Enantioselective hydrogenation of ethyl pyruvate catalyzed by alumina support rhodium modified with quinine

Article abstract of DOI:10.1016/j.tetasy.2005.02.036

Alumina supported rhodium catalyst using cinchonidine as a stabilizer exhibited excellent performance in the asymmetric hydrogenation of ethyl pyruvate with the addition of quinine. Quinine as a chiral modifier can not only induce the enantioselectivity, but also greatly accelerate the reaction. Under the optimum conditions: 293 K, 7.0 MPa of hydrogen pressure and 4.6 × 10^-3 mol/L of quinine concentration in THF, TOF of Rh/2(cinchonidine)-γ-Al₂O₃ as catalyst and ee value of (R)-ethyl lactate can achieve 894 h^-1 and 71.6% ee, respectively.

Full text of DOI:10.1016/j.tetasy.2005.02.036

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Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1449–1452
Enantioselective hydrogenation of ethyl pyruvate catalyzed
by alumina support rhodium modified with quinine
Wei Xiong,a,b Hongxia Ma,a Yanyi Hong,a Hua Chena and Xianjun Lia,*
aKey Lab of Green Chemistry and Technology, Ministry of Education, The Institute of Homogeneous Catalysis,
Department of Chemistry, Sichuan University, No. 29 Wangjiang Road, Chengdu, Sichuan 610064, PR China
bDepartment of Chemistry, Xichang College, Xichang 615022, PR China
Received 22 December 2004;accepted 25 February 2005
Abstract—Alumina supported rhodium catalyst using cinchonidine as a stabilizer exhibited excellent performance in the asymmetric
hydrogenation of ethyl pyruvate with the addition of quinine. Quinine as a chiral modifier can not only induce the enantioselectivity,
but also greatly accelerate the reaction. Under the optimum conditions: 293 K, 7.0 MPa of hydrogen pressure and 4.6 · 10À3 mol/L
of quinine concentration in THF, TOF of Rh/2(cinchonidine)-c-Al2O3 as catalyst and ee value of (R)-ethyl lactate can achieve
894 hÀ1 and 71.6% ee, respectively.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
metals such as Ru, Rh, Pd and Ir were used as the active
element in the supported catalyst, the enantioselectivity
decreased greatly. For example, the ee value was only
20–30% in hydrogenation of ethyl pyruvate using Rh/
c-Al2O3 as catalyst and cinchonidine as chiral modifier.
In order to improve the catalytic performance some new
methods for preparing the supported nanocluster cata-
lysts were studied in our group.14–17 c-Al2O3 supported
Rh nanocluster catalyst, which was prepared by a new
method and was stabilized by polyvinylpyrrolidone
(PVP) and modified by cinchonidine, exhibited high
activity and middle enantioselectivity (65%, ee) in the
hydrogenation of ethyl pyruvate. However, it was found
that the aggregation of nanoparticles occurred easily in
the preparation process and would influence the metal
dispersion on the support surface. Herein we report a
further improved preparation method by using cincho-
nidine as the stabilizer and quinine as the modifier.
These Rh/c-Al2O3 catalysts displayed better enantiose-
lectivities in the asymmetric hydrogenation of ethyl
pyruvate. The effect of the modification and reaction
conditions on the hydrogenation are also discussed.
The asymmetric hydrogenation of a prochiral ketone is
an important approach to obtain optically active alco-
hols and its investigation has received more and more
attention in the recent years.1,2 Homogeneous catalysis
is a main method for preparing chiral alcohols, however,
the separation of a chiral catalyst from products is diffi-
cult and thus the application of this method is limited.
Heterogeneous catalysis could overcome the problem
and would become rapidly growing field.3,4 One of the
best known heterogeneous asymmetric reactions is the
enantioselective hydrogenation of a-ketoesters catalyzed
by an alumina supported platinum cluster using
cinchona alkaloid as modified. It has been studied
extensively by Orito et al.5 Baiker et al.,6,7 Blaser
et al.,8 Wells et al.9 and Augustine et al.10 and some inter-
esting progress being obtained. In the hydrogenation of
methyl or ethyl pyruvate catalyzed by cinchonidine
modified Pt/c-Al2O3, an enantiomeric excess (ee) of
95% could be achieved.8,11,12 Bonnemann and Braun13
synthesized several Pt colloidal clusters with dihydrocin-
chonidine and examined their enantioselectivities in the
hydrogenation of ethyl pyruvate. An ee of 80% of the
product could be achieved. When other transition
2. Results and discussion
2.1. Acceleration and chiral induction of quinine
*
The effect of the chiral modifier on the activity and
enantioselectivity of Rh/2(cinchonidine)-c-Al2O3 in
Corresponding author. Tel./fax: +86 28 85412904;e-mail: scuulixj@
mail.sc.cninfo.net
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.02.036

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W. Xiong et al. / Tetrahedron: Asymmetry 16 (2005) 1449–1452
asymmetric hydrogenation of ethyl pyruvate was inves-
tigated with the results shown in Figure 1. When cincho-
8(cinchonidine)-c-Al2O3) prepared and their catalytic
performances were examined under the standard reac-
tion conditions. The data in Table 1 show the obvious
differences of their catalytic activities and enantioselec-
tivities in the asymmetric hydrogenation of ethyl pyru-
vate. Among the four catalysts, the performance of
Rh/2(cinchonidine)-c-Al2O3 was the best. The results
suggest that when the ratio of Rh/cinchonidine was in
an appropriate range, the optimum configuration of
the active centre on the surface of catalyst would
form.18,19 If the molar ratio of Rh/cinchonidine was lar-
ger than 2, a portion of rhodium surface would be cov-
ered and thus the catalytic activity and enantioselectivity
would decrease. Therefore, the catalytic performance of
Rh/2(cinchonidine)-c-Al2O3 was investigated in detail
under different reaction conditions.
nidine was used as
a stabilizer in the catalyst
preparation, the catalytic activity and enantioselectivity
of Rh/2(cinchonidine)-c-Al2O3 were very low in the
absence of quinine. With the addition of quinine, the
catalyst activities and enantioselectivity increased
greatly. When the quinine concentration was increased
to 4.6 · 10À3 mol/L, TOF and ee value of product
achieved 894 hÀ1 and 71.6%, respectively. Upon further
increase of quinine concentration, the TOF and ee de-
creased slightly. The data indicated that not only could
quinine accelerate the reaction, but it also had a stronger
chiral induction effect for preferential formation of (R)-
ethyl lactate in comparison to when just cinchonidine
was used as the stabilizer and chiral modifier.17 Under
the optimum concentration of quinine there was a max-
imum of TOF and ee. If the concentration of quinine
was excessively high, a portion of the metal active
centres of the catalyst could be covered, resulting in
a decrease in activity and enantioselectivity also.
2.3. Chiral induction comparison of cinchonidine and
quinine
The comparison of the catalytic activity and enantiose-
lectivity of Rh/2(cinchonidine)-c-Al2O3 and Rh/2(quin-
ine)-c-Al2O3 in Table 2 indicated that cinchonidine
and quinine could almost play the same stabilization
role in the catalyst preparation. However, when they
were used as the chiral modifier, quinine exhibited the
better chiral induction. The ee of the products in ethyl
pyruvate hydrogenation was 5–6% higher for quinine
than that for cinchonidine. The results show that the
catalytic activity of Rh/c-Al2O3 was not sensitive
enough for the composition and structure of the stabi-
lizer, which was used in the preparation of catalyst,
because the main function of stabilizer was to avoid
metal nanoparticle aggregation and to keep their high
dispersion on the support surface. However, when cin-
chonidine and quinine were used as the chiral modifier
in the asymmetric hydrogenation, their composition and
structure were key factors for the enantioselectivity.
Thus the delicate difference between cinchonidine and
quinine was displayed in the reaction process. It is
possible that the steric effect of the methoxy group in
quinine exerted a favourable influence on the transition
state with an (R)-configuration. The difference of the
cinchona modification from the report in the literature17
was ascribed to the different preparation method of two
1000
800
600
400
200
0
100
80
60
40
20
0
TOF
e.e.
0
2
4
6
8
[Quinine]x10-3 mol/L
Figure 1. The effect of quinine concentration on the enantioselective
hydrogenation. Reaction conditions: catalyst Rh/2(cinchonidine)-c-
Al2O3 (containing 1.0 · 10À3 mmol rhodium): THF (2.0 mL), ethyl
pyruvate (1.0 mmol), PH2 = 7.0 MPa, T = 293 K, reaction time 1 h.
2.2. Effect of Rh/cinchonidine ratio
Four catalysts with different molar ratios of Rh/cincho-
nidine (Rh/1(cinchonidine)-c-Al2O3, Rh/2(cinchoni-
dine)-c-Al2O3, Rh/4(cinchonidine)-c-Al2O3 and Rh/
Table 1. The effect of molar ratio of rhodium to cinchonidine
Catalyst
Mole conversion (%)
TOF (hÀ1
)
Ee (%)
Configuration
Rh/1(cinchonidine)-c-Al2O3
Rh/2(cinchonidine)-c-Al2O3
Rh/4(cinchonidine)-c-Al2O3
Rh/8(cinchonidine)-c-Al2O3
76.0
95.0
61.2
59.3
715
894
576
558
60.3
71.6
59.7
59.0
R
R
R
R
Reaction conditions are the same as those listed in Figure 1, except Rh/n(cinchonidine)-c-Al2O3.
Table 2. Modification comparison of cinchonidine and quinine
Catalyst
Modifier
Mole conversion (%)
TOF (hÀ1
)
Ee (%)
Configuration
Rh/2(cinchonidine)-c-Al2O3
Rh/2(cinchonidine)-c-Al2O3
Rh/2(quinine)-c-Al2O3
Quinine
95.0
96.6
92.6
93.2
894
909
871
877
71.6
65.2
67.2
62.0
R
R
R
R
Cinchonidine
Quinine
Cinchonidine
Rh/2(quinine)-c-Al2O3
Reaction conditions are the same as those listed in Figure 1.

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W. Xiong et al. / Tetrahedron: Asymmetry 16 (2005) 1449–1452
1451
catalysts and the different properties of both supports, c-
Al2O3 and TS-1.
ues reduced upon further increase of hydrogen pressure,
suggested that the competitive adsorption of hydrogen
on the metal surface would influence the access of the
substrate.21 At the same time, a too high hydrogen pres-
sure could cause further hydrogenation of the quinoline
ring of the dihydroquinine, which would weaken the
dihydroquinine chiral induction and its adsorption on
a metal surface.22,23
2.4. Effect of solvent
The effect of the solvent property on the behaviours of c-
Al2O3 supported rhodium catalyst (Rh/2(cinchonidine)-
c-Al2O3) is listed in Table 3. The results indicate that
there is no clear correlation between the catalytic perfor-
mance of Rh/2(cinchonidine)-c-Al2O3 and the solvent
polarity. This is different from the conventionally sup-
ported platinum/cinchonidine catalyst, whose activity
and enantioselectivity were generally better in polar
solvents than those in apolar ones.3,20 This might be as-
cribed to the different interactions between the solvent
and the modified rhodium cluster. Toluene and alcohol
were not suitable solvents for the reaction. The reaction
was fast but the enantioselectivity was very low in water.
Among the solvents investigated, tetrahydrofuran was
the most suitable for the reaction, in which the TOF
and ee were 894 hÀ1 and 71.6%, respectively. This is in
agreement with our previous reports.14,17
The effect of temperature on the catalytic behaviours is
shown in Figure 3. The data showed that the conversion
increased drastically when increasing the temperature
from 0 ꢁC to 20 ꢁC, while enantioselectivity rose slightly.
When the temperature was over 20 ꢁC, the enantioselec-
tivity of the product decreased gradually from 71.6% ee
at 20 ꢁC to 56.5% ee at 60 ꢁC, although the catalytic
activity did not obviously change. This phenomena16
could be attributed to the substrate adsorption mode
on rhodium surface changing and the energy difference
between transition states of two enantiomers becoming
smaller with increasing temperature.
75
Table 3. Effect of solvent on the activity and enantioselectivity
900
Solvent
Dielectric
constant
TOF
(hÀ1
Ee
(%)
Configuration
70
800
)
700
600
Toluene
Tetrahydrofuran
Ethanol
2.38
7.60
24.3
33.6
80.4
134
894
213
241
604
14.4
71.6
18.7
23.7
3.2
R
R
R
R
R
65
60
Methanol
H2O
500
TOF
e.e.
55
50
400
300
Reaction conditions are the same as those listed in Figure 1, except
quinine concentration is 4.6 · 10À3 mol/L.
0
10
20
30
40
50
60
Temperature(ºC)
2.5. Effect of hydrogen pressure and temperature
Figure 3. The effect of temperature. Reaction conditions are the same
as those listed in Figure 1, except quinine concentration is 4.6 · 10À3
mol/L.
The effect of hydrogen pressure on the asymmetric
hydrogenation of ethyl pyruvate is shown in Figure 2.
It was observed that the TOF and ee values increased
initially when increasing hydrogen pressure. The in-
crease of hydrogen pressure was favourable for the
formation of dihydroquinine, which could promote the
effect of chiral induction. The fact that TOF and ee val-
3. Experimental
3.1. Materials
Ethyl pyruvate, quinine and cinchonidine were used as
received from Acros without further purification. THF
was treated by sodium metal and distilled before use.
RhCl3Æ3H2O and other reagents are of analytical grade.
The purity of hydrogen was 99.99%. The specific surface
areas of c-Al2O3 were 154 m2/g.
1000
900
800
700
600
500
400
80
75
70
65
60
55
50
3.2. Preparation of Rh/n(cinchonidine)-c-Al2O3 catalyst
c-Al2O3 (1.0 g), suitable amount of cinchonidine
(n · 10À2 mmol, n = 5, 10, 20, 40) and a mixed solvent
of 50 mL (containing ethanol, i-propanol, distilled water
and formic acid, their volume ratio = 11:11:2:1) were
added into a round flask of 100 mL and stirred for
16 h at room temperature. Then RhCl3Æ3H2O
(5.0 · 10À2 mmol) was introduced and continually stir-
red for 1 h. After the solution was refluxed at 100–
120 ꢁC for 3–5 h, c-Al2O3 supported rhodium catalyst
TOF
e.e.
2
3
4
5
6
7
8
9
Hydrogen Pressure(MPa)
Figure 2. The effect of hydrogen pressure. Reaction conditions are the
same as those listed in Figure 1, except quinine concentration is
4.6 · 10À3 mol/L.

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1452
W. Xiong et al. / Tetrahedron: Asymmetry 16 (2005) 1449–1452
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was filtrated and washed with distilled water several
times. The Rh/n(cinchonidine)-c-Al2O3 (here n is molar
ratio of cinchonidine/Rh, n = 1, 2, 4, 8) catalysts were
dried under vacuum at 50 ꢁC for 8 h. The rhodium con-
tent of all catalysts was 0.5 wt %. Rh/2(quinine)-c-Al2O3
catalyst was also prepared by a similar method (here the
molar ratio of quinine/Rh is 2).
3.3. Catalytic hydrogenation
9. Sutherland, I. M.;Ibbotson, A.;Moyes, R. B.;Wells, P. B.
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clave with a glass linear and magnetic stirrer. The
catalyst (20 mg, containing 1 · 10À3 mmol rhodium),
quinine or cinchonidine (4.6 · 10À3 mol/L) and solvent
(2.0 mL) were added into the autoclave and then hydro-
gen introduced up to 5.0 MPa. After the solution was
stirred for 1 h at 298 K, ethyl pyruvate (1.0 mmol) was
added into the autoclave and purged with hydrogen sev-
eral times. The reaction was carried out under the
designed conditions for a desired period of time. The
products were determined by GC960 with FID detector
and b-DEXTM120 chiral capillary column (30 m ·
0.25 mm, 0.25 lm film) at 80 ꢁC.
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