One-pot synthesis of amides by aerobic oxidative coupling of alcohols or aldehydes with amines using supported gold and base as catalysts

Article abstract of DOI:10.1039/c2cc16768a

Synthesis of amides by aerobic oxidative coupling of alcohols or aldehydes with amines via intermediate formation of methyl esters is highly efficient and selective when using a catalytic system comprised of supported gold nanoparticles and added base in methanol. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc16768a

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COMMUNICATION
One-pot synthesis of amides by aerobic oxidative coupling of alcohols or
aldehydes with amines using supported gold and base as catalystsw
Søren Kegnæs, Jerrik Mielby, Uffe V. Mentzel, Thomas Jensen, Peter Fristrup and
Anders Riisager*
Received 1st November 2011, Accepted 10th January 2012
DOI: 10.1039/c2cc16768a
Synthesis of amides by aerobic oxidative coupling of alcohols or
aldehydes with amines via intermediate formation of methyl esters is
highly efficient and selective when using a catalytic system com-
prised of supported gold nanoparticles and added base in methanol.
Scheme 1 Synthesis of amides by aerobic oxidative coupling of
alcohols or aldehydes with amines using supported gold nanoparticles
Selective oxidation of alcohols is one of the most important
and base as catalysts.
reactions in organic chemistry and finds use in the manufacture
Here, we show that the combination of supported gold
of many bulk commodities, high-value fine chemicals, agro-
nanoparticles and base forms an efficient and highly selective
chemicals, and pharmaceuticals. Traditionally, oxidations of
catalytic system for the one-pot, two-step synthesis of amides
alcohols are performed with stoichiometric amounts of high-
by aerobic oxidative coupling of alcohols or aldehydes with
valent inorganic oxidants such as chromate or permanganate,
amines, see Scheme 1.
which inevitable leads to the generation of large amounts of
In the first step of the reaction, the gold-catalysed oxidation of
metal waste. In the search for a more sustainable chemical
the alcohol or aldehyde in methanol yields a methyl ester.16 In
production, researchers have put considerable effort into the
the second step, amine is added and the ester is converted into the
development of catalytic oxidations using air or molecular
dioxygen as the stoichiometric oxidant.1,2 From the standpoint of
desired amide by base-catalysed aminolysis. As the same base is
promoting both steps of the reaction, the synthesis can be
green chemistry these aerobic oxidations are attractive, because
performed in a convenient one-pot procedure without cumbersome
dioxygen is a cheap and abundant oxidant that produces water as
isolation or purification of the intermediate. The employed oxidant
the only by-product.
Since the first fundamental studies by Bond et al.,3 Hutchings,4
is pure dioxygen and the reaction can be performed under mild
Haruta et al.,5 and Prati and Rossi6 supported gold nanoparticles
have been recognised as surprisingly active and selective catalysts
for a number of aerobic oxidations.7 For instance, supported
gold nanoparticles have been used for oxidation of alcohols to
aldehydes,8 carboxylic acids9 and esters.10,11 Furthermore,
interesting results have been reported for the oxidation of amines
and oxidative coupling of alcohols with amines. In particular,
supported gold nanoparticles have been used in the synthesis of
azo-compounds,12 imines,13 secondary amines,14 and amides.15
Although the increasing number of reports on oxidations
with nitrogen-containing compounds represents an interesting
development, the field still needs further improvement in terms
of catalytic efficiency and practical applicability. For instance,
under mild reaction conditions the oxidation of alcohols often
requires a strongly alkaline solution and in some systems this
represents a strong limitation as various side reactions may
decrease the selectivity.2
reaction conditions (25–65 1C, atmospheric pressure).
Initially, we used benzyl alcohol as a model compound to
study the gold catalysed oxidative esterification in methanol.
The results from these experiments showed that methyl benzoate
could be obtained in 92% yield at full conversion after 24 hours
employing KOMe as a base and Au/TiO2 as a heterogeneous
catalyst. Under the same reaction conditions, we found that
addition of hexylamine to methyl benzoate resulted in the
formation of N-hexylbenzamide (see ESIw).
The two base-promoted reactions were combined in a novel
one-pot reaction procedure and tested for the oxidative
coupling of a number of substrates, including different alcohols,
aldehydes and amines. All reactions were performed under
identical reaction conditions and no optimisation was attempted
for the individual substrates.
Table 1 compiles the results from the oxidative coupling of
different alcohols and aldehydes with N-hexylamine to form
the corresponding N-hexylamides. All examined alcohols,
i.e. benzyl alcohol, cinnamyl alcohol, and 1-heptanol, were
oxidised with high selectivity to form the corresponding methyl
ester. While the oxidation of the aromatic alcohols achieved full
conversion in 24 hours, 1-heptanol only achieved 34% conversion
at room temperature (Table 1, entry 5). Higher yields of aliphatic
Centre for Catalysis and Sustainable Chemistry, Department of
Chemistry, Technical University of Denmark, Building 207,
2800 Kgs. Lyngby, Denmark. E-mail: ar@kemi.dtu.dk
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc16768a
c
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Chem. Commun., 2012, 48, 2427–2429 2427

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Table 1 Yield of ester and amide obtained in the oxidative coupling
of alcohols and aldehydes with N-hexylaminea
Table 2 Yield of ester and amide obtained in the oxidative coupling
of benzyl alcohol with aminesa
Alcohol/
Entry aldehyde
Ester
Amide
Ester
Amide
Product
yield [%] yieldb [%]
Entry Amine
Product
yield [%] yieldb [%]
1
92
93
90 (59)
92 (64)
1
92
92
92
90 (59)
54 (15)
38 (16)
2
3
2
3
4
>99
74
46 (34)
74 (18)
34 (25)
4
5
92
—
5
6
34
92
92
—
6
41c
>99
73
99 (84)
73 (73)
a
R = (CH2)5CH3. Reaction conditions: benzyl alcohol (5 mmol),
methanol (50 mmol), anisole (0.5 mmol), KOMe (1.25 mmol), 1 wt%
Au/TiO2 (197 mg). After 24 hours 25 mmol amine was added and the
7
b
mixture was heated to 65 1C for additional 96 hours. Number in
parenthesis is the yield after 24 hours. Isolated yield.
c
a
R = (CH2)5CH3. Reaction conditions: alcohol or aldehyde (5 mmol),
methanol (50 mmol), anisole (0.5 mmol), KOMe (1.25 mmol), 1 wt%
Au/TiO2 (197 mg). After 24 hours 25 mmol amine was added and the
b
mixture was heated to 65 1C for additional 96 hours. Number in
parenthesis is the yield obtained after 24 hours.
methyl esters have previously been reported at high temperatures
and increased pressure of oxygen.11 As expected, both
aromatic aldehydes, i.e. benzaldehyde and furfural, were oxidised
to the corresponding methyl esters in high yields (Table 1,
entries 2 and 6).
Scheme 2 The reaction pathway from methyl ester to amide via an
anionic, tetrahedral intermediate, which forms the basis for the
computational study.
Table 1 also shows that all the investigated methyl esters
reacted with N-hexylamine to form the corresponding amide
in good yields. It is notable that the second step of the reaction
occurred with excellent selectivity when using N-hexylamine
(>99%) independent of the structure of the ester.
thorough conformational search, which was performed using
the OPLS-2005 force-field18 in MacroModel19 with the built-in
GB/SA solvation model (water).20 The 10 best conformations
was then subjected to further optimization using DFT/B3LYP21
in Jaguar,22 using the 6-31G** basis set23 in combination with
the PBF continuum solvation model for methanol.24 To account
for the difference in protonation state we used hydroxide,
hydronium and water, which were solvated by three additional
water molecules.25 The clusters were embedded in the same PBF
solvation model for methanol.
Table 2 summarises the results from the oxidative coupling of
benzyl alcohol with different amines to form the corresponding
amides. The reaction proceeded smoothly when employing
benzylamine, while the more sterically demanding amines aniline
and pentan-3-amine were unable to react under the applied reaction
conditions. Furthermore, the oxidative coupling of benzyl alcohol
with ammonia resulted in formation of benzamide.
The calculated energetic profiles of the aminolysis for the five
different amines are shown in Fig. 1. The three successful examples
(NH3, EtNH2 and BnNH2) all have relatively low energies for
both the tetrahedral intermediate and the amide product. In
contrast, the amide formed from pentan-3-amine is also thermo-
dynamically favoured by 7 kJ molÀ1 (similar to ethylamine), but
the tetrahedral intermediate is disfavoured by 12 kJ molÀ1 relative
to the one derived from ethylamine. This illustrates that the more
sterically demanding pentan-3-amine cannot form the tetrahedral
intermediate as the reaction is kinetically controlled.
To investigate the observed structure–reactivity relationship
for the aminolysis of methyl benzoate in Table 2 we performed a
computational study. The exchange reaction is expected to take
place via formation of an anionic, tetrahedral intermediate.17 By
determining the relative energies (in solution phase) of the
methyl ester, tetrahedral intermediate and amide for the various
amines we were aiming to correlate this with the experimental
results. The overall process is illustrated in Scheme 2.
We investigated the reaction between methyl benzoate and
ammonia, ethylamine, diethylamine, aniline and benzylamine.
For the amines larger than NH3 it was necessary to carry out a
With aniline the tetrahedral intermediate is similar in energy
to the other mono-substituted amines, however, the amide
product is almost 40 kJ molÀ1 higher in energy than the ester.
c
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to 65 1C for 24 hours. The reaction mixture was dissolved in
water and neutralised to pH 7 by addition of 0.1 M HCl. The
product benzamide was recovered by extraction with ethyl acetate
which was subsequently removed on a rotary evaporator to give
41% in isolated yield.
We gratefully acknowledge the support of the Danish
Council for Independent Research, Grant No. 10-093717l.
Notes and references
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In conclusion, we have presented a novel approach for the two-
step synthesis of amides via the corresponding methyl ester and
showed that the combination of supported gold nanoparticles and
base forms an efficient catalytic system for the reaction. As the
same base is promoting both steps of the reaction, the synthesis
can be performed in a convenient one-pot procedure without
isolation or purification of the intermediate. The employed oxidant
is pure molecular oxygen and the reactions can be performed under
mild reaction conditions. Furthermore, the reactions can be
performed with a number of substrates, which demonstrates the
versatility of the method. By employing theoretical DFT calcu-
lations we were able to rationalise the differences between
successful and unsuccessful amine coupling partners based on
a mechanism involving a tetrahedral, anionic intermediate. The
good correlation between experiment and theoretical modelling
obtained in this study allows us to use DFT calculations in a
predictive manner when designing new experiments.
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All chemicals and reagents were purchased from a commercial
source and used without further purification. The employed
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 gÀ1. The size of the gold nano-
particles has previously been determined to be 4–8 nm by means
of transmission electron microscopy (TEM).26
In a typical experiment, alcohol or aldehyde (5 mmol), anisole
(internal standard, 0.5 mmol), base (alkaline metal methoxide,
1.25 mmol) and methanol (50 mmol) were charged to a 20 ml
reaction tube and connected to a reaction station providing
stirring, heating and O2 for the oxidation (atmospheric pressure).
The system was flushed with O2 and 197 mg Au/TiO2 catalyst
was added, corresponding to an Au/substrate molar ratio of
1/500. After 24 hours amine (10 or 25 mmol) was added and the
reaction mixture was heated to 65 1C for methanol refluxing.
Samples were periodically collected, filtered and analysed by
GC-FID and GC-MS using a HP-5 column from Agilent Tech-
nologies Inc. The amounts of substrates and reaction products
were quantified by correlating to anisole as the internal standard.
The synthesis of benzamide (Table 2, entry 6) was performed
in a pressure tube. After oxidising benzyl alcohol in methanol
for 24 hours at room temperature under 1 bar of oxygen the
tube was cooled in an ice bath and bubbled through with
ammonia for 20 min. The tube was then sealed and heated
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Goddard III, J. Chem. Theory Comput., 2009, 5, 1016.
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and A. Riisager, ChemSusChem, 2009, 2, 672.
c
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Chem. Commun., 2012, 48, 2427–2429 2429