New data to the origin of rate enhancement on the Pt-cinchona catalyzed enantioselective hydrogenation of activated ketones using continuous-flow fixed-bed reactor system

Article abstract of DOI:10.1016/j.jcat.2008.10.004

A study on the origin of rate enhancement (RE) in the enantioselective heterogeneous catalytic hydrogenation of methyl benzoylformate (MBF), ketopantolactone (KPL) and pyruvic aldehyde dimethyl acetal (PA) under the Orito reaction conditions over Pt catalyst modified with parent cinchona alkaloids, as compared to the unmodified catalyst is presented. The hydrogenations were carried out in continuous-flow fixed-bed reactor system over 20-100 mg Pt/Al₂O₃ catalyst in 1 mL min^-1 flow of toluene/acetic acid 9/1 solvent mixture under 40-80 bar H₂ pressure, at 283 or 293 K using 0.044-2 mM modifier concentration and 45 mM substrate concentration. Our results obtained using racemic hydrogenations followed by three changes of the chiral modifier (on the same catalyst) supported the so-called "ligand acceleration" phenomenon in the enantioselective hydrogenation of activated ketones such as MBF, KPL and PA. In our opinion, RE produced by the first modifier added after racemic hydrogenation can also be explained by the purifying effect of the cinchona. REs observed following further exchanges of modifiers are indicative of the intrinsic character of the phenomenon. This research suggested that the origin of enantiodifferentiation and rate enhancement is the same, namely, both may be traced back-probably in different ways-to the role of the intermediate complexes of the hydrogenation, to its formation and transformation, which in turn depends on numerous factors.

Full text of DOI:10.1016/j.jcat.2008.10.004

Journal of Catalysis 260 (2008) 245–253
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Journal of Catalysis
www.elsevier.com/locate/jcat
New data to the origin of rate enhancement on the Pt-cinchona catalyzed
enantioselective hydrogenation of activated ketones using continuous-flow
fixed-bed reactor system
György Szöllo˝si a,∗, Szabolcs Cserényi b, Ferenc Fülöp a,c, Mihály Bartók a,b,∗
a
Stereochemistry Research Group of the Hungarian Academy of Sciences, Dóm tér 8, H-6720 Szeged, Hungary
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u 6, H-6720 Szeged, Hungary
b
c
a r t i c l e i n f o
a b s t r a c t
study on the origin of rate enhancement (RE) in the enantioselective heterogeneous catalytic
Article history:
A
Received 18 August 2008
Revised 6 October 2008
Accepted 6 October 2008
Available online 31 October 2008
hydrogenation of methyl benzoylformate (MBF), ketopantolactone (KPL) and pyruvic aldehyde dimethyl
acetal (PA) under the Orito reaction conditions over Pt catalyst modified with parent cinchona alkaloids,
as compared to the unmodified catalyst is presented. The hydrogenations were carried out in continuous-
−1
flow fixed-bed reactor system over 20–100 mg Pt/Al2O3 catalyst in 1 mL min
flow of toluene/acetic
acid 9/1 solvent mixture under 40–80 bar H2 pressure, at 283 or 293 K using 0.044–2 mM modifier
concentration and 45 mM substrate concentration. Our results obtained using racemic hydrogenations
followed by three changes of the chiral modifier (on the same catalyst) supported the so-called “ligand
acceleration” phenomenon in the enantioselective hydrogenation of activated ketones such as MBF, KPL
and PA. In our opinion, RE produced by the first modifier added after racemic hydrogenation can also be
explained by the purifying effect of the cinchona. REs observed following further exchanges of modifiers
are indicative of the intrinsic character of the phenomenon. This research suggested that the origin of
enantiodifferentiation and rate enhancement is the same, namely, both may be traced back—probably
in different ways—to the role of the intermediate complexes of the hydrogenation, to its formation and
transformation, which in turn depends on numerous factors.
Keywords:
Asymmetric hydrogenation
Platinum
Cinchona alkaloids
Methyl benzoylformate
Ketopantolactone
Pyruvic aldehyde dimethyl acetal
Continuous-flow fixed-bed-reactor
Origin of rate enhancement
Ligand acceleration
© 2008 Elsevier Inc. All rights reserved.
1. Introduction
and rate enhancement (RE) in this context. The investigations on
the mechanism of the reaction used mostly ethyl pyruvate (EP) as
model substrate. One of the basic starting points of the studies on
EP was the observation that the modified reaction is 20–100 times
faster than the unmodified reaction [28–31]. The recognition of RE
led to application of the concept of ligand accelerated (LA) catalysis
to the Orito reaction, introduced for the enantioselective homoge-
neous transformations in solution: “A reaction is considered ligand
accelerated if there is a slower unmodified (unselective) cycle and
a faster modified (selective) cycle [29].” “It also appears from the
pertinent literature that research groups involved in this research
agree that RE and enantiodifferentiation are closely connected ef-
fects and should be discussed together” [32].
The so-called CD:EP 1:1 interaction model [28–36] has been
accepted for many years for the interpretation of RE and enantio-
differentiation. Based on this model, the interpretation of RE has
been supplemented and corrected [37–41], which has also been
included in the reviews discussing the Orito reaction [21,26,27,32,
38,42–48]. Reviews that do not deal with this subject have also
been published [22,49,50]. In connection with ligand acceleration,
it is important to recall the observation made by Baiker’s group in
1992: “. . . rate acceleration and chiral induction may not be of the
The most important aim of the organic catalytic research is the
improvement of the reactions selectivities (e.g. [1–6]). Nowadays,
ensuring high optical purities in asymmetric catalytic synthetic
transformations is also of increased significance. Two of the most
intensively studied heterogeneous enantioselective catalytic reac-
tions are the enantioselective hydrogenations of C=O and C=C
bonds containing compounds on Pt and Pd catalysts modified by
cinchona alkaloids (Orito reaction [7], Scheme 1) and hydrogena-
tion on Ni catalysts modified by tartaric acids [8–12]. The Orito
method allows the realization of enantiomeric excess (ee) as high
as 90–98% for certain compounds [13–20]. As a result of exten-
sive investigations many details of the reaction became known.
Progress has been reported in several reviews (since 2005 [21–27]).
The main objective of the recent studies on the Orito reaction
has been to expand its field of utilization, to elucidate the reaction
mechanism and to interpret the origin of enantiodifferentiation
Corresponding author.
*
E-mail address: bartok@chem.u-szeged.hu (M. Bartók).
0021-9517/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2008.10.004

246
G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
Scheme 1. The Orito reaction.
same origin, although they appear to be correlated” [51], which
has apparently not caught the readers’ attention. In the coming
years, however, experimental data were published on situations
where high ee values were attained even though there was no
great difference between the rates of racemic and enantioselective
hydrogenations [45,52–60]. Moreover in the gas phase hydrogena-
tion the Pt–CD chiral catalyst showed a decrease in reaction rate
compared to the unmodified catalyst [61].
tion. In our opinion the results obtained in the hydrogenation of
methyl benzoylformate (MBF), ketopantolactone (KPL) and pyruvic
aldehyde dimethyl acetal (PA) as substrates using continuous-flow
fixed-bed reactor (CFBR) system under reaction conditions gener-
ally applied for the Orito reaction confirmed the intrinsic feature
of RE observed in this heterogeneous catalytic reaction.
2. Experimental
These experimental observations as well as catalyst deactiva-
tion due to decomposition and oligomerization of EP in the ab-
sence of CD and/or H2 [62–68] led to the suggestion that the
origin of RE should be interpreted on the basis of a model other
than the one based on ligand acceleration. Experimental evidence
for this hypothesis was published by Jenkins et al. in 2005 [69]
and Toukoniitty and Murzin in 2006 [70]: “Rate enhancement in
the presence of an alkaloid modifier is attributed to the inhibi-
tion of pyruvate ester polymerization at the Pt surface and results
from reaction occurring at a normal rate at an increased num-
ber of sites, not (as was once thought) to reaction occurring at
an enhanced rate at a constant number of sites” [69]. “The enan-
tiodifferentiating interactions that induce ee occur between EP and
CD whereas the ligand acceleration originates from CD’s ability to
hinder side reactions, leading to EP decomposition and catalyst de-
activation” [70].
2.1. Materials
MBF, PA, KPL, parent cinchona alkaloids (CD, CN, QN, QD) and
solvents were from Aldrich or Fluka, and used as received, ex-
cept MBF (b.p. 391–393 K at 5 Hg mm) and PA (b.p. 325–327 K at
25 Hg mm) were distilled in vacuum using Vigreaux-column. From
the catalyst pretreatment methods (high temperature, ultrasound
[76–78]) we have used the former method. The catalyst, Engelhard
5% Pt/Al2O3 (E4759) was pretreated in a fixed-bed reactor by flush-
−1
ing with 30 mL min
He at 300–673 K for 30 min then hold in
−1
30 mL min
H2 at 673 K for 100 min. After cooling to room tem-
perature in H2, the catalyst was flushed with He for 30 min and
was stored under air until use. Merck 101097 aluminum oxide 90
was used to fill the catalyst cartridge.
The conclusions drawn in refs [69,70] were followed by a de-
bate [71–74] with the following main conclusion according to
Mallat and Baiker: “We believe that the chiral modifier induces
enantioselection and intrinsic rate acceleration in the Pt-catalyzed
hydrogenation of various activated ketones” [74]. In our opinion
the experimental data leading to the two different standpoints are
not easy to compare, either because catalysts of different types
were studied [69], or because the data were obtained under exper-
imental conditions significantly different from those of the Orito
reaction (e.g. gas phase [61], low concentration of EP [70]). It has
to be noted that, in contrast to his earlier view [70], Murzin very
recently comments on the kinetic character of RE [75].
Nearly simultaneously with the debate, a review was published
by Blaser and Studer entitled “Cinchona-Modified Platinum Cat-
alysts: From Ligand Acceleration to Technical Processes” [26], in
which the authors maintain their earlier standpoint on the role of
LA in the enantioselective heterogeneous catalytic hydrogenation
of activated ketones: “Kinetic studies aimed at understanding the
mode of action of the catalyst revealed that the cinchona mod-
ifier not only renders the catalyst enantioselective but strongly
accelerates the hydrogenation. This was the first case of ligand ac-
celeration with a heterogeneous catalytic system.”
2.2. Hydrogenations in CFBR system
Continuous hydrogenations were carried in H-Cube high-pres-
sure continuous-flow system purchased from Thales Nanotech-
nology Inc. [79]. The experimental set-up has been described in
previous publications [80,81]. In the tubular catalyst cartridge of
2 mm inner diameter and 30 mm length the given amount of
catalyst was placed and was filled with additional alumina. The
catalyst was rinsed 0.5 h with 1 mL min
−1
flow of toluene/AcOH
9/1 solvent mixture followed by 0.5 h pretreatment with H2 in
the same solvent. After the racemic hydrogenation the reactant
and the first modifier were dissolved in the solvent and this solu-
tion was delivered to the hydrogenation system via a HPLC pump
(Knauer WellChrom HPLC-pump K-120) mixed with H2 under the
desired pressure and passed through the catalyst bed obtaining
an ascendant flow of the reaction components. The catalyst car-
tridge holder was externally cooled to the desired temperature.
The modifier was changed by replacing the solutions delivered to
the pump. Samples of 1 mL were taken at regular time intervals
from the product flow and analyzed [80,81]. Standard conditions
were: 50 mg E4759 catalyst, solvent: toluene/AcOH 9/1, liquid flow
1 mL min−1, modifier concentration 0.044 mM, substrate concen-
tration 45 mM, 80 bar H2 pressure, 283 2 K.
The objective of the present manuscript is to produce further
experimental data for elucidate the origin of RE in the Orito reac-

G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
247
2.3. Product analysis
CN and QD as chiral modifiers, Baiker et al. took their stand in
favor of the intrinsic character of RE [72].
The products were identified by mass spectrometric (HP 6890 N
GC-HP 5973 MSD, HP-1MS, 60 m capillary column) analysis. Con-
versions and enantiomeric excesses, ee% = ([R] − [S]) × 100/([R] +
[S]), were determined by gas chromatography (HP 6890 N GC-FID,
30 m long Cyclodex-B chiral capillary column). Retention times
(min): KPL 398 K, 21.65 psi He: 10.6 of (S)-PL, 11.2 of (R)-PL; MBF
383 K, 25 psi He: 21.7 of MBF, 29.9 of (R)-MM, 30.9 of (S)-MM;
PA 338 K, 21.65 psi He: 5.2 of PA, 8.6 of (R)-LA, 9.1 of (S)-LA. The
reproducibility was 2%. Turnover frequencies (TOF, h−1) were cal-
culated as described in a recent publication [72]. Transformation of
the cinchona alkaloids was checked by ESI-MS measurements (AG-
ILENT 1100 LC-MSD TRAP SL ion-trap MS) operated under positive
ion and auto MS-MS mode as described earlier [63,64].
3.1. Studies on MBF hydrogenation (Figs. 1 and 2)
The enantioselective hydrogenation of MBF is shown in Sche-
me 2. Some of the relevant results of our experiments on MBF
hydrogenation are summarized in Figs. 1 and 2. Under the given
standard experimental conditions, good mass transport was en-
sured in the system under a H2 pressure of 80 bar. In the case
of CD feeding the conversion was over 90%. Experiments using
catalyst E4759 or its crushed form also indicated good mass trans-
fer, which plays a determinant role especially in enantioselective
liquid-phase heterogeneous catalytic hydrogenations [84,85].
Figs. 1 and 2 clearly demonstrate the occurrence of RE in the
enantioselective hydrogenations, similar to the case of EP [72], rec-
ognized already in the initial phase of the experiments [28–31]. In
CFBR studies on the origin of RE we made use of the transient be-
havior of the cinchonas CD, CN and QN in the hydrogenation of
MBF. High ee was to be expected only at nearly 100% conversion,
when changes in RE are difficult to detect at the time of the re-
placement of the chiral modifier [72]. Because of the well-known
effect of the adsorption strength of cinchonas on RE [27,86–88],
hydrogenation conditions allowing easy determination of the effect
of the replacement of the chiral modifier on RE had to be chosen.
This means somewhat lower conversion, which can be achieved by
3. Results and discussion
We studied the enantioselective hydrogenation of MBF, KPL and
PA in CFBR using the transient method, under experimental con-
ditions similar to those employed by Baiker’s group [72,82]. The
essence of the transient method is the serial replacement of the
cinchona alkaloids serving as chiral modifiers in continuous-flow
hydrogenation with others that produce the opposite enantiomer.
Continuous sampling allows the determination of changes in ee
and conversion. Measurement series were started over unmodified
catalyst. After certain time, racemic hydrogenation was followed by
the addition of the first cinchona, and continued by replacement of
the first one with a second and later with a third one.
The activated ketones to be hydrogenated can be classified into
two groups based on their stabilities under the conditions of the
Orito reaction. PA, like EP, is a compound capable of enolization;
MBF and KPL, however, are not. The products of enolization and
of the oligomerization and other transformations of α-methyl ke-
tones are well-known catalyst poisons [62–68], and this deactiva-
tion leads to a considerable decrease in enantiodifferentiation and
RE. We used the experiences described in [72] for minimizing side
reactions, i.e. deactivation. The H-Cube instrument, however, did
not allow independent modifier flows as described in Ref. [72]. In
contrast to Refs. [67,72], the solvent we used was a 9/1 mixture
of toluene/AcOH rather than AcOH, in order to avoid the poten-
tial effects of the structural materials of the H-Cube instrument.
This circumstance, however, did not prevent the most important
conclusions to be drawn, as seen later. The purity of the initial
compounds, the conversion of cinchona alkaloids in the course of
hydrogenation and the role of potential side reactions were studied
by ESI-MS and GC-MS methods.
applying lower H2
pressure or less catalyst (see also for KPL). Un-
der such conditions some limitation in mass transfer might occur
but, in our opinion, that would not affect the most important con-
clusions.
The initial conversion in racemic hydrogenation depends on the
surface condition of the catalyst. Earlier, it was found that, fol-
lowing the high-temperature pretreatment, the catalyst surface is
altered upon standing [16,78]. In addition to freshly pretreated
catalyst (e.g. Fig. 1b), we also used catalyst pretreated 1–3 days
earlier (e.g. Fig. 1a) that resulted in lower initial conversion. In the
racemic hydrogenation the continuous decrease of conversion sug-
gest catalyst deactivation. The larger conversion of enantioselective
hydrogenation as compared to racemic hydrogenation points to the
importance of the purifying effect of chiral modifiers and/or to the
role of the LA concept. These experimental results, however, do not
allow differentiation between the two phenomena.
After 40 min hydrogenation over unmodified catalyst (racemic
hydrogenation) in case of enantioselective hydrogenation the
change of the sense of chirality by replacing CD with CN and again
with CD and using the opposite order, that is change of CN to CD
and again to CN are shown in Figs. 1a and 1b. The figures show not
only the changes in the ee but also in the conversions. From ∼90%
(R)-MM in presence of CD the ee changed to ∼60% (S)-MM when
CN was fed and then schifted again to ∼90% (R)-MM as effect of
feeding CD for the second time.
CFBR measurements were started with EP [83], the most com-
monly used model compound in the Orito reaction. The objective
of these experiments was to demonstrate the suitability of the
H-Cube hydrogenator for studying the LA phenomenon using the
procedure described by Baiker et al. [72]. The data supplied by
the experiments on EP hydrogenation made possible the selection
of the experimental conditions [83]. Based on experiments using
high-purity EP and assumedly preventing the oligomerization and
decomposition of EP (although it cannot be established what ex-
actly happens on the catalyst surface) in their studies using CD,
Changes in conversion due to feeding of various modifiers are
easily detected: starting from ∼50% conversion in racemic hydro-
genation, the addition of CD increases the conversion to ∼90% (i.e.
a significant RE is observed). The conversion of enantioselective
hydrogenation is somewhat reduced by CN and is again increased
by CD feeding (Fig. 1a). Similar changes in ee and conversion can
Scheme 2. Asymmetric hydrogenation of methyl benzoylformate (MBF) over Pt/Al2O3 modified by parent cinchona alkaloids.

248
G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
(a)
(b)
Fig. 1. Transient behavior in MBF hydrogenation using CFBR: changes in conversion (") and enantioselectivity (Q) by addition—after racemic hydrogenation—of CD followed
by CN and again CD (a), and in opposite order (b) using 0.44 mM modifier concentration (otherwise standard conditions, (a) over catalyst stored for 3 days after pretreatment,
(b) over freshly pretreated catalyst).
(a)
(b)
Fig. 2. Transient behavior in MBF hydrogenation using CFBR: changes in conversion (") and enantioselectivity (Q) by addition—after racemic hydrogenation—of QN followed
by CN and again QN (a), and in opposite order (b), for reaction conditions see Fig. 1 ((a) over freshly pretreated catalyst and (b) over catalyst stored for 1 day).
also be observed in the racemic–CN–CD–CN measurements series.
Again in this case, the highest conversion is observed in the case of
CD feeding: CDconv. > CNconv. > racconv.. Since, according to earlier
results, the reaction rate is proportional to the adsorption strength
of cinchonas [27,86–88], these measurements also confirm the ad-
sorption strength order: CD > CN.
In our opinion the measurement series presented in Figs. 1a
and 1b justifies the assumption of the intrinsic character of RE.
In order to interpret RE brought about by CN feeding following
racemic hydrogenation (Fig. 1b), one may suppose that RE is a
consequence of the so-called purifying effect by CN. However, REs
elicited by the effect of subsequently added CD and CN, are in-
dicative of an intrinsic phenomenon, because the suppression of
catalyst deactivation of cinchona alkaloids cannot be so different
for the individual cinchonas, i.e. it cannot show a regularity of this
kind.
Similar interpretations of the racemic–QN–CN–QN and the
racemic–CN–QN–CN measurement series (Figs. 2a and 2b) and

G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
249
Scheme 3. Asymmetric hydrogenation of ketopantolactone (KPL) over Pt/Al2O3 modified by parent cinchona alkaloids.
drogenation produced (R)-PL in 60% ee and the subsequent CN
feeding yielded (S)-PL in ∼45% ee, followed by another inversion
on feeding again CD. Conversion is modified slightly (since even
the conversion in racemic hydrogenation is close to 100%) but per-
ceptibly by the various feeding sequences. Identical changes in ee
and conversion values can also be observed in the racemic–CN–
CD–CN measurement series. The hydrogenation is the fastest on
CD-modified catalyst, somewhat slower in the case of CN and the
slowest on unmodified catalyst (racemic hydrogenation). Thus, RE
also occurs in the enantioselective hydrogenation of KPL.
Important conclusions can be drawn from the experiments us-
ing QN–CN cinchona pair (Figs. 4a, 4b and 4c). Changes in conver-
sion are more obvious in these runs than as presented in Fig. 3,
which spectacularly showed and consequently demonstrated the
changes in RE caused by different cinchona alkaloids, in accor-
dance with the adsorption abilities of cinchona–KPL complexes.
The course of all measurement series (the slopes of the curves)
clearly show that CD replaces, i.e. desorbs CN from the Pt sur-
face faster than vice versa, and CN desorbs QN from the surface
faster than vice versa. By reusing the catalyst (Fig. 4b), the racemic
hydrogenation that followed the measurement series presented in
Fig. 4a showed some residual ee (the wash with MeOH was too
short). After the measurement series shown in Fig. 4b, the cat-
alyst was washed with MeOH for 2 h and the subsequent reuse
(Fig. 4c) in racemic hydrogenation no more indicated the presence
of any active chiral centers. In our opinion the measurement se-
ries in Figs. 4a, 4b and 4c convincingly demonstrate that—similarly
to MBF—in addition to the purifying effect of cinchonas, LA is also
present in RE.
Fig. 3. Transient behavior in KPL hydrogenation using CFBR: changes in conversion
(") and enantioselectivity (Q) by addition—after racemic hydrogenation—of CD fol-
lowed by CN and again CD under 40 bar H2 pressure, at 293 2 K and over 30 mg
catalyst (otherwise standard conditions).
combination with the conclusions of the measurements shown
in Figs. 1a and 1b yielded the adsorption strength order: CD >
CN > QN, which is not identical with the order established for
EP hydrogenation under similar conditions (CD > QN > CN) [83].
The difference is presumably due to the different properties of the
complexes formed by cinchona alkaloids adsorbed on the catalyst
surface and the substrates to be hydrogenated.
The TOF values calculated from the data series presented in
Fig. 4a showed well that the as effect of QN the TOF increased with
∼20% compared with the racemic hydrogenation, which further
varied with ∼10–10% on subsequent CN and QN feeding. In our
opinion in the first TOF enhancement both the so-called purifying
effect of the cinchona alkaloid and the LA played role, while the
subsequent changes in the TOF may be ascribed to LA. To sum up
the above, the order of conversions is: CDconv. > CNconv. > QNconv.
,
3.2. Studies on KPL hydrogenation (Figs. 3 and 4)
and that of adsorption strength is CD > CN > QN, an order that is
identical with that identified for MBF (Section 3.1.) and different
from that observed in the course of EP hydrogenation [83].
The enantioselective hydrogenation of KPL is illustrated in
Scheme 3. Experimental evidence to date [87,89] showed that,
among activated ketones, hydrogenation of KPL is the fastest.
Therefore conditions significantly milder than those used for MBF
had to be chosen in order to be able to follow and evaluate the
conversions of hydrogenation in the presence and absence of vari-
ous modifiers. As shown in Fig. 3, conversions exceeded 90% even
under these milder conditions. The use of KPL “as received” usu-
ally allows ee values of 50–60% to be attained in hydrogenations
in toluene/AcOH 9/1. In the representative figures selected from
numerous measurement series the 60 min racemic hydrogenation
on prehydrogenated catalyst was followed by hydrogenations on
modified catalysts, also 60 min each.
3.3. Studies on PA hydrogenation (Figs. 5 and 6)
The enantioselective hydrogenation of PA is outlined in Sche-
me 4. PA is a special case of the hydrogenation of activated ketones
under the conditions of the Orito reaction, in as much as enantios-
elective hydrogenation in this case is associated with high ee even
at low reaction rates [15,16,90,91]. Ee values of over 90% can be
attained on Pt modified by either of the four parent cinchonas in
AcOH [20,91], whereas hydrogenation in toluene produces signif-
icantly lower ee values (50–60%). Because of this, in the solvent
mixture chosen for these studies (toluene/AcOH 9/1) ee values ex-
ceeding 90% were not expected; however, to allow comparison
with the other substrates, it was expedient to adhere to the above
solvent mixture. Because of the slow hydrogenation rate of PA,
Similarly to Section 3.1, Figs. 3 and 4 represent the conver-
sions and ee values of the measurement series racemic–CD–CN–CD
(Fig. 3), racemic–QN–CN–QN (Figs. 4a and 4b) and racemic–CN–
QN–CN (Fig. 4c). Fig. 3 reveals that CD feeding after racemic hy-

250
G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
(a)
(b)
(c)
Fig. 4. Transient behavior in KPL hydrogenation using CFBR: changes in conversion (") and enantioselectivity (Q) by addition—after racemic hydrogenation—of QN followed
by CN and again QN (a,b), and in opposite order (c) (for reaction conditions see Fig. 3, using (a) fresh catalyst, (b) reused after (a) series and (c) reuse after (b) series).
however, conditions somewhat more stringent than those applied
in the previous cases were needed, namely a larger amount of cat-
alyst (100 mg), a higher cinchona concentration (1–2 mM) and
a higher temperature (293 instead of 283 K) to accelerate prod-
uct desorption. These were the problems that were highlighted by
the measurement series outlined in Figs. 5a and 5b, in which a
cinchona concentration of 0.044 mM was used. In Fig. 5a the un-
expected decrease in ee brought about by the time on stream over
QN- and QD-modified catalyst is, in our opinion, a consequence of
slow product desorption. The high ee observed after the 160 min
reaction time elicited by CD feeding and the maximal conversion
on Pt over the entire measurement cycle are quite conspicuous
(Fig. 5a). The situation was somewhat improved by slightly in-
creasing the temperature (Fig. 5b), but ee decreased and at the
end of the measurement series, conversion decreased even relative
to racemic hydrogenation (from 17 to 11%), due to the relatively
long reaction time and, more importantly, to the higher tempera-
ture. The course of RE in the presence of the four parent cinchonas,
however, appears very characteristically even in these preliminary
experiments.
In view of the fact that RE is well detectable in PA hydro-
genation catalyzed by Pt–CD and Pt–CN (Figs. 5a and 5b), further
experiments were performed on the Pt–CN–Pt–QN catalyst system.
Experimental parameters (temperature, modifier concentration, H2

G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
251
Scheme 4. Asymmetric hydrogenation of pyruvaldehyde dimethyl acetal (PA) over Pt/Al2O3 modified by parent cinchona alkaloids.
(a)
(b)
Fig. 5. Transient behavior in PA hydrogenation using CFBR: changes in conversion (") and enantioselectivity (Q) by addition—after racemic hydrogenation—of QN followed
by QD, CD and finally by CN at 283 2 K (a), or addition of CD followed by CN, QN and QD at 293 2 K (b) over 100 mg catalyst (otherwise standard conditions).
pressure, reaction time) were varied in order to optimize the re-
action conditions; two characteristic measurement series are pre-
sented in Figs. 6a and 6b. Maximal conversions attained are in the
range of 50–60%; the ee value for Pt–CD was ∼75% (R), whereas
in the case of Pt–CN catalyst formation of the (S) enantiomer in
a somewhat lower ee was observed. In the present case, mea-
surement series consisted 40 min cycles, i.e. a 40 min racemic
hydrogenation was followed by 40 min hydrogenations on various
modified catalysts. Fig. 6a and 6b show changes in the conversion
and ee values of the racemic–QN–CN–QN and racemic–CN–QN–CN
measurement series, respectively, as a function of time on stream.
Changes in conversion on Pt–CN and Pt–QN catalysts are less spec-
tacular than those observed in the case of MBF and KPL. By the
evidence of the two measurement series it appears as if hydro-
genation on Pt–CN catalyst proceeded at a slightly higher conver-
sion than on the Pt–QN catalyst.
Although the catalyst is strongly deactivated in the course of
the time on stream—probably because of the enolization tendency
of PA—the occurrence of RE relative to racemic hydrogenation,
however, is unambiguous also in the case of PA. We think that be-
cause of the multiply-proven differences between the adsorption
strengths of cinchonas, the intrinsic character of RE cannot be ex-
cluded neither in case of PA. It is remarkable that in the course of
racemic hydrogenation, conversion is not changed during the time
on stream, even though it is slightly and continuously decreas-
ing in the entire range studied (160–280 min), whereas changes
in conversion over modified catalyst show a picture compatible
with the intrinsic character of RE. In our opinion the change in
RE brought about by different cinchonas can be interpreted on the
basis of its intrinsic character. To sum up we obtained the conver-
sion order: CD > CN > QN > QD and the same order of adsorption
strength values: CD > CN > QN > QD, respectively, an order nearly
identical with that determined for MBF and KPL.
4. Conclusion
Hydrogenation results obtained under the generally utilized
experimental conditions of the Orito reaction, in the CFBR sys-
tem, with methyl benzoylformate, ketopantolactone and pyruvic
aldehyde dimethyl acetal substrates on modified and unmodified
Pt catalyst, in racemic–cinchona 1–cinchona 2–cinchona 1 mea-
surement series confirm the intrinsic nature of RE. The order of
the conversions of the hydrogenations taking place on unmodi-
fied (Ptum) and modified catalysts (Pt–CD, Pt–CN, Pt–QN, Pt-QD)
is the following: Pt–CD > Pt–CN > Pt–QN > Pt–QD > Ptum. In our
opinion such a regular dynamics of the changes in conversions as
observed in the presented measurements series is caused by the
certain cinchona alkaloids. Consequently, these new experimental
data presented in this manuscript not only suggest the validity of
the LA based interpretation of RE [29], but also confirm its gen-
eral character in the conditions of the Orito reaction. As regards
the results presented in Refs. [69,70], they reflect phenomena tak-
ing place under conditions other than those of the Orito reaction,
which are also able to elucidate many of the experimentally ob-
served effects.

252
G. Szöllo˝si et al. / Journal of Catalysis 260 (2008) 245–253
(a)
(b)
Fig. 6. Transient behavior in PA hydrogenation using CFBR: changes in conversion (") and enantioselectivity (Q) by addition—after racemic hydrogenation—of QN followed
by CN and again QN (a), and in opposite order (b) using 2 mM modifier concentration, at 293 2 K, over 100 mg catalyst (otherwise standard conditions).
Manifold studies carried out to date have verified that in the
Orito reaction (i) cinchona alkaloids inhibit the deactivation of the
Pt catalyst, (ii) they form chiral surface active sites and (iii) surface
intermediate complexes with the substrate. These three effects of
cinchonas are responsible for enantioselection and RE. The contri-
bution of these three effects to chiral induction and RE depend on
numerous, probably as yet unknown factors. The role of any of the
above effects cannot be doubted. Based on the results to date, in
our opinion the novel experimental data published in the present
manuscript confirm that LA cannot be excluded from the interpre-
tation of RE occurring in the Orito reaction.
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Acknowledgments
Financial support by the Hungarian National Science Fundation
(OTKA Grants T 048764 and K 72065) is highly appreciated.

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