Mechanism of the chemo-bio catalyzed cascade synthesis of R-1-phenylethyl acetate over Pd/Al2O3, lipase, and Ru-catalysts

Article abstract of DOI:10.1007/s11164-010-0129-2

One-pot synthesis of R-1-phenylethyl acetate was investigated starting from acetophenone hydrogenation performed over Pd/Al₂O₃ and PdZn/Al₂O₃ catalysts followed by acylation of the intermediate secondary alcohol, R-1-phenylethanol, over an immobilized lipase. Furthermore, the performance of a third type of catalyst, Ru supported on hydroxyapatite (HAP) was evaluated for racemization of S-1-phenylethanol in one pot together with the two other catalysts. The main objectives of this work were to separate the effects of different catalysts and to reveal the reaction mechanism. For this purpose not only acetophenone, but also (R,S)-1- phenylethanol, S-1-phenylethanol, R-1-phenylethyl acetate, and styrene were used as reactants in combination with Pd/Al₂O₃, lipase and Ru/HAP as catalysts. The results revealed that the main side product, ethylbenzene, was formed in two different ways, via dehydration of (R,S)-1-phenylethanol to styrene, followed by its rapid hydrogenation to ethylbenzene, and via debenzylation of the desired product, R-1-phenylethyl acetate to ethylbenzene. The true one-pot synthesis, however, was demonstrated over Shvo's catalyst, but Ru/HAP was not sufficiently active in the racemization step. Ru/Al₂O₃ was a promising catalyst for racemization of S-1-phenylethanol and for dynamic kinetic resolution of (R,S)-1- phenylethanol, when using only small amounts of the acyl donor ethyl acetate. The challenge in racemization is that the activity of heterogeneous Ru catalysts was inhibited by esters. Springer Science+Business Media B.V. 2010.

Full text of DOI:10.1007/s11164-010-0129-2

Res Chem Intermed (2010) 36:193–210
DOI 10.1007/s11164-010-0129-2
Mechanism of the chemo–bio catalyzed cascade
synthesis of R-1-phenylethyl acetate over Pd/Al2O3,
lipase, and Ru-catalysts
•
Alexey Kirilin Paivi Maki-Arvela Matthias Rupp
•
•
¨
Esa Toukoniitty Narendra Kumar Krizstian Kordas
¨
•
•
•
•
Leonid M. Kustov Tapio Salmi Dmitry Yu. Murzin
•
Received: 22 May 2009 / Accepted: 19 November 2009 / Published online: 19 March 2010
Ó Springer Science+Business Media B.V. 2010
Abstract One-pot synthesis of R-1-phenylethyl acetate was investigated starting
from acetophenone hydrogenation performed over Pd/Al2O3 and PdZn/Al2O3 cat-
alysts followed by acylation of the intermediate secondary alcohol, R-1-phenyl-
ethanol, over an immobilized lipase. Furthermore, the performance of a third type of
catalyst, Ru supported on hydroxyapatite (HAP) was evaluated for racemization of
S-1-phenylethanol in one pot together with the two other catalysts. The main
objectives of this work were to separate the effects of different catalysts and to
reveal the reaction mechanism. For this purpose not only acetophenone, but also
(R,S)-1-phenylethanol, S-1-phenylethanol, R-1-phenylethyl acetate, and styrene
were used as reactants in combination with Pd/Al2O3, lipase and Ru/HAP as cat-
alysts. The results revealed that the main side product, ethylbenzene, was formed in
two different ways, via dehydration of (R,S)-1-phenylethanol to styrene, followed
by its rapid hydrogenation to ethylbenzene, and via debenzylation of the desired
product, R-1-phenylethyl acetate to ethylbenzene. The true one-pot synthesis,
however, was demonstrated over Shvo’s catalyst, but Ru/HAP was not sufficiently
active in the racemization step. Ru/Al2O3 was a promising catalyst for racemization
of S-1-phenylethanol and for dynamic kinetic resolution of (R,S)-1-phenylethanol,
when using only small amounts of the acyl donor ethyl acetate. The challenge in
¨
A. Kirilin Á P. Maki-Arvela (&) Á M. Rupp Á E. Toukoniitty Á N. Kumar Á
T. Salmi Á D. Yu. Murzin
˚
˚
Process Chemistry Centre, Abo Akademi University, Turku/Abo 20500, Finland
e-mail: Paivi.Maki-Arvela@abo.fi
K. Kordas
University of Oulu, Oulu, Finland
A. Kirilin
Mendeleev University of Chemical Technology, Moscow, Russia
L. M. Kustov
Zelinsky Institute of Organic Chemistry, Moscow, Russia
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racemization is that the activity of heterogeneous Ru catalysts was inhibited by
esters.
Keywords Chemo–bio cascade Á Acetophenone hydrogenation Á
Acylation Á Pd Á Ru Á Lipase
Introduction
Cascade catalysis is of high interest in synthesizing organic molecules, because it
has several benefits compared with traditional multi-step synthesis [1]. In cascade
reactions the basic idea is to perform several reaction steps in one pot. This
approach is, however, demanding if the catalysts are of different nature, being
chemical and enzymatic. The optimum reaction conditions can be very different for
different catalysts and furthermore, they can interrelate indicating that some
undesirable side reactions can occur.
One very demanding reaction is the combination of three different catalysts in
one-pot, which is the case in the synthesis of R-1-phenylethyl acetate starting from
hydrogenation of acetophenone over a heterogeneous supported metal catalyst,
kinetic resolution of the intermediate secondary alcohol, R-1-phenylethanol, over an
enzyme, and racemization of S-1-phenylethanol over another heterogeneous
catalyst. This reaction has been successfully demonstrated using a homogeneous
Ru complex as a hydrogenation and racemization catalyst and with lipase used for
kinetic resolution [2], and confirmed in this work also. As far as we are aware there
are no reports in which all three reactions have been successfully performed over
heterogeneous catalysts, which is industrially more attractive than use of the
homogeneous counterparts.
Hydrogenation and kinetic resolution in one-pot can be achieved by use of a low
acidity Pd/Al2O3 catalyst for hydrogenation and an immobilized lipase for
resolution [3–6]. The drawback in this approach was, however, the lack of
racemization step, which limiting the yield of the desired product to 50%. It would
thus be desirable to develop an active racemization catalyst for S-1-phenylethanol
for the one-pot synthesis of R-1-phenylethyl acetate starting from acetophenone
hydrogenation (Fig. 1).
Racemization of secondary alcohols has been demonstrated over homogeneous
Ru-complex catalysts [7]. The following reaction mechanism has been proposed for
this reaction [8]. In the first step an Ru–alcoholate species is formed, and in the next
step b-hydride elimination results in the formation of the corresponding ketone, in
this case acetophenone. This step, in which deprotonation of the alcohol occurs, is
promoted under alkaline conditions. In the third step the ketone is reduced to an
enantiomeric alcohol with the aid of Ru–hydride species. There are, however, other
reaction mechanisms also, e.g. the one in which racemization occurs via
isomerization, with Ru–alcoholate as an intermediate and the ketone is produced
via complete of an alcohol. This was proposed as the operative mechanism because
in the b-hydride elimination mechanism addition of acetophenone did not suppress
formation of the ketone [9].
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Mechanism of the chemo–bio catalyzed cascade synthesis
195
Racemization catalyst
OH
O
OH
OAc
H2
EtOAc, Lipase
–EtOH
Pd/Al2O3
AP
R,S–PE
R–PEAC
S–PE
H2, Pd/Al2O3
–H2O
–H2O
–AcOH
H2, Pd/Al2O3
very fast
H2, Pd/Al2O3
–H2O
or via styrene formation
STY
EB
Fig. 1 Reaction scheme for one-pot synthesis of R-1-phenylethyl acetate starting from acetophenone
hydrogenation. Notation: AP acetophenone, R,S-PE (R,S)-1-phenylethanol, R-PEAC R-1-phenylethyl
acetate, S-PE S-1-phenylethanol, STY styrene, EB ethylbenzene
Racemization of secondary alcohols has been demonstrated over several types of
heterogeneous catalysts, for example zeolites [10] and supported Ru catalysts [8, 9].
Zeolites are too acidic to be used as catalysts in one-pot synthesis of R-1-
phenylethyl acetate, in which dehydration of (R,S)-1-phenylethanol is catalyzed by
strongly acidic catalysts. Two different types of Ru catalysts have been reported to
be active in racemization of S-1-phenylethanol, i.e. Ru supported on hydroxyapatite
(HAP) [8] and on Al2O3 [11]. The alkaline hydroxyapatite has been reported to
promote deprotonation of S-1-phenylethanol during racemization. The active
species in racemization was proposed to be Ru3? [8].
One objective of this work was to separate the effects of different catalysts in
one-pot synthesis of R-1-phenylethyl acetate from acetophenone hydrogenation.
One undesired reaction is formation of ethylbenzene and the question which should
be answered is whether ethylbenzene is formed via dehydration of (R,S)-1-
phenylethanol, followed by its rapid hydrogenation to ethylbenzene, or by
debenzylation of R-1-phenylethyl acetate over Pd species. The following experi-
ments were performed:
(1) hydrogenation of acetophenone over Pd/Al2O3 and over Ru/HAP;
(2) hydrogenation and kinetic resolution over Pd/Al2O3 and lipase; and
(3) hydrogenation and dynamic kinetic resolution using Pd/Al2O3, lipase, and
Ru/HAP.
Furthermore, the different catalysts can affect the reaction intermediates in an
unexpected way and thus their effects were studied in transformations of (R,S)-1-
phenylethanol over Pd/Al2O3 and Al2O3, styrene hydrogenation over Pd/Al2O3, and
reactions of R-1-phenylethyl acetate over Al2O3 and lipase. Apart from these
experiments, racemization of S-1-phenylethanol was also investigated over three
different types of supported Ru catalysts:
(1) Ru/HAP calcined and prereduced;
(2) Ru/HAP only calcined; and
(3) Ru/Al2O3 prepared by the method reported elsewhere [12, 13].
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For comparison with Pd/Al2O3 as catalyst few experiments were also performed
with Pd–Zn/Al2O3 catalyst together with lipase.
Experimental
Kinetic experiments
Three different types of catalysts were tested in acetophenone hydrogenation and its
(dynamic) kinetic resolution. Pd/Al2O3 was used as a hydrogenation catalyst. It was
prepared by vacuum evaporation impregnation techniques described elsewhere [4]
using palladium nitrate as a Pd source. A commercial immobilized lipase, Novozym
435 was used for kinetic resolution of R-1-phenylethanol. Two different supported
Ru catalysts were investigated as racemization catalysts, namely Ru supported on
hydroxyapatite and Ru prepared by an ion-exchange method.
Hydroxyapatite was prepared by the method used in Ref. [14]. Shvo’s catalyst
(Sigma) (1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-
one)-l-hydrotetracarbonyldiruthenium(II)) was also applied in one-pot synthesis of
R-1-phenylethyl acetate at 70 °C in ethyl acetate in flowing hydrogen, using an
initial acetophenone concentration of 0.02 mol/L.
Hydrogenation of acetophenone (Fluka) was performed in a glass reactor with
the liquid phase volume of 250 mL using ethyl acetate as solvent and as an acetyl
group donor. Before the reaction the catalyst was reduced at either 100 or 200 °C.
Thereafter the reaction was started by injecting the solvent containing the
acetophenone, at the initial concentration of 0.02 M, together with lipase (Novozym
435) into the reactor. Typically, 250 mg Pd/Al2O3 in the presence or absence of
racemization catalyst, Ru/HAP (125 mg) and lipase (125 mg) were used. Further-
more, catalytic transformations of S-1-phenylethanol (Aldrich, 97%) and (R,S)-
phenylethyl acetate (Acros Organics, [98%) were investigated.
The reaction mixture was analyzed by gas chromatography with a chiral column
(Supelco Beta-Dex 225 (30 m 9 250 lm 9 0.25 lm)) using a flame ionization
detector. The temperature program was: 66 °C (5 min) – 20 °C/min - 111 °C
(10 min) - 20 °C/min - 190 °C. The products were identified by GC–MS (GC:
6890N Network GC Systems, Agilent technologies; column: Agilent DB-Petro
(50 m 9 200 lm 9 0.5 lm); mass spectrometer: Agilent 5973 Network).
Catalyst preparation and characterization
Pd/Al2O3 (5 wt%) was prepared by impregnation of alumina with an aqueous
solution of palladium nitrate (Degussa) as palladium source. Thereafter, it was dried
at 110 °C and calcined in a muffle oven.
Complex PdZn(OAc)4.H2O for Pd–Zn/Al2O3 (2 wt% Pd, 0.63 wt% Zn) catalyst was
prepared as follows[15]. Palladiumacetate (Sigma–Aldrich, 99.9? % metal basis)and
zinc acetate (Fluka, [99.5% (KT)) were used without further purification. Glacial
acetic acid was purchased from Merck (100%, GR for analysis). To a 25-mL round-
bottomed flask equipped with a magnetic stirrer and reflux condenser, flushed with Ar
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Mechanism of the chemo–bio catalyzed cascade synthesis
197
for 10 min before use, Zn(OAc)2.2H2O (220 mg, 1 mmol) and Pd(OAc)2.2H2O
(224 mg, 1 mmol) were loaded followed by addition of glacial acetic acid (10 mL).
The mixture was stirred under gentle reflux until complete dissolution of the salts and
then for 40 min longer. The resulting solution was filtered through a Schott filter (#3)
and evaporated on a rotary evaporator (8 mbar, 30 °C). The remaining acetic acid was
removed by evaporation of the resulting mixture with benzene (5 times 9 15 mL,
30 mbar, 30 °C) affording a sand-colored crystalline powder. The presence of the
complex was confirmed by 1H NMR (600.13 MHz, CDCl3): 2.02 (s, 4OAc).
The Pd–Zn/Al2O3 catalyst was prepared using the wetness-incipient technique
[16]. The above mentioned complex PdZn(OAc)4.H2O (82.6 mg) was dissolved in
absolute methanol (3 mL) at room temperature. The resulting solution was added
dropwise to alumina (UOP) (1 g) and the resulting mixture was thoroughly stirred to
a homogeneous paste and left overnight at room temperature. The catalyst prepared
in this way was pretreated before the reaction by use of the following temperature
procedure: Ar flow, 5 °C/min to 80 °C and kept for 2 h, switched to H2, 5 °C/min to
250 °C and kept for 1 h, switched to Ar and kept for 20 min at 250 °C, cooling to
room temperature in Ar flow.
Ru on HAP (1.75 wt% Ru) was prepared by the vacuum-impregnation method
from hydroxyapatite and a solution of Ru(acac)3 in toluene. Hydroxyapatite (HAP)
was synthesized by a method described elsewhere [14]. HAP (2 g) was added to a
solution of ruthenium acetylacetonate (140 mg, Aldrich, 97%) in toluene (60 mL,
J.T. Baker) and the reddish slurry was vigorously stirred for 4 h at ambient
temperature. The solvent was removed at reduced pressure and the solid material
obtained was dried under vacuum followed by calcination in a muffle oven (320 °C,
12 h, heating rate 5 °C/min, and normal atmosphere) resulting in a beige powder
(1.8 g). The ion-exchanged Ru/HAP was prepared using RuCl3ÁxH2O as an Ru
source, using a method described elsewhere [8]. Ru/Al2O3 (4 wt%) catalyst was
prepared by a method described elsewhere [12, 13].
Catalysts were characterized by nitrogen adsorption to determine the specific
surface area, temperature programmed reduction, and CO chemisorption and TEM
to elucidate the metal particle size and metal dispersion. Nitrogen adsorption was
measured by use of Carlo Erba equipment; the BET equation was used for
determination of the specific surface area and the DH method for determination of
pore-size distribution. Temperature-programmed reduction of the catalyst was
performed with AutoChem Micromeritics using the programs: 10 °C/min - 400 °C
for Ru/HAP and Ru/Al2O3 and 5 °C/min - 400 °C for Pd/Al2O3. Metal particle
size was investigated by TEM and by CO-chemisorption, using EFTEM: LEO 912
Omega and AutoChem 2900 (Micromeritics) equipment, respectively.
Results and discussion
Catalyst characterization results
Metal dispersion and average metal particle sizes were measured by TEM, by CO
chemisorption, and by XRD techniques. The mean Pd particle sizes of Pd/Al2O3
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A. Kirilin et al.
catalyst reduced either at 100 °C or at 200 °C, determined by XRD, were 7.1 nm [6]
and 8.6 nm, respectively, indicating that slight sintering of Pd particles occurred after
reduction at 200 °C. The corresponding average Pd particle size after reducing the
catalyst at 200 °C was determined by TEM (Fig. 2), and was 4.2 nm. The Ru/HAP
had 4 nm average Ru particle size after reduction at 200 °C for 30 min, correspond-
ing to metal dispersion of 32%. It should, however, be pointed out that at this
temperature Ru is not completely reduced, which was confirmed by temperature-
programmed reduction (see below). CO is thus adsorbed by Ru3? species forming
surface carbonyl species. For Ru/Al2O3 catalyst the average metal particle size was
determined from a TEM image to be 1.3 nm (picture not shown here).
The BET specific surface area of Pd/Al2O3, measured by nitrogen adsorption,
was 306 m2/g. The alumina support used in Pd/Al2O3 contained low concentrations
of Bronsted and Lewis acid sites—7 and 156 lmol/gcat., respectively [17].
Temperature programmed reduction was used to determine the temperature at
which the metal was reduced (Fig. 3). The reduction of palladium on alumina
occurred close to 71 °C, whereas Ru/HAP was reduced at 174 °C. It should,
however, be pointed out here that there was a second hydrogen-consuming peak
occurring at 268 °C indicating that Ru was not totally in the metallic state below
200 °C. The ion-exchange Ru species supported on hydroxyapatite needed slightly
higher reduction temperatures than the Ru/HAP catalyst prepared by the impreg-
nation method. The reduction temperature for Ru in 4 wt% Ru/Al2O3 was shown to
be 137 °C according to TPR, indicating, analogously to Ref. [18], that it remained
as Run? during the hydrogenation of acetophenone at 70 °C. Furthermore, the
reduction of Pd in Pd–Zn/Al2O3 catalyst occurred at 115 °C, whereas a high-
temperature peak was obtained at 351 °C; this most probably indicates reduction of
Zn species. It was, however, confirmed by XAFS that alloy formation had already
occurred at 250 °C [16].
Fig. 2 TEM picture of Pd/Al2O3 catalyst reduced at 200 °C
123

Mechanism of the chemo–bio catalyzed cascade synthesis
199
(a)
5% Pd/Al2O3 (UOP) – C
70.6°C
0.60
0.59
0.58
0.57
0.56
0.55
170,1°C
0
50 100 150 200 250 300 350 400 450
T°C
(b)
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
a) 1,75% Ru/HAP-C
b) 3,8% Ru/HAP-IE
174,3°C
190,7°C
267,6°C
374,6°C
a
b
0
50 100 150 200 250 300 350 400 450
T°C
Fig. 3 Temperature programmed reduction from a Pd/Al2O3 and b Ru/HAP
Results from the kinetic studies
The mechanism in one-pot synthesis of R-1-phenylethyl acetate starting from
acetophenone hydrogenation was of interest in this work. To reveal the reaction
mechanism, the following types of kinetic studies were performed: acetophenone
hydrogenation, acetophenone hydrogenation combined with kinetic resolution, one-
pot synthesis of R-1-phenylethyl acetate, and some transformations of reaction
intermediates and products over different catalysts. The catalysts investigated were:
Pd-100 and Pd-200, which are Pd/Al2O3 catalysts reduced at 100 °C and 200 °C,
respectively, for 30 min, and Pd-100–Ru and Pd-200–Ru, which are a mixture of
Pd/Al2O3 and Ru/HAP reduced at either 100 °C or 200 °C, respectively. The
notation Lip stands for lipase in, e.g., Pd-100–Lip. Furthermore, a catalytic system
containing three catalysts, i.e. Pd-200–Ru–Lip indicating Pd/Al2O3, Ru/HAP
reduced at 200 °C for 30 min, and lipase was applied. Results from the different
reaction types are presented below.
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A. Kirilin et al.
Hydrogenation of acetophenone
The kinetics of hydrogenation of acetophenone were investigated using Pd/Al2O3
catalysts reduced at either 100 °C or 200 °C for 30 min and also using Pd-100–Ru
and Pd-200–Ru. The lowest initial hydrogenation rate was observed for Pd-100,
despite the fact the Pd was reduced at 71 °C according to TPR (see above). The
hydrogenation, however, proceeded faster after about 90 min. This result indicated
that part of Pd was being reduced during the initial induction time and that 30 min
reduction time at 100 °C was not enough to reduce Pd completely. The initial rates
decreased with the three more active catalysts in the order: Pd-100–Ru [ Pd-
200 [ Pd-200–Ru. Furthermore, when conversion levels after 200 min (Table 1;
Fig. 4a) over different catalysts are compared it can be observed that the most active
system catalyst was Pd-100–Ru. This result can be explained by the fact that Pd was
slightly sintered according to XRD results, after its reduction at 200 °C. The
question why Pd-100–Ru was the most active catalyst combination is not trivial to
answer, because Ru/HAP catalyst was inactive in the hydrogenation of acetophe-
none in ethyl acetate as solvent (Table 1, entry 8). At the moment we consider the
higher activity of the Pd-100–Ru system to be explained by lower deactivation of
the catalyst mixture compared with Pd-200. Catalyst deactivation occurs because
of deacylation of a target phenylethyl acetate molecule and hydrogenolysis of
intermediate R,S-phenylethanols. Additionally only low hydrogenation activity of
Ru/HAP was achieved for acetophenone using toluene as solvent (Table 1, entry 9).
The formation of R-1-phenylethanol as a function of temperature, shown in
Fig. 4b, follows the same order in the formation rates as obtained for acetophenone
Table 1 Kinetics of acetophenone hydrogenation, kinetic resolution, and dynamic kinetic resolution
over Pd/Al2O3, Ru/HAP and lipase at 70 °C in ethyl acetate
Entry Catalyst
Init. rate
(mmol/min/gMe
Conversion after Selectivity of
R-PEAC (%)
Selectivity of
ethylbenzene (%)
)
200 min (%)
at 70% conversionc at 70% conversiond
1
2
3
4
5
6
7
8
9
a
Pd-100
0.6
2.4
1.1
1.0
4.8
1.7
55 (98)
62 (97)
43 (98)
23 (78)
95 (98)
64 (98)
64 (98)
Inactive
8
0
1 (11)
1 (5)
1 (17)
1 (8)
4 (76)
1 (12)
1 (37)
–
Pd-200
0
Pd-100–Lip
Pd-200–Lip
Pd-100–Ru
Pd-200–Ru
6 (16)
23e
0
0
Pd-200–Ru–Lip 0.9
Ru/HAPa
Ru/HAPa, b
10 (32)
0
0
0
Very low
0
Catalyst prereduced at 200 °C
Toluene as solvent
b
c
After 1200 min in parentheses
d
At the conversion level of 97% in parentheses
Conversion only 78% after 1200 min
e
123

Mechanism of the chemo–bio catalyzed cascade synthesis
201
(a)
0.025
0.02
0.015
0.01
0.005
0
0
0
0
200 400 600 800 1000 1200 1400 1600
Time (min)
(b)
0.014
0.012
0.01
0.008
0.006
0.004
0.002
0
200 400 600 800 1000 1200 1400 1600
Time (min)
(c)
0.016
0.014
0.012
0.01
0.008
0.006
0.004
0.002
0
20
40
60
80
100
Conversion (%)
Fig. 4 Kinetics of hydrogenation of acetophenone, a, R-1-phenylethanol, b, and ethylbenzene, c, as a
function of conversion over Pd/-100 (u), Pd-200 (j), Pd-100–Ru (d) and Pd-200–Ru (m)
reaction rates. Analogous curves were achieved for S-1-phenylethanol because of
racemic hydrogenation and dehydration of the secondary alcohol. In these
experiments there was no lipase present and thus the decrease in the concentration
of R-1-phenylethanol over Pd-100–Ru catalyst was because of dehydration of the
123

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A. Kirilin et al.
secondary alcohol to styrene followed by its rapid hydrogenation to ethylbenzene.
This is also apparent in Fig. 4c, in which the formation of ethylbenzene is presented
as a function of acetophenone conversion. The selectivity to ethylbenzene at the
97% conversion level was about 76% (Table 1). It can thus be concluded that the
presence of Ru/HAP catalyzed dehydration of (R,S)-1-phenylethanol.
When comparing ethylbenzene formation over Pd-100 and Pd-200 catalysts, it was
clearly visible that over smaller Pd particles (Pd-100) more ethylbenzene was formed
compared with larger Pd particles (Pd-200) (Fig. 4b; Table 1). Analogously in the
hydrogenation of acetophenone over Pd/C catalysts in the liquid phase using hexane
as a solvent the main product was ethylbenzene when the reaction temperature
exceeded 85 °C whereas only 40% ethylbenzene was achieved at 60 °C [19].
The activity of Pd/Al2O3 after prolonged reaction times in acetophenone
hydrogenation was investigated by adding 2.2 mmol acetophenone three times
during the reaction (Fig. 5). This result indicated that the Pd/Al2O3 catalyst was
active in acetophenone hydrogenation after prolonged reaction times.
Hydrogenation of acetophenone and kinetic resolution of R-1-phenylethanol
In acetophenone hydrogenation combined with kinetic resolution two different
catalyst systems were compared—Pd-100–Lip and Pd-200–Lip (Table 1, entries 3,
4; Fig. 6). The initial hydrogenation rates for both catalysts were about the same.
The reaction proceeded, however, much faster over the former catalyst system than
over the latter (Fig. 6a) indicating that catalyst deactivation was more prominent for
Pd-200–Lip than for Pd-100–Lip.
The conversion level of Pd-200–Lip was only 78% after 1200 min reaction time,
whereas close to 100% conversion was achieved over Pd-100–Lip (Table 1, entries
3, 4). The reason for the more severe deactivation for Pd-200–Lip catalyst compared
with Pd-100–Lip is the faster debenzylation of R-1-phenylacetate over Pd-200–Lip
AP
0.025
AP
0.02
0.015
0.01
0.005
0
AP
0
500
1000
1500
Time (min)
Fig. 5 Hydrogenation of acetophenone (AP) over Pd/Al2O3 catalyst in ethyl acetate at 70 °C. The initial
concentration of acetophenone was 0.02 mol/L and three batches of acetophenone (2.2 mmol) were
added after prolonged reaction times
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Mechanism of the chemo–bio catalyzed cascade synthesis
203
(Fig. 6d), which enhanced coking of the Pd-200–Lip catalyst. At the same time the
rate of acylation was much faster over Pd-200–Lip than over Pd-100–Lip (Fig. 6c).
Mechanistically, it was interesting to observe that ethylbenzene formation was
more selective in the presence of lipase than in its absence (Table 1, entry 1, 3). This
result indicates that the debenzylation of R-1-phenylethyl acetate is faster than the
dehydration of the secondary alcohol (R,S)-1-phenylethanol to styrene followed by
its hydrogenation to ethyl benzene.
Hydrogenation of acetophenone and dynamic kinetic resolution
of R-1-phenylethanol
One-pot synthesis of R-1-phenylethyl acetate from acetophenone was investigated
over the Pd-200–Ru–Lip catalyst system (Table 1, entry 7; Fig. 7a). Hydrogenation
of acetophenone proceeded with the same rates over Pd-200–Ru and over Pd-200–
Ru–Lip, indicating that lipase had no effect on the hydrogenation of acetophenone.
The formation of R and S-1-phenylethanol proceeded faster over Pd-200–Ru and
Pd-200–Ru–Lip than over Pd-200–Lip (Fig. 7a). No racemization, however,
occurred over Pd-200–Ru, because the level of S-1-phenylethanol remained constant
after prolonged reaction times. Separate racemization experiments (see below)
confirmed this result. When using the Pd-200–Ru–Lip combination of catalysts, the
concentration of R-1-phenylethanol was maximum after approximately 310 min,
after which it reacted further to both R-1-phenylethyl acetate and ethylbenzene
(a)
(c)
0.004
0.003
0.002
0.001
0
0.025
0.02
0.015
0.01
0.005
0
0
20
40
60
80
100
0
200 400 600 800 1000 1200 1400
Time (min)
Conversion (%)
0.0035
0.003
0.0025
0.002
0.0015
0.001
0.0005
0
(b)
(d)
0.01
0.008
0.006
0.004
0.002
0
0
200 400 600 800 1000 1200 1400
0
20
40
60
80
100
Time (min)
Conversion (%)
Fig. 6 Kinetics of hydrogenation of acetophenone, a, and formation of R-1-phenylethanol, b, R-1-
phenylethyl acetate, c, and ethylbenzene, d, as a function of conversion over Pd/Al2O3-100–lipase (u)
and over Pd/Al2O3-200–lipase (j)
123

204
A. Kirilin et al.
(Fig. 7c, d). In contrast, the rate of formation of (R,S)-1-phenylethanol decreased
after 90 min reaction time because of deactivation of the Pd/Al2O3 catalyst. The
reason for this behavior was coking of the Pd catalyst. The initial hydrogenation
activity of Pd-200–Lip was high, but hydrogenation activity decreased relatively
rapidly because of debenzylation of R-1-phenylethyl acetate. At the same time the
rate of formation of ethylbenzene increased, which is clearly visible from the low
value (12) of the ratio of the initial rate of formation of (S,R)-1-phenylethanol to that
of ethylbenzene (Table 2, entry 2). The two other catalyst systems, i.e. Pd-100–Lip
and Pd-200–Ru–Lip, exhibited high initial rates of formation of secondary alcohols
compared with that of ethylbenzene.
Comparison of the kinetics of formation of R-1-phenylethyl acetate and
ethylbenzene is of interest for Pd-100–Lip, for Pd-200–Lip, and for Pd-200–Ru–
Lip mixtures (Table 2). The ratio of the initial rate of formation of 1-phenylethyl
acetate to that of ethylbenzene decreased in the order Pd-200–Ru–Lip [ Pd-100–
Lip [ Pd-200–Lip for the three combinations tested. This result, i.e. that more of
the desired product, R-1-phenylethyl acetate, was formed over Pd-200–Ru–Lip than
over the other catalyst systems, can be explained by the fact that there are more
adsorption sites available for reaction intermediates and thus the debenzylation of
R-1-phenylethyl acetate, which is catalyzed by Pd, is retarded because of the
lowered relative concentration of Pd in Pd-200–Ru–Lip compared with the Pd-200–
Lip system. Furthermore, Ru/HAP was inactive in transforming R-1-phenylethyl
acetate (see below).
(a)
(c)
0.025
0.02
0.015
0.01
0.005
0
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0
0
200 400 600 800 1000 1200 1400 1600
0
20
40
60
80
100
Conversion (%)
Time (min)
(b)
(d)
0.014
0.012
0.01
0.008
0.006
0.004
0.002
0
0.008
0.006
0.004
0.002
0
0
200 400 600 800 1000 1200 1400 1600
0
20
40
60
80
100
Time (min)
Conversion (%)
Fig. 7 Kinetics in the hydrogenation of acetophenone, a, and formation of R-1-phenylethanol, b, R-1-
phenylethyl acetate, c, and ethylbenzene, d, as a function of conversion over Pd/Al2O3-200 and lipase
(j), Pd/Al2O3-200–Ru/HAP (m), and Pd/Al2O3-200–Ru/HAP and lipase (u)
123

Mechanism of the chemo–bio catalyzed cascade synthesis
205
Table 2 Comparison of the ratio of the initial rate of formation of R-1-phenylethyl acetate to that of
ethylbenzene, and the ratio of the initial rate of formation of (R, S)-1-phenylethanol to that of ethyl-
benzene, over different catalysts
Entry
Catalyst
rR-PEAC/rEB
r(S,R)-PE/rEB
1
2
3
Pd-100–Lip
7.0
3.1
8.3
205
12
Pd-200–Lip
Pd-200–Ru–Lip
243
Acetophenone hydrogenation, dynamic kinetic resolution of (R,S)-1-phenyleth-
anol, and acylation of R-1-phenylethanol in one pot were demonstrated using,
simultaneously, Shvo’s catalyst and lipase at 70 °C in ethyl acetate (Fig. 8). The
molar fraction of the R-1-phenylethyl acetate formed was 66% corresponding to
selectivity of 74% at the conversion level of 89%. This result indicated that dynamic
kinetic resolution, i.e. racemization of S-1-phenylethanol, happened during the
reaction, because the molar fraction of R-1-phenylethanol was above 50%. The
concentration of R-1-phenylethanol was close to zero during the reaction, indicating
that it reacted further to R-1-phenylethyl acetate and no ethylbenzene was formed.
Mechanistic studies
Transformations of (R,S)-1-phenylethanol and R-1-phenylethyl acetate over
different materials
Transformation of (R,S)-1-phenylethanol was studied over Pd/Al2O3 catalyst
reduced at 100 °C under hydrogen or argon atmosphere (Table 3, entries 1 and
2). The main product in both cases was acetophenone, indicating that dehydroge-
nation of phenylethanol was the main reaction, whereas only small amounts of
ethylbenzene were formed. Styrene is a product in the dehydration of phenylethanol
0.025
0.02
0.015
0.01
0.005
0
0
10
20
30
40
50
Time (min)
Fig. 8 Kinetics in one-pot synthesis of R-1-phenylethyl acetate over Shvo catalyst (0.25 g) together with
lipase (0.25 g) using 0.02 mol/L initial acetophenone concentration in ethyl acetate at 70 °C. Symbols:
(u) acetophenone, (m) S-1-phenylethanol, (j) R-1-phenylethanol, and (X) R-1-phenylethyl acetate
123

206
A. Kirilin et al.
and its rapid hydrogenation to ethylbenzene over Pd/Al2O3 was confirmed in a
separate experiment (Table 3, entry 4).
Transformations of (R,S)-1-phenylethyl acetate
The support material alumina, with a low concentration of acid sites, was inactive in
debenzylation of R-1-phenylethyl acetate (Table 3, entry 5). Furthermore, it was not
active in the dehydration of (R,S)-1-phenylethanol (Table 3, entry 6). Debenzylation
of the desired product R-1-phenylethyl acetate did not occur over lipase (Table 3,
entry 7). The debenzylation of R,S-1-phenylethyl acetate took place, however, on
Pd/Al2O3 catalyst reduced at 100 °C (Table 3, entry 8).
Racemization of S-1-phenylethanol over different Ru catalysts
Separate racemization experiments were performed for S-1-phenylethanol over
Ru/HAP prepared either by the impregnation method (IMP) or by ion-exchange (IE)
at temperature of 70 °C or 90 °C using two different solvents, ethyl acetate and
toluene, and either hydrogen or argon as gas atmosphere (Table 4). The results
revealed that Ru/HAP(IMP) was inactive in the racemization of S-1-phenylethanol
in ethyl acetate as solvent (Table 4, entries 1-3). In toluene, however, low activity
was observed, but the enantiomeric excess of S-1-phenylethanol remained at 91%
only, which is too high, because in dynamic kinetic resolution the enantiomeric
excess should be close to zero. Furthermore, dehydrogenation of S-1-phenylethanol
to acetophenone occurred over Ru/HAP(IMP) in toluene. According to the literature
Ru3? species are active in the racemization of S-1-phenylethanol forming, in the
first step, a ketone which, in turn, will hydrogenate via transfer hydrogenation [13].
The results in this study, however, showed that neither Ru/HAP(IMP) nor Ru/
HAP(IE) were very active in the racemization of S-1-phenylethanol. Ru/Al2O3, was
a more effective racemization catalyst than Ru/HAP and promising results were
achieved using only three equivalents of ethyl acetate in toluene (Table 4, entries
8–10). These results are in accordance with the literature [9], in which the catalyst
Table 3 Mechanistic studies using different intermediates and catalysts. Ethyl acetate was used as a
solvent and the reaction temperature was 70 °C
Entry Catalyst Substrate
Pretreatment with
H2 at temperature ( °C)
Atmosphere Conversion Comment
(%)
1
2
Pd-100 (R,S)-PE
Pd-100 (R,S)-PE
100
100
H2
Ar
97
93
3% EB
Main product AP,
6% EB, no styrene
3
4
5
6
7
8
Pd-100 (R,S)-PE
100
100
–
H2
H2
H2
Ar
H2
H2
15
100
0
3% AP and 12% EB
Pd-100 Styrene
EB
Al2O3
Al2O3
(R,S)-PEAC
(R,S)-PE
–
–
0
–
Lipase (R,S)-PEAC
Pd-100 (R,S)-PEAC
–
0
–
–
47
46% EB
123

Mechanism of the chemo–bio catalyzed cascade synthesis
207
was tested under conditions very close to those required for performing the desired
cascade reactions in a one-pot manner.
Preliminary studies were conducted using Ru/Al2O3–lipase for dynamic kinetic
resolution of (R,S)-1-phenylethanol and PdZn/Al2O3–Ru/Al2O3–lipase catalysts in
one-pot synthesis of R-1-phenylethyl acetate. Because Ru/Al2O3 was active in the
racemization experiments (see above), it was also tested in dynamic kinetic
resolution of (R,S)-1-phenylethanol using lipase as a transesterification catalyst
(Fig. 9). The results revealed that 94% conversion of R-1-phenylethanol was
achieved within 1315 min and, furthermore, that 11% of the S-1-phenylethanol was
converted via R-1-phenylethanol to R-1-phenylethyl acetate, indicating that
dynamic kinetic resolution over this catalyst was possible.
To develop a working catalyst for one pot synthesis of R-1-phenylethyl acetate,
bimetallic PdZn/Al2O3 was used for hydrogenation of acetophenone either together
with lipase or with lipase and Ru/Al2O3 as a racemization catalyst. The benefit of a
bimetallic catalyst is, according to the literature, that it should be more selective
than a monometallic Pd catalyst and able to produce less ethylbenzene than the
latter [18]. The initial reaction rate in acetophenone hydrogenation was close to the
rate achieved over Pd-200, when using the same Pd-to-acetophenone ratio of 0.02.
Furthermore, it can be observed from Fig. 10a that Ru/Al2O3 did not have any effect
on the acetophenone conversion. The reason for this is that Ru is not in the metallic
state (see above).
The formation rates for R-1-phenylethanol were also initially the same, but after
prolonged reaction times R-1-phenylethanol reacted more rapidly over PdZn/
Al2O3–Ru/Al2O3–lipase catalysts than over PdZn/Al2O3–lipase (Fig. 10b) and
smaller amounts of the desired product were obtained over the former catalyst than
when using PdZn/Al2O3–lipase catalysts (Fig. 10c). Furthermore, debenzylation of
Table 4 Kinetics for racemization of S-PE over Ru/HAP and over Ru/HAP(IE) using the glass reactor
with a liquid phase volume of 250 mL, if not stated otherwise
Entry Catalyst
Substrate/ Atmosphere/
metal ratio solvent
Temperature Conversion ee (%)c
(°C)
(%)
1
2
Ru/HAP (IMP)a 112
H2/toluene
70
70
70
90
70
70
90
90
70
70
Inactive
\4
[99
Ru/HAP (IMP)
Ru/HAP (IMP)
Ru/HAP (IMP)
Ru/HAP (IE)
Ru/HAP (IE)
Ru/HAP (IE)
Ru/Al2O3
33
33
H2/toluene
92
3
Ar/toluene
Inactive
Low
1
99
4
33
Ar/toluene
91 (AP = 17%)
97
5
112
112
33
33b
33b
33b
H2/ethyl acetate
H2/toluene
6
[8
96
7
Ar/toluene
10
97, 10% AP
4.3 (AP = 62%)
99 (AP = 24%)
85 (AP = 35%)
8
Ar/toluene
98
9
Ru/Al2O3
Ar/ethyl acetate
25
10
Ru/Al2O3
Ar/3 eq of ethyl
acetate in toluene
45
a
Catalyst prereduced at 200 °C
In 8 mL vessel, 1000 rpm stirring
b
c
Acetophenone molar fraction in the parentheses
123

208
A. Kirilin et al.
0.012
0.010
0.008
0.006
0.004
0.002
0.000
0
200
400
600
800 1000 1200 1400
time, min
Fig. 9 Dynamic kinetic resolution of (R,S)-1-phenylethanol at 70 °C over 4 wt% Ru/Al2O3 catalyst,
using 3 equivalents of ethyl acetate, in toluene as solvent. The initial concentrations of (R,S)-1-
phenylethanol and ethyl acetate were 0.02 mol/L and 0.06 mol/L, respectively. The catalyst and lipase
amounts were 100 mg and 62.5 mg, respectively. Symbols: (j) R-1-phenylethanol, (d) S-1-
phenylethanol, and (m) R-1-phenylethyl acetate
R-1-phenylethyl acetate occurred over the PdZn/Al2O3–lipase catalyst system,
because a maximum was visible in the concentration profile of R-1-phenylethyl
acetate (Fig. 10c). The formation of ethylbenzene was at the same level for all three
catalyst systems, i.e. for Pd-200–Lip, for PdZn/Al2O3–Ru/Al2O3–lipase, and for
PdZn/Al2O3–lipase, indicating that use of the bimetallic catalyst did not, as
expected, suppress the hydrogenolysis reaction. When formation of S-1-phenyleth-
anol was plotted against R-1-phenylethanol (Fig. 10d) it was seen that the initial
formation rates for S and R-1-phenylethanol were the same, but after 30 min
reaction time accumulation of S-1-phenylethanol in the reaction mixture was faster
than that of R-1-phenylethanol, because R-1-phenylethanol reacted to the ester
whereas S-1-phenylethanol reacted only slowly to ethylbenzene, but no racemiza-
tion of it occurred. Finally the concentrations of both R and S-1-phenylethanol
decreased because of formation of ethylbenzene.
As a conclusion it can be stated that these preliminary results indicated that
Ru/Al2O3 was active in dynamic kinetic resolution of (R,S)-1-phenylethanol, but
that one-pot synthesis using PdZn/Al2O3–Ru/Al2O3–lipase was not successful. The
reason for this is most probably the sensitivity of the Ru/Al2O3 catalyst toward
esters depending on their structure as stated elsewhere [8]. A detailed kinetic study
starting from acetophenone hydrogenation using PdZn/Al2O3–Ru/Al2O3–lipase as
catalyst will be the topic of a forthcoming publication.
Conclusions
Three different types of catalysts were investigated in one-pot synthesis of R-1-
phenylethyl acetate, i.e. Pd/Al2O3 for hydrogenation of acetophenone, immobilized
123

Mechanism of the chemo–bio catalyzed cascade synthesis
209
(a)
(c)
0.020
0.015
0.010
0.005
0.000
0.0025
0.0020
0.0015
0.0010
0.0005
0.0000
0
300
600
900
1200 1500 1800
0
300
600
900
1200 1500 1800
Time (min)
Time (min)
(b)
(d)
0.010
0.008
0.006
0.004
0.002
0.000
0.006
0.005
0.004
0.003
0.002
0.001
0.000
0
300
600
900
1200 1500 1800
0.0000 0.0005 0.0010 0.0015 0.0020 0.0025
Time (min)
Concentration of R-PE (mol/l)
Fig. 10 Kinetics for acetophenone hydrogenation, a, and formation of R-1-phenylethanol, b, R-1-
phenylethyl acetate, c, and formation of S-1-phenylethanol versus R-1-phenylethanol, d, over (d) PdZn/
Al2O3 and lipase and (j) PdZn/Al2O3 and Ru/Al2O3 and lipase. The amounts of lipase, PdZn/Al2O3, and
Ru/Al2O3 were 62.5, 312, and 100 mg, respectively. The initial acetophenone and ethyl acetate
concentrations were 0.02 and 0.06 mol/L, respectively
lipase for kinetic resolution of R-1-phenylethanol, and Ru supported on hydroxyap-
atite for racemization of R-1-phenylethanol. In the hydrogenation of acetophenone the
effect of the Pd/Al2O3 reduction temperature was investigated. Reduction at 200 °C
resulted in more active catalyst than that reduced at 100 °C. The reaction was,
however, the fastest over Pd/Al2O3 combined with Ru/HAP which were reduced at
100 °C, despite the fact that Ru hydroxyapatite alone was inactive in the hydroge-
nation of acetophenone. When all three catalysts, Pd/Al2O3, Ru/HAP, and lipase, were
used as a mixture simultaneously in the system, it was observed that ethylbenzene
formation was promoted in the presence of lipase. This result indicates that
debenzylation of R-1-phenylethyl acetate is faster than dehydration of R,S-1-
phenylethanol. As a conclusion it can be stated that the largest amounts of the desired
product, R-1-phenylethyl acetate were achieved after prolonged reaction over the Pd/
Al2O3–Ru/HAP–lipase catalyst system because of minor deactivation of the Pd/Al2O3
catalyst leading to high conversions of acetophenone and in the presence of additional
sites on Ru/HAP leading to reduced debenzylation of R-1-phenylethyl acetate.
The main product formed from (R,S)-1-phenylethanol over Pd/Al2O3 catalyst
was acetophenone, under hydrogen or argon, indicating that dehydrogenation of a
123

210
A. Kirilin et al.
secondary alcohol was favored over this catalyst. The desired product, R-1-
phenylethyl acetate was stable over lipase and over alumina support, but its
debenzylation occurred over Pd/Al2O3.
In the racemization experiments Ru supported on hydroxyapatite led to
acetophenone from (R,S)-1-phenylethanol via dehydrogenation, with racemization
occurring to a minor extent only. Another racemization catalyst, Ru/Al2O3, was
more active in racemization than Ru/HAP, giving the lowest enantiomeric excess of
91% at low conversion level in toluene. Ru/Al2O3 was active in dynamic kinetic
resolution of (R,S)-1-phenylethanol, but not, however, in one-pot synthesis of R-1-
phenylethyl acetate together with PdZn/Al2O3 and lipase catalysts. It can be
tentatively concluded that the activity of the supported Ru catalysts was sufficient
for one-pot synthesis of R-1-phenylethyl acetate including dynamic kinetic
resolution. One-pot synthesis of R-1-phenylethyl acetate was, however, confirmed
using a homogeneous Shvo’s catalyst.
˚
Acknowledgements This work is part of the activities at the Abo Akademi Process Chemistry Centre
˚
(AA-PCC) within the Finnish Centre of Excellence Programme (2000–2011) appointed by the Academy
of Finland. Krisztian Kordas acknowledges the Academy of Finland for funding (120853, 124357,
128626).
References
1. A. Bruggink, R. Schoevaart, T. Kieboom, Org. Proc. Res. Dev. 7, 622 (2003)
2. H. Jung, J.H. Koh, M.-J. Kim, J. Park, Org. Lett. 2(16), 2487 (2000)
¨
¨
3. P. Maki-Arvela, S. Sahin, N. Kumar, J.-P. Mikkola, K. Eranen, T. Salmi, D.Yu. Murzin, React. Kinet.
Catal. Lett. 94, 281 (2008)
¨
¨
4. P. Maki-Arvela, S. Sahin, K. Kumar, T. Hekkila, V.-P. Lehto, T. Salmi, D.Yu. Murzin, Appl. Catal.
A Gen. 350, 24 (2008)
¨
¨
5. P. Maki-Arvela, S. Sahin, N. Kumar, J.-P. Mikkola, K. Eranen, T. Salmi, D.Yu. Murzin, Catal. Today
140, 70 (2009)
¨
¨
6. P. Maki-Arvela, S. Sahin, N. Kumar, T. Heikkila, V.-P. Lehto, T. Salmi, D.Yu. Murzin, J. Mol. Catal.
A Chem. 285, 132 (2008)
7. A. Dijksman, J.M. Elzinga, Y.-X. Li, I.W.C.E. Arends, R.A. Sheldon, Tetrahedron Asymmetry. 13,
879 (2002)
8. S. Wuyts, D.E. De Vos, F. Verpoort, D. Depla, R. De Gryse, P. Jacobs, J. Catal. 219, 417 (2003)
9. A. Zsigmond, K. Kecskemti, F. Bogr, E. Notheisz, Mernyk, Catal. Commun. 6, 520 (2005)
10. S. Wuyts, K. De Temmerman, D.E. De Vos, P.A. Jacobs, Chem. Eur. J. 11, 386 (2005)
11. W.H. Kim, R. Karvembu, J. Park, Bull. Korean Chem. Soc. 25, 931 (2004)
12. K. Yamaguchi, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, J. Am. Chem. Soc. 122, 7144 (2000)
13. K. Yamaguchi, T. Koike, M. Kotani, M. Matsushita, S. Shinachi, N. Mizuno, Chem Eur. J. 11, 6574
(2005)
14. S.J. Joris, C.H. Amberg, J. Phys. Chem. 75, 3167 (1971)
15. N.Yu. Kozitsyna, S.E. Nefedov, F.M. Dolgushin, N.V. Cherkashina, M.N. Vargaftik, I.I. Moiseev,
Inorg. Chim. Acta 359, 2072 (2006)
16. O.P. Tkachenko, A.Yu. Stakheev, L.M. Kustov, I.V. Mashkovsky, M. van der Berg, W. Grunert,
N.Yu. Kozitsyna, Z.V. Dobrokhotova, V.I. Zhilov, S.E. Nefedov, M.N. Vargaftik, I.I. Moiseev,
Catal. Lett. 112, 155 (2006)
¨
¨
17. P. Maki-Arvela, N. Kumar, V. Nieminen, R. Sjoholm, T. Salmi, D.Yu. Murzin, J. Catal. 225, 155
(2004)
18. K. Yamaguchi, T. Koike, J.W. Kim, Y. Ogasawara, N. Mizuno, Chem. Eur. J. 14, 11480 (2008)
19. M. Lenarda, M. Casagrande, E. Moretti, L. Storaro, R. Frattinin, S. Polizzi, Catal. Lett. 114, 79
(2007)
123