Hydrogenation of Nitrobenzene
MultiMax Appliaction Note
Dr. Fabio Visentin
Mettler-Toledo AG, AutoChem
Herbert Briggeler Mettler-Toledo AG, AutoChem
Dr. Olivier Ubrich Mettler-Toledo AG, AutoChem
1. Introduction
Catalytic hydrogenation of aromatic
nitro compounds is an industrially
important process for the introduc-
tion of amino functionality into
pharmaceutical and agrochemical
intermediates and in the polyure-
thane chemistry. Aromatic nitro
compounds are hydrogenated very
easily, and hydrogenations have
been carried out under a wide
range of conditions including the
vapor phase. They are known to
™
be potentially hazardous reactions,
especially because the hydroxyl-
amine intermediates formed are
often thermally unstable and can
disproportionate with a significant
temperature increase causing large
explosions [1].
2. Apparatus
Technology that reduces the time
required for screening, optimiza-
tion, characterization, and scale-up
of target compounds holds sig-
nificant time-to-market value for
chemical and pharmaceutical com-
panies and contract manufacturing
services. Automated laboratory
reactors (ALR) are essential tools
for these purposes.
Pharmaceutical and chemical
companies are turning to this
to Aniline
During aryl-nitro hydrogenation,
formation of the bimolecular azo
and azoxy compounds is also
possible [2]. These compounds
can be hydrogenated to arylamine
along with formation of hydrazo
compounds. The extent of azo
and azoxy formation depends on
temperature and accumulation of
arylhydroxylamine [3].
Hydrogenation of nitro-compounds
was studied at lab scale to under-
stand the process.
In order to access the role of mass
transfer, experiments with differ-
ent stirrer speeds were performed.
Experiments with different pressure
were also done. The goal was to
define the necessary rules to run
new technology to decrease time
to market while increasing their
knowledge base of the chemical
processes at earlier stages of the
development cycle.
The information gained directly
impacts the areas of process
research, organic synthesis,
process development, and manu-
facturing.
The ALR deliver precise and repeat-
able control of critical reaction
variables (temperature, stirrer
No. 03-2007
the hydrogenation experiments in
the chemical reaction regime or at
least to monitor the influence of the
mass transfer with different reaction
conditions [4].
To do this, the hydrogen uptake
was measured by two methods,
the first one using a mass flow
meter, the second one by measur-
ing the pressure drop in a small
gas reservoir where the hydrogen
was stored.
The reaction was also studied in
term of heat flow monitoring, i.e. by
monitoring the difference between
the temperature of the reactor con-
tents and the temperature of the
jacket (Tr -Tj).
speed, etc.) and automation of
routine experimental procedures
(dosing, pH control, etc.), allowing
the rapid optimization of critical
reaction variables (catalyst, sol-
vent, pressure, dosing rate, etc.).
Thanks to integrated real-time
analytics, the reaction behavior
can be observed at each moment
without taking samples.
Experiments can be run on scales
from as little as 25 mL during the
characterization phase.
Hydrogenation of Nitrobenzene
to Aniline
™
The MultiMax RB04-50 Reac-
tor Box with Hastelloy® reactors
of 25-50 ml as a working volume
™ Pressure sensor
(part of the MultiMax family) is
™
used here. MultiMax is an auto-
mated parallel reactor system,
designed for process screening and
optimization. It allows increasing
the productivity while taking benefit
from precise, reproducible and
documented experiments.
™
MultiMax is very versatile so
that a wide range of experiments
can be performed. It features the
temperature control of the reaction
mixture and jacket simultane-
ously as well as multiple dosing,
magnetic or mechanical stirring,
pH, volumetric and gravimetric
dosing controls. Each reactor is
independent from the other, offering
enhanced flexibility. The high qual-
ity of the temperature control and
measurement allows the user to get
valuable information such as reac-
3. Hydrogenation of nitrobenzene
using a MultiMax™ system
To allow reactions under pressure,
™ Tube for sampling
the MultiMax system is provided
with an automatic gas uptake
system (A10 and A60) or with a
manual gas uptake system (M30,
M100 and M200).
The automatic gas uptake is
provided with a pressure regula-
tor LMPress10 (up to 10 bar) or
LMPress60 (up to 60 bar) that
allows controlling the pressure
in the reactor automatically. The
manual pressure regulator instead,
allows the user to control the pres-
sure in the reactor manually up
tion initiation, reaction end point Automatic Gas Uptake Manual Gas Uptake
and relative thermal data.
™ LMPress60
The MultiMax intuitive software
interface has been designed for
easy experiment definitions, data Pressure regulating
valve
visualization as well as data
export. Reservoir
Reactor
To improve the information content
RB04-50
of a single measurement of a reac-
tion, reactors are often combined ReactIR400
with further analytical sensors such
Figure 1
as an IR-ATR probe.
MultiMaxIR system with an RB04-50 Reactor B
METTLER TOLEDO has developed
the patented ReactIR reaction
monitoring system, which comes Pressure gauge Powerful stirrer motor
Pt100 sensor
in several different configurations Needle valve
for sampling and
including a 6mm diameter probe discharging
Rupture disc units
- 200 bar
or a system integrated into the bot- Bent 1/4” connections - 100 bar
- 30 bar
tom a Hastelloy vessel [5, 6]. Easy closure
The probe fixed on the bottom of 2 mm flexible tubing
Optional with
the 50 ml vessel is used here in DiComp sensor Additional opening
this work. The Hastelloy reactor Figure 2
vessel is also available without the Overview of one reactor with magentic coupling, sensors and IR
probe on the bottom of the reactor
IR-ATR probe.
to 200 bar. A mass flow meter Kalrez O-ring
(optionally) and a reservoir are Tube for dosing
used to measure the hydrogen con-
sumption (see Figure 1). and discharging
Moreover, for each pressure ves-
Tr sensor tube
sel the gassing stirrer has been Possibility to dismantle dosing
installed to improve the mass Gassing stirrer and dip tube
transfer effect by pumping the gas Figure 3
Configurable reactor setup
into the liquid phase (see Figure 3).
The inserts can be dismantled
individually. Stirrer blades with
larger dimensions can be used,
too. The stirrer has been designed
in such a way that even at high
liquid levels a significant gas mass
transfer is guaranteed.
Hydrogenation of Nitrobenzene
to Aniline
4. Experimental procedure
NO2
35-60°C
MetOH
+ 3H2
Pd/C 5%
2-4-6 bar
The reactor was filled initially with
35 mL of methanol, 0.03 mg of
5 % Pd/C and 3.1 g (0.0252 mol)
of nitrobenzene.
The desired reaction temperature
was set to 50 °C, and as soon as
the set temperature was reached,
to start the reaction two ways were
followed: adding the hydrogen in
the reactor at the desired pressure
5. Results and discussion
5.1 Hydrogen uptake
The reaction was monitored by
measuring the consumption of
the hydrogen using a Mass Flow
Meter (see Figure 6 and 12) and by
measuring the pressure drop in the
reservoir used to feed hydrogen to
the reactor (volume of 150 mL and
maximum pressure of 250 bar, see
Figure 1 and 7).
A comparison is shown in Figure
8. It may be noted that the reac-
tion was carried out at a constant
hydrogen pressure.
Using the Mass Flow Meter, the
software allows the user to moni-
Solvent: Methanol, 35 mL
Catalyst: Pd/C, 5%
Substrate: Nitrobenzene, 3.1 g = 0.025 mol
NH2
Ratio catalyst/substrate: 1.25 g·mol-1
Stirrer speed: Variable, rpm
+ 2H2O Temperature of the reactor contents: 50 °C
Pressure in the reactor: 2.4, 4 and 6.3 bar (H2, const.)
Table 1
Recipe for the hydrogenation of nitrobenzene
or increasing the stirrer speed up to
1200 rpm.
As Figure 5 shows, the software
allows monitoring eight signals at
the same time in a graph.
Here, the most relevant signals are
displayed: (Tr - Tj), pressure of the
reactor, pressure of the reservoir,
temperature of the reservoir and the
H2 uptake.
tor the instantaneous and the total Figure 5
View of the evolution of the monitored signals during
hydrogen consumption. the experiment.
Using the volumetric method to
measure the H2 uptake, the pres-
sure and the temperature in the
reservoir have to be monitored as
shown in Figure 5.
Figure 7 instead shows the agree-
ment between the heat flow trend-
ing and the gas consumption.
A comparison between the hydro-
gen uptake using the Mass Flow
Meter and the volumetric method is Figure 6
Totalizer integrated in the MultiMax™ software
shown in Figure 8. The two meth-
ods give the same result [7].
Figure 7
Monitoring of the pressure in the reservoir and the pressure in
the reactor
Hydrogenation of Nitrobenzene
to Aniline
5.2 Mass transfer effects
Influence of the stirrer speed
(external diffusion)
In order to assess the role of the
external mass transfer on the
reaction rate, the effect of the stir-
rer speed was studied. The stirrer
speed was varied from 200 to
900 rpm (see Figure 9). The overall
effect of an increasing stirrer speed
is that the rate of the reaction
increases.
This trend can be explained by an
increase of the H2 absorption in the
liquid phase with increasing stirrer
speed. By this the mass transfer
increases, too.
As it can be seen in Figure 9, a
significant change in the rate of
reaction occurred when the stir-
rer speed was varied from 200 to
900 rpm. This indicates the pres-
ence of the mass transfer limitation
for the diffusion of hydrogen from
the gas-liquid interface to the bulk
liquid and subsequently to the
external surface of the catalyst.
™
The MultiMax is a very precise
instrument. It allows the user to see
small variations in the gas con-
sumption as shown in Figure 9b.
In hydrogenation reactions, the
knowledge of the influence of the
stirrer speed is crucial to under-
stand the mixing regime of the sys-
tem. In order to optimize the reac-
tion conditions (catalyst, catalyst
loading, pressure, temperature …),
a distinction has to be made
between
• reactions limited by the mass
transfer and
Figure 8
• reactions where the rate deter- Comparison between the H2 uptake using the Gas Flow Meter
mining step is assumed to be and the hydrogen uptake using the reservoir and the concentra-
tion profile of the aniline measured by FTIR (see below).
the surface reaction between the
organic substrate and H2.
Therefore, the stirrer speed plays
a fundamental role to distinguish
between mass transfer limitation
and process optimization.
5.3 Pressure effects
The effect of a change in partial
pressure of hydrogen on the rela-
tive concentration of nitrobenzene
was studied in the range of 2.4 Figure 9a
to 6.3 bar and shown in Figure Effect of the change in the stirrer speed (200 to 900 rpm) on the
reaction rate of the hydrogenation of nitrobenzene
10. When the hydrogen pressure
was increased, the rate of reaction
increased, too.
Figure 10 shows that when the
pressure was changed from 2.4 to
6.3 bar, a significant change in the
rate of reaction occurred, indicat-
ing the possibility to optimize the
reaction by adjusting the pressure
™
conditions. The MultiMax shows
again very precise measurements:
(approximately) the same amount Figure 9b
of hydrogen consumed for three Zoom of a region between 1400 and 1800 seconds. Reaction
conditions: substrate: nitrobenzene (0.025 mol); catalyst: 5%
different pressures is shown in Pd/C (~0.03 g); solvent: methanol (35 ml); pressure: ~6 bar;
Figure 10. temperature: 50 °C; ratio catalyst/substrate = 1.25 g • mol-1
Hydrogenation of Nitrobenzene
to Aniline
5.4 The heat flow trending of the
reaction
Preliminary information of the heat
flow trending of the reaction is
given by the difference between Tr
and Tj where Tr is the temperature
of the reactor contents and Tj the
temperature of the jacket (Tr - Tj).
The heat flow trending can be seen
as a “rate meter” [8]. It allows the
user to have a qualitative overview
of the reaction kinetics. To get
quantitative information, one needs
to perform experiments with a calo-
rimeter with high performances. A
reactor with these requirements is
the METTLER TOLEDO RC1.
The profiles shown in Figure 11
represent the typical profiles of the
heat of reaction for hydrogenations
of nitro groups. The experiments
are the same as described in chap-
ter 5.3 where the hydrogen uptake
at different pressures is shown (see
Figure 10).
The Tr - Tj profile shows, as first
result, the start and the end of the
reaction and its shape gives an
overview of the reaction kinetics.
Kinetics is the study of the reac-
tion rates or the study of how fast
reactions occur under different
conditions. It usually includes a
study of the mechanism of reac-
tions, which is a look at how the
reacting molecules break apart
and then form new molecules. This
knowledge allows chemists to con-
trol reactions and/or design new or
better ways to produce the desired
products.
Figure 10
Effect of partial pressure of hydrogen (2.4, 4 and 6.3 bar) for
The heat flow trending (Tr -Tj) the hydrogenation of nitrobenzene. Reaction conditions: sub-
shows that the reaction shows strate: nitrobenzene (0.025 mol); catalyst: 5% Pd/C (~0.03 g);
solvent: methanol (35 ml); temperature: 50 °C; ratio catalyst/
zero order behavior. The reaction substrate = 1.25 g • mol-1.
rate is therefore independent of
the concentration of reactant and
accumulation of nitrobenzene is
observed. The reaction is therefore
not dosing-controlled. Doubling the
concentration has no effect on the
reaction rate.
An interesting result is the compari-
son between the integration of the
hydrogen uptake and the tempera-
Figure 11
ture difference Tr –Tj.
Effect of partial pressure of hydrogen (2.4 to 6.3 bar) on the
heat flow signal for the hydrogenation of nitrobenzene.
As shown in Figure 12, the two sig- Reaction conditions: substrate: nitrobenzene (0.025 mol); cata-
lyst: 5% Pd/C (~0.03 g); solvent: methanol (35 ml); pressure:
nals are comparable (overlapping). 2.4 to 6.3 bar; temperature: 50 °C; ratio catalyst/substrate =
Due to this comparison, it can be 1.25 g • mol-1
proved again that the instrument
has high precision also under
pressure and with heterogeneous
reactions.
Figure 12
Comparison between the measurements done with the Mass
Flow Meter (gas flow) and the difference of Tr-Tj (heat flow).
Reaction conditions: substrate: nitrobenzene (0.025 mol); cata-
lyst: 5% Pd/C (~0.03 g); solvent: methanol (35 mL); stirrer
speed: 900 rpm; pressure: 2.4 to 6.3 bar; temperature: 50 °C;
ratio catalyst/substrate = 1.25 g • mol-1.
Hydrogenation of Nitrobenzene
to Aniline
5.5 IR measurements
As mentioned previously and
shown in Figure 1, the MultiMax™
system is provided with an FTIR.
The spectrophotometer is directly
™
connected in the MultiMax
software as shown in Figure 13
™
(MultiMax IR ).
The IR spectra were acquired using
the ReactIR4000 Spectrophotom-
eter and the ReactIR software. The
spectra were measured using an
attenuated total reflectance (ATR)
probe coupled to the spectropho-
tometer.
The spectra were measured in the
range of 1100 to 1800 cm-1. The
peak at 1505 cm-1 corresponds
to the C-H bending, the peaks at
1605 cm-1 and 1630 cm-1 corre-
spond to the NH2 bending absorp-
tion of aniline, the peak at 1530
cm-1 to the NO2 asymmetric stretch
absorption, and the peak at 1350
cm-1 to the NO2 symmetric stretch
absorption of nitrobenzene. All
these peaks were chosen to follow
the reaction (see Figure 14) [4, 7].
Figure 13
The time-dependent profiles of The MultiMax™ software can communicate with different instru-
the initial compound and the final ments, including the ReactIR
product can be estimated using
the ConcIR software. This software
uses the principle component
analysis to extract the relative
concentration and the pure spectra
(see Figure 8).
Figure 14
Part of the IR spectrum recorded as a function of time during the
hydrogenation of nitrobenzene at 50 °C. The peaks indicated at
1530 and 1350 cm-1 were used to determine the decreasing
concentration of nitrobenzene and the peaks indicated at 1505,
1605 and 1630 cm-1 were used to determine the increasing
concentration of aniline during the hydrogenation reaction.
Hydrogenation of Nitrobenzene
to Aniline
6 Conclusions
™
The MultiMax RB04-50 Reactor
Box (four reactors of 50 mL each)
has been used to investigate the
hydrogenation of nitrobenzene.
The main advantage of these
reactors is the small amount of
compounds necessary to investi-
gate the reaction. In addition, the
reactors are completely indepen-
dent of temperature controlling,
pressure and stirrer speeds.
This enables the user to investi-
gate more than one parameter at
the same time and logging all
the data.
It has been shown that even at the
50 mL scale the hydrogenation
can be investigated in details.
™
The MultiMax experiment pro-
vides some very good informa-
tion related to kinetics and mass
transfer.
7 References
[1] Tong W. R., Seagrave R. L.,
Wiederhorn R., 3,4-Dichloroaniline
autoclave incident.
Loss Prevention. 1977, 11, 71-75.
[2] Kosak J. R. Hydrogenation of
nitroarenes - The hydroxylamine
intermediate. Catalysis of Organic
Reactions, edited by Rylander P. N.,
Greenfield H. and Augustine R. L.,
Marcel Dekker. 1988.
[3] Rains R. K., Lambers E. A.; Genetti R.
A., Hydrogenation of nitroarenes –
the effect of ring substituents on
hydroxylamine accumulation.
Mettler-Toledo AutoChem Inc.
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Phone +1-410 910 8500
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Subject to technical changes.
©05/2007 Mettler-Toledo AG
Printed in Switzerland
Marketing RC/ALR
Three-phase reactions under
pressure such as hydrogenations
of nitrobenzene have been per-
formed in order to demonstrate
the advantage and the quality of
the instrument’s measurement
™
with the MultiMax IR RB04-50
system for high pressure com-
bined with a real-time FTIR
spectrophotometer.
The rate of hydrogenation of
nitrobenzene to aniline over a 5%
Pd/C catalyst in a three-phase
reaction at 50 °C is strongly
influenced by the intraparticle
mass transfer as well as by the
gas-liquid and liquid-solid mass
transfer.
Therefore, the effects of H2 pres-
sure and stirrer speed on the ini-
tial rates were discussed to asses
the role of mass transfer.
Chemical Industries (Dekker).
Catalysis of Organic Reactions.
1996, 68, 43-52.
[4] Visentin F., Kinetic Study of Hydro-
genation Reactions of Aromatic Nitro
Compounds Using a New Pressure
Resistant Reaction Calorimeter
Combined with a FTIR-ATR Device.
Diss. ETH, Zurich, 2005.
[5] ReactIRTM iC10, ReactIRTM 4000,
MultiMaxIRTM, http://www.mt.com/
AutoChem (Mettler Toledo).
[6] Visentin F., Gianoli S. I.; Kut O. M.,
Hungerbühler K., A Pressure-Resistant
Small-Scale Reaction Calorimeter That
www.mt.com/MultiMax
The hydrogen uptake and the heat
flow trending (Tr -Tj) have also
been used to characterize the
chemical reaction.
The heat flow trending (Tr -Tj)
shows as a first qualitative result
that accumulation of reagent
takes place, i.e. the reaction in not
dosing-controlled.
Moreover, to improve the infor-
mation content of a single
measurement of a reaction, the
™
MultiMax has been combined
with an IR-ATR probe per vessel.
The absorbance spectra for all
the components of the reaction
have therefore been acquired and
studied.
The Hastelloy vessels are easily
exchangeable and available with
and without the IR-ATR probe.
Combines the Principles of Power
Compensation and Heat Balance
(CRC.v4). Organic Process Research
& Development. 2004, 8, 725-737.
[7] Visentin F., Puxty G., Kut O. M.,
Hungerbühler K., Study of the
Hydrogenation of Selected Nitro
Compounds by Simultaneous
Measurements of Calorimetric, FT-IR,
and Gas-Uptake Signals. Ind. Eng.
Chem. Res. 2006, 45, 4544-4553.
[8] Hawkins Joel, Heat Flow Profiling as
a Tool for Process Optimization: Tr–Tj
as a «Rate Meter» for Every Flask.
MT User Forum, Newport. 2002.
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