Direct dehydrogenative amide synthesis from alcohols and amines catalyzed by γ-alumina supported silver cluster

Article abstract of DOI:10.1002/chem.200901896

The heterogeneously catalyzed reaction of alcohols with amines to form amides and H₂ using the easily prepared and inexpensive heterogeneous catalyst, Ag/Al₂O₃ has been reported. Aromatic and aliphatic amides are functiona

Full text of DOI:10.1002/chem.200901896

COMMUNICATION
DOI: 10.1002/chem.200901896
Direct Dehydrogenative Amide Synthesis from Alcohols and Amines
Catalyzed by g-Alumina Supported Silver Cluster
Ken-ichi Shimizu,* Keiichiro Ohshima, and Atsushi Satsuma[a]
Aromatic and aliphatic amides are functional groups of
great importance in polymers, natural products, and pharma-
ceuticals.[1] Synthesis of amides is mostly based on activated
acid derivatives (acid chlorides and anhydrides) or rear-
rangement reactions induced by an acid or base.[2] Alterna-
tive procedures include the Staudinger ligation,[3a] aminocar-
bonylation of aryl halides,[3b] oxidative amidation of aldehy-
des,[3c–f] and amidation of alcohols with excess amount of hy-
drogen acceptor.[3g] However, all these methods require stoi-
chiometric amounts of various reagents and lead to
equimolar amounts of byproducts. A more environmentally
friendly protocol, first reported by Milstein et al.,[4] is the
direct amidation from alcohols and amines catalyzed by Ru
complexes accompanied by H2 removal. They proposed that
the reaction is based on alcohol dehydrogenation to give an
aldehyde intermediate which reacts with the amine to give a
hemiaminal that is subsequently dehydrogenated to the
amide. In this highly chemoselective reaction, a hydrogen
acceptor is not needed and the “dearomatized” aminometh-
yl phosphinomethyl pyridine as a pincer ligand plays an
active role in the hydrogen abstraction and liberation pro-
cess (cooperative ligand). To date, only two homogeneous
catalysts using platinum-group metal (PGM), Ru, with mo-
lecularly designed cooperative ligands, have been report-
ed.[4,5] However, these expensive catalysts do not tolerate
secondary amines and are problematic in terms of the cata-
lyst/product separation and necessity of special handling of
metal complexes. From the environmental and economic
point of view, a reaction with inexpensive (PGM-free) heter-
ogeneous catalyst is desired.
that gold as an inert d10 element shows similar or higher cat-
alytic activity for various reactions than PGM-based cata-
lysts when several nanometer-sized gold clusters are sup-
ported on a specific support.[6] Silver as a less expensive
Group IB metal is very popular in research field of cluster
synthesis.[7] However, compared with a research of gold cat-
alysis, surprisingly less attempts have been focused on spe-
cific catalysis of silver cluster as well as a structure–activity
relationship of silver cluster catalysis.[8–10] Among a few ex-
amples, g-alumina-supported silver cluster (Ag/Al2O3)[9,10]
reported by our group acts as heterogeneous catalyst for the
oxidant-free dehydrogenation of alcohols[10a] and one-pot
À
C C cross-coupling reaction from secondary and primary al-
cohols.[10b] The unprecedented activity of Ag/Al2O3 for reac-
À
tions initiated by C H activation of alcohols led us to inves-
tigate the possibility of using Ag/Al2O3 as new environmen-
tally benign catalyst for the title reaction. Herein, we dem-
onstrate the first example of a heterogeneously catalyzed re-
action of alcohols with amines to form amides and H2 using
the easily prepared and inexpensive heterogeneous catalyst,
Ag/Al2O3. Systematic studies on the structure–activity rela-
tionship are also shown to provide a new synthetic strategy
À
of C H activation catalyst using non-PGM material with in-
organic cooperative ligands, that is, OHd+/OHdÀ groups on
alumina.
The catalyst precursors were prepared by impregnating
oxides with an aqueous solution of silver nitrate followed by
evaporation to dryness at 808C and calcination at 6008C. By
controlling the H2 reduction temperature, silver clusters
(5 wt%) with similar size were supported on various metal
oxides: Ag/MOx-5 (MOx =CeO2, MgO, ZrO2, Al2O3, SiO2).
Our previous results of Ag K-edge extended X-ray absorp-
tion fine structure (EXAFS) showed that silver species in all
samples are in a range 0.84–3.0 nm.[10] For Al2O3-supported
catalysts, a series of catalysts with average particle diameter
from 0.73 to 30 nm was also prepared by changing the Ag
content (1, 3, 5, 10, 50 wt%); the particle diameter in-
creased with Ag content (see Figure S1 in the Supporting In-
formation).[10]
Metal clusters have interesting chemical properties, which
are unusual for bulk solids. For example, it is well known
[a] Dr. K.-i. Shimizu, K. Ohshima, Prof. Dr. A. Satsuma
Department of Molecular Design and Engineering
Graduate School of Engineering, Nagoya University
Nagoya 464-8603 (Japan)
Fax : (+81)52-789-3193
E-mail: kshimizu@apchem.nagoya-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901896.
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9977

Initially, the reaction of equimolecular amounts 4-fluoro-
benzyl alcohol (1) and morpholine (2) was chosen for the
test reaction in order to optimize all different parameters.
First, various transition-metal clusters supported on Al2O3
and silver cluster catalysts supported on various metal
oxides were tested in the presence of Cs2CO3 (Table 1). Ag/
Al2O3 showed higher activity than Al2O3-supported PGM
catalysts. Al2O3 was the most suitable support of silver in
terms of both yield of 3 and the rate of formation of 3.
Among the Ag/Al2O3 catalysts with different Ag loading,
the catalyst with Ag loading of 5 wt% showed the highest
yield and rate of formation for 3. These trends are the same
tries 3, 8–10). The reaction rate increased as the temperature
was raised from 1008C to the reflux temperature (entries 3,
11). The molar ratio of alcohols and amines also had an in-
fluence on the amide yield; the alcohol/amine ratio of 1:2
gave the highest yield for 3 (91%) with no formation of
ester (entry 14). Under the optimized reaction conditions
(alcohol/amine ratio 1:2, 4 mol% Ag/Al2O3-5, 20 mol%
Cs2CO3, under reflux condition, see Figure S2 in the Sup-
porting Information) after 24 h, the yield of 3 (91%) was
nearly identical to the yield of gas-phase H2 (88%), indicat-
ing that H2 was generated quantitatively.
The reaction was stopped by the removal of Ag/Al2O3-5
from the reaction mixture; after stirring the reaction mix-
ture for 2 h (yield 20%), the catalyst was immediately re-
moved by centrifugation at 1008C, and the reaction did not
proceed any further when the filtrate was heated for 22 h.
This result excludes a possible contribution of homogeneous
catalysis of leached silver species. Next, we studied the
reuse of the Ag/Al2O3-5 catalyst. The catalyst can be easily
separated from the reaction mixture by centrifugation. For
each successive use, the catalyst was washed with water to
remove Cs2CO3, followed by calcination in air at 6008C for
10 min, and by reduction with H2 at 1508C for 5 min. After
this treatment, the recovered catalyst was reused at least
two times without marked loss in the activity (Table 2, en-
tries 10–12). In the solvent with a higher boiling point (o-
xylene), a good yield (82%) was obtained for the reaction
of 1 and 2 with small amount of Ag/Al2O3-1 (0.6 mol%)
(Table 1, entry 3), and the total turnover number (TON)
based on the total Ag content was 135.
as those found in our previous studies for the reactions initi-
[10]
À
ated by C H activation of alcohols.
Table 1. Reaction of 1 with 2 by various catalysts.[a]
Entry
Catalysts-x[b]
D[c] [nm]
Yield of 3 [%]
V[d] [mmolhÀ1 gÀ1
]
1
Ag/Al2O3-1
Ag/Al2O3-1
Ag/Al2O3-1
Ag/Al2O3-3
Ag/Al2O3-5
Ag/Al2O3-10
Ag/Al2O3-50
Rh/Al2O3-1
Pt/Al2O3-1
Ru/Al2O3-1
Pd/Al2O3-1
Au/Al2O3-1
Cu/Al2O3-8
Ag/SiO2-5
Ag/ZrO2-5
Ag/CeO2-5
Ag/MgO-5
Ag powder
AgNO3
0.73
0.73
0.73
0.78
0.84
1.2
30
1.9
1.3
–
1.5
1.9
–
1.2
1.6
0.9
3.0
–
61
80
82
84
87
82
31
0
2.9
2.1
18
27
2.2
8.1
43
0
0.38
–
2[e]
3[f]
4
0.67
0.64
0.79
0.63
0.069
0
0.008
0.024
0.079
0.142
0.029
0.069
0.37
0
5
6
7
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
14
15
16
17
18
19
Table 2. Reaction of primary alcohols with amines.[a]
Entry Alcohol
Amine
Yield[%]
1
2
3
benzyl alcohol
benzyl alcohol
benzyl alcohol
benzyl alcohol
piperidine
pyrrolidine
82
92
N-methylbenzylamine 78(10[c]
)
)
8.0
1.6
1.1
0.064
0.007
0.004
4[b]
5
benzylamine
cyclohexylamine
61(17[d]
benzyl alcohol
48 (29[d], 6[c]
)
–
6
7
8
9
10
11[e]
12[f]
13[b]
14[b]
15[b]
benzyl alcohol
1
4-methoxybenzyl alcohol
4-methylbenzyl alcohol
1
1
1
1-hexanol
1-octanol
cyclohexylmethanol
2
93
79
93
84
91
87
88
83
71
[a] Yield of 3 was determined by GC. [b] x is metal loading (wt%).
[c] Average particle size of supported metal. [d] The initial rate of 3 for-
mation measured under the condition where conversions were below
50%. [e] t=48 h. [f] Ag=0.6 mol%, in o-xylene under reflux condition.
pyrrolidine
2
2
2
2
2
2
2
2
With the standard catalyst, Ag/Al2O3-5, the reaction con-
ditions were optimized for the reaction through variation of
the base, temperature, and solvent (see Table S1 in the Sup-
porting Information for details). The nature of base was
tested first (entries 1–7). Amide 3 was not obtained in the
absence of a base (entry 7). Among the alkaline carbonates
added, the conversion of alcohol and the yield of the prod-
uct 3 increased with the increase in the basicity of the carbo-
67(12[c]
)
[a] Alcohol (1 mmol), amine (2 mmol), toluene (2 mL), under reflux, Ag/
Al2O3-5 (4 mol%), Cs2CO3 (20 mol%), t=24 h. Yields were determined
by GC. [b] in o-xylene under reflux condition. [c] Yield of the corre-
sponding ester. [d] Yield of the corresponding imine. [e] First reuse.
[f] Second reuse.
nates in a following order: Li2CO3 < Na2CO3 < K2CO3
<
Cs2CO3 (entries 3–6). However, KOH and NaOH as stron-
ger bases gave lower yields and reaction rates than Cs2CO3
(entries 1,2). Among the bases tested, Cs2CO3 was found to
be the best. The activity was affected by the amount of
Cs2CO3; 20 mol% was enough to give optimal yield (en-
To determine the scope and limitation of the method, var-
ious alcohols and amines were employed as substrates
(Table 2). The reactions of 2 with various primary alcohols,
including benzyl alcohols with an electron-donating or an
electron-withdrawing substituent (entries 6,8,9) and aliphatic
9978
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Chem. Eur. J. 2009, 15, 9977 – 9980

Direct Dehydrogenative Amide Synthesis
COMMUNICATION
primary alcohols (entries 13–15), proceeded in good to mod-
erate yields. The reactions of benzyl alcohol with various
secondary amines (entries 1–3) were also successful. The re-
action of primary amines resulted in moderate yields (en-
tries 4,5).
On the basis of the mechanism proposed for direct amida-
tion catalyzed by Ru complexes[4,5] and the mechanism of
the Ag/Al2O3 catalyzed alcohol dehydrogenation in our pre-
vious study,[10a] we tentatively propose the mechanism de-
picted in Scheme 1. The reaction does not proceed through
face Ag sites versus the average particle size is shown in
Figure 1. The silver cluster with smaller particle size gave
higher intrinsic activity. Taking into account the fact that the
fraction of corner Ag atoms dramatically increase when the
Ag particle size was less than 2 nm,[8a] a dramatic increase in
TOF below 2 nm indicates that the present reaction by Ag/
Al2O3 is a structure-sensitive reaction, demanding coordina-
tively unsaturated Ag sites. These sites should be required
À
for the rate-determining C H cleavage of alkoxide or hemi-
aminal species.
To investigate the effect of acid–base characteristics of
the support, the yield of product 3 and the initial rate were
plotted as a function of the electronegativity of metal spe-
cies in support material (Figure 2), which has been used as a
parameter of acidity of metal oxides. The silver clusters sup-
ported on alumina, which has both acidic and basic surface
OH groups,[11] showed the highest catalytic activity. The sup-
port with strong basic character (CeO2 and MgO) and that
with acidic character (SiO2)[11c] resulted in low activity. This
suggests that both acidic and basic surface sites are necessa-
ry for this reaction. We reported similar tendency for oxi-
dant-free dehydrogenation of alcohols and established the
following roles of acid and base sites.[11a] Basic sites at the
silver-support interface deprotonate alcohol to give alkoxide
intermediate on the support oxide surface, and protonic
(electrophilic) OH groups adjacent to silver sites facilitate
the removal of hydride species from the silver sites to regen-
erate a coordinatively unsaturated site on silver cluster. The
result in Figure 2 suggests that these roles of acid–base sites
on the support are applicable in the present reaction. It
should be noted that, with increase in the Ag particle size,
the fraction of the Ag atoms adjacent to the surface OH
groups of the support decreases. Taking into account the
above-mentioned mechanism that the acidic and basic OH
groups located at the metal-support interface play significant
role in the catalytic cycle, the decay in reactivity in Figure 1
can be partly explained by the decreased fraction of the
metal-support interface, not only by the high reactivity of
low coordinated Ag atoms.
Scheme 1. Proposed mechanism for the direct amidation of amines by al-
cohols catalyzed by Ag/Al2O3.
an intermediate ester, because treatment of methyl 4-fluoro-
benzoate with 2 and the catalyst did not afford the corre-
sponding amide. The reaction between 4-fluorobenzalde-
hyde and benzylamine under the same conditions led to ex-
clusive formation of the corresponding imine and neither
amide nor amine was observed. The imine did not react in
the presence of Ag/Al2O3-5 and Cs2CO3; this did not change
by adding water (10 mmol) or by conducting the reaction
under a H2 atmosphere. These results suggest that the amide
formation does not proceed through a free aldehyde but
through aldehyde-like species adsorbed on the catalyst. Sub-
sequent attack by the amine afforded the hemiaminal on the
catalyst. The amide was then formed after hydride elimina-
tion by silver cluster. A portion of a free aldehyde or hemia-
minal release from the catalyst, which led to the formation
of an unreactive imine as shown in Table 2 (entries 4,5). We
examined the relationship between the relative rates and
the Brown–Okamoto (s+) parameter for the reactions of 2
with benzyl alcohols with an electron-donating or an elec-
tron-withdrawing substituent (see Figure S3 in the Support-
ing Information). A series of different benzylic alcohols was
catalyzed by Ag/Al2O3-5, and the order of reactivity for
benzyl alcohol was p-CH3O> p-CH3 > p- H> p-Cl. There
is a good linearity with a negative slope (1=À0.36, r2 =
0.95), which suggests that a transition state of the rate-deter-
mining step involves a positive charge at a-carbon atom ad-
In summary, alumina-supported silver cluster with weak
base (Cs2CO3) is presented as the first example of heteroge-
neous catalyst for the direct amide synthesis from alcohols
and amines. Studies on the structure–activity relationship
and reaction mechanism show that the reaction proceeds by
À
jacent to the phenyl ring. Therefore, C H cleavage of the
alkoxide or hemiaminal by silver cluster can be the rate-de-
termining step in the present reaction.
For Ag/Al2O3, the number of surface silver atoms for
each catalyst was statistically determined from the average
silver particle size.[10] The turnover frequency (TOF) per sur-
Figure 2. Yield (*) and formation rate (*) of 3 versus electronegativity
of support cation.
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K.-i. Shimizu et al.
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Keywords: amides · cluster compounds · heterogeneous
catalysis · silver
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Received: July 8, 2009
Published online: September 16, 2009
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