Functionalized organocatalytic nanoreactors: Hydrophobic pockets for acylation reactions in water

Article abstract of DOI:10.1021/ma2027462

The effect of covalently attaching 4-(dimethylamino)pyridine (DMAP) functionality to the hydrophobic core of a polymeric micelle in water has been investigated in the context of acylation reactions employing non-water-soluble substrates. For this purpose a novel temperature-responsive polymeric micelle has been synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. The reactivity of the tethered organocatalyst within the nanostructure was found to be extremely high, improving in some cases the acylation rates up to 100 times compared to those for unsupported DMAP in organic solvents. Moreover, the catalytic nanoreactors have been demonstrated to be capable of reuse up to 6 times while maintaining high activity.

Full text of DOI:10.1021/ma2027462

Article
pubs.acs.org/Macromolecules
Functionalized Organocatalytic Nanoreactors: Hydrophobic Pockets
for Acylation Reactions in Water
Pepa Cotanda, Annhelen Lu, Joseph P. Patterson, Nikos Petzetakis, and Rachel K. O’Reilly*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom
S
* Supporting Information
ABSTRACT: The effect of covalently attaching 4-(dimethylamino)pyridine (DMAP) functionality to the hydrophobic core of a
polymeric micelle in water has been investigated in the context of acylation reactions employing non-water-soluble substrates.
For this purpose a novel temperature-responsive polymeric micelle has been synthesized using reversible addition−fragmentation
chain transfer (RAFT) polymerization techniques. The reactivity of the tethered organocatalyst within the nanostructure was
found to be extremely high, improving in some cases the acylation rates up to 100 times compared to those for unsupported
DMAP in organic solvents. Moreover, the catalytic nanoreactors have been demonstrated to be capable of reuse up to 6 times
while maintaining high activity.
wide range of artificial catalysts based on star polymers or
dendrimers, where the catalytic active cores are isolated from the
outer environment.6−14
INTRODUCTION
■
The use of water as a solvent for organic reactions has increased
in the past decade, as it is the most abundant and cheapest liquid
on earth, it is safe, and it has shown unique properties such as
improving rate and selectivity in some organic reactions.1−4
However, the use of water for synthetic organic chemistry is
restricted because most organic compounds are nonpolar and
hence insoluble in water. Based on previous results from
Breslow and Rideout,1 in 2005 the group of Sharpless reported
the “on water” protocol where organic substrates were added to
water and stirred vigorously forming small droplets of reactants,
and the products were easily isolated by phase separation or
filtration.2 This protocol showed an unexpected increase in rates
for several organic reactions using hydrophobic reactants in
aqueous solutions compared to those in organic solvents or neat
conditions.
Nevertheless, the environmental and economic assessment of
an aqueous reaction is shown to involve a complex set of
parameters.5 Catalysts are often the most expensive component
in organic reactions and are usually very toxic; hence, there is
great interest in the immobilization of catalysts for simplification
of product work-up, separation, isolation, and facile recovery. In
nature, enzymes make use of a compartmentalized hydrophobic
cavity within the structure, protected by a hydrophilic shell. The
isolated hydrophobic pocket allows for efficient, selective
catalysis. Inspired by enzymes, several groups have designed a
Indeed, the development of new systems to create organic
microenvironments in aqueous media using surfactants has been
widely investigated.15,16 These amphiphiles form spherical
aggregates with hydrophilic surfaces and hydrophobic cores; the
hydrophobic reactants are concentrated within the core, resulting
in the observed acceleration in reaction rate and introducing
selective effects. Kobayashi et al. carried out dehydration reactions
in water using dodecylbenzenesulfonic acid as a surfactant-type
catalyst.17,18 In this system, the catalyst enhanced the reaction rate
and the hydrophobic interior of the droplets facilitated the
exclusion of the water, obtaining esters in high yields for highly
hydrophobic substrates.
DMAP is a useful nucleophilic catalyst which can be used in
a variety of reactions such as esterifications with anhydrides,
the Baylis−Hillman reaction, hydrosilylations, tritylation, the
Steglich rearrangement, Staudinger synthesis of β-lactams, and
many more.19−21 Although it is not remarkably expensive,
this organocatalyst exhibits high dermal toxicity; hence, its
incorporation to a solid support to avoid dissemination in the
Received: December 20, 2011
Revised: February 20, 2012
Published: February 29, 2012
© 2012 American Chemical Society
2377
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
environment is an important target. DMAP containing polymers
have been a subject of interest in the past decades;22,23 linear
polymers, dendrimers, multiarm star copolymers, polymeric
capsules, polymer brushes, and cross-linked polymers containing
DMAP functionality have been synthesized and used in sup-
ported catalysis.12,24−27
In 2006, McQuade et al. published the first example of
catalysis using encapsulated linear polymer−catalyst conjugates.
The copolymerization of a DMAP-modified monomer with
styrene and encapsulation by interfacial polymerization gave a
DMAP-functionalized microcapsule that showed higher activity
for DMAP-catalyzed acylation than when supported on cross-
linked polystyrene.25
imidazole block forming the corona.31 They found that in the
presence of the catalytic micelles the rate of esterolysis increased
up to 7 times, and they suggested that this was due to the
hydrophobic affinity of the reactants for the hydrophobic NIPAM
core brought the reactants in close proximity to the catalytic shell
and increased their local concentration.
In order to explore how the incorporation of the catalyst into
the hydrophobic core of a polymeric micelle will affect its
catalytic activity, Zhao et al. used atom transfer radical poly-
merization (CRP technique) to synthesize a diblock copolymer
containing DMAP functionality tethered within the temper-
ature-responsive block which formed the hydrophobic core of
the micelle upon heating.26 They envisioned that if the partition
coefficient of the substrate between micelles and water is
sufficiently high, the substrates could be concentrated in the
core of the micelle, resulting in an enhanced reaction rate.
However, on the contrary to their hypothesis, the DMAP-
containing polymer did not accelerate the rate of the reaction
upon self-assembly. They related this observation to a mass
transport limitation of their starting materials from the water to
the core of the micelles.
The unique hydrophobic environment created in the core of a
polymeric micelle can be tuned by selecting the degree of
hydrophobicity of the core block.37 Weck and co-workers, based
on previous work by Weberskrich, designed an optimal system
for the hydrolytic kinetic resolution of epoxides in water.30,32 In
this work, the high local concentration of catalyst in the
hydrophobic core of the micelle together with the small amount
of water that can penetrate during catalysis has been proven to
be crucial to achieve higher activity and better enantioselectivity
than that obtained under homogeneous conditions in organic
media. In addition, the system exhibited outstanding recycling
properties.
́
In 2005, Frechet et al. demonstrated that DMAP modified
monomers can be copolymerized, assembled and encapsulated for
applications in homogeneous catalysis.12 In this work the authors
reported a one-pot reaction cascade performed with two different
star polymers (unimolecular micelles), each containing a different
catalytic group confined in its core. The same year, the group
reported how the nanoenvironment and polymer architecture
play an important role in acylation reactions catalyzed by DMAP-
containing dendrimers.24 By comparing two DMAP dendritic
polymers with different polarities within the core domain, they
proved the “concentrator effect” whereby catalytic reactions
benefit from the gradient polarity core−shell. Their system
behaves like a free energy driven catalytic pump that favors the
migration of the polar substrate from the nonpolar medium
(hexane) to the more polar core containing DMAP. Recent work
by Meijer and co-workers reported a compartmentalized catalyst
synthesized by supramolecular folding of a single polymer chain
that catalyzes carbonyl reductions in water; the authors described
this system as an enzyme mimic.28 Inspired by this work, it would
be desirable to synthesize a system that combines the use of water
for the reaction of hydrophobic organic substrates using a
hydrophobic environment to improve the reaction rates with the
advantages of the facile synthesis of amphiphilic diblock
copolymer supported catalysts.
The overall objective of our work is to synthesize new polymer
supported catalytic micelles with stimuli-responsive properties,
where DMAP is selectively supported in the hydrophobic core.
These micelles will act as nanoreactors to carry out catalysis of
hydrophobic organic molecules in aqueous media and hopefully
accelerate the reaction rates by the “concentrator effect” reported
A strategy that has successfully been employed is the
synthesis of functionalized monomers, which can be incorpo-
rated selectively into the hydrophobic domain of a polymeric
micelle via copolymerization techniques.26,29−32 The covalent
attachment of the catalytic motifs within the hydrophobic core
block (protected by the hydrophilic corona) allows for the
selective reaction of hydrophobic reagents in an overall aqueous
environment. The main advantage of these polymeric self-
assembled systems over surfactant-based micelles is their
stability and the facile recovery of the catalyst by precipitation
or ultrafiltration methods.33
New advancements in controlled radical polymerization
techniques (CRP) such as RAFT have enabled the facile
synthesis of many different polymer architectures with fine
control over their molecular weight, polydispersity, and chain-end
functionality.34 The application of RAFT to the synthesis of
functionalized amphiphilic homo- and block copolymers which
contain hydrophobic and hydrophilic groups is particularly
important for their self-assembly in water.35 Moreover, the
incorporation of stimuli-responsive blocks and/or functional
groups is essential for their use in so-called “smart” applications.36
Following this strategy, Liu and co-workers used RAFT to
synthesize stimuli-responsive block copolymers, poly(N-isopro-
pylacrylamide)-b-poly(N-vinylimidazole) (PNIPAM-b-PVim),
which self-assembled above the LCST of NIPAM (∼32 °C)
into micelles with the hydrophobic NIPAM core and the catalytic
by Frec
́
het and co-workers.24 The temperature-responsive
PNIPAM shell is envisioned to facilitate the recovery of the
catalyst without the need of organic solvents.38
RESULTS AND DISCUSSION
■
Synthesis of DMAP Containing Micelles 4. Styrene-
based polymers chain extended with a water-soluble block
are known to form kinetically frozen micelles in water.39,40
We hypothesize that the confinement of the catalytic moiety
in a completely hydrophobic glassy core will create a water-free
environment and mimic nonpolar hydrophobic conditions for
efficient catalysis reactions.
In order to obtain stable micelles with the catalytic func-
tionality locked into the hydrophobic core, a styrenic monomer
1 containing DMAP was synthesized from commercially
available 4-vinylbenzoic acid and 4-(N-methyl-N-(2-hydro-
xyethyl)amino)pyridine at room temperature by established
procedures using Steglich esterification route (Scheme 1).41,42
The product was isolated as a white powder in 60% yield
1
and characterized by H and 13C NMR spectroscopy, high-
resolution mass spectroscopy (HR-MS), and IR spectroscopy
(Supporting Information).
The DMAP containing monomer, 1, was copolymerized with
styrene by RAFT using dodecyl 1-phenylethyltrithiocarbonate,
2378
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
a
Scheme 1. Synthesis of Micelles, 4, That Contain DMAP Functionality Covalently Attached in the Hydrophobic Core
a
Reactants and conditions: (i) CH2Cl2, EDCI, RT; (ii) DMF, 110 °C; (iii) AIBN, THF, 65 °C; (iv) solvent switch from acetone to water at 5 °C.
as trithiocarbonates are known to be good chain transfer agents
(CTA) for the polymerization of styrene and styrenic
monomers.43,44 RAFT is one of the most versatile CRP
techniques due to its tolerance to functionality and its ability to
polymerize a wide range of monomers in a controlled manner
in both aqueous and organic media.34,45−49 A kinetic study of
the copolymerization using 1 was carried out in order to gain
further polymerization data regarding the degree of living
behavior and rate of polymerization with an intended 5%
incorporation of 1, with a view of obtaining an overall target DP
of ca. 50. Samples were taken from the polymerization ampule
at different times and analyzed by SEC (THF eluent) and
1H NMR spectroscopy in CDCl3 (Table S1). As shown in
Figure S3, the kinetic plot is linear, which indicates a controlled
polymerization process is occurring with a constant radical con-
centration. Given the higher rate of polymerization for 1 than
St (kp(styrene) = 0.0262 min−1 and kp(1) = 0.0573 min−1),
there is a higher than predicted incorporation of the functional
monomer at low monomer conversion. Hence, the polymers
have a gradient type structure, and the resultant polymers
contain significantly more than the expected 5% incorporation
of monomer 1.
overlap of the UV signal at 309 nm (characteristic wavelength
for the trithiocarbonate end group) with the RI response for the
same sample using both detectors in the SEC (see Figure S2).
PNIPAM has been widely studied mainly because of the
sharpness of its phase transition, the closeness of its LCST about
32 °C, to physiological temperature, and the easiness to vary its
LCST by copolymerization, addition of salts or surfactants to the
polymer solution.50−58 Applications of this switchable behavior
include the dissolution of amphiphilic block copolymer to form
micelles in an aqueous media and its reversible switching upon
heating above its LCST to a double hydrophobic block
copolymer which will collapse and precipitate for facile recovery.
For the preparation of the targeted DMAP containing
micelles, the macro-CTA 2 was chain extended with NIPAM to
form a diblock copolymer with a permanently hydrophobic
styrenic−DMAP block and a temperature responsive block,
which is hydrophilic at room temperature (3, Mn(NMR) =
20.5 kDa, Mw/Mn = 1.42). The degree of polymerization of
NIPAM and its molecular weight were determined using the 1H
NMR spectrum of the resultant polymer by comparing the
signals attributable to monomer 1 in polymer 2 (ca. 4.4 and
8.2 ppm) and the signals for the NIPAM proton at ca. 4.0 ppm
(Figure 1). Because of the length of the hydrophilic NIPAM
block (degree of polymerization = 140), the hydrophobic chain
end of the RAFT CTA was not expected to play an important
role in the self-assembly of the polymer. The validity of this
assumption was evident from the characterization data showing
spherical micelles, which is the morphology predicted based on
the packing parameter for the given block lengths.59
A copolymer DMAP-co-St, 2, with an overall degree of poly-
merization of 38, containing 10% of monomer 1 was obtained
with good polymerization control (Mn(NMR) = 5.1 kDa, Mw/
Mn = 1.11). The degree of incorporation of functional
1
monomer 1 was determined by examination of the H NMR
spectrum of the resultant polymer via the comparison of the
signals attributable to monomer 1 (ca. 4.4 and 8.2 ppm) and
the signals for the backbone at ca. 1.5 ppm with those for the
CTA at 0.85 ppm (see Figure S1). These calculations assume
complete end-group fidelity; this was supported by the good
The amphiphilic block copolymer was dissolved in a minimum
amount of acetone (at 100 mg/mL), which is a good solvent for
both blocks. Cold water was added dropwise, with stirring, to the
2379
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
1
Figure 1. H NMR spectrum of diblock copolymer 3 in CDCl3.
Figure 2. Representative TEM micrograph of catalyst 4 stained with uranyl acetate (1% solution) and histogram. Scale bar 100 nm.
polymer solution using a peristaltic pump (rate = 15 mL/h) to
form spherical micelles 4 following evaporation of the acetone
under reduced pressure at low temperature. This yielded DMAP-
functionalized micelles, 4, at a micellar concentration of ca.
6.8 mg/mL. The resulting spherical micelles were found to be
ca. 25 nm in diameter, determined by both TEM (Figure 2,
Dav = 23.8 nm) and DLS analysis (Dh = 31.2 nm, PD = 0.234,
Figure S5).
The LCST of micelles 4 was measured spectrophotometri-
cally by determining the turbidity of the solution at various
temperatures (Figure 3). It has been previously reported that
temperature responsive polymers exhibit lower phase separa-
tion temperatures when self-assembled into micelles.60 Our
DMAP containing micelles presented an LCST of 27 °C, which
is 5 °C lower than that reported for PNIPAM homopolymer.
The broad hysteresis observed in the cooling process, first
observed by Wu et al.,61 indicates that the solution must be
cooled below 32 °C to re-form the micelles.
Figure 3. Normalized transmittance versus temperature plot for 4 at
1 mg/mL in water.
overall aqueous media, the well-established DMAP catalyzed
acylation reaction of an alcohol was investigated as a model
system. DMAP-containing micelles in water were tested as
Acylation Reactions. In order to probe the effects of
encapsulating a catalyst in a hydrophobic environment in an
2380
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
catalytic nanoreactors for different substrates, as indicated in
Table 1. Similar conditions to those reported by Frechet were
́
higher limit appears to be dependent on the amount of
hydrophobic materials that the nanoreactor can house inside
the hydrophobic core domain.
Effect of Substrates on the Equilibrium Position. In
order to overcome the above-mentioned mass transport limita-
tion and achieve higher acylation conversion, further experi-
ments were carried out using different alcohol and anhydride
substrates (entries 2−5, Table 1). We expect that the use of
more hydrophobic starting materials will favor the diffusion of
reactants to the core and hence increase the conversions before
equilibrium is reached. In all cases the acylation reaction of
different substrates in the aqueous solution containing DMAP
micelles 4 reached the equilibrium position after 15 min.
Initially, a less water-soluble alcohol (R = ethyl versus methyl)
was targeted, but unfortunately, the hydrophobicity of the
alcohol did not show any significant contribution to the reaction
rate at this point (entry 2, Table 1).
Studies by Steglich et al. based on kinetic measurements of the
DMAP-catalyzed acetylation of alcohols concluded that the rate-
determining step of esterification reactions of this type is the
reaction of the N-acylpyridinium carboxylate with the alcohol.62
Neither DMAP nor the auxiliary base enters the kinetic equation.
Hence, in our micellar system the use of a more hydrophobic
anhydride seems to be key, as suggested by the reaction
mechanism (Figure 4).
Table 1. Data Showing Conversions after 15 min for
Acylation Reactions in the Micelles, 4
a
entry
R
R′
% conv (15 min) % conv (24 h)
1
2
3
CH3
CH3
CH3
26
28
47
65
94
32
29
53
66
98
CH2CH3
CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
b
4
b
CH3
5
CH2CH3
a
All reactions contained 8 mol % DMAP, [OH] = 0.02 M, 1.5 equiv of
auxiliary base (TEA), 1 equiv of alcohol, and 3 equiv of anhydride.
Conversions determined by HPLC measurements with mesitylene as
b
the internal standard. N,N-Diisopropylethylamine (DIPEA) was used
as auxiliary base instead of TEA.
targeted.24 However, anhydrides partially hydrolyze to their
corresponding acids in aqueous solutions; hence, an excess of
anhydride was employed (3 equiv vs 1.5 equiv) due to the
aqueous environment of our system. All catalytic reactions were
carried out with stirring at 5 °C to ensure polyNIPAM was
completely dissolved. Aliquots were taken from the reaction
mixture at different times and the conversion was determined
by HPLC analysis. All reactions were performed in triplicate. In
these reactions 8 mol % of DMAP was employed, taking into
account that each polymer chain contain an average of 4 units
of the catalytic active DMAP.
In the first approach (entry 1, Table 1) the acylation reaction
was carried out using 1 equiv of 1-phenylethanol (0.02 M) with
3 equiv of anhydride and 1.5 equiv of TEA in the aqueous
micelle solution 4 (at 8 mol % DMAP loading). When using
acetic anhydride as the substrate, the reaction reached 26%
conversion in 15 min and then appeared to stop. The drastic
decrease in the reaction rate after achieving ∼25% conversion
may be attributed to a mass transport limitation as predicted by
Zhao and co-workers.26 If the hydrophobicity of the reactants is
the driving force of the reaction, when the product is more
hydrophobic than the substrates, the nanoreactor will eventually
become saturated, preventing the starting materials in the water
from moving into the reactive hydrophobic core and hence
stopping the reaction. This hypothesis was investigated by
adding a new batch of starting materials (alcohol, anhydride, and
auxiliary base) to the micellar solution after reaching this point.
As expected, only 25% of this additional batch was acylated, and
the reaction stopped when the ratio of reactants−products
reached the equilibrium between the hydrophobic core of
the reactor and the water. The addition of fresh starting
materials was repeated four times, and the results observed were
reproducible; the acylation reached equilibrium, and in all cases
only 25% conversion was observed 15 min after each addition
(see Figure S8).
Figure 4. Proposed mechanism for the DMAP-catalyzed acylation.62,63
When using the more hydrophobic butyric anhydride in
exactly the same conditions as previously discussed (entry 3,
Table 1), the conversion of the esterification reaction increased,
obtaining an acceptable 47% after 15 min. This promising result
was slightly improved by introducing a more hydrophobic
auxiliary amine, N,N-diisopropylethylamine (DIPEA), which
increased the conversion to 65% (entry 4, Table 1). However,
when a more hydrophobic alcohol, anhydride, and auxiliary
amine were used, the acylation reaction was completed within
15 min (entry 5, Table 1). This is not unexpected that the use
of longer alkyl chains on the starting materials afforded higher
conversions due to improved partitioning and concentration
within the catalytically active micellar core. On the other hand,
when the reactions were carried out in THF using unsupported
DMAP as a catalyst, the use of more hydrophobic substrates
did not significantly affect the reaction rates (see Figure S7 and
The addition of a fifth batch ([OH] = 0.10 M) resulted in
the partial precipitation of the polymer. This observation gave
us an indication about the concentration limits of our micellar
system. While the lower limit ([OH] = 0.02 M) is determined
by the detection limit of the method of analysis (HPLC), the
2381
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
Table S2). These results emphasize the importance of the
hydrophobicity of the substrates in our micellar system.
Comparison with Organic Solvents and Bulk. To obtain
further data about how the environment created inside the
micelle affects the rates of reaction, the acylation of 1-phenyl-
propanol with butyric anhydride was carried out in different
solvents and in neat conditions using unsupported DMAP as a
catalyst. The reaction proceeded very fast in less polar solvents
(hexane) and solvent-free conditions compared to more
polar solvents such as THF or water (entries 1−4, Table 2).
Table 2. Data Showing Reaction Conversion Determined by
HPLC after 15 min and 24 h for the Acylation Reactions in
a
Different Solvent Conditions
Figure 5. Conversions vs reaction times for DMAP-catalyzed acylation
◇
□
△
reactions in Table 2: entry 2 ( ), entry 3 ( ), entry 4 ( ), entry 6
○
( ), and entry 7 (×); R = CH2CH3, R′ = CH2CH2CH3.
new block copolymer PSt38-b-PNIPAM140 (5, Mn (NMR) =
19.2 kDa, Mw/Mn (GPC) = 1.29, which contained no DMAP
functionality) was synthesized and self-assembled into micelles
6, via the procedure described for the DMAP nanoreactors.
DLS and TEM studies show that the unfunctionalized micelles
6 were of similar size to the DMAP containing micelles 4
(Dav = 23.1 nm, Dh = 35.4 nm, Figures S4 and S6). DMAP
small molecule (8 mol % loading) was added to micellar
solution 6 and stirred for 1 h before addition of the alcohol,
anhydride, and DIPEA. The aliquots taken from the reaction
after 24 h showed that the acylation does not occur in water if
the DMAP functionality is not covalently attached within the
hydrophobic environment. We attribute this important observa-
tion to two different factors: unlike the starting materials,
DMAP is water-soluble, and given the small amount added to
the solution (1.3 mg in 8 mL of water), it is unlikely that the
organic substrates find any DMAP in the hydrophobic core.
Second, it is likely that the DMAP catalyst is poisoned by
protonation from the acid created by the excess of anhydride
hydrolyzed in the aqueous media.
The rate of acylation using polymer-supported DMAP 3 in
THF is lower and less efficient than the nonsupported DMAP
(entries 2 and 7, Table 2). THF is a good solvent for both
blocks of the amphiphilic polymer; hence, self-assembly into
micelles does not occur, and the acylation will proceed as a con-
ventional “polymer supported” catalyzed reaction, where unlike
the nonsupported catalyst, the DMAP functionality is more
sterically hindered. These results demonstrate the advantages of
tethering the catalyst into a polymeric nanoreactor rather than just
a simple polymer support. The high local concentration of catalyst
leads to enhanced activity similar to that for organic solvents or
neat conditions, and the hydrophobic core creates a hydrophobic
nonpolar environment preventing DMAP protonation.
% conversion
entry
catalyst
solvent
15 min
24 h
b
1
2
3
4
5
6
7
DMAP
DMAP
DMAP
DMAP
DMAP
3
water
THF
hexane
bulk
2
13
85
58
0
8
87
86
96
3
b
b
b
b
c
6
c
4
94
2
98
60
3
THF
a
All reactions were carried out with 8 mol % DMAP, [OH] = 0.02 M,
1.5 equiv of auxiliary base, 1 equiv of alcohol, and 3 equiv of anhydride.
Conversions were determined by HPLC measurements, with
mesitylene as the internal standard. R = CH2CH3, R′ = CH2CH2CH3.
b
c
Unsupported DMAP was used as a catalyst. Micelle in water.
This behavior has previously been reported by Ishihara and
co-workers for the acylation reactions of a range of alcohols
under different conditions.63 The use of less polar solvents aids
the regeneration of the DMAP catalyst which results in higher
reactivities, while polar solvents cause the formation of
ammonium salts and leads to a decrease in reactivity.
For this reason it is not surprising that the acylation in water
only achieved 8% conversion when nonsupported DMAP was
used (entry 1, Table 2). It is noteworthy that, although the
reactions in bulk and in the micellar system (entries 4 and 6)
yielded the same conversion at the equilibrium position, the
reaction in the aqueous micelles is 8 times faster than that in
hexane, which can be attributed to the “concentrator effect”
observed by Frec
́
het and co-workers.24
On the other hand, the higher conversion for the DMAP-
containing micelle system 4 compared to the acylation in bulk
(entries 4 and 6, Table 2) agree with the polarity effects
observed by Ishihara et al.63 The substrates themselves are a
more polar solvent than hexane, resulting in a deceleration of
the acetylation under solvent-free conditions. These reactions
confirm that the micelles create a more favorable environment
for the acylation to occur in pure water similar to that created in
organic solvent or neat conditions. We were also interested
in whether simple addition of DMAP to a unfuctionalized
micellar system would allow for similar activities. Hence, we
next explored the requirement of encapsulating the catalyst in
the hydrophobic environment of a micelle. For this purpose a
Catalyst Loading. To further investigate the potential of
our DMAP-containing micelles, the amount of catalyst was
reduced to 0.8 and 0.08 mol %. When the most efficient esterifi-
cation reaction (entry 5, Table 1) was repeated, lowering the
catalyst 10 times only resulted in a 10% drop in conversion, and
similarly the equilibrium point was reached in 15 min. However,
lowering the catalyst 100 times lead to a significant decrease in
conversion, achieving ca. 50% of the acylation product at the
equilibrium position after 6 h (Figure 6).
To provide a direct comparison the acylation was explored
under the same conditions with DMAP small molecule in THF
and hexane (Figure 6). The reduction of the catalyst content in
2382
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
Figure 6. Acylation reactions using 0.8% (A) and 0.08% (B) DMAP catalyst in the micelles (triangle) compared to the small molecule reaction in
THF (square) or hexane (circle) for conditions shown in Table 2.
the THF homogeneous system induced a drastic decrease in
reaction rates compared to those from the DMAP-containing
micelles. By reducing the nonsupported catalyst to 0.8 mol %
(Figure 6A), the conversion decreased more than 50%, and
furthermore, no reaction was observed after 24 h when the
amount of catalyst was reduced to 0.08% (Figure 6B). When
homogeneous catalysis was carried out in hexane, the reaction
rates decreased compared to those for the same conditions using
8% catalyst; however, both reactions (0.8 and 0.08% catalyst)
achieved more than 95% conversion.
In our experiments with lower catalyst loading the micelle
solution 4 was diluted to the desired concentration; however,
given the kinetically frozen nature of our micelles we
hypothesize that this essentially resulted in a reduction in the
total number of micelles in the solution and hence less “catalytic
pumps” to catalyze the reaction. For this reason we believe that
the equilibrium of the substrates between water and the micelles
is reached faster, leading to lower conversions compared to
those for hexane. We postulate that the synthesis of a new
polymer containing lower DMAP loadings but retaining the
same block lengths as 3 will allow us to reduce the amounts of
catalyst but maintaining the same number of “hydrophobic
pockets” and hence potentially reaching higher conversions.
This work is currently ongoing.
Recycling Experiments. One of the main advantages of
tethering the catalyst to a polymeric support over the widely
studied catalysis using surfactants is the facile recovery of the
polymer for recycling. In our recycling experiments 0.8 mol %
DMAP-supported catalysts from a diluted solution of 4 was
employed to catalyze the acylation reaction of 1-phenylpropanol
with 3 equiv of butyric anhydride and 1.5 equiv of DIPEA as
auxiliary base. The reactants together with a known amount of
mesitylene were added to the micelles solution at 5 °C, and after
1 h a sample was taken and analyzed by HPLC to calculate
the conversion. The product was extracted with diethyl ether
and the same aqueous solution was reused in a new reaction.
The catalyst was reused with little or no change in reaction rate
or conversion for five times (80%, 74%, 83%, 70%, and 79%
after 1 h). However, after this point it was noted that the
reaction mixture became brown due to the excess of water-
soluble auxiliary base in solution, which is not removed by
organic extraction.
above 50 °C. At this temperature, the polymer exists as a fine
powder and was collected by centrifugation. The recovered
catalyst was reused in another reaction cycle using the same
amount of reactants and water to keep the concentration of
reactants the same as in a fresh cycle, achieving 85% conversion
after 1 h reaction. The product was extracted with diethyl ether
after the six recycling cycles, and the aqueous solution was
1
freeze-dried in order to analyze the solid residue by H NMR
spectroscopy; integration of the DMAP peak at ca. 4.4 ppm
confirms that the DMAP functionality is present and still
attached to the polymer backbone following recycling.
The polymer can be purified to be used in a different reaction
by heating the micellar solution above the LCST of the micelles.
The precipitated polymer can then be recovered by filtration
and washed with ethyl acetate in order to remove all organics.
A 1H NMR spectrum of the clean polymer after reaction can be
found in the Supporting Information (Figure S9).
CONCLUSIONS
■
A new temperature-responsive amphiphilic block copolymer
containing DMAP functionality incorporated within the hydro-
phobic block has been successfully synthesized by RAFT and
self-assembled into micelles by dissolution in water at low
temperatures. The catalytic activity of these DMAP nano-
reactors in the acylation of hydrophobic substrates in aqueous
media was determined and compared to that of unsupported
DMAP in organic solvents. The data indicate that the high local
concentration of catalyst and the hydrophobic environment
created in the core of the nanoreactors are crucial to achieving
high acylation reactivities. The reaction rates in the aqueous
micellar system are comparable and in some instances greater
than those for homogeneous reactions in organic media.
Moreover, the polymeric catalyst could be reused in six
consecutive cycles without loss of activity, and the stimulus-
responsive property could be utilized to assist in the recovery
of the active polymer. The applicability of the system has been
shown to be very dependent on mass transport limitations of
reagents, products, and regenerative species, and a deep
mechanistic understanding of the reaction catalyzed is necessary.
Studies on how the hydrophobicity/stability of the hydrophobic
core could be tuned to improve reaction conditions are ongoing.
These new synthetic methodologies will provide the basis for
further development of a range of polymeric stimuli-responsive
supported catalysts for utilization in organic synthesis.
Hence, a new recycling route was investigated using the
stimulus-responsive property of our system. After extraction of
the synthesized product with diethyl ether, the aqueous phase
containing the micellar catalyst was heated to a temperature
2383
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384

Macromolecules
Article
(27) Jiang, X.; Wang, B.; Li, C. Y.; Zhao, B. J. Polym. Sci., Part A:
Polym. Chem. 2009, 47, 2853.
(28) Terashima, T.; Mes, T.; De Greef, T. F. A.; Gillissen, M. A. J.;
Besenius, P.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2011,
133, 4742.
(29) Ievins, A. D.; Wang, X. F.; Moughton, A. O.; Skey, J.; O’Reilly,
R. K. Macromolecules 2008, 41, 2998.
(30) Rossbach, B. M.; Leopold, K.; Weberskirch, R. Angew. Chem.,
Int. Ed. 2006, 45, 1309.
(31) Ge, Z. S.; Xie, D.; Chen, D. Y.; Jiang, X. Z.; Zhang, Y. F.; Liu,
H. W.; Liu, S. Y. Macromolecules 2007, 40, 3538.
ASSOCIATED CONTENT
* Supporting Information
Further synthetic procedures and characterization data for the
monomer, CTA, acylation products, copolymer and nanostruc-
tures. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
■
́
(32) Liu, Y.; Wang, Y.; Wang, Y.; Lu, J.; Pinon, V.; Weck, M. J. Am.
̃
Chem. Soc. 2011, 133, 14260.
ACKNOWLEDGMENTS
(33) O’Reilly, R. K. Philos. Trans. R. Soc., A 2007, 365, 2863.
(34) Moad, G.; Rizzardo, E.; Thang, S. H. Polymer 2008, 49, 1079.
(35) McCormick, C. L.; Sumerlin, B. S.; Lokitz, B. S.; Stempka, J. E.
Soft Matter 2008, 4, 1760.
(36) Vriezema, D. M.; Aragones, M. C.; Elemans, J.; Cornelissen, J.;
Rowan, A. E.; Nolte, R. J. M. Chem. Rev. 2005, 105, 1445.
■
The EPSRC, AWE, and the Royal Society are thanked for
financial support. Guillermo Frank Cotanda is thanked for
micelle images. The GPC equipment used in this research was
obtained through Birmingham Science City: Innovative Uses
for Advanced Materials in the Modern World (West Midlands
Centre for Advanced Materials Project 2), with support from
Advantage West Midlands (AWM) and part funded by the
European Regional Development Fund (ERDF).
(37) Lejeune, E.; Drechsler, M.; Jestin, J.; Muller, A. H. E.;
̈
Chassenieux, C.; Colombani, O. Macromolecules 2010, 43, 2667.
(38) Bergbreiter, D. E.; Case, B. L.; Liu, Y. S.; Caraway, J. W.
Macromolecules 1998, 31, 6053.
(39) Zhang, L.; Eisenberg, A. Polym. Adv. Technol. 1998, 9, 677.
(40) Zhang, L.; Eisenberg, A. Macromolecules 1999, 32, 2239.
(41) Deratani, A.; Darling, G. D.; Frechet, J. M. J. Polymer 1987, 28,
825.
(42) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522.
(43) Benaglia, M.; Chiefari, J.; Chong, Y. K.; Moad, G.; Rizzardo, E.;
Thang, S. H. J. Am. Chem. Soc. 2009, 131, 6914.
(44) Skey, J.; O’Reilly, R. K. Chem. Commun. 2008, 4183.
(45) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T.
P. T; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Moad, G.;
Rizzardo, E.; Thang, S. H. Macromolecules 1998, 31, 5559.
(46) Lowe, A. B.; McCormick, C. L. Prog. Polym. Sci. 2007, 32, 283.
(47) Moad, G.; Rizzardo, E.; Thang, S. H. Aust. J. Chem. 2005, 58,
379.
(48) Moad, G.; Rizzardo, E.; Thang, S. H. Aust. J. Chem. 2006, 59,
669.
(49) Perrier, S.; Takolpuckdee, P. J. Polym. Sci., Part A: Polym. Chem.
2005, 43, 5347.
(50) Schild, H. G. Prog. Polym. Sci. 1992, 17, 163.
(51) Liu, B.; Perrier, S. J. Polym. Sci., Part A: Polym. Chem. 2005, 43,
3643.
(52) Eeckman, F.; Moes, A. J.; Amighi, K. Int. J. Pharm. 2004, 273,
109.
(53) Schilli, C. M.; Zhang, M. F.; Rizzardo, E.; Thang, S. H.; Chong,
Y. K.; Edwards, K.; Karlsson, G.; Muller, A. H. E. Macromolecules 2004,
37, 7861.
(54) Arotcarena, M.; Heise, B.; Ishaya, S.; Laschewsky, A. J. Am.
Chem. Soc. 2002, 124, 3787.
(55) Virtanen, J.; Arotcarena, M.; Heise, B.; Ishaya, S.; Laschewsky,
A.; Tenhu, H. Langmuir 2002, 18, 5360.
(56) Nuopponen, M.; Ojala, J.; Tenhu, H. Polymer 2004, 45, 3643.
(57) Hong, C. Y.; You, Y. Z.; Pan, C. Y. J. Polym. Sci., Part A: Polym.
Chem. 2004, 42, 4873.
REFERENCES
■
(1) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816.
(2) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
(3) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009,
351, 33.
(4) Scroggins, S. T.; Chi, Y.; Frec
2010, 49, 2393.
(5) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem., Int. Ed. 2007, 46, 3798.
(6) Bosman, A. W.; Vestberg, R.; Heumann, A.; Frec
Hawker, C. J. J. Am. Chem. Soc. 2002, 125, 715.
(7) Terashima, T.; Kamigaito, M.; Baek, K.-Y.; Ando, T.; Sawamoto,
M. J. Am. Chem. Soc. 2003, 125, 5288.
(8) Terashima, T.; Ouchi, M.; Ando, T.; Sawamoto, M. J. Polym. Sci.,
Part A: Polym. Chem. 2010, 48, 373.
(9) Chi, Y. G.; Scroggins, S. T.; Frechet, J. M. J. J. Am. Chem. Soc.
2008, 130, 6322.
́
het, J. M. J. Angew. Chem., Int. Ed.
́
het, J. M. J.;
(10) Grayson, S. M.; Frec
(11) Helms, B.; Frechet, J. M. J. Adv. Synth. Catal. 2006, 348, 1125.
́
het, J. M. J. Chem. Rev. 2001, 101, 3819.
́
(12) Helms, B.; Guillaudeu, S. J.; Xie, Y.; McMurdo, M.; Hawker,
C. J.; Frechet, J. M. J. Angew. Chem., Int. Ed. 2005, 44, 6384.
(13) Helms, B.; Meijer, E. W. Science 2006, 313, 929.
(14) Yu, J.; RajanBabu, T. V.; Parquette, J. R. J. Am. Chem. Soc. 2008,
130, 7845.
(15) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005,
44, 7174.
(16) Wang, Y.; Xu, H.; Ma, N.; Wang, Z.; Zhang, X.; Liu, J.; Shen, J.
Langmuir 2006, 22, 5552.
(17) Manabe, K.; Sun, X.-M.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 10101.
(18) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 11971.
(19) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43,
(58) Hales, M.; Barner-Kowollik, C.; Davis, T. P.; Stenzel, M. H.
Langmuir 2004, 20, 10809.
(59) Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. J. Chem. Soc.,
Faraday Trans. 2 1976, 72, 1525.
5436.
(20) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed.
̈
̈
(60) Ieong, N. S.; Redhead, M.; Bosquillon, C.; Alexander, C.;
Kelland, M.; O’Reilly, R. K. Macromolecules 2011, 44, 886.
(61) Wang, X.; Qiu, X.; Wu, C. Macromolecules 1998, 31, 2972.
(62) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H.
Chem.Eur. J. 2005, 11, 4751.
1978, 17, 569.
(21) Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. 1969, 8, 981.
(22) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401.
(23) Vaidya, R. A.; Mathias, L. J. J. Am. Chem. Soc. 1986, 108, 5514.
(24) Helms, B.; Liang, C. O.; Hawker, C. J.; Frec
̈
́
het, J. M. J.
(63) Sakakura, A.; Kawajiri, K.; Ohkubo, T.; Kosugi, Y.; Ishihara, K.
J. Am. Chem. Soc. 2007, 129, 14775.
Macromolecules 2005, 38, 5411.
(25) Price, K. E.; Mason, B. P.; Bogdan, A. R.; Broadwater, S. J.;
Steinbacher, J. L.; McQuade, D. T. J. Am. Chem. Soc. 2006, 128, 10376.
(26) O’Lenick, T. G.; Jiang, X.; Zhao, B. Polymer 2009, 50, 4363.
2384
dx.doi.org/10.1021/ma2027462 | Macromolecules 2012, 45, 2377−2384