(b) R. N. Loeppky, S. P. Singh, S. Elomari, R. Hastings and
T. E. Theiss, J. Am. Chem. Soc., 1998, 120, 5193–5202;
(c) M. Tanaka, E. Muro, H. Ando, Q. Xu, M. Fujiwara,
Y. Souma and Y. Yamaguchi, J. Org. Chem., 2000, 65, 2972–
2978; (d) S. R. Gwaltney, S. V. Rosokha, M. Head-Gordon
and J. K. Kochi, J. Am. Chem. Soc., 2003, 125, 3273–3283.
7 (a) K. Jahnisch, V. Hessel, H. Lowe and M. Baerns, Angew.
Chem., 2004, 116, 410–451; K. Jahnisch, V. Hessel, H. Lowe
and M. Baerns, Angew. Chem., Int. Ed., 2004, 43, 406–446;
(b) D. R. J. Acke and C. V. Stevens, Green Chem., 2007, 9,
386; (c) T. H. Yoon, S. H. Park, K. I. Min, X. Zhang,
S. J. Haswell and D. P. Kim, Lab Chip, 2008, 8, 1454–1459;
(d) F. E. Valera, M. Quaranta, A. Moran, J. Blacker,
A. Armstrong, J. T. Cabral and D. G. Blackmond, Angew.
Chem., 2010, 122, 2530–2537; F. E. Valera, M. Quaranta,
A. Moran, J. Blacker, A. Armstrong, J. T. Cabral and
D. G. Blackmond, Angew. Chem., Int. Ed., 2010, 49, 2478–
2485; (e) R. A. Maurya, C. P. Park, J. H. Lee and D. P. Kim,
Angew. Chem., 2011, 123, 6074–6077; R. A. Maurya,
C. P. Park, J. H. Lee and D. P. Kim, Angew. Chem., Int. Ed.,
2011, 50, 5952–5955; (f) J. Wegner, S. Ceylan and
A. Kirschning, Chem. Commun., 2011, 47, 4583–4592;
(g) A. Nagaki, K. Imai, H. Kim and J.-i. Yoshida, RSC Adv.,
2011, 1, 758–760; (h) T. Illg, V. Hessel, J. C. Schouten and
P. Loeb, Green Chem., 2012, 14, 1420–1433.
The work reported in this article was financially supported
by research grants from the National Natural Science Foun-
dation of China (No. 21225627), Ministry of Science and Tech-
nology of China (Nos. 2009CB219903, 2012BAA08B02), and the
frame work of the Sino-French project MIGALI via the National
Natural Science Foundation of China (No. 20911130358).
Notes and references
1 (a) D. Moreland, F. Farmer and G. Hussey, Pestic. Biochem.
Physiol., 1972, 2, 342–353; (b) S. Traore and J. J. Aaron,
Analyst, 1989, 114, 609–613; (c) J. W. Benbow,
E. L. Bernberg, A. Korda and J. R. Mead, Antimicrob. Agents
Chemother., 1998, 42, 339–343.
8 (a) J. R. Burns and C. Ramshaw, Chem. Eng. Commun.,
2002, 189, 1611–1628; (b) R. Halder, A. Lawal and
R. Damavarapu, Catal. Today, 2007, 125, 74–80.
9 P. B. Palde and T. F. Jamison, Angew. Chem., 2011, 123,
3587–3590; P. B. Palde and T. F. Jamison, Angew. Chem., Int.
Ed., 2011, 50, 3525–3528.
2 (a) A. Walker and W. Bond, Pestic. Sci., 1977, 8, 359–365;
(b) S. Piutti, A. L. Marchand, B. Lagacherie, F. Martin-
Laurent and G. Soulas, Pest Manage. Sci., 2002, 58, 303–312. 10 (a) Y. C. Zhao, G. W. Chen and Q. Yuan, AIChE J., 2007, 53,
3 (a) C. Bunton, E. Hughes, G. Minkoff and R. Reed, Nature,
1946, 158, 514–515; (b) D. E. O’Reilly and E. M. Peterson,
J. Chem. Phys., 1972, 56, 2262; (c) J. Antes, D. Boskovic,
H. Krause, S. Loebbecke, N. Lutz, T. Tuercke and
W. Schweikert, Chem. Eng. Res. Des., 2003, 81, 760–765;
3042–3053; (b) H. S. Cao, G. W. Chen and Q. Yuan, Ind.
Eng. Chem. Res., 2009, 48, 4535–4541; (c) H. S. Cao,
G. W. Chen and Q. Yuan, Ind. Eng. Chem. Res., 2010, 49,
6215–6220; (d) Y. H. Su, Y. C. Zhao, G. W. Chen and
Q. Yuan, Chem. Eng. Sci., 2010, 65, 3947–3956.
(d) L. Ducry and D. M. Roberge, Angew. Chem., 2005, 117, 11 G. R. Clemo and J. M. Smith, J. Chem. Soc., 1928, 2414–2422.
8186–8189; L. Ducry and D. M. Roberge, Angew. Chem., Int. 12 Y. Z. Chen, Y. H. Su, F. J. Jiao and G. W. Chen, RSC Adv.,
Ed., 2005, 44, 7972–7975; (e) R. Andreozzi, V. Caprio, I. Di
2012, 2, 5637–5644.
Somma and R. Sanchirico, J. Hazard. Mater., 2006, 134, 13 (a) R. Schenk, V. Hessel, C. Hofmann, J. Kiss, H. Löwe and
1–7; (f) J. N. Shen, Y. C. Zhao, G. W. Chen and Q. Yuan,
Chin. J. Chem. Eng., 2009, 17, 412–418.
4 L. A. Daniel, US 4621157, 1986.
A. Ziogas, Chem. Eng. J., 2004, 101, 421–429; (b) V. Hessel,
D. Kralisch and U. Krtschil, Energy Environ. Sci., 2008, 1,
467–478.
94 | Green Chem., 2013, 15, 91–94
This journal is © The Royal Society of Chemistry 2013