Substrate-controlled adsorption of cinchonidine during enantioselective hydrogenation on platinum

Article abstract of DOI:10.1016/j.jcat.2010.03.003

It is commonly accepted that the origin of enantioselection on chirally modified metals is the control of the adsorption and reactivity of the substrate by the chiral environment of the modifier. Here, we provide the first experimental evidence to a mutual process, namely, that the substrate controls the adsorption and reactivity of cinchonidine (CD) on the metal surface. Our approach is to follow the competing hydrogenation of the quinoline ring, the anchoring moiety of CD, in the presence or absence of an activated ketone substrate. On Pt/Al₂O₃ in the weakly interacting solvent toluene, CD (and 10,11-dihydro-CD) favors a C(4′) - pro(S) adsorption geometry and saturation of the heteroaromatic ring gives 1′,2′, 3′,4′(S),10,11-hexahydro-CD {(S)-CDH₆} in excess. Addition of methyl benzoylformate, ketopantolactone, or ethyl pyruvate inverts the dominant conformation of CD to C(4′) - pro(R) as indicated by the major product (R)-CDH₆, and even the rate is higher by about 30% ("inverse ligand acceleration"). Acetic acid that interacts strongly with CD exerts a similar effect on quinoline hydrogenation. In contrast, the product α-hydroxyester interacts weakly with CD, decelerates the hydrogenation of the quinoline ring and the de of CDH₆ depends on the chirality of the α-hydroxyester. These unexpected observations provide a fundamentally new insight into the complexity of the surface conformation of CD and the origin of high enantioselectivity on cinchona-modified Pt.

Full text of DOI:10.1016/j.jcat.2010.03.003

Journal of Catalysis 272 (2010) 140–150
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Substrate-controlled adsorption of cinchonidine during enantioselective
hydrogenation on platinum
*
Erik Schmidt, Tamas Mallat, Alfons Baiker
Institute of Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, Hönggerberg, HCI, CH-8093 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
It is commonly accepted that the origin of enantioselection on chirally modified metals is the control of
the adsorption and reactivity of the substrate by the chiral environment of the modifier. Here, we provide
the first experimental evidence to a mutual process, namely, that the substrate controls the adsorption
and reactivity of cinchonidine (CD) on the metal surface. Our approach is to follow the competing hydro-
genation of the quinoline ring, the anchoring moiety of CD, in the presence or absence of an activated
ketone substrate. On Pt/Al2O3 in the weakly interacting solvent toluene, CD (and 10,11-dihydro-CD)
Received 5 January 2010
Revised 2 March 2010
Accepted 2 March 2010
Available online 28 March 2010
Keywords:
favors
a – pro(S) adsorption geometry and saturation of the heteroaromatic ring gives
C(40)
Cinchonidine adsorption
Asymmetric hydrogenation
Ligand acceleration
10,20,30,40(S),10,11-hexahydro-CD {(S)-CDH6} in excess. Addition of methyl benzoylformate, ketopantolac-
tone, or ethyl pyruvate inverts the dominant conformation of CD to C(40) – pro(R) as indicated by the
major product (R)-CDH6, and even the rate is higher by about 30% (‘‘inverse ligand acceleration’’). Acetic
acid that interacts strongly with CD exerts a similar effect on quinoline hydrogenation. In contrast, the
a-Ketoester
product
a
-hydroxyester interacts weakly with CD, decelerates the hydrogenation of the quinoline ring
-hydroxyester. These unexpected observations pro-
and the de of CDH6 depends on the chirality of the
a
vide a fundamentally new insight into the complexity of the surface conformation of CD and the origin of
high enantioselectivity on cinchona–modified Pt.
Ó 2010 Elsevier Inc. All rights reserved.
1. Introduction
Asymmetric induction is a complex phenomenon that includes
chiral recognition by intermolecular interaction of modifier and
The concept of modifying a supported noble metal catalyst by
adsorption of a chiral compound led to high enantioselectivities
in the asymmetric hydrogenation of activated ketones [1–5]. The
most successful catalytic system is platinum modified by cinchona
alkaloids that afford up to 98% ee [6,7] even under very mild con-
ditions [8].
Significant progress in the understanding of the mechanistic de-
tails of this reaction has been achieved in the past years. Theoret-
ical calculations as well as surface science studies focused on the
adsorption of the modifier on the metal surface [9–20]. In case of
cinchonidine (CD), spectroscopic investigations at the relevant so-
lid–liquid interface revealed two major species: the alkaloid ad-
substrate, which concept is supported by complex formation in
solution [28,29]. Most of the adsorption studies, however, focus
on the behavior of the chiral modifier in the absence of the sub-
strate. Recent attempts to overcome this shortcoming by theoreti-
cal calculations are highly demanding [30,31], while spectroscopic
investigations are complicated by the intensive absorbance of the
substrate being present in large excess to the alkaloid [32,33].
Numerous feasible conformations of the adsorbed modifier
have been determined by DFT calculations [9,11,30]. The structures
that are probable candidates for interacting with the ketone during
hydrogen uptake can be divided into two major groups, which dif-
fer in the orientation of the quinoline ring at the metal surface, rel-
ative to the rest of the molecule (Scheme 1). Concerning the
hydrogenation of the quinoline ring of the alkaloid (Scheme 2), in
the first group CD is adsorbed pro(S) at C(40) and in the other group
pro(R). Importantly, inter-conversion of the structures belonging to
the different groups is not possible on the Pt surface but requires
desorption and re-adsorption. The possible rotation around the
C(40)–C(9) and C(9)–C(8) bonds gives rise to several different
conformations which have been designated as surface open (SO),
surface closed (SC), and surface quinuclidine bound (SQB), but all
of them belong to either the pro(R) {SO(3), SC(2), SQB(2)} or the
pro(S) group {SO(4), SC(1), SQB(1)} [11]. Experimental data that
sorbed via the quinoline ring
p-bound nearly parallel to the
metal surface and a tilted adsorption mode via the N-lone pair of
the heteroaromatic ring. The relative amount of these structures
depends strongly on the reaction conditions (concentration, pres-
sure, temperature, solvent) and the structure of the metal surface
[1,12,21–26], and even competition with strongly adsorbing mole-
cules may have a remarkable influence on the adsorption geometry
[27].
* Corresponding author. Fax: +41 44 632 1163.
E-mail address: baiker@chem.ethz.ch (A. Baiker).
0021-9517/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2010.03.003

E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
141
ing ketone hydrogenation and offers a deeper understanding of the
relevant surface interactions involved in enantioselection.
X
N
2. Experimental
2.1. Materials
In general, analytical grade reagents and solvents were used.
Toluene (Fluka, >99.7%) was dried over activated mole sieve 4A;
acetic acid (Acros organics, 99.8%), and CD (Fluka, >98% alkaloid)
were used as received. Pt/Al2O3 (5 wt%) catalyst was purchased
from Engelhard (Engelhard 4759).
Details on the synthesis and purification of the hydrogenation
products of CD (Scheme 2) and their characterization by 1H NMR
spectroscopy (Bruker 200 MHz) can be found elsewhere [41].
X
N
X
N
2.2. Catalytic hydrogenations
pro(R)
pro(S)
According to the standard procedure, hydrogenation of 3–6 mg
(10–20 lmol) of CD in the absence of a ketone substrate was per-
formed in 10 ml solvent (toluene or acetic acid) at 298 K and 2–
50 bar hydrogen, in a 50-ml stainless steel reactor equipped with a
glass-liner and magnetic stirrer (750 rpm). The pressure was con-
trolled with a constant–volume constant–pressure system (Büchi
BPC 9901). The amount of catalyst was 20 mg of 5 wt% Pt/Al2O3,
which waspretreated in flowingH2 at 400 °C (673 K) for 90 minprior
to use, resulting in a Pt dispersion of 0.2 as determined by TEM [44].
Samples were taken regularly from the reaction mixture via syr-
inge in order to follow the conversion and selectivity with time. In
case of the solvent toluene, the samples were first washed with
0.5 M HCl in water. The pH of the separated aqueous phase was
set to 12 with 0.5 M NaOH before repeated extraction with toluene.
The combined organic phases were washed with 0.1 M NaOH sat-
urated with NaCl. When the reaction was carried out in acetic acid
solvent, the samples were first treated with excess aqueous 1 M
NaOH before extraction with toluene three times. The organic
phase was treated then analogously to the samples taken from
the toluenic reaction mixture. Finally, the samples were filtered
and analyzed by gas chromatography (Thermo Quest Trace 2000,
HP-5 capillary column, FID). Details on the preparation and charac-
terization of the hydrogenated CD derivatives are given in the sup-
porting information of our former report [41].
Enantioselective hydrogenation of methyl benzoylformate
(MBF, Acros organics, 99%) was carried out according to the stan-
dard procedure using 40 mg catalyst at 10 bar. MBF (4–20 mmol)
was added either before starting the reaction or after a time delay
of 30 min in the transient experiments. GC analysis of CD and its
hydrogenation products was made analogously to the experiments
in the absence of ketones. The conversion and enantioselectivity in
the hydrogenation of MBF were followed by gas chromatography
(Thermo Finnigan Trace 2000, CP-Chirasil-Dex CB capillary column,
FID). Samples were taken regularly from the reaction mixture, the
catalyst was filtered off, and the filtrate was diluted with ethyl ace-
tate before analysis.
Scheme 1. Two major adsorption modes of cinchonidine on Pt affording (S)- or (R)-
CDH6-A upon hydrogenation according to Scheme 2. X in the formula represents the
non-aromatic part of the alkaloid.
could verify these theoretical predictions on the conformational
structure of the modifier–substrate complex adsorbed on the Pt
surface are not available, and thus the origin of chiral recognition
is still a matter of debate, as summarized in some recent reviews
[1,3,4,34].
Transformation of CD by hydrogenation of its aromatic anchor-
ing unit has been observed spectroscopically [21,35] and was
shown to be the most important side reaction limiting the
performance of this catalytic system in terms of enantioselectivity
[36–40]. The theoretical importance of this side reaction is that it
allows us to study the adsorption behavior of the modifier indi-
rectly by following its hydrogenation products [36,38,41,42]. It
has been shown recently that Pt nanoparticles rich in Pt{1 0 0} face
exhibit higher activity in this reaction, while the Pt{1 1 1} surface is
more diastereoselective [40,41]. The selectivity depends remark-
ably on the presence of acids either as a solvent or surface residue
[41]. Formation of 10,20,30,40(S),10,11-hexahydro-CD ((S)-CDH6-A) is
preferred in the weakly polar aprotic solvent toluene (Scheme 2).
Assuming hydrogen uptake from the Pt surface, this observation
indicates a pro(S) adsorption geometry of CD. On the other hand,
predominantly 10,20,30,40(R),10,11-hexahydro-CD ((R)-CDH6-A)
with opposite absolute configuration at C(40) is formed in the pres-
ence of acetic acid and poly(acrylic acid) capping agent [41], which
is an evidence to the higher abundance of pro(R) CD species under
these conditions.
Interestingly, the hydrogenation of a-ketoesters and a-ketolac-
tones does not show such solvent dependency, i.e. always the same
(R)-enantiomer is formed in the presence of CD [1,43]. Two possi-
ble conclusions might be drawn from these observations: (i) either
both adsorption geometries of the modifier {pro(S) or pro(R) at
C(40)} favor the formation of the same enantiomer in the asymmet-
Hydrogenation of 540 mg (4.2 mmol) ketopantolactone (KPL,
Hoffmann-La Roche, 99%) was investigated in the presence of
1 mg CD (3.5
lmol) at 50 bar H2 pressure and 298 K using 5 mg
catalyst in 10 ml toluene. Hydrogenation of 0.5 ml (4.5 mmol)
ethyl pyruvate (EP, Acros organics, 98%, freshly distilled before
use) was carried out using the standard procedure at 2 bar and
298 K in toluene. GC analysis of KPL or EP and their hydrogenation
products was made after filtration and dilution of the samples,
similarly to the experiments with MBF.
ric hydrogenation of
a-ketoesters and a-ketolactones, or (ii) the
adsorption behavior of CD is controlled by the presence of the acti-
vated ketone substrate. To clarify this point, we studied the hydro-
genation of CD under truly in situ conditions, during the
hydrogenation of methyl benzoylformate (MBF), ethyl pyruvate
(EP), and ketopantolactone (KPL, Scheme 3). This study provides di-
rect evidence for the adsorption mode of CD on the Pt surface dur-
The standard procedure was applied also for the experiments on
the hydrogenation of CD in the presence of the hydrogenation

142
E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
11
10
3
H
H
2
7
H
H
8
H
5'HO
9'
H
HO
H
H
4
N
N
9
4'
5
1
6
6'
3'
2'
CDH2
7'
CD
10'
8'
N1'
N
CDH6
H
H
H
H
HO
H
H
N
H
H
N
HO
N
H
(R)-A and (S)-A
B
N
H
H
H
HO
H
N
CDH12
N
H
Scheme 2. Stepwise hydrogenation of cinchonidine (CD) to CDH12 on Pt/Al2O3.
products of MBF. Therein 0.7 g (4.2 mmol) of either (R)-methyl
mandelate (TCI Europe, >98%), (S)-methyl mandelate (ABCR, 99%),
or rac-methyl mandelate (Fluka, >98%) has been added to the tol-
uenic solution. The samples taken from the reaction mixture were
treated and analyzed as described previously for MBF.
Hydrogenation of cyclohexene (Fluka, >99.5%) was investigated
in the presence and absence of CD under the conditions used for
ethyl pyruvate hydrogenation (20 mg catalyst, 3 mg CD, 4.5 mmol
cyclohexene, 2 bar, 298 K). The products of cyclohexene hydroge-
nation were analyzed by gas chromatography (Thermo Quest Trace
2000, HP-FFAP capillary column, FID).
fast saturation of its vinyl group affording dihydrocinchonidine
(CDH2) (Scheme 2). Under standard conditions, all CD was con-
verted to CDH2 within 10 min. This facile transformation has
barely any influence on the enantio-differentiating ability of the
alkaloid [3]. The following hydrogenation of the quinoline moiety
afforded hexahydrocinchonidines (CDH6), i.e. no tetrahydrocinch-
onidines could be detected. The reaction was faster in acetic acid
than in toluene in the whole conversion range (Fig. 1A). The corre-
sponding turnover frequencies (TOF, Table 1) related to the conver-
sion of CDH2 were calculated based on the number of Pt surface
atoms. The rate of the hydrogenation of CDH2 is somewhat smaller
compared to the recently published values [36,41], which is prob-
ably due to the different catalyst pretreatment procedure applied
in the former work. The further reaction of CDH6 to the fully hydro-
genated diastereomers of dodecahydrocinchonidine (CDH12) has
recently been described [41] but was not followed in detail in
the present work.
The estimated error in the determination of the diastereomeric
excess (de) and the ee was about 0.5% and that of the reaction rate
(TOF) was in the range 10%.
3. Results and discussion
3.1. Hydrogenation of CD in the absence of a ketone substrate
The chemo- and diastereoselectivity of the CDH2 ? CDH6 trans-
formation depends strongly on the reaction conditions. Unless
otherwise stated, the selectivity was determined at 40 5% conver-
sion of CDH2. At this conversion, no CD was left in solution and the
At first, the hydrogenation of cinchonidine (CD) was followed in
the absence of any ketone. As previously shown [41], CD undergoes

E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
143
O
OH
*
CD, H2
O
O
toluene or AcOH,
2-50 bar, 298 K
O
O
MBF
OH
*
O
CD, H2
toluene, 2 bar
298 K
O
O
O
O
EP
O
O
CD, H2
HO
O
*
O
O
toluene, 50 bar
298 K
KPL
Scheme 3. Hydrogenation of methyl benzoylformate (MBF), ethyl pyruvate (EP), and ketopantolactone (KPL) on CD-modified Pt/Al2O3.
selectivity to the fully saturated molecule CDH12 was always about
10%.
[52,53]. No hydrogenation of the phenyl ring of MBF was observed
under our conditions. Furthermore, the absence of an -H atom in
a
The favored hydrogenation of the heteroaromatic ring results in
the formation of the two diastereomers (R)- and (S)-CDH6-A with
opposite absolute configuration at the new center of chirality at
C(40) (Scheme 2). The main product is (S)-CDH6-A with a de of
about 16% under standard conditions in toluene (Table 1). The dia-
stereoselectivity was almost independent of the conversion of
CDH2 (Fig. 1B). Hydrogenation of the homoaromatic ring to give
CDH6-B was slow under the conditions applied as shown by the
high A/B ratio in Table 1.
The most important solvent effect is the inversion of the major
diastereomer in acetic acid compared to the dominant product in
toluene (Fig. 1B) [41]. In addition, in acetic acid, the reaction was
less selective to CDH6-A (lower A/B ratio, Table 1), which is in good
agreement with the literature data [36,41,45].
Acetic acid is able to form acid–base pairs with CD [36], and
probably also with CDH2, and this interaction may be the reason
for the favored formation of (R)-CDH6-A with a de of 55% under
standard conditions (Table 1). This interaction is of fundamental
importance in the enantioselective hydrogenation of unsaturated
carboxylic acids on cinchona–modified Pd [1]. According to the lat-
est spectroscopic and theoretical study [46], this interaction has a
rather complex stoichiometry and interaction geometry (cyclic or
acyclic) in solution and there is no in situ experimental evidence
yet in favor of any of those structures on the surface of Pt [47] or
Pd [48,49]. Note that CD can also be protonated by the Pt/H2 sys-
tem, as shown by spectroscopic investigations and theoretical cal-
culations [10,50].
MBF prevents self-condensation catalyzed by the Pt surface and
the basic quinuclidine N of the alkaloid, which makes this molecule
– and also KPL – suitable substrates for mechanistic studies [5].
Hydrogenation of CD to CDH2 was not affected by the addition
of MBF. In the subsequent transformation of CDH2 to CDH6 in tol-
uene, the main diastereomer was switched from (S)- to (R)-CDH6-A
and the selectivity to the homoaromatic product CDH6-A decreased
(Table 1). In general, the selectivities in toluene became very sim-
ilar to those measured in acetic acid, while in the latter medium
the selectivities were barely affected by the presence of MBF. From
the similar selectivities we can conclude that the presence of MBF
in toluene affects the adsorption geometry of CD molecules similar
as acetic acid solvent does. This chiral switch is illustrated in
Scheme 4, where two dominant conformations, the SO(4) and
SO(3) are used to represent the C(40) pro(S) and C(40) pro(R)
adsorption geometries, respectively [11]. The N–H–O type modi-
fier–substrate interaction used here for illustration is based on
our mechanistic model [1,32,54].
The rate of the aromatic hydrogenation of CDH2 increased in the
presence of MBF by about 30% in toluene and 5% in acetic acid (Ta-
ble 1). The estimated error of the rate determination was in the
range 10%, so only the rate enhancement in toluene is significant.
The unexpected rate enhancement was confirmed by transient
experiments. Hydrogenation of CD was started in the absence of
MBF in toluene and the substrate was added only after 30 min.
The de of about 16% for (S)-CDH6-A at 20–30 min (Fig. 2B) and
the initial rate of about 1.6 hꢀ1, calculated from the slope of the
conversion–time plot (Fig. 2A) correspond well to the values given
in Table 1. After 30 min, 8.4 mmol MBF was injected to the reaction
mixture. The rate (TOF ꢁ 3700 hꢀ1) and enantioselectivity (91% ee)
of the hydrogenation of MBF were similar to the values obtained
when starting the reaction in the presence of MBF (see Table 2).
Addition of MBF increased the slope of the conversion–time plot
(Fig. 2A) corresponding to an enhanced rate of CDH2 hydrogenation
(TOF ꢁ 2.1 hꢀ1). Note that this value is almost identical to the rate
observed when starting the reaction with MBF (Table 1), confirm-
3.2. Hydrogenation of CD in the presence of methyl benzoylformate
(MBF)
Hydrogenation of MBF under standard conditions in toluene
gives more than 90% ee to (R)-methyl mandelate (Table 2). This va-
lue is in good agreement with the literature data [43,51], although
98% ee was achieved in the hydrogenation of the ethyl ester under
carefully optimized conditions and with ultrasonicated Pt/Al2O3

144
E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
than that of the alkaloid, since at full conversion of ketopantolac-
100
80
60
40
20
0
A
tone the Pt surface was still covered by (some) CD. Unfortunately,
the usual CD/substrate molar ratio necessary under optimized con-
ditions is orders of magnitude higher in the hydrogenation of some
other substrates, for example of acetophenone derivatives [56,57].
AcOH
3.3. Hydrogenation of CD in the presence of ethyl pyruvate (EP) and
ketopantolactone (KPL)
toluene
We extended the study of the competing hydrogenation of CD
during enantioselective hydrogenations on Pt involving EP and
KPL as substrates. Hydrogenation of EP is the mostly used test reac-
tion of the Pt–cinchona system, although extensive side reactions
such as aldol-type self-condensation and decarbonylation [58,59]
may distort the observations. KPL is an interesting model com-
pound because of the higher rigidity of the lactone structure, and
it does not undergo aldol condensation due to the absence of an
0
120
180
240
300
360
60
H atom in
a-position to the keto-carbonyl group, and also no
time / min
decarbonylation was observed [32].
Generally, reasonable good ee’s were obtained in the hydroge-
nation of both substrates (Table 2) under slightly different reaction
conditions compared to the experiments using MBF (see Section 2).
The hydrogen pressure was adjusted to 50 bar for KPL and 2 bar for
EP. In the absence of ketones, the reaction rate in the hydrogena-
tion of CDH2 increased with increasing H2 pressure, but the effect
on the chemo- and diastereoselectivities was minor (compare data
in Tables 1 and 3). The presence of EP or KPL, however, changed the
main diastereomer to (R)-CDH6-A with 48% and 68% de, respec-
tively. Also the A/B ratio decreased to 15 and 34, respectively, sim-
ilar to the results in the hydrogenation of CDH2 in the presence of
MBF. In the presence of both ketones, the reactivity of CDH2 in-
creased by about 30%, in good agreement with the rate acceleration
in the presence of MBF.
70
60
50
40
30
20
10
0
(R)
B
AcOH
de/%
-10
-20
-30
toluene
Obviously, all three substrates MBF, EP, and KPL have a very
similar effect on the adsorption and hydrogenation of CDH2
(Scheme 4). The significant enhancement of the activity in the
hydrogenation of the aromatic anchoring unit of the modifier and
the switch of the main product from (S)- to (R)-CDH6-A indicate
(S)
0
120
180
240
300
360
60
time / min
a strong interaction of modifier and substrate. The
a-ketoester
Fig. 1. Solvent effect on the rate of conversion of CDH2 (A) and the diastereose-
lectivity of CDH6-A (B); standard conditions, 10 bar, 3 mg CD in toluene and 6 mg
CD in acetic acid.
function, which is common for all three substrates, controls the
conformation of CD on the Pt surface, its reactivity, and the product
distribution in the hydrogenation of the quinoline ring. The struc-
tural differences in the three substrates, such as the steric bulki-
ness or molecular rigidity, play only a minor role in controlling
CD hydrogenation. Interestingly, steric effects were found to be
ing that the higher rate of the saturation of the aromatic ring of
CDH2 is caused by the presence of the
a-ketoester. The ratio of
minor also in the hydrogenation of various
chona–modified Pt [54,60].
a-ketoesters on cin-
the two CDH6-A diastereomers changed sharply after addition of
MBF (Fig. 2B). The calculated differential de revealed that addi-
tional CDH2 was hydrogenated with about 40–50% excess to (R)-
CDH6-A, in good agreement with the value observed when starting
the reaction in the presence of MBF (Table 1). The amount of the
heteroaromatic product CDH6-B also increased (the A/B ratio de-
creased) immediately after addition of MBF (not shown). Obvi-
ously, the adsorption of CDH2 on the Pt surface is strongly
affected by the presence of MBF. The substrate–modifier interac-
tion controlled the surface conformation of CD and thus the selec-
tivity and reactivity in the hydrogenation of the quinoline ring.
Finally, we have to emphasize that the observed rate accelera-
tion in the hydrogenation of CD does not contradict to the known
high efficiency of the Pt–cinchona system. The key to understand
this point is not the absolute but the relative rates of the hydroge-
nation of the ketone substrate and the quinoline ring of the alka-
loid. In the best case, in the hydrogenation of ketopantolactone, a
CD/substrate molar ratio of only 4 ppm was sufficient to achieve
the highest ee at full conversion [55]. This ratio implies that the
hydrogenation of the substrate was more than 250,000 times faster
3.4. Hydrogenation of CD in the presence of a-hydroxyesters
Addition of MBF to the slurry of Pt/Al2O3 and CD in toluene
accelerated the hydrogenation of the quinoline ring and inverted
the major product from (S)- to (R)-CDH6-A (Scheme 4). Vice versa,
the chiral modifier CD induced a sixfold rate enhancement in the
hydrogenation of MBF and the preferred formation of (R)-methyl
mandelate with 92% ee (Table 2). Obviously, the origin of these
changes is the modifier–substrate interaction on the Pt surface.
An important question is whether the product
a-hydroxyester is
involved in the interactions. To clarify this point, we investigated
the hydrogenation of CD in the presence of methyl mandelate
and a mixture of methyl mandelate and MBF.
No conversion of methyl mandelate, i.e. no phenyl ring hydro-
genation or C–O bond hydrogenolysis was observed under the mild
conditions applied. The presence of (R)-methyl mandelate inverted
the absolute configuration of the dominant CDH6 product at C(40),
compared to the transformation of CD alone (Table 4). The

E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
145
CDH2 on Pt
N
H
SO(3)
H
OH
N
OH
H
O
H
N
O
H
N
O
SO(4)
H2
H2
H
H
H
H
H
H
HO
H
H
N
N
HO
R
S
CDH6
N
H
N
H
(
S
)-A
(R)-A
47% de
16% de
Scheme 4. Adsorption and hydrogenation of CDH2 in toluene (left) and the change of the dominant adsorption mode in the presence of MBF (right). (For the sake of
simplicity, only the hydrogenation of the heteroaromatic ring is shown here.)
preferred formation of (R)-CDH6-A is analogous to the influence of
MBF on the hydrogenation of CD (Table 1), although the de is lower
in the presence of methyl mandelate. Addition of (S)-methyl man-
delate doubled the small excess of (S)-CDH6-A measured in the
hydrogenation of CD alone (Table 4). Another interesting effect of
the experiment in the presence of MBF (Table 1). The correspond-
ing TOF of about 1.8 hꢀ1 was very close to the value given in Table
1 for the absence of (S)-methyl mandelate, too.
The analogous experiment with (R)-methyl mandelate and MBF
(Fig. 4) proved that MBF interacts stronger than the (R)-a-hydroxy-
the addition of the (R)- or (S)-
a
-hydroxyesters is the deceleration
ester product, although in this case the replacement of the
hydroxyester by the ketoester in the interacting complex was sig-
nificantly slower, as indicated by the delayed changes in the differ-
ential de (Fig. 4B).
of the saturation of the quinoline ring compared to the neat CD
solution (Table 4). The decrease of the rate (TOF) was slightly big-
ger in the case of the (S)-enantiomer. These observations indicate
that interaction of CD with the product methyl mandelate involves
coordination to the hydroxyl group of mandelate; a feasible struc-
ture for this interaction is plotted in Scheme 5.
These transient experiments suggest that the
a-ketoester sub-
strate MBF interacts stronger with CDH2 and controls its adsorp-
tion geometry and hydrogenation selectivity even in the presence
Next, the hydrogenation of CDH2 was followed in the presence
of racemic methyl mandelate to clarify which enantiomer interacts
stronger with the modifier. The results in terms of activity and
selectivity are almost identical to the experiment using enantiome-
rically pure (R)-methyl mandelate (Table 4). The clear preference
to the (R)-CDH6-A diastereomer shows that the interaction of CD
with (R)-methyl mandelate is stronger than the alternative interac-
tion with the (S)-enantiomer.
Finally, the competition between MBF and methyl mandelate
was investigated. Hydrogenation of CD was started in the presence
of (S)-methyl mandelate and MBF was added to the reaction mix-
ture after 30 min (Fig. 3). The initial TOF and de to (S)-CDH6-A was
of the a-hydroxyester product. The order of interaction strength
is MBF > (R)-methyl mandelate > (S)-methyl mandelate.
3.5. ‘‘Ligand acceleration’’ and ‘‘inverse ligand acceleration’’
Rate acceleration of ketone hydrogenation over the chirally
modified Pt surface compared with that on unmodified Pt has some
analogy to the ligand acceleration first described in homogeneous
asymmetric catalysis [61]. Considerable experimental evidence has
been collected in favor of this concept (for recent reports see Refs.
[40,51,62,63]) and any mechanistic model for enantioselection on
Pt has to rationalize this phenomenon. Note also that the term ‘‘li-
gand acceleration’’ is a good description for chiral metal complexes
since the number of active sites remains unchanged by addition of
the ligand, while on chirally modified metals an unknown fraction
of the active surface sites are covered by the strongly adsorbing
controlled by the
a-hydroxyester (compare Fig. 3 and Table 4).
After injection of MBF, however, additional CDH2 was hydroge-
nated preferentially to (R)-CDH6-A and the calculated differential
de of about 40% (Fig. 3B) was only slightly lower than the de ob-
served in the absence of (S)-methyl mandelate, i.e. when starting

146
E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
Table 2
100
80
60
40
20
0
Enantioselective hydrogenation of activated ketones; standard conditions.
A
MBF injection
Ketone substrate Solvent
Pressure (bar) CD Activity
TOF (hꢀ1
ee (%)
MBF
)
REa
–
MBF
MBF
MBF
MBF
Toluene 10
Toluene 10
ꢀ
+
570
3500
530
–
6.1 92
AcOH
AcOH
10
10
ꢀ
–
–
+
3200
6.0 85
KPL
KPL
Toluene 50
Toluene 50
ꢀ
10,700
50,000
–
–
CDH2
+
4.7 82
EP
EP
Toluene
Toluene
2
2
ꢀ
335
870
–
–
+
2.6 78
2.1 h-1
a
1.6 h-1
RE corresponds to rate enhancement, related to the unmodified reaction.
Table 3
0
20
40
60
80
100
120
Effect of KPL or EP on the hydrogenation of CDH2 to CDH6 in toluene; standard
conditions.
time / min
Ketone substrate
H2 pressure (bar)
CD hydrogenation
60
50
40
30
20
10
0
TOF (hꢀ1
)
de (%)
A/B
(R)
MBF injection
B
–
KPL
50
50
3.2
4.2
18 (S)
68 (R)
37
15
Δ
de
–
EP
2
2
1.1
1.5
12 (S)
48 (R)
52
34
de
Table 4
de/%
Effect of methyl mandelate on the hydrogenation of CDH2 to CDH6 in toluene
(standard conditions, 10 bar).
Methyl mandelate additivea
CD hydrogenation
-10
-20
-30
TOF (hꢀ1
)
de (%)
A/B
–
(R)
(S)
Racemic
1.7
1.1
0.8
1.1
16 (S)
28 (R)
34 (S)
27 (R)
39
20
36
22
(S)
0
20
40
60
80
100
120
a
time / min
No conversion of methyl mandelate was detectable.
Fig. 2. Effect of methyl benzoylformate (MBF) addition after 30 min on the rate of
CDH2 conversion (A) and the diastereoselectivity of CDH6-A (B); standard condi-
tions, toluene, 10 bar. The numbers in the top part represent the TOF values of CDH2
hydrogenation before and after addition of MBF.
tion is a structure-insensitive, facile reaction [64], and no interac-
tion between the substrate adsorbed via the C@C bond and the
alkaloid is expected. Under standard conditions at 2 bar, the pres-
ence of CD diminished the reaction rate by a factor of 37 (Scheme
6). The missing interaction between CD and cyclohexene was con-
firmed by the analysis of the hydrogenation of CD: no significant
change in the reaction rate or the chemo- and diastereoselectivities
could be detected. This drop in reactivity of cyclohexene is in line
with the expectation that the alkaloid covers a great part of the
available Pt surface sites. Assuming a similar correlation in the
hydrogenation of MBF and KPL, we propose that the chiral modifier
may induce intrinsic rate acceleration by about two orders of mag-
nitude. This estimate is supported by the 98% ee in the hydrogena-
tion of ethyl benzoylformate [52,53], i.e. the (R)-mandelate may be
produced 99 times faster than the (S)-enantiomer.
Table 1
Effect of MBF on the hydrogenation of CDH2 to CDH6 (standard conditions, 10 bar).
Ketone substrate
Solvent
TOF (hꢀ1
)
Selectivity
de (%)
A/B
–
MBF
Toluene
Toluene
1.7
2.2
16
47
(S)
(R)
39
10
–
MBF
AcOH
AcOH
6.1
6.4
55
57
(R)
(R)
7.9
8.1
The study of the hydrogenation of CD under truly in situ reac-
tion conditions revealed the inverse phenomenon, the accelerated
hydrogenation of the modifier itself in the presence of the ketone
substrate. Cinchona alkaloids are not stable under the conditions
of ketone hydrogenation. The critical side reaction is the saturation
of the quinoline ring, the so-called anchoring unit, that weakens
the adsorption of the alkaloid on Pt and thus diminishes the
enantioselectivity [36–40]. In the weakly interacting solvent tolu-
ene, addition of the activated ketone substrate induced a small
but significant rate acceleration of the quinoline ring hydrogena-
tion. The extent of the ‘‘inverse ligand acceleration’’ was very sim-
modifier and these sites are not available for the hydrogenation of
the substrate.
In the hydrogenation of KPL and MBF, for which the reactions
are not distorted by side reactions, rate acceleration by a factor
of 4.7–6.1 was observed (Table 2). As mentioned earlier, the intrin-
sic rate acceleration related to the actual number of Pt surface sites
available for ketone hydrogenation after CD adsorption is un-
known. To estimate this value, we investigated the hydrogenation
of cyclohexene in the presence and absence of the alkaloid. This
simple unsaturated compound was chosen because its hydrogena-

E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
147
CDH2 on Pt
N
N
OH
H
H
SO(3)
SO(4)
H
H
OH
HO
HO
H
N
H
O
O
N
O
O
(S)-methyl mandelate
(R)-methyl mandelate
H2
H2
H
H
H
H
H
H
HO
H
H
N
N
HO
CDH6
R
S
N
N
H
H
(S)-A
(R)-A
34% de
28% de
Scheme 5. Adsorption and hydrogenation of CDH2 on Pt/Al2O3 in the presence of the products of MBF hydrogenation.
ilar in the hydrogenation of all three activated ketones, despite of
their different structure and the partly different conditions (2–
50 bar, Tables 1 and 3). In the presence of MBF, KPL, and EP, the
rate of the quinoline ring hydrogenation increased by 29%, 31%,
and 36%, respectively.
than in the case when CD is adsorbed alone. Note that these
assumptions require independent confirmation by, for example,
in situ spectroscopic measurements.
3.6. Conformation of cinchonidine on the Pt surface: mechanistic
considerations
The ‘‘inverse ligand acceleration’’ effect may be related to the
change in the adsorption mode of the alkaloid on the Pt surface.
Most experimental studies revealed adsorption via the quinoline
ring being in a tilted position relative to the Pt surface at suffi-
ciently high concentration in solution [12–14]. In contrast, the
majority of the mechanistic models developed for the hydrogena-
tion of activated ketones assume that in the interacting CD–ketone
complex, the quinoline ring is close to parallel to the metal surface
(see [1,34] and references therein). This adsorption mode has also
been supported by theoretical calculations. Thus, a plausible expla-
nation would be that the higher rate of quinoline hydrogenation is
due to the change in the adsorption geometry by interacting with
the ketone. This explanation is based on the assumption that the
hydrogenation rate increases when the quinoline ring is adsorbed
close to parallel to the Pt surface and decreases in a tilted or per-
pendicular position.
From a mechanistic point of view, the most important observa-
tion is the switch of the adsorption of CD from pro(S) to pro(R)
upon addition of the activated ketone substrate (Schemes 1 and
2). The same chiral switch was observed in the hydrogenation of
the alkaloid when the weakly interacting solvent toluene was re-
placed by acetic acid (Tables 1 and 3). A critical point is that hydro-
genation of CDH2 led to the same major diastereomer (R)-CDH6-A
during hydrogenation of the ketone substrate, independent of the
solvent. This is a confirmation that the adsorption of the modifier
in the presence of the substrate is controlled by the formation of
a defined modifier–substrate complex whose structure is barely af-
fected by the reaction conditions or the solvent. This interpretation
is in good agreement with the observation of the preferred forma-
tion of the same a-hydroxyester enantiomer regardless of the sol-
Using the same logic, the rate deceleration by 35–47% in the
vent (toluene, acetic acid).
hydrogenation of CD in the presence of the
a
-hydroxyester product
Several different models have been proposed for the origin of
(Table 4) may also be rationalized, assuming that the H-bonding
interaction between the OH function of the product and the quinu-
clidine N of the alkaloid (Scheme 5) favors an adsorption geometry
where the quinoline ring is more tilted relative to the Pt surface
enantioselection in the hydrogenation of a-ketoesters and other
activated ketones (see [1,34] and references therein). Most of these
models include a direct 1:1 interaction of the chiral modifier and
the substrate. A limitation of these concepts is that the exact con-

148
E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
100
80
60
40
20
0
100
A
A
MBF injection
MBF injection
MBF
80
MBF
60
CDH2
40
CDH2
1.8 h-1
20
1.8 h-1
1.2 h-1
1.0 h-1
0
0
20
40
60
80
100
120
0
20
40
60
80
100
120
time / min
time / min
60
50
40
30
20
10
0
(R)
(R)
MBF injection
B
MBF injection
B
50
40
30
20
Δ
de
Δ
de
de
de
de/%
de/%
-10
-20
-30
-40
(S)
0
20
40
60
80
100
120
0
20
40
60
80
100
120
time / min
time / min
Fig. 3. Competition between (S)-methyl mandelate and methyl benzoylformate
(MBF, added after 30 min) as indicated by the rate of CDH2 conversion (A) and the
diastereoselectivity of CDH6-A (B); standard conditions, toluene, 10 bar.
Fig. 4. Competition between (R)-methyl mandelate and methyl benzoylformate
(MBF, added after 30 min) as indicated by the rate of CDH2 conversion (A) and the
diastereoselectivity of CDH6-A (B); standard conditions, toluene, 10 bar.
formational structure of the modifier–substrate complex is mainly
based on assumptions or theoretical calculations and only sparsely
supported by direct in situ experimental observations [32]. The
remarkable effect of the ketone substrate on the rate and diastere-
oselectivity of CD hydrogenation offers useful hints concerning the
modifier–ketone interaction leading to enantioselection. The
observation of a significant rate of aromatic hydrogenation of CD
under these conditions, together with the ‘‘inverse ligand acceler-
ation’’ phenomenon, clearly disproves mechanistic models that as-
sume a modifier–substrate complex without adsorption of the
quinoline unit of CD nearly parallel to the Pt surface. This is the
case with Margitfalvi’s ‘‘shielding model’’ [65–67]. According to
any mechanistic concept that adopts tilted or perpendicular
adsorption of the quinoline ring of the alkaloid [68].
Note that the preferred pro(R) adsorption of CD at C(40) in the
presence of ketones stands in contrast to recent results by DFT cal-
culations, which suggested that the most stable modifier–substrate
complex on Pt is an SO(4) conformation {C(40) pro(S)} of the mod-
ifier [30]. This disagreement indicates the obvious limitation of
theoretical calculations in a complex system where the interaction
of five reaction components: substrate, modifier, metal surface,
hydrogen, and solvent has to be determined.
The similar observations in the presence of three different sub-
strates (MBF, EP, KPL) indicate that the conformational structure of
this modifier–substrate complex is a general property, at least for
this model the
a-ketoester substrate forms an adduct with CD
and this adduct is adsorbed on Pt, where the substrate is located
between the Pt surface and the alkaloid modifier with the quino-
line ring being in a strongly tilted position relative to Pt. Clearly,
this fixed conformation of CD does not allow hydrogenation of
the quinoline ring and the presence of the substrate should lead
to rate deceleration, not rate acceleration. It is more likely that
CD is adsorbed via its quinoline moiety being nearly parallel to
the use of a-ketoester and a-ketolactone substrates. This interpre-
tation is supported by the striking similarities of such substrates in
terms of their hydrogenation activity and enantioselectivity, i.e. all
substrates are hydrogenated with an enhanced rate to high excess
of the (R)-alcohol in the presence of CD [51,54]. An extension of
this work to other solvents and cinchona alkaloids, and also to
structurally different substrates such as 1,1,1-trifluoromethyl ke-
tones [69] is, however, necessary to evaluate the nature of the
modifier–substrate interaction [34,70,71] more closely.
the Pt surface (p-bound), a prerequisite for the aromatic hydroge-
nation (Scheme 4). Analogous arguments can be applied against

E. Schmidt et al. / Journal of Catalysis 272 (2010) 140–150
149
TOF = 6.3 s-1 without CD
TOF = 0.17 s-1 with CD
Pt/Al2O3, H2
toluene, 2 bar, 298 K
Scheme 6. Hydrogenation of cyclohexene on CD-modified Pt/Al2O3 and in the absence of CD.
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We have shown that hydrogenation of CD, a well-known com-
peting reaction during enantioselective hydrogenation on Pt-group
metals, can be used as a ‘‘probe’’ to elucidate the conformation of
the alkaloid on the metal surface during its interaction with the
substrate. This experimental strategy was applied in the enantiose-
lective hydrogenation of
a-ketoesters and an a-ketolactone. The
study revealed that the adsorption geometry of the chiral modifier
is strikingly different in the presence or absence of the substrate,
but the hydrogenation products and the solvent possessing a polar
functional group may also induce conformational changes. Among
these interactions, binding with the activated ketone substrate is
clearly preferred, which relation is of fundamental importance in
achieving high ee even at high conversion of the ketone.
As a result of the strong modifier–substrate interaction, both
molecules are hydrogenated faster and with different selectivity
than in the absence of their binding partner. From the point of view
of the hydrogenation of the activated ketone such rate acceleration
(‘‘ligand acceleration’’) and the high ee up to 98% are well known.
The concomitant hydrogenation of the aromatic anchoring unit of
the modifier undergoes a rate acceleration by about 30% (‘‘reverse
ligand acceleration’’) and a remarkable inversion of the diastere-
oselectivity from (S)- to (R)-CDH6-A (Scheme 4). We show that
interaction of CD with the ketone substrate inverts the dominant
adsorption mode of the modifier from pro(S) to pro(R) at C(40)
(Scheme 1). The probable origin of the ‘‘reverse ligand accelera-
tion’’ is a change in the conformation of the quinoline ring relative
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pro(R) conformation at C(40) (most likely SO(3)).
The study revealed the formation of an almost identical modi-
fier–substrate complex in case of three structurally different sub-
strates (MBF, EP, KPL) and the conformational structure of this
modifier–substrate adduct was not affected by the reaction
conditions.
Another important conclusion emerging from this work is that
investigation of the adsorption and interaction of modifier and
substrate by theoretical calculations or spectroscopic methods un-
der not truly in situ conditions has inherent limitations in provid-
ing a useful bases for mechanistic studies in such a complex
system.
The approach of using the competing hydrogenation of the chi-
ral modifier as a probe to characterize the adsorption of the mod-
ifier and its interaction with the substrate during reaction can
probably be extended to other modifiers, substrates, and metals,
and it may provide fundamentally new information for mechanis-
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Acknowledgment
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Financial support by the Swiss National Science Foundation is
kindly acknowledged.
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