A materials approach to site-isolation of grubbs catalysts from incompatible solvents and m-chloroperoxybenzoic acid

Article abstract of DOI:10.1002/chem.200800094

The development of a method for site-isolation of Grubbs second-generation catalyst from MCPBA is described. In these reactions, Grubbs catalyst was dissolved in a solvent consisting of a mixture (1:1 v/v) of 1-butyl-3- methylimidazolium hexafluorophosphate and methylene chloride and completely encapsulated within a thimble fabricated from polydimethylsiloxane (PDMS). A series of molecules that react by cross metathesis or ring-closing metathesis were added to the interior of the thimble and allowed to react. In the last step, m-chloroperoxybenzoic acid (MCPBA) dissolved in MeOH/H₂O (1:1 v/v) was added to the exterior of the PDMS thimble. Small organic molecules diffused through the PDMS to react with MCPBA to form epoxides, but the Grubbs catalyst remained encapsulated. This result is important because Grubbs catalyst catalytically decomposes MCPBA at ratios of MCPBA to Grubbs of 3000 to 1. The yields for this two-step cascade sequence ranged from 67 to 83%. The concept behind this sequence is that small organic molecules have high flux through PDMS but large molecules - such as Grubbs catalyst - and ionic reagents-such as MCPBA-have much lower flux through PDMS. Small molecules can thus react both outside and inside PDMS thimbles, whereas incompatible catalysts and reagents remain site-isolated from each other. This method does not require alteration of structures of the catalysts or reagents, so it may be applied to a wide range of homogeneous catalysts and reagents. To demonstrate further that the catalyst was encapsulated, the Grubbs catalyst was successfully recycled within the cascade sequence.

Full text of DOI:10.1002/chem.200800094

DOI: 10.1002/chem.200800094
A Materials Approach to Site-Isolation of Grubbs Catalysts from
Incompatible Solvents and m-Chloroperoxybenzoic Acid
Martin T. Mwangi, M. Brett Runge, Kevin M. Hoak, Michael D. Schulz, and
Ned B. Bowden*[a]
Abstract: The development of
method for site-isolation of Grubbs
second-generation catalyst from
a
added to the exterior of the PDMS
thimble. Small organic molecules dif-
fused through the PDMS to react with
MCPBA to form epoxides, but the
Grubbs catalyst remained encapsulat-
ed. This result is important because
Grubbs catalyst catalytically decompos-
es MCPBA at ratios of MCPBA to
Grubbs of 3000 to 1. The yields for this
two-step cascade sequence ranged from
67 to 83%. The concept behind this se-
quence is that small organic molecules
have high flux through PDMS but
large molecules—such as Grubbs cata-
lyst—and ionic reagents—such as
MCPBA—have much lower flux
through PDMS. Small molecules can
thus react both outside and inside
PDMS thimbles, whereas incompatible
catalysts and reagents remain site-iso-
lated from each other. This method
does not require alteration of struc-
tures of the catalysts or reagents, so it
may be applied to a wide range of ho-
mogeneous catalysts and reagents. To
demonstrate further that the catalyst
was encapsulated, the Grubbs catalyst
was successfully recycled within the
cascade sequence.
MCPBA is described. In these reac-
tions, Grubbs catalyst was dissolved in
a solvent consisting of a mixture (1:1
v/v) of 1-butyl-3-methylimidazolium
hexafluorophosphate and methylene
chloride and completely encapsulated
within a thimble fabricated from poly-
dimethylsiloxane (PDMS). A series of
molecules that react by cross metathe-
sis or ring-closing metathesis were
added to the interior of the thimble
and allowed to react. In the last step,
m-chloroperoxybenzoic acid (MCPBA)
dissolved in MeOH/H2O (1:1 v/v) was
Keywords:
cascade reactions
·
epoxidation · metathesis · recycling
Introduction
Numerous cascade reactions have been developed, and
many of them use one catalyst that catalyzes multiple steps,
such as in a recent report in Nature of a catalytic reaction
with a proline derivative to form four stereocenters in one
pot.[1] The use of single catalysts to carry out multiple reac-
tions has been very successful, but these cascade reactions
typically require the development of new catalysts and
cannot be integrated with numerous homogeneous catalysts
that are often commercially available and are excellent cata-
lysts for one reaction.[3] The main reason for this limitation
is that these catalysts often poison one another or are pois-
oned by reagents required by a second catalyst. Thus, only
one can be added to a reaction vessel, and no cascade se-
quence is possible. What is needed to advance the field of
cascade reactions is a new method to integrate multiple cat-
alysts and reagents to take advantage of mature homogene-
ous catalysts that catalyze one reaction very well.
The capability to carry out multiple reactions in one flask is
an important goal in chemistry because of the need to speed
the synthesis of molecules while producing less waste and
requiring fewer hours of effort.[1–38] These reactions are
often called cascade or domino reactions; their names refer
to how several reactions occur in a predicted sequence in
the same reaction vessel. These reactions are terrific exam-
ples of green chemistry because they require less solvent
and produce less waste than the traditional method of isolat-
ing and characterizing products after each reaction.[5,30,39]
[a] M. T. Mwangi, M. B. Runge, K. M. Hoak, M. D. Schulz,
Prof. N. B. Bowden
Department of Chemistry, University of Iowa
Iowa City, IA 52242 (USA)
Because many catalysts and reagents poison one another,
they must be site-isolated from each other, such that multi-
ple catalysts or reagents can be integrated into one reaction
vessel for cascade reactions.[28,40–42] Site-isolation involves
Fax : (+1)319-335-1270
E-mail: ned-bowden@uiowa.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
modifying the catalysts or reagents such that they do not
come into contact and poison one another. Numerous meth-
ods for site-isolation exist, such as attachment to a polymer
backbone, attachment of a catalyst to a solid polymeric sup-
port, attachment of catalysts to a heterogeneous surface,
trapping a catalyst inside a zeolite cage, or using catalytic
enzymes in which the active sites are protected by the
enzyme from interacting with the active site of another
enzyme.[10,17,20,43–60] These methods have been very successful
in some instances: for example, FrØchet and Hawker at-
tached both acidic and basic residues to the interiors of star
polymers to integrate acid- and base-catalyzed reactions in
one vessel.[48,49] In another example, heterogeneous acidic
and basic clays were added to the same reaction vessel to
carry out concurrent acid- and base-catalyzed reactions.[61]
One critical limitation that hinders development of this ap-
proach is that most methods for site-isolation require the
structure of the catalyst be altered for attachment to a poly-
mer or solid support. These alterations may require several
synthetic steps and affect the reactivity and selectivity of
catalysts, or may simply not be possible with a wide variety
of reagents. In this paper we report a simple method for
site-isolation of a homogeneous, organometallic catalyst
from a reagent through the use of a polymeric membrane.
This method does not require the structures of the catalyst
or reagent to be altered and will, we believe, be a general
method for site-isolation of a variety of catalysts and re-
agents without affecting their structures.[62]
to a solvent in the interiors of the PDMS thimbles and
MCPBA to the exteriors of the thimbles. The Grubbs cata-
lysts and MCPBA poison each other even at low loadings of
the Grubbs catalyst, but they were site-isolated by the
PDMS walls, whereas small molecules readily diffused
through the walls to react with the catalyst and reagent. Cas-
cade reactions with the Grubbs catalyst and MCPBA were
therefore possible even though these molecules were vastly
incompatible with each other.
This work builds on and greatly expands our prior work
on site-isolation of Grubbs catalysts by occlusion inside of
PDMS slabs.[63,64] In this prior work, the Grubbs catalysts
were swollen into a solid PDMS slab such that PDMS was
the new solvent for the catalyst. Occlusion was very success-
ful for site-isolation of the Grubbs catalyst, but limits re-
mained as to the choice of solvents that could be used and
some reagents reacted by olefin isomerization rather than
metathesis. Occlusion was therefore useful for a set of re-
agents, but not a wider solution to site-isolation.
Encapsulation in a PDMS thimble allows the catalyst to
remain dissolved in an organic solvent, is amenable to reac-
tions with polar or apolar substrates, and is a general
method for site-isolation of catalysts and reagents. It is criti-
cally important to note that we do not change the structures
of the Grubbs catalyst or the MCPBA. We site-isolated the
Grubbs catalyst by encapsulation even while it was freely
dissolved in a solvent at reasonable concentrations.
In this paper we describe our method to fabricate PDMS
thimbles and show how they can be used for site-isolation of
the Grubbs catalysts from MCPBA. This site-isolation
method allows cascade reactions that are not possible with-
out PDMS thimbles. The immediate impact of this paper is
that cascade reactions using metathesis catalysts and
MCPBA will be possible for the first time. The long-term
impact is a simple method to integrate organometallic cata-
lysts with reagents that poison one another into cascade re-
actions without having to affect the structures either of the
catalyst or of the reagent. This method should allow for a
wide variety of catalysts and reagents to be integrated into
cascade reactions without introduction of extra synthetic
steps.
Our method for site-isolation of catalysts and reagents
uses polydimethylsiloxane (PDMS) thimbles (Scheme 1). To
begin this work, hollow PDMS thimbles 1.2 cm in diameter
and 5 cm in height and with PDMS walls that were 105 mm
thick were constructed. The bottoms of these thimbles were
composed of PDMS, but the tops were left open for easy
filling with solvent and catalyst. The concept behind the
work in this paper is simple: the Grubbs catalyst was added
Results and Discussion
Determining the optimum solvent for encapsulating Grubbs
catalysts in PDMS thimbles: A set of conditions was desired
for site-isolation of the Grubbs catalysts in the interior of a
PDMS thimble while allowing small molecules to diffuse
from the exterior to the interior to react (Scheme 2). Specif-
ically, a method was desired for adding reagents to the exte-
rior of a PDMS thimble, having them diffuse into the thim-
ble where the Grubbs catalyst was dissolved, reacting with
the Grubbs catalyst, and diffusing out of the thimble while
the Grubbs catalyst remained encapsulated. It would be nec-
essary to keep the Grubbs catalysts site-isolated in the inte-
rior of the thimbles (rather than allow them to diffuse
Scheme 1. a) Schematic representation of the PDMS thimbles used in
this work, which were shaped as cylinders with a PDMS bottom and an
open top. b) and c) The metathesis reaction occurs on the interior of the
thimble, and the oxidation occurs on the exterior of the thimble. Here,
G2 is Grubbs second-generation catalyst.
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6781

N. B. Bowden et al.
Table 1 shows the results for the reaction sequence shown
in Scheme 2 in the presence of Grubbs first-generation cata-
lyst and different solvents. Because [BMIM][PF6] does not
A
swell PDMS, we first studied whether the diethyl diallylmal-
onate could diffuse into the interior of the thimble at a rea-
sonable rate. From Entries 1 and 2 in Table 1 it is clear that,
although the rate of diffusion is enhanced by heating, the
levels of conversion were low. An additional problem with
this solvent was the poor solubility of the Grubbs catalyst.
A
N
ride to be present to dissolve the catalyst fully. When meth-
ylene chloride was used, however, the catalyst rapidly dif-
fused from the interior as seen visually. Grubbs catalyst
forms a red solution when dissolved in methylene chloride;
after reaction with a substrate resulting in the formation of
a methylidene, this becomes an orange solution. Because of
these colors, it was obvious by eye whether the catalyst was
Scheme 2. Reaction scheme for selective reagent transport and site-isola-
tion of Grubbs catalyst from MCPBA. Diethyl diallylmalonate was
added to the exterior of the PDMS thimble and diffused into the interior
to react with the Grubbs catalyst. The product was then free to diffuse
into the exterior.
through the PDMS) because
this would allow a second reac-
tion to take place outside the
thimble without concern for
whether reagents in the exterior
would be poisoned by the
Grubbs catalyst.
Although there exists a vast
amount of literature on the
rates of diffusion and the fluxes
Table 1. The effect of different solvents and temperatures on the ring-closing metathesis of diethyl diallylmal-
onate as shown in Scheme 2.
Entry[a]
Solvent[b]
[BMIM]
[BMIM]
CH2Cl2
t [h]
T [8C]
Conversion [%][c]
Leaching[d]
1
2
3
G
72
72
NA
3
25
60
25
25
25
25
40
45
5
62
no
no
yes
yes
yes
no
ACHTREUNG
NA[e]
100
100
72
4
5
5:1 CH2Cl2/
3:1 CH2Cl2/
ACHTREUNG
A
5
6
1:1 CH2Cl2/
1:1 CH2Cl2/
1:1 CH2Cl2/
N
9
13
1
7
100
100
no
no
8[f]
through PDMS for a variety of [a] Solvent in the interior (1.5 mL) together with 4 mol% of Grubbs first-generation catalyst were added to
the interior of the thimble, whereas the same solvent (4.0 mL) was added to the exterior. [b] [BMIM] is the ab-
organic molecules, these data
breviation for [BMIM][PF6]. The ratios are based on volumes. [c] Conversion of the diethyl diallylmalonate to
A
are incomplete for many of the
molecules of interest for our
work and are not directly appli-
cable if PDMS is swelled by an
organic solvent. Prior literature
thus provides a useful guide for
the cyclized product as determined by 1H NMR spectroscopy. [d] Evidence for leaching of Grubbs catalyst
from the interior of the thimble was monitored by eye through the color change of the solvent outside the
thimble. [e] Conversion was not measured. [f] Grubbs second-generation catalyst was used.
our work, but it is not possible to predict the correct solvent
without measuring the flux for numerous molecules of inter-
est under different solvent conditions. The literature was
therefore used as a guide to select solvents and to test them
for the ring-closing metathesis of diethyl diallylmalonate
(Scheme 2).
leaching from the interior of the PDMS thimble. Different
solvent mixtures of methylene chloride and [BMIM][PF6]
were tested, and it was found that a 1:1 (v/v) mixture
worked best.
To determine whether the Grubbs catalyst was remaining
encapsulated, ring-closing experiments were carried out as
shown in Scheme 2 with a 1:1 (v/v) solvent mixture of
ACHTREUNG
Methylene chloride and 1-butyl-3-methylimidazolium hex-
afluorophosphate [BMIM]
A
CH2Cl2/
G
N
liquid) were used as solvents for this reaction. Methylene
chloride is a common solvent for Grubbs metathesis cata-
outside. Every four hours an aliquot was removed from the
exterior and analyzed to determine the concentration of Ru
by inductively coupled plasma-mass spectrometry (ICP-MS).
The results in Table 2 show that the Grubbs catalyst re-
mained mostly encapsulated, but it did leach to a small
degree. To minimize the amount of catalyst that leached, we
used a 1:1 (v/v) solvent mixture of MeOH/H2O outside the
thimble and repeated these experiments. This solvent mix-
ture was chosen because the Grubbs catalyst is insoluble in
it. The results in Table 2 clearly demonstrate that over
99.5% of the catalyst remained encapsulated in the interior
of the thimble even after 16 h.
lysts and swells PDMS well. [BMIM][PF6] is a relatively
A
new solvent that has been shown to be useful for metathesis
reactions and is the opposite of methylene chloride in that it
does not swell or diffuse into PDMS.[65–69] This result is not
surprising and can be understood on the basis of the incom-
patibility of the hydrophobic matrix of PDMS and the ionic
character of [BMIM][PF6]. Through the choice of these two
G
sets of solvents, it was possible to test the effect of swelling
PDMS on the rates of reaction and whether it affected the
encapsulation of Grubbs catalysts.
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Grubbs Catalysts
FULL PAPER
Table 2. Amount of Ru measured outside the PDMS thimbles as a function of time.
CH2Cl2/
A
G
MeOH/H2O outside
[b]
[b]
t
[Ru]
[G2]outside
Total G2 outside
[%][c]
[Ru]
[G2]outside
[G2]interior
Total G2 outside
[%][c]
[a]
[a]
[h]
G
]
U
]
[G2]outside
G
]
A
]
[G2]outside
4
8
12
16
0.066
0.144
0.154
0.196
0.55
1.21
1.30
1.65
76
35
32
26
4.6
0.0040
0.0069
0.0073
0.0092
0.034
0.058
0.061
0.077
1300
740
700
560
0.28
10.0
10.7
13.6
0.41[d]
0.36[d]
0.36
[a] Measured by ICP-MS of an aliquot (0.5 mL) taken from outside the PDMS thimble. [b] Ratio of the concentration of the Grubbs catalyst in the inte-
rior of the thimble to that outside. [c] The percentage of the amount of catalyst added to the reaction that leached from the interior of the thimble to the
outside. [d] The percentage of G2 on the outside was lowered in the measurements made at 8 to 12 h because of the removal of 0.5 mL of solvent from
outside the thimble to measure the concentration of Ru.
Metathesis with CH2Cl2/
A
[PF6] 1:1 (v/v) in the interi-
thimbles and MeOH/H2O as the solvent outside (Scheme 3).
Diethyl diallylmalonate was added to the solvent outside
the thimble and diffused through the PDMS walls to react.
After 4 and 9 h, the levels of conversion outside the PDMS
thimbles were determined to be 100%, and we then added
another batch of diethyl diallylmalonate. The level of con-
version outside the thimbles was immediately measured
after the addition of diethyl diallylmalonate, and was found
to be approximately 10% and 13% for the two times. The
low levels of conversion reflect the fact that the diethyl dia-
llylmalonate was added to the thimble exteriors whereas the
or and MeOH/H2O 1:1 (v/v) outside: The results in the pre-
vious section demonstrated that the Grubbs catalyst would
remain encapsulated if MeOH/H2O was used as the solvent
outside the thimbles. We allowed several reagents to react
in the presence of encapsulated Grubbs catalysts to learn if
this choice of solvents was compatible with our method. The
results in Table 3 show that these reactions were complete
in reasonable times with good yields.
Table 3. Metathesis reactions in the presence of encapsulated catalyst
product preferentially partitioned in the CH2Cl2/
A
dissolved in CH2Cl2/
A
AHCTREUNG
MeOH/H2O (1:1 v/v) outside the thimble.
2 mL of solvent from outside the thimbles was immediately
removed and placed in a Schlenk flask under N2. After 17 h,
levels of conversion for the reactions carried out in the pres-
ence and in the absence of the PDMS thimbles were mea-
sured. The results indicated that little or no active metathe-
sis catalyst was present in the solvent outside the thimbles
after both 4 and 9 h. Thus, although less than 0.5% of the
Ru had leached from the interiors of the thimbles, no active
catalyst was found on the exterior. All of the metathesis re-
actions took place within the thimble, even though the re-
agents had been added to the exterior.
Entry
1
Substrate
Catalyst[a]
G2
t [h]
Yield [%][b]
93
2.5
2
G2
2.5
87
3
4
5
G2
G2
G2
19
26
12
84
69
72
Cascade reactions with Grubbs catalyst and MCPBA: Our
motivation in carrying out this research was to find a
method for site-isolation of the Grubbs catalyst such that it
could be used in cascade reactions with a poisonous second
reagent. To demonstrate this method, we chose to allow sub-
strates to undergo metathesis on the interiors of PDMS
thimbles and epoxidation with MCPBA outside the thim-
bles. These two reactions were chosen because the impor-
tance of metathesis reactions and epoxidations in organic
[a] These reactions were run at 4 mol% Grubbs second-generation cata-
lyst at 458C. [b] Isolated yield after the reaction was complete.
Importantly, no color change of the MeOH/H2O outside
the thimble was observed even for the longest reaction
times. In addition, the ICP-MS experiments described in
Table 2 demonstrated that less than 0.5% of the Ru had
leached into the exterior of the thimble after 16 h, but
whether it was active metathe-
sis catalyst or not still had to be
determined. To answer this
question, diethyl diallylmalo-
nate was allowed to react in the
presence of Grubbs second-gen-
eration
catalyst
and
CH2Cl2/
A
ACHTREUNG
Scheme 3. Reaction scheme used in the two control experiments to investigate leaching of Grubbs catalyst. No
vent in the interiors of the active Grubbs catalyst leached from the interiors of the thimbles to the outside.
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N. B. Bowden et al.
chemistry would make their combination in cascade reac-
tions a useful discovery.[70–77] In addition, evidence in the lit-
erature suggested that the Grubbs catalyst and MCPBA
were incompatible.[78–86] In related work by others, it was
shown that ruthenium compounds readily react with
MCPBA to generate ruthenium oxo species.[79–82,85–87] These
species oxidize alkenes and alkanes even at low loadings of
Ru. This work made it reasonable to ask if the Grubbs cata-
lyst was stable in the presence of MCPBA and whether it
would catalytically poison MCPBA.
Control experiments were performed to demonstrate that
the Grubbs catalyst poisons MCPBA. These control experi-
ments were necessary to show that they must be site-isolated
from each other—such as through the use of PDMS thim-
bles—and that the Grubbs catalyst catalytically decomposes
MCPBA. In these control experiments, diethyl diallylmalo-
nate was treated with Grubbs second-generation catalyst (4
to 0.1 mol%) to yield the cyclized product, and then
MCPBA was added (Table 4). PDMS thimbles were not
used, so the Grubbs catalyst was exposed to MCPBA. The
metathesis reaction was first performed in CH2Cl2 (1 mL),
and then MeOH with MCPBA (8 mL) was added. The
levels of conversion were poor even for the lowest catalyst
loadings. Entry 4 is notable be-
After the metathesis reaction was complete, MCPBA in
MeOH/H2O (8 mL) was added to the thimble exterior, and
the epoxidation was allowed to go to completion. This se-
quence was successful, and the results for eight cascade re-
actions are shown in Table 5.
Recycling of the Grubbs catalyst within a cascade sequence:
A key aspect to any claim of site-isolation is that the cata-
lyst can be recycled. Our system allows for ease of recycling
of a catalyst merely by removing the exterior solvent after
the reaction is complete. To demonstrate this, Grubbs
second-generation catalyst, CH2Cl2 (1 mL), and diethyl dia-
llylmalonate were placed in the interior of a PDMS thimble.
After one hour for the metathesis reaction, MeOH (20 mL)
was added to the thimble exterior and was then removed
after two hours. This procedure was repeated with the addi-
tion of more diethyl diallylmalonate to the thimble interior,
followed again by MeOH (20 mL) to the thimble exterior.
Scheme 5a shows that the levels of conversion were quanti-
tative and that the yields were high over five recycling steps.
The amount of ruthenium present in the thimble exterior
for each cycle was measured by ICP-MS. It was found that
over 97% of the catalyst remained encapsulated within the
cause there were 3000 equiva-
Table 4. Control experiments to demonstrate that MCPBA is incompatible with Grubbs catalyst.
lents of MCPBA for every
equivalent of Grubbs catalyst,
yet the catalyst decomposed
most of the MCPBA, resulting
in only 22% conversion into
epoxide. Additional reactions in
which the cyclization was com-
Entry
Solvent 1[a]
Solvent 2
G2 [equiv][b] MCPBA [equiv][b] MCPBA/G2 Epoxide [%][c]
1
2
3
4
5
6
CH2Cl2 (1 mL)
MeOH (8 mL)
0.04
0.01
3
3
3
3
3
3
75:1
300:1
750:1
3000:1
75:1
<5
<5
8
same as above
same as above
same as above
0.004
0.001
0.04
22
<5
<5
CH2Cl2/BMIM 1:1
CH2Cl2/BMIM 1:1 MeOH/H2O 1:1
MeOH
0.04
75/1
[a] In each of these reactions the diethyl diallylmalonate (approximately 300 mg) and the indicated mol per-
cent of Grubbs catalyst were added to solvent 1 and the system was allowed to react for 4 h. Next, solvent 2
was added together with the indicated equivalents (based on moles of diethyl diallylmalonate) of MCPBA,
and the system was allowed to react for 7 h. [b] Equivalents based on diethyl diallylmalonate. [c] The level of
conversion of the epoxide was determined by H NMR spectroscopy; the remaining cyclic olefin had not react-
ed.
pleted in
a
CH2Cl2/
[BMIM]-
ACHTREUNG
lowed by the addition of
MCPBA dissolved in either
MeOH or MeOH/H2O, were at-
tempted. Again, a vigorous re-
action between MCPBA and
the Grubbs catalyst was ob-
served, and the epoxide was not
1
1
seen by H NMR spectroscopy.
These reactions were important
because they demonstrate the
incompatibility of even catalytic
amounts of Grubbs catalyst
with MCPBA.
To carry out the cascade re-
action, a two-step sequence was
used to minimize leaching of
the Grubbs catalyst from the
PDMS thimble (Scheme 4). In
these reactions, diethyl diallyl-
malonate was added to the inte-
rior of
CH2Cl2/
a
thimble containing
Scheme 4. The two-step, one-pot method used to carry out a cascade sequence. Firstly, diethyl diallylmalonate
G
ACHTREUNG
was allowed to react with encapsulated Grubbs catalyst in CH2Cl2/
A
E
1 mL) and the Grubbs catalyst. MCPBA dissolved in MeOH/H2O (1:1) to the thimble exterior.
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Grubbs Catalysts
FULL PAPER
Table 5. Cascade reactions with a variety of reagents as shown in Scheme 4.
organometallic catalysts for use
in cascade reactions and in re-
actions requiring that the cata-
lyst be recycled. Although
many useful homogeneous or-
ganometallic and inorganic cat-
alysts that carry out one reac-
tion in high yields have been
developed over the preceding
decades, they remain poorly in-
tegrated into cascade reactions
because they are often pois-
oned by each other or by other
reagents. To add these catalysts
to cascade reactions successful-
ly, they must be site-isolated
from each other. Our method is
a major advance in this field
because we have site-isolated
Grubbs catalyst without requir-
ing a change in its ligand struc-
ture or attachment to a solid
support. Furthermore, site-iso-
lation was accomplished simply
by addition to a PDMS thimble.
These criteria are critical be-
cause they strongly suggest that
our method may be applicable
to other catalysts. We envision
adding multiple catalysts or re-
agents straight from the manu-
facturer to different PDMS
thimbles and carrying out cas-
Substrate
Product
tmetathesis
tepoxidation
Mol% G2 (MCPBA
[equiv])[b]
Yield
[%][c]
[h][a]
[h][a]
4
4
6
12
12
14
4 (3)
4 (10)
4 (5)
71
83
83
6
5
9
4 (5)
4 (5)
67
68
11
6
5
9
4 (5)
4 (5)
72
69
15
[a] These times refer to how long the metathesis and epoxidations reactions were allowed to run. [b] The
mol% of Grubbs catalyst is shown, and the equivalents of MCPBA based on the moles of diethyl diallylmalo-
nate are shown in parentheses. [c] Isolated yields.
thimble. To demonstrate the importance of this method fur-
ther, the Grubbs catalyst was recycled even as it was inte-
grated into a cascade sequence with MCPBA (Scheme 5b).
It is particularly noteworthy that high yields were obtained
for these reactions even after several recycling steps. The
Grubbs catalyst can thus be recycled simply by removing
the thimble from the reaction mixture, and this method is
compatible with cascade reactions.
cade reactions that are not possible at the current time. In
future work, we will explore these opportunities to increase
the scope of our method such that a wider variety of cascade
reactions can be envisioned.
Experimental Section
Materials: Grubbs first- and second-generation catalysts were purchased
from Aldrich, stored in a glovebox under nitrogen, and used as supplied.
Substrates and reagents were purchased from Acros/Fisher (diallylamine,
4-acetoxystyrene, 4-methoxystyrene, styrene, 4-vinylbenzyl chloride,
MCPBA, 1-chlorobutane, N-methylimidazole) or from Aldrich (diethyl
diallylmalonate, hepta-1,6-dien-4-ol) and used as supplied. Organic sol-
vents (except for the ionic liquid) were purchased from Acros or Aldrich
Conclusion
A simple, new method for site-isolation of Grubbs second-
generation catalyst and MCPBA from each other is de-
scribed; it allows them to be integrated into cascade reac-
tions. Our method relies on the solid-state properties of
PDMS thimbles for site-isolation of the large Grubbs cata-
lyst from the polar MCPBA. These thimbles have high
fluxes for small molecules, but ionic and large molecules
have much lower fluxes; this allows them to be site-isolated
within the PDMS thimbles. They remain either in the
PDMS thimble interior or in the thimble exterior, while
small molecules freely react on both sides.
at the highest purity and used as supplied. [BMIM][PF6] was prepared by
A
literature procedures.[65–69] All solvents used for metathesis reactions were
degassed and maintained under nitrogen. The polydimethylsiloxane
(PDMS) preparation kit (Sylgard 184) was purchased from Essex Brow-
nell and used as supplied. Casting molds were made of brass. All reac-
tions were performed under a nitrogen atmosphere with use either of
Schlenk flasks or of a glove box unless otherwise stated.
Characterization: 1H and 13C NMR spectra were recorded on a Bruker
DPX 300 instrument with CDCl3 as solvent and TMS as an internal stan-
dard. Leaching of ruthenium from the thimbles was determined by ICP-
MS on a Varian Ultra mass 700 ICP-MS with sensitivity of 0.001 mgmLÀ1
at the University of Iowa hygiene laboratories.
The significance of this research is the demonstration of a
new and simple method for site-isolation of homogeneous
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6785

N. B. Bowden et al.
Scheme 5. a) Diethyl diallylmalonate was added to the interior of a PDMS thimble, it was allowed to react for 1 h, MeOH (20 mL) was added to the
thimble exterior, cyclized product diffused to the thimble exterior, and the solvent was removed from the thimble exterior. The Grubbs catalyst was suc-
cessfully recycled five times. b) A similar procedure was followed in a recycling/cascade sequence in which MCPBA was added to the solvent taken from
the thimble exterior.
Preparation of PDMS thimbles: The two components from the PDMS
kit were mixed in a ratio of 1:10 (w/w). The mixture was then degassed,
placed in an oven maintained at 658C for ca. 5 min, and coated onto the
brass rods. The PDMS was cured at 658C for 2 h, and the procedure was
repeated once to yield tubes with thicknesses of 105 Æ 22 mm. Once
cured, the tubes were cut, and bottoms were added by placing thin films
of degassed, partially pre-cured PDMS onto Petri dishes and allowing the
tubes to stand in the PDMS while they fully cured. The finished thimbles
were then cut to the desired height, soaked in hexanes followed by meth-
ylene chloride, and dried before use. The thicknesses of the thimbles
were measured with a calibrated Fisher Micromaster optical microscope
interfaced to a computer fitted with Micron1 imaging software.
elution with EtOAc in hexanes (5%) to give the title compound as a
light yellow liquid (0.25 mg, 1.16 mmol, 93% yield). The products from
Table 3 had literature precedents; their characterization can be found in
the Supporting Information.
Procedure for cascade reactions—diethyl 6-oxa-bicyclo[3:1.0]hexane-3,3-
N
dicarboxylate (1): In a glove box, Grubbs second-generation catalyst
(43 mg, 0.05 mmol) was placed in a PDMS thimble contained in a
Schlenk flask. The flask was sealed, removed from the glove box, and
placed under N2. Solvent (1 mL of CH2Cl2/
N
N
the interior of the thimble, followed by diethyl diallylmalonate (300 mL,
1.25 mmol). The reaction mixture was allowed to stir at ambient condi-
tions for 3 h, after which the flask was slowly charged with MCPBA (1 g,
3.7 mmol in MeOH/water 1:1 v/v, 8 mL) on the thimble exterior, and stir-
ring was continued for a further 12 h. Solvent on the thimble exterior
was removed, washed repeatedly with saturated NaHCO3, and extracted
with CH2Cl2 (3”10 mL). The thimble contents were extracted with hex-
anes (10 mL). The hexane and DCM extracts were pooled, washed with
brine, and dried over anhydrous MgSO4. Solvent was then removed in
vacuo, and the product was purified on a silica gel column with elution
with EtOAc (10%) to give the target epoxide in 71% yield (0.203 g,
0.89 mmol). The full characterization of molecules 1–6 is given in the
Supporting Information.
General procedure for olefin metathesis reactions—diethyl cyclopent-3-
ene-1,1-dicarboxylate: In a glove-box, Grubbs second-generation catalyst
(43 mg, 0.05 mmol) was placed in a PDMS thimble contained in a
Schlenk flask. The flask was sealed, removed from the glove box, and
placed under N2. Solvent mixtures (CH2Cl2/BMIM (1:1 v/v, 1 mL) and
MeOH/H2O (1:1 v/v, 4 mL) were added to the interior and exterior of
the thimble. Next, diethyl diallylmalonate (300 mL, 1.25 mmol) was added
to the thimble exterior, and the flask was placed in an oil bath main-
tained at 458C for 2.5 h. The reaction was cooled to room temperature,
and the product was extracted with hexanes (3”10 mL). The hexane ex-
tracts were dried over anhydrous MgSO4, solvent was removed in vacuo,
and the product was purified by passage through a silica gel column with
Control experiments to demonstrate that the metathesis reaction was oc-
curring in the interiors of the PDMS thimbles (Scheme 3): In a glove
6786
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Chem. Eur. J. 2008, 14, 6780 – 6788

Grubbs Catalysts
FULL PAPER
box, Grubbs second-generation catalyst (43 mg, 0.05 mmol) was placed in
a PDMS thimble contained in a Schlenk flask. The flask was sealed and
removed from the glove box. With maintenance under nitrogen with the
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E
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hydrous MgSO4 and concentrated in vacuo. The sample was analyzed by
1H NMR spectroscopy to determine the level of conversion. Fresh diethyl
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and analyzed by NMR spectroscopy as detailed above. Next, half of the
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under N2 to a Schlenk flask. Both flasks were heated at 458C for 14 h,
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Control experiments to demonstrate that Grubbs metathesis catalyst poi-
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was allowed to stir for 7 h, after which an aliquot was analyzed by
1H NMR spectroscopy to determine the degree of conversion to the ep-
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tures and different ratios of Grubbs second-generation catalyst to
MCPBA as summarized in Table 4.
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Procedure for recycling encapsulated Grubbs second-generation catalysts
(Scheme 5): In a glovebox, Grubbs second-generation catalyst (53 mg,
0.06 mmol) was placed in a PDMS thimble contained in a Schlenk flask.
The flask was sealed, removed from the glove box, and placed under N2.
CH2Cl2 (1 mL) was added to the thimble, followed by diethyl diallylmalo-
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Procedure for recycling encapsulated Grubbs second-generation catalysts
in a metathesis/epoxidation cascade sequence: The catalyst was recycled
as described above, except that for each cycle the solvent in the thimble
exterior was removed and placed in a new flask containing MCPBA
(0.92 g, 3.74 mmol). The epoxidation reaction was allowed to run for
12 h. Conversion of the ring-closed olefin into the epoxide was confirmed
to be >98% by 1H NMR spectroscopy. The reaction mixture was then
dissolved in CH2Cl2 (50 mL) and washed with water (100 mL), followed
by saturated sodium bicarbonate (3”50 mL). The organic extract was
dried over anhydrous MgSO4 and concentrated in vacuo. The product
was purified by column chromatography with EtOAC in hexanes (10%)
as the eluent. This procedure was repeated for a total of five cycles.
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We are grateful to the Research Corporation for a Research Innovation
Award, the Roy J. Carver Charitable Trust, and the Mathematics and
Physical Sciences Funding Program at the University of Iowa for gener-
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Received: January 16, 2008
Published online: June 18, 2008
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