FAST Hydrogenations as a Continuous Platform for Green Aromatic Nitroreductions

Article abstract of DOI:10.1055/s-0037-1610751

A continuous-flow packed-bed catalytic reactor has been developed for hydrogenation of aromatic nitrobenzoic acids in water to produce the corresponding anilines. These hydrogenations are green, more efficient, less consumptive, and safer than the conventional reduction process. Various industrially important aromatic amines have been produced in excellent yields and with high throughput. The optimized continuous-flow reduction process produces no detectable genotoxic intermediates, unlike the corresponding batch reduction. The reactor is modular in design and can be scaled up to produce several kilograms of product per day without extensive redesign.

Full text of DOI:10.1055/s-0037-1610751

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M. T. Rahman et al.
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FAST Hydrogenations as a Continuous Platform for Green Aromatic
Nitroreductions
MD Taifur Rahmana,b
Scott Wharrya
PNBA
COOH
H2
5–10 bar)
MFC
Megan Smyth*a
Haresh Manyar*b
0
0
0
0-0
0
0
2-2
7
7
1-0
3
8
2
(
NO2
Thomas S. Moodya,c
a
Almac Sciences Ltd., 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, UK
megan.smyth@almacgroup.com
Theoretical and Applied Catalysis Research Cluster, School of Chemistry
and Chemical Engineering, Queen’s University Belfast, David Keir Building,
Stranmillis Road, Belfast, BT9 5AG, UK
5
% Pd-C
Packed-bed
6–21 cm
80 °C
b
h.manyar@qub.ac.uk
Arran Chemical Company, Unit 1 Monksland Industrial Estate, Athlone, Co.
Roscommon, Ireland
PABA
COOH
c
Excess
H2
G/L
BPR
Published as part of the ISySyCat2019 Special Issue
MFC = mass flow controller
G/L = gas-liquid separator
BPR = back-pressure
NH2
Received: 03.12.2019
Accepted after revision: 27.01.2020
Published online: 13.02.2019
this laboratory-scale flow rig. A complementary rig offers
direct scale up to a larger packed-bed reactor capable of a
throughput of up to 10 kg/week. The critical factors for the
design of a custom flow rig for nitro reductions and the pro-
cess-development considerations from PoC to manufacture
are highlighted. The versatility of the flow hydrogenation
rig has been demonstrated by using aromatic nitrobenzoic
acid substrates, exploiting their acid functionality to facili-
tate water-mediated processing to produce the correspond-
ing aminobenzoic acid. This method has also resulted in
critical control over the formation of genotoxic impurities
DOI: 10.1055/s-0037-1610751; Art ID: st-2019-b0646-c
Abstract A continuous-flow packed-bed catalytic reactor has been de-
veloped for hydrogenation of aromatic nitrobenzoic acids in water to
produce the corresponding anilines. These hydrogenations are green,
more efficient, less consumptive, and safer than the conventional
reduction process. Various industrially important aromatic amines have
been produced in excellent yields and with high throughput. The opti-
mized continuous-flow reduction process produces no detectable
genotoxic intermediates, unlike the corresponding batch reduction.
The reactor is modular in design and can be scaled up to produce sever-
al kilograms of product per day without extensive redesign.
(
GTIs), which is of pronounced importance in the manufac-
3
ture of active pharmaceutical ingredients (APIs).
Keywords green chemistry, catalytic hydrogenation, continuous-flow
packed-bed reactor, nitrobenzoic acids, anilines
Aminobenzoic acids and their derivatives belong to an
important class of chemicals that are relevant in the phar-
4
maceutical, dye, and flavour and fragrance industries. Cat-
Approximately 25% of marketed drugs require at least
one hydrogenation step in their manufacturing process.1
Flow-mediated hydrogenation offers many advantages over
conventional batch processing, including increased safety
due to the small dosage of hydrogen, improved temperature
alytic hydrogenation of nitrobenzoic acids is a direct and
straightforward way of accessing these aniline derivatives.
5
However, nitrobenzoic acids and the resulting aminobenzo-
ic acids have limited solubility in alcohols (ethanol, methyl-
ated spirits, isopropyl alcohol, etc.), which are economic
and process-friendly solvents.6 Poor solubility of starting
materials, products, and any intermediates or byproducts
formed in a synthetic process is one of the most formidable
challenges in implementing continuous-flow technology
for any process chemistry and for scale up. Precipitation of
any reaction component can lead to clogging of a flow reac-
tor, back-pressure build-up, and eventual process failure. To
maximize throughput from the process, the reaction con-
centration should be as high as possible while sufficient
2
control, and reduced solvent volumes. It also results in im-
proved substrate–gas–catalyst interactions, the ability to
achieve stringent reaction control, and minimal byproduct
formation (offering the potential for removal of purification
steps).
A custom-built packed-bed flow hydrogenation rig,
suitable for proof-of-concept (PoC) studies and low-kilo-
gram levels of manufacture has been designed and built.
The PoC hydrogenations reported here were carried out on
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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M. T. Rahman et al.
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solubility is ensured. In this work, the presence of the car-
boxylic acid moiety provides adequate solubility in aqueous
alkaline solutions. This has two benefits for processing, in
permitting the use of a high-concentration reaction feed-
stock and the use of water as a green and economical sol-
vent. Counter to that, the use of an aqueous medium has a
drawback in catalytic hydrogenation in that H has a lower
2
solubility in water than in more-conventional organic sol-
vents; for example, the solubility of hydrogen in water is
least one order of magnitude lower than that in acetonitrile
7
or ethanol. In addition, the presence of a base (NaOH) fur-
7
ther reduces the solubility of hydrogen. Hence, aqueous-
phase hydrogenations of nitrobenzoic acids under alkaline
conditions require an elevated hydrogen pressure, which
can create gas–liquid mass-transfer limitations when the
reaction is scaled up, due to lowering of the gas–liquid con-
tact area-to-volume ratio.
Considering these factors, we used Almac’s flow-assist-
ed synthesis technology (FAST) platform to demonstrate the
catalytic hydrogenation of nitrobenzoic acids in aqueous
solutions at low H pressures. Model substrates were select-
Scheme 1 Catalytic p-nitrobenzoate reduction mechanism
2
ed that are industrially relevant, namely p-, o-, and m-nitro-
benzoic acids. Derivatives of the resulting aminobenzoic
acids are used as dermatological drugs and as local anaes-
thetics, as well as in the dye industry and in pharmaceuti-
the lower concentration of hydrogen in the solution phase
(Figure 3). From analysis of the batch experiments, a key
observation was that despite the complete consumption of
7
4,8
cals (Figure 1).
Figure 1 Model substrates for flow hydrogenations
Batch Investigations
To establish process parameters and generate reference ma-
terials, the hydrogenation was first performed in a conven-
tional autoclave reactor. 30 mL of an aqueous solution of p-
nitrobenzoic acid (PNBA; 2.5 g, 0.5 M) and NaOH (0.695 g,
0
.58 M) was hydrogenated at 10 bar H pressure and 80 °C
2
at various catalyst loading (wtcatalyst/wtsubstrate%: 2, 4 and 8
9
wt/wt %). Further experimental details are provided in the
Supporting Information. The reaction mixture was periodi-
1
cally sampled and then analyzed by H NMR spectroscopy
to determine the percentage conversion of PNBA and the
percentage yield of the product and associated intermedi-
ates (Scheme 1). The rate of conversion of PNBA increased
linearly with increasing loading of the palladium catalyst
3
(
g/cm ) in the reaction mixture, indicating an absence of
external mass-transfer resistance (Figure 2).
When the hydrogen pressure was reduced from 10 bar
to 5 bar with an 8 wt/wt% catalyst loading, the conversion
of PNBA proceeded at a much slower rate, possibly due to
Figure 2 Effect of the catalyst loading on the conversion of PNBA
under 10 bar of hydrogen pressure
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PNBA, which occurred at 10 and 20 minutes at hydrogen
pressures of 10 and 5 bar, respectively, this did not correlate
to 100% product formation. H NMR spectroscopy showed
that significant amounts of the reaction intermediates 4, 5,
and 6 (Scheme 1), which are potential GTIs, were present
along with the target product, PABA.
hydrogen pressure (5 bar), the reaction mixture contains
more GTIs at all conversion levels of PNBA than observed in
the reaction performed at 10 bar hydrogen pressure (Figure
3). At a larger scale, gas–liquid–solid mass transfer will be a
decisive factor in the production of high-purity amines if
the formation of GTIs is to be avoided.
1
Another important economic aspect of catalytic hydro-
genations is the necessity for an expensive transition-metal
catalyst, such as palladium or platinum. Flow hydrogena-
tions offer a number of advantages in this respect. Investi-
gations into catalyst recovery and reuse were carried out in
experiments with 200 mg of 5 wt% Pd/C (8 wt/wt% catalyst
loading). The rate of PNBA conversion with recycled catalyst
was similar when compared with the reaction using fresh
catalyst (Figure 4). However, the rate of formation of the
PABA product with fresh catalyst was significantly higher
than that with recycled catalyst. With recycled catalyst,
faster accumulation and slower conversion of intermediates
4, 5, and 6 contributed to lower yields of the PABA product,
even at higher percentage conversions to PABA; further
details are provided in the Supporting Information.
Figure 3 Pressure effect on conversion and yield under batch conditions
Nitro-to-amine reduction through catalytic hydrogena-
tion is a well-studied reaction for nitroaromatic com-
10
pounds. The reaction proceeds by one of the two path-
ways, as shown in Scheme 1. Pathway 1 proceeds via the ni-
troso compound 2 and the hydroxylamine intermediate 3
to give the product 7. Pathway 2 involves condensation of
nitroso compound 2 with the hydroxylamine 3 to give
azoxy derivative 4, which undergoes successive hydrogena-
tions to produce azo compound 5, hydrazo compound 6,
and, finally, the amine product 7.
Figure 4 Catalyst recycling under batch conditions
In the batch experiments for conversion of PNBA to
PABA, analysis of products in the liquid phase indicated that
the reaction proceeds through the second pathway, with
Excellent multiphase mass transfer and mixing are attri-
butes of continuous-flow chemistry in general and for gas–
liquid–solid reactions in particular.11 In continuous-flow
catalytic reactions, catalysts are generally packed in car-
tridge-type beds for continuous operation, regeneration,
and reuse. Under typical reaction conditions, a mixture of
reactive gas and liquid flowing through a packed-bed reac-
tor assumes a trickle-flow behaviour. This results in a thin
liquid film that is in contact with solid catalyst particles and
in tandem flow with the gas layer. This configuration per-
mits rapid diffusion of the gas into the thin film of liquid,
resulting in rapid mixing of the dissolved gas, substrate, and
catalyst, and consequently a faster reaction rate.12
evidence of all three intermediates (4, 5, and 6), but neither
1
2
nor 3 was detectable by H NMR. Condensation of 2 and 3
to produce an azoxy derivative is an irreversible process
and is facilitated by basic conditions in the reaction mix-
4a
ture. Since the second pathway requires a total of 4.5
equivalents of hydrogen (in comparison to the nitroso–
hydroxylamine route, which requires 3 equivalents), the equi-
librium hydrogen concentration in the reaction mixture not
only dictates the overall reaction rate, but also contributes
in the build-up of GTIs in the reaction mixture. At a lower
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M. T. Rahman et al.
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Flow Investigations
After characterization of the reactor, model flow reac-
tions were carried out at hydrogen pressures of 5 and
The reduction of nitro moieties should benefit from rapid
hydrogen transfer from the gaseous phase to an aqueous
phase and the more rapid saturation of the aqueous phase
with hydrogen. This should facilitate faster (higher produc-
tivity) conversion of the substrate in a continuous-flow set-
up. The FAST hydrogenation rig (Figure 5) was used with
hydrogen (5 or 10 bar) gas metered by a mass flow control-
ler (MFC) and mixed at a T-mixer with a 0.5 M aqueous
solution of PNBA delivered to the system by a HPLC pump.
The resulting gas–liquid mixture trickled down a packed-
bed column (1.0 g of 5% Pd/C catalyst and 5.9 g of 212–300
1
0 bar (Figure 6). A 0.5 M aqueous solution of PNBA with
0.58 M NaOH was injected through the packed bed (6 cm
length) at 80 °C and various flow rates from 0.5 to 5.0
mL/min. At slower liquid flow rates (0.5 or 1.0 mL/min),
complete conversion of PNBA to PABA was achieved at both
5 and 10 bar of hydrogen pressure. When the flow rate was
increased, the PNBA conversion gradually fell. At slower
liquid flow rates, PNBA spent a sufficient residence time in
contact with the catalyst and hydrogen gas to ensure
complete conversion into the product PABA.

m glass beads) housed in a stainless-steel tube that was
externally heated to maintain a constant reaction tempera-
ture. A back-pressure regulator (BPR) fitted downstream
maintained the target pressure inside the catalyst bed. A
gas-liquid separator permitted ready separation of the reac-
tion solution from unused hydrogen gas as an effluent. The
reaction mixture was subsequently separated and analyzed
offline to monitor the progress of the reaction.13
Figure 6 PABA yield obtained relative to flow rates
1
Under continuous flow, H NMR analysis of the reaction
samples showed that only two reaction components were
predominantly present: PNBA and PABA. At faster flow
rates, such as 3 or 5 mL/min, <5% of intermediates 4 and 5
were observed at relative conversions of 22 and 42%, re-
spectively. At flow rates of 2.0 or 0.5 mL/min, when 85 and
1
00% conversion was achieved, only traces of intermediates
14
or no intermediates were observed (Figure 7). This indi-
cates that the hydrogenation follows the same pathway as
the batch reaction, but with much faster subsequent con-
version of intermediates into PABA. Note that the reaction
in a batch process (300 mg 5% Pd/C catalyst; 12 wt/wt% cat-
alyst loading) showed the presence of significant amounts
of intermediates at comparable conversions of PNBA after 2,
6, 8, or 10 minutes of reaction time: percentage conversion
Figure 5 FAST hydrogenation flow rig. MFC = mass flow controller; G/L
=
gas–liquid separator; BPR = back-pressure regulator.
(percentage intermediate) = 22% (11%), 42% (19%), 85%
51%), and 100% (57%), respectively. The observed differenc-
(
A residence-time distribution (RTD) study was per-
es in the composition of the reaction mixture indicates that
under continuous flow, the aqueous phase is saturated with
sufficient hydrogen to convert any intermediates formed
during the residence time into the final amine product,
whereas under batch conditions, a lack of sufficient of hy-
drogen in the solution phase results in the accumulation of
intermediates over time.
formed by injecting 50 L of p-aminobenzoic acid (0.5 M) as
a tracer through the packed bed (6 cm length) along with
aqueous NaOH solution (2 mL/min) under 10 bar of hydro-
gen pressure at 80 °C. The effluent solution was collected
and analyzed by UV–vis spectroscopy; details of the RTD
analysis are provided in the Supporting Information. The
mean residence time was determined to be 6.6 minutes.
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M. T. Rahman et al.
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continued control over the formation of intermediates. The
robustness of the flow protocol developed was also demon-
strated for meta- and ortho-substituents, m-aminobenzoic
acid (MABA) and anthranilic acid both being obtained in
quantitative yields and without the presence of any detect-
able intermediates.
Figure 7 Comparison between flow and batch conditions at compara-
ble conversion levels of PNBA (approximately 20, 40, 85, and 100%)
To demonstrate the robustness of the flow system and
the catalyst bed for long-term efficient operation over an
extended period of time, a continuous operation was car-
ried out over six hours. In comparison with the batch pro-
cess, the confined catalyst packed bed showed undimin-
ished activity over six hours of continuous operation at 10
bar hydrogen pressure and 0.5 mL/min flow of 0.5 M PNBA
Figure 9 Scaling up of the FAST hydrogenation of nitrobenzoic acids
In conclusion, the benefits of FAST hydrogenations with
an environmentally favourable aqueous protocol have been
demonstrated by using a custom-built packed-bed flow rig.
This flow system gave superior results to those achieved
under batch conditions in terms of both productivity and
minimization of GTI formation. The robustness of this flow-
mediated hydrogenation has been shown by its application
to a range of ortho-, meta-, and para-substituted benzoic
acid substrates under aqueous alkaline conditions. The use
of water increased the product yield, lowered impurity lev-
els, and maximized the utilization of hydrogen gas, afford-
ing a greener and safer chemical process.
(Figure 8). In this process, samples collected at regular
intervals showed quantitative conversion, with no GTIs
identified in the product solution.
Funding Information
The authors gratefully acknowledge the financial support from Inno-
vate UK under the Knowledge Transfer Partnership (KTP) programme
for KTP Associate funding for MDTR for the project ‘Flow-mediated
Figure 8 Catalyst packed-bed stability study with the FAST hydrogena-
tion rig
Amine Synthesis Technology Platform’.
I
n
n
o
v
ate
U
K
(K
T
P
0
1
1
4
3
8)
The system was then scaled up with a packed bed three
times larger, as shown in Figure 9. In the larger packed bed,
the flow rate could be quadrupled to 2 mL/min and a quan-
titative conversion of PNBA into PABA was observed with
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610751.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
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References and Notes
known amount of DMSO as an external standard, and filtered
through a syringe filter to remove any suspended catalyst. The
percentage conversion of PNBA and the percentage yields of p-
aminobenzoic acid (PABA) and its various intermediates were
(
(
(
1) (a) Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.; Benaglia, M. Org.
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quantified by means of H NMR analysis. Reference samples for
(c) Russell, C. C.; Baker, J. R.; Cossar, P. J.; McCluskey, A. In New
PNBA and PABA were prepared from commercially available
HPLC-grade reagent samples. Intermediates 4, 5, and 6,
observed in the reaction mixtures, were subsequently isolated
and synthesized by separate batch reactions, as described in the
Supporting Information. Quantitative analysis of these interme-
diates in the batch reaction mixtures was performed by com-
parison with these authentic samples.
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cations; IntechOpen: London, 2017, 269; DOI: 10.5772/65518.
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12) (a) Ranade, V. V.; Chaudhari, R. V.; Gunjal, P. R. Trickle Bed Reac-
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9, 4343. (c) Pandarus, V.; Ciriminna, R.; Beland, F.; Pagliaro, M.
The construction of the packed-bed reactor and its associated
gas- and liquid-feed lines, gas–liquid separators, etc., are
described in the Supporting Information. For a flow experi-
ment, the reactor was primed with a continuous flow of 0.58 M
NaOH solution under 10 bar of hydrogen pressure. The gas flow
rate was measured by using bubble flowmeter; the average flow
rate under atmospheric conditions was 83 mL/min. The gas and
liquid flow were kept under 10 bar pressure for 30 min to equil-
ibrate the gas–liquid flow inside the packed bed and to stabilize
the gas–liquid flow through the packed bed of 5% Pd/C. The
liquid flow was then stopped and the packed bed was sealed by
closing the upstream and downstream one-way valves to main-
tain a 10 bar hydrogen pressure at 80 °C to prereduce the cata-
lyst. After 2 h of prereduction of the catalyst, the valves were
opened and hydrogen flow was maintained along with the
desired flow rate of the PNBA solution (0.5 M in 0.58 M NaOH aq
solution). The initial reaction mixture (three times the internal
volume of the packed-bed reactor column) collected at the gas–
liquid separator was discarded. The subsequent mixtures, after
flow equilibration and attainment of a steady state, were col-
(
(
3
Catal. Sci. Technol. 2011, 1, 1616.
(
7) (a) Khan, M.; Joshi, S.; Ranade, V. Chem. Eng. J. (Amsterdam,
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8) (a) Vardanyan, R. S.; Hruby, V. J. Synthesis of Essential Drugs;
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Davies, D. J. G. J. Invest. Dermatol. 1982, 79, 354.
(9) Batch Hydrogenation of p-Nitrobenzoic Acid
The batch reactions were all performed in a 100 mL stainless-
steel stirred-tank reactor (Autoclave Engineers, Erie, PA). In a
typical reaction, the reactor was charged with 5 wt% Pd/C cata-
lyst (0.02 g) and an aqueous mixture (30 mL) of p-nitrobenzoic
acid (PNBA; 2.5 g, 15 mmol) and NaOH (0.695 g, 17.4 mmol).
The concentrations of PNBA and NaOH in the aq solution were
0.50 M and 0.58 M, respectively. The reactor was sealed and
purged three times with N , and then the mixture was heated to
1
9
2
lected for H NMR analysis as described for the batch reaction.
8
1
0 °C with stirring at 1250 rpm. The reactor was pressurized to
0 or 5 bar with H , at which point the reaction started. 200 L
(
14) Yang, C.; Teixeira, A. R.; Shi, Y.; Born, S. C.; Lin, H.; Song, Y. L.;
Martin, B.; Schenkel, B.; Lachegurabia, M. P.; Jensen, K. F. Green
Chem. 2018, 20, 886.
2
aliquots of the reaction mixtures were withdrawn from the
reactor at 2, 4, 6, 8 10, 15, 20, 25, 30, 35, 40, 45, 60, and 90 min.
Each sample was diluted with 1.8 mL of D O containing a
2
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–F