Supported Gold Nanoparticle-Catalyzed Hydration of Alkynes under Basic Conditions

Article abstract of DOI:10.1021/ol5033859

TiO₂-supported nanosize gold particles catalyze the hydration of alkynes using morpholine as a basic cocatalyst. Unlike most homogeneous cationic gold catalysts, the TiO₂-Au/morpholine system is weakly basic and is compatible with acid-sensitive functional groups (e.g., silyl ethers, ketals) or with a strongly coordinating group such as pyridine. What's more, this gold catalyst can be recycled by simple filtration and works well in flow reactors. (Chemical Equation Presented).

Full text of DOI:10.1021/ol5033859

Letter
pubs.acs.org/OrgLett
Supported Gold Nanoparticle-Catalyzed Hydration of Alkynes under
Basic Conditions
Shengzong Liang,† Jacek Jasinski,‡ Gerald B. Hammond,*,† and Bo Xu*,†
‡
†Department of Chemistry and Institute for Advanced Materials and Renewable Energy, University of Louisville, Louisville,
Kentucky 40292, United States
S
* Supporting Information
ABSTRACT: TiO2-supported nanosize gold particles catalyze the
hydration of alkynes using morpholine as a basic cocatalyst. Unlike
most homogeneous cationic gold catalysts, the TiO2−Au/morpho-
line system is weakly basic and is compatible with acid-sensitive
functional groups (e.g., silyl ethers, ketals) or with a strongly
coordinating group such as pyridine. What’s more, this gold catalyst
can be recycled by simple filtration and works well in flow reactors.
omogeneous cationic gold catalysis is a landmark addition
Corma and co-workers.3d Although the above systems are
efficient, they do have the following shortcomings: (1) they are
not compatible with substrates containing acid-sensitive func-
tional groups; (2) they are not suitable for use with strongly
coordinating groups like pyridine because of the strong affinity
between the cationic gold and bases; and (3) they cannot be
easily recycled. Even the silver-free gold (L−Au−NTf2)-
catalyzed hydration of alkynes reported by Corma and co-
workers19performed at room temperature in the absence of
other acid promotersled to non-negligible amounts of
decomposition products (from 15% to 100%) when acid-
sensitive groups such as silyl ethers and triphenylmethyl (Tr)
were present in the starting material. This phenomenon could
have been caused by the Lewis acidity of the cationic gold itself.
We chose the hydration of phenylacetylene 1a as our model
reaction together with the commercially available AUROlite
series (AuNPs supported by TiO2, ZnO or Al2O3, 1 wt %/wt
loading, average size of AuNPs 2−3 nm). Au−TiO2 itself
performed poorly at 120 °C for 1 h under microwave conditions
(Table 1, entry 1). A strong inorganic base like NaOH (20 mol
%) (Table 1, entry 2) did not fare better. Tertiary amines
(triethylamine and DMAP, Table 1, entries 3 and 4) inhibited the
reaction; however, primary and secondary amine bases (p-
toluenesulfonamide, 4-chloroaniline, benzylamine, diphenyl-
amine, piperazine, piperidine, N-methylaniline, and morpholine)
accelerated the hydration, affording the product in yields ranging
from 17% to 76% (Table 1, entries 5−12). Morpholine proved to
be the best cocatalyst in the lot (Table 1, entry 12), although
morpholine itself did not catalyze the hydration (Table 1, entry
13). Using a higher loading of Au−TiO2 (1 mol %) (Table 1,
entry 14) and reducing the amount of morpholine (5%) (Table
1, entry 15) further improved the yield of the reaction. Toluene
and nitromethane were not as good solvents as dioxane (Table 1,
H
to the field of organic synthesis.1 Cationic gold catalysts
are regarded as the most powerful catalysts for the electrophilic
activation of alkynes toward a variety of nucleophiles.1a However,
a cationic gold catalytic system may not be compatible with
substrates containing highly acid-sensitive functional groups such
as silyl ethers or ketals because of the acidity of cationic gold
catalysts and the acid promoters that are used to generate
cationic gold. Although addition of bases to the reaction system
may stabilize substrates containing acid-sensitive functional
groups, more often than not, a base will quench the reactivity
of cationic gold catalysts by inhibiting or slowing down multiple
stages in the cationic gold catalytic cycle.2
Supported gold nanosize particles (AuNPs) have been used as
heterogeneous catalysts for oxidation, reduction, silylation, and
C−C coupling reactions,3 but their use in the electrophilic
activation of alkynes/alkenes has received less attention.4 The
catalytic activity of AuNPs could be attributed to its partial
oxidation, by oxygen or other oxidants, to higher valence gold
species.5 We speculated that AuNPs activated by partial
oxidation could be more tolerant toward bases. AuNP-based
catalysts are softer and weaker Lewis acids, and they may be less
affected by the presence of bases, although on the other hand,
their electrophilic activation ability may be weaker than that of
homogeneous cationic gold catalysts because of their weaker
cationic character. Thus, a combination of supported AuNPs and
a suitable basic cocatalyst could work well for substrates
containing acid-sensitive functional groups.
For a proof of concept, we chose the hydration of alkynes,
which is a straightforward and atom-economical way to prepare
carbonyl compounds.6 Many homogeneous catalysts like Hg,7
Pd,8 Pt,9 Fe,10 Ag,11 Co,12 Ir,13 Ru.14 and Brønsted acids15 can
catalyze this reaction. Homogeneous gold catalysts are
particularly effective.16 Notable examples include the [(PPh3)-
AuMe]/H2SO4 system reported by Hayashi and co-workers,16f,17
the IPrAuCl/AgSbF6 system reported by Nolan and co-
workers,18 and the small gold clusters/HCl system reported by
Received: December 2, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Screening of Reaction Conditions
Table 2. Substrate Scope of Alkyne Hydration Catalyzed by
Au−TiO2/Morpholine
entry
base (mol %)
NaOH (20)
Au−TiO2 (mol %)
solvent
yield (%)
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
MeNO2
dioxane
dioxane
dioxane
6
2
2
3
Et3N (20)
4
4
DMAP (20)
0
5
TsNH2 (20)
20
57
30
17
33
29
30
76
0
6
4-chloroaniline (20)
benzylamine (20)
diphenylamine (20)
piperazine (20)
piperidine (20)
N-methylaniline (20)
morpholine (20)
morpholine (20)
morpholine (20)
morpholine (5)
morpholine (5)
morpholine (5)
morpholine (5)
morpholine (5)
morpholine (5)
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
88
90
18
0
b
18
85
81
e
c
19
d
20
a
Reaction conditions: concentration of phenylacetylene is 1 M,
1
microwave at 120 °C for 1 h, yields were determined by H NMR.
b
c
d
H2O (1 equiv) was used. H2O (5 equiv) was used. Au/ZnO or Au/
e
Al2O3 was used. A relative complex mixture.
entries 16 and 17). The amount of water had a minor influence
on the reaction (Table 1, entries 18 and 19). We also tested other
gold supports (Au/ZnO or Au/Al2O3), but they produced
complex mixtures (Table 1, entry 20).
With optimized conditions in hand, we investigated the
substrate scope (Table 2). Phenylacetylenes substituted with
electron-donating or electron-withdrawing groups gave good
yields of hydration product 2 (Table 2, entries 1−4). Terminal
aliphatic alkynes also worked well if higher gold catalyst loading
(4 mol %) and lower temperature (110 °C) were used (Table 2,
entries 5 and 6).
Common functional groups such as nitrile, ester or, alkene
groups were well tolerated in the hydration (Table 2, entries 7, 8,
and 17). We were pleased to find that our catalyst system was
compatible with a wide range of acid-sensitive functional groups.
Alkynes containing triisopropylsilyl (TIPS), tert-butyldimethyl-
silyl (TBDMS), and tert-butyldiphenylsilyl (TBDPS) ethers gave
the desired hydration product with excellent yields (Table 2,
entries 9−11). No deprotection products were detected. Two
other acid-labile functional groups, triphenylmethyl (Tr) and
allyl ether, were compatible with our reaction conditions (entries
12 and 13). Acetals or ketals are usually more acid sensitive than
silyl ethers or Tr, but to our delight, they withstood the reaction
conditions. Indeed, alkynes containing a cyclic tetrahydropyranyl
ether (THP) moiety (1n), a noncyclic acetal group (1o), or a
structurally complex glycoside (1p) yielded the corresponding
hydration products in excellent yields (Table 2, entries 14−16).
Most of these acid-sensitive groups could not have withstood the
strong Lewis acidic catalysts reported in the literature.6 2-
Ethynylpyridine (1r) was also a challenging substrate because the
nitrogen in pyridine strongly binds to most metal catalysts used
in hydration.6 However, 1r gave a very good yield of the
a
b
Isolated yields. Conditions A: Au−TiO2 (1 mol %), morpholine (5
c
mol %), H2O (2 equiv), MW 120 °C for 1 h. Conditions B: Au−TiO2
(4 mol %), morpholine (10 mol %), H2O (2 equiv), MW 110 °C for 2
d
e
h. Conditions A with Au−TiO2 (2 mol %). Conditions B except
f
reaction time is 1 h. Au−TiO2 (4 mol %), morpholine (20 mol %),
H2O (4 equiv), MW 140 °C for 2 h.
hydration product using our methodology (Table 2, entry 18).
The internal alkyne diphenylacetylene (1s) gave the correspond-
ing hydration product (2s) in 80% yield (Table 2, entry 19) and
B
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Letter
so did a diyne such as 1,4-diethynylbenzene (1t), although higher
temperatures were needed in the reaction (Table 2, entry 20).
The pH of the reaction mixture remained weakly basic (pH 8−
9) throughout the reaction. This could explain why acid-sensitive
compounds were well tolerated. To learn whether the leaching of
gold species from the TiO2 support promoted the reactivity of
our system, we filtered off the solid Au−TiO2 after the reaction,
added more 1a (1 equiv) and morpholine (5 mol %) to the
filtrate, and subjected the resulting mixture to our standard
reaction conditions (eq 1). We found that no conversion took
place in this manner, an indication that the catalysis was
heterogeneous in nature.
Flow chemistry has become a popular tool in many organic
transformations.22 Compared with a conventional start-and-stop
batch reaction, it has many advantages like better control of the
reaction conditions, faster heat and mass transfer, a better safety
profile, and an easier scale up.23 Flow reactors are especially
suitable for heterogeneous catalysis. Because our Au/TiO2 could
be recycled easily (see eq 3), we designed a flow reactor to take
full advantage of this recyclability (Figure S-4, Supporting
Information). Our catalyst worked quite well under flow
conditions. We found that the conversion decreased slowly
over time, a common phenomenon in industrial heterogeneous
catalysis because of deactivation.
Frequent reasons given for heterogeneous metal catalyst
deactivation include agglomeration of metal nanoparticles,
change of oxidation state,24 poisoning, or physical loss of
metal.25 We studied the STEM images of fresh and spent gold
catalyst. These images clearly showed that agglomeration of gold
nanoparticles took place in the spent catalyst (Figure 1).
To support our previous assertion that a homogeneous
cationic gold catalyst is usually incompatible with basic additives,
we decided to investigate the effect of morpholine on the
reactivity of a gold catalyst (Scheme 1). A homogeneous gold
Scheme 1. Effect of Base on the Reactivity of Homogeneous
Gold Catalysis
Figure 1. STEM images of fresh and spent catalysts.
catalyst such as PPh3AuNTf2 catalyzed the hydration of alkyne 1a
efficiently at room temperature (Scheme 1a), but it became
inactive in the presence of morpholine, either at room
temperature (Scheme 1b) or under microwave conditions
(Scheme 1c). This experiment proved that morpholine could
deactivate a homogeneous gold catalyst but not a AuNP-based
catalyst.
We also investigated the role of morpholine in the reaction. To
this end, we conducted the hydration of phenylacetylene 1a in
dry dioxane and found significant amounts of the hydro-
amination product (eq 2).20 This result seems to indicate that
enamines are plausible intermediates in the hydration of
alkynes.21
Furthermore, XPS studies determined that there was no
significant change in the oxidation state of AuNPs before or
after the reaction (Figure S-5, Supporting Information). We
concluded that agglomeration was the major reason for the
partial deactivation of AuNPs over time.
In summary, we have developed an efficient alkyne hydration
catalyzed by heterogeneous gold under basic conditions. Our
method worked well for various alkynes bearing different
functional groups, and it was especially useful with substrates
bearing acid-sensitive functionalities. This gold catalyst was easily
handled and fairly air stable and could be recycled by simple
filtration; furthermore, it worked well in flow reactors.
ASSOCIATED CONTENT
* Supporting Information
■
S
General procedures, flow reactor experimental design, XPS
studies, and STEM and TEM images of supported AuNPs. This
material is available free of charge via the Internet at http://pubs.
acs.org.
To investigate the recyclability of our supported AuNP
catalyst, we carried out four straight runs of phenylacetylene
hydration under the standard conditions. After each run, Au-
TiO2 was recovered by simple filtration. The yields after each run
decreased only slightly (eq 3).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gb.hammond@louisville.edu.
C
dx.doi.org/10.1021/ol5033859 | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(13) Hirabayashi, T.; Okimoto, Y.; Saito, A.; Morita, M.; Sakaguchi, S.;
Ishii, Y. Tetrahedron 2006, 62, 2231−2234.
*E-mail: bo.xu@louisville.edu.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation for financial
support (CHE-1111316 and CHE-1401700). We also acknowl-
edge with gratitude the experimental support provided by Luisa
C. Hammond, a summer undergraduate researcher from
Williams College, Williamstown, MA.
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Kurokawa, H.; Miura, H.; Chihara, T. J. Cluster Sci. 2007, 18, 845−853.
(b) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Synlett 2000,
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