Pd nanoparticles as catalysts for green and sustainable oxidation of functionalized alcohols in aqueous media

Article abstract of DOI:10.1016/j.tet.2009.11.007

The previously described catalyst system for the aerobic oxidation of alcohols, comprising palladium(II) acetate in combination with neocuproine in a 1:1 mixture of water and a water-miscible cosolvent such as ethylene carbonate or dimethylsulfoxide, was shown to involve palladium nanoparticles as the active catalyst. The latter are formed in situ or can be preformed by reduction of the palladium-neocuproine complex with hydrogen and they are stabilized by both the neocuproine ligand and the cosolvent. This catalyst system was successfully used for the selective aerobic oxidation of the steroidal secondary alcohols, nandrolone and 5α-pregnan-3α-ol-20-one, to the corresponding ketones.

Full text of DOI:10.1016/j.tet.2009.11.007

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Tetrahedron 66 (2010) 1040–1044
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Pd nanoparticles as catalysts for green and sustainable oxidation of functionalized
alcohols in aqueous media
*
Maria Mifsud, Ksenia V. Parkhomenko, Isabel W.C.E. Arends, Roger A. Sheldon
Biocatalysis and Organic Chemistry Group, Department of Biotechnology, Delft University of Technology, Julianalaan 136, 2628BL Delft, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2009
Accepted 18 August 2009
Available online 6 November 2009
The previously described catalyst system for the aerobic oxidation of alcohols, comprising palladium(II)
acetate in combination with neocuproine in a 1:1 mixture of water and a water-miscible cosolvent such
as ethylene carbonate or dimethylsulfoxide, was shown to involve palladium nanoparticles as the active
catalyst. The latter are formed in situ or can be preformed by reduction of the palladium–neocuproine
complex with hydrogen and they are stabilized by both the neocuproine ligand and the cosolvent. This
catalyst system was successfully used for the selective aerobic oxidation of the steroidal secondary
Keywords:
Aerobic oxidation of alcohols
Palladium nanoparticles
Steroidal alcohols
Water
alcohols, nandrolone and 5
a
-pregnan-3
a
-ol-20-one, to the corresponding ketones.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
attractive from both an economic and environmental viewpoint.11
However, as was pointed out by Dunn and Perry and co-workers,4
there are serious safety issues associated with the use of dioxygen to
aerate flammable solvents. It is also worth noting, in this context,
that decomposition of hydrogen peroxide leads to the formation of
dioxygen. These concerns can be reduced by using a mixture
of <10% oxygen in nitrogen but still these methods lie on the edge of
what is acceptable with regard to scalability. An improved safety
profile is obtained by performing such oxidations in an aqueous
medium, thus avoiding the use of volatile and flammable organic
solvents. Hence, we have a longstanding interest in the green, cat-
alytic aerobic oxidation of alcohols12 in general and employing
water as the reaction medium in particular.
The oxidation of primary and secondary alcohols to the corre-
sponding carbonyl compounds plays a central role in organic syn-
thesis.1 However, standard organic textbooks2 still recommend
classical oxidation methods using stoichiometric quantities of in-
organic oxidants, notably chromium VI reagents,3 which are highly
toxic and/or environmentally polluting. According to a recent pub-
lication4 the three most popular oxidants used by Pfizer’s medicinal
chemists for the oxidation of primary alcohols to the corresponding
aldehydes are the Dess–Martin periodinane5 or its precursor IBX,
the Swern reagent6 and tetrapropyl perruthenate, TPAP.7 All of these
methods have poor atom efficiencies8 and significant scale-up is-
sues. The Dess–Martin periodinane, for example, is a high energy,
potentially explosive molecule that is, prohibitively expensive for
use on a multi-kilogram scale. The Swern oxidation is used at pilot
plant scale but generates toxic by-products and the stench of
dimethylsulfide. The use of stoichiometric TPAP is also prohibitively
expensive for large-scale use. A more environmentally friendly and
scalable procedure that has become popular in recent years is the
use of hypochlorite (household bleach) in conjunction with a stable
nitroxy radical such as tetramethylpiperidinyloxy (TEMPO)9 or its
oligomeric equivalent, PIPO.10
Palladium(II) salts have long been known to catalyze the aerobic
oxidation of alcohols.13 The use of PdCl2–NaOAc, for example, was
reported in 1977.14 However, activities were very low, with turnover
frequencies of the order of 1 hꢀ1. Other systems, which were sub-
sequently studied include Pd(OAc)2–NaHCO3 in DMSO or ethylene
carbonate,15 PdCl2, in combination with sodium carbonate and
a tetraalkylammonium salt as a phase transfer catalyst16 and
Pd(OAc)2 in combination with pyridine and 3 Å molecular sieves in
toluene at 80 ꢁC.17 The best results were turnover frequencies (TOFs)
of the order of 10 hꢀ1
.
The ultimate green oxidants are dioxygen (air) and hydrogen
peroxide, that form water as the sole coproduct, and catalytic
methodologies employing these terminal oxidants are particularly
The catalytic mechanism involves the reduction of palladium to
the zerovalent state by the alcohol substrate and its subsequent
reoxidation to palladium(II) by dioxygen. The transient Pd(0) spe-
cies is metastable and prone to aggregation to bulk palladium metal
(Pd black) with concomitant loss of catalytic activity.18 One app-
roach to avoid this is to add coordinating ligands, which stabilize
the transient Pd(0) species. We previously reported19 the use of
* Corresponding author. Fax: þ31 15 2781415.
E-mail address: r.a.sheldon@tudelft.nl (R.A. Sheldon).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.007

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M. Mifsud et al. / Tetrahedron 66 (2010) 1040–1044
1041
Pd(OAc)2 / L (0.1-0.5mol%)
NaOAc (5-25mol%)
+
H2O
+ 0.5 O2
air (30 bar) / 80 °C / 4h
O
OH
SO3Na
SO3Na
NaO3S
NaO3S
N
N
N
N
N
N
L
(2)
(3)
1800
H2O/ DMSO (1:1)
(1)
50
H2O
TOF (h-1)
Solvent
150
H2O
Figure 1. Palladium(II) complexes of dinitrogen ligands.
water-soluble palladium complexes of chelating dinitrogen ligands,
notably bathophenanthroline disulfonate (1) (Fig.1) as active, stable
and recyclable catalysts for the aerobic oxidation of alcohols in
water in the absence of organic solvents. A typical protocol involved
the use of 0.25 mol % of a mixture of a 1:1 mixture of Pd(OAc)2 and
(1) together with 5 mol % of sodium acetate.19 The latter was shown
to stabilize the catalyst by suppressing the formation of palladium
black and an amount corresponding to 5 mol % was found to be the
optimum. The sodium acetate is not consumed in the reaction, that
is, it is a cocatalyst. The palladium(II) bathophenanthroline complex
proved to be an active catalyst for the selective aerobic oxidation of
a variety of primary and secondary alcohols to the corresponding
acids or aldehydes and ketones, respectively. However, alcohols
bearing functional groups containing heteroatoms, such as N and S,
were unreactive. Hence, we continued our search for an active
catalyst that exhibited a broader scope in organic synthesis.
1:1 mixtures of water with water-miscible organic solvents, mainly
DMSO, to ensure dissolution of the substrates and facilitate mea-
surement of relative rates. The 1:1 palladium(II) complex of neo-
cuproine (3) was shown to catalyze the aerobic oxidation of
alcohols bearing a variety of heteroatom (O, N and S)-containing
functional groups under these conditions.20 Typically 0.1–0.5 mol %
of the Pd complex was used together with 5–25 mol % of NaOAc as
cocatalyst (see above). We now report a further study of this in-
teresting catalyst.
2. Results and discussion
2.1. Catalyst characterization
A more detailed examination of our previous results20 revealed
a remarkable difference between the Pd(II) complexes of (1) and (3)
in the oxidation of the alcohol (4) containing a remote olefinic
double bond (Fig. 2). With the complex of (1) the major product
(75% selectivity) was the keto alcohol (5) formed by Pd catalyzed
Wacker-type oxidation of the olefinic double bond. We had pre-
viously shown that this Pd complex catalyzes the aerobic oxidation
of olefins to the corresponding ketones.21 The diketone (7) was
formed as a minor product (8%), probably via further oxidation of
(5). In stark contrast, essentially exclusive (>99% selectivity) for-
mation of (6), resulting from the selective oxidation of the alcohol
moiety, was observed when the Pd complex of (3) was the catalyst.
In our original studies19 of the Pd–bathophenanthroline system
we noted that the kinetics were consistent with dissociation of
a hydroxyl bridged dimer to give the corresponding monomer,
which was the active catalyst. Hence, we reasoned that dimers
derived from phenanthroline ligands substituted at the 2 and 9
positions would be sterically crowded and more readily dissociate,
resulting in a higher concentration of the active monomer complex.
To this end we designed the palladium complexes of ligands (2) and
(3) and measured their activities in the oxidation of a wide variety
of primary and secondary alcohols.20 Reactions were performed in
L = (1)
L = (3)
OH
O
75%
O
(5)
LPd(OAc)2 (0.5mol%)
NaOAc (25mol%)
OH
+
O2
~2%
8%
>99%
DMSO / H2O (1:1 v/v)
30 bar air / 80°C / 4h
(4)
(6)
O
O
(7)
Figure 2.

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1042
M. Mifsud et al. / Tetrahedron 66 (2010) 1040–1044
Figure 3. TEM photograph of Pd nanoparticles (a) before and (b) after oxidation reaction.
This remarkable difference led us to suspect that a different
nanoparticles were prepared using different cosolvents: PEG-600,
dipropylene glycol and ethylene carbonate. The cosolvent plays
a dual role: it acts as a solvent for the oxidation reaction and as an
additional stabilizing agent for the nanoparticles. The best conver-
sions were obtained with ethylene carbonate (Entries 1, 3, 4, 5, Table
1). The influence of the anion in the palladium salt precursor was
studied by comparing palladium acetate with palladium tri-
fluoroacetate and no differences were observed (Entries 1, 6, Table 1).
mechanism was involved. Indeed, the highly selective oxidation of
the alcohol moiety in the presence of an olefinic double bond was
reminiscent of earlier reports by Moiseev and co-workers22,23 who
showed that giant Pd clusters (nowadays known as Pd nano-
particles) are effective catalysts for the oxidation of alcohol moie-
ties and are able to selectively oxidize allylic C–H bonds in olefins.
More recently, Pd nanoparticles supported on hydroxyapatite,24
entrapped in aluminium hydroxide,25 dispersed in a resin26 or
27
stabilized with poly(ethylene glycol) in scCO2 or with microgels
Table 1
in water28 were shown to catalyze aerobic alcohol oxidations.
We first examined the synthesis of Pd nanoparticles in the
presence of neocuproine (3) using a standard procedure. To this end
a 1:1 mixture of palladium (II) trifluoroacetate and neocuproine,
dissolved in a 1:1 mixture of water and a cosolvent, consisting of
ethylene carbonate, dipropylene glycol or polyethylene glycol (PEG-
600), was reduced with hydrogen gas. The particle size of the
resulting nanoparticles was determined with transmission electron
microscopy (TEM). The particles had a homogeneous size distri-
bution of 2–4 nm diameter (see Fig. 3a). An oxidation reaction was
then performed with these presynthesized Pd nanoparticles and
TEM analysis showed an increase in particle size from 2–4 nm be-
fore to 4–6 nm after the reaction (Fig. 3b).
Oxidation of 2-hexanol to 2-hexanonea
Entry Catalyst
Catalyst amount Conversion
(mol %)
(%)
1
2
3
4
5
6
7
8
9
Pd(O2CCF3)2–neocuproine (1:1)
0.5
72
H2O–ethylene carbonate (1:1)
Pd(O2CCF3)2–neocuproine (1:1)
H2O–ethylene carbonate (1:1)
Pd(O2CCF3)2–neocuproine (1:0.25)
H2O–ethylene carbonate (1:1)
Pd(O2CCF3)2–neocuproine (1:1)
H2O–PEG-600 (1:1)
Pd(O2CCF3)2–neocuproine (1:1)
H2O–dipropylene glycol (1:1)
Pd(OAc)2–neocuproine (1:1)
H2O–ethylene carbonate (1:1)
Pd(OAc)2–bathophenanthroline (1:1) 0.5
H2O–PEG-600 (1:1)
Pd–neocuproine complex
H2O–ethylene carbonate (1:1)
Pd–neocuproine complex
H2O–DMSO (1:1)
0.1
0.5
0.5
0.5
0.5
17
25
54
54
73
30
72
67
Pd nanoparticles were also formed when the separately prepared
Pd(II)–neocuproine complex was added to a solution of 2-hexanol
dissolved in the water–cosolvent (1:1) and the mixture stirred for
10 min at room temperature. In this case the alcohol substrate acts as
the reducing agent that converts the Pd(II) to Pd(0). Our results
clearly indicate that, in the presence of (3) and an alcohol substrate
a Pd(II) salt rapidly forms Pd nanoparticles and that the latter con-
stitute the actual catalyst in aerobic oxidations mediated by the Pd(II)
complex of (3) in aqueous media. In contrast, the Pd(II) complex of
(1) is a homogeneous catalyst that does not undergo nanoparticle
formation in the presence of an alcohol substrate. A plausible ex-
planation for this difference is that the steric crowding caused by the
methyl groups at the 2 and 9 positions in the Pd(II) complexof (3) not
only facilitates the desired dissociation of the hydroxyl bridged di-
mer to the catalytically active monomer (see above) but also pro-
motes dissociation of the latter to Pd nanoparticles. By analogy with
the known stabilization of palladium nanoparticles by unsubstituted
phenanthroline ligands,22 we assume that neocuproine (3) stabilizes
the Pd nanoparticles in our system.
0.5
0.5
a
Reaction conditions: 10 mmol 2-hexanol, 0.5 mmol NaOAc, 100 ꢁC, 2 h,
750 rpm, 50 bar, 8% O2/N2; selectivity to 2-hexanone was essentially quantitative.
When the catalyst amount was reduced from 0.5 mol % to
0.1 mol % the conversion decreased from 72% to 17% (Entries 1, 2). A
decrease in conversion was also observed when the neocuproine/
palladium ratio was reduced from 1:1 to 1: 4 (Entries 1, 3, Table 1)
or when bathophenanthroline sulfonate (1) was used instead of
neocuproine (3) as the ligand in the pre-synthesis of the nano-
particles (Entries 1 and 7, Table 1).
We compared the catalytic behaviour of the presynthesized
nanoparticles with that of the Pd–neocuproine complex under the
same conditions and observed the same conversions after 2 h re-
action time (Entries 1 and 8).
2.2. Catalytic activity in 2-hexanol oxidation
2.3. Oxidation of steroidal alcohols
The catalytic activity of the presynthesized Pd nanoparticles was
determined in the aerobic oxidation of 2-hexanol. The effect of the
cosolvent (stabilizing agent), catalyst amount, nature of the palla-
dium salt precursor and Pd/ligand ratio on the reaction rate was
investigated and the results are shown in Table 1. Palladium
In order to study the catalytic activity of the neocuproine-sta-
bilized palladium nanoparticles with industrially relevant func-
tionalized alcohols as substrates we chose the steroidal alcohols,
nandrolone (8) and 5
a-pregnan-3a-ol-20-one (9) (see Fig. 4). With
these less reactive alcohols we needed to add more catalyst to

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M. Mifsud et al. / Tetrahedron 66 (2010) 1040–1044
1043
O
OH
Pd (O2CCF3)2 / (3)
NaOAc (50mol%)
H
H
H
H
(EtO)2CO/H2O (1:1v/v)
H
H
H
H
O
50 bar 8% O2 / N2 ,100 °C, 4h
O
(8)
mol% catalyst
conversion (%)
1
5
25
100
O
O
Pd (O2CF3)2 / (3) (5mol%)
NaOAc (50mol%)
H
H
H
H
H
H
(EtO)2CO/H2O (1:1v/v)
HO
O
H
H
50 bar 8% O2 / N2 ,100 °C, 4h
59% conversion
> 99% selectivity
(9)
Figure 4. Aerobic oxidation of nandrolone (8) and 5
a
-pregnan-3a-ol-20-one (9).
achieve relatively smooth conversions. For example, (8) underwent
only 25% conversion in 4 h with 1 mol % Pd–neocuproine complex.
On increasing the catalyst loading to 5 mol %, in conjunction with
50 mol % NaOAc (not optimized), we observed complete conversion
of nandrolone in 4 h. Under the same conditions (9) underwent 60%
conversion in 4 h with 5 mol % catalyst. In both examples the se-
lectivity to the corresponding ketone was quantitative, no side
products were observed.
was stirred for 1 h and the cosolvent (stabilizing agent, 12.5 mL)
was added. After 3 min the mixture was reduced under H2 with
vigorous stirring during 15 min.
4.3. Catalyst characterization
The particle size of the Pd catalyst was determined by trans-
mission electron microscopy. The TEM shows a Pd particle size of
2–4 nm. TEM was performed using a Phillips CM30 T electron mi-
croscope with a LaB6 filament as a source of electrons operated
a 300 kV. Samples were mounted on QuantifoilÒ microgrid carbon
polymer supported on a copper grid by placing a few droplets of
solution on the grid, followed by drying at ambient conditions.
3. Conclusions
We conclude that the active alcohol oxidation catalyst, formed
in situ by reaction of palladium(II) salts with the neocuproine li-
gand and the alcohol substrate, is not the expected homogeneous
Pd(II) complex but rather Pd nanoparticles stabilized by the neo-
cuproine ligand and the cosolvent. It is an effective catalyst for the
aerobic oxidation of a broad range of alcohols in aqueous/organic
media, from simple aliphatic alcohols such as 2-hexanol to more
complicated substrates, such as steroidal alcohols, containing other
functional groups. Minor differences in particle size were observed
between the palladium nanoparticles generated in situ from the
palladium–neocuproine complex and the alcohol substrate and
those that were presynthesized by reduction with molecular hy-
drogen but this did not seriously effect their catalytic behaviour.
4.4. Oxidation of 2-hexanol
Standard catalytic experiments were carried out in a closed
Hastelloy C autoclave (150 mL). 2-Hexanol (10 mmol) and NaOAc
(0.5 mmol, 41 mg) were added to a solution of the palladium–
neocuproine complex or a suspension of the Pd nanoparticles in the
1:1 water/cosolvent mixture (25 mL) and pressurized with 8% O2 in
N2 to 50 bar and heated to 100 ꢁC, while stirring at 750 rpm.
After the reaction the autoclave was cooled to room temperature
and depressurised. The product mixture was extracted with Et2O
and the organic layer was washed with water and dried over
MgSO4, n-dodecane was added as external standard to the organic
solutions and the latter were analysed by GC.
4. Experimental section
4.1. General
Neocuproine was purchased from Acros.
4.5. Oxidation of steroidal alcohols
Nandrolone and 5
Diosynth.
a-pregnan-3a-ol-20-one were gifts from
The reactions were carried out in a closed Hastelloy C autoclave
(150 mL). The alcohol (1 mmol, dissolved in 1 mL MeOH) and NaOAc
(0.5 mmol, 41 mg) were added to the palladium–neocuproine so-
lution (see in preparation of catalyst) and the mixture pressurized
with 8% O2 in N2 to 50 bar and heated to 100 ꢁC, while stirring at
750 rpm during 4 h. After the reaction the autoclave was cooled to
room temperature and depressurised. The product mixture was
extracted with EtOAc, the organic layer was washed with water and
The (neocuproine)Pd(OAc)2 complex was prepared according to
the literature procedure.20
4.2. Preparation of the Pd nanoparticles
Neocuproine (0.05 mmol, 10.6 mg) was added to a solution of
Pd(O2CCF3)2 (0.05 mmol, 16.6 mg) in water (12.5 mL). The mixture