Asymmetric hydrogenation using chiral Rh complexes immobilised with a new ion-exchange strategy

Article abstract of DOI:10.1039/b501359c

Rh diphosphine complexes using DuPhos and JosiPhos as chiral ligands have been immobilised by ion exchange into the mesoporous material MCM-4]. When used as catalysts for the enantioselective hydrogenation of dimethyl itaconate and methyl-2-acetamidoacrylate. these heterogeneous catalysts give catalytic performance in terms of yield and enantioselection that arc comparable to the corresponding homogeneous catalysts. Furthermore, the heterogeneous catalysts can be readily recovered and reused without loss of catalyst performance. A second immobilisation strategy is described in which [Rh(COD)₂] ⁺BF₄4^- is initially immobilised by ion exchange and subsequently modified by the chiral diphosphine and this give comparable catalyst performance. This immobilisation strategy opens up the possibility of easy ligand-screening for parallel synthesis and libraries. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b501359c

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A R T I C L E
Asymmetric hydrogenation using chiral Rh complexes immobilised
with a new ion-exchange strategy
a
b
a
a
a
William P. Hems, Paul McMorn, Stewart Riddel, Simon Watson, Frederich E. Hancock
b
and Graham J. Hutchings*
a
Johnson Matthey PCT, 28 Cambridge Science Park, Milton Road, Cambridge, UK CB4 0FP
School of Chemistry, Cardiff University, Cardiff, UK. E-mail: hutch@cardiff.ac.uk;
Fax: (+44)29 2087 4030; Tel: (+44)29 2087 4805
b
Received 26th January 2005, Accepted 10th March 2005
First published as an Advance Article on the web 18th March 2005
Rh diphosphine complexes using DuPhos and JosiPhos as chiral ligands have been immobilised by ion exchange into
the mesoporous material MCM-41. When used as catalysts for the enantioselective hydrogenation of dimethyl
itaconate and methyl-2-acetamidoacrylate, these heterogeneous catalysts give catalytic performance in terms of yield
and enantioselection that are comparable to the corresponding homogeneous catalysts. Furthermore, the
heterogeneous catalysts can be readily recovered and reused without loss of catalyst performance. A second
+
−
immobilisation strategy is described in which [Rh(COD)
2
] BF
4
is initially immobilised by ion exchange and
subsequently modified by the chiral diphosphine and this give comparable catalyst performance. This immobilisation
strategy opens up the possibility of easy ligand-screening for parallel synthesis and libraries.
Introduction
but we have also used this approach to design heterogeneous
15 16 17
enantioselective dehydration, epoxidation, Diels–Alder and
18
The ability to synthesise pure enantiomers is of crucial im-
portance for the preparation of modern pharmaceuticals and
agrochemicals. Most early progress has been focussed on
the design of molecular catalysts operating as homogeneous
catalysts, work which culminated in the award of the Nobel
imino–ene reactions. We have now used this immobilisation
strategy to synthesise stable reusable catalysts for enantioselec-
tive hydrogenation.
Asymmetric hydrogenation reactions continue to demand
attention using a whole library of chiral phosphine ligands,
however, in many cases the enantioselectivity achieved with the
immobilised complex can be significantly lower than those ob-
served for the non-immobilised catalyst. It should be noted that
other strategies for the stabilisation of homogeneous catalysts
are being considered, for example the use of ionic liquids is
1
Prize for Chemistry in 2001 to Noyori, Sharpless and Knowles.
However, industry has been slow to take up these synthetic
methodologies since separation of the catalyst from the reaction
mixture can be difficult and hence catalyst recycle and reuse can
be very difficult. For this reason, attention has recently focussed
on the design of immobilised catalysts which can overcome these
19–21
producing interesting results,
but most research effort has
2,3
problems.
been directed towards immobilisation strategies. Progress can
only considered to be made if the enantioselection or overall
turnover numbers achieved with the stabilised or immobilised
catalyst is comparable to the homogeneous catalyst, and to date
In general, progress in the design of robust heterogeneous
enantioselective catalysts has proved to be much more elusive,
and they tend to be very specific for particular reactions and
classes of substrates, and there remain very few examples of
heterogeneously catalysed reactions giving high enantioselec-
tion. Unfortunately, almost invariably, poorer enantioselection
is achieved with the immobilised complex compared to the
comparable homogeneous catalysts. However, there are a
number of studies indicating that improved enantioselectivity
can be achieved by immobilisation. In 1991, this was pio-
6,18
there are only few examples of such improvement.
There have been numerous previous studies concerning the
design of immobilised asymmetric hydrogenation catalysts,
due primarily to the central importance of hydrogenation
4
22,23
as a unit process in industrial organic synthesis.
Noyori
24
et al. prepared an immobilised Ru-BINAP-diamine system that
compared favourably with its homogeneous counterpart. Recent
attention has focussed on the immobilisation of phosphine
containing catalysts onto inorganic supports since their rigid
structure prevent intermolecular aggregation of the active cata-
lyst species which can lead to loss of activity in the polymer sup-
ported catalysts. Robust asymmetric catalysts using inorganic
5
6
neered by the Corma and co-workers. In 2000 Raynor et al.
showed that a carefully planned immobilisation strategy could
result in enhanced enantioselection being observed with the
immobilised catalyst when it is constrained within the ordered
mesopores of MCM-41. They demonstrated this for the allylic
amination of cinnamyl acetate using a catalyst based on 1,1 -
bis(diphenylphosphino)ferrocene anchored to the inner wall
ꢀ
6
supports, such as MCM-41 have been reported by Raynor et al.,
25
26
H o¨ lderich and co-workers, de Rege et al. and by Augustine
et al. for heteropolyacids. These researchers have shown that
2
+
27
of MCM-41 and coordinated to Pd . The approach was
subsequently extended to the enantioselective reduction of ethyl
nicotinate. The improved effect of immobilisation is noted in
chiral Rh diphosphine complexes can be immobilised on MCM-
41. However, these catalysts, although initially effective, tend to
give lower enantioselection compared with their homogeneous
counterparts and also typically required long reaction times. For
7–9
other studies and is considered to be due to a containment
10
effect observed for the immobilised systems.
25
We have used a different immobilisation strategy in which
catalytically active cations are electrostatically immobilised
within microporous and mesoporous materials by ion exchange
and they are subsequently modified by chiral ligands. Until now,
we have concentrated our attention on the heterogeneous asym-
example, H o¨ lderich and co-workers immobilised Rh diphos-
phine complexes by adsorption onto MCM-41 and, although
the catalysts were stable and could be reused, the ee obtained
with the immobilised catalyst (85–92%) was significantly lower
than that observed with the homogeneous catalyst (99%) and
these catalysts required 24 h to achieve complete conversion.
In this paper we demonstrate immobilisation strategies for
2
11–14
2+
metric aziridination of alkenes
into zeolite H-Y modified by chiral bis(oxazoline) ligands,
using Cu ion-exchanged
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 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 4 7 – 1 5 5 0
1 5 4 7

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enantioselective hydrogenation based on immobilisation of
rhodium complexes into mesoporous materials. We demonstrate
that comparably high enantioselection can be achieved with
these supported catalysts using two immobilisation strategies
using electrostatic forces. Furthermore, we demonstrate that the
manner in which the immobilisation is achieved is of crucial
importance in achieving high sustained enantioselectivity and
reusability for these catalysts.
for 1 h, filtration and washing of the yellow solid to give the
supported catalyst [Rh(R,R-MeDuPhos)(COD)]–Al-MCM-41
3. This immobilised catalyst was then tested in the hydrogenation
of dimethyl itaconate (Scheme 1).
The results are shown in Table 1 for several successive
experiments using a substrate : Rh molar ratio of 250 : 1 and
◦
1 h reaction time at 20 C. After the reaction the catalyst was
allowed to settle and the liquid phase was removed and analysed.
No rhodium was found in the liquid product and no activity was
observed if fresh reactants were added to this solution. Fresh
substrate was added to the recovered catalyst, with the same
substrate : Rh molar ratio, and the experiment was repeated.
Table 1 also shows the results for the homogeneous catalysts
under the same reaction conditions and it is apparent that
the immobilised catalysts give comparable enantioselection even
after 8 reuses. Use of higher substrate : Rh molar ratio of 5000 : 1
is also possible, but some activity is lost on reuse possibly due to
loss of the chiral ligand, but the ee is retained and is comparable
to the homogeneous catalyst (Table 1).
Results and discussion
To overcome the problems associated with the earlier immo-
bilised enantioselective hydrogenation systems we considered
that it is desirable to anchor the catalyst using electrostatic
forces which does not require ligand modification that is often
necessary for the preparation of immobilised catalysts using
5,19,20
covalent linking of the ligand to the inorganic support.
It is also more specific than just using physical adsorption, a
method that is known to give extensive leaching of the active
2
components, leading to poor stability. We have previously
In a subsequent set of experiments we used the immobilised
catalyst 3 for the hydrogenation of methyl-2-acetomidoacrylate.
The results (Table 2) show that this substrate can also effectively
successfully used this approach for the immobilisation of copper
2
bis(oxazoline) complexes, and now we extend this methodology
to the supporting of chiral Rh phosphine complexes, using
DuPhos 1 and Josiphos 2 ligands as representative examples.
Table 2 Hydrogenation of methyl-2-acetamidoacrylate using [Rh(R,R-
MeDuPhos)(COD)]–MCM-41
Number of times used Time for complete conversion/min Ee (%)
1
2
3
4
10
10
10
15
20
95
99
97
97
92
99
Our initial immobilisation methodology was carried
5
a
1
0
out by direct immobilisation of the preformed [(R,R-
+
−
+
MeDuPhos)Rh(COD)] BF
4
complex onto (H )Al-MCM-41.
a
Homogenous catalyst [Rh(R,R-MeDuPhos)(COD)]BF
comparable conditions.
4
used under
Direct ion exchange of the acidic sites on MCM-41 was achieved
by stirring a solution of the Rh complex with (H )Al-MCM-41
+
Scheme 1
Table 1 Hydrogenation of dimethyl itaconate using [Rh(R,R-MeDuPhos)(COD)]–Al-MCM-41
Substrate : Rh molar ratio
Number of times used
Time/h
Conversion (%)
Ee (%)
2
50 : 1
1
2
3
4
1
1
1
1
1
>99
>99
>99
>99
99
>99
>99
>99
>99
98
5
6
7
1
1
98
95
96
95
8
—
1
2
3
1
1
1
2.5
12
1
99
95
99
96
97
94
99
a
2
5
50 : 1
>99
>99
98
97.5
>99
000 : 1
a
5
000 : 1
—
a
4
Homogeneous catalyst [Rh(R,R-MeDuPhos)(COD)]BF used under the same conditions.
1
5 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 4 7 – 1 5 5 0

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be asymmetrically hydrogenated and the catalyst can be readily
recovered and reused.
Table 3 Hydrogenation of dimethyl itaconate using [Rh(R,S-
JosiPhos)(COD)]–Al-MCM-41
Subsequently, we investigated the direct immobilisation of the
+
−
Number of times used
Conversion (%)
Ee (%)
preformed [(R,R-MeDuPhos)Rh(COD)] BF
H )Al-SBA-15. Direct ion exchange of the acidic sites on SBA-
4
complex onto
+
(
1
(
1
2
3
4
5
6
7
8
9
99
99
99
99
99
98
98
99
98
98
99
94
92
92
92
91
91
91
92
91
90
96
5 was achieved by stirring a solution of the Rh complex with
+
H )Al-SBA-15 for 1 h, filtration and washing of the yellow solid
to give the supported catalyst [Rh(R,R-MeDuPhos)(COD)]–
Al-SBA-15 4. This immobilised catalyst was then tested in the
hydrogenation of dimethyl itaconate and methyl-2-acetomidoac-
rylate. The initial usage of 4 as a heterogeneous catalyst gave re-
action times for complete conversion and ee comparable to that
observed for the homogeneous complex. However, the immobi-
lised catalyst was not stable and significant quantities of Rh were
leached during use, this may be due to the structure of Al-SBA-
1
_
0
a
a
Homogeneous catalyst [Rh(R,S-JosiPhos)(COD)] used under the same
conditions.
1
4
5 since the Al may have not been as accessible as in Al-MCM-
1 due to the thickness of the wall structure. Consequently, the
immobilised catalyst could not be readily reused and longer
reaction times were required to achieve complete conversion and
the ee also decreased significantly. For example, for the hydro-
genation of methyl-2-acetomidoacrylate with 4, using the same
conditions as in Table 2, for the first three catalyst uses the time
for complete reaction increased from 1 h to 2.5 h and 12 h, and
the ee decreased from 96–97% to 94%. This is in contrast to cata-
lyst 3 prepared using MCM-41 but is in agreement with the very
The results shown in Table 3 show that the catalyst can be reused
several times without marked loss of catalyst performance.
Conclusions
Our results show that chiral Rh complexes can be easily
immobilised by electrostatic interaction with negatively charged
inorganic supports. Furthermore, the catalysts can be immo-
bilised directly or the complex can be constructed within the
pores of the support by first immobilising the active cation
and subsequently modifying with the chiral ligand. We have
found that the metal does not leach from the immobilised
catalyst when MCM-41 is used as the support and that these
catalysts can be readily recovered and reused effectively. The
key observation is that high enantioselection and reactivity
can be achieved using catalysts immobilised in this way which
compare favourably with their homogeneous counterparts. In
addition, the ion-exchange methodology is far simpler than
the previously investigated immobilisation procedures using
covalent linking of the chiral modifier to the inorganic support.
Furthermore, the new two stage preparation strategy opens up
the possibility of easy ligand-screening for parallel synthesis and
libraries. Consequently, we consider this methodology provides
a readily proven accessible pathway to highly enantioselective
immobilised hydrogenation catalysts.
28
recent studies by Simons et al. in which similar Rh complexes
were immobilised by ion exchange onto a new aluminosilicate
AlTUD-1 which showed extensive leaching. These studies
demonstrate the importance of the structure of the inorganic
support with respect to catalyst stability and clearly immobili-
sation using the MCM-41 structure produces stable catalysts.
Following these initial successful experiments using the
MCM-41 immobilised complex, a second, more flexible, immo-
bilisation strategy was investigated which involved building the
chiral Rh complex within the pores of the aluminosilicate. The
+
−
Rh precursor, [Rh(COD)
2
] BF , was initially ion-exchanged
4
onto the (H+)Al-MCM-41 support, isolated by filtration and
washed. Reaction of chiral ligands with this immobilised pre-
cursor allowed for a simple procedure for the preparation in situ
of these complexes on the solid support. Initial treatment with
R,R-MeDuPhos gave the immobilised catalyst 3. This catalyst
was evaluated for the hydrogenation of dimethyl itaconate, as
◦
before, with a substrate : Rh molar ratio of 1000 : 1 at 20 C and
again 100% conversion with 98% ee was obtained. The material
could be successfully reused several times without loss of Rh.
Hence, no differences were observed in the catalytic performance
or stability between the two immobilisation procedures. This
demonstrates that the immobilised catalyst can be prepared
either by direct immobilisation of the chiral complex or by
formation of the chiral complex within the pores of the
catalyst. We consider that this two step preparation strategy for
immobilised catalysts offers great flexibility for catalyst design
with a range of inorganic substrates particularly for use in high
throughput studies since a range of ligands can be rapidly tested
with a single immobilised catalyst precursor. We consider this
novel strategy for immobilisation that significantly simplifies
the strategy required for the synthesis of stable asymmetric
immobilised catalysts.
The success of this approach allows for the simple immobili-
sation of other ligands without having to isolate the preformed
catalyst. We have used an alternative chiral ligand, R,S-JosiPhos,
to demonstrate the general applicability of our experimen-
tal methodology. [Rh(R,S-JosiPhos)(COD)]–Al-MCM-41 was
prepared by reacting the free ligand 2 with the immobilised
Experimental
All experiments using metal complexes were performed under
inert gas conditions using standard Schlenk techniques using
anhydrous solvents.
MCM-41 mesoporous aluminosilicate (Si : Al = 10 : 1, Si :
H
2
O = 40 : 1) was prepared as follows. Tetramethylammo-
nium hydroxide (101.21 g), cetyltrimethylammonium bromide
(118.45 g), aluminium isopropoxide (26.56 g) and de-ionised
◦
water (860 ml) were stirred at 35 C for 1 h. Fumed silica (78.0 g)
was added and the mixture was stirred at room temperature for
1 h. The gel was then transferred to an autoclave, purged with
nitrogen gas and heated at 150 C for 48 h. After cooling to
ambient temperature, the material was recovered by filtration
and washed with de-ionised water (1 l) and ethanol (500 ml).
The white solid was then oven-dried overnight (110 C, 16 h)
before being heated under nitrogen at 550 C for 16 h. After
this, the solid was calcined in air at 550 for 4 h.
◦
◦
◦
◦
SBA-15 mesoporous aluminosilicate (Si : Al = 8 : 1) was
prepared as follows. Tetraethylorthosilicate (27 g), aluminium
isopropoxide (3.9 g) and aqueous hydrochloric acid (30 ml, pH =
[
Rh(COD) ]–Al-MCM-41 precursor. This catalyst was used for
2
◦
the hydrogenation of dimethyl itaconate using a substrate : Rh
1.5) were stirred at 35 C for 3 h. This was added to a sec-
◦
molar ratio of 500 : 1 at 20 C with a reaction time of 15 min.
ond solution comprising poly(ethylene glycol)–poly(propylene
glycol)–poly(ethylene glycol) tri-block copolymer (12 g, Mav
5800) dissolved in aqueous hydrochloric acid (450 ml, pH =
Following reaction the catalyst was allowed to settle and the
liquid was removed and analysed. As before fresh reagents were
added using the same substrate : Rh molar ratio and condition.
◦
1.5). The mixture was stirred (25 C, 1 h) and then transferred
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 4 7 – 1 5 5 0
1 5 4 9

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◦
to an autoclave, purged with nitrogen gas and heated at 100 C
for 64 h. After cooling to ambient temperature, the material
was recovered by filtration and washed with de-ionised water
with hydrogen again. Products were analysed by chiral gas
chromatography using a LIPODEX-E column.
(
1 l) and ethanol (500 ml). The white solid was then oven-dried
◦
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◦
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+
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5
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◦
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support became orange in colour. The mixture was filtered and
the yellow–orange solid washed with dry degassed methanol
(
remained within the catalyst, the catalyst was then dried and
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was prepared in an analogous manner.
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+
−
MCM-41 (Si/Al = 10, 0.2 g) and [Rh(COD)
2
] BF
4
(0.020 g,
3
◦
0
.05 mmol) were stirred in degassed methanol (5 cm ) at 50 C
for 16 h under a nitrogen atmosphere. The solid material
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1
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Rh(R,R-MeDuPhos)(COD)]–Al-MCM-41 was then prepared
by reacting [Rh(COD) ]–Al-MCM-41 (0.176 mg) with R,R-
2
]–Al-MCM-41 was dried under vacuum.
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[
1
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MeDuPhos (16 mg, 55 lmol) by stirring in degassed methanol
◦
(
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1
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from pale orange to yellow, whilst the methanol solution also
◦
became a pale yellow colour. The mixture was cooled to 25 C
1
1
1
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approximately 1 M solution and the 5 cycles of pressurising–
releasing with hydrogen were repeated. Finally the autoclave
2
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2
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2
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1
5 5 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 4 7 – 1 5 5 0