Hydrogenation of α-ketoesters and ketopantolactone on rhodium modified by cinchona and isocinchona alkaloids

Article abstract of DOI:10.1016/j.jcat.2007.02.026

Various Rh catalysts and cinchona-type modifiers were tested in the hydrogenation of ethyl pyruvate, ethyl 3-methyl-2-oxobutyrate, and ketopantolactone. The experiments were completed with the study of the nonlinear behavior of modifier mixtures, and UV and NMR analysis of hydrogenation of the modifiers. From this study, β-isocinchonine emerged as an outstanding modifier of Rh/Al₂O₃ that gave up to 68% ee in the hydrogenation of ketopantolactone to (R)-pantolactone in toluene, at full conversion and without the formation of any detectable byproducts. Careful prereduction of the catalyst at elevated temperature is critical to achieve good enantioselectivity. The loss of ee, or even the formation of the opposite enantiomer in small excess, in protic solvents is attributed to the formation of solvent-substrate and solvent-modifier complexes that disturb the enantioselection on cinchona-modified Rh. In the weakly interacting solvent toluene, only a few ppm of β-isocinchonine related to ketopantolactone was sufficient to induce enantioselection. This unique feature of the conformationally rigid isocinchona alkaloid is attributed to the stronger adsorption on Rh and weaker adsorption on Al₂O₃, and to the higher resistance against hydrogenation of its quinoline ring "anchoring moiety" compared with the corresponding values of cinchonine and cinchonidine.

Full text of DOI:10.1016/j.jcat.2007.02.026

Journal of Catalysis 248 (2007) 11–19
www.elsevier.com/locate/jcat
Hydrogenation of α-ketoesters and ketopantolactone on rhodium modified
by cinchona and isocinchona alkaloids
∗
Fatos Hoxha, Tamas Mallat, Alfons Baiker
Institute of Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Hönggerberg, HCI, CH-8093 Zurich, Switzerland
Received 29 January 2007; revised 27 February 2007; accepted 28 February 2007
Available online 29 March 2007
Abstract
Various Rh catalysts and cinchona-type modifiers were tested in the hydrogenation of ethyl pyruvate, ethyl 3-methyl-2-oxobutyrate, and ke-
topantolactone. The experiments were completed with the study of the nonlinear behavior of modifier mixtures, and UV and NMR analysis of
hydrogenation of the modifiers. From this study, β-isocinchonine emerged as an outstanding modifier of Rh/Al O that gave up to 68% ee in
2
3
the hydrogenation of ketopantolactone to (R)-pantolactone in toluene, at full conversion and without the formation of any detectable byproducts.
Careful prereduction of the catalyst at elevated temperature is critical to achieve good enantioselectivity. The loss of ee, or even the formation of
the opposite enantiomer in small excess, in protic solvents is attributed to the formation of solvent–substrate and solvent–modifier complexes that
disturb the enantioselection on cinchona-modified Rh. In the weakly interacting solvent toluene, only a few ppm of β-isocinchonine related to
ketopantolactone was sufficient to induce enantioselection. This unique feature of the conformationally rigid isocinchona alkaloid is attributed to
the stronger adsorption on Rh and weaker adsorption on Al O , and to the higher resistance against hydrogenation of its quinoline ring “anchoring
2
3
moiety” compared with the corresponding values of cinchonine and cinchonidine.
2007 Elsevier Inc. All rights reserved.
©
Keywords: Ethyl pyruvate; Ethyl 3-methyl-2-oxobutyrate; Ketopantolactone; β-Isocinchonine; Asymmetric hydrogenation; Nonlinear phenomenon; Inversion of
enantioselectivity
1
. Introduction
the modifier to the metal surface, and its saturation leads to a
successive loss of enantioselection [20,21].
From a synthetic standpoint, there are only three attractive
chirally modified metal catalysts that offer better than 90%
ee: (in historical order) the Ni-tartaric acid [1,2], Pt-cinchona
A possible reason for the limited success is that up to now,
only a few chiral modifiers have been tested with Rh. The
best modifiers are cinchona alkaloids [10–16] and O-phenyl-
cinchonidine [19]. The less bulky ether derivatives and the N-
alkylated and N-arylated derivatives of CD [14,15] are barely
efficient.
Interesting derivatives of cinchona alkaloids are the isocin-
chona alkaloids [22], for example, β-isocinchonine (β-iCN,
Scheme 1). Its structure is more rigid than that of the parent
alkaloid and does not contain a free OH group, the function of
which may interact with the ketone substrate (beside the ba-
sic quinuclidine N atom [23]). Application of this and other
isocinchona alkaloid modifiers in the Pt-catalyzed enantiose-
lective hydrogenation of α-ketoesters [24–30] and ketopanto-
lactone [28] did not reveal any advantage compared with the
performance of CN or CD. Because α-isocinchonine exists only
in “open” conformation, the reasonably good enantioselectiv-
[
3–6], and Pd-cinchona systems [7,8]. Whereas in homoge-
neous catalysis, the enantioselectivity of chiral Rh complexes
is excellent in the hydrogenation of ketones [9], application of
chirally modified, supported Rh in the reduction of C=O bonds
is characterized by moderate chemoselectivity and enantiose-
lectivity [10–18]. An exception is the hydrogenation of hydrox-
yketones on cinchonidine (CD)-modified Rh/Al2O3, with up to
8
0% ee [19]. Even in this reaction, however, the reaction rate
was low and a high modifier/substrate molar ratio (M/S) was
necessary, due mainly to the competing hydrogenation of the
modifier itself. In cinchona alkaloids, the quinoline ring anchors
*
Corresponding author.
E-mail address: baiker@chem.ethz.ch (A. Baiker).
0021-9517/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2007.02.026

12
F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
Beta-isocinchonine (β-iCN) was synthesized according to
the method described by Bartók and coworkers [26], but with
some changes in the reaction and separation conditions to im-
prove the yield and purity; 5 g CN (16.98 mmol) was dis-
solved in 85% concentrated sulphuric acid (30 ml). The reac-
◦
tion mixture was stirred for 7 h at 70 C and then overnight at
◦
room temperature. After cooling to 0 C, ammonia was added
dropwise until a pH of 11 was achieved. The white suspen-
sion was diluted with ethanol, stirred for 10 min, and filtered
off. The filtrate was concentrated in vacuum and the product
was purified by repeated column chromatography on silica gel.
The eluent was ethyl acetate:ethanol = 1:1 in the presence of
0
.002 vol% ammonia. Finally, 1 g of pure β-iCN was obtained
(
ca. 20% yield). The product was identified by NMR spec-
troscopy (Bruker Advance spectrometer operating at 500 MHz).
The NMR spectrum agreed well with that published by Thiel et
al. [22]. GC/MS analysis indicated 99.5% purity and the ab-
sence of cinchonine.
2
.2. Catalyst pretreatment methods
The 5 wt% Rh/Al2O3 catalyst was always pretreated at ele-
Scheme 1. Hydrogenation of ethyl pyruvate, ethyl 3-methyl-2-oxobutyrate, and
ketopantolactone on a 5 wt% Rh/Al O catalyst in the presence of cinchona
and isocinchona alkaloids.
vated temperature before use. According to this standard pre-
treatment procedure, the catalyst was flushed in a fixed-bed
2
3
◦
reactor at 400 C with nitrogen for 30 min, followed by a re-
ductive treatment in flowing hydrogen for 90 min at the same
temperature. After cooling to room temperature in hydrogen,
the catalyst was flushed with nitrogen for another 10 min and
immediately transferred to the reactor (under solvent) without
exposure to air.
ity achieved with this modifier in pyruvate hydrogenation on
Pt [31] confirmed the relevance of this conformation in various
mechanistic models [23].
The situation is different on rhodium, as we discuss later in
the hydrogenation of some activated ketones (Scheme 1). We
compare the performance of the conformationally rigid β-iCN
with that of the commonly used cinchona modifiers CD, CN,
QD, and QN (Scheme 1).
Alternatively, additional catalyst treatments (after the stan-
dard reductive heat pretreatment) were used. In method 1, an
ultrasonic pretreatment of the catalyst [32] was performed at
room temperature in a 50-ml glass reactor equipped with a
gas inlet and a rubber septum. Before sonication, β-iCN and
the 5 wt% Rh/Al2O3 catalyst were added in the solvent and
flushed with nitrogen (or hydrogen) for 15 min. The irradiation
was performed for 30 min in a closed nitrogen (or hydrogen)
atmosphere. An ELMA TI-H-5 multiple-frequency ultrasonic
device was used at 25 kHz. The sonication in air was performed
directly without flushing the reactor. In method 2, the pretreat-
2
. Experimental
2
.1. Materials
Most of the chemicals were used as received: 2-propanol
(
Acros, extra dry, water <50 ppm), t-butanol (Fluka, over mole-
cular sieve, ꢀ99.7%), dichloromethane (Fluka, over molecular
◦
ment in the liquid phase at 111 C was performed in a 25-ml
sieve, ꢀ99.5%, water ꢁ0.005%), dimethylformamide (DMF)
two-necked reaction flask equipped with a cooler, a gas inlet,
and a rubber septum. The catalyst and β-iCN were added to
the solvent (toluene), flushed with nitrogen (or hydrogen) for
(
Acros, over molecular sieve, ꢀ99.9%, water <50 ppm),
acetic acid (Fluka, p.a.), 1,1,1-trifluoroacetic acid (TFA) (Fluka,
>
98%), cinchonidine (CD) (Fluka, ꢀ98% alkaloid), cincho-
1
5 min, stirred under refluxing toluene for 30 min, and then the
nine (CN) (Fluka, ꢀ98% alkaloid), quinine (QN) (Fluka, ∼99%
alkaloid), quinidine (QD) (Fluka, 99% alkaloid), ketopanto-
lactone (Roche AG, 99%), molecular sieve (Zeochem, Z4-01,
mixture was transferred to the autoclave under nitrogen (or hy-
drogen). In method 3, the catalyst and β-iCN were stirred in
toluene under air, nitrogen, or hydrogen in a 50 ml glass reactor
for 30 min at room temperature.
2
–3 mm), 5 wt% Rh/Al O (Engelhard 8001, ESCAT 34). The
2 3
solvents toluene (Fluka, 99.7%), tetrahydrofuran (THF) (J.T.
Baker, 99.5%), and t-BuMe ether (Fluka ꢀ99.5%) were freshly
distilled from Na before use. Acetonitrile (Fluka, ꢀ99.5%) was
2
.3. Catalytic hydrogenation
distilled from P O . The substrates ethyl pyruvate (Acros, 98%,
2
5
0
.02% ethyl lactate after distillation) and ethyl 3-methyl-2-
Hydrogenations were carried out in a 100-ml stainless steel
oxobutyrate (Aldrich, 97%) were carefully distilled in vacuum
before use.
autoclave equipped with a 50-ml glass liner, a PTFE cover,
and a magnetic stirrer. The autoclave was also equipped with

F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
13
a valve for sample collection or substrate addition. Under stan-
dard conditions, 21 mg of catalyst, 0.92 mmol of substrate,
Table 1
The efficiency of cinchona alkaloids and β-isocinchonine as chiral modifiers of
Rh/Al O in the hydrogenation of ethyl pyruvate; standard conditions
2
3
6
.8 µmol of modifier (M/S = 0.74 mol%), and 5 ml of sol-
Solvent
ee (%) [Conversion (%)]
vent were stirred magnetically (750 rpm) at 10 bar and room
temperature for 60 min. The pressure was held at a constant
value with a computerized constant volume–constant pressure
device (Büchi BPC 9901). At the end of the reaction, 40 ml of
ethyl acetate was added to the slurry and stirred for 5 min be-
fore filtration. The conversion and enantioselectivity (ee) were
determined by GC analysis of the filtrate, using an HP 6890
gas chromatograph and a Chirasil-DEX CB (Chrompack 7502
β-iCN
CN
CD
QN
QD
Toluene
27 (R)
40.5 (S)
45.5 (R)
56.5 (R)
40 (S)
[100]
[100]
[100]
[100]
[100]
2-Propanol
34 (R)
15 (S)
27 (R)
–
–
[100]
[100]
[100]
Acetic acid
7 (R)
3 (R)
8 (R)
13.5 (R)
11.5 (S)
[100]
[100]
[100]
[100]
[100]
2
5 m× 0.25 mm× 0.25 µm) capillary column. All experiments
Toluene +
3 (S)
[97]
6 (R)
[92]
4 (S)
[98]
–
–
were carried out at least twice; the average values are shown
in the tables and figures. The estimated standard deviation of
enantiomeric excess (ee) was about ± 0.5% (± 1% at <5% ee).
In most cases, the ee was determined at full conversion of the
ketones.
10 µL TFA
Table 2
The efficiency of cinchona alkaloids and β-isocinchonine as chiral modifiers
of Rh/Al O in the hydrogenation of ethyl 3-methyl-2-oxobutyrate; standard
2
3
Hydrogenation of the modifiers β-iCN, CN, and CD was car-
ried out in the same autoclave as the ketone hydrogenations.
The conversion was followed by UV spectroscopy with a Cary
conditions
Solvent
ee (%) [Conversion (%)]
β-iCN
CN
CD
QN
QD
4
00 spectrometer and a 25-mm path length quartz cuvette. The
Toluene
33 (R)
43 (S)
50.5 (R)
[100]
29 (R)
[90]
19 (S)
[78]
conditions were as follows: 2 mg of modifier in 5 ml mixture of
toluene (90 vol%) and THF (10 vol%) was added to 21 mg of
[100]
[99]
t-Butanol
Acetic acid
Toluene +
28 (R)
2 (R)
9 (R)
[99]
–
–
5
wt% Rh/Al2O3 and hydrogenated at 90 bar and room temper-
[100]
[99]
ature. The samples were diluted fourfold before UV measure-
ments. A calibration curve was used to calculate the modifier
concentration in solution. NMR spectroscopy (Bruker Advance
spectrometer operating at 500 MHz) was used to confirm the
structure of the hydrogenation products. The NMR analysis was
performed in CCl3D and CH3COOD for β-iCN and CN, re-
spectively.
21 (R)
4 (R)
4 (R)
[99]
9 (R)
[99]
6 (S)
[97]
[100]
[98]
4 (R)
5.5 (S)
13.5 (R)
[15]
–
–
10 µL TFA
[20]
[14]
Table 3
The efficiency of cinchona alkaloids and β-isocinchonine as chiral modifiers of
Rh/Al O in the hydrogenation of ketopantolactone; standard conditions, ee at
2
3
3
. Results and discussion
full conversion
Solvent
ee (%)
In a preliminary screening, 10 different commercial Rh cat-
alysts were tested in the hydrogenation of ethyl pyruvate, ethyl
-methyl-2-oxobutyrate, and ketopantolactone (Scheme 1). The
β-iCN
CN
CD
QN
QD
Toluene
t-BuMe ether
THF
54 (R)
46 (R)
51 (R)
35.5 (R)
47 (R)
35.5 (R)
29 (R)
35.5 (R)
11 (R)
9.5 (R)
25 (S)
9 (S)
9 (S)
–
47 (R)
38 (R)
38 (R)
–
11.5 (R)
–
–
–
–
–
–
–
4 (S)
–
–
–
–
–
–
–
3
catalysts contained carbon or alumina as supports; unsupported
Rh black was also tested. In weakly polar solvents in the pres-
ence of CD, a 5 wt% Rh/Al2O3 (Engelhard) proved to be the
most promising, and this catalyst was applied in the further ex-
periments. Recently, an in situ prepared Rh(CD)/Al2O3 using
cinchonidine as a stabilizer of Rh particles and additional QN as
modifier has been proposed as an outstanding catalyst for ethyl
pyruvate hydrogenation [16]. Unfortunately, we could not re-
produce the good enantioselectivity reported earlier and found
a low reaction rate.
CCl H
2
2
DMF
t-Butanol
Acetonitrile
–
–
7 (R)
–
2 (R)
1 (R)
4 (S)
6.5 (R)
–
20 (R)
4 (R)
10.5 (R)
2-Propanol
Acetic acid
Toluene +
10 µL TFA
4 (R)
–
2 (S)
–
formed in excess in the presence of CD, QN, and β-iCN, and
the (S)-alcohol formed in the presence of CN and QD.
3
.1. Comparison of β-iCN with cinchona alkaloids in different
solvents
An interesting observation was the significant variation in
the efficiency of cinchona alkaloids in the hydrogenation of
the structurally closely related ketones. In the hydrogenation
of ethyl pyruvate, ethyl 3-methyl-2-oxobutyrate, and ketopan-
tolactone, the best modifiers were QN, CD, and β-iCN, re-
spectively. In addition, QD and QN, which are reasonably
good modifiers in the hydrogenation of the flexible pyruvate
molecule, were barely efficient in the reduction of the cyclic
Hydrogenation of the activated ketone substrates was car-
ried out in a broad range of solvents in the presence of β-iCN
and four cinchona alkaloids as chiral modifiers (Tables 1–3).
In the weakly polar solvent toluene, in which the solvent effect
would be expected to be the smallest, the (R)-alcohol always

14
F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
Fig. 2. Influence of hydrogen pressure on the enantioselectivity in the hy-
drogenation of ketopantolactone to (R)-pantolactone over β-iCN-modified
Fig. 1. Solvent effect on the enantioselectivity in the hydrogenation of ke-
topantolactone over β-iCN-modified Rh/Al O ; standard conditions, ee to
the (R)-enantiomer was determined at full conversion. Solvents: toluene (1),
t-BuMe ether (2), THF (3), dichloromethane (4), DMF (5), t-butanol (6), ace-
tonitrile (7), 2-propanol (8), acetic acid (9).
2
3
Rh/Al O ; standard conditions, toluene, full conversion.
2
3
tic model. It is more likely that H-bonding interactions between
the protic polar solvents and the substrate and/or modifier are
responsible for the loss of enantioselectivity and that the occa-
sional minor inversion is insignificant due to the corresponding
very small energy difference. We have shown earlier [35,36],
based on FTIR studies [37], that CD forms various 1:1- and
1:2-type complexes with carboxylic acids, and these complexes
may be the actual modifiers that interact with the substrate.
The results in Tables 1–3 show that, compared with the state
of art [10–19], the most promising reaction is the hydrogenation
of ketopantolactone in the presence of β-iCN. We analyze the
characteristics of this reaction below.
and rigid ketopantolactone. Apparently, aryl-substitution of the
quinoline ring in QN and QD at the 6 position (Scheme 1) dis-
ꢀ
turbs the enantioselection in ketopantolactone hydrogenation.
Considering the role of solvents, in the hydrogenation of all
ketones with all five modifiers, the highest enantioselectivities
were obtained in toluene. The ee decreased with increasing sol-
vent polarity, as illustrated in Fig. 1 for the example of ketopan-
tolactone hydrogenation in the presence of β-iCN as a modifier.
The solvents are characterized by their empirical solvent para-
N
T
meter E [33]. A similar negative effect of polar solvents on the
enantioselectivity was observed in earlier studies in the hydro-
genation of ketopantolactone on Pt [34] and Rh [15] modified
by CD and its ether derivatives.
3.2. Ketopantolactone hydrogenation on β-iCN-modified Rh
The loss of ee relative to that achieved in toluene was partic-
ularly significant in acidic medium, and even the opposite enan-
tiomer formed in excess in the hydrogenation of ethyl pyruvate
in the presence of β-iCN, CN, and CD (Table 1) and in the
reduction of ketopantolactone on CN-modified Rh (Table 2).
Note that inversion of the major enantiomer caused by replac-
ing toluene with acetic acid as solvent was also observed in
the hydrogenation of ethyl pyruvate [25–27] and ketopantolac-
tone [28] on β-iCN-modified Pt.
Rationalization of the change in the sense of enantioselec-
tion in protic solvents is not straightforward. Bartók et al. [25]
proposed that protonation of the quinuclidine N and the result-
ing shift in the reaction mechanism from a nucleophilic attack
by the quinuclidine N in toluene to an N–H–O type modifier–
substrate interaction in acetic acid would be the origin of in-
version. This proposal cannot interpret the inversion observed
by replacing toluene with t-butanol and 2-propanol in the pres-
ence of CN (Tables 2 and 3) and the formation of the same
enantiomer in both acidic and nonacidic solvents, which is the
general case in the hydrogenation of α-ketoesters and ketopan-
tolactone on Pt modified by cinchona alkaloids. It also must be
considered that the ee’s to the opposite enantiomers are minor
in most cases, and such low values cannot support a mechanis-
The Rh-catalyzed hydrogenation of ketopantolactone in the
presence of β-iCN was very fast, with full conversion reached
within 7 min under standard conditions at 10 bar. The aim of
the present study was to analyze the influence of reaction condi-
tions on the enantioselectivity at high (full) conversion to avoid
possible complications at low conversion (initial transient pe-
riod [38–41]).
The influence of pressure on the hydrogenation of ketopan-
tolactone was investigated under standard conditions at a M/S
ratio of 0.74 mol%. As shown in Fig. 2, the higher the pres-
sure and thus the surface hydrogen concentration, the higher
the enantioselectivity. For comparison, using CD and the same
Rh/Al O catalyst, the ee reached a (broad) maximum at 20 bar
2
3
in the same reaction (M/S = 0.37 mol%) [15]. The lower ee at
higher pressure was attributed to hydrogenation of the quinoline
moiety of CD. An even greater effect of modifier stability was
reported for the very slow hydrogenation of α-hydroxyketones
on Rh, where the positive effect of increased pressure could
be utilized only by increasing the amount of CD considerably
(M/S = 11.8 mol%) [19]. Because (partial) saturation of the
quinoline ring weakens the adsorption of the alkaloid, it is re-
placed on the metal surface by CD from the solution. Note
that Rh belongs to the best catalysts for the hydrogenation of

F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
15
Fig. 3. Comparison of the catalytic performance of Rh/Al O modified with
β-iCN, CN, and CD in the hydrogenation of ketopantolactone at 10 and 90 bar,
respectively. Standard conditions, 6.8 µmol modifier, full conversion.
2
3
Fig. 5. Influence of modifier/substrate molar ratio (M/S) on the enantiose-
lectivity in the hydrogenation of ketopantolactone to (R)-pantolactone over
β-iCN-modified Rh/Al O ; standard conditions, toluene, 90 bar, full conver-
2
3
sion.
Table 4
Influence of catalyst treatments on the enantioselectivity in the hydrogenation
of ketopantolactone to (R)-pantolactone over 5 wt% Rh/Al O modified by
2
3
β-iCN (standard conditions, toluene, 90 bar, full conversion). SP: standard pre-
◦
treatment at 400 C in flowing hydrogen. Additional treatments: mixtures of
freshly reduced catalyst (after SP) and β-iCN were sonicated (method 1), re-
fluxed (method 2), or stirred (method 3) in toluene for 30 min
◦
Method
No
Atmosphere
–
p (bar)
T ( C)
ee (%)
44
–
–
SP
H
1
400
64
2
1
1
1
1
2
3
3
3
3
air
1
1
1
1
1
1
1
1
90
25
25
25
111
111
25
25
25
25
61
60.5
52
56.5
53.5
58
59.5
52
N
H
N
2
2
2
Fig. 4. Influence of temperature on the enantioselectivity in the hydrogenation
H2
air
N2
of ketopantolactone to (R)-pantolactone over β-iCN-modified Rh/Al O ; stan-
2
3
dard conditions, toluene, 90 bar, full conversion.
H
H
2
2
63.5
aromatic and heteroaromatic compounds [42]. The enantiose-
lectivities achieved at 10 and 90 bar in the presence of β-iCN,
CN, and CD are shown in Fig. 3 for comparison. The most in-
teresting result is the contradictory effect of high pressure when
β-iCN or the parent alkaloid CN is used. This deviation is due
mainly to the different resistance of the modifiers against self-
hydrogenation, as we discuss later.
responding to 0.37 mmol L 1 β-iCN). Note that even a M/S
molar ratio of only 10 ppm (i.e., <1 µmol L β-iCN in the
reaction mixture), is sufficient for a significant enantioselec-
tion (28% ee). For comparison, a racemic mixture was obtained
when <4 µmol L β-iCN was applied in the hydrogenation of
ethyl pyruvate on Pt/Al2O3 [27]. Apparently, β-iCN is a more
effective modifier on Rh than on Pt.
Finally, we attempted to improve the enantioselectivity with
additional treatments of Rh/Al2O3, as summarized in Table 4.
−
−
1
−
1
The good performance of β-iCN-modified Rh/Al O was
2
3
limited to room temperature or below, as illustrated in Fig. 4.
This is a general feature of the hydrogenations on cinchona-
modified Rh [11–13,16] and Pt [43–47], and only tartaric acid-
◦
◦
modified Ni gives high enantioselectivities at 60–80 C [1,2].
A reductive treatment at 400 C in a continuous-flow reactor,
◦
The 68% ee to (R)-pantolactone achieved at −10 C and 90 bar
the method used in all reactions discussed up to now, improved
the ee by 20%. The likely explanation for this significant change
is the complete reduction of surface metal oxides and the clean-
ing of the surface from impurities originating from the catalyst
preparation and storage. Unfortunately, none of the additional
treatments applied in the liquid phase after the standard gas-
phase prereduction increased the enantioselectivity. We assume
that the special effect of these treatments is covered by the
was the highest enantioselectivity in this reaction on Rh. This
enantioselectivity was obtained at full conversion and without
the formation of any detectable byproducts.
The influence of modifier/substrate molar ratio (M/S) was
studied by varying the amount of modifier at constant sub-
strate concentration (Fig. 5). The correlation is characterized
by a broad maximum at a M/S ratio of about 0.4 mol% (cor-

16
F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
Table 5
a
Some characteristic data of β-iCN, CN, and CD used to modify Rh/Al O
2
3
0
0
Modifier
r
r
Ads.
(%)
S
M
−
1
−1
−1 −1
(µmol min g )
cat
(
mmol min
g
)
cat
β-iCN
CN
CD
12.5
8.5
10
14
24
25
12
21
21
a
0
S
r —initial reaction rate in the hydrogenation of the substrate ketopantolac-
0
M
tone; standard conditions, 10 bar. r —initial reaction rate in the hydrogenation
of the quinoline ring of the modifiers; standard conditions, 90 bar. Ads.—the
relative decrease of modifier concentration (in %) in solution due to adsorp-
tion on Rh/Al O , as determined by UV spectroscopy; standard conditions, the
2
3
mixture of modifier and catalyst in toluene + 10% THF were stirred for 5 min
under nitrogen.
ethyl pyruvate and ketopantolactone. It seems that the superior
behavior of β-iCN in mixtures with CN is limited to Rh.
The solubility of CN in toluene was much lower than that of
β-iCN; we can speculate that the inferior behavior of CN de-
duced from Fig. 6 is only apparent and due to differences in
the actual concentrations of dissolved modifiers. Because the
enantioselection with CN in polar solvents was poor (Table 3),
we conducted some control experiments in a 90% toluene–
Fig. 6. Hydrogenation of ketopantolactone over Rh/Al O modified by β-iCN–
2
3
CN mixtures; standard conditions, toluene. The dashed line represents the ideal
calculated) behavior.
(
detrimental effect of (slow) reoxidation of the surface of Rh par-
ticles. This interpretation is supported by the negligible changes
when the treatment according to method 3 was carried out un-
der hydrogen at high pressure (Table 4, last line).
1
0% THF mixture and introduced a 5-min preadsorption pe-
riod under nitrogen before starting ketopantolactone hydro-
genation, to allow equilibration (a deviation from the standard
procedure). Under these modified conditions, hydrogenation
of ketopantolactone gave 25% (S)-pantolactone and 42% (R)-
pantolactone in the presence of CN and β-iCN, respectively.
3
.3. Nonlinear phenomenon
The study of the nonlinear behavior of modifier mixtures
(
The lower enantioselectivities may be due in part to the detri-
by the classical “static” method in batch reactors [48–50] and
by transient methods in batch [51] and continuous-flow reac-
tors [52] is presently the only possible way to estimate the
relative adsorption strength of modifiers under truly in situ con-
ditions. A key requirement is that two modifiers alone give the
opposite enantiomers of the product in excess.
mental effect of stirring in nitrogen; for comparison, see the
effect of method 3 in Table 4.) Using the same procedure with
equimolar amounts of β-iCN and CN, the ee was 30% to the
(
R)-enantiomer, confirming the inferior behavior of CN in the
presence of β-iCN. Clearly, the low solubility in toluene is not
the origin of the nonlinear phenomenon.
Here we applied the classical method commonly used in
homogeneous catalysis [53]. The nonlinear behavior of mix-
tures of β-iCN and CN in the hydrogenation of ketopantolac-
tone is illustrated in Fig. 6. The “expected” or theoretical ee
Previous studies showed that on Pt, CD adsorbs stronger
than any other chiral modifier. Modifiers β-iCN and CD cannot
be compared directly, because they provide (R)-pantolactone
in excess, therefore we compared them with CN. The hy-
drogenation of ketopantolactone was carried out under stan-
dard conditions in toluene on Rh/Al O . In the presence of an
(
dashed line) was calculated assuming that the molar ratios of
the modifiers in solution and on the Rh surface are identical,
the modifier–modifier interactions on the surface are unimpor-
tant, and the hydrogenation rates and ee’s are linear combina-
tions of those measured by using the modifiers alone. There
was considerable deviation from the ideal behavior, and β-
iCN governed the enantioselection in the entire concentration
range. Only 7.5% β-iCN in the mixture was sufficient to pro-
duce the (R)-pantolactone in slight excess (1.5% ee), although
the calculated ee for this modifier mixture was 16.5% to the
2
3
equimolar mixture of CN and CD, the ee was 19% to the (R)-
enantiomer. The “expected” or theoretical value was 16.5% to
(R)-pantolactone, revealing a minor deviation of only 2.5% to
the (R)-enantiomer. Note that this relation is similar to that
observed on Pt/Al O [48]. It demonstrates that on Rh, CD
2
3
adsorbs more strongly than CN, although the difference is sig-
nificant smaller than that between β-iCN and CN (16%, Fig. 6).
From this comparison, we can deduce the following order of ad-
sorption strength on Rh: β-iCN > CD > CN.
(
S)-enantiomer (corresponding to 18% deviation from linear-
ity). With equimolar amounts of β-iCN and CN, the deviation
from the theoretical value was 16% to the (R)-enantiomer.
In contrast to the large differences in the adsorption strength
on Rh, very similar adsorptions of β-iCN and CN on Pt/Al O
were reported by Bartók et al. [27,28]. These authors used the
transient method in a batch reactor [51] in the hydrogenation of
The initial hydrogenation rates of ketopantolactone on
Rh/Al O in the presence of β-iCN, CN, and CD are given
in Table 5. Interestingly, the order of initial reaction rates in
the presence of the three modifiers is the same as the order of
the adsorption strength of the modifiers. This is not a general
situation; many exceptions have been reported using Pt [51,54].
2
3
2
3

F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
17
Fig. 7. UV spectrum of quinoline (a), 1,2,3,4-tetrahydroquinoline (b), 5,6,7,8-
tetrahydroquinoline (c), and decahydroquinoline (d). Concentrations: 0.34
−
1
mmol L in a mixture of toluene (90 vol%) and THF (10 vol%).
3
.4. Stability of modifiers under reaction conditions: UV and
NMR spectroscopy
As discussed previously, a major limitation of Rh is its
high activity in the saturation of aromatic rings, leading to
extensive degradation of cinchona-type modifiers during ke-
tone hydrogenation [19]. Saturation of the quinoline ring of
the modifier leads to weaker adsorption on the catalyst, and
the hydrogenated modifier is replaced by an intact modifier
from the solution [51,55–57]. This side reaction necessitates
uneconomic high M/S ratios and produces waste. To estimate
the stability of β-iCN on Rh/Al2O3, we compared the hydro-
genation of the quinoline rings of β-iCN, CN, and CD under
standard conditions used in the enantioselective hydrogenation
of ketones. (Note that another side reaction, the hydrogenation
of the vinyl group of CN and CD is even faster but does not
influence enantioselection.) In each experiment, the modifier
and catalyst in 5 ml mixture of toluene (90 vol%) and THF
Fig. 8. Hydrogenation of the quinoline ring of CN (A) and β-iCN (B) over
Rh/Al O followed by UV spectroscopy; standard conditions, 5 ml mixture of
2
3
toluene (90 vol%) and THF (10 vol%), 90 bar. (a) Initial solution before con-
tacting with the catalyst; (b) the mixture of modifier and catalyst was stirred for
5 min under nitrogen; (c–f) hydrogenation for 2, 5, 10, and 30 min, respectively.
(
10 vol%) were stirred for 5 min in nitrogen before hydrogena-
tion. Disappearance of the modifier from solution during this
period was considered adsorption on the catalyst. The change of
modifier concentration in solution was followed by a UV spec-
troscopic method in the range of 280–350 nm [51]. A compari-
son of the UV spectra of quinoline, 1,2,3,4-tetrahydroquinoline,
and decahydroquinoline (Fig. 7) with the spectra of CD (not
shown), CN, and β-iCN confirmed that the UV spectra of
the modifiers were determined by the quinoline chromophore
(
Figs. 8A and 8B). The concentration of modifiers with intact
aromatic ring was determined by the quinoline chromophore at
15 nm.
The amounts of modifiers adsorbed on the catalyst includ-
Scheme 2. Hydrogenation pathways of the quinoline moiety of CN and β-iCN
3
over Rh/Al O .
2
3
ing both Rh and alumina are shown in Table 5. Adsorption
of CN and CD was similar and almost twice that of β-iCN.
A major reason for the difference is that β-iCN has no free
OH-group to interact with the basic sites of the support. Ear-
lier we found a similar difference between the adsorption of
CD and its O-methylated derivative MeOCD on Pt/Al2O3 [58].
The interaction of β-iCN with alumina is limited mainly to that
of the basic quinuclidine N with the OH groups of the support
[
59–61]; adsorption via the quinoline N seems to be less im-
portant, based on the basicity difference by about six orders of
magnitude [62].
In the hydrogenation of CN (Fig. 8A) and CD (not shown),
the rapid saturation of the quinoline ring resulted in the first step
preferentially in the formation of the 1,2,3,4-tetrahydroquino-
line derivative A (Scheme 2). Because the broad band of the UV

18
F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
spectrum (max. at 308 nm) of the 1,2,3,4-tetrahydroquinoline
ring interfered with the characteristic band of the quinoline ring
at 315 nm (Fig. 7), hydrogenation of these modifiers could be
followed quantitatively only at low conversion, in the first 2 min
β-iCN > CD > CN. UV and NMR analysis showed different
chemoselectivities of the saturation of the quinoline moieties
of the three alkaloids. Our data suggest that the adsorption
modes of β-iCN and the parent alkaloid CN during enantiose-
lective hydrogenation on Rh are considerably different. We are
currently investigating the origin of this difference in our labo-
ratory using ATR-IR spectroscopy.
(Fig. 8A). Thus, these values were used to determine the initial
rate of modifier conversion in Table 5.
Hydrogenation of the quinoline ring of β-iCN was signifi-
cantly different. After 30 min (a multiple of the time required
to reach full conversion of ketopantolactone), the concentra-
tion of β-iCN in solution was still more than half the initial
concentration. The initial hydrogenation rates of the modifiers
Acknowledgments
Financial support was provided by the Swiss National Foun-
dation. The authors thank A. Dutly and H. Rüegger for the
synthesis and identification of β-iCN, and D. Ferri for help with
the UV measurements.
(
Table 5) followed the order CD ≈ CN > β-iCN. The UV spec-
tra indicate another major difference, the chemoselectivity of
the saturation of the quinoline ring. In the case of β-iCN, the
formation of the 1,2,3,4-tetrahydroquinoline derivative was not
important.
References
NMR analysis corroborated the observation made with UV
spectroscopy. Hydrogenation of CN for 2 min was sufficient to
completely hydrogenate the vinyl group. The conversion of the
quinoline ring was around 15%. The saturation was nonselec-
tive, and both products A and B in Scheme 2 were formed in
similar amounts. (In the hydrogenation of CN over Pt/Al2O3,
the product B was formed in excess [63].) The conversion of
β-iCN was about 20% after about 10 min, confirming the much
lower reactivity of this modifier compared with that of the par-
ent alkaloid CN. Both products A and B (Scheme 2) were
formed with a ratio of approximately 1:3. Complete saturation
of the quinoline rings of modifiers CN and β-iCN (product C in
Scheme 2) were observed only in trace amounts.
[
1] T. Sugimura, Catal. Surv. Jpn. 3 (1999) 37.
[2] T. Osawa, T. Harada, O. Takayasu, Curr. Org. Chem. 10 (2006) 1513.
[3] P.B. Wells, A.G. Wilkinson, Top. Catal. 5 (1998) 39.
[4] A. Baiker, J. Mol. Catal. A Chem. 163 (2000) 205.
[5] D.Y. Murzin, P. Maki-Arvela, E. Toukoniitty, T. Salmi, Catal. Rev. Sci.
Eng. 47 (2005) 175.
[6] M. Bartók, Curr. Org. Chem. 10 (2006) 1533.
[7] W.R. Huck, T. Mallat, A. Baiker, New J. Chem. 26 (2002) 6.
[8] Y. Nitta, J. Watanabe, T. Okuyama, T. Sugimura, J. Catal. 236 (2005) 164.
[9] T. Ohkuma, R. Noyori, in: E.N. Jacobsen, A. Pfalz, H. Yamamoto (Eds.),
Coprehensive Asymmetric Catalysis, Springer, Berlin, 1999, p. 200.
[
[
[
[
[
10] H.U. Blaser, H.P. Jalett, D.M. Monti, J.F. Reber, J.T. Wehrli, Stud. Surf.
Sci. Catal. 41 (1988) 153.
11] Y.L. Huang, J.R. Chen, H. Chen, R.X. Li, Y.Z. Li, L.E. Min, X.J. Li,
J. Mol. Catal. A Chem. 170 (2001) 143.
12] Y.L. Huang, Y.Z. Li, J.Y. Hu, P.M. Cheng, H. Chen, R.X. Li, X.J. Li, C.W.
Yip, A.S.C. Chan, J. Mol. Catal. A Chem. 189 (2002) 219.
13] H.X. Ma, H. Chen, Q. Zhang, X.J. Li, J. Mol. Catal. A Chem. 196 (2003)
4
. Summary
Hydrogenation of activated ketones on cinchona-modified
131.
Rh is moderately enantioselective and complicated by the ex-
tensive hydrogenation of the quinoline ring, the “anchoring
moiety” of the modifiers to the metal surface. Here we report
that β-iCN, a cinchona derivative that has not yet been used to
modify Rh, is an outstanding and reasonably stable modifier in
the hydrogenation of ketopantolactone. This is the first report
of β-iCN being superior to other cinchona alkaloids.
This conclusion is based on the screening of 11 different
catalysts and 5 cinchona alkaloids (CD, CN, QN, QD, and
β-iCN) in the hydrogenation of ethyl pyruvate, ethyl 3-methyl-
14] R. Hess, F. Krumeich, T. Mallat, A. Baiker, J. Mol. Catal. A Chem. 212
(2004) 205.
[15] M. Maris, T. Mallat, A. Baiker, J. Mol. Catal. A Chem. 242 (2005) 151.
16] W. Xiong, H.X. Ma, Y.Y. Hong, H. Chen, X.J. Li, Tetrahedron: Asymme-
try 16 (2005) 1449.
17] E. Toukoniitty, S. Franceschini, A. Vaccari, D.Y. Murzin, Appl. Catal.
A 300 (2006) 147.
[18] M. Maris, D. Ferri, L. Konigsmann, T. Mallat, A. Baiker, J. Catal. 237
(2006) 230.
19] O.J. Sonderegger, G.M.W. Ho, T. Bürgi, A. Baiker, J. Catal. 230 (2005)
[
[
[
[
[
499.
20] H.U. Blaser, H.P. Jalett, D.M. Monti, A. Baiker, J.T. Wehrli, Stud. Surf.
Sci. Catal. 67 (1991) 147.
21] M. Bartók, T. Bartók, G. Szöll o˝ si, K. Felföldi, Catal. Lett. 61 (1999) 57.
[22] J. Thiel, A. Katrusiak, P. Fiedorow, J. Mol. Struct. 561 (2001) 131.
23] T. Bürgi, A. Baiker, Acc. Chem. Res. 37 (2004) 909.
2
-oxobutyrate, and ketopantolactone. The highest ee (68%)
was achieved in the transformation of ketopantolactone to
R)-pantolactone on a commercial 5 wt% Rh/Al2O3 catalyst.
(
[
[
This enantioselectivity is the best reported so far in ketopan-
tolactone hydrogenation on Rh. A further advantage is the high
resistance of β-iCN against hydrogenation of its quinoline moi-
ety compared with those of the commonly used CD and the
parent alkaloid CN. This attractive feature allows the use of low
M/S ratios.
The higher stability of β-iCN was expected to be accom-
panied by its weaker adsorption on Rh. In contrast, our study
of the nonlinear behavior of β-iCN, CD, and CN revealed this
order of adsorption strength of the alkaloids. The initial rates
of ketopantolactone hydrogenation followed the same order:
24] G. Szöll o˝ si, K. Felföldi, T. Bartók, M. Bartók, React. Kinet. Catal. Lett. 71
(
2000) 99.
25] M. Bartók, M. Sutyinszki, K. Felföldi, G. Szöll o˝ si, Chem. Commun.
2002) 1130.
[26] M. Bartók, M. Sutyinszki, K. Felföldi, J. Catal. 220 (2003) 207.
[27] M. Bartók, M. Sutyinszki, I. Bucsi, K. Felföldi, G. Szöll o˝ si, F. Bartha,
T. Bartók, J. Catal. 231 (2005) 33.
28] M. Bartók, K. Balázsik, I. Bucsi, G. Szöll o˝ si, J. Catal. 239 (2006) 74.
29] J.L. Margitfalvi, E. Tálas, Appl. Catal. A 301 (2006) 187.
30] K. Sz o˝ ri, K. Balázsik, K. Felföldi, M. Bartók, J. Catal. 241 (2006) 149.
31] M. Bartók, K. Felföldi, B. Török, T. Bartók, Chem. Commun. (1998)
2605.
[
(
[
[
[
[

F. Hoxha et al. / Journal of Catalysis 248 (2007) 11–19
19
[
[
[
32] B. Török, K. Felföldi, G. Szakonyi, K. Balázsik, M. Bartók, Catal. Lett. 52
[47] E. Toukoniitty, P. Maki-Arvela, M. Kuzma, A. Villela, A.K. Neyestanaki,
T. Salmi, R. Sjoholm, R. Leino, E. Laine, D.Y. Murzin, J. Catal. 204
(2001) 281.
[48] K.E. Simons, P.A. Meheux, A. Ibbotson, P.B. Wells, Stud. Surf. Sci. Catal.
75 (1993) 2317.
(1998) 81.
33] C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley–
VCH, Weinheim, 1988.
34] M. Schürch, O. Schwalm, T. Mallat, J. Weber, A. Baiker, J. Catal. 169
(
1997) 275.
[49] A. Tungler, K. Fodor, T. Mathe, R.A. Sheldon, Stud. Surf. Sci. Catal. 108
(1997) 157.
[50] L. Balazs, T. Mallat, A. Baiker, J. Catal. 233 (2005) 327.
[51] W.R. Huck, T. Bürgi, T. Mallat, A. Baiker, J. Catal. 216 (2003) 276.
[52] D.M. Meier, T. Mallat, D. Ferri, A. Baiker, J. Catal. 244 (2006) 260.
[53] H.B. Kagan, Synlett (2001) 888.
[
[
[
[
35] W.R. Huck, T. Bürgi, T. Mallat, A. Baiker, J. Catal. 205 (2002) 213.
36] M. von Arx, T. Bürgi, T. Mallat, A. Baiker, Chem. Eur. J. 8 (2002) 1430.
37] D. Ferri, T. Bürgi, A. Baiker, J. Chem. Soc. Perkin Trans. 2 (1999) 1305.
38] T. Mallat, Z. Bodnar, B. Minder, K. Borszeky, A. Baiker, J. Catal. 168
(1997) 183.
[
39] K. Balázsik, M. Bartók, J. Catal. 224 (2004) 463.
[54] S. Diezi, T. Mallat, A. Szabo, A. Baiker, J. Catal. 228 (2004) 162.
[55] C. LeBlond, J. Wang, A.T. Andrews, Y.K. Sun, Top. Catal. 13 (2000) 169.
[56] M. Bartók, G. Szöll o˝ si, K. Balázsik, T. Bartók, J. Mol. Catal. A Chem. 177
(2002) 299.
[57] M. von Arx, T. Mallat, A. Baiker, Top. Catal. 19 (2002) 75.
[58] W.R. Huck, T. Mallat, A. Baiker, unpublished data.
[59] N.V. Nikolenko, I.B. Taran, I.L. Plaksienko, N.K. Vorobev, Colloid J. 59
(1997) 476.
[60] T.J. Dines, L.D. MacGregor, C.H. Rochester, Langmuir 18 (2002) 2300.
[61] E. Kassab, M. Castella-Ventura, J. Phys. Chem. B 109 (2005) 13716.
[62] C. Drzewiczak, A. Suszkopurzycka, J. Skolik, Pol. J. Chem. 67 (1993) 45.
[63] G. Szöll o˝ si, P. Forgó, M. Bartók, Chirality 15 (2003) S82.
[40] X.B. Li, R.P.K. Wells, P.B. Wells, G.J. Hutchings, J. Catal. 221 (2004)
653.
[
[
41] A. Kraynov, A. Suchopar, R. Richards, Catal. Lett. 110 (2006) 91.
42] S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogenation for
Organic Synthesis, Wiley, New York, 2001.
[
[
43] P.A. Meheux, A. Ibbotson, P.B. Wells, J. Catal. 128 (1991) 387.
44] W.A.H. Vermeer, A. Fulford, P. Johnston, P.B. Wells, J. Chem. Soc. Chem.
Commun. (1993) 1053.
[
45] N. Künzle, A. Szabo, M. Schürch, G.Z. Wang, T. Mallat, A. Baiker, Chem.
Commun. (1998) 1377.
[46] M. Schürch, N. Künzle, T. Mallat, A. Baiker, J. Catal. 176 (1998) 569.