The first case of competitive heterogeneously catalyzed hydrogenation using continuous-flow fixed-bed reactor system: Hydrogenation of binary mixtures of activated ketones on Pt-alumina and on Pt-alumina-cinchonidine catalysts

Article abstract of DOI:10.1007/s10562-011-0705-0

Under the experimental conditions of the Orito reaction the competitive hydrogenations of four binary mixtures of ethyl pyruvate (EP), methyl benzoylformate (MBF), pyruvic aldehyde dimethyl acetal (PA) and 2,2-diethoxyacetophenone (DAP) on unmodified Pt/Al₂O₃ (racemic hydrogenation) and catalyst modified by cinchonidine (chiral hydrogenation) were studied using continuous-flow fixed-bed reactor system (CFBR). Conversions of chiral and racemic hydrogenations were determined under 4 MPa H₂ pressure, at 293 K using toluene/acetic acid 9/1 as solvent. In the competitive chiral hydrogenation of MBF + EP and DAP + PA binary mixtures (S1 + S2) a new phenomenon was observed: namely the EP and PA are hydrogenated faster than MBF and DAP, whereas in racemic one the MBF and DAP are hydrogenated faster than the former ketones. The phenomenon verified for the first time in CFBR is dependent on the adsorption mode of the surface complexes of various compositions (S1-Pt, S2-Pt, S1-CD-Pt, S2-CD-Pt, CD = cinchonidine). In the chiral hydrogenation of DAP a rate decrease, i.e., "ligand deceleration" was observed instead of rate enhancement. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-011-0705-0

Catal Lett (2011) 141:1616–1620
DOI 10.1007/s10562-011-0705-0
The First Case of Competitive Heterogeneously Catalyzed
Hydrogenation using Continuous-Flow Fixed-Bed Reactor
System: Hydrogenation of Binary Mixtures of Activated
Ketones on Pt-Alumina and on Pt-Alumina-Cinchonidine
Catalysts
•
•
•
} }
Gyorgy Szollosi Zsolt Makra Ferenc Fulop
¨
Mihaly Bartok
¨ ¨
´
´
Received: 27 July 2011 / Accepted: 11 September 2011 / Published online: 24 September 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Under the experimental conditions of the Orito
reaction the competitive hydrogenations of four binary
mixtures of ethyl pyruvate (EP), methyl benzoylfor-
mate (MBF), pyruvic aldehyde dimethyl acetal (PA) and
2,2-diethoxyacetophenone (DAP) on unmodified Pt/Al2O3
(racemic hydrogenation) and catalyst modified by cincho-
nidine (chiral hydrogenation) were studied using continu-
ous-flow fixed-bed reactor system (CFBR). Conversions of
chiral and racemic hydrogenations were determined under
4 MPa H2 pressure, at 293 K using toluene/acetic acid 9/1
as solvent. In the competitive chiral hydrogenation of
MBF ? EP and DAP ? PA binary mixtures (S1 ? S2) a
new phenomenon was observed: namely the EP and PA are
hydrogenated faster than MBF and DAP, whereas in
racemic one the MBF and DAP are hydrogenated faster
than the former ketones. The phenomenon verified for the
first time in CFBR is dependent on the adsorption mode of
the surface complexes of various compositions (S1–Pt,
S2–Pt, S1–CD–Pt, S2–CD–Pt, CD = cinchonidine). In the
chiral hydrogenation of DAP a rate decrease, i.e., ‘‘ligand
deceleration’’ was observed instead of rate enhancement.
Keywords Chiral and racemic hydrogenation ꢀ Platinum ꢀ
Cinchonidine ꢀ Ethyl pyruvate ꢀ Methyl benzoylformate ꢀ
Pyruvic aldehyde dimethyl acetal ꢀ
2,2-Diethoxyacetophenone ꢀ Continuous-flow reactor
1 Introduction
The investigation of heterogeneous asymmetric syntheses
methods is one of the most important fields of research in
organic chemistry [1–7]. Such methods are the hydroge-
nation reactions effected by hydrogen over metal catalysts,
particularly in continuous-flow fixed-bed reactor systems
(CFBR) [8, 9]. CFBR has been successfully utilized in the
chiral hydrogenation of activated ketones [10–23], not only
to simplify the practical realization of the reactions, but
also to study the mechanism of the Orito reaction [24].
Competitive hydrogenation of mixtures of ketones over
metal catalysts is a widely used method in studies on the
reaction mechanism of different types of organic compounds
(e.g., [25–31]). Research on competitive hydrogenations has
yielded new information on the effect of the electronic and
3D structure of the substrates on their adsorption over the
catalyst and on surface reactions. In view of the total lack of
published results concerning competitive chiral hydrogena-
tion of binary mixtures (with the exception of the Orito
reaction [32] and the hydrogenation of prochiral carboxylic
acids [33]), it was expected that experimental results
obtained in CFBR would provide new information on the
enantioselective catalytic hydrogenation of activated
ketones, an otherwise widely studied field.
} }
¨
´
G. Szollosi (&) ꢀ F. Fu¨lop ꢀ M. Bartok
Stereochemistry Research Group of the Hungarian Academy
´
of Sciences, Dom Ter 8, 6720 Szeged, Hungary
e-mail: szollosi@chem.u-szeged.hu
´
´
Z. Makra ꢀ M. Bartok (&)
Department of Organic Chemistry, University of Szeged,
´ ´
Dom Ter 8, 6720 Szeged, Hungary
e-mail: bartok@chem.u-szeged.hu
Recently, it was reported that in the competitive
hydrogenation of methyl benzoylformate (MBF) ? ethyl
pyruvate (EP) binary mixture on Pt/Al2O3 modified by CD
¨
F. Fu¨lop
Institute of Pharmaceutical Chemistry, University of Szeged,
¨ ¨
Eotvos U 6, 6720, Szeged, Hungary
123

Competitive Hydrogenation using Continuous-Flow Fixed-Bed Reactor
1617
(enantioselective or chiral hydrogenation) using atmo-
spheric batch reactor under the experimental conditions of
the Orito reaction: kEP [ kMBF, but over unmodified cata-
lyst (racemic hydrogenation) kMBF [ kEP. This phenome-
non is dependent on the adsorption strength of the surface
complexes of various compositions (MBF–Pt, EP–Pt,
MBF–M–Pt, EP–M–Pt, M = chiral modifier) [32]. In view
of the above unexpected experimental observation, it
seemed expedient to study the competitive hydrogenation
of binary activated ketone mixtures in the CFBR system so
far not studied, as unlike the batch method, this method
enables to maintain identical substrate concentration
throughout the entire time of the measurement.
has been described in detail in our previous publication
[20]. The same catalyst was used per measurement cycle
(160 min), with the catalyst washed (1 h with solvent) in
between substrate exchanges (S1, S2, S1 ? S2, S1). A
typical series of measurements began with pre-hydroge-
nation of the catalyst (60 min) and continued with chiral or
with racemic hydrogenations of individual substrates, fol-
lowed by chiral or racemic hydrogenation of binary mix-
tures. The measurement series were ended by a second
chiral or racemic hydrogenation under conditions identical
with those of the first chiral hydrogenations. The purpose
of the latter was to monitor the deactivation of the catalyst
in the course of the measurement cycle (160 min).
The objective of the research was to study the hydro-
genation of four binary mixtures (MBF ? EP, MBF ? PA,
MBF ? DAP, DAP ? PA) using the activated ketones
shown in Fig. 1 under the experimental conditions of the
Orito reaction (Scheme 1). Comparison of the experiments
on unmodified and CD-modified catalysts was the main
aim of the study. The present studies on the hydrogenation
of these binary mixtures not only confirmed the unexpected
experimental observation obtained by the batch method,
but generalized it and also contributed to the interpretation
of the new phenomenon.
Standard conditions were: 50 mg E4759 catalyst, 293 K,
4 MPa hydrogen pressure, solvent: toluene/acetic acid
(AcOH) 9/1, liquid flow 1 mL min-1, modifier concentra-
tion: 0.44 mM, substrate concentration 11 mM. In our ear-
lier experiments we verified that our measurements proceed
in a kinetic regime, which is also confirmed by the high ee
values, since it is well-known that mass transfer limitations
can dramatically decrease ee values [4]. Conversions and
enantiomeric excesses, ee% ¼ j½Rꢁ ꢂ ½Sꢁjꢃ 100=ð½Rꢁ þ ½SꢁÞ,
were determined by gas chromatography (HP 6890 N
GC-FID, 30 m Cyclodex-B chiral capillary column). The
reproducibility of the results was 1%.
2 Experimental
3 Results and Discussion
2.1 Materials
Hydrogenation of activated ketones under the conditions of
the Orito reaction in a batch reactor has been discussed in
numerous reviews (e.g., [36–40] in the last 4 years). The
majority of the reports studies EP, a smaller fraction
investigates MBF, whereas only very few publications
report experiments on PA [41, 42] and DAP [41]. Results
of experiments using CFBR are reported in the publications
mentioned [10–23]. However, no experimental observa-
tions on the competitive hydrogenation of binary mixtures
have been reported yet in the CFBR.
Cinchonidine (CD), the activated ketones (EP, MBF, PA,
DAP) and solvents were purchased from Aldrich or Fluka.
EP, MBF, PA and DAP were distilled under vacuum using a
Vigreux-column. Engelhard 5% Pt/Al2O3 (E4759) was pre-
treated in a fixed-bed reactor by flushing with 30 mL min-1
He at 300–673 K for 30 min and 30 mL min-1 H2 at 673 K
for 100 min. After cooling to room temperature in H2, the
catalyst was flushed with He for 30 min and was stored under
air before use [34, 35]. The properties of E4759 catalyst:
Pt-content, 5% (w/w); Pt dispersion (after pretreatment),
25%; mean Pt particle size, 4.4 nm.
The results of the measurements on binary mixtures are
presented in Table 1, and a typical measurement series
using DAP ? PA mixture is shown as an example in
Fig. 2. In both series (chiral and racemic), hydrogenation
of the first substrate is followed by that of the second one,
and next by hydrogenation of the mixture of the two sub-
strates; finally, the last experiment of the series is again the
hydrogenation of the first compound. According to Fig. 2,
catalyst activity is somewhat diminished with the progress
of reaction time. Deactivation is mainly the consequence of
the side reactions of substrates (decomposition accompa-
nied by CO formation, occasional oligomerization). Due to
the character of the measurement, steady state cannot be
reached within the hydrogenation time of 160 min. The
2.2 Hydrogenations in Flow System
Continuous hydrogenations were carried in H-cube high-
pressure continuous-flow system. The experimental set-up
O
O
O
O
OEt
OMe
OEt
OEt
OMe
OMe
Me
Ph
Ph
DAP
Me
PA
O
H
H
O
MBF
EP
Fig. 1 Activated ketones studied in this research
123

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G. Szollosi et al.
1618
Scheme 1 The Orito reaction
of binary mixtures
O
OH
O
O
OH
R
O
+H2, Pt-CD
O
O
R
R'
R
R'
R
R'
R
R'
+
R
+
rt, solvent,
CFBR
O
O
O
O
R'
R'
R = Me, Ph; R' = Me, Et
CD = cinchonidine
Table 1 Conversion (%) of racemic and chiral hydrogenations of individual substrates (CSi) and of competitive hydrogenations of binary
mixtures (CSm) and enantiomeric excesses (ee, %) obtained over chiral catalysta
Racemic hydrogenation (r)
over unmodified catalyst
Chiral hydrogenation (c) over modified catalyst
Conversion (%) ee (%, R)
S1 ? S2
CS1i
37
CS2i
20
8
CS1m
23
CS2m
14
4
CS1i
49
CS2i
77
CS1m
43
CS2m
60
S1i
83
89
92
75
S2i
74
90
77
90
S1m
87
S2m
77
MBF ? EPb
MBF ? PA
MBF ? DAP
DAP ? PA
a
80
68
95
53
88
38
87
90
87
30
8
80
17
7
95
20
90
12
92
76
35
31
13
54
10
40
77
92
Reaction conditions: 50 mg Pt/Al2O3 (E4759) catalyst, 293 K, 4 MPa hydrogen pressure, solvent: toluene/AcOH 9/1, liquid flow 1 mL min-1
CD concentration: 0.44 mM, substrate concentration 11 mM
,
b
20 mg E4759 catalyst, 283 K, others as previously given
Subscript i = hydrogenation of the individual substrate, m = hydrogenation of the binary mixture
reproducibility: it is well-known that catalyst systems
treated with chiral modifiers are somewhat more sensitive
than ‘‘ordinary’’ hydrogenation catalysts. The reason for
this is, among others, that, depending on the initial state of
the catalyst, the chiral modifier brings about dynamic and
continuous changes in the quality of the active sites. This
effect of the modifier also depends on its irreversible
adsorption under a great variety of conditions [43, 44].
Based on the experimental results summarized in
Table 1, the following conclusions can be drawn.
(i) The experimental data of MBF ? EP in Table 1 are
not comparable with the other data in all aspects,
because there are differences among the experimental
conditions. The reason for this is that hydrogenation of
MBF ? EP had to be conducted under milder exper-
imental conditions, since conversions close to 100%
were not suitable for recognition of the supposed and
expected tendency [32]. Performing measurements on
MBF ? EP at a temperature lower by 10 K and using
a lower amount of catalyst did not hinder the most
important conclusions to be drawn.
Fig. 2 The conversion (closed symbols) and ee (open symbols) as a
function of time on stream in the successive hydrogenation of PAi,
DAPi, PAm ? DAPm and PAi using CFBR system over unmodified
(PA: filled diamond; DAP: filled triangle) and CD-modified (PA:
filled circle, open circle; DAP: filled square, open square) Pt/Al2O3
catalysts (for reaction conditions see Table 1, subscript i = individ-
ual, m = mixture)
(ii) In racemic hydrogenation, conversion of substrates
containing aromatic skeletons (MBF, DAP) is higher
than that of substrates without aromatic moiety, most
probably due to their stronger adsorption.
decrease in conversion during hydrogenation of the mix-
ture is a consequence of the double substrate load on the
catalyst, since in the case of individual measurements the
substrate concentration is 11.25 mM, whereas in the case
of a substrate mixture it is 11.25 mM per substrate. Some
of the CSi data in Table 1 indicate inconsistent
(iii) The course of the conversion in chiral hydrogena-
tions is much more varied than that in racemic
hydrogenations, because changes in conversion of
the MBF ? PA and MBF ? DAP mixtures and of
123

Competitive Hydrogenation using Continuous-Flow Fixed-Bed Reactor
1619
Table 2 Calculated relative conversions (CS1/S2) for racemic (r) and chiral (c) hydrogenations of individual substrates and competitive
hydrogenations of binary mixturesa and Cc/Cr values
S1 ? S2
Racemic hydrogenation (r)
Chiral hydrogenation (c)
Cc/Cr
CS1i/S2i
CS1m/S2m
CS1i/S2i
CS1m/S2m
S1i
S2i
S1m
S2m
MBF ? EPb
MBF ? PA
MBF ? DAP
DAP ? PA
a,b
1.9
9.0
2.9
5.0
1.6
17.0
4.7
0.6
1.8
4.8
0.3
0.7
2.3
7.5
0.3
1.3
1.2
1.1
0.4
3.9
6.6
0.6
6.8
1.9
1.3
1.1
0.3
4.3
9.5
0.7
5.7
4.4
For reaction conditions see Table 1
R
O
R
PA
O
O
R
R
O
*
CrPA
CcPA
O
Me
R
+
N
H
*
(
R
)-alcohols
+
)-alcohols
+H2, Pt
+H2, Pt-CD
toluene/AcOH
CcDAP
*
(
R
)-alcohols
H
HO
O
toluene/AcOH
(
S
O
R
H
CrDAP
or Me
O
*
N
O
CrDAP > CrPA
CrDAP < CrPA
*
*
R = Me or Et
*
*
DAP
*
Scheme 2 Racemic and chiral hydrogenation of DAP ? PA binary mixtures
individual substrates are similar to those in racemic
The essentials of the chemical conversions taking place are
illustrated by Scheme 2. From the high ee it follows that the
Pt-coverage by the modifier is high. The quinoline moiety will
strongly adsorb. Because of the non-flatness of the other part
(quinuclidine moiety), the ketone substrate can be accommo-
dated with the chiral part of the modifier and catalyst. Smaller
ketones (PA in Fig. 2) will be more easily positioned in this
way than larger ones (DAP, also lower ee). In the absence of
modifier DAP will win in a competition with PA due to its
relatively strongly adsorbing aromatic ring (Scheme 2).
hydrogenations. However, in the case of the chiral
hydrogenation of MBF ? EP and DAP ? PA, the
conversion of the latter substrates (S2 = EP and PA)
exceeds those of MBF and DAP, respectively. The
phenomenon is well demonstrated by the experi-
mental data shown in Fig. 2. Namely, in racemic
hydrogenation CDAP [ CPA (40% [ 8%, 31% [
7%), whereas in chiral hydrogenation CDAP \ CPA
(13% \ 54%, 10% \ 40%).
(iv) Irrespective of the conversion, high ee values could
be attained especially in the chiral hydrogenation of
MBF and PA (87–92%), in spite of the fact that no
optimization was done.
4 Conclusion
The similar tendencies of experimental results obtained in
batch and continuous-flow reactors allowed convincing
conclusions to be drawn. Namely, results of the competi-
tive hydrogenation of binary mixtures of activated ketones
under the conditions of the Orito reaction also confirm the
so-called adsorption model of the reaction mechanism
[6, 36–38, 40]. Naturally, this does not exclude the possi-
bility that in the case of certain substrates, substrate–cin-
chona adducts may already form in the liquid phase, i.e.,
without the participation of Pt, and the structure of such
adducts changes favorably or unfavorably for chiral
induction in the course of adsorption on the surface of Pt.
The interpretation of the differences between the results
The several calculated data on the basis of Table 1 are
shown in Table 2. The first and second columns of each
hydrogenation in Table 2 present the ratio of reactivities of
S1 and S2 in chiral or racemic in both individual and com-
petitive hydrogenation. As it is well-known, in the Orito
reaction chiral hydrogenation is usually faster than racemic
hydrogenation, i.e., rate enhancement (so called ‘‘ligand
acceleration’’) takes place [36–40]. The values of Cc/Cr are
the largest for PA both when hydrogenated individually and
in binary mixtures. In the chiral hydrogenation of DAP,
however, a rate decrease (‘‘ligand deceleration’’) is observed
(Cc/Cr \ 1) instead of rate enhancement.
123

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G. Szollosi et al.
1620
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18. Toukoniitty E, Maki-Arvela P, Kumar N, Salmi T, Murzin DYu
(2004) Catal Lett 95:179
obtained in batch and in continuous flow reactors neces-
sitates further studies and a more profound knowledge of
reaction kinetics.
19. Meier DM, Mallat T, Ferri D, Baiker A (2006) J Catal 244:260
¨ ¨
´ ´
¨ }
20. Szollosi Gy, Cserenyi Sz, Fulop F, Bartok M (2008) J Catal
260:245
Acknowledgments Financial support by the Hungarian National
Science Foundation (OTKA Grant K 72065) is highly appreciated.
´
´
¨ }
21. Szollosi Gy, Cserenyi Sz, Bartok M (2010) Catal Lett 134:264
´
´ ´
22. Szollosi G, Cserenyi S, Bucsi I, Bartok T, Fulop F, Bartok M
¨ }
(2010) Appl Catal A Gen 382:263
¨ ¨
´
The study was supported by the Janos Bolyai Research Scholarship of
the Hungarian Academy of Sciences (Gy. Szollosi).
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