Controlled autocatalytic nitration of phenol in a microreactor

Article abstract of DOI:10.1002/anie.200502387

(Chemical Equation Presented) Scaled-down approach: The nitration of phenol is an autocatalytic, strongly exothermic reaction and is thus difficult to handle on an industrial scale. Continuous nitration in a microreactor (see picture) affords higher yield

Full text of DOI:10.1002/anie.200502387

Communications
reaction thanks to their efficient mixing and heat transfer,
[
5]
as already described for nitration reactions. The nitration of
phenol (1) was chosen as a model reaction to investigate the
potential of microreactors from both a chemical and a safety
point of view.
The general mechanism for the acid-catalyzed nitration of
aromatic compounds is electrophilic and involves the nitro-
+
[6]
nium ion (NO ) as the reactive species. The nitration of
2
phenol (1) and other aromatic substrates activated toward
electrophilic substitution is, however, essentially different in
[
7]
that it is catalyzed by nitrous acid. The rate of phenol
nitration by nitric acid in water was first reported by
Martinsen, who showed that the reaction is autocatalyzed
[
8]
by the nitrous acid it produces. The importance of the
presence of HNO could suggest that the nitrosonium ion
2
+
(NO ) acts as the reactive species. Catalysis by nitrous acid
can not, however, involve a nitrosation followed by an
oxidation by HNO , since nitrosation is para-selective
3
whereas nitration affords a mixture of ortho- and para-
[
9]
nitrophenols. Evidence has since been gained that phenol
nitration mainly occurs by a radical mechanism involving a
[
10]
single electron-transfer reaction.
The autocatalytic nature of phenol nitration was first
verified by carrying out the reaction in a Mettler RC1
calorimeter (Table 1, entries 1 and 2). The addition of 65%
HNO to a 23% phenol solution in CH CO H (6%, used to
3
3
2
Synthetic Methods
increase the phenol solubility) and water (71%) was carried
out in two portions (Figure 1). Essentially no reaction took
DOI: 10.1002/anie.200502387
place during the addition of the first HNO portion (corre-
3
sponding to 0.67 equiv). The small heat signal observed
during this addition corresponds to the slightly exothermic
dilution of the acid. A first exothermic reaction (35 kJmol )
Controlled Autocatalytic Nitration of Phenol in a
Microreactor
À1
was observed shortly after the first addition. Once this
reaction was over, the HNO addition was resumed; again,
the reaction did not start immediately. It was only towards the
Laurent Ducry* and Dominique M. Roberge*
3
end of the second addition (2.0 equiv HNO added in total)
3
Nitration reactions can often show extremely exothermic
behavior, and this, combined with the decomposition or
explosion potential of many nitro compounds, places them
amongst the most hazardous
that the strongly exothermic reaction took place
(170 kJmol ; 1158Ctotal adiabatic temperature rise). It is
important to note that despite the relatively small reaction
À1
[
1]
industrial processes. In this
context, continuous processes
are attractive for safety reasons
because of the much smaller
[
2]
reaction volumes used. Con-
tinuous production is of com-
mercial importance for very
fast nitrations, such as that of
[
3]
phenol (Scheme 1).
over, microreactors
More-
should
Scheme 1. Nitration of phenol (1) affords the mononitro isomers 2 and 3 as main products. Some
hydroquinone (4), dinitrophenols (5 and 6), and polymericside-produ ct s are also formed. para-Nitro-
[
4]
allow better control of the phenol (2) is the most valuable regioisomer commercially.
[
*] Dr. L. Ducry, Dr. D. M. Roberge
Lonza Ltd.
Valais Works
volume (< 1 L) and the efficient cooling system of the
calorimeter, a significant temperature rise occurred (558C).
Scaling-up such a semibatch reaction would almost certainly
be impracticable for safety reasons. Analysis of the final
organic phase by differential scanning calorimetry (DSC)
3930 Visp (Switzerland)
Fax : (+41)27-948-6067
E-mail: laurent.ducry@lonza.com
dominique.roberge@lonza.com
À1
showed a small exotherm starting at 1048C(30 Jg ) followed
7972
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Chemie
[
a]
Table 1: Phenol nitration in semibatch or in continuous mode (microreactor, MR).
Entry
Equipment
T
HNO3
[equiv]
CH CO H
[%]
H O
[%]
Yield
[%]
Ratio 2/3
Purity
[wt%]
1
4
5
6
Polymers
[area%]
3
2
2
[8C]
[wt%]
[area%]
[area%]
[area%]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
RC1
RC1
MR
MR
MR
MR
MR
MR
batch
batch
batch
MR
MR
MR
MR
MR
MR
MR
25
25
35
45
45
45
45
60
0
10
20
20
20
20
5
1.5
2.0
1.5
1.1
1.2
1.5
1.8
1.6
2.0
2.0
2.0
1.4
2.0
2.3
1.7
1.7
1.7
1.7
1.7
1.7
6
6
6
6
6
6
6
6
0
0
0
0
0
0
0
0
0
0
0
0
71
71
71
71
71
71
71
71
78
78
78
10
10
10
10
10
10
10
10
10
54
55
70
65
68
73
75
76
30
32
21
77
69
65
74
70
70
69
65
65
1.2
1.2
1.1
1.2
1.2
1.1
1.1
1.0
1.2
0.7
0.6
1.0
1.0
0.9
0.9
0.9
0.9
0.9
0.9
0.9
56.5
57.8
71.1
65.8
67.4
74.8
79.4
78.2
25.3
17.9
12.8
74.6
73.9
72.4
77.4
75.7
74.5
73.1
70.7
69.3
0.1
0.0
0.1
4.6
0.6
0.0
0.0
0.0
0.0
0.0
0.0
0.3
0.4
0.4
0.0
0.3
0.3
0.3
0.4
0.4
0.6
0.0
0.8
0.8
1.6
1.4
1.6
2.4
0.0
0.0
0.0
3.8
2.3
2.0
2.9
2.9
3.1
3.2
2.8
3.1
0.5
0.0
0.0
0.0
0.0
0.6
0.0
0.8
0.0
0.0
0.0
4.2
6.8
7.8
3.2
4.2
5.5
6.6
7.4
8.7
0.0
1.9
0.0
0.0
0.0
0.0
0.6
0.0
0.0
0.0
0.0
1.9
2.7
3.0
0.0
1.3
1.9
2.3
2.4
2.8
32.3
32.2
18.0
18.8
20.4
13.2
9.0
8.6
64.7
72.1
77.2
7.1
6.6
7.4
6.5
6.9
6.6
6.8
1
1
1
1
1
1
1
1
1
2
2
15
25
35
45
55
MR
MR
8.7
8.5
[a] The nitrated solution was analyzed by GC (quantitative results for 1, 2 and 3, area% for the side-products). The yield (calcd) and purity correspond
to the total amount of mononitro products 2 and 3. The water concentration does not take into account the water contained in nitric acid.
A glass microreactor with a 10 ” 0.5-mm channel width
and 2.0 mL internal volume was next used for the nitration
experiments (entries 3–8). The phenol solution (23%) in a
mixture of CH CO H (6%) and water (71%, feed 1) and the
3
2
6
5% HNO3 solution (feed 2) were continuously pumped
through the mixer at a total flow rate of approximately
À1
À1
2
1 gmin
(phenol throughput of 3.7 gmin ). The split
between the phenol (1) and the nitric acid solutions was
varied between 3.9:1 and 2.3:1, which corresponds to 1.1 to
1
.8 equivalents of HNO . The efficient cooling of the micro-
3
reactor allowed safe control of the exothermic reaction. With
1
.5 equivalents of HNO , a one-minute delay was observed at
3
4
58Cbefore the start of the autocatalysis (Figure 2). The
autocatalysis started immediately at a higher temperature
with 1.5 equivalents of HNO (entry 8), whereas at lower
3
temperatures the autocatalysis did not start at all, was
extinguished, or partially took place outside the microreactor.
Similar trends were also observed on variation of the amount
of HNO : the nitration was completed within the micro-
3
reactor with 1.8 equivalents of HNO (entry 7), while the
3
reaction proved slower and occurred partially outside the
reactor (residence time: 7 s) at a lower stoichiometry. One
advantage of a glass microreactor is the possibility to observe
the reaction as it takes place. After the start of the
autocatalysis, the violent evolution of a colorless gas suggests
that gaseous nitrogen dioxide (N O ) is formed in the catalytic
Figure 1. Semibatch nitration of phenol at 258C with acetic acid
Table 1, entry 2): a) heat signal (Q, positive values denote exothermic
reactions); b) reaction temperature (T, c) and temperature of the
cooling system (T, a); c) addition rate (m) versus reaction time (t).
2
4
(
cycle. However, the true reactive species for this reaction is
presumably the dissociated nitrogen dioxide radical (NO2C)
which couples with the radical cation from the phenol in a
[
10]
single electron-transfer mechanism.
Reduced amounts of polymeric side-products, increased
purities, and up to 20% higher yields were obtained when
performing the reaction continuously in a microreactor. Only
À1
by a large one at 1858C(1500 Jg ), which actually corre-
sponds to a thermal runaway scenario.
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7973

Communications
Figure 2. Phenol nitration in a microreactor at 458C with acetic acid
Table 1, entry 6): a) temperature of the thermal fluid inlet (T, a),
(
temperature of the thermal fluid outlet (T, g), and temperature of
the reaction mixture outlet (T, c); b) phenol addition rate (F, c)
and nitrica ci d addition rate ( F, a) versus time on stream (t).
about 9% of polymers were formed when 1.6 and 1.8 equiv-
alents of HNO were used (entries 7 and 8). Lower HNO3
3
Figure 3. Batchwise phenol nitration at 0 (c), 10 (a), and 208C
g) without acetic acid (Table 1, entries 9–11): a) heat signal (Q)
obtained from the difference of the reactor and jacket temperatures;
b) reaction temperatures (T); c) mass of nitric acid added (m) versus
reaction time (t).
stoichiometries resulted in intermediate amounts of polymers,
possibly reflecting the part of the nitration which took place
outside the microreactor (batch instead of flow reaction).
While the para isomer 2 was slightly favored in batch
reactions, especially at lower temperature, no significant
regioselectivity was observed with the microreactor.
(
In a second set of experiments, phenol nitration was
studied without CH CO H. For comparison purposes, the
À1
throughput of 2.8 gmin ). Under these concentrated con-
3
2
reaction was again first performed batchwise in a jacketed
00-mL reactor. Continuous addition of 65% HNO to a 24%
aqueous phenol solution was carried out at various temper-
atures (Figure 3). These conditions correspond to a liquid–
liquid biphasic system where the phenol (1) is dispersed as a
fine emulsion. The reactions only started after a delay of 15,
ditions the autocatalysis always started spontaneously in the
mixing zone of the microreactor, thus allowing safe control of
the reaction. The amount of polymeric components decreased
by a factor of 10 compared to batch experiments, with the
yield of the mononitro products 2 and 3 increasing corre-
spondingly. However, the amount of hydroquinone (4) and of
dinitro compounds 5 and 6 also increased. The best yield
(77%) and purity (74.6%) of nitrophenols 2 and 3 were
obtained with 1.4 equivalents of nitric acid at 208C(entry 12).
Some unreacted phenol remained at lower stoichiometries,
1
3
1
8, and 24 minutes at 20, 10, and 08C, respectively, as judged
by the heat signal. Not surprisingly, the lower the temper-
ature, the longer the time required to start the autocatalysis.
In each case, the exotherm was such that a 508Ctemperature
rise occurred. These conditions led mainly to polymer
formation and only 21–32% yield of nitrophenols 2 and 3
presumably a consequence of HNO consumption in over-
3
nitration and oxidation reactions. In contrast to the series with
acetic acid, ortho isomer 3 was slightly favored.
(
entries 9–11).
The phenol nitration without CH CO H was next inves-
The results described above indicate that higher yields of
nitrophenols are obtained when the nitration of phenol is
performed in a microreactor (both with and without
CH CO H). Enhanced heat exchange, good mixing proper-
3
2
tigated using the microreactor. The phenol concentration was
increased to 90% (feed 1) because of the difficulty to
continuously dose a liquid–liquid emulsion. The HNO3
solution (feed 2) was first diluted with water to obtain the
same concentration as in the batch experiments. Based on the
good temperature control obtained with the microreactor, the
concentration of the nitric acid solution was increased
3
2
ties, and very rapid radical propagation in a confined volume
account for this result. In addition to the small reacting
volumes present at any given time, continuous phenol
nitration in a microreactor allows for better control of the
exothermic reactions. Running the nitration under more
concentrated conditions, almost solvent-free and without
H SO or CH CO H, is important to ensure that the nitration
stepwise and commercial 65% HNO solution was finally
3
used (entries 12–20). Thus, these experiments were per-
formed solvent-free, except for the 10% water used to liquefy
the phenol and the water present in the nitric acid. The flow
2
4
3
2
takes place within the microreactor. Thus, the resulting
improved yields and enhanced process safety make micro-
À1
rate was reduced to about 8 gmin (1.6:1 split, phenol
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Angew. Chem. Int. Ed. 2005, 44, 7972 –7975

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reactor technology attractive to operate autocatalytic reac-
tions such as nitrations on an industrial scale.
Received: July 8, 2005
Published online: November 10, 2005
Keywords: autocatalysis · microreactor · nitration · oxidation ·
.
syntheticmethods
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