Sonochemical asymmetric hydrogenation of isophorone on proline modified Pd/Al2O3 catalysts.

Article abstract of DOI:10.1039/b315244h

The sonochemical asymmetric hydrogenation of isophorone (3,3,5-trimethyl-2-cyclohexenone) by proline-modified Pd/Al2O3 catalysts is described; presonication of a commercial Pd/Al2O3-proline catalytic system resulted in highly enhanced enantioselectivities

Full text of DOI:10.1039/b315244h

Sonochemical asymmetric hydrogenation of isophorone on proline
modified Pd/Al2O3 catalysts
Shilpa C. Mhadgut, Imre Bucsi, Marianna Török and Béla Török*
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931,
USA. E-mail: btorok@mtu.edu
Received (in Corvallis, OR, USA) 24th November 2003, Accepted 26th February 2004
First published as an Advance Article on the web 19th March 2004
The sonochemical asymmetric hydrogenation of isophorone
(3,3,5-trimethyl-2-cyclohexenone)
by
proline-modified
Pd/Al2O3 catalysts is described; presonication of a commercial
Pd/Al2O3-proline catalytic system resulted in highly enhanced
enantioselectivities (up to 85% ee).
As one of the most versatile methods in asymmetric synthesis,
enantioselective hydrogenations pioneered by Knowles, Noyori,
and Kagan have attracted great attention.1 Heterogeneous catalytic
hydrogenation processes modified by inexpensive, readily availa-
ble natural products are, however, novel alternatives for homoge-
neous methods.2 The recyclable, stable solid catalysts could replace
sensitive, toxic metal complexes.3 The vigorous expansion in the
field of heterogeneous chiral hydrogenations has been summarized
in several reviews.4,5 Especially, asymmetric hydrogenation of a-
ketoesters on cinchona-modified platinum catalysts has received
significant attention.5 A number of successful examples when
enantiomeric excesses (ee) exceed 95% have been published
recently.6 Similar high ee values were reported in the hydro-
genation of b-ketoesters on tartrate-modified Raney-Ni catalyst.7
In contrast, highly selective heterogeneous processes are still
under development for enantioselective hydrogenation of CNC
double bonds. Chiral hydrogenation of methoxypyrone on cin-
chona-modified Pd/TiO2 gave very high enantioselectivity (up to
94% ee) at small scales (1 mg), but selectivity was lost at higher
substrate/catalyst ratios.8 Other remarkable examples include the
hydrogenation of 2-methyl-2-pentenoic acid (66% ee)9 and a-
phenylcinnamic acid (72% ee).10 Besides cinchona alkaloids, (S)-
proline was also used as chiral modifier for CNC double bond
hydrogenation of isophorone.11 The system was extensively
studied and the highest ee obtained was 56%.12 A recent review by
Studer et al. gives complete coverage on heterogeneous catalytic
asymmetric hydrogenations.13
After the first application of ultrasound in catalysis14 it has been
extended to asymmetric hydrogenations as reviewed.15 A detailed
study concerning the effect of ultrasonic variables on asymmetric
hydrogenations was published recently.16 As the growing number
of recent papers indicates, the application of ultrasounds in
heterogeneous catalysis is expanding rapidly.17
Continuing our efforts on heterogeneous asymmetric catalysis,
here we report the highly improved asymmetric hydrogenation of
isophorone over proline modified Pd/Al2O3 catalysts.† The great
advantage of ultrasonic pretreatment will be shown and an
interpretation for this effect will be proposed.
Since our reaction conditions do not involve high temperature
reaction of proline and isophorone, formation of 5 can be highly
suppressed (less than 5%). As a result, a 5% Pd/Al2O3 (Engelhard,
code 40692) reference catalyst was selected for further studies.
Testing proline derivatives (e.g. isomeric hydroxy-prolines, proli-
nols, or proline esters) and related structures (e.g. MacMillan’s
catalyst or nicotine) as modifiers we found that, in agreement with
the literature,11 the best modifier is proline. Both proline enantio-
mers gave ee values up to 35% ee. The proline derivatives resulted
in decreased ee values, and other modifiers gave poor enantiose-
lectivities. It is worth noting, that the recently developed MacMil-
lan catalyst,19 that induces excellent ee in homogeneous reactions,
completely failed in the hydrogenations. It is most likely due to the
weak adsorption capability of the MacMillan catalyst. According to
the above data further studies were carried out using (S)-proline as
modifier.
The application of ultrasonic irradiation is usually beneficial in
catalytic hydrogenations.16 It was found that the major effect is
enhanced adsorption of the chiral modifier as sonication removes
surface impurities. Accordingly, we studied the effect of ultrasonics
on the present system. The effect of different presonication
methods on the catalyst under standard conditions are summarized
in Table 1.
The data clearly show that presonication results in enantio-
selectivity improvement only when both catalyst and modifier are
present in the solvent. “Modifier-free” presonication and presence
of substrate during pretreatment decreased enantioselectivity.
Similar to our previous experience the ee values passed through
a maximum as a function of sonication time. It was found that 20
min presonication resulted in the highest optical yields. Based on
the above experiments we concluded that for our model system, the
optimum occurs when the catalyst/modifier system is sonicated in
the solvent for 20 min. Further investigations will be carried out
using these conditions.
As the effect of hydrogen is crucial in hydrogenation systems, we
studied the effect of hydrogen pressure on the reaction. The ee vs.
hydrogen pressure functions with and without presonication are
illustrated on Fig. 1.
Although use of (S)-proline as a modifier in enantioselective
hydrogenations11,12,18 was established long ago, recent publica-
tions on application of proline and similar systems in asymmetric
catalysis19 renewed the interest in this “old-new” chiral modifier.
As a test reaction, the hydrogenation of isophorone was selected.
The mechanism proposed earlier involves formation and hydro-
genation of intermediate 1 to dihydroisophorone (4).12 As a result
of a possible side reaction, 5 can also form in the system. Other
chiral auxiliaries resulted in no ee increase.18 Pd/C catalysts
showed the best performance.11
Although, we did not have access to those catalysts,12 our
experience with commercial Pd/C catalysts was not favourable.
Among the catalysts tested Pd/Al2O3 gave the best ee values. The
chemoselectivity (ratio of 4 and 5) was also found to be favourable.
Table 1 Effect of presonication method on the hydrogenation of isophorone
at RT and 10 bar hydrogen pressure (standard system (see Notes), 20 min
presonication) ((S) product formed in excess)
Components in the pretreated system
Presonication
ee (%)
Catalyst + Solvent + Modifier
Catalyst + Solvent
Catalyst + Solvent + Modifier
Catalyst + Solvent + Modifier + Reactant
No
34
18
52
22
Yes
Yes
Yes
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C h e m . C o m m u n . , 2 0 0 4 , 9 8 4 – 9 8 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Notes and references
†
All chemicals used were of analytical grade and purchased form
Aldrich and Acros. The catalyst used was 5% Pd/Al2O3 (Engelhard, code
40692).
General procedure for hydrogenation of isophorone. Presonication of
catalyst-modifier systems and hydrogenation reactions were carried out at
25 °C as described earlier.20 The standard system included 50 mg of 5%
Pd/Al2O3, 1.0 mmol of (S)-proline, 5 ml of MeOH, and 1.0 mmol substrate.
Alterations will be noted separately. The absolute configuration of the major
product was determined by comparison with a known sample. Product
identification was monitored by GC-MS (Shimadzu QP 5050 System),
while the enantiomeric excesses (ee % = ¡[R] 2 [S]¡ 3 100/([R] + [S]))
were determined at close to 100% conversion ( > 98%) by gas chromatog-
Fig. 1 Effect of hydrogen pressure on enantiomeric excess in the
hydrogenation of isophorone on (S)-proline modified Pd/Al2O3 catalyst (-
no sonication, / 20 min presonication, standard system.
raphy (HP 5890 GC-FID, 30
column).
Transmission electron microscopy (TEM). Measurements were per-
formed with a JEOL 4000FX HREM as described earlier.20
m long Betadex (Supelco) capillary
As the results show, presonication increased optical yields
throughout the hydrogen pressure range. The best ee value obtained
with presonication exceeds 80% ee. As we are able to achieve a
steady ee value above 40 bar hydrogen pressure 50 bar pressure was
selected for further investigations.
The effect of catalyst/substrate ratio on selectivity is also an
important parameter. We studied the effect of different substrate
amounts on enantioselectivity. Fig. 2 illustrates the ee vs.
isophorone amount obtained with and without ultrasonic irradia-
tion. We observed maximum ee in both cases corresponding to a
1 : 2 isophorone–proline ratio. Using optimized conditions we were
able to obtain an unprecedented high enantiomeric excess (85% ee
for (S) product) in the present reaction.
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Fig. 2 Effect of reactant amount on enantiomeric excess in the hydro-
genation of isophorone on (S)-proline modified Pd/Al2O3 catalyst (- no
sonication, / 20 min presonication, standard system, 50 bar).
As ultrasounds initiate important changes on the catalyst16 we
studied the catalysts by high-resolution electron microscopy. It was
observed that presonication decreased the mean metal particle size
from 4.1 nm to 3.2 nm (after 10 min), 1.8 nm (after 20 min), 1.4 nm
(after min), respectively. The particle size decrease was not
dependent on the use of proline. According to Table 1, modifier-
free sonication decreased ee values. As a result we propose that the
surface cleaning effect of ultrasounds enhanced both adsorption of
the modifier and the modifier induced surface restructuring of the
metal.21 The joint effect of the two phenomena resulted in more
effective enantiodifferentiation. We also suggest that the key factor
(or the first step in the mechanism) in achieving high ees in this
system is adsorption of proline on the catalyst surface. Without
strong modifier adsorption high enantioselectivity cannot be
achieved in these cases.
In conclusion, our method successfully enhanced the enantio-
differentiation (up to 85% ee) in the hydrogenation of isophorone
by proline-modified Pd/Al2O3 catalyst. Most importantly, our
results clearly indicated that enhanced modifier adsorption is a
crucial factor in this process. Based on these findings design of new
catalysts capable of strong adsorption of proline may open up new
effective heterogeneous catalytic processes for CNC double bond
hydrogenation of a,b-unsaturated carbonyl compounds.
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20 B. Török, K. Felföldi, G. Szakonyi, K. Balázsik and M. Bartók, Catal.
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Financial support provided by the Michigan Space Grant
Consortium, ACS Petroleum Research Fund and Michigan Techno-
logical University is highly appreciated. Authors thank Prof. D. K.
Bates for valuable discussion.
21 R. Hess, F. Krumeich, T. Mallat and A. Baiker, Catal. Lett., 2004, 92,
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C h e m . C o m m u n . , 2 0 0 4 , 9 8 4 – 9 8 5
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