Selective catalytic amination of halogenated aldehydes with calcined palladium catalysts

Article abstract of DOI:10.1039/c8ra01987h

This work focuses on understanding the influence of the conditions used in the calcination step of palladium catalysts on the performance of this catalyst in the reductive amination of halogen-containing substrates. The results show that increasing the calcination temperatures (from 100 °C to 400 °C) has a detrimental effect on catalytic activity but a strong positive effect on the selectivity (from 45 to 96%), avoiding the undesired dehalogenation reaction. TEM investigation showed that the reason for the different selectivity can be addressed to different Pd mean particles size and particle size distribution. In particular, larger Pd particles obtained at the highest calcination temperature (400 °C) showed the best selectivity to halogenated benzylamines (96%), with a good stability in terms of both activity and selectivity as confirmed by performing recycling tests.

Full text of DOI:10.1039/c8ra01987h

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Selective catalytic amination of halogenated
aldehydes with calcined palladium catalysts
Cite this: RSC Adv., 2018, 8, 15202
ab
b
Alberto Villa,
and Laura Prati
Kim Dumoleijn,c Claudio Evangelisti,
*
Kristof Moonenc
ab
This work focuses on understanding the influence of the conditions used in the calcination step of
palladium catalysts on the performance of this catalyst in the reductive amination of halogen-containing
substrates. The results show that increasing the calcination temperatures (from 100 ꢀC to 400 ꢀC) has
a detrimental effect on catalytic activity but a strong positive effect on the selectivity (from 45 to 96%),
avoiding the undesired dehalogenation reaction. TEM investigation showed that the reason for the
different selectivity can be addressed to different Pd mean particles size and particle size distribution. In
particular, larger Pd particles obtained at the highest calcination temperature (400 ꢀC) showed the best
selectivity to halogenated benzylamines (96%), with a good stability in terms of both activity and
selectivity as confirmed by performing recycling tests.
Received 6th March 2018
Accepted 13th April 2018
DOI: 10.1039/c8ra01987h
rsc.li/rsc-advances
literature mostly use a hydride reagent such as sodium boro-
hydride which can results in a high selectivity towards the
halogenated tertiary amine14,15 or the use of hydrogen gas as the
reducing agent in combination with a metal catalyst which
results in no salt formation but suffers from selectivity losses
due to dehalogenation.16–19
Introduction
The selective conversion of one functional group in a multi-
functional feed substrate has been an area of continuous high
interest throughout the chemical, pharmaceutical and agro-
chemical industry.1–5 In particular, halogen atoms are oen
incorporated next to other functional groups in active ingredi-
ents or in precursors of those active ingredients. Moreover,
more than 25% of the registered drugs contain a tertiary amine
group which make them a very important class of pharmaco-
phores. However, the methods described in literature for the
selective synthesis of halogenated tertiary benzylamines mostly
involve equimolar amounts of salt formation or suffer from low
selectivities. The ability to synthesize these halogenated tertiary
amines on an industrial efficient way can open new possibilities
for the synthesis of these pharmacophores and agrochemical
Therefore, there is a need for a new and readily available
catalytic system for the selective amination of halogenated
aldehydes to form multifunctional tertiary amines which can be
applied in a multi-step synthesis of different end products such
as API's or agrochemicals. If a catalytic system could be found
that uses hydrogen as the reducing agent, eliminates the
formation of salts as by-product and reduces the amount of
dehalogenation, an industrial efficient and green synthesis
route towards these halogenated tertiary amines becomes
feasible.
Palladium has been widely used for the reductive amination
of carbonyl compounds.20–22 The drawback of using Pd catalysts
in the case of amination of halogen substituted carbonyl
compound is its capability to displace the halogen atom by
a hydrogen atom. A strategy to avoid the undesired dehaloge-
nation is to modify the Pd active sites. This modication can be
done by for example a modication of the support. It has been
shown, indeed, that the use of hierarchical-porosity silica
monoliths, obtained by post graing of sulfonic groups as
intermediates.6,7
A widely used synthesis route of these
compounds involve the substitution reaction of benzylhalides
by a secondary amine with the formation of an equimolar
amount of ammonium salts.8–13 The reductive amination reac-
tion of halogenated aldehydes as a way to obtain halogenated
benzylamine have also gained interest in the last decades. The
synthetic protocol involves the formation of an imine or imi-
nium intermediate upon exposure of a carbonyl compound to
a secondary amine followed by an in situ reduction to an alky-
lated amine (Scheme 1). However, procedures described in
a
`
Universita degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi 19, 20133
Milano, Italy. E-mail: Laura.Prati@unimi.it
bInstitute of Molecular Science and Technologies, CNR, Via G. Fantoli 16/15, Milano,
Italy
Scheme 1 Scheme of reaction of the reductive amination of halogen
substituted benzaldehyde.
cEastman Chemical Company, Taminco BVBA, Pantserschipstraat 207, Ghent, Belgium
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a support in the hydrogenation of halogenated nitro aromatics the company Sigma Aldrich and 12 mL of dimethyl amine in
could decrease the dehalogenation signicantly.23 The xation methanol solution having a 2 M concentration. The reactor was
of palladium nanoparticles inside beta zeolite crystals in the sealed and the gas phase was ushed three times with nitrogen
hydrogenation of halogenated nitroarenes also showed a bene- and then pressurized at 5 bar by the addition of nitrogen gas.
ꢀ
cial effect in comparison with conventional palladium nano- The reactor was heated to 80 C and then continuously stirred
particles supported on zeolite crystals and commercial available for 60 minutes at a temperature of 80 ꢀC and a pressure of 5 bar.
Pd/AC catalysts.24 Another way to modify the Pd active sites is by Then, the reactor was cooled to 30 ꢀC and degassed. 8 mg of the
the addition of a second metal. For example, the addition of Ag catalyst was added to the autoclave. The autoclave was heated in
ꢀ
to Pd can suppress the dehalogenation during the reductive 15 minutes to 100 C and hydrogen was added to a nal pres-
amination of halogen substituted benzaldehyde.25,26 Probably sure of 40 bar. The reductive amination reaction was allowed to
ꢀ
the addition of Ag poisoned the most reactive Pd sites respon- proceed for the indicated time at 100 C. Then the reactor was
sible of the dehalogenation. Bair et al. also describes the addi- cooled down and degassed at room temperature. Subsequently,
tion of Pb to a Pd/AC catalyst for the selective synthesis of a sample of the reaction product liquid was taken and analyzed
aromatic haloamines out of aromatic halonitroamines by sup- by gas chromatography (GC) using a HP 7820A gas chromato-
pressing the unwanted dehalogenation reaction. While graph equipped with a capillary column HP-5 30 m ꢂ 0.32 mm,
a commercial available Pd/AC catalyst shows almost complete 0.25 mm lm, by Agilent Technologies. Identication of the
dehalogenation, the addition of Pb could decrease the dehalo- products was performed using a Thermo Scientic Trace ISQ
genation down to levels of 5%.27 In this work we showed that QD Single Quadrupole GC-MS equipped with a capillary column
a similar effect can be obtained by pretreating Pd/AC catalyst at HP-5 30 m ꢂ 0.32 mm, 0.25 ꢂ m lm, by Agilent Technologies.
different temperatures before the utilization in the amination of Recycling tests were carried out under the same experimental
halogen (Cl, Br) substituted benzaldehyde with dimethylamine conditions. The catalyst was recycled in the subsequent run
(DMA).
aer ltration without any further treatment.
Experimental
Catalyst treatment
Characterization
Electron micrographs were obtained using a ZEISS LIBRA200FE
microscope equipped with a 200 kV FEG source. Energy-
dispersive X-ray spectra (EDS – Oxford INCA Energy TEM 200)
and elemental maps were collected along with HAADF-STEM
(high angular annular dark eld scanning transmission elec-
tron microscopy) images. Before the analysis, the samples were
suspended in isopropanol and sonicated, then each suspension
was dropped onto a holey carbon-coated copper grid (300 mesh)
and the solvent was evaporated. Histograms of the particle size
distribution were obtained by counting at least 300 particles
onto the micrographs; the mean particle diameter (dm) was
A 5% wt palladium catalyst (Pd/AC) was obtained from the
company Evonik (30% wt wet). An amount of 10 g of this catalyst
was dried at 80 ꢀC (Pd80/AC) in static air for 3 hours and
subsequently heat-treated under a nitrogen ow of 30 mL minꢁ1
at 100, 200 or 400 ꢀC temperatures for 4 hours. The catalysts
were labelled as Pd100/AC, Pd200/AC and Pd400/AC, respectively.
As a comparison, the catalyst was also calcined at 400 ꢀC
without being dried beforehand (Pd400wet/AC).
Catalytic tests
In a typical experiment, a 100 mL autoclave (Parr) was loaded calculated by using the formula dm ¼ Sdini/Sni where ni was the
with 2.5 g of a halogen substituted benzaldehyde obtained from number of particles of diameter di.
Table 1 Reductive amination of 2-Cl-benzaldehyde with DMA using Pd/AC catalystsa
Entry
Catalyst
Reaction time (min)
Conv (%)
BDMA (%)
2-Cl-BDMA (%)
Others (%)
1
2
3
4
5
Pd/AC
15
15
15
15
15
30
15
30
15
15
15
15
99.9
99.8
99.7
94.3
44.0
82.3
81.2
98.9
98.3
95.6
80.6
72.2
44.8
44.9
45.1
42.4
2.1
2.4
7.4
12.2
0.5
1.5
34.4
34.6
34.7
39.3
97.8
96.2
91.2
87.4
98.2
96.2
96.2
98.9
20.5
20.4
19.8
18.0
—
—
—
—
0.9
—
Pd80/AC
Pd100/AC
Pd200/AC
Pd400/AC
6
Pd400wet/AC
7
8
9
10
PdCu/ACb
PdAu/ACb
PdNi/ACb
PdAg/ACb
0.8
—
—
—
a
Reaction conditions: 2.5 g of a halogen substituted benzaldehyde and 12 mL of dimethyl amine in methanol (2 M). 1st step: 80 ꢀC, 5 bar N2. 2nd
step: 100 ꢀC, 40 bar H2, 8 mg catalyst. b Data from ref. 25.
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Results and discussion
Commercial 5% palladium catalyst supported on carbon
(20% wt wet) was tested in the reductive amination of halogen
substituted benzaldehyde with dimethyl amine in methanol
solution. The aim of this work is to elucidate the effect of the
heat treatment on the morphology and the catalytic activity of
a Pd/AC catalyst. Therefore, before utilization, a portion of the
ꢀ
catalyst was dried at 80 C in static air for 3 hours and subse-
quently heat-treated under a nitrogen ow of 30 mL minꢁ1 at
ꢀ
100, 200 or 400 C for 4 hours. In comparison, the wet catalyst
was calcined at 400 ꢀC without being dried beforehand. The
reaction was performed in two steps. In the rst step, the proper
amount of halogen substituted benzaldehydes and dimethyl
amine in methanol solution were added to the reactor and then
ꢀ
continuously stirred for 60 minutes at a temperature of 80 C
and a pressure of 5 bar of N2, to form the halogen imine
(Scheme 1). Then, the reactor was cooled to 30 ꢀC, degassed and
the catalyst was added to the autoclave. The successive reductive
ꢀ
amination reaction was performed at 100 C and at 40 bar of
hydrogen. Table 1 reports the results obtained using the palla-
dium catalysts treated at different temperature in the reductive
amination of 2-Cl-benzaldehyde with DMA. All the catalysts
were very active reaching full conversion aer 15 minutes (entry
Fig. 1 High resolution TEM micrographs (left side and middle) and
ꢀ
1–4), except when treated at 400 C (entry 5 and 6).
histogram of particle size distribution (right side) of Pd/AC (A), Pd200
/
Pd400/AC showed a conversion of 44 and 82.3% aer 15 and
30 minutes, respectively (entry 5). The calcination carried out on
the wet Pd/AC sample affected less the activity being the
conversion obtained aer 15 min of 81.2% instead of 44% for
the catalyst calcined in the dried form (entry 6 vs. 5).
Pd/AC produced benzyldimethylamine (BDMA) as main
product (44.8%, entry 1) whereas the selectivity to the desired 2-
Cl-benzyldimethylamine (2-Cl-BDMA) was lower (34.4% – entry
1). As expected from previous works, the untreated Pd/AC was
efficient in the reductive amination but also promoted the
dehalogenation of the aromatic group.25 No changes in the
selectivity were observed drying the sample in static air at 80 ꢀC
or calcining the sample under N2 ow at 100 ꢀC (34.6 and 34.7%
of selectivity to 2-Cl-BDMA, entry 2 and 3), whereas the heat
treatment at 200 ꢀC moderately improved the selectivity (39.3%,
entry 4).
AC (B), Pd400/AC (C), Pd400wet/AC (D).
(dm) of 2.1 nm with a narrow particle size distribution (1.0–4.0
nm) (Fig. 1a). The drying step of the sample at 80 ꢀC or the
calcination at 100 ꢀC did not affect the morphology of the
catalyst (data not shown), whereas the treatment of the Pd
catalyst at 200 ꢀC results in a slight increase in the particle size
(2.9 nm) and a larger particle distribution (Fig. 1b). Evident
changes in the Pd particle sizes were observed when the sample
was calcined at 400 ꢀC, with an increase of mean diameter from
2.1 nm to 6.3 nm together with a broadening of the size
distribution (2.5–10.0 nm) (Fig. 1c). It is worth noting that the
ꢀ
same thermal treatment (calcination at 400 C) carried out in
A much higher selectivity to 2-Cl-BDMA (93.6%) was
observed for the catalyst heat-treated at higher temperature (400
ꢀ
ꢀC) (entry 5). Interestingly, calcining the Pd catalyst at 400 C
without a drying step at 80 ꢀC (Pd400wet/AC), a lower selectivity to
2-Cl-BDMA (87.4%, entry 6) compared to Pd400/AC was ob-
tained. Pd/AC catalyst performances in terms of both activity
and selectivity appeared to be very sensitive to the initial
amount of water during the calcination, water being detri-
mental in terms of selectivity. Pd400/AC showed results compa-
rable to the best bimetallic systems reported in the literature
(Table 1).
To better understand the effect of the heat treatment on the
catalytic activity, the morphology of the catalysts was investi-
gated by transmission electron microscopy (TEM). The
commercial Pd/AC catalysts showed a mean particle diameter
Fig. 2 Stability tests using Pd400/AC in the amination of 2-Cl-benz-
aldehyde with DMA.
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Table 2 Reductive amination of halogenated-benzaldehyde with DMA using Pd/AC catalystsa
Substrate
Time of reaction (min)
Conv (%)
BDMA (%)
Halogenated BDMA (%)
Others (%)
Pd/AC
2 Cl-aldehyde
4 Cl-aldehyde
2,4 Cl-aldehyde
2 Br-aldehyde
15
15
15
15
99.9
83.1
78.3
74.8
45.8
48.3
48.2
58.3
33.4
30.2
30.5
25.5
20.6
20.3
19.7
14.3
Pd400/AC
2 Cl-aldehyde
15
30
15
30
15
30
15
30
44.0
82.3
38.2
78.6
35.9
76.8
36.8
71.4
2.1
2.4
5.4
6.6
7.4
9.4
27.8
34.1
97.8
96.2
92.6
91.3
93.2
88.3
62.5
53.6
—
0.8
0.1
0.3
0.5
0.7
7.8
10.1
4 Cl-aldehyde
2,4 Cl-aldehyde
2 Br-aldehyde
a
Reaction conditions: 2.5 g of a halogen substituted benzaldehyde and 12 mL of dimethyl amine in methanol (2 M). 1st step: 80 ꢀC, 5 bar N2. 2nd
step: 100 ꢀC, 40 bar H2, 8 mg catalyst.
ꢀ
ꢀ
the presence of water (i.e. without the drying step) leads to 100 C to 400 C) has a positive effect on the selectivity toward
a nal mean particle diameter of 4.6 nm, evidencing the role of halogenated benzylamines, avoidingꢀ the undesired dehaloge-
water in limiting the Pd particles growth (Fig. 1d).
nation. A drying pre-treatment at 80 C appeared fundamental
Correlating the structure of the different catalysts with their in improving the catalyst selectivity. Correlating the catalytic
activity and above all their selectivity, it clearly appears that the results with TEM investigation it appeared that there is a clear
catalytic performances (activity and selectivity) are ruled out correlation between catalytic activity and the catalyst
from the particle size. The catalysts with larger particles are less morphology. In particular, bigger Pd particles obtained at the
active but less prone to remove the halogen group, resulting in highest calcination temperature (400 ꢀC) showed the best
a higher selectivity to 2-Cl-BDMA.
selectivity to halogenated benzylamines (92–98%), with a good
Indeed, the following correlations were observed for particle stability as conrmed performing recycling tests. Pd400/AC
size Pd/AC (2.1 nm) ¼ Pd80/AC (2.1 nm) ¼ Pd100/AC (2.1 nm) < showed results comparable to best ones reported in the litera-
Pd200/AC (2.9 nm) < Pd400wet/AC (4.6 nm) < Pd400/AC (6.3) and for ture using bimetallic systems.
the selectivity to 2-Cl-BDMA, Pd/AC (34.3%) ¼ Pd80/AC (34.6%)
¼ Pd100/AC (34.6%) < Pd200/AC (39.3%) < Pd400wet/AC (91.2%) <
Conflicts of interest
Pd400/AC (96.2%).
There are no conicts to declare.
The long-term stability of the most selective catalyst, Pd400
/
AC, was then investigated. Recycling tests were carried out by
ltering the catalyst and reusing it without any further puri-
cation for the next run. The results highlighted the excellent
stability for six cycles in terms of both activity and selectivity as
shown in Fig. 2.
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