Formation of imines by selective gold-catalysed aerobic oxidative coupling of alcohols and amines under ambient conditions

Article abstract of DOI:10.1039/c0gc00126k

The formation of imines by aerobic oxidative coupling of mixtures of alcohols and amines was studied using gold nanoparticles supported on titanium dioxide, TiO₂, as a heterogeneous catalyst. The reactions were performed at ambient conditions (room temperature and atmospheric pressure) and occurred with excellent selectivity (above 98%) at moderate conversion under optimized conditions. The effect of catalytic amounts of different bases was studied, along with reaction temperature and time. Utilisation of a selective catalyst system that uses dioxygen as an oxidant and only produces water as by-product represents a new green reaction protocol for imine formation.

Full text of DOI:10.1039/c0gc00126k

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Formation of imines by selective gold-catalysed aerobic oxidative coupling
of alcohols and amines under ambient conditions
Søren Kegnæs,a Jerrik Mielby,a Uffe V. Mentzel,a,b Claus H. Christensenc and Anders Riisager*a
Received 19th May 2010, Accepted 21st June 2010
First published as an Advance Article on the web 13th July 2010
DOI: 10.1039/c0gc00126k
The formation of imines by aerobic oxidative coupling of mixtures of alcohols and amines was
studied using gold nanoparticles supported on titanium dioxide, TiO2, as a heterogeneous
catalyst. The reactions were performed at ambient conditions (room temperature and atmospheric
pressure) and occurred with excellent selectivity (above 98%) at moderate conversion under
optimized conditions. The effect of catalytic amounts of different bases was studied, along with
reaction temperature and time. Utilisation of a selective catalyst system that uses dioxygen as an
oxidant and only produces water as by-product represents a new green reaction protocol for imine
formation.
In addition to the above-mentioned oxidations, interesting
Introduction
studies have also recently been performed on oxidation of
In recent years there has been a rising demand for efficient
amines and mixtures of amines and alcohols or aldehydes. Thus,
heterogeneously catalysed processes for the oxidation of alcohols
supported gold nanoparticles have been used in oxidation of
for production of both fine and bulk chemicals.1 So far, these
amines to amides,23,24 azo-compounds,25 and – prior to this
industrially important oxidations have often been carried out
study – in formation of imines26,27 and secondary amines.28 So
using stoichiometric amounts of high-valent inorganic reagents,
far, the application range of supported gold is still limited in
such as chromate or permanganate, which inevitably leads to the
generation of large amounts of metal waste.2
In order to avoid undesirable waste formation, considerable
organic chemistry, and the increasing number of reports on
oxidation of nitrogen-containing hydrocarbons thus represents
a very interesting development in this emerging field.
effort has been put into the development of aerobic oxidation
In this work, we show that gold nanoparticles supported
methods using molecular oxygen as the stoichiometric reagent.
on titanium dioxide, TiO2, are an active and highly selective
These methods represent a much greener and highly atom-
heterogeneous catalyst in the oxidative coupling of alcohols
efficient alternative, as oxygen is a cheap and abundant oxidant
(particularly benzylic alcohols) with amines to form the cor-
that produces water as the only by-product. Efficient aerobic ox-
responding imines, as depicted in Scheme 1. The employed
idation is, however, strongly dependent on a good heterogeneous
catalyst which readily provides oxygen activation.3
Dissolved gold metal has rich coordination and organometal-
oxidising agent was molecular oxygen and the reactions were
conducted under ambient conditions (room temperature and
atmospheric pressure). The effect of adding catalytic amounts
lic chemistry.4 In contrast, bulk gold metal is chemically inert and
of different bases was studied along with the effect of reaction
the element has therefore often been regarded as a poor catalyst.
temperature and time. Catalytic and selective synthesis of
imines at ambient condition with dioxygen and a catalytic
amount of base is an attractive extension of current “green”
oxidations.
Fundamental studies by Bond et al.,5 Hutchings,6 Haruta
et al.7 and Prati and Rossi8 have triggered renewed interest in
heterogeneous gold catalysis, and during recent years it has been
shown that supported gold nanoparticles (typically with particle
sizes of 1–5 nm) are surprisingly active and selective catalysts in
a number of oxidation reactions of organic substrates.9-11 For
instance, gold nanoparticles have been successfully used in the
Scheme 1 Au-catalysed formation of imines by oxidative coupling of a
primary or secondary alcohol and a primary amine.
oxidation of alcohols to aldehydes,12 carboxylic acids8,13,14 or
esters,15,16 in the oxidation of aldehydes to esters17,18 or acids,19,20
and in the epoxidation of alkenes.21,22
The oxidation procedure was performed successfully with
a number of primary and secondary benzylic alcohols and
aCentre for Catalysis and Sustainable Chemistry, Department of
Chemistry, Technical University of Denmark, DK-2800, Kgs. Lyngby,
Denmark. E-mail: ar@kemi.dtu.dk; Fax: +45 4588 3136;
Tel: +45 4525 2233
primary amines, demonstrating the benign reaction protocol
to be versatile and applicable to a broad range of substrates.
This makes the method an attractive alternative to previously
reported approaches, including the recently reported synthe-
sis route by Gnanaprakasam et al.29 using a homogeneous
ruthenium-based catalyst.
bCenter for Sustainable and Green Chemistry, Department of Chemistry,
Technical University of Denmark, DK-2800, Kgs. Lyngby, Denmark
cHaldor Topsøe A/S, Nymøllevej 55, DK-2800, Kgs. Lyngby, Denmark
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Table 2 N-benzylidenehexan-1-amine formation from oxidative cou-
pling of benzyl alcohol and 1-hexylamine as a function of the amount
of base added.a
Results and discussion
Initially, benzyl alcohol (A) and 1-hexylamine (B) were used as
substrates to study the effects of different reaction parameters in
the synthesis of N-benzylidenehexan-1-amine (C), see Scheme 2.
Entry
Catalyst
Added KOCH3 [mol%]b
Yield [%]
1
2
3
4
5
Au/TiO2
Au/TiO2
Au/TiO2
Au/TiO2
Au/TiO2
0
5
10
20
30
1
45
49
52
52
Scheme 2 Synthesis of N-benzylidenehexan-1-amine (C) from benzyl
alcohol (A) and 1-hexylamine (B) by oxidative coupling in the presence
of Au/TiO2 catalyst.
a All reactions were carried out at room temperature under atmospheric
pressure of oxygen for 24 h. b As mole base/mole alcohol.
The results in Table 1 show the effect on conversion and
selectivity after a reaction time of 24 h by addition of different
bases to the reaction. Methanol solutions of lithium methoxide,
sodium methoxide, and potassium methoxide were purchased
and applied as base reagents. In principle, however, the solid
methoxides or corresponding hydroxides could also have been
utilised directly.
As is evident from Table 1, it proved possible to couple benzyl
alcohol and 1-hexylamine at ambient conditions, forming N-
benzylidenehexan-1-amine in very high selectively (97–98%).
Only small amounts of N-hexylbenzamide were formed (con-
firmed by GC-MS). The gold-catalysed formation of amides
from alcohols and amines has previously been reported by Chris-
tensen et al.23 at high temperatures, i.e. >90 ◦C. The formation
of amides was, however, suppressed at lower temperature and
only the imines were formed at room temperature.
The presence of a catalytic amount of base was found to be
essential for the conversion of substrate (Table 1, entry 1–3),
since no reaction occurred in the absence of base (Table 1, entry
4). Additionally, the yield of imine was apparently dependent
on the alkaline metal applied in the methoxide base. Hence,
lithium methoxide resulted in an overall imine yield of 17%,
sodium methoxide in 39% and potassium methoxide in 49%,
under identical reaction conditions. This observation suggests
a possible interference of the alkali ions with the gold catalysts
resulting in a promoting effect. Promoted gold catalysts with
alkali or alkaline earth metal have previously been reported in
the literature for carbon monoxide oxidation.30,31
Carrying out the reaction with pure TiO2 (Table 1, entry 5)
did not result in any conversion, which verified that the gold
nanoparticles were required to obtain catalytic activity.
The effect of potassium methoxide was further investigated by
altering the catalytic amount from 0% to 30% (mole base/mole
alcohol). Table 2 shows the yield of N-benzylidenehexan-1-
Table 3 Yield of N-benzylidenehexan-1-amine formed from oxidative
coupling of benzyl alcohol and 1-hexylamine as a function of the
reaction temperature.a
Entry
Catalyst
T [◦C]
Yield [%]
1
2
3
4
Au/TiO2
Au/TiO2
Au/TiO2
Au/TiO2
20
40
60
65
49
56
57
44
a All reactions were carried out under atmospheric pressure of oxygen
for 24 h using 10 mol% KOCH3 (mole base/mole alcohol).
amine formed as a function of the amount of potassium
methoxide added, after 24 h of reaction.
The yield of imine increased significantly from around 1%
with no added base, to a yield of 49% at 10 mol% potassium
methoxide, clearly signifying the requirement for having base
present during the reaction, as shown previously for other Au-
catalysed oxidations.16,17 Further increase of the amount of base
to 20 or 30 mol% had little effect on the yield. It is worth noting
that the reaction selectivity remained high and unaffected by the
amount of base in all reactions.
Table 3 shows the effect on formation of N-benzylidenehexan-
1-amine by varying the reaction temperature. The temperature
effect was investigated by maintaining the amount of base at
10 mol% potassium methoxide and the reaction time at 24 h.
As shown in Table 3, the yield only increased slightly from
49% at room temperature to 56% at 40 ◦C and to 57%
at 60 ◦C, respectively. However, at 65 ◦C (boiling point of
methanol) the yield dropped to 44%, suggesting that the rate
of formation was possibly reduced due to inadequate oxygen
solubility. Importantly, the increased temperatures had no effect
on the selectivity and the only by-product formed was N-
hexylbenzamide in yields less than 2–3%.
In order to investigate if oxygen solubility was rate-limiting
(also at lower temperatures), a reaction was performed in
a thoroughly stirred autoclave at room temperature at 10
bars of oxygen in presence of 10 mol% potassium methoxide.
Under these conditions the amount of dissolved oxygen in the
methanol solvent was expected to be significantly higher than
at ambient pressure. After a reaction time of 24 h 47% of the
1-hexylamine was converted into N-benzylidenehexan-1-amine
with 92% selectivity, corresponding to an overall imine yield
of 43%. This showed that an increased amount of dissolved
oxygen had no significant effect on the conversion, but that the
selectivity was decreased somewhat as more amide was formed.
Table 1 Synthesis of N-benzylidenehexan-1-amine from benzyl alco-
hol and 1-hexylamine using different bases.a
Entry
Catalyst
Base
Conversion [%]
Selectivity [%]
1
2
3
4
5
Au/TiO2
Au/TiO2
Au/TiO2
Au/TiO2
pure TiO2
LiOCH3
NaOCH3
KOCH3
None
18
40
51
1
97
98
98
97
0
KOCH3
0
a All reactions were carried out at room temperature under atmospheric
pressure of oxygen for 24 h using 10 mol% base (mole base/mole
alcohol).
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Table 4 Conversion and selectivity obtained in the oxidative couplings of 1-hexylamine (B) and different alcohols (see Scheme 1 and Scheme 2).a
Entry
1
Alcohol
Product
Conversion [%]
51
Selectivity [%]
98
2
3
63
14
99
99
4
0
—
a Reactions were carried out at room temperature under atmospheric pressure of oxygen for 24 h using 10 mol% KOCH3 (mole base/mole alcohol).
Thus, the limited increase in yield as a function of temperature
could not be directly related to the amount of dissolved oxygen.
In an attempt to increase the yield of N-benzylidenehexan-
1-amine formation, the reaction was also performed using
ten times more catalyst, i.e. 875 mg of catalyst (0.2 mol%) instead
of 87.5 mg (0.02 mol%) as used in the prior experiments. Product
formation in analogous reactions with different amounts of
catalysts was followed as a function of the reaction time, shown
in Fig. 1.
reaction. This observation indicated that reaction progression
was governed by the substrate availability.
The protocol for the oxidative coupling of alcohol and amine
mixtures was extended to investigate imine formation more
generally. A number of alternative alcohols and amines were
therefore used instead of benzyl alcohol and 1-hexylamine,
including a range of primary and secondary benzyl alcohols and
different types of primary amines; see Table 4 and Table 5. All
reactions were performed by the general oxidation procedure, i.e.
0.02 mol% catalyst (87.5 mg), 10 mol% potassium methoxide,
room temperature, ambient pressure oxygen, 24 h of reaction
time (no optimisation was attempted). Table 4 compiles the
conversion and selectivity results obtained in the oxidative
couplings of 1-hexylamine and different alcohols.
All the examined alcohol substrates: benzyl alcohol, cinnamyl
alcohol, and the secondary alcohol 1-phenylethanol, were
oxidised and coupled with 1-hexylamine to produce the desired
imine products (Table 4, entry 1–3) in high selectivity. How-
ever, the more sterically demanding alcohol diphenylmethanol
(Table 4, entry 4) surprisingly failed to undergo oxidation.
Recently Mitsudome et al.32 showed that it is possible to oxidize
both 1-phenylethanol and diphenylmethanol to the ketone with
gold nanoparticles. Accordingly, it seems therefore likely that
the coupling reaction with the amine was the demanding step in
the performed reaction with diphenylmethanol. Of the examined
alcohol substrates, the conversion of cinnamyl alcohol (Table 4,
entry 2) was the highest, with an overall yield of 62%.
Fig. 1 Yield of N-benzylidenehexan-1-amine formed from oxidative
coupling of benzyl alcohol and 1-hexylamine as a function of the
reaction time. Reactions were carried out at room temperature under
atmospheric pressure of oxygen using 10 mol% KOCH3 with 87.5 mg
(0.02 mol%) (᭹) and 875 mg (0.2 mol%) (¥) of Au/TiO2 catalyst,
respectively.
Table 5 shows the conversion and selectivity obtained when
benzyl alcohols were reacted with different amines. As seen in
Table 5, all of the applied amine substrates reacted with high
selectivity (above 98%) with benzyl alcohol to give the desired
products. 3-Pentylamine (Table 5, entry 1) underwent compara-
ble conversion as to 1-hexylamine, whereas the aromatic aniline
(Table 5, entry 2) and benzyl amine (Table 5, entry 3) experienced
lower conversion than both aliphatic amines. Similar results
have also recently been reported by Sun et al.27 who suggested
As expected, the yield increased with both reaction time and
the amount of added catalyst. Hence, for the reaction containing
0.02 mol% (87.5 mg) of catalyst the yield of imine increased from
49% after 24 h to 53% after 48 h, whereas the yield increased
from 71 to 76% after 24 and 48 h, respectively, for the reaction
containing 0.2 mol% (875 mg) of catalyst. Notably, the initial
reaction rates were found to be practically identical for the two
reactions despite the much higher content of catalyst in the latter
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Table 5 Conversion and selectivity obtained in the oxidative couplings of benzyl alcohol (A) and different amines (see Scheme 1 and Scheme 2).a
Entry
1
Amine
Product
Conversion [%]
53
Selectivity [%]
99
2
3
7
99
23
100
a Reactions were carried out at room temperature under atmospheric pressure of oxygen for 24 h using 10 mol% KOCH3 (mole base/mole alcohol).
that the high basicity of aliphatic amines facilitates the proton
abstraction step in the oxidation of the alcohol, which is believed
to be the first and rate-determining step in the overall reaction.
The employed gold catalyst was commercial gold on titanium
dioxide (1 wt% Au/TiO2, supplied by Mintek) with a Brunauer–
Emmett–Teller (BET) surface area of 49 m2 g-1. The size of the
gold nanoparticles has previously been determined to be 4–8 nm
by means of transmission electron microscopy (TEM).20
Conclusions
In this work we have shown that gold nanoparticles supported on
titanium dioxide very selectively (above 98%) catalyse the oxida-
tive coupling of alcohols and amines to form the corresponding
imines. The reactions were conducted at room temperature with
atmospheric pressure of dioxygen. Only limited effect on the
reaction progression was found when increasing the temperature
and increasing the catalyst amount, indicating the substrate
availability to be limiting in the reactions. Furthermore, the
necessity of adding a catalytic amount of base was proven.
Different alkaline metal methoxides were applied as a base for
the reaction and potassium methoxide was shown to be the best,
thus suggesting a promoting effect of the cation. This aspect will
be examined in detail in future studies.
Oxidation procedure
In a typical experiment, alcohol (20 mmol), amine (20 mmol),
anisole (internal standard, 1 mmol), base (alkaline metal
methoxide, 2 mmol) and methanol (50 mmol) were charged into
a 25 ml two-necked, round-bottomed flask equipped with a con-
denser and a stirring bar. The reactor system was connected to a
manifold providing molecular O2 for the oxidation (atmospheric
pressure). The system was flushed with O2 and 87.5 mg of the
catalyst was added, corresponding to an Au/substrate molar
ratio of 1/4500 (i.e. 0.02 mol% Au). The reaction mixture was
either kept at ambient temperature (around 293 K) or heated
using an oil bath for 24 h.
The introduced oxidative coupling reaction was applied to
a number of different alcohols and amines to demonstrate
the versatility of the reaction protocol to a broader range of
substrates. Furthermore, the reactions were intentionally carried
out at relatively high substrate concentration under benign
reaction conditions to comply with some of the most important
principles of green and sustainable chemistry.
Product analysis
During the oxidation reactions samples of 0.1 ml were peri-
odically collected, filtered and analysed by GC-FID and GC-
MS using a HP-5 column from Agilent Technologies Inc. The
amounts of substrates and reaction products were quantified
using anisole as an internal standard.
Conversions and selectivities were calculated based on con-
verted amine. The reported values converged with 5% (abs.)
with the analogous values calculated based on converted
alcohol.
Experimental
Materials
All chemicals and reagents were purchased from commer-
cial sources and used without further purification; anisole
(99%, Sigma-Aldrich), benzyl alcohol (>99%, Aldrich), 1-
hexylamine (99%, Aldrich), lithium methoxide (LiOCH3, 1.0 M
in methanol, Aldrich), sodium methoxide (NaOCH3, 25 wt%
in methanol, Sigma-Aldrich), potassium methoxide (KOCH3,
25 wt% in methanol, Aldrich), methanol (>99.6%, Sigma-
Aldrich), diphenylmethanol (>99%, Fluka), 1-phenylethanol
(98%, Aldrich), cinnamyl alcohol (98%, Aldrich), aniline (97%,
BDH Chemicals), 3-pentylamine (97%, Aldrich), benzylamine
(98%, Fluka), oxygen (>99.9%, Air Liquide).
Acknowledgements
The work was supported by the Danish National Research
Foundation (PhD studentship for Uffe V. Mentzel).
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