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N-benzylamine (3h) also reacted well (entry 16). Aliphatic
aldehydes 2h and 2j gave tertiary amides with 3e in high
yields (entries 17 and 18). High amide yields obtained with
aliphatic aldehydes without undesired enamine formation
and concomitant aldol products also highlight another useful
feature of our catalytic systems (entries 8, 9, 17, and 18).
Cinnamaldehyde (2k) gave amide 4ke at 08C with complete
integrity of the double bond (entry 19). Almost 1:1 mixtures
of aldehydes and amines were sufficient to obtain amides
effectively in most cases. In addition, a catalytic amount of
base was enough to achieve satisfactory results (Table 2,
entries 6, 8, 10, 11, 13, and 14). Moreover, in the cases of
aliphatic aldehydes with a secondary amine or aniline,
improved yields were obtained, probably because of sup-
pressed side-reactions (Table 2, entries 11, 17, and 18).
Finally, formylation reactions using formalin worked well
(entries 20 and 21), hence the reaction proceeds through
a hemiaminal intermediate. This mechanism is similar to that
reported by Sakurai et al. using Au :PVP,[15c] but is at odds with
mechanisms proceeding via methylformate as a major inter-
mediate, as proposed by Ishida et al. and by Tanaka and Asao
et al. using Au-NPs and Au nanopore.[14d,20]
Further investigations using Au-NPs of medium size were
carried out as shown in Table 3 (also see SI, Schemes S1–S4).
In the oxidation reaction of 4-methoxy-a-methylbenzylalco-
hol (6) to 4-methoxyacetophenone (7) (Table 3A),[16d] very
different oxidation rates were observed for Au-NPs with
different sizes; the oxidation rate with 1e was much slower
than 1a (8 vs. 85% yield of 7), indicating that Au-NPs of
medium size have less activity than small Au-NPs in a simple
alcohol oxidation. Different activity depending on the size of
the NPs was also observed in amide synthesis from 4-
methylbenzylalcohol (8a) and benzylamine (3a; Table 3B).
With 1a, the starting materials were almost completely
consumed after 12 h, but the major product was imine 5aa
(entry 1). On the other hand, 1e gave a higher yield of 4aa
and better selectivity than 1a, despite a lower conversion
(entry 2), and good yield of 4aa was obtained under slightly
optimized reaction conditions (entry 3). In contrast, the use of
1 f resulted in a very slow reaction rate and poor selectivity
(entry 4). The substrate scope of amide synthesis from
alcohols and amines by using Au-NPs of medium size is
shown in the SI (Table S2).
We assume that there are two important factors that need
to be considered to achieve excellent selectivity: efficiency in
reaction integration and oxidation ability. First, oxidative
amide formation from an aldehyde and an amine integrates
two reaction steps: hemiaminal formation and oxidation.
Friend et al. proposed a continuous reaction of hemiaminal
formation and subsequent oxidation on an oxygen-covered
metallic Au surface.[21] A similar cascade process without
dissociation of a hemiaminal in the presence of molecular
oxygen and an externally added base could proceed on Au-
NPs of medium size (see SI, Figures S11A and B). On the
other hand, such efficient reaction integration may be difficult
on the surface of small Au-NPs. It is well accepted that Au-
NPs strongly interact with amide/amine,[22] and Tsukuda et al.
reported that such interaction is larger with small NPs
compared with large ones.[6c,23] We also confirmed that
simple secondary alcohol oxidations using small Au-NPs
were significantly suppressed by amide/amine (Table 3A).
Deprotonation of an amine adsorbed on NPs by a base, which
is essential to the following hemiaminal formation,[24] is
facilitated by electronic influence of molecular oxygen on the
same surface, because various studies suggested partial
electron transfer from ligated Au-NPs to adsorbed
oxygen.[25] Available sites for oxygen adsorption are, however,
decreased by strong interaction of amines with the surface,
hence the hemiaminal formation becomes slower.[26] Large
excess amines that have stronger interaction with the surface
facilitate the hemiaminal desorption, thus the dissociated
hemiaminal decomposes or is dehydrated to afford undesired
imine. Generated amide also shows strong interaction with
the surface of small NPs as Tsukuda et al. and Okumura et al.
reported,[6c,22a] hence the slow dissociation of the amide
decreases the available sites for catalysis and limits the
turnover of the catalytic cycle.
Second, based on our previous studies[6b] and on the
control experiments involving simple alcohol oxidation
smaller/medium-sized Au-NPs possess higher oxidation abil-
ity than larger Au-NPs (Table 3A).
Table 3: Further investigations with catalyst 1e.
It is assumed that these two factors are well balanced in
Au-NPs of medium size, resulting in the smooth catalytic
turnover and observed excellent amide selectivity (see SI,
Figure S11C).
On the other hands, in the case of amide formation from
an alcohol, a lower oxidation ability to transform an alcohol
to an aldehyde is preferred to avoid undesired background
Schiff base formation, because slow but continuous supply of
an aldehyde can be realized by the reduced oxidation rate of
Au-NPs of medium size. This is similar to the effect of slow
addition of an aldehyde.
In summary, we found a clear influence of Au-NPs size on
amide formation from aldehydes and amines by using
polymer-incarcerated Au-NPs and molecular oxygen. Au-
NPs of medium size (4.5–11 nm diameter) were found to be
optimal for the selective oxidative amidation from aldehydes
Entry
Cat.
T [oC], t [h]
Conv.[b]
4aa[b]
4aa/5aa[b]
1
2
1a
1e
1e
1f
25, 12
25, 12
30, 24
25, 12
95%
73%
>95%
63%
45%
66%
94%
24%
45:55
90:10
95:5
3[c]
4
50:50
[a] Determined by GC analysis with respect to anisole as internal
standard. [b] Determined by 1H NMR analysis with respect to tetra-
chloroethane as internal standard. [c] 2 mol% of 1e.
7566
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 7564 –7567