MultiMax Appliaction Note
™
Dr. Fabio Visentin
Herbert Briggeler
Dr. Olivier Ubrich
Hydrogenation of Nitrobenzene
to Aniline
Mettler-Toledo AG, AutoChem
Mettler-Toledo AG, AutoChem
Mettler-Toledo AG, AutoChem
1. Introduction
Catalytic hydrogenation of aromatic
nitro compounds is an industrially
important process for the introduction of amino functionality into
pharmaceutical and agrochemical
intermediates and in the polyurethane 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 hydroxylamine intermediates formed are
often thermally unstable and can
disproportionate with a significant
temperature increase causing large
explosions [1].
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].
2. Apparatus
Technology that reduces the time
required for screening, optimization, characterization, and scale-up
of target compounds holds significant time-to-market value for
chemical and pharmaceutical companies and contract manufacturing
services. Automated laboratory
reactors (ALR) are essential tools
for these purposes.
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 manufacturing.
Pharmaceutical and chemical
companies are turning to this
Hydrogenation of nitro-compounds
was studied at lab scale to understand the process.
In order to access the role of mass
transfer, experiments with different stirrer speeds were performed.
Experiments with different pressure
were also done. The goal was to
define the necessary rules to run
The ALR deliver precise and repeatable 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 measuring 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 contents 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, solvent, 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 Reactor Box with Hastelloy® reactors
of 25-50 ml as a working volume
™
(part of the MultiMax family) is
™
used here. MultiMax is an automated 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 simultaneously 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 quality of the temperature control and
measurement allows the user to get
valuable information such as reac-
tion initiation, reaction end point
and relative thermal data.
™
The MultiMax intuitive software
interface has been designed for
easy experiment definitions, data
visualization as well as data
export.
3. Hydrogenation of nitrobenzene
using a MultiMax™ system
To allow reactions under pressure,
™
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 regulator 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 pressure in the reactor manually up
to 200 bar. A mass flow meter
(optionally) and a reservoir are
used to measure the hydrogen consumption (see Figure 1).
Moreover, for each pressure vessel the gassing stirrer has been
installed to improve the mass
transfer effect by pumping the gas
into the liquid phase (see Figure 3).
To improve the information content
of a single measurement of a reaction, reactors are often combined
with further analytical sensors such
as an IR-ATR probe.
METTLER TOLEDO has developed
the patented ReactIR reaction
monitoring system, which comes
in several different configurations
including a 6mm diameter probe
or a system integrated into the bottom a Hastelloy vessel [5, 6].
The probe fixed on the bottom of
the 50 ml vessel is used here in
this work. The Hastelloy reactor
vessel is also available without the
IR-ATR probe.
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.
Automatic Gas Uptake Manual Gas Uptake
LMPress60
Pressure sensor
Pressure regulating
valve
Reservoir
Reactor
RB04-50
ReactIR400
Figure 1
MultiMaxIR system with an RB04-50 Reactor B
Pressure gauge
Needle valve
for sampling and
discharging
Bent 1/4” connections
Easy closure
Optional with
DiComp sensor
Powerful stirrer motor
Pt100 sensor
Rupture disc units
- 200 bar
- 100 bar
- 30 bar
2 mm flexible tubing
Additional opening
Figure 2
Overview of one reactor with magentic coupling, sensors and IR
probe on the bottom of the reactor
Kalrez O-ring
Tube for dosing
Tube for sampling
and discharging
Tr sensor tube
Gassing stirrer
Figure 3
Configurable reactor setup
Possibility to dismantle dosing
and dip tube
Hydrogenation of Nitrobenzene
to Aniline
4. Experimental procedure
NO2
+ 3H2
35-60°C
MetOH
Pd/C 5%
2-4-6 bar
Solvent:
Methanol, 35 mL
Catalyst:
Pd/C, 5%
Substrate:
NH2
Ratio catalyst/substrate:
Stirrer speed:
+ 2H2O
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
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.
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 reaction was carried out at a constant
hydrogen pressure.
Using the Mass Flow Meter, the
software allows the user to moni-
tor the instantaneous and the total
hydrogen consumption.
Using the volumetric method to
measure the H2 uptake, the pressure and the temperature in the
reservoir have to be monitored as
shown in Figure 5.
Temperature of the reactor contents:
Pressure in the reactor:
Nitrobenzene, 3.1 g = 0.025 mol
1.25 g·mol-1
Variable, rpm
50 °C
2.4, 4 and 6.3 bar (H2, const.)
Table 1
Recipe for the hydrogenation of nitrobenzene
Figure 5
View of the evolution of the monitored signals during
the experiment.
Figure 7 instead shows the agreement between the heat flow trending and the gas consumption.
A comparison between the hydrogen uptake using the Mass Flow
Meter and the volumetric method is
shown in Figure 8. The two methods give the same result [7].
Figure 6
Totalizer integrated in the MultiMax™ software
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 stirrer 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 stirrer speed was varied from 200 to
900 rpm. This indicates the presence 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 consumption as shown in Figure 9b.
In hydrogenation reactions, the
knowledge of the influence of the
stirrer speed is crucial to understand the mixing regime of the system. 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
• reactions where the rate determining step is assumed to be
the surface reaction between the
organic substrate and H2.
Figure 8
Comparison between the H2 uptake using the Gas Flow Meter
and the hydrogen uptake using the reservoir and the concentration profile of the aniline measured by FTIR (see below).
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 relative concentration of nitrobenzene
was studied in the range of 2.4
to 6.3 bar and shown in Figure
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, indicating the possibility to optimize the
reaction by adjusting the pressure
™
conditions. The MultiMax shows
again very precise measurements:
(approximately) the same amount
of hydrogen consumed for three
different pressures is shown in
Figure 10.
Figure 9a
Effect of the change in the stirrer speed (200 to 900 rpm) on the
reaction rate of the hydrogenation of nitrobenzene
Figure 9b
Zoom of a region between 1400 and 1800 seconds. Reaction
conditions: substrate: nitrobenzene (0.025 mol); catalyst: 5%
Pd/C (~0.03 g); solvent: methanol (35 ml); pressure: ~6 bar;
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 calorimeter 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 chapter 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 reaction rates or the study of how fast
reactions occur under different
conditions. It usually includes a
study of the mechanism of reactions, which is a look at how the
reacting molecules break apart
and then form new molecules. This
knowledge allows chemists to control reactions and/or design new or
better ways to produce the desired
products.
The heat flow trending (Tr -Tj)
shows that the reaction shows
zero order behavior. The reaction
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 comparison between the integration of the
hydrogen uptake and the temperature difference Tr –Tj.
As shown in Figure 12, the two signals are comparable (overlapping).
Due to this comparison, it can be
proved again that the instrument
has high precision also under
pressure and with heterogeneous
reactions.
Figure 10
Effect of partial pressure of hydrogen (2.4, 4 and 6.3 bar) for
the hydrogenation of nitrobenzene. Reaction conditions: substrate: nitrobenzene (0.025 mol); catalyst: 5% Pd/C (~0.03 g);
solvent: methanol (35 ml); temperature: 50 °C; ratio catalyst/
substrate = 1.25 g • mol-1.
Figure 11
Effect of partial pressure of hydrogen (2.4 to 6.3 bar) on the
heat flow signal for the hydrogenation of nitrobenzene.
Reaction conditions: substrate: nitrobenzene (0.025 mol); catalyst: 5% Pd/C (~0.03 g); solvent: methanol (35 ml); pressure:
2.4 to 6.3 bar; temperature: 50 °C; ratio catalyst/substrate =
1.25 g • mol-1
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); catalyst: 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 Spectrophotometer and the ReactIR software. The
spectra were measured using an
attenuated total reflectance (ATR)
probe coupled to the spectrophotometer.
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 correspond to the NH2 bending absorption 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].
The time-dependent profiles of
the initial compound and the final
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 13
The MultiMax™ software can communicate with different instruments, including the ReactIR
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 investigate the reaction. In addition, the
reactors are completely independent of temperature controlling,
pressure and stirrer speeds.
This enables the user to investigate 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 provides some very good information 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.
7075 Samuel Morse Drive
Columbia, MD 21046, USA
Phone +1-410 910 8500
Fax
+1-410 910 8600
E-Mail: autochem.marketing@mt.com
Mettler-Toledo AG, AutoChem
Sonnenbergstrasse 74
CH-8606 Schwerzenbach, Switzerland
Phone +41-44 806 77 11
Fax
+41-44 806 72 90
E-Mail: ALR.marketing@mt.com
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 performed in order to demonstrate
the advantage and the quality of
the instrument’s measurement
™
with the MultiMax IR RB04-50
system for high pressure combined 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 pressure and stirrer speed on the initial 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 Hydrogenation 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
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 information 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.
www.mt.com/MultiMax
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