Steric and electronic effects in the enantioselective hydrogenation of activated ketones on platinum: Directing effect of ester group

Article abstract of DOI:10.1016/j.jcat.2006.02.001

Steric effects in the Pt-catalyzed asymmetric hydrogenation of nine different α-ketoesters were studied by variation of the bulkiness at the keto and ester side of the substrates, and by using cinchonidine (CD), its 6′-methoxy derivative quinine, and o-ph

Full text of DOI:10.1016/j.jcat.2006.02.001

Journal of Catalysis 239 (2006) 255–262
www.elsevier.com/locate/jcat
Steric and electronic effects in the enantioselective hydrogenation of
activated ketones on platinum: Directing effect of ester group
Simon Diezi, Sven Reimann, N. Bonalumi, Tamas Mallat, Alfons Baiker ∗
Institute of Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Hönggerberg, HCI, CH-8093 Zurich, Switzerland
Received 19 December 2005; revised 1 February 2006; accepted 2 February 2006
Available online 6 March 2006
Abstract
Steric effects in the Pt-catalyzed asymmetric hydrogenation of nine different α-ketoesters were studied by variation of the bulkiness at the keto
ꢀ
and ester side of the substrates, and by using cinchonidine (CD), its 6 -methoxy derivative quinine, and o-phenyl derivative PhOCD as chiral
modifiers. In the presence of CD, the (R)-enantiomer always formed in good to high ee (up to 96%), independent of the steric bulkiness of the
α-ketoester. None of the mechanistic models developed for ketone hydrogenation on Pt are conform to the observations. Only additional steric
effects in the modifiers and replacement of toluene by acetic acid as a reaction medium enhanced the sensitivity of the catalyst system to steric
effects in the substrates (ee = 0–94%). An important mechanistic consequence of the observations is that on CD-modified Pt preferred adsorption
of the α-ketoester on the si-side is directed by the position of the ester group relative to the modifier, independent of the steric bulkiness on
any side of the keto-carbonyl group. Ester, carboxyl, amido, carbonyl, acetal, and trifluoromethyl functions have similar directing effects, but
when both trifluoromethyl and an ester or carbonyl groups are present in the molecule, the latter function is dominant. The directing effect of the
electron-withdrawing (-activating) function on adsorption of the ketone is obviously related to the electronic environment provided by the chiral
modifier. The critical role of electronic interactions is supported by the remarkable influence of aryl substituents in the hydrogenation of ethyl
benzoylformates.
 2006 Elsevier Inc. All rights reserved.
Keywords: Enantioselective hydrogenation; α-Ketoester; α-Hydroxyester; Cinchonidine; Quinine; o-Phenyl-cinchonidine; Pt/Al O ; Mechanism
2
3
1. Introduction
in the synthesis of α-hydroxyesters using CD [14–16] or QN
[17] as chiral modifiers of supported and colloidal Pt.
The only systematic study of the structural effects in the hy-
drogenation of α-ketoesters revealed that an increase in the size
of the alkyl group (from methyl to t-butyl) in the ester group of
pyruvate barely decreased the ee [18]. Introduction of a t-butyl
group in α-position to the keto group reduced the ee to 81%,
probably due to hindered adsorption of the keto group. The
electronic effects of substituents on the performance of chirally
modified Pt have been studied in only two series of acetophe-
none and trifluoroacetophenone derivatives [19–21].
Several mechanistic models have been developed and refined
to rationalize the stereochemical outcome of the hydrogena-
tion of α-ketoesters (for a recent overview see Ref. [22]). Most
models postulate a 1:1-type interaction between substrate and
modifier, involving an N–H–O-type hydrogen bond interaction
[23–27] or a nucleophylic attack of the basic N atom of the
modifier on the keto C atom [28–33]. A common limitation of
Optically active α-hydroxyesters and α-hydroxyacids are
important building blocks for the synthesis of biologically ac-
tive natural products and analogues thereof [1]. A viable option
for this synthesis is the heterogeneous enantioselective hydro-
genation of α-ketoesters on cinchona-modified Pt. Since the
first description of the route by Orito et al. in 1979 [2,3], sev-
eral research groups have been fascinated by the potential of
this catalyst system (for recent reviews see Refs. [4–13]). Hy-
drogenation of ethyl pyruvate (1, Scheme 1) is the most stud-
ied heterogeneous enantioselective hydrogenation reaction and
now serves as a standard model reaction for chirally modified
Pt. After years of optimization, 97–98% ee has been achieved
*
Corresponding author.
E-mail address: baiker@chem.ethz.ch (A. Baiker).
0021-9517/$ – see front matter  2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2006.02.001

256
S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
and stored over activated molecular sieve. Cinchonidine (CD,
92%, Fluka; impurities: 1% quinine, 7% quinidine, determined
by HPLC at Fluka) and quinine (QN, 99%, Fluka) were used
without further purification. o-Phenyl-cinchonidine (PhOCD)
was synthesized as described earlier [34]. The 5 wt% Pt/Al2O3
(E4759) catalyst was purchased from Engelhard.
2.2. Catalytic hydrogenation
The hydrogenation reactions were carried out in a mechan-
ically stirred eight parallel pressure reactor system (Argonaut
Technologies) or in a magnetically stirred stainless steel auto-
clave controlled by a computerized constant-volume, constant-
pressure equipment (Büchi BPC 9901). Optimally, the 5-wt%
Pt/Al2O3 catalyst was prereduced before use in a fixed-bed re-
actor by flushing with N2 at 400 ◦C for 30 min, followed by
reductive treatment in H2 for 60 min at the same temperature.
After cooling to room temperature in H2 (30 min), the catalyst
was used directly for hydrogenation. Under standard condi-
tions, 42 mg of catalyst, 1.84 mmol of substrate, 6.8 µmol of
modifier, and 5 ml of solvent were stirred (1000 rpm) at 10 bar
and room temperature (23–25 ◦C) for 2 h. In the hydrogenation
of 1–9 over Pt/Al2O3 modified by CD and QN, (almost) always
the (R)-α-hydroxy ester was produced in excess, whereas the
(S)-α-hydroxy ester was the major enantiomer in the presence
of PhOCD.
Scheme 1. Enantioselective hydrogenation of α-ketoesters 1–9 over Pt/Al O
modified by CD, QN, and PhOCD.
2
3
these models is that only transformation of the simplest sub-
strates, usually methyl or ethyl pyruvate, are described, and
steric effects relevant in the hydrogenation of bulkier molecules
have not been considered.
The aim of the present study was to analyze the steric and
electronic effects on the Pt-catalyzed enantioselective hydro-
genation of α-ketoesters. Nine different substrates were hydro-
genated in the presence of CD, its 6ꢀ-methoxy derivative QN,
and o-phenyl derivative PhOCD (Scheme 1). That is, not only
was the bulkiness of α-ketoesters at the keto and the ester side
varied, but also additional steric effects were introduced in the
modifier. The additional functions of CD influence the adsorp-
tion mode and strength of the modifier [17,31,34–36], and thus
the shape of the chiral pocket available for adsorption of the
α-ketoester, while interacting with the alkaloid during hydro-
gen uptake.
2.3. Analyses
Conversion and ee were determined by a Thermo Finigan
trace gas chromatograph using a Chirasil-DEX CB (25 m ×
0.25 mm × 0.25 µm) capillary column for the hydrogenation
products of 1, 2, 4, 6, and 7, or by HPLC using a Merck
LaChrom system with a CHIRACEL OD (4.6 mm i.d., 240 mm
length, 10 µm particle size) chiral column for the hydrogenation
products of 3, 5, 8, and 9. The HPLC analysis was carried out
at 10 ◦C with a liquid flow rate of 0.5 ml/min. The UV detector
was set at 210 nm. For all substrates, a n-hexane/isopropanol
(90%/10%) mixture was used as eluent. Products were iden-
tified by GC/MS (HP-6890 coupled with a HP-5973 mass
2. Experimental
2.1. Materials
1
spectrometer) and by H and 13C NMR. All NMR data were
recorded on a Bruker Avance 500 with TMS as an internal
standard. The enantiomers of 1 was verified by GC analysis
of the commercially available product, and those of 3 [2] and
4 [40] were verified by comparing the sign of their optical ro-
tation (Jasco DIP-1000 polarimeter) with literature data. In the
hydrogenation of 2 and 5–9, the products were identified by as-
suming the analogous chromatographic separation of the prod-
ucts. The conversion values could be reproduced within 1%
by repeating the experiments. The reproducibility of ee was at
best 0.5% in GC analysis, but the error increased with HPLC
analysis (to 1%) and particularly at ee values <5% ee, as ex-
pected.
Ethyl pyruvate 1 (Fluka) and ethyl benzoylformate 3
(Aldrich) were carefully distilled in vacuum before use. t-Butyl
benzoylformate 4 was synthesized via α-oxo-benzeneacetyl
chloride by treating the acid chloride with t-butanol in basic
medium [37,38]. α-Oxo-benzeneacetyl chloride was synthe-
sized from benzoylformic acid by chlorination with dichloro-
methyl methyl ether [37,38]. Ethyl t-butylglyoxylate 2, ethyl
3,5-dimethylbenzoylformate 5, ethyl 3,5-difluorobenzoylfor-
mate 6, ethyl 3,5-di(trifluoromethyl)benzoylformate 7, ethyl
3,5-dimethoxybenzoylformate 8, and ethyl naphthylglyoxy-
late 9 were prepared by reaction of the corresponding Grig-
nard reagents with diethyl oxalate according to a known
method [39]. All synthesized substrates underwent flash chro-
matography and had their purity (>99%) confirmed by GC,
HPLC, and NMR analysis. Acetic acid (AcOH, 99.8%, Fluka)
was used as received, and toluene (99.5%, J.T. Baker) was dried
2.4. Vibrational circular dichroism spectroscopy
Vibrational circular dichroism (VCD) spectra were mea-
sured using a Bruker PMA 37 accessory coupled to a VEC-

S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
257
TOR 33 Fourier transform infrared spectrometer. A photoe-
Table 1
Enantioselective hydrogenation of 1–9 in toluene (standard conditions) (as an
lastic modulator (Hinds PEM 90) set at λ/4 retardation was
used to modulate from right to left circular polarized light at
a frequency of 50 kHz. The demodulation was performed by
a lock-in amplifier (Stanford Research Systems SR830 DSP).
The sensitivity of the lock-in amplifier was set at 1 mV for
the samples, with a dynamic reserve of 40 dB. To enhance the
1
2
example: entry 1, R –CH , R –CH CH )
3
2
3
Substrate
No modifier CD
ee (%)
QN
PhOCD
ee (%)
[conv.]
ee (%)
[conv.]
[conv.]
signal-to-noise ratio, an optical low-pass filter (<1800 cm−1
)
–
80 (R)
[100]
21 (R)
[100]
21 (S)
[100]
1
2
3
4
–CH
–CH H
2 3
3
was set before the photoelastic modulator. The samples were
analyzed in a transmission cell equipped with KBr windows
and a 0.2-mm Teflon spacer. A single-beam spectrum of the
neat solvent served as the reference for the absorption spectrum,
and a spectrum of the neat solvent recorded in VCD mode was
subtracted from the VCD spectrum of the dissolved molecules.
Calculations were performed using the Gaussian 98 program
package [41]. All internal coordinates of the molecules were
optimized at the density-functional B3LYP level of theory, us-
ing a 6-31G (dp) basis set. For the minimized structures, a nor-
mal coordinate analysis was performed. Rotational and dipole
strengths associated with the normal modes were calculated to
simulate adsorption and VCD spectra [42].
[100]
–
56 (R)
12 (R)
41 (S)
–CH CH
2
3
3
[100]
[91]
[61]
[98]
–
86 (R)
[100]
79 (R)
[100]
57 (S)
[100]
–CH CH
2
[100]
–
95 (R)
89 (R)
78 (S)
[61]
[94]
[43]
[52]
–
92 (R)
[100]
75 (R)
[97]
52 (S)
[100]
5
6
7
–CH CH
2
3
3
3
[100]
–
87 (R)
[100]
76 (R)
[99]
68 (S)
[99]
–CH CH
2
3. Results
[93]
Hydrogenation of 1–3 on CD-modified Pt has been reported
previously [2,3,18,35,43]. In this study, slightly modified reac-
tion conditions and a broader range of modifiers were applied,
and these substrates are used for comparison.
–
66 (R)
[94]
47 (R)
[90]
48 (S)
[94]
–CH CH
2
[38]
–
94 (R)
[95]
84 (R)
[100]
73 (S)
[100]
Although a detailed kinetic analysis was beyond the scope of
this study, a comparison of the conversions achieved in toluene
in 2 h in the high-throughput screening enables a qualitative as-
sessment of the reactivity of α-ketoesters 1–9 in the presence
and absence of the modifiers CD, QN, and PhOCD (Table 1).
Hydrogenation of 2, 4, and 9 indicates that rate acceleration due
to the presence of a cinchona alkaloid (CD or QN) is not a gen-
eral feature of α-ketoester hydrogenation, in agreement with
recent observations also in pyruvate hydrogenation [43–45].
Note, however, that a reliable kinetic analysis of α-ketoester
hydrogenation is complicated by numerous side reactions cat-
alyzed by the amine-type modifier and the Pt surface [8,46–49].
8
9
–CH CH
2
3
3
[100]
–
86 (R)
[100]
60 (R)
[32]
31 (S)
[31]
–CH CH
2
[48]
3.1. VCD spectroscopy
In the hydrogenation of 2 and 5–9, the products were iden-
tified by assuming the analogous chromatographic separation
of the products. This assumption was confirmed by VCD spec-
troscopy for the most critical substrates 2, 7, and 8, because the
greatest effect of the functional groups on adsorption on the
chiral chromatographic column was expected in these cases.
The absolute configuration of the major enantiomers was de-
termined by comparing the calculated VCD spectrum of one
enantiomer with the experimental VCD spectrum of the prod-
uct of the hydrogenation reaction on CD-modified Pt/Al2O3.
As a representative example, Fig. 1a shows the theoretical VCD
spectrum and Fig. 1b shows the experimental VCD spectrum of
the product for substrate 8. Matching of the spectra allows as-
Fig. 1. (a) Theoretical VCD spectra; (b) experimental VCD spectra of the mix-
ture of enantiomers obtained by the hydrogenation of 8 in the presence of CD
(0.2 M in methylene chloride-d ).
2

258
S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
signment of the absolute configuration of the main product of
hydrogenation as R.
3.2. Steric effects of substrates and modifiers
Variations in the rate and ee in the hydrogenation of 1–9
in toluene (Table 1) may be attributed to steric and electronic
effects of R1 and R2 (Scheme 1). In some cases the steric ef-
fects are dominant. For example, the lower reactivity of the
α-ketoester due to bulkiness of the ester group is shown by the
replacement of the ethyl group (3) by a tert-butyl group (4). In-
terestingly, the bulky ester group had a negative effect only on
the reactivity of 4; the enantioselectivities were highest in this
series with all three modifiers. In contrast, replacement of the
methyl group at the keto-carbonyl function in 1 by a t-butyl
group in 2 decreased both the rate and the enantioselectivity
(except with PhOCD). Another example of the steric effects is
the lower rate and ee in the hydrogenation of 9 compared with 3,
due to replacement of the phenyl group by a naphthalene ring
next to the keto-carbonyl group.
Fig. 2. The influence of electron withdrawing and releasing aryl substituents
of ethyl benzoylformate (3) on the enantiomeric excess (standard condi-
tions, in toluene). The (R)-enantiomer is formed with CD and QN, and the
(S)-enantiomer with PhOCD.
be tuned by aryl substitution without significantly changing the
environment in the close neighborhood of the carbonyl group.
Moreover, in the weakly polar toluene, the distorting effect of
solvent–substrate interactions is expected to be minor.
The data in Table 1 demonstrate that even stronger steric
effects can be induced by variations in the modifier structure.
Replacement of CD by its 6ꢀ-methoxy derivative QN caused a
general negative effect on the ee. The probable explanation for
this is that the aromatic methoxy function occupies a part of the
chiral pocket available for adsorption of the substrate. This ob-
servation is in line with the mechanistic models assuming that
in the enantiodifferentiating complex, the quinoline ring of the
alkaloid, being in the so-called “open-3” conformation [50], is
“flipped” toward the α-ketoester adsorbed in the neighborhood
of the modifier [22,51]. Replacing the OH function of CD by
a phenoxy group in PhOCD inverted the major enantiomer, in
agreement with earlier reports on the hydrogenation of some
other ketones [34–36]. The inversion is probably due to the
steric bulkiness of the phenoxy group relative to that of OH
function, and also to a change in the adsorption geometry of
the alkaloid, resulting in a shift in the position of the interacting
function, the quinuclidine N atom.
For all three modifiers, the highest ee was achieved in
the hydrogenation of 8, the substrate of which contains the
strongest electron-releasing substituents, two methoxy groups
(Scheme 1). In contrast, ee was lowest in the hydrogenation
of 7, the substrate of which contains the strongest electron-
withdrawing substituents, two CF3 groups. The enantioselec-
tivity is between the two extremes in the hydrogenation of ethyl
benzoylformate 3, the substrate of which has an unsubstituted
aromatic ring. Considering all five α-ketoesters, the correlation
between the electron-releasing or -withdrawing effects of the
substitutents and the ee is the best for CD-modified Pt, and de-
viations become more significant with increasing steric effects
in the modifiers.
A general observation is that additional steric effects in the
chiral modifiers increase the “sensitivity” of the catalyst system
to steric effects in the substrates, as indicated by the greater dif-
ferences in enantioselectivities when CD was replaced by QN
or PhOCD in the hydrogenation of 1–9.
3.4. Influence of acidic medium
In the commonly used model reaction, the hydrogenation of
ethyl pyruvate (1), the enantioselectivities in toluene and acetic
acid are similar [53]. Extending the study to structurally more
demanding substrates reveals significant differences between
weakly polar and acidic medium (Tables 1 and 2). Because hy-
drogenolysis of the C–O–C (ether) bond of PhOCD is catalyzed
by acids [35], only CD and QN could be used in acidic medium.
The hydrogenation rates in toluene and acetic acid are rather
similar. The greatest drop in conversion was measured for the
hydrogenation of 9 on CD-modified Pt when changing to acidic
medium. This behavior may be traced to the strong, competing
adsorption of acetic acid.
3.3. Electronic effects of aryl substituents
The α-ketoesters 3 and 5–8 have the same ester group
but different aryl substituents on the keto side. The electron-
withdrawing and -releasing properties of the functional groups
at the phenyl ring, characterized by the Hammett σ-cons-
tants [52], correlate reasonably well with the enantioselectiv-
ities achieved in toluene. To provide a better visualization of
this relationship, the important data in Table 1 are plotted in
Fig. 2. In all reactions the conversion was >90%; hence the ee’s
represent the final, integral values. The advantage of this mod-
ification is that the electron density at the carbonyl group can
In acetic acid, the highest ee of 94% was achieved with
CD-modified Pt in the hydrogenation of 8. Introduction of
the 6ꢀ-methoxy group in QN mostly diminished the ee in this
medium, with the important exception of the hydrogenation of

S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
259
ethyl pyruvate (1), in which reactions up to 98% ee were ob-
tained [17].
Clearly, the negligible difference between acidic and non-
acidic solvents in the hydrogenation of pyruvates is the excep-
tion rather than the rule.
Interestingly, in the hydrogenation of 2, a low ee to the oppo-
site enantiomer was observed. Considering the estimated error
of the analytical method at low ee, it is better to evaluate the
result as a loss of enantioselection. Nonetheless, the effect of re-
placement of the methyl group at the keto side in 1 by a t-butyl
group in 2 is dramatic. Hydrogenation of 3 and 9 was also non-
selective.
3.5. The role of reaction conditions
The influence of some reaction parameters was further in-
vestigated for the two most selective reactions, the hydrogena-
tion of 4 and 8 in toluene, in the presence of CD (Table 3).
Working at higher pressure (i.e., at higher surface hydrogen
concentration) either had no influence (4) or even diminished
the ee (8). A similar negative effect of high surface hydro-
gen concentration was found in the Pt-catalyzed enantioselec-
tive hydrogenation of some other ketones, including acetophe-
none [54], 2,2,2-trifluoroacetophenone [19], ring-substituted
acetophenones [21], and fluorinated β-diketones [55]. This cor-
relation is opposite to the typical behavior of the Pt-cinchona
system in the hydrogenation of α-ketoesters [56].
Reaction temperatures below room temperature increased ee
at the expense of conversion. Changes in the amounts of cata-
lyst and solvent did not significantly improve enantioselectivity.
Applying a mixture of toluene and acetic acid (1:1), a favorable
medium in the hydrogenation of 3 over CD-modified Pt [43],
diminished the ee in the hydrogenation of 4 and 8. Ultrasoni-
cation of the catalyst slurry in the presence of CD likewise had
no positive effect. Finally, the best ee’s in the hydrogenation of
4 (96%) and 8 (95%) were only marginally better than those
achieved in the preliminary screening.
Table 2
Enantioselective hydrogenation of 1–9 in acetic acid (standard conditions)
Substrate
CD
QN
ee (%)
ee (%)
[conv.]
[conv.]
88 (R)
92 (R)
1
2
–CH
–CH CH
2
3
3
3
[100]
27 (R)
[100]
2 (S)
–CH CH
2
[99]
[99]
86 (R)
4 (R)
3
4
–CH CH
2
3
[100]
70 (R)
[73]
[100]
24 (R)
[64]
80 (R)
[100]
31 (R)
[100]
5
6
7
–CH CH
2
3
3
3
4. Mechanistic considerations
86 (R)
[100]
76 (R)
[100]
–CH CH
2
Hydrogenation of α-ketoesters 1–9 on CD-modified Pt/
Al2O3 demonstrates that the (R)-enantiomer always forms in
good to excellent ee, independent of the steric bulkiness of the
ester group and the size and electronic structure of the alkyl and
functionalized aryl group on the other side of the keto func-
tion (Table 1). The lowest ee, 56% in the hydrogenation of 2,
is probably due to sterically hindered adsorption and hydro-
genation of the keto-carbonyl group by the neighboring t-butyl
group, as suggested previously [18]. Note also that a limited
optimization of the reaction conditions resulted in an improve-
ment to 81% ee in the same reaction [18].
72 (R)
[98]
72 (R)
[98]
–CH CH
2
94 (R)
[94]
80 (R)
[91]
8
9
–CH CH
2
3
3
46 (R)
[31]
0 (R)
[7]
–CH CH
2
The steric effects in the substrates are more pronounced
when additional steric effects in the alkaloid are introduced: the
Table 3
Influence of temperature, pressure and acid additive on the hydrogenation of 4 and 8 over CD-modified Pt/Al O (standard conditions)
2
3
◦
Substrate
Pressure (bar)
Temperature ( C)
Solvent (ml)
Conversion (%)
ee [(R), %]

10
25
25
25
25
25
25
10
0
Toluene (5)
Toluene (5)
Toluene (5)
Toluene (5)
Toluene (2.5) + AcOH (2.5)
Toluene (5)
Toluene (5)
Toluene (5)
Toluene (5)
Toluene (2.5) + AcOH (2.5)
94
99
40
25
100
95
95
96
95
93










10

10
25
10
10
10
25
25
10
0
95
95
37
23
100
94
91
94
95
93










10

260
S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
methoxy group in QN and the phenoxy group in PhOCD (Ta-
ble 1). We assume that both modifications change the “chiral
pocket” available for adsorption of the ketone while interact-
ing with the modifier during hydrogen uptake and thus modify
the efficiency of Pt. Even though we expect these results to be
valuable in refining the mechanistic concepts, we limit the fol-
lowing discussion to the commonly used and most understood
catalyst, CD-modified Pt.
The mechanistic models developed mainly for pyruvate hy-
drogenation assume two interactions between the amine-type
modifier and the ketone: an N–H–O- or N–C-type attractive in-
teraction (as discussed in the Introduction), and a second attrac-
tive [26] or repulsive [22] interaction to direct the adsorption
of the ketone on Pt. (Note that some models describe only the
nature of the attractive interaction and do not explain the ori-
gin of enantioselection.) Careful scrutiny of the data in Table 1
reveals that none of the models can account for the observed
enantioselectivities. For example, in case of ethyl pyruvate (1),
the ester group is the bulky and electron-rich substituent. The
situation is different for 8 or 9; the ester group is less bulky
than the aromatic function, but the (R)-enantiomer still forms
with excellent ee. Obviously, the model operating with a sec-
ond, repulsive interaction [22] based on the different bulkiness
on the two sides of the keto group needs to be refined. Simi-
larly, the proposed second attractive interaction [26] involving
a H bond between the small methyl group of ethyl pyruvate
(R1 in 1) and the quinoline ring of CD cannot be valid with
substrates 3–9.
It seems to be more likely that the ester group serves not
only as an activating group for carbonyl hydrogenation, but also
as a directing group that is mainly responsible for favoring the
adsorption on one side of the substrate. In this respect, it is in-
teresting to compare the dominant adsorption mode of various
activated ketones on CD-modified Pt. The drawings in Fig. 3
are based on the stereochemical outcomes of the hydrogena-
tion reactions. The model for the CD-α-ketoester interaction
(Fig. 3a) was published a few years ago [57], and the feasi-
bility of the uptake of a proton by CD from the Pt surface in
aprotic medium was demonstrated recently [58]. Assuming H
uptake from the Pt surface (from “below”), a similar adsorp-
tion on the si-side would be expected for α-ketoacids [59],
α-ketoamides [60], ketopantolactone [61], pyrrolidine-2,3-5-
triones [62], α-ketoacetals [63,64], and α-diketones [65–67].
Besides α-ketoesters, α, α, α-trifluoromethyl ketones are the
most studied substrates on cinchona-modified Pt. A probable
model for their hydrogenation – interaction of the quinuclidine
N atom of CD with the O atom of the ketones – is depicted in
Fig. 3b. (Note that a bifurcated H bond also involving one F
atom is also feasible.) In the hydrogenation of simple alkyl and
aryl trifluoromethyl ketones, CD favors the formation of (R)-
alcohol in a weakly polar reaction medium, in which solvent
effects are less important [68–72].
Fig. 3. Schematic illustration of the adsorption of α-ketoesters (a), tri-
fluoromethyl ketones (b), a trifluoromethyl-β-ketoester (c), and a trifluoro-
methyl-β-diketone (d) on Pt during interaction with CD. These adsorption
modes lead to the formation of the major enantiomers, assuming hydro-
gen-uptake from the metal surface.
β-position seems to be responsible for adsorption on the re-
side of the substrate (Fig. 3a). Apparently, the ester group is a
stronger directing function than the trifluoromethyl group and
inverts the adsorption mode of the substrate relative to that of
simple α, α, α-trifluoromethyl ketones. A similar case – the hy-
drogenation of a trifluoromethyl β-diketone that affords the (S)-
enantiomer in excess in weakly polar solvents [55] – is shown
in Fig. 3d, although in the absence of the directing effect of the
second carbonyl group, the (R)-trifluoromethyl alcohol is ex-
pected to be the major enantiomer.
An interesting case is the hydrogenation of a trifluoromethyl
β-ketoester (Fig. 3c), where (S)-alcohol is the major enan-
tiomer on CD-modified Pt, indicating adsorption on the re-side
of the activated carbonyl [73]. The trifluoromethyl group in
α-position activates the carbonyl, whereas the ester group in
Analysis of the hydrogenation of aryl-substituted α-keto-
esters 3 and 5–8 (Fig. 2) on CD-modified Pt provides fur-

S. Diezi et al. / Journal of Catalysis 239 (2006) 255–262
261
ther information on the directing effect of the ester group. In
Acknowledgment
these reactions, electron-withdrawing substituents (F, CF3) de-
creases the ee, whereas electron-releasing substituents (CH3,
OCH3) have a minor positive effect. Because the nature of the
substrate–modifier interaction is expected to be the same for all
substrates, the observed differences in ee are (mainly) attributed
to variations in the electron density at the carbonyl group. In
α-ketoesters, the carbonyl group is already activated by the es-
ter group. The results illustrated in Fig. 2 show that additional
activation on the other side of the keto group via the phenyl ring
(6, 7) is disadvantageous to enantioselectivity. It seems that ac-
tivation should come from only one side of the carbonyl group,
indicating the critical role of the electronic effect in enantiodif-
ferentiation.
Aryl substituents have an opposite effect on the hydrogena-
tion of acetophenone derivatives [21]. Electron-withdrawing
substituents on the phenyl ring (CF3, F, ester group) increase
the hydrogenation rate and the ee (from 17 to 60%), whereas
the electron-releasing methoxy function diminishes both the
rate and the ee. The inverse effect of aryl substituents is proba-
bly connected to the absence of activating function on the other
side of the keto group of acetophenones. In other words, in the
hydrogenation of ketones on cinchona-modified Pt, the highest
enantioselectivity may be expected for substrates in which the
electronic effects of functional groups point in the same direc-
tion.
Financial support from the Swiss National Science Founda-
tion is gratefully acknowledged.
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5. Conclusion
The unexpected steric and electronic effects observed in the
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