A high-output, continuous selective and heterogeneous nitration of p -difluorobenzene

Article abstract of DOI:10.1021/op300350v

A practical continuous nitration process for 2,5-difluoronitrobenzene via nitration of p-difluorobenzene with fuming nitric acid in 98% yield has been developed. The excellent yield of this liquid/liquid biphasic reaction resulted from the advantages of a continuous flow system. The 2.0 equiv sulfuric acid could be used three times directly with product yields in the range of 96-98%, and further recycling of waste acid could be partly achieved by adjusting the concentration of sulfuric acid. Reaction time could be brought down to 2 min by increasing the reaction temperature and thereby taking advantage of superior mass and heat transfer of this continuous flow system.

Full text of DOI:10.1021/op300350v

Technical Note
pubs.acs.org/OPRD
A High-Output, Continuous Selective and Heterogeneous Nitration
of p‑Difluorobenzene
Zhiqun Yu,† Yanwen Lv,†,‡ Chuanming Yu,*,† and Weike Su†
†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
‡College of Chemistry and Materials Engineering, Quzhou University, Quzhou 324000, P.R. China
ABSTRACT: A practical continuous nitration process for 2,5-difluoronitrobenzene via nitration of p-difluorobenzene with
fuming nitric acid in 98% yield has been developed. The excellent yield of this liquid/liquid biphasic reaction resulted from the
advantages of a continuous flow system. The 2.0 equiv sulfuric acid could be used three times directly with product yields in the
range of 96−98%, and further recycling of waste acid could be partly achieved by adjusting the concentration of sulfuric acid.
Reaction time could be brought down to 2 min by increasing the reaction temperature and thereby taking advantage of superior
mass and heat transfer of this continuous flow system.
reported an industrial nitration process with high efficiency and
selectivity. Gage et al.10 scaled up a continuous nitration of a
pyridine derivative to 100-kg scale successfully; however, no
obvious improvement of yield was achieved, and no mention of
the recycling of waste acid was made.
INTRODUCTION
■
Nitroaromatics are widely used in various fields and are
produced in quantities from bulk to kilogram scale.1 Electro-
philic nitration is the major synthetic route to nitroaromatics;
however, the reaction is often difficult to control due to the
strong exothermic nature. It presents serious hazardous
particularly in large-scale production. In addition, inefficient
heat transfer in large reaction vessel leads to more undesired
side reactions such as further nitration, sulfonation, nucleophilic
substitution, oxidation, and other reactions (Scheme 1).2
Over the last 10 years, rapid development of continuous flow
technology has opened new horizons both in academia and
industry. In comparison to the batch reactor, the continuous
flow reactor offers several advantages such as better mass and
heat transfer, fewer transport limitations, more precise control
of reaction variables, safer operation, and easier scaling-up.3
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 surface-to-volume ratio is higher, which
significantly reduces the possibility of side-product formation,
and significantly improves the yield of the main product.
Several reports of nitration in continuous microreactors on
lab scale are in the literature. For example, (a) Panke et al.4
used a stainless steel microreactor for the high energetic
nitration reactions. (b) Burns and Ramshaw5 reported the
nitration of benzene and toluene using mixed acids in a
microreactor. (c) Pelletier and Renaud6 detailed the nitration of
3-alkylpyrazoles with an inexpensive continuous flow micro-
reactor. (d) Kulkarni et al.7 described the nitration of
benzaldehyde and salicylic acid with continuous flow stainless
steel microreactors. (e) Ducry et al.8 reported the nitration of
phenol using a glass microchannel reactor. There are also many
patents describing industrial applications of these continuous
flow nitration reactors. However, detailed reports in the open
literature describing actual implementation of nitration on
large-scale production with continuous flow reactors are scarce.
Notable exceptions are as follow: Braune and coworkers9
We have previously reported expeditious and kilogram-scale
continuous flow synthesis of 7-ethyltryptophol and o-
difluorobenzene both in high yield and purity.11 Herein, we
have developed a facile and practical continuous flow nitration
reactor for nitroaromatics. p-Difluorobenzene (1) was chosen
for this study, and its mononitration product (2) is useful in the
pharmaceutical and liquid crystal industry.12 Compound 2 can
be prepared in conventional batch reactors by adding a mixed
concentrated sulfuric acid and fuming nitric acid to 1 in 80%
yield, the side products being the dinitro compound 3, phenols
4, and 5 (Scheme 2). This motivated us to explore a more
selective and continuous nitration system under safer
conditions.13
RESULTS AND DISCUSSIONS
■
Process A. The initial process designed was the direct
conversion of commonly used batch technology to a
heterogeneous continuous flow system. The equipment
consists of two peristaltic pumps (P1, P2, Baoding Longer,
China) loaded with tubing connected by a T-joint to a mixer
which was connected to the reacting tube (SS316, 4 mm i.d., 6
mm o.d.).14 The reacting tube was immersed in a thermostat-
controlled water bath (Scheme 3). Nitrating acid mixture (2.0
equiv concentrated sulfuric acid and 1.1 equiv fuming nitric
acid) and p-difluorobenzene were pumped into the reactor at
room temperature by P1 and P2, respectively. After a residence
time in the reacting tube, the stream flowed through the outlet.
The reaction was quenched by ice water (∼20 mol mol−1
reactant) in the collection vessel. The mixture was extracted
with EtOAc. The combined organic extracts were neutralized
Received: December 5, 2012
Published: February 11, 2013
© 2013 American Chemical Society
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Organic Process Research & Development
Technical Note
Scheme 1. Main side reactions of nitration reaction
Scheme 2. Nitration of p-difluorobenzene 1 in batch affords the mononitro 2 as the main product, with some dinitro 3 and
difluorophenols 4 and 5 as side products
Scheme 3. Schematic of process A; coil is SS316 coil with 4 mm i.d. and 6 mm o.d.
with saturated sodium bicarbonate.15 Mononitro product 2 was
obtained after solvent removal and was analyzed by GC.
Different residence times were investigated by adjusting tube
lengths while maintaining the same flow rate. The results
(shown in Figure 1) indicated that the isolated yields of 2 and 3
increased with prolonged residence times. However, very little
4 or 5 was found, which supposedly resulted from the superior
heat transfer of the continuous flow reactor. However, the
dinitro 3 was still generated at about 5% yield, even the yield of
2 was only 71%, and nearly 24% of 1 remained at 8 min. The
selectivity was not satisfactory. A possible explanation is that
the biphasic stream gradually separates again downstream from
the mixer, resulting in increasingly inefficient mass transfer and
low selectivity. On the basis of the results of 1.1 equiv of nitric
acid, we thought that the reduction of nitric acid could restrain
further nitration. However, whether the amount of nitric acid
was increased (1.3 equiv) or decreased (1.04 equiv) had hardly
Figure 1. Change of yields of 2 and 3 with residence time in process A.
As the reaction proceeds, the concentration of the reactants decreases,
and the reaction rate is very slow, so the yield of product 2 increased
very slowly. All yields are isolated yields. The rest of the composition
remains the starting material.
any effect on the reaction selectivity. This fact confirms the
literature’s argument that the biphasic nitration is a mass
transfer-controlled reaction.16 The inefficient mass transfer rate
can account for the low selectivity. In addition, quenching the
reaction by water resulted in a large amount of diluted waste
acid which was difficult to handle.
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Organic Process Research & Development
Technical Note
a
Scheme 4. Schematic of process B: coil is SS316 coil with 4 mm i.d. and 6 mm o.d.
a
Due to the high concentration of reactants at the initial stage, the nitration rate is fast and accompanied with a rapid exotherm, and therefore a 30−
35 °C bath was used to remove the heat (Module I). As the reaction proceeds, the concentration of the reactants becomes low, the nitration rate is
slow, and another mixer and a higher temperature bath (Module II) were used to accelerate the reaction; however, the amounts of side products
were not significantly increased in 1 min. In a cooling bath (Module III), the amount of the reactants is less, and the reaction rate becomes very slow,
and a “quench” zone can be seen.
Process B. With the problems of process A in mind, an
improved process was developed by connecting two reacting
modules and a cooling module in series (Scheme 4). Nitrating
acid mixture (2.0 equiv concentrated sulfuric acid and 1.1 equiv
fuming nitric acid) and p-difluorobenzene were pumped into
the reactor by P1 and P2 at the flow rates of 106 mL/min and
67 mL/min, respectively. The two-phase stream flowed through
reacting module I which was immersed in 30−35 °C water bath
with a residence time of 1 min (τ1), and then flowed though
reacting module II which was immersed in 65−70 °C water
bath with another residence time of 1 min (τ2). The reaction
was quenched by rapid cooling to below 0 °C and extracting
with EtOAc in collection vessel. Product 2 was obtained in 98%
yield with 99% GC purity. Byproducts were hardly generated in
this process due to the superior mass and heat transfer and
more precise control of reaction variables. Under these
conditions, this apparatus has an output of 6.25 kg/h.
shows that the mixing time increases with tube diameter. In our
experiments, the smaller diameter yielded more side products,
whereas the larger diameter led to lower conversion rates. On
the basis of nitration being a mass transfer-controlled reaction,
the explanation could be that the mass transfer of the smaller-
diameter tube is more efficient and leads to more side products
within the same residence time; however, the inefficient mass
and heat transfer of the larger-diameter tube results in worse
selectivity and conversion. In other words, the residence time is
too long in thinner tubes, and 6 mm of diameter is too large.
dt2
4D
τmix
=
(1)
Comparative Batch Experiment. For comparison, a
typical batch nitration reaction was run under conditions
analogous to those used in the continuous flow system (4 mm
i.d.). Experimental details can be found in the Experimental
Section. Results are shown in Table 2. Obviously, the
continuous flow nitration process was established successfully
with higher yield, and higher efficiency.
Different tube diameters (1.5−6 mm) were studied using the
premise of τ1 = τ2 = 1 min and τ3 = 0.3 min at the same feeding
mole ratio and temperatures in process B. Results are shown in
Table 1. All these small-scale biphasic flow systems have
Table 2. Comparison of results
Table 1. Results of different tube diameters18
operate
manner
continuous
yield (%)
flow
batch
tube diameter (mm)
flow rate (mL/min)
2 (%)
3 (%)
yield (%) 98
80
a
purity (%) 99 (crude
product)
99.5 (after distillation)
1.5
25
42
81
86
98
12
9
a
2
reaction
time
2.3 min
stirred for another hour after completing the
addition of mixed acid
4
167
376
<1
6
b
6
82
b
output
6.25 kg/h
based on the volume of vessel
a
Some other side-products were also detected. ∼10% of p-
difluorobenzene was not reacted.
Recycling of Waste Acid. Recycling experiments were
carried out using the conditions of process B with the addition
of 1.0 equiv HNO3 to the waste acid in every run.19 The results
are shown in Table 3. The waste acid collected from process B
consists of H2SO4, H2O, and HNO3. On the basis of the
assumption of 100% conversion and addition of 1.0 equiv
HNO3 to the waste acid after each run, the theoretical and
measured ratios of waste acid after nitration are shown in Table
Reynolds numbers significantly less than 2000, which means
these systems demonstrate laminar flow. The lack of turbulence
and recirculation eddies in the reactor means that radial mixing
is strictly due to diffusion.17 The solution to Fick’s law (eq 1) is
frequently cited as a characteristic mixing time (τmix) where dt is
the tube diameter and D is the diffusion coefficient. Fick’s law
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Organic Process Research & Development
Technical Note
mixed acid, the temperature was kept below 15 °C. The
mixture was stirred vigorously for another 1 h when addition
was complete. The reaction was quenched by pouring the
mixture into the ice−water bath to keep the temperature below
10 °C. The mixture was extracted with EtOAc (50 mL × 2),
and the combined organic extracts were neutralized with 100
mL of saturated sodium bicarbonate and washed with 100 mL
of water. The brownish-yellow liquid was obtained after solvent
removal. Crude product was distilled in vacuo, and 127 g of
yellowish liquid in 80% yield and 99.5% GC purity was
obtained. 1H NMR (400 MHz, CDCl3) δ/ppm: 7.81−7.77 (m,
1H), 7.40−7.34 (m, 1H), 7.33−7.27 (m, 1H). 19F NMR (376.5
MHz, CDCl3) δ/ppm: −114.72, −122.74.
Continuous Flow Experiment. A mixture of fuming nitric
acid (730 g, 11 mol) and concentrated sulfuric acid (2000 g, 20
mol) was prepared. The mixed acid and p-difluorobenzene
(1140 g, 10 mol) were pumped into the reactor (Scheme 4) by
P1 and P2 at the flow rates of 106 mL/min and 67 mL/min,
respectively. The stream flowed through the first mixer with a
residence time of 1 min in reacting module I which was
immersed in a 30−35 °C water bath, and then flowed through
the second mixer with another residence time of 1 min in
reacting module II which was immersed in a 65−70 °C water
bath. Then the mixture was immediately cooled to below 0 °C
(within 0.3 min) when flowed through the cooling tube in
module III, and was extracted with EtOAc (500 mL × 2) in the
collection vessel. The combined organic extracts were
neutralized with 1 L saturated sodium bicarbonate and washed
with 1 L water. An amount of 1558 g of yellowish liquid was
obtained after solvent removal in 98% yield and 99% GC
purity. The waste acid (about 2290 g) was collected for
recycling.
Table 3. Results of recycling of waste acid
yield (%)
recycling times
2
3
1
2
3
4
98
96
77
45
<1
<1
<1
<1
4. With an increased ratio of water in the acid mixture, the yield
of 2 decreased, but not much more dinitro 3 was generated.
The reaction selectivity did not decrease, although the nitration
reaction rate was slower at a lower concentration of acid. In
other words, the 2.0 equiv sulfuric acid could be recycled two
times directly with excellent product yields, and further
recycling of waste acid can be partly achieved by adjusting
the concentration of sulfuric acid to more than 80 wt % (H2SO4
wt % = H2SO4/(H2SO4 + H2O)) with concentrated sulfuric
acid. This was confirmed by operating the nitration reaction
using the adjusted acid, and all five runs yielded 97−98% of 2 at
98−99% GC purities. The amount of sulfuric acid can be cut
down from 2.5 mol of H2SO4 per mol of product 2 to 0.68 mol
of H2SO4 per mol of product 2 based on two direct recycles of
waste acid.
CONCLUSIONS
■
In summary, a green and practical continuous heterogeneous
nitration process for 2 has been developed. Excellent yield was
achieved with the use of a continuous flow system. The 2.0
equiv of sulfuric acid can be used three times directly, and
further recycling of waste acid can be partly achieved by
adjusting the concentration of sulfuric acid. The simplicity,
especially with regard to controlling flow into the reactor,
makes it easily amenable for other liquid/liquid heterogeneous
flow reactions and for scaling up by operating several reactors
in parallel with higher output in parallel.
Recycling of Waste Acid. Fuming nitric acid (663 g, 10
mol) was added to the collected acid. 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% GC purity.
Further recycling experiments were run analogously.
EXPERIMENTAL SECTION
■
All GC analysis was conducted on an Agilent 7890A. GC
conditions: HP-INNOWAX column, 30 m × 0.25 mm ×0.25
μm, Carrier gas: helium (1.5 mL/min), Injection temp.: 250
°C, Detector temp.: 260 °C, Oven: 100 °C (3 min hold) →
AUTHOR INFORMATION
■
Corresponding Author
*Telephone/fax: (+86)57188320752. E-mail: pharmlab@zjut.
edu.cn.
280 °C (10 °C/min, 10 min hold). H and 19F spectra were
1
recorded in CDCl3 with tetramethylsilane (TMS, δ = 0) as an
internal standard at ambient temperature on a Varian 400 MHz
spectrometer at 400 and 376.5 MHz, respectively.
Notes
The authors declare no competing financial interest.
Batch Experiment. p-Difluorobenzene (114 g, 1 mol) was
placed in a 1-L glass jar which was immersed in an ice−water
bath. A mixture of fuming nitric acid (73 g, 1.1 mol) and
concentrated sulfuric acid (200 g, 2 mol) was prepared at room
temperature. When 1 was cooled to 10 °C, the mixed acid was
added to it. Nitration was initiated by the slow addition of the
ACKNOWLEDGMENTS
■
We are grateful for the National Natural Science Foundation of
China (No. 21176222) and Zhejiang Technology and Service
Platform of New Drug Innovation (PNDI) (No. 2011E61003)
for financial support.
Table 4. Theoretical and measured ratios of waste acid
theoretical ratios (wt %)
measured ratios (wt %)
waste acid
HNO3
H2SO4
H2O
HNO3
H2SO4
H2O
a
a
waste acid 1
waste acid 2
waste acid 3
waste acid 4
2.8
2.5
2.3
2.2
87.4 (89.9 )
9.8
18.9
25.2
30.6
2.9
2.6
2.5
−
87.2 (89.8 )
9.9
19.3
27.1
−
a
a
78.6 (80.6 )
78.1 (80.2 )
a
a
72.5 (74.2 )
70.4 (72.2 )
a
67.2 (68.7 )
−
a
H2SO4 wt % = H2SO4/(H2SO4 + H2O)
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