Synthesis of secondary amines by reductive amination of aldehydes with nitroarenes over supported copper catalysts in a flow reactor

Article abstract of DOI:10.1016/j.catcom.2017.09.001

Supported copper catalysts were investigated for the one-pot reductive amination of aldehydes with nitroarenes in a continuous flow reactor. This process is considered advantageous compared to current traditional methods, which present several drawbacks, such as toxicity of reducing or alkylation agent, lack of monoalkylation selectivity and large amounts of waste produced. Various secondary amines were synthesized in good to excellent yields in the reactions of aliphatic aldehydes with nitroarenes using molecular hydrogen as a reducing agent. It was found that the yield of secondary amine depends on the rate of formation of intermediate imine.

Full text of DOI:10.1016/j.catcom.2017.09.001

Accepted Manuscript
Synthesis of secondary amines by reductive amination of
aldehydes with nitroarenes over supported copper catalysts in a
flow reactor
A.L. Nuzhdin, E.A. Artiukha, G.A. Bukhtiyarova, E.A.
Derevyannikova, V.I. Bukhtiyarov
PII:
DOI:
Reference:
S1566-7367(17)30374-6
doi: 10.1016/j.catcom.2017.09.001
CATCOM 5183
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Catalysis Communications
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Revised date:
Accepted date:
20 June 2017
28 August 2017
3 September 2017
Please cite this article as: A.L. Nuzhdin, E.A. Artiukha, G.A. Bukhtiyarova, E.A.
Derevyannikova, V.I. Bukhtiyarov , Synthesis of secondary amines by reductive amination
of aldehydes with nitroarenes over supported copper catalysts in a flow reactor. The
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ACCEPTED MANUSCRIPT
Synthesis of secondary amines by reductive amination of aldehydes with nitroarenes over
supported copper catalysts in a flow reactor
A. L. Nuzhdina,*, E. A. Artiukhaa, G. A. Bukhtiyarovaa, E. A. Derevyannikovaa,b, V. I.
Bukhtiyarova,b
a Boreskov Institute of Catalysis SB RAS, Lavrentieva Ave. 5, Novosibirsk 630090, Russia
b Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russia
* Corresponding author. E-mail address: anuzhdin@catalysis.ru (A. L. Nuzhdin)
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Abstract
Supported copper catalysts were investigated for the one-pot reductive amination of aldehydes
with nitroarenes in a continuous flow reactor. This process is considered advantageous compared
to current traditional methods, which present several drawbacks, such as toxicity of reducing or
alkylation agent, lack of monoalkylation selectivity and large amounts of waste produced.
Various secondary amines were synthesized in good to excellent yields in the reactions of
aliphatic aldehydes with nitroarenes using molecular hydrogen as a reducing agent. It was found
that the yield of secondary amine depends on the rate of formation of intermediate imine.
Keywords: one-pot reductive amination, aldehyde, nitroarene, supported copper catalyst,
continuous flow reactor, molecular hydrogen.
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1. Introduction
Secondary amines are important compounds in the chemical industry and are extensively
used for the production of pharmaceuticals, agrochemicals and fine chemicals [1]. Traditional
methods for their synthesis include reduction of nitroarenes to corresponding anilines [2] and
further reaction with alkyl halides, alcohols or carbonyl compounds [3]. However, these
processes have significant drawbacks, such as toxicity of reducing or alkylation agents, lack of
monoalkylation selectivity and large amounts of waste produced. Hence, there is a continuing
interest in cost-effective and environmentally friendly synthesis of secondary amines [4,5].
One-pot reductive amination of aldehydes with nitroarenes over heterogeneous catalysts
using molecular hydrogen or other “green” reducing agents is an atom-economical and
environmentally attractive method for the synthesis of secondary aromatic amines [6–21]. This
process involves three cascade reactions: hydrogenation of nitroarene into primary aromatic
amine, reversible condensation of primary amine with aldehyde to imine, and hydrogenation of
imine to the desired secondary amine. In general, the reaction is realized in the presence of noble
metal-based catalysts, such as Pd [6–11], Pt [11,12] and Au [13–16]. However, the high price
and limited availability of these precious metals have spurred interest in heterogeneous catalysis
utilizing more earth-abundant metal alternatives.
Recently, reductive amination of aldehydes with nitroaromatic compounds over Fe- and
Co-based catalysts has been described [17–22]. The catalysts comprised of Fe2O3 particles [17],
Co/Co3O4 nanocomposites [18], and Co nanoparticles [19–22] embedded in mesoporous
nitrogen-doped carbon were found to be active and selective in this reaction. However, the use of
expensive organic compounds, such as 1,10-phenanthroline [17,18], 2-methylimidazole [20,22]
and phthalocyanine [21,23] for catalyst preparation hinders the application of these materials.
Heterogeneous copper catalysts are attractive for the one-pot synthesis of secondary
amines from aldehydes and nitroarenes due to their activity in hydrogenation of nitroarenes (e.g.,
nitrobenzene [24], nitrotoluenes [24] and chloronitrobenzenes [25, 26]) and reductive amination
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of carbonyl compounds with anilines [27]. In addition, a range of N,N-dimethylanilines was
synthesized with high yields in the reaction of nitroarenes with H2 and HCHO over skeletal Cu
catalyst [28]. However, Cu-based catalysts have not been tested for the synthesis of secondary
amines through a reductive amination of carbonyl compounds with nitroarenes.
Generally, the reductive amination of aldehydes with nitroarenes is performed in batch
reactors [6-13, 16-22]. Meanwhile, continuous-flow synthesis has emerged in recent years as an
attractive alternative to more traditional batch protocols. Potential benefits of flow chemistry
include an enhanced safety profile, superior interfacial mass and energy transfer properties,
reducing the formation of the side products through a better control over process variables, and
shortening the development time from laboratory to final production levels [29,30]. Herein, the
behavior of supported copper-based catalysts in the reductive amination of aldehydes with
nitroarenes has been studied using a continuous flow reactor and hydrogen as a reducing agent.
The facile synthetic procedure and the most common supports, such as silica and γ-alumina,
have been used to prepare the Cu-containing supported catalysts.
2. Experimental
2.1 Chemicals
Copper(II) nitrate trihydrate (99 %), nitrobenzene (99%), o-chloronitrobenzene (99+%),
p-chloronitrobenzene (99%), p-bromonitrobenzene (99%), p-nitroanisole (99+%), o-nitrotoluene
(99+%),
m-nitrotoluene
(99%),
p-nitrotoluene
(99%),
n-heptanal
(95%),
3-
phenylpropionaldehyde
(95%),
benzaldehyde
(98+%),
p-anisaldehyde
(99+%),
p-
chlorobenzaldehyde (98.5+%), p-tolualdehyde (99+%), 2-heptanone (98%) and n-decane
(99+%) from Acros Organics, as well as n-dodecanal (95%) from Sigma-Aldrich, were used
without additional purification. Toluene (99.5%, ECOS (Russia)), methanol (99.8%, J.T. Baker),
tetrahydrofuran (THF, ≥99.9%, Sigma-Aldrich) and isopropanol (≥99.7%, Sigma-Aldrich) were
employed as solvents.
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The γ-alumina support was prepared by extrusion of a paste obtained by mixing of
aluminum oxide (Puralox TH 100/150, Sasol), aluminum hydroxide (Disperal, Sasol) and
aqueous solution of nitric acid as described earlier [15]. The silica (KSKG) was supplied from
KhromAnalit (Russia).
2.2 Catalyst preparation
Supported copper catalysts were prepared by impregnating the support (grain size of 250–
500 m) with an aqueous solution of copper (II) nitrate followed by drying at 70 C under
vacuum and calcination in air at 300 C for 3 h. Then the solids were cooled to room
temperature, purged in N2 and then stored in a glass flask before being used.
2.3 Catalyst characterization
The copper content was analyzed by XRF using an ARL instrument. Textural
characteristics were determined from nitrogen adsorption-desorption isotherms (77 K)
obtained on a Micromeritics ASAP 2400 analyzer. Powder XRD patterns were obtained
on a Bruker D8 diffractometer (Cu Kα radiation) equipped with a LynxEye position
sensitive detector.
2.4 Catalysts performance
The catalytic activity was investigated under continuous-flow conditions in an H-Cube
ProTM setup (Thalesnano, Hungary) equipped with packed-bed reactors CatCart®30 (length of
30 mm, inner diameter of 4 mm) [15]. Before each catalytic run, the catalyst (0.200 g,
CuO/Al2O3) was reduced in a mixture of hydrogen with toluene at T=120 °C and P=50 bar for 1
h (flow rates of toluene and H2: 0.5 and 60 mL min-1, respectively). The inlet was then switched
to the flask containing the solution of nitroarene (0.025 M) or nitroarene (0.025 M) and aldehyde
(0.0375 M) in toluene. This point in time was chosen as the starting point of the reaction. The
catalytic tests were carried out in the 110–125 C range, 50 bar hydrogen pressure, where liquid
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and hydrogen feed rates were set to 0.35 and 60 mL min−1, respectively. As a result of special
tests, there was no influence of external or internal mass transfer limitations under the conditions
used [31]. The performance of a given catalyst was evaluated by analysis of the samples taken
40–45 min after the start of the experiment. Conversion, selectivity and yield were determined
by GC (Agilent 6890N instrument with a HP 5-MS capillary column 60m×320μm×0.25μm) and
n-decane was used as the internal standard. The reaction products were identified by GC–MS
(Agilent 7000B Triple Quad System) as well as comparing the GC retention times with the
authentic compounds [14].
2.5 Catalyst regeneration
The spent catalyst was washed with a mixture of toluene and isopropanol (1:2 v/v) for 30
min (flow rate of 0.5 mL min-1) and dried in vacuum at 100 C for 2 h. Afterwards, the catalyst
sample was heated in an air oven from room temperature to 330 °C at a heating rate of 5 °C min-
1 and maintained at this temperature for 2 h [15].
3. Results and Discussion
3.1 Catalyst preparation and characterization
Supported CuO/Al2O3 and CuO/SiO2 samples containing approximately 5 wt.% Cu were
prepared by the incipient wetness impregnation of γ-alumina and silica grains with an aqueous
solution of copper (II) nitrate with a subsequent drying at 70 C under vacuum and calcination in
air at 300 C for 3 h. The copper content and textural characteristics of the catalysts are
presented in Table 1. It was found that the CuO phase of these materials can be reduced to
supported metallic copper by a mixture of hydrogen with toluene at 120 °C and 50 bar in a flow
reactor. The characteristic peaks of metallic copper can be seen in the XRD pattern of pre-
reduced catalysts that confirms the reduction of CuO phase to supported metallic copper under
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the conditions used (Fig. 1 and Electronic Supplementary Information, ESI). The optimal pre-
reduction time is 60 min (see ESI).
3.2 Catalytic performance
The catalytic performance of the pre-reduced Cu/Al2O3 and Cu/SiO2 solids have been
evaluated for the liquid-phase hydrogenation of nitroarenes to anilines, which is the first stage of
one-pot synthesis of secondary amines. The Cu/Al2O3 catalyst is shown to provide a highly
selective hydrogenation of nitroarenes containing –Cl, –Br and –OCH3 group to the
corresponding anilines (Table 2, entries 3–10). Hydrogenation of nitroarenes containing –Cl and
–Br substituents occurs more slowly than in the case of nitrobenzene and p-nitroanisole.
Moreover, the use of methanol instead of toluene results in a significant increase in the
hydrogenation rate (Table 2, entries 5 and 7). The Cu/SiO2 catalyst exhibits a much lower
activity than Cu/Al2O3 (Table 2, entries 11 and 12), and this could be attributed to the faster
adsorption of o-chloronitrobenzene through the nitro group on γ-alumina than on silica [32,33].
Encouraged by the good activity of Cu/Al2O3 catalyst for the nitroarene hydrogenation,
this catalyst was tested in one-pot reductive amination of aldehydes with nitroarenes in the
presence of molecular hydrogen. Since aldehyde could produce the corresponding alcohol in a
side reaction [14,15], the reaction was carried out at a 1.5-fold excess of aldehyde. As shown in
Table 3, various secondary amines could be obtained over the Cu/Al2O3 catalyst with a yield up
to 97% using toluene as a solvent. Aliphatic aldehydes (n-heptanal, 3-phenylpropionaldehyde
and n-dodecanal) give higher yields of secondary amine in the reaction with p-nitrotoluene as
compared with benzaldehyde derivatives (Table 3, entries 3, and 6–15). This result can be
explained by the faster interaction between p-toluidine formed in the course of the reaction and
aliphatic aldehydes, due to the stronger electrophilic properties of the latter [14]. The utilization
of ketone (2-heptanone) instead of aldehydes led to the formation of secondary amines in
negligible yields, which is connected with the much weaker electrophilic properties of ketones.
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The effect of the substituent’s nature and its position in nitroaromatic compound on the
reductive amination of aldehydes was investigated using the reactions between n-heptanal and
various nitrobenzenes. It was shown that the introduction of electron-donating substituents (–
CH3, –OCH3) in the para-position of the nitrobenzene improved the yield of secondary amines
(Table 3, entries 1, 3 and 16). At the same time, in the case of nitroarenes with electron-
withdrawing substituent (–Cl, –Br), the reduction in the yield of the desired products was
observed under the same reaction conditions (Table 3, entries 17 and 18). The observed effect of
substituents with the electron-donating or electron-withdrawing properties can be explained by
their impact on the nucleophilic properties of the intermediate primary aromatic amines [15].
The position of the substituent in nitroarene structure also has a strong influence on the reaction.
Therefore, the yield of secondary amine in the reaction of n-heptanal and o-nitrotoluene is much
lower than with p-nitrotoluene and m-nitrotoluene (Table 3, entries 3, 19 and 20). It is explained
by the weaker nucleophilic properties of o-toluidine formed during the reaction due to the steric
hindrance effect created by a methyl group in ortho-position that leads to a decrease of the imine
formation rate through the reaction with aldehyde [15]. Thus, the yield of secondary amine is
determined by the rate of imine formation. At the same time, the complete conversion of
nitroarenes and low yields of imines (Table 3) indicate a fast hydrogenation of nitroarenes and
imines in most of the experiments.
The influence of solvent, hydrogen pressure and pre-reduction duration on the course of
the reaction was also studied. The utilization of methanol as a solvent led to a significant
decrease in the yield of secondary amines (Table 3, entries 1 and 2), probably due to the higher
hydrogenation rate of aldehydes in methanol than in toluene [14]. At the same time, no reaction
was observed when THF or isopropanol was used as a solvent. These results can be explained by
the fast deactivation of the catalyst during the pre-reduction procedure caused by the
hydrogenation of solvent molecules over Cu/Al2O3 with the subsequent formation of
carbonaceous deposits. Moreover, it was found that a decrease in both the hydrogen pressure
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(from 50 to 40 bar) and pre-reduction duration (from 60 min to 30 min) leads to a visible
reduction in the yield of secondary amines (Table 3, entries 3–5).
In previous studies, we found that 2.5 wt% Au/Al2O3 catalyst with a mean gold particle
size of 3.4 nm provides the one-pot reductive amination of aldehydes with nitroarenes in a flow
reactor [14,15]. The secondary amines were synthesized with a yield up to 99% at 80–100 C
and P(H2)=50 bar. To compare the catalytic performance of supported copper and gold catalysts,
the space time yield (STY) of 5.3 wt% Cu/Al2O3 and 2.5 wt% Au/Al2O3 catalysts were
calculated. The STY is defined as the mass of the secondary amine (g) produced during 1 h per
mass of metal (g) in the catalyst [34]. As shown in Table 4, STY of the secondary amines for the
Cu/Al2O3 catalyst was only 3.3–4.1 times lower than those for the Au/Al2O3 catalyst.
The evolution of the reaction products over the Cu/Al2O3 catalyst in the course of the
reductive amination of n-heptanal with p-nitrotoluene showed a slight deactivation of the catalyst
with time-on-stream (Fig. 2), which can be explained by the formation of carbonaceous deposits
on the catalyst surface [14,15,35]. The activity of the spent Cu/Al2O3 catalyst could be recovered
after washing with a mixture of toluene/isopropanol (1:2 v/v) followed by oxidative treatment in
air at 330 °C for 2 h (Fig. 3). Importantly, no leaching of Cu from the Cu/Al2O3 catalyst or
deterioration of its textural structure was detected after reaction and regeneration (Table 1).
4. Conclusions
In summary, inexpensive and easily prepared Cu/γ-Al2O3 catalyst provided
chemoselective hydrogenation of nitroarenes to anilines and one-pot reductive amination of
aldehydes with nitroarenes in a continuous flow reactor. Various secondary amines were
synthesized in 82–97% yields by one-pot reaction of aliphatic aldehydes with nitroarenes using
molecular hydrogen as a reducing agent. The yield of secondary amine is determined by the
rate of imine formation.
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Acknowledgements
The authors thank Dr. A. Yu. Gladky for his help in carrying out this study. This work was
conducted within the framework of project No. 0303-2016-0006 (Boreskov Institute of
Catalysis).
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Table 1
Textural characteristics of supports and supported CuO catalysts.
Cu Content BET surface
Total pore
Mean pore
(wt%)
area (m2 g-1) volume (cm3 g-1) diameter
(nm)
γ-Al2O3
SiO2
–
179
300
169
260
160
0.61
0.81
0.59
0.74
0.56
13.7
10.6
13.8
11.0
13.6
–
CuO/Al2O3
CuO/SiO2
5.3
5.4
a
Regenerated CuO/Al2O3 5.1
a The catalyst after two cycles (~4 h on-stream) of the reductive amination of n-heptanal (0.0375
M) with p-nitrotoluene (0.025 M) at 115 C and 50 bar.
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Table 2
Catalytic performance of supported copper catalysts in a flow reactor for the liquid-phase
hydrogenation of nitroarenes to anilines.a
Entry Catalyst
R
H
H
T (°C) Conversion (%) Selectivity (%)
1
Cu/Al2O3
Cu/Al2O3
115
125
115
125
115
125
115
125
99
99.7
100
95
2
100
72
3
Cu/Al2O3 o-Cl
Cu/Al2O3 o-Cl
Cu/Al2O3 p-Cl
Cu/Al2O3 p-Cl
Cu/Al2O3 p-Cl
Cu/Al2O3 p-Br
4
99
98
5
76
100
99.5
100
99
6
100
100
96
7b
8
9
Cu/Al2O3 p-OCH3 115
Cu/Al2O3 p-OCH3 120
99
99.8
99.7
100
100
10
11c
12c
100
16
Cu/SiO2
Cu/SiO2
o-Cl
o-Cl
115
125
27
a Reaction conditions: nitroarene (0.025 mol L-1), catalyst (200 mg, CuO/Al2O3), toluene, 50 bar
H2, pre-reduction time 60 min, reaction time 40–45 min. Conversion and selectivity were
determined by GC analysis.
b in methanol.
c Catalyst loading: 156 mg (CuO/SiO2).
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ACCEPTED MANUSCRIPT
Table 3
Reductive amination of aldehydes with nitroarenes over the Cu/Al2O3 catalyst.a
Entry
T
Conversion Conversion Yield (%)b
1
2
(°C)
of 1 (%)
of 2 (%)
3
4
5
1
115
115
100
100
100
100
18
41
0
0
82
59
2c
3
115
115
115
100
100
100
100
99
94
9
16
16
0
1
2
91
83
82
4d
5e
6
7
8
105
110
115
100
100
100
100
100
100
16
14
15
0
0
0
84
86
85
9
125
100
82
12
1
87
10
11
12
110
115
120
100
100
100
95
100
100
33
32
32
6
1
1
61
67
67
13
14
15
16
17
18
19
20
115
115
125
125
125
125
115
115
100
100
80
100
100
62
36
40
16
3
1
63
60
22
97
11
10
49
85
0
42
0
100
74
100
47
30
42
51
15
33
19
0
71
53
100
100
100
100
0
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ACCEPTED MANUSCRIPT
a Reaction conditions: 1 (0.025 mol L-1), 2 (0.0375 mol L-1), catalyst (200 mg, CuO/Al2O3),
toluene, 50 bar H2, pre-reduction time 60 min, reaction time 40–45 min.
b The product yields were calculated based on the nitro-compounds using GC.
c in methanol.
d P(H2)=40 bar.
e Pre-reduction time: 30 min.
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ACCEPTED MANUSCRIPT
Table 4
Space time yield (STY) of secondary amines for the Cu/Al2O3 and Au/Al2O3 catalysts.a
-1
Entry Catalyst
Product
T, °C STY, g g-metal h-1
1
5.3% Cu/Al2O3
2.5% Au/Al2O3
5.3% Cu/Al2O3
2.5% Au/Al2O3
5.3% Cu/Al2O3
2.5% Au/Al2O3
115
80
7.8
2
3
4
5
6
26.9 [14]
9.2
115
80
30.4 [14]
6.5
115
80
26.9 [14]
a Reaction conditions: nitroarene (0.025 mol L-1), aldehyde (0.0375 mol L-1), toluene, 50 bar H2.
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ACCEPTED MANUSCRIPT
Figure captions
Fig. 1. Powder XRD patterns of CuO/Al2O3 and pre-reduced Cu/Al2O3 catalysts.
Fig. 2. Evolution of product yields with time-on-stream for the reductive amination of n-heptanal
(0.0375 M) with p-nitrotoluene (0.025 M) at 115 C and 50 bar over the Cu/Al2O3 catalyst.
Fig. 3. The time dependence of secondary amine yield in the reaction between p-nitrotoluene
(0.025 M) and n-heptanal (0.0375 M) over the as-prepared and regenerated Cu/Al2O3 catalysts at
115 C and 50 bar.
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ACCEPTED MANUSCRIPT
Figure 1
21

ACCEPTED MANUSCRIPT
100
80
60
40
20
0
Secondary amine
Imine
p-Toluidine
Conv. of heptanal
Conv. of p-nitrotoluene
0
20
40
60
80
100
120
Time-on-stream (min)
Figure 2
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ACCEPTED MANUSCRIPT
100
80
60
40
20
0
As-prepared
Regenerated
40
60
80
100
120
Time-on-stream (min)
Figure 3
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ACCEPTED MANUSCRIPT
Graphical abstract
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ACCEPTED MANUSCRIPT
Highlights



Cu/Al2O3 catalystis effectivefor reductive amination of aldehydes with nitroarenes
Various secondary amines were obtained in ahigh yield underflow conditions
The yield of secondary amine is determined by the rate of imine formation
25