PAPER
High Energetic Nitration Reactions in Microreactors
2829
actant solutions were used: Solution A, compound 1 (15.0 g, 89.2
mmol) filled up with conc. H2SO4 (total volume: 150 mL). Solution
B, HNO3 (5.2 mL, 125.5 mmol) filled up with conc. H2SO4 (total
volume 150 mL). The reaction mixture was quenched at the end of
the system (ice-water) and the product was collected by filtration of
the precipitated white solid; mp 123–126 °C (Lit.5a mp 124–
127 °C). A sample of 30 mL was taken over a period of 15 min. The
product 2 was isolated in 73% yield (1.39 g from 30 mL).
11 but in an unfavourable distribution (Table 1). Howev-
er, treatment of 8 with acetyl nitrate at only 30 °C resulted
in a higher selectivity and the major products 2-nitrotolu-
ene (9) and 4-nitrotoluene (10) were obtained in improved
amounts of 54 and 39%, respectively. In contrast to meth-
od 1, the formation of the dinitrated product 13 was com-
pletely suppressed.
IR (KBr): 1339 cm–1 (NO2).
1H NMR (CDCl3, 300 MHz): = 1.0 (t, 3 H, J = 7.4 Hz), 1.7 (m, 2
H), 2.9 (t, 2 H, J = 7.7 Hz), 4.2 (s, 3 H), 12.0 (br, 1 H).
13C NMR (CDCl3, 75 MHz): = 13.8, 21.4, 29.0, 40.5, 131.0,
132.4, 149.8, 159.1.
Table 1 Product Distribution of the Nitrotoluene Isomers
8
9
10
11
12
13
–
Conventional12
Method 1
–
53.3
48.4
54.0
38.0
36.0
39.1
3.3
3.9
2.7
5.4
8.3
4.2
1.2
–
2.2
–
2-Methyl-5-nitroindole (5)
According to the general procedure the system was configured as
follow: System volume 1.2 mL, = 0.8 min, throughput 2.2 g/h,
T = 3 °C, flow rate 0.72 mL/min on each channel. The following re-
actant solutions were used: Solution A, 2-methylindole (4; 5.45 g,
41.6 mmol) filled up with conc. H2SO4 (total volume 100 mL). So-
lution B, NaNO3 (3.5 mL, 41.2 mmol) filled up with conc. H2SO4
(total volume 100 mL). A sample of the product was taken at the
product outlet (85 mL) and quenched with ice-water. A yellow solid
precipitated overnight at 4 °C. This material was filtered off and
washed with ice-water. The wet solid was dissolved in CH2Cl2 (150
mL) and the solution was washed with brine and dried (Na2SO4).
Evaporation of the solvent provided compound 5 in 70% yield (2.17
g from 85 mL) as a yellow solid in > 99% GC purity; mp 173–
174 °C (Lit.9 mp 176–176.5 °C).
Method 2
Although the reaction temperature was strictly kept at
30 °C, a throughput rate of 16.2 g/h was achieved (in the
flask experiment it took 2 h for the conversion of 4.6 g of
8). Although acetyl nitrate is known as an explosive,13
safe processing in such high starting material concentra-
tions was possible because of the low in situ concentration
of the acetyl nitrate and its immediate conversion into the
final product. It has to be pointed out that all these data re-
sult from non-optimised experiments.
Continuous operation provides an attractive approach for
handling hazardous processes and reagents in a safe man-
ner from bench to production scale. Microreactors with
enhanced heat exchange and mixing properties combined
with small reaction cell dimensions offer an excellent tool
to fulfil the requirements of these processes. Moreover,
acceleration is obtained for fast reactions delayed so far in
the flask experiment due to extensive addition times as a
result of problematic temperature control. Some of its su-
perior properties compared to batch processing have been
validated in this contribution. High throughput rates in
combination with good yields along with the utilisation of
inexpensive reagents will turn this process into an attrac-
tive tool for research and development just as for manu-
facturing applications.
IR (KBr): 1335 cm–1(NO2).
1H NMR (CDCl3, 300 MHz): = 2.5 (s, 3 H), 6.4 (s, 1 H), 7.3 (d, 1
H, J = 8.8 Hz), 8.0 (dd, 1 H, J = 8.8, 2.2 Hz), 8.35 (br, 1 H), 8.5 (d,
1 H, J = 2.2 Hz).
4-Nitropyridine-N-oxide (7)
According to the general procedure the system was configured as
follows: System volume 70 mL, = 78 min, throughput 2.2 g/h,
T = 120 °C, flow rate 0.45 mL/min on each channel. The following
reactant solutions were used: Solution A, pyridine-N-oxide (6; 50 g,
0.53 mol) filled up with conc. H2SO4 (total volume 200 mL). Solu-
tion B, HNO3 (41.5 mL, 1.0 mol) in H2SO4 (200 mL). A sample of
128 mL from the product outlet was collected in ice water (400 mL,
work-up procedure according to lit.10). The aqueous solution was
neutralised with Na2CO3 until crystals of Na2SO4 precipitated. The
solid material was filtered off and the aqueous solution was extract-
ed with CH2Cl2 (3 × 250 mL). The combined organic layers were
dried (Na2SO4) and the solvent was evaporated. Recrystallisation
from acetone provided compound 7 in 78% yield (18.51 g from 128
mL) as yellow rhombs; mp 161 °C (Lit.10 mp 159 °C).
Experiments in CYTOS Microreactors; General Procedure
The temperature inside the microreactor and the residence unit(s)
was adjusted using an external thermostat (Huber Tango). Pump A
and B of the microreaction system were calibrated to the desired
flow rates. The residence time was calculated according to the
equation: (min) = volume (mL)/total flow rate (mL/min) and the
reactants were pumped through the two inlet pipes into the microre-
action system. First samples of product were collected from the out-
let of the system after 1.5 residence times to ensure steady-state
conditions. The consistency of the flow rate was verified by measur-
ing the consumed volume of starting material on a certain period.
After finishing the sequence the system was cleaned with at least
twice the volume of solvent.
IR (KBr): 1343 cm–1 (NO2).
1H NMR (CDCl3, 300 MHz): = 8.11–8.16 (m, 2 H), 8.25–8.30 (m,
2 H).
2-Nitrotoluene (9) and 4-Nitrotoluene (10)
According to the general procedure the system was configured as
follows: System volume 70 mL, = 70 min, throughput 16.7 g/h,
T = 30 °C, flow rate 0.5 mL/min on each channel. The following re-
actant solutions were used: Solution A, toluene (8; 205 mL, 1.93
mol) in pure Ac2O (270 mL, 2.86 mol) and conc. H2SO4 (0.6 mL).
Solution B, HNO3 (neat). A sample of 3 mL each was taken at the
product outlet and quenched with ice-water (15 mL). The crude
product was extracted with dichloromethane (3×20 mL) and the
combined organic layers were dried (Na2SO4). The composition of
the mixture was analysed using gas chromatography (confirmation
by co-injection with authentic materials from commercial suppli-
1-Methyl-2-nitro-3-propyl-1H-pyrazole-5-carboxylic Acid (2)
According to the general procedure the system was configured as
follows: System volume 70 mL, = 35 min, throughput 5.5 g/h,
T = 90 °C, flow rate 1.0 mL/min on each channel. The following re-
Synthesis 2003, No. 18, 2827–2830 © Thieme Stuttgart · New York