One-pot reductive amination of carboxylic acids: a sustainable method for primary amine synthesis

Article abstract of DOI:10.1039/d0gc01441a

The reductive amination of carboxylic acids is a very green, efficient and sustainable method for the production of (bio-based) amines. However, with current technology, this reaction requires two to three reaction steps. Here, we report the first (heterogeneous) catalytic system for the one-pot reductive amination of carboxylic acids to amines, with solely H2 and NH3 as the reactants. This reaction can be performed with relatively cheap ruthenium-tungsten bimetallic catalysts in the green and benign solvent cyclopentyl methyl ether (CPME). Selectivities of up to 99% for the primary amine could be achieved at high conversions. Additionally, the catalyst is recyclable and tolerant for common impurities such as water and cations (e.g. sodium carboxylate).

Full text of DOI:10.1039/d0gc01441a

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One-pot reductive amination of carboxylic acids: a sustainable
DOI: 10.1039/D0GC01441A
method for primary amine synthesis
Robin Coeck and Dirk E. De Vos, cMACS, KU Leuven, Leuven, Belgium
The reductive amination of carboxylic acids is a very green, efficient and sustainable method for the production
of (bio-based) amines. However, with current technology, this reaction requires two to three reaction steps. Here,
we report the first (heterogeneous) catalytic system for the one-pot reductive amination of carboxylic acids to
amines, with solely H2 and NH3 as the reactants. This reaction can be performed with relatively cheap ruthenium-
tungsten bimetallic catalysts in the green and benign solvent cyclopentyl methyl ether (CPME). Selectivities of up
to 99% for the primary amine could be achieved at high conversions. Additionally, the catalyst is recyclable and
tolerant for common impurities such as water and cations (e.g. sodium carboxylate).
Introduction
Amines are important compounds in the chemical and pharmaceutical industry. With an annual
production of more than 6 million ton/year, they are widely used for the production of agrochemicals,
pharmaceutical ingredients, dyes, polymers, fabric softeners, detergents, solvents, lubricants etc.1-3
Historically, reductive amination of carbonyl compounds is one of the most popular methods for amine
synthesis.1,4 While in the past the starting compounds were often oil-based, progress has been made
in recent years in producing amines from bio-based compounds like alcohols, ketones, aldehydes and
amino acids.5-17 While these methods are very successful, reductive amination of carboxylic acids could
be a desirable complementary method for sustainable amine synthesis.
Carboxylic acids are generally cheap and readily available, e.g. from fermentation18 or from
hydrocarbon oxidation; many fatty acids can be gained from biomass or from industrial waste
streams19. This makes them suitable platform chemicals. For the production of several bio-based
amines, carboxylic acids are already the main starting material, e.g. fatty acids for fatty amines, or
sebacic acid for 1,10-diaminodecane, which allows synthesis of high-value polyamides . Additionally,
in a biorefinery, the production of carboxylic acids is generally more efficient than the fermentative
production of the corresponding aldehydes or alcohols.20-21
Currently, carboxylic acids can be converted to the corresponding primary amine via one of two
possible pathways (Figure 1). The first pathway runs through the corresponding alcohol (upper
pathway Figure 1). Since the catalytic reduction of carboxylic acids is more difficult than ester
hydrogenations, the molecule is esterified first22-23. Next, the ester is reduced after which, in a third
reaction step, a classic amination occurs. In order to shorten this pathway to a two-step procedure,
one can immediately reduce the carboxylic acid to the alcohol. Over the years, many reduction
catalysts have been described for this reaction. However, these catalysts are expensive, since most of
them are based on a platinum group metal (PGM) or/and Re, and easily overreduce the carboxylic acid
towards unfunctionalized alkanes.24-41 The second pathway involves the formation of an amide, which
is dehydrated towards a nitrile at temperatures above 250°C, typically with a ZnO catalyst, and reduced
afterwards (lower pathway Figure 1). This is the most common synthesis method for fatty amines.42
We recently demonstrated that the direct hydrogenation of primary amides is a very efficient and
green method to produce primary amines, reducing this second pathway to a two-step procedure as
well.43 Nevertheless, a one-pot synthesis of primary amines from carboxylic acids would be a significant
improvement in comparison with the current multi-step pathways, regarding energy cost, reactor cost
and product isolation.

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DOI: 10.1039/D0GC01441A
Current routes
R
R
OH
Alcohol
Alkane
t
l
u
c
i
f
f
i
d
R
O
NH2
O
R
Amine
R
R"
OH
Acid
O
Ester
t
l
u
c
i
f
f
i
d
O
N
high T
R
R
NH2
Amide
Nitrile
This work
One-pot
O
O
R
R
NH2
Amine
R
NH2
Amide
OH
Acid
Figure 1 – Synthesis pathways to amines from carboxylic acids.
The direct synthesis of primary amines from carboxylic acids is a fairly unexplored domain, especially
using NH3 and H2.44-45, 63 To the best of our knowledge, the only report of a (heterogeneous) catalyst
for the reductive amination of carboxylic acids, is a CuCrO2-catalyst described by Barrault et al.63 Their
catalytic system, however, leaves much room for improvement; the substrate scope was limited to
dodecanoic acid, relatively severe reaction conditions were required (i.e. 300°C) and only 27% yield of
dodecylamine was obtained. For the N-alkylation of amines with carboxylic acids, a closely related
reaction, several homogeneous catalysts have been described based on Ru, Pt, Ir, B etc. using silanes
(resulting in stoichiometric amounts of waste) or H2 as the reducing agent.46-53 Especially in the teams
of Beller and Cole-Hamilton extensive research was performed, with a Ru-Triphos complex as a
commonly used alkylation catalyst.49-53 Although both teams achieved excellent yields for a variety of
products, it appears that the catalyst requires an activated amine, in particular an aromatic amine. The
synthesis of primary aliphatic amines with this Ru-Triphos catalyst was not successful, as was
demonstrated by Margo et al.: a direct hydrogenation of nonanoic acid in the presence of NH3 only
yielded 15% nonylamine and 47% dinonylamine. Another closely related work was performed by Jamil
et al.54 They successfully converted triglycerides into amines with a heterogeneous Pt/ZrO2 catalyst,
bypassing the amide pathway entirely (Figure 1). Although a significant yield of 59% dodecylamine and
32% didodecylamine was achieved, the reaction required an extremely long reaction time of 36 h, with
5 mol% Pt.
In this work, we report recyclable supported RuWOx-catalysts as highly efficient catalysts for the
one-pot reductive amination of a wide variety of carboxylic acids, yielding primary amines (70-96%)
and the corresponding secondary amine as the main side product. Reactions were performed in the
green and benign cyclopentyl methyl ether (CPME) as solvent, under mild hydrogenation conditions,
i.e. with limited addition of NH3 and H2. To our knowledge, this is the first report of an efficient
(heterogeneous) reductive amination system for carboxylic acids, yielding primary amines.

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DOI: 10.1039/D0GC01441A
Results and discussion
Unraveling the reaction network
When performing hydrogenation reactions with amides, in the presence of NH3, it was noticed that
replacing the amide reactant with a carboxylic acid resulted in high yields of the corresponding amine
as well.43 Therefore, a time profile was made to look more closely into the reaction network of the
octanoic acid (1) amination, using a RuWOx/MgAl2O4 catalyst at 200°C (Figure 2). It appears that at the
onset of the reductive amination, the acid is quite rapidly converted to the amide. Since this catalyst
was designed for the reduction of primary amides, a further hydrogenation towards the primary amine
proceeded smoothly. However, there are several differences compared to a ‘simple’ amide
hydrogenation. Firstly, whereas the dehydration of the ammonium carboxylate to the amide is very
fast at the onset of the reaction, it takes a very long time to fully deplete the carboxylic acid. This is
remarkable, since this dehydration in the absence of H2 is fully completed within two hours (Figure S 2).
Thus, it appears that the carboxylic acid forms a rather stable salt with the freshly formed alkylamine,
drastically lowering the dehydration rate. Secondly, full defunctionalization and secondary amide
formation are two noticeable side reactions. While these side reactions were nearly negligible in amide
hydrogenation reactions, here 10% of the initial product was lost at full conversion (yields of
5% N-octyloctanamide (7), 3% heptane (6), 2% octane (5); see reaction scheme in Figure 3. These two
observations suggest that, although a one-step reaction is possible, it may be more effective to first
form the amide in the absence of H2, and next pressurize the vessel with H2.
Octanoic acid (1)
Dioctylamine (4)
Octanamide (2)
Octane (5)
Octylamine (3)
Heptane (6)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
N-Octyloctanamide (7)
0
2
4
6
8
10
12
Time [h]
Figure 2 – Time profile for the reductive amination of octanoic acid. Reaction conditions: octanoic acid (1 mmol), 200°C,
6 bar NH3, 50 bar H2, 5 mol% Ru (4 wt% Ru on RuWOx/MgAl2O4), undecane standard (20 μL), CPME (10 mL).

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DOI: 10.1039/D0GC01441A
-H2O
+NH3
O
OH
NH2
O
+H2
-H2O
NH2
OH
NH
(1)
(2)
+H2
+H2
NH2
OH
O
(3)
-NH3
NH
(5)
R
(6)
(4)
O
O
R
R
R
Additional side reaction:
+
OH
NH2
N
H
(7)
Figure 3 – Reaction network for the catalytic reductive amination of carboxylic acids
Catalyst evaluation
These results raise the question how the primary amide is formed, and whether the dehydration of
the ammonium carboxylate is a catalytic or spontaneous reaction. It appears that the catalyst support
is essential for the dehydration towards primary amides. Several supports were screened for their
dehydration activity (Figure 4). Generally, these experiments suggest that the dehydration could be
catalyzed by either basic or acidic sites. On the one hand, the rather basic supports MgAl2O4 and ZrO2
yielded 82% and 85% octanamide (2) respectievely.43,61 On the other hand, the clearly acidic support
Nb2O5, featuring both Brønsted and Lewis acid sites yielded 75% of octanamide (2) and was even able
to promote the dehydration to the nitrile, resulting in 10% octanenitrile.62 TiO2 performed well as
well.55-56 The only slightly acidic SiO2 and the homogeneous Lewis acid catalyst Y(OTf)3 performed
poorly. In the blank reaction, only small amounts of primary amide were formed (4% yield). It should
be noted that in the hydrogenation of primary amides with bimetallic catalysts, a basic support is
recommended to steer the selectivity to primary amines instead than to secondary amines. When
inserting the amide formation as a first step, a basic nature of the support is useful to improve the
catalytic activity as well. For MgAl2O4, ZrO2 and TiO2, CO2- and NH3-TPD measurements were
performed. The measured acidic and basic properties are very similar to those described in literature
(Figure S 7 and Table S 1).55-56,61
Octanamide (2)
Octanenitrile
Octanoic acid (1)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
MgAl O ZrO
MgAl22O4 ZrO2
TiO
TiO2
SiO
SiO2
Y(OTf) Nb O Blank
Y(OTf)33 Nb22O5 Blank
4
2
2
2
5
10 mol%
Figure 4 – Dehydration of ammonium carboxylate, formed from octanoic acid and ammonia, in the presence of different
supports. Reaction conditions: octanoic acid (1 mmol), 200°C, 6 bar NH3, 0.126 g catalyst support, undecane (20 μL), CPME
(10 mL), 1 h.

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Next, a catalyst evaluation was performed. In our previous work, RuWOx-catalysts were proven to be
DOI: 10.1039/D0GC01441A
highly efficient for the reduction of aliphatic amides. Such a bimetallic catalyst contains a noble metal
and a Lewis acid metal oxide, in order to facilitate the adsorption of the amide to the catalyst’s surface.
While the catalyst support only mildly affects catalytic activity in the separate amide reaction, it now
accomplishes the dehydration of the ammonium carboxylate. It is therefore unclear how
RuWOx-catalysts position themselves (in terms of catalytic activity) compared to commercially
available and other highly active amide hydrogenation catalysts. For this reason, several WOx-modified
Ru catalysts were prepared and compared to commercial PGM/C, as well as to the highly active amide
reduction catalyst PtV/hydroxyapatite (Figure 5).57 The commercial catalysts performed poorly: the
carbon supports are not suitable for promoting the dehydration reactions, and up to 36% octanoic acid
(1) was still present after 7 h of reaction time.43 Additionally, the unpromoted noble metals lack amide
hydrogenation activity. Only in the case of Ru/C, a noticeable 34% octylamine (3) yield was formed
along with 12% of the dead-end product N-octyloctanamide (7). PtV/hydroxyapatite performed better;
the basic support ensured a rapid dehydration of the ammonium octanoate, while the promoted Pt
provides a considerable hydrogenation activity.57-58 The catalyst, however, lacks selectivity for the
primary amine; a lot of n-octanol is formed, along with N-octyloctanamide (7) and octane (5)
(selectivities of respectively 20%, 7% and 6%). The RuWOx-catalysts are by far superior. RuWOx/TiO2
and RuWOx/ZrO2 behave very similarly; yields of 74% and 72% octylamine (3), and 11% and 14%
dioctylamine (4) were obtained respectively. RuWOx/MgAl2O4 is, due to its superior hydrogenation
activity, the most active catalyst, leading to a full conversion.43 However, as a result of the consecutive
condensation reaction (primary to secondary amines), the n-octylamine (3) yield is slightly lower, i.e.
70% octylamine (3) and 20% dioctylamine (4). This small drop can be prevented by shortening the
reaction time or adding less catalyst to the reaction mixture; yields of 76% octylamine (3) and 8%
dioctylamine (4) were obtained after a reaction with 6.5 mol% Ru instead of 7.5 mol% (5 h under H2).
Octanoic acid (1)
Octanamide (2)
Octane (5)
Heptane (6)
N-octyloctanamide (7) Octanol
Dioctylamine (4)
Octylamine (3)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Figure 5 – Catalyst evaluation for the reductive amination of octanoic acid. Reaction conditions: fed-batch reaction,
octanoic acid (1 mmol), 200°C, 6 bar NH3 (initial 2 h), 6 bar NH3 + 50 bar H2 (5 h), 7.5 mol% PGM, undecane (20 μL), CPME
(10 mL).

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DOI: 10.1039/D0GC01441A
Influence of impurities
Industrial streams of (bio-based) carboxylic acids never have a purity of 100%. Common impurities are
cations, e.g. in the form of sodium salts, or water. Therefore, with the aim of achieving an industrially
viable process, the influence of impurities was investigated (Figure 6). In general, the catalyst deals
very well with these impurities. Small quantities of sodium, e.g. added as 5 % of sodium octanoate, do
not have a large effect on the catalytic activity. However, the presence of a larger quantity of strong
base induces the decarboxylation of sodium salts to alkanes, leading to 21% heptane (6) yield with
0.2 equivalents NaOH.59 A reaction with pure sodium octanoate did not yield any hydrogenation
products. The addition of 1 vol% water did not hinder the dehydration of the ammonium octanoate,
but decreased the hydrogenation rate significantly (35% yield, 90% selectivity for n-octylamine (3) after
4 h). We demonstrated before that solvents with alcohol functional groups preferentially adsorb on
the W Lewis acid sites of the catalyst, lowering the amide hydrogenation rate.43 Thus, whereas the
catalyst keeps its selectivity, in order maintain a high activity, it is important to have as little water in
the reaction mixture as possible. Since the reaction is performed in CPME, this is a relatively simple
task. Water has an extremely low solubility in CPME; as little as 0.35 vol% water would result in phase
separation at room temperature. Additionally, Dobson et al. clearly demonstrated that drying zeolites
could easily remove any water, even at 200°C, ensuring a rapid amide hydrogenation.60 Low quantities
of water do not hinder the reaction (Figure 6 and S 3).
Octanoic acid (1)
Heptane (6)
Octylamine (3)
Octanamide (2)
N-octyloctanamide (7)
Octane (5)
Dioctylamine (4)
100%
80%
60%
40%
20%
0%
No
hydrogenation
products
/
0.05 eq NaOH 0.2 eq NaOH
1 eq NaOH
1 eq H2O
1 vol% H2O
Additives to reaction mixture
Figure 6 – Influence of sodium and water on the catalytic system. Reaction conditions: batch reaction, octanoic acid (1 mmol),
200°C, 6 bar NH3, 50 bar H2, 5 mol% Ru (4 wt% Ru on RuWOx/MgAl2O4), undecane (20 μL), CPME (10 mL), 4 h.

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Recyclability of the catalyst
A recycling test was performed to check the stability of the RuWOx-catalyst. A first series of recycling
tests was unsuccessful; after each run with RuWOx/MgAl2O4, there was a significant drop in catalytic
activity (Figure S 4). ICP measurements clearly showed that there was a lot of Mg, Ru and W leaching.
Since no leaching was observed when performing this recycling test with octanamide (2) as the
employed substrate and the addition of 1 eq. water (Figure 7), a logical cause is the partial dissolution
of the support, caused by the carboxylic acid.43,65 As a result, promoted Ru nanoparticles (~2 nm
diameter) would float freely in solution, resulting in positive ICP measurements. This hypothesis was
proven to be correct; replacing the spinel with insoluble TiO2 (rutile) or ZrO2 allowed to maintain the
catalytic activity over at least 4 consecutive runs (Figure 8 and Figure S 6).66-67
Thus, for the production of amines from carboxylic acids, we propose a fed-batch set-up in which
RuWOx/TiO2 or RuWOx/ZrO2 is the employed catalyst; after completing a relatively quick dehydration
of the ammonium carboxylate (under NH3 atmosphere), H2 is fed to the reactor and the hydrogenation
is performed. This method bypasses several issues of a batch reaction, such as side reactions and
reaction inhibition due to amine formation. Although the employed RuWOx/TiO2 or RuWOx/ZrO2
catalysts are slightly less active than RuWOx/MgAl2O4, they can perfectly withstand the carboxylic
acid’s corrosivity.66-67
Octanamide
N-octyloctanamide
Octane
Dioctylamine
Heptane
Octylamine
Octanamide
Octane
Heptane
Octylamine
N-octyloctanamide Dioctylamine
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Fresh
Recycle 1
Recycle 2
Recycle 3
Fresh
Recycle 1
Recycle 2
Recycle 3
Recycle 4
Figure 7 – Recycling of RuWOx/MgAl2O4. Reaction conditions:
batch reaction, octanamide (1 mmol), water (1 eq.) 200°C,
6 bar NH3, 50 bar H2, 5 mol% Ru, undecane (20 μL), CPME
(10 mL), 4 h.
Figure 8 – Recycling of RuWOx/TiO2. Reaction conditions:
fed-batch reaction, octanoic acid (1 mmol), 200°C, 6 bar NH3
(initial 2 h), 6 bar NH3 + 50 bar H2 (5 h), 7.5 mol% Ru,
undecane (20 μL), CPME (10 mL).

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DOI: 10.1039/D0GC01441A
Substrate scope investigation
Finally, a substrate scope investigation was performed to illustrate the range of applicability (Table 1
& Table S 2). High yields of the corresponding primary amines were obtained for all linear
monofunctional carboxylic acids (entries 1–7). These high yields and selectivities (70–85% at nearly full
conversion) are consistently obtained for carboxylic acids with chain lengths between C4 and C14. As
one might expect, the more reactive corresponding ester of such an acid is rapidly converted towards
the amine as well (entry 4). Any unsaturated C-C bonds, like in alkenes and aromatic rings are also
readily reduced, as can be expected for a Ru catalyst (entries 5, 9, 10, 19, 21, 26, 28, 29). Preferably,
the trans-isomer is formed (entries 10, 21, 29). For branched substrate molecules a clear drop in
catalytic activity was observed (entries 8, 11–19). These more bulky molecules are sterically hindered
and require a longer reaction time. However, when the aliphatic carboxylic acid is branched at the -
position, the condensation reaction towards secondary amines is nearly completely halted (entries 11–
19). This results in extremely high selectivities and yields for the primary amine, with selectivities up
to 99%. Even after a reaction time of 5 days with the very bulky 2-propylpentanoic acid (entry 17), only
7% is converted towards the corresponding secondary amine, while the primary amine yield amounts
to 82%. Any stereocenters on the -position, however, will be lost due to the imine-enamine
tautomerism. Dicarboxylic acids have the tendency to form cyclic molecules, as was also the case for
diamides. Thus, reactions with adipic acid yielded high amounts of azepane and caprolactam (53% and
39% yield respectively; entry 20). Only traces of hexamethylenediamine were formed. Similar results
were observed for isophthalic acid, with formation of a bicyclic secondary amine (entry 21). Longer
dicarboxylic acids, such as sebacic acid, do not have this tendency towards cyclization. A yield of at
least 30% 1,10-diaminodecane was observed. A reaction with an amino acid, i.e. (L)-valine, led mainly
to decarboxylation products (entry 23). However, protecting groups on the amine functionality of the
amino acid were helpful to obtain the desired diamine (entry 24). As one can expect, based on the
proposed reaction scheme (Figure 3), alcohols are easily transformed into amines (entries 25-26). Our
catalytic system seems to be extremely selective for the amination of secondary alcohols, resulting in
e.g. 98% yield of 2-octylamine form 2-octanol (entry 25). Aliphatic C-Cl bonds are liable to nucleophilic
substitution with NH3, possibly followed by cyclization to a lactam, or directly with the formed primary
amine. A reaction with 5-chlorovaleric acid mainly resulted in the formation of piperidine (85%), with
2-piperidinone (9%) as the main side product. The formation of these products is not surprising;
industrially, 11-aminoundecanoic acid (polyamide 11 precursor) is synthesized from
11-bromoundecanoic acid in the presence of NH3 (spontaneous reaction, even at low temperature
< 90°C).64 Aromatic C-halogen bonds are degraded upon hydrogenation of the aromatic ring. The major
product after an attempted reductive amination of pentafluorobenzoic acid was cyclohexane (55%
yield, Table S 2). Finally, the stability of ether bonds was investigated. Ether bonds both located in and
(especially) substituted on aromatics rings are somewhat unstable (entries 28-29). However, aliphatic
ether bonds are very stable (entry 30).

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DOI: 10.1039/D0GC01441A
Table 1 – Substrate scope investigation with RuWOx-catalyst.
[Ru] (5 mol%), 200°C
1 mmol acid groups, 10 mL CPME
O
R
NH2
R
N
R
+
R
OH
H
1. 6 bar NH3
2. 6 bar NH3 + 50 bar H2 (6.5 h)
X a
S b
[%]
S b
[%]
Substrate
Main product
[%]
Minor product
O
N
H
NH2
1
2
3
4
95
85
5
OH
O
NH
NH2
> 99
95
76
80
76
13
8
OH
O
NH
NH2
NH2
OH
O
O
NH
NH
96
12
O
O
O
4
5
7
NH2
NH2
NH2
5
6
7
8
87 c
97
81
76
70
8
OH
OH
OH
4
5
7
4
5
7
4
5
7
NH
NH
16
20
18
> 99
79
O
NH
76
81
NH2
OH
O
NH2
N
9
96 c
99 c
H
8
OH
O
NH2
81
N
H
10
11
OH
(57d)
O
O
N
NH2
NH2
NH2
NH2
H
11
12
13
90
> 99 e
76
99
96
99
< 1
3
OH
OH
N
H
O
N
H
< 1
OH
O
N
14
47
92
< 1
H
OH

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O
DOI: 10.1039/D0GC01441A
NH2
NH2
NH2
NH2
N
H
15
16
17
91 f
18
93 f
96
3 f
OH
O
N
H
< 1
8 g
OH
OH
O
N
H
94 g
88 g
O
N
18
19
20
74
99
87
53
< 1
6
H
OH
O
53 h
OH
NH2
H
N
H
N
O
O
> 99 i
39
HO
OH
O
H
N
O
O
NH2
11
21
> 99
57
HO
HO
OH
(73d)
H2N
H2N
O
NH2
NH
5
22
23
24
> 99
94
30
54
20
55
5
OH
NH2
5
5
O
COOH
NH2
NH2
NH2
N
H
O
COOH
NH2
BOC
> 99
37
N
H
NH2
NH2
25 j
26
> 99
> 99
98
50
1
NH2
OH
COOH
NH2
NH2
10
OH
O
H
H
N
N
O
27
> 99
85
9
Cl
OH
NH2
O
O
28
29
30
> 99
> 99
96
43
44
84
10
COOH
NH2
O
O
COOH
COOH
O
NH2
29
NH2
(22d)
NH2
N
H
8
O
O
O
a Conversion, remaining substrate is the primary amide. b Selectivity. c aromatic ring or alkene is
f
hydrogenated. d Diastereomer excess. e After reaction time of 16 h. After reaction time of 48 h.
g After reaction time of 120 h. h batch reaction for 14h. i 1 mmol diacid in reactor. j No pre-treatment
with NH3 overnight.

Page 11 of 14
Green Chemistry
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DOI: 10.1039/D0GC01441A
Conclusion
In conclusion, these bimetallic and bifunctional ruthenium – tungsten catalysts perform excellently for
the direct reductive amination of carboxylic acids. The employed catalytic system is green, recyclable
and relatively cheap. We also demonstrated that the catalyst is tolerant for common impurities (e.g.
cations such as Na+ or water), although it is best to work with as pure as possible reactant streams.
Finally, an extensive substrate scope investigation was performed. Good yields and selectivities for the
corresponding primary amine were achieved, with values up to 96% and 99% respectively. To our
knowledge, this is the first report of a (heterogeneous) reductive amination system for carboxylic acids,
yielding primary amines selectively.
Experimental section
Reactions
Reactions were performed in a 25 mL pressure Parr batch reactor. In a typical fed-batch reaction, the reactor is filled with a
carboxylic acid (e.g. octanoic acid), RuWOx-catalyst (5 mol%, 4 wt% Ru, Ru-W ratio of 8-1), undecane (internal standard, 20 μL)
and cyclopentyl methyl ether (CPME, 10 mL). Then, the reactor is sealed, purged, pressurized with the desired amounts of
NH3 (typically 6 bar NH3) and heated to the desired temperature (200°C, stirred at 830 rpm). After the appropriate reaction
time the second gas (H2) was added. For safety reasons, the reactor is first cooled down in an ice bath, after which a desired
amount of H2 is fed to the reactor (50 bar). After a reaction time of 6h30 at 200°C, the reactor is cooled down for the second
time in another ice bath. The pressure is then released after which the reactor can be opened. The reaction mixture is
transferred to a glass reaction vial (11mL) which is then sealed and centrifuged. The mixture is then analyzed via GC, GC-MS
and NMR.
Recycling test
After each reaction, the catalyst was separated from the reaction mixture and washed 2x with ethanol. The catalyst was dried
in an oven at 60°C overnight and was reused afterwards. Small quantities of catalyst (1%) that were lost in the process, were
replenished with fresh catalyst.
Author information
Corresponding Author
E-mail: dirk.devos@kuleuven.be.
ORCID
Robin Coeck: 0000-0002-0630-3753.
Funding
R.C. thanks the FWO for his SB PhD fellowship. D.E.D.V. acknowledges FWO for research project
funding, as well as KULeuven for funding in the Metusalem program Casas.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors deeply appreciate the assistance of Thomas Cuypers & Sam Van Minnebruggen, Carlos
Marquez and Paul Van der Aerschot with NH3- & CO2-TPD experiments, ICP-OES measurements and
technical support.

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DOI: 10.1039/D0GC01441A
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