The role of additional solvents in transition metal complex catalyzed asymmetric reductions in ionic liquid containing systems

Article abstract of DOI:10.1016/j.jorganchem.2005.03.017

When ionic liquids (ILs) are employed as solvents for transition metal complex (TMC) catalyzed reductions, a second solvent can be added to increase the efficiency of the catalytic cycle and the solubility of the reactant in the IL phase. Two industrially relevant asymmetric hydrogenations, the enantioselective reductions of methyl 2-acetamidoacrylate with Rh-EtDuPHOS and methyl acetoacetate with Ru-BINAP, were performed in different catalytic systems including 1-butyl-3-methylimidazolium hexafluorophosphate/ tetrafluoroborate as ILs. Product separation and TMC recycling was performed by extracting the product from the reaction mixture. This can be accomplished by cooling the system, by adding an excess of the second solvent or by adding a third solvent. A high solubility of the second solvent in the IL catalytic phase favors the reaction activity, but can induce leaching of the IL and TMC.

Full text of DOI:10.1016/j.jorganchem.2005.03.017

Journal of Organometallic Chemistry 690 (2005) 3558–3566
www.elsevier.com/locate/jorganchem
The role of additional solvents in transition metal complex
catalyzed asymmetric reductions in ionic liquid containing systems
Adi Wolfson a,*, Ivo F.J. Vankelecom b,*, Pierre A. Jacobs b
a
Department of Chemical Engineering, Sami Shamoon College of Engineering, Bialik/Basel Sts., Beer Sheva, 84100, Israel
b
Faculty of Agricultural and Applied Biological Sciences, Centre for Surface Chemistry and Catalysis, Interphase Chemistry,
Katholieke Universiteit Leuven, Kasteelpark Arenberg 23, 3001 Leuven, Belgium
Received 11 January 2005; received in revised form 11 March 2005; accepted 11 March 2005
Available online 19 April 2005
Abstract
When ionic liquids (ILs) are employed as solvents for transition metal complex (TMC) catalyzed reductions, a second solvent can
be added to increase the efficiency of the catalytic cycle and the solubility of the reactant in the IL phase. Two industrially relevant
asymmetric hydrogenations, the enantioselective reductions of methyl 2-acetamidoacrylate with Rh-EtDuPHOS and methyl aceto-
acetate with Ru-BINAP, were performed in different catalytic systems including 1-butyl-3-methylimidazolium hexafluorophosphate/
tetrafluoroborate as ILs. Product separation and TMC recycling was performed by extracting the product from the reaction mix-
ture. This can be accomplished by cooling the system, by adding an excess of the second solvent or by adding a third solvent. A high
solubility of the second solvent in the IL catalytic phase favors the reaction activity, but can induce leaching of the IL and TMC.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: Ionic liquids; Transition metal complexes; Hydrogenation; Rh-DUPHOS; Ru-BINAP
1
. Introduction
When transition metal complexes (TMCs), which act
as very active and selective catalysts in many reactions
[2], are the catalysts of choice, employing ILs also has
economical and practical benefits. Since many TMCs
dissolve easily in ILs, catalytic reactions can be per-
formed easily in this medium, while product separation
can be readily accomplished by distillation or extrac-
tion with an organic solvent [1]. Moreover, the
IL-phase and the catalyst can be re-used. The heterog-
enization of TMCs was intensely studied over the past
30 years [3]. Different heterogenization methods have
been reported, including the immobilization or entrap-
ment of TMCs in solid organic or inorganic supports,
separation of the complex via membrane filtration [4],
or the use of biphasic systems. Water-organic biphasic
systems were traditionally employed [5], yet prelimin-
ary modification of the complex to ensure its solubility
in the water phase is necessary. Modification of TMCs
Ionic liquids (ILs) have gained increased attention in
the past decade as an alternative green medium for or-
ganic synthesis [1]. Their unique and versatile physical
and chemical properties can be tuned and tailored, thus
making them very attractive solvents. Numerous cata-
lytic and non-catalytic reactions have been successfully
run already in a variety of ILs. In this respect, imidazo-
lium based ILs and especially 1,3-dialkylimidazolium
cations combined with hexafluorophosphate and tetra-
fluoroborate anions, are the most commonly employed
[
1].
*
Corresponding authors. Tel.: +32 1632 1594; fax: +32 1632 1998.
E-mail addresses: adiw@sce.ac.il (A. Wolfson), ivo.vankelecom@
biw.kuleuven.ac.be,
Vankelecom).
ivo.vankelecom@agr.kuleuven.ac.be
(I.F.J.
0
022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.03.017

A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
3559
is also required when fluorinated solvents are used [6].
Supercritical fluids have also been reported as green
solvents for catalysis, but the critical conditions limited
their use [7].
hexafluorophosphate/tetrafluoroborate (bmimPF /BF )
6 4
as ILs.
Even though ILs have a high potential as solvents for
catalytic reactions with TMCs, some issues still limit
their use. The activity of many TMCs catalyzed reac-
tions in ILs is lower than the activity of the correspond-
ing homogeneous reaction in conventional organic
solvents [1]. It can be attributed to several factors. First,
in many catalytic reactions the nature of the solvent can
influence catalytic performance [8]. When TMCs are em-
ployed, the organic solvent can coordinate to the com-
plex and assist in the catalytic cycle to make it more
efficient [9]. On the other hand, the coordination of
the solvent might block the complex and hence decrease
its activity. Lower concentration of reagents (gases, liq-
uids and solids) in the IL catalytic phase, or mass trans-
fer limitations in the highly viscous ILs can also occur.
In addition, it should be taken into account that prod-
ucts with high solubility in the IL phase require large
amounts of extracting solvent to ensure their recovery
and to recycle the complex [1]. TMCs catalyzed hydro-
genations are good examples for the above mentioned
drawbacks [10]. Not only because molecular hydrogen
has a relatively low solubility in ILs [11], but mainly be-
cause coordination of the solvent to the TMCs activates
the catalytic cycle [9].
In this paper, we report on various IL containing
catalytic systems with TMCs where the addition of a
second solvent during the reaction step enhances cata-
lytic performance, while product separation and
catalyst recycling are still feasible. Two industrially
relevant asymmetric hydrogenations, the enantioselec-
tive reductions of methyl 2-acetamidoacrylate (MAT)
with Rh-EtDuPHOS [12] (Fig. 1(a)) and methyl aceto-
acetate (MAA) as representative b-ketoester with
Ru-BINAP [9] (Fig. 1(b)), were performed in different
catalytic systems including 1-butyl-3-methylimidazolium
2. Results and discussion
2.1. Homogeneous reference reactions
As a reference, both hydrogenations were preformed
in ILs under the typical conditions reported in literature
[9,12]. Although both TMCs and substrates dissolved in
the both ILs easily, no reaction took place (Table 1, en-
tries 1 and 2). As stated previously, the hydrogen solu-
bility in the two selected ILs is rather low [11], but
even a higher hydrogen pressure for several hours did
not trigger the reaction. Hence, it was considered
whether the absence of reaction in pure ILs could be as-
cribed to the absence of organic solvent in the catalytic
cycle of the reaction. It would thus mean that, in order
to perform the reaction, another solvent apart from the
IL is necessary (hereafter called reaction solvent, RS).
According to the literature, the homogeneous asym-
metric hydrogenation of MAT with Rh-EtDuPHOS
can be performed with high enantiomeric excess (ee) in
several solvents, with alcohols inducing the highest
activities [12]. The best reaction rates for the enantiose-
lective reduction of MAA with Ru-BINAP have also
been reported in short chain alcohols [9]. For the latter,
the alcohol was actually participating in the reaction as
a proton donor [9b]. The homogeneous reference reac-
tions of both hydrogenations were thus performed in
methanol, ethanol, and isopropanol (IPA) (Table 1, en-
tries 3–5). Methanol yielded the highest performance for
both hydrogenations. Since methanol is miscible in both
ILs, the monophasic hydrogenations in mixtures of
ILs + methanol (RS/IL = 1/1 v/v) were examined (en-
tries 8 and 9). It yielded activities and selectivities equal
to those of the homogeneous systems. This Ôhomoge-
neous-likeÕ performance can be explained by (1) the
COOCH3
H
H
COOCH3
Rh-EtDuPHOS/H2
H C
H
3
-
-
PF /BF
6
4
NHCOCH3
NHCOCH3
+
N
N
H C
(CH ) CH
2 3 3
3
(
(
a) Asymmetric reduction of methyl 2-acetamidoacrylate with Rh-EtDuPHOS
O
O
OH
H
O
Ru-BINAP/H2
H C
O CH3
-
-
H C
O CH3
3
PF /BF
3
6
4
+
N
N
H C
(CH ) CH
2 3 3
3
b)
Asymmetric reduction of methyl acetoacetate with Ru-BINAP
Fig. 1. Representative asymmetric reduction with TMCs in ILs.

3560
A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
Table 1
Asymmetric reductions with TMCs in ionic liquid containing systems
a
b
Entry
Solvent(s)
Rh-EtDuPHOS
Ru-BINAP
ꢀ
1
ꢀ1
c
Selec. (%) (Re-use)
TOF (h ) (Re-use)
ee (%) (Re-use)
TOF (h ) (Re-use)
ee (%) (Re-use)
d
Homogeneous
1
2
3
4
5
6
7
bmimPF
bmimBF
6
0
0
0
0
0
4
0
0
0
0
0
Methanol
Ethanol
3225
3220
2950
2560
1352
97
98
96
97
97
105
92
71
7
99
99
99
21
99
85
87
93
100
89
IPA
Methanol + water
Methanol + hexane
e
e
60
e
Monophasic: dilution/extraction
8
9
0
bmimPF
6
/methanol
3012 (2953)
2605
1601
97 (98)
93
92
99
86
–
99
84
–
91
93
–
bmimBF
bmimBF
4
/methanol
/water
1
4
f
Biphasic
11
12
13
14
bmimPF
bmimPF
bmimPF
bmimPF
6
/hexane
/ether
/IPA
0
0
0
0
0
6
6
6
179 (180)
460 (453)
1025 (998)
96 (96)
95 (94)
96 (97)
0
0
0
21 (20)
1.9
97 (96)
93
83 (84)
100
/water
Reversible phase
g
1
5
6
a
b
c
BmimPF
BmimBF
6
/ethanol
/2-propanol
758 (755)
–
98 (99)
–
63 (65)
32 (32)
95 (96)
89 (88)
93 (93)
91 (91)
h
1
4
1
2
lmol Rh-EtDuPHOS, substrate over catalyst molar ratio of 500, hydrogen pressure of 5 bar, reaction temperature of 20 °C.
lmol Ru-BINAP, substrate over catalyst molar ratio of 140, hydrogen pressure of 40 bar, reaction temperature of 60 °C.
Selectivity to methyl hydroxybutyrate.
d
e
2
1
2
mL solvent, 5 min.
mL of each solvent, 5 min.
mL IL and 2 mL solvent, 20 min. Re-use of the catalyst was done by addition of fresh substrate after extraction of the IL with 6 mL of the
f
solvent.
g
1
0
.1 mL bmimPF
.8 mL bmimBF
6
and 0.9 mL ethanol (33 wt% ethanol). Re-use of the catalyst phase after addition of 3.2 mL ethanol to extract.
and 1.2 mL 2-propanol (50 wt% 2-propanol). Re-use of the catalyst phase after adding 3.2 mL 2-propanol to extract.
h
4
presence of a solvent that can participate in the catalytic
cycle during the reaction, and (2) by the increased
hydrogen solubility in the ILs + methanol mixtures.
as well as the losses of IL and complex to the extracting
phase should be considered when selecting a combina-
tion of IL + RS + ES. Thus, several representative polar
and non-polar solvents were tested as ES and combined
with several RS + IL couples (ES/(RS + IL) = 1/1 v/v)
(Table 2). Methanol, which is fully miscible in both
ILs (entries 1–8), and water, which is miscible in
The reactions in bmimBF showed lower activities and
4
selectivities, probably due to impurities left from the
synthesis of this particular IL [1b].
2
.2. Extractions from IL phase
bmimBF (entries 9 and 10), were added as RS. Two
4
combinations with ESs that mix partly or fully with
the IL, such as IPA and water in bmimBF (entries 2
When a miscible solvent is added as a RS to the IL
4
catalytic phase, product separation and recycling of
the IL phase and the catalyst within look at first sight
complicated. However, it will be shown below that some
elegant methods exist due to some particularities of the
investigated ILs.
Since distillation is limited to compounds with rela-
tively low boiling point, extraction of the products from
the IL + RS system with a third solvent (hereafter:
extraction solvent, ES) was investigated. Depending on
their mutual miscibility, the RS could be co-extracted
by the ES (Fig. 2(a), type A) or not (type B), while the
three solvents formed one-phase in still other cases (type
C). Both the extraction yields of the organic compounds
and 8), resulted in type C systems. Obviously, this type
of system is non-practical for extraction. However,
employing hydrophobic solvents which are immiscible
with the ILs, yielded type B systems with methanol pref-
erably dissolved in the polar IL phase (entries 3 and 4).
Still other ESs co-extracted the RS, resulting in type A
systems (entries 1, 5–7, 9–10).
The leaching of both complexes in the various
(IL/RS/ES)-combinations as well as the extraction yields
of MAA in one extraction step are also summarized in
Table 2. It should be considered that MAA is a repre-
sentative organic compound, but one with a high solu-
bility in both ILs, and thus very challenging to

A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
3561
Fig. 2. IL containing catalytic systems: (a) monophasic system: dilution/extraction concept; (b) biphasic system; (c) reversible phase system.
recover. It can be concluded in general that when type A
systems are formed, the extraction yields are full, yet
there is often some leaching of the complexes. On the
other hand, type B systems resulted in lower extraction
yields, but negligible TMC leaching. It thus seems that
co-extracting the RS (type A) efficiently extracts the
product from the IL, but it also extracts some of the
IL and hence the complex within. On the contrary, sys-
tems that do not co-extract the RS (type B), do not ex-
tract the IL and the complex either. However, the
extraction yields of the organic compounds from the
IL phase are lowered.

3562
A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
Table 2
The type of system formed by adding an ES to the (IL + RS) mixture and the extraction yield with such system for MAA and leaching for the two
a
selected TMCs
Entry
IL anion
Reaction
solvent
Extraction
solvent
System
type
Extraction
b
yield (%)
Leaching of
Ru-BINAP (%)
Leaching of
Rh-DuPHOS (%)
c
d
e
1
2
3
4
5
6
7
8
9
PF
BF
PF
BF
PF
BF
PF
6
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Water
IPA
IPA
A
C
B
B
A
A
A
C
B
B
100
–
1 (8)
–
7
–
0
0
0
4
2
–
0
0
4
6
Hexane
Hexane
Ether
Ether
Water
Water
Hexane
Ether
6
0 (0)
0
4
5
6
100
100
100
–
0
4
1
6
1 (3)
BF
BF
BF
4
4
4
–
0
0
0
1
0
a
b
c
Water
31
1
0
1
1
mL IL and 1 mL reaction solvent, 2 mL extraction solvent.
.014 g MAA.
lmol Ru-BINAP.
lmol Rh-EtDuPHOS.
d
2
.3. Monophasic reactions, followed by extraction
All the above findings were finally combined in the
allowing hexane for the subsequent extraction. A similar
system was studied by Ngo and co-authors using a phos-
phinic acid derived Ru-BINAP [13]. In agreement with
this report, the activity of the asymmetric reduction of
two representative hydrogenations with both ILs under
monophasic reaction conditions, followed by extraction
MAA with Ru-BINAP in the (bmimPF /methanol) mix-
6
(
Table 1 (entries 8–10)). As previously mentioned, when
ture was again comparable to the best homogeneous
activity (Table 1, entries 8 and 3, respectively). Addition
of 2 mL hexane to the reaction mixture resulted in the
extraction of 8% of the product in the first step.
methanol was employed as the RS, the activity of Rh-
EtDuPHOS in MAT hydrogenation was comparable
to those of the best homogeneous system (entries 8
and 9). The ES was chosen so that the methanol would
not be co-extracted, since this would cause complex and
IL leaching. Hexane clearly fulfilled these requirements
2.4. Biphasic reactions
(
Type B system). However, only 7 wt% of the reaction
Another approach commonly used in the literature, is
performing the reaction in a biphasic system [10]. Guer-
nik et al. studied the asymmetric reduction of MAT with
product could be extracted by hexane in one step. In or-
der to increase the extraction yield, an alternative mon-
ophasic-IL system was tested with bmimBF4 as IL,
water as RS and ether as ES (Table 1, entry 10). Indeed,
the product extraction yield could be increased now to
Rh-MeDuPHOS in bmimPF /IPA biphasic system and
6
the activity in the biphasic system was 4–5 times lower
than the activity of the homogeneous reaction in IPA
[10c]. In such a system, the RS and ES are the same sol-
vent with a low miscibility in the IL. It can thus both
activate the reaction and extract the product at the
end of the reaction (Fig. 2(b)). Various representative
solvents were thus combined with the two selected ILs
in the two asymmetric hydrogenations (Table 1). While
hexane as RS did not allow any reaction in the asymmet-
ric reduction of MAT with Rh-EtDuPHOS (entry 11),
1
9% in one step without complex or IL leaching, but this
took place at the expense of a lower activity and slightly
decreased ee. The former is probably due to the fact that
methanol is a better solvent for this reaction than water,
the latter to the fact that bmimBF had to be used here
4
and possible chlorine leftovers from the IL synthesis
might harm the Rh-EtDuPHOS performance [1b]. Re-
use of the IL-containing Rh-DuPHOS phase after five
sequential extraction steps and addition of extra MAT
was successful (entry 8, numbers between brackets).
In the asymmetric reduction of MAA with Ru-BI-
NAP, the choice of reaction solvent is even more crucial,
and thus limited [9b]. Homogeneous reactions can only
be performed in alcoholic or chlorinated solvents, but
the alcoholic solvents yield much higher activities, due
to the participation of the alcoholic solvent in the cata-
lytic cycle. Furthermore, addition of high amounts of
water severely decreases the catalyst performance.
Therefore, only methanol could be selected as the RS,
combining bmimPF with ether, IPA or water yielded
6
activities (entries 12–14) that were lower than the activ-
ity of the homogeneous reactions in alcohols (entries 3–
5). The absence of reaction with hexane illustrates that
hexane cannot participate in the catalytic cycle (entry
7). The lower activities in the biphasic systems can be
attributed to the low concentration of the RS in the IL
catalytic phase, but also to the distribution of the sub-
strate between the two phases present during reaction.
The amount of MAT in the catalyst containing IL phase
was determined by extraction of the IL phase with the

A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
3563
Table 3
The effect of solvent type in the (bmimPF
on the extraction yields of MAT and MAA and on TMCs leaching
6
+ solvent)-biphasic systems
a
Entry Solvent MAA MAT Leaching of Leaching
extraction extraction Ru-BINAP
of Rh-
DuPHOS
d
(%)
yield
b
yield
c
(%)
e
(
%)
(%)
1
2
3
IPA
Water
Ether
24
23
19
38
27
19
0
1
0
0
1
0
a
b
c
1
1
4
1
1
mL bmimPF
40 mg MAA.
5 mg MAT.
6
, 1 mL solvent, room temperature.
d
e
lmol Ru-BINAP.
lmol Rh-EtDuPHOS.
three solvents (Table 3). It was found to increase in the
order ether > water > IPA, as expressed by the decrease
of the amount of MAT extracted from the IL phase
from IPA to diethyl ether. Hence, if a higher concentra-
tion of the substrate in the IL catalytic phase would have
been the only reason for the higher reaction rate, the
reaction should have proceeded faster in ether than in
water, which is clearly not the case. In the enantioselec-
tive reduction of MAA with Ru-BINAP, IPA was the
only solvent that could work (entry 13), as expected,
but the activity was only 20% of the best homogeneous
system in methanol (entry 3) and about 30% of the
homogeneous reaction in IPA (entry 5).
The superior reaction rate of the (bmimPF /water) bi-
6
Fig. 3. Biphasic systems with bmimPF
and a few seconds after mixing (bottom picture).
6
before mixing (top picture)
phasic system can be thus mainly attributed to the excel-
lent mixing in this system. In fact, visual observations
supported this suggestion (Fig. 3). The combination of
moval of the products by extraction with extra amounts
of the RS and showed similar performance as in the first
run (Table 1, values between brackets in entries 9–11).
The small decrease in the activity of the re-use of the
bmimPF with hexane or IPA resulted in visibly big
6
droplets of the organic solvent in the IL-continuous
phase. The addition of water to bmimPF on the other
6
hand, resulted in a much better dispersed system, as re-
flected in the turbid aspect of the mixture, indicating the
presence of smaller droplets. The different mixing of the
various IL-biphasic systems can be explained by the dif-
(bmimPF /water) system is probably due to the loss of
6
some IL and catalyst during extraction (Table 1, entry
14).
ference in their mutual solubility with bmimPF [14a].
6
2.5. Reversible phase catalytic systems
While hexane has negligible solubility in the IL due to
its insignificant polarity and hydrogen bonding charac-
ter, IPA has a higher solubility in bmimPF and water
Finally, it was found that the phase behavior of the
two selected ILs with some alcohols could combine the
advantages of homogeneous and heterogeneous cataly-
sis. These solvent combinations showed a temperature
and concentration dependent reversible phase behavior,
as can be seen in Table 4. While methanol was miscible
with both ILs over the full temperature range, longer
alcohols like pentanol showed poor miscibility in the
same ILs. However, ethanol, IPA and 2-butanol
displayed solubility at the two selected temperatures
which are suitable for catalytic applications. By increas-
ing the temperature from 20 to 60 °C, the solubility of
6
the highest solubility. The solubility of water in
bmimPF and of bmimPF in water were found to be
around 2 wt% [14b].
6
6
Although the conversions of the biphasic systems
were lower than the conversion of the homogeneous
and monophasic reactions, the products could be fully
extracted after three sequential extractions with 2 mL
of the corresponding solvent. The leaching of both com-
plexes from the IL phase was negligible, except for a
small loss of complex when water was used as RS due
to some leaching of the IL to the water (Table 3). The
IL catalytic phase was thus successfully re-used after re-
ethanol in bmimPF doubled, while the solubility of
6
IPA and 2-butanol in bmimBF increased 5- and 8-fold,
4

3564
A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
Table 4
Solubilities of alcohols in the two selected RTILs at different
tions, followed by a straightforward phase separation
induced by either cooling or by addition of excess sol-
vent or by a combination of both. After fast phase sep-
aration the formed products can be easily extracted,
while the TMCs could be recycled without loss of
activity.
a
temperatures
b
b
IL
Alcohol
wt% (20 °C)
wt.% (60 °C)
BmimPF
6
Methanol
Ethanol
Full
17
Full
35
2-butanol
Negligible
Negligible
BmimBF
4
Methanol
Ethanol
Full
Full
Full
Full
3
. Conclusions
1
5
5
75
40
2-butanol
n-Pentanol
ILs can be employed as green solvents in heterogeni-
Negligible
Negligible
a
zation of TMCs whereas the products can be extracted
by an extraction solvent which is immiscible in the IL
phase. However the hydrogenations of many molecules
with TMCs cannot be performed in pure IL and thus
require the existence of another solvent during the reac-
tion. The reaction solvent and the extraction solvent
can be the same, partially miscible (reversible phase
system) or immiscible (biphasic system) in the IL phase.
Alternatively, the reaction solvent can be fully miscible
in the IL while the product is extracted by another
immiscible solvent (monophasic reactions, followed by
extraction). In general, increasing the solubility of the
reaction solvent in the IL catalytic phase increases the
reaction activity. It is attributed to the activation of
the catalytic cycle by the reaction solvent as well as
to increase of the concentration of organic reactant
and hydrogen in the IL phase. In addition, when fully
or partly miscible solvents are added to the IL during
the reaction, extraction of the product by the same sol-
vent or another extracting solvent that co-extracts the
reaction solvent results in high extraction yields of or-
ganic compound, yet part of the IL and catalyst within
will also leach to the extraction solvent. On the other
hand, employing of a second solvent which has poor
miscibility with the IL, or an extracting solvent that
does not co-extract the reaction solvent, yields lower
extraction yield without any loss of the IL and the
TMC. Hence, the combination of IL, reaction solvent
and extraction solvent is primarily depending on the
reaction requirements, yet it should be optimized
regarding reaction activity, product extraction and cat-
alyst recycling.
Measured by addition of the alcohol to the IL under stirring, until
phase separation was observed.
b
Weight of alcohol/weight of alcohol and IL.
respectively. This behavior would allow the use of these
alcohols for the two representative reactions as both the
RS and ES. It means that a partially miscible solvent can
be added to the IL already during reaction and allow
catalysis to take place under Ôhomogeneous-likeÕ condi-
tions, while a simple decrease in temperature or further
increase of the dilution degree with the same solvent al-
lows easy separation of the catalyst from the product
Fig. 2(c)). Similar phase behavior of IL with supercrit-
ical carbon dioxide was employed to recycle several
TMCs [15].
The two selected enantioselective hydrogenations
were run in (bmimPF /ethanol) and (bmimBF /IPA)
(Table 1, entries 15 and 16). As previously shown, the
BF -system yielded a lower activity and enantioselectiv-
ity (entry 16). Addition of an extra 2 mL of ethanol to
the monophasic hydrogenation of MAT with Rh-EtDu-
PHOS in (bmimPF /ethanol) resulted in a 36 wt% prod-
uct extraction yield. The complex of entry 15 was
successfully recycled after three successive extractions
of the IL phase adding such excess of ethanol. Alterna-
tively, Ru-BINAP was successfully recycled (Table 1,
entry 15) with removal of the methyl hydroxybutyrate
saturated top layer after simple cooling to room temper-
ature. This yielded 13% of the product. Combining ex-
cess solvent addition with cooling via the addition of
(
6
4
4
6
2
mL of cold ethanol to the reaction mixture, increased
the extraction yield to 46%. A similar successful extrac-
tion and re-use procedure was also done with the
(
bmimBF /IPA) system. The activities and selectivities
4
4. Experimental
during the second run in both reactions were found to
be equal to those of the first one. This proved already
the negligible TMC leaching during the extraction pro-
cedure, as could be confirmed by direct ICP-analysis
of the ethanol phase for Ru and Rh (<2% leaching).
Only ꢁ1 wt% of the IL was detected in the extractant
phase.
This remarkable reversible phase behavior of mix-
tures of certain ionic liquids and organic solvents thus
allows to perform reactions under homogeneous condi-
4.1. General
Rh-EtDuPHOS was purchased from Strem, while
0
0
Ru-BINAP (2,2 -Bis(diphenylphosphino)-1,1 -binaph-
thalene]chloro(p-cymene)ruthenium chloride), methyl
2-acetamidoacrylate, methyl acetoacetate and ILs were
purchased from Fluka. The solvents were purchased
from Across. Both the homogeneous and heterogeneous
reactions were performed in a 10 mL stainless steel

A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
3565
pressure reactor with magnetic stirring. In a typical reac-
4.5. Reversible phase reactions
tion, the complex was first added to the reaction mixture
under nitrogen atmosphere, followed by the addition of
the substrate.
The amount of catalysts and substrates as well as
reactions conditions is the same as in the homoge-
neous reactions. The reactions in the reversible sys-
tems were performed in 1.1 mL bmimPF6 and
0.9 mL ethanol (33 wt% ethanol), or 0.8 mL bmimBF4
and 1.2 mL isopropanol (50 wt% isopropanol). Re-use
of the catalyst phase was done by addition of 3.2 mL
ethanol or isopropanol to extract the products and
addition of the corresponding amount of fresh sub-
strate and alcohol.
Conversion and selectivity were determined after
extraction of the substrate and the product from the
IL containing phase by GC analysis in a suitable col-
umn. Conversion were calculated by the amounts of
substrate and product in the extracting solvent (or sol-
vent mixture) taking into account also the different dis-
tribution constants of both substrate and product
between the IL and the extracting solvent. The extrac-
tions yields were determined by calculating the amount
of the substances in the extracting solvent by GC analy-
sis (using a standard) divided by the total amount that
was added to the IL phase. Leaching of the metal com-
plexes was detected by atomic adsorption spectroscopy
in accuracy of 0.05 lg/ml. In all cases, the solvent
mixture was carefully evaporated and the residue was
re-dissolved in 5 mL methanol.
Acknowledgements
AW acknowledges a postdoctoral fellowship in the
frame of an IAP-network on supramolecular chemistry
and catalysis, sponsored by the Belgian Federal Minis-
try of Science Policy. The research is done within the
same framework.
4
.2. Homogenous reactions
References
For the asymmetric hydrogenation of MAT with Rh-
EtDuPHOS, 1 lmol of the complex was added to 2 mL
of solvent under nitrogen atmosphere followed by the
addition of the substrate (71.5 mg). Hydrogen was fed
at a pressure of 5 bar, after flushing with nitrogen and
hydrogen. For the enantioselective hydrogenation of
MAA with Ru-BINAP, 2 lmol of the complex was
added to 2 mL of solvent under nitrogen atmosphere
with 32.5 mg of substrate and the reactions proceeded
at 40 bar hydrogen pressure and 60 °C.
[
1] (a) M.J. Earle, K.R. Seddon, Pure & Appl. Chem. 72 (2000)
1391;
(
(
(
b) R.A. Sheldon, Chem. Commun. 23 (2001) 2399;
c) H. Olivier, L.J. Mangna, Mol. Catal. 182 (2002) 419;
d) D. Zhao, M. Wu, Y. Kou, E. Min, Catal. Today 74 (2002)
1
57;
e) C.M. Gordon, Appl. Catal. A 222 (2001) 101;
(f) T. Welton, Chem. Rev. 99 (1999) 8;
(
(
(
(
(
g) J. Dupont, R.F. de Souza, P.A.Z. Suarez, Chem. Rev. 102
2002) 3667;
h) T. Welton, Coord. Chem. Rev. 248 (2004) 2459;
i) P. Wasserscheid, T. Welton, Ionic Liquids in Synthesis, Wiley-
4
.3. Monophasic reactions
VCH, Weinheim, 2003.
[
[
2] M. Beller, C. Bolm (Eds.), Transition Metals for Organic
Synthesis, Building Blocks and Fine Chemicals, Wiley-VCH,
Weinheim, Germany, 1998.
The amount of catalysts and substrates as well as
reactions procedures and conditions are the same as in
the homogeneous reactions apart form the solvent
which was in the monophasic reaction a mixture of
3] (a) K. Fodor, S.G.A. Kolmschot, R.A. Sheldon, Enantiomer 4
(
(
1999) 497;
b) D. De Vos, I.F.J. Vankelecom, P.A. Jacobs, Chiral Catalyst
1
mL of IL and 1 mL of a solvent which is miscible in
Immobilisation and Recycling, Wiley-VCH, Weinheim, Germany,
000.
4] (a) I.F.J. Vankelecom, Chem. Rev. 102 (2002) 10, 3779;
b) K. De Smet, S. Aerts, E. Ceulemans, I.F.J. Vankelecom, P.A.
Jacobs, Chem. Commun. (2001) 597;
c) I.F.J. Vankelecom, L.E.M. Gevers, in: C.A.M. Afonso, J.G.
2
the IL. Re-use of the complex was done by extraction
of the IL + RS mixture with 6 mL ES after the first
run to remove the residual product and substrate. Fresh
substrate was then added to the IL phase.
[
(
(
Crespo (Eds.), Pressure-Driven Membrane Filtration in Green
Separation Processes, Wiley-VCH, Weinheim, Germany, 2005.
5] B. Cornils, W.A. Herrmann, Applied Homogeneous Catalysis
with Organometallic Compounds, Wiley-VCH, Weinheim, Ger-
many, 2002.
4
.4. Biphasic reactions
[
The amount of catalysts and substrates as well as
reactions conditions is the same as in the homogeneous
reactions. Both the substrate and complex were added to
[
6] (a) I.T. Horv a´ th, J. R a´ bai, Science 266 (1994) 72;
(b) R.H. Fish, Chemistry – A European Journal 5 (1997) 1677.
[7] P.G. Jessop, T. Ikariya, R. Noyori, Chem. Rev. 99 (1999)
[
[
2
mL of IL under nitrogen followed by addition of 2 mL
4
75.
of a non-miscible solvent. Re-use of this system was
done after extraction of the products in three sequential
extraction steps of 2 mL of the solvent that was em-
ployed during the reaction.
8] R. Christian, Solvent Effects in Organic Chemistry, Verlag
Chemie, Weinheim, 1979.
9] (a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, John
Wiley, New York, 1994;

3
566
A. Wolfson et al. / Journal of Organometallic Chemistry 690 (2005) 3558–3566
b) A. Wolfson, I.F.J. Vankelecom, S. Geresh, P.A. Jacobs, J. (b) J.L. Anthony, E.J. Maginn, J.F.J. Brennecke, Phys. Chem. B
(
Mol. Catal. A 198 (2003) 39;
106 (2002) 7315.
[12] (a) M.J. Burk, J.E. Feaster, W.A. Nugent, R.L.J. Harlow, Am.
Chem. Soc. 115 (1993) 10125;
(
c) S. Akutagawa, Appl. Catal. 128 (1995) 171;
d) R. Noyori, T. Ohkuma, M.J. Kitamura, Am. Chem. Soc. 109
1987) 5856;
(
(
(
(b) M.J. Burk, Y.M. Wang, J.R.J. Lee, Am. Chem. Soc. 118
(1996) 5142.
e) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H. Kumobyashi,
S. Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am. Chem.
Soc. 110 (1988) 629.
10] (a) Y. Chauvin, L. Mussmann, H. Olivier, Angew. Chem. Int. 34
[13] H.L. Ngo, A. Hu, W. Lin, Chem. Commun. (2003) 1912.
[14] (a) W.M. Reichert, J.D. Holbrey,, J.G. Huddleston, R.D. Rogers,
Abs. 2269, 206th Meeting, The Electrochemical Society, Inc,
2004;
[
[
(
(
1995) 2341;
b) A.L. Monteiro, F.K. Zinn, R.F. de Souza, J. Dupont,
(b) J.L. Anthony, E.J. Maginn, J.F.J. Brennecke, Phys. Chem. B
105 (2001) 10942.
Tetrahedron Asymm. 8 (1997) 177;
c) S. Guernik, A. Wolfson, M. Herskowitz, N. Greenspoon, S.
Geresh, Chem. Commun. 22 (2001) 2314.
(
[15] (a) F. Liu, M.B. Abrams, R.T. Baker, W. Tumas, Chem.
Commun. (2001) 433;
11] (a) A. Berger, R.F. de Souza, M.R. Delgado, J. Dupont,
Tetrahedron Asymm. 12 (2001) 1825;
(b) R.A. Brown, P. Pollet, E. McKoon, C.A. Eckert, C.A. Liotta,
P.G. Jessop, J. Am. Chem. Soc. 123 (2001) 1254.