European Polymer Journal 47 (2011) 435–446
Contents lists available at ScienceDirect
European Polymer Journal
journal homepage: www.elsevier.com/locate/europolj
Feature Article
Synthesis of glycopolymers via click reactions
Stacy Slavin, James Burns, David M. Haddleton, C. Remzi Becer ⇑
Department of Chemistry, University of Warwick, CV4 7AL, Coventry, United Kingdom
a r t i c l e
i n f o
Article history:
Received 28 June 2010
Accepted 21 September 2010
Available online 29 September 2010
Dedicated to Professor Nikos Hadjichristidis
in recognition of his contribution to polymer
science.
Keywords:
Glycopolymer
Glycomonomer
Click reaction
Controlled living polymerization
Functional polymers
a b s t r a c t
This mini-review describes recent work in the field of glycopolymer synthesis, with a focus
on methods that have employed ‘‘click chemistry” and controlled polymerization methodology. A variety of carbohydrates with clickable groups such as azide, alkyne, and thiol
moieties provide new routes to glycopolymers. Several studies use copper catalyzed
azide-alkyne cycloaddition (CuAAC) reactions to synthesize glycomonomers or to incorporate carbohydrates into a clickable polymeric backbone. Alternatively, there are many thiol
based click reactions which provide metal-free synthesis, which are discussed in details.
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1. Introduction
Synthetic carbohydrate-containing macromolecules or
glycopolymers have attracted increasing attention in
various fields of science with particular interest to the
biological sciences due to their recognition properties
[1–3]. Advances in synthetic chemistry allow for the preparation of well defined and multi-functional glycopolymers
in a relatively facile manner [4]. The carbohydrate units
critically control the specific biological functions of cells
and also play an important role in cell–cell recognition
[5,6]. It is desirable to be able to control the chain length,
composition and topology of the glycopolymer since these
factors determine the location and distance between the
carbohydrates on the polymer chain [7,8]. Importantly,
precise recognition properties can be achieved by an absolute control over the microstructure of the glycopolymer.
The synthesis of glycopolymers became popular in the
1990s with an effort towards Biomimics, and most of the
attempts were based on the polymerization of monomers
⇑ Corresponding author. Tel.: +44 24765222263.
E-mail address: [email protected] (C.R. Becer).
containing carbohydrate moieties [9–13]. These glycomonomers (sugar carrying monomers) were reported to be
polymerized by free radical, controlled radical, anionic,
cationic, ring opening and ring opening metathesis
polymerization techniques [10,14,15]. Until the last decade, there had been limited attempts to react a functional
polymeric backbone with a carbohydrate to obtain a glycopolymer. A significant reason for this was the difficulty of
introducing sufficiently reactive pendant groups onto the
polymer backbone to react with carbohydrates. One successful attempt, involved the modification of poly(vinylalcohol) with 4-nitrophenyl carbonate groups to yield such a
reactive polymer backbone. The reactive nitrophenyl carbonate groups were transformed with glucosamine into
glycopolymers, which were subsequently investigated for
their interaction with a commonly used lectin, Concanavalin A (Con A) [16].
The concept of ‘‘click chemistry” as, a number of highly
efficient organic reactions, was introduced by Sharpless
[17] and has captured the attention of synthetic chemists
in many fields of chemistry [17,18]. According to the criteria drawn by Sharpless, a click reaction should be ‘‘modular and wide in scope, highly efficient, generate
inoffensive or no byproducts, be stereospecific, use readily
0014-3057/$ - see front matter Crown Copyright ! 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.eurpolymj.2010.09.019
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S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
available starting materials, use benign or no solvent, and
require simple purification techniques”. One of the most
widely employed click reactions has been the copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction [19–
21]. The principle of a simple and highly efficient click
reaction is advantageous towards post-polymerization
modification; a route which has proven effective in the
synthesis of glycopolymers. The combination of the
CuAAC reaction and metal-mediated living radical polymerization has been inevitable since they both use a similar catalyst and could even be conducted in a one-pot
reaction [22,23]. Synthesis of glycomonomers using
the CuAAC click reaction have been demonstrated by
Haddleton et al. and Stenzel et al., which will be discussed further in this mini review [23–26]. In general, a
well-defined and functional backbone has been prepared
using various polymerization techniques and azide functional sugars have been clicked on the backbone. This
allows for the preparation of glycopolymers in a more
controlled manner by means of backbone length or
comonomer ratios. In a practical sense, it is usually more
challenging to structurally characterize a glycopolymer
due to their bulky carbohydrate groups, therefore this
method provides added benefit.
Alternatively, thiol based click reactions have attracted
attention in the last 5 years due to the commercial availability of a wide range of thiols [27,28]. The versatility of
thiol click reactions has been demonstrated by preparing
tailor-made macromolecular architectures varying from
telechelic homopolymers to highly complex dendritic
structures [29–36]. Glycopolymers have been synthesized
from reactions of thiols with various functional groups
such as alkenes, alkynes, para-fluoro phenyl and halides
[37,38]. Most of these reactions are highly efficient and
provide high yields under the employed conditions,
Scheme 1. In the case of thiol-ene click reactions, it is possible to use UV-light and a photo-initiator to provide a radical source during the click reaction. The remaining thiol
click reactions however, are either catalyzed by base or
are nucleophilic in nature and proceed under ambient conditions. In terms of synthesis, preparation of thiol-sugars
seems to be more demanding than azide-sugars. Nevertheless, some thiol-sugars are commercially available, which
helps to reduce the number of synthetic steps required
for the preparation of glycopolymers. Moreover, it is relatively easy and versatile to obtain polymers with alkene,
alkyne, para-fluoro, and halide pendant groups, which
can then undergo thiol-click chemistry.
Carbohydrates with various functionalities can be
incorporated into a polymer either by clicking onto the
polymeric backbone or by polymerizing them as glycomonomers. Indeed, even with glycomonomer synthesis various click reactions have been utilized recently offering
facile routes to glycomonomers. Moreover, sugars with
azide, alkyne, and thiol groups have been reported for their
use in the synthesis of glycopolymers via click reactions.
Selected examples for the various combinations of click
reactions and polymerization techniques that are used to
prepare glycopolymers have been listed in Table 1.
In this mini review, we highlight the selected examples
where clickable sugars are used either to synthesize gly-
Scheme 1. Various click reactions that are employed in the synthesis of
glycopolymers.
comonomers, which will lead to a glycopolymer, or to directly click onto a polymeric backbone. The combination
of different polymerization techniques, i.e. free radical
polymerization (FRP), reversible addition fragmentation
chain transfer (RAFT) polymerization, nitroxide mediated
polymerization (NMP), metal-mediated living radical
polymerization (ATRP), cobalt catalyzed chain transfer
polymerization (CCCTP), and ring opening polymerization
(ROP), with selected click reactions are discussed.
1.1. Azide-alkyne click reactions
The Copper Catalyzed Azide-Alkyne Cycloaddition
(CuAAC) reaction has been influential in improving synthetic strategies, not only in polymer chemistry but also
in other research fields, such as biochemistry, medicinal
chemistry and surface chemistry. This has become popular
within many different disciplines due to advantages over
other chemical transformations. The reaction is simple to
perform, tolerates various conditions and functional
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
437
Table 1
Selected examples on different combinations of click reactions and polymerization techniques to synthesize glycopolymers.
Click reaction
Polymerization method
Backbone
CuAAC
ATRP
Methacrylate
[39]
CuAAC
ATRP
Methacrylate
[25]
CuAAC
ATRP
Methacrylate
[40]
CuAAC
RAFT
Acrylate/Methacrylate
[41]
CuAAC
RAFT
4-Vinyl-1,2,3-triazole
[24]
CuAAC
ROP
e-Caprolactone
[42]
CuAAC
CCTP (Cobalt)
Methacrylate
[36]
p-fluoro-thiol
Thiol-ene
NMP
Cationic
Pentafluorostyrene
N-Acylalkyleneimine
[37]
[43]
Thio-halogen
Thiol-ene
Thiol-yne
Thiol-ene
RAFT
RAFT
RAFT
ROP
Styrene
Acrylate/Methacrylate
Acrylate/Methacrylate
Ester
[44]
[41]
[41]
[45]
groups, it is highly stereospecific and provides near quantitative conversions that eliminate purification steps.
The copper (I) catalyst has a crucial role in the ‘‘click”
process. Prior to copper being used into the reaction, Huisgen and co-workers studied the azide-alkyne cycloaddition
and realized that since organic azides are relatively
reactive compounds, but also selective, they were able to
undergo a dipolar cycloaddition reaction with alkynes
and olefins [46]. However, this reaction is slow and results
in a mixture of both 1,4- and 1,5- disubstituted 1,2,3-triazole regioisomers being formed with unsymmetrically
substituted alkynes. Meldal and Sharpless independently
investigated and introduced copper as a catalyst for this
reaction which solved these previous problems associated
with this reaction [47,48]. Through the use of a copper catalyst, the reactions proceed faster at and below ambient
temperature and with complete conversion to the 1,4disubstituted 1,2,3-triazole product. An excellent tutorial
Saccharide
Refs.
review has been recently published by Fokin and Hein,
which provides extensive details into the CuAAC reaction
and mechanism [49]. This type of click reaction has a major
role in polymer chemistry since it provides a variety of new
routes to synthesizing glycopolymers.
Prior to the use of click chemistry the synthesis of sugar-monomers was hindered due to the number of synthetic steps necessary to protect functional groups and
ensure chemo- and stereoselectivity. The incorporation of
the CuAAC process allows sugar monomers to be prepared
with ease by the introduction of azide functionality. The
original synthetic strategy first protects the hydroxyl
groups on the sugar by acetylation, followed by the activation of the anomeric leaving group by a Lewis acid to selectively convert to a bromo group via displacement [50]. The
azide can then be introduced via nucleophilic substitution
followed by deprotection to provide the sugar azide. It is
now possible to carry out the azide functionalization with-
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out the need to protect the hydroxyl groups via the use of a
strong acid cation exchanger resin, simplifying the method
further. Using these methods a variety of sugars have been
functionalized with azides, which in conjunction with the
CuAAC process broadens the synthetic scope of glycopolymers [51]. Another facile method involves a one-pot direct
synthesis of sugar azides reported by Shoda et al. with the
reaction mediated by 2-chloro-1,3-dimethylimidazolinium
chloride (DMC) [51]. The reaction is carried out without
any protection chemistry since the DMC is able to directly
activate the anomeric hydroxyl group followed by intermolecular nucleophilic attack by the azide ion. The selectivity exists due to the lower pKa value of the hemiacetal
anomeric hydroxyl groups compared to that of the other
hydroxyl groups present on the sugar. The aforementioned
synthetic routes to sugar azides highlight the progress and
ease of which sugar azides can be attained.
Transition metal-mediated living radical polymerization (TMM-LRP), also known as atom transfer radical polymerization (ATRP), is a well established route to synthesize
polymers which are well-defined with precise functionality [52–55]. Functional groups can be introduced easily
into polymers via living radical polymerization techniques.
By introducing functionality to the initiator this is then
incorporated into the polymer chain with a simple linker
between the functional group and the initiator fragment
to avoid any side reactions occurring during the polymerization. The functionality remains intact on the a-chain end
of the polymer. The chain length is controlled via rapid
reversible deactivation of propagating radicals to keep
their concentration low along with fast initiation to ensure
all propagating species grow simultaneously. The deactivation of the propagating radicals is carried out by the copper(II) bromide-ligand complex [56–59].
Haddleton et al. reported a versatile synthetic strategy
that generates a library of glycopolymers with exactly the
same molar mass, polydispersity index (PDi), and polymer
architecture [3]. Moreover, a protected maleimide initiator
was used that enables convenient conjugation to available
thiol residues present in proteins after deprotection. These
glycopolymers are suitable for probing interactions with
mannose-binding lectin, whilst omitting the effects of chain
length or architecture. A combination of ATRP and CuAAC
was implemented to create well-defined maleimide endfunctionalized glycopolymers. One of the most attractive
features of this work is the simplicity and efficiency in which
a wide range of glycopolymers can be synthesized.
Three different synthetic strategies have been demonstrated to synthesize well defined glycopolymers, Scheme 2.
The first route (Route A) produces a sugar methacrylate
monomer via CuAAC click reaction. This monomer is then
polymerized by ATRP without the need to protect the hydroxyl groups present on the sugar molecule, which is typically
required in glycopolymer synthesis [60]. Remarkably, the final step to deprotect the maleimide end group can simply be
carried out in a vacuum oven at 80 "C, avoiding the use of
any organic solvents or further purification.
The second reported route to glycopolymers (Route B)
reveals the advantages of using click chemistry. It involves
the one step synthesis of a trimethylsilyl (TMS) protected
propargyl methacrylate monomer. After polymerization
via ATRP, a deprotection step generates the reactive propargyl units providing a ‘clickable’ scaffold, onto which a
variety of azide functional sugars can react. A final retroDiels–Alder deprotection of the maleimide end-group
was necessary for the polymer to undergo site specific conjugation to proteins. This synthetic route was optimized to
ensure fewer steps were needed to synthesize sugar azides.
In essence, it is possible to generate a library of polymers
all containing the same macromolecular characteristics
with the only difference being the sugar chosen to be
‘clicked’ onto the scaffold. Furthermore, Haddleton et al.
successfully conjugated the glycopolymers onto bovine
serum albumin (BSA) to create a glycoprotein mimic,
which was shown to induce immunological behavior via
interaction with mannose-binding lectin (MBL). Through
the use of ATRP and click chemistry a range of well defined
functional glycopolymers were successfully synthesized
and proven to show biological activity.
A third route has been investigated in which glycopolymers were synthesized via a one-pot process with simultaneous CuAAC and living radical polymerization [26]. The
mechanism for both of these processes is not yet fully
understood, however Haddleton et al. demonstrate that it
is possible to have both reactions proceeding at the same
time in the same reaction mixture. Furthermore, by changing experimental conditions such as solvent, temperature
and catalyst concentration it was possible to influence
the rate of each process. This is an important feature of this
work since any un-clicked alkyne groups may undergo side
reactions in situ which would lead to a less controlled polymerization. An additional advantage of this one-pot system
is that there is no need to use sugar functional methacrylate monomers. This method is useful as it reduces the
number of synthetic steps involved to make well defined
glycopolymers.
Synthesis of chain end functional polymers with high
fidelity has been challenging for polymer chemists. In the
case of metal-mediated living radical polymerization, the
polymer chain carries a terminal halide atom, which undergoes several activation-deactivation cycles. It should be
noted that there is the possibility of side reactions in which
loss of halide end groups leads to a loss of chain end fidelity.
Alternatively, cobalt catalyzed chain transfer polymerization (CCCTP) is a versatile technique to produce x-end
functional polymers with a high chain end fidelity and controlled molecular weight. This technique benefits from the
stability of the bis(boron difluorodimethylglyoximate) cobalt(II) (CoBF) catalyst in neutral aqueous media, allowing
polymerizations of acidic monomers, which are unsuitable
for anionic polymerization. In anionic polymerization
these acidic monomers would react rapidly with carbanions and eventually terminate the polymerization. With
monomers containing an a-methyl group termination
and initiation occur principally by the chain transfer reaction from CoBF to the active center. Thus, products contain,
invariably, an unsaturated end group. A vinyl terminated
chain end allows facile modification of the polymer chain
by a thiol-ene click reaction.
The combination of CCCTP and click chemistry to synthesize glycopolymers has been recently reported by
Haddleton et al. (Scheme 3) in which a protected alkyne
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
439
Scheme 2. Various synthetic routes to glycopolymers using ATRP and CuAAC employed by Haddleton et al.
monomer is homopolymerized in the presence of CoBF and
AIBN to yield protected alkyne polymers with vinyl end
groups [36]. Various azide-sugars, i.e. mannose, galactose
and cellobiose, were reacted with the alkyne groups of
the glycopolymer after the removal of the deprotection
groups. An attractive feature of this work is the ability of
these polymers to undergo further functionalization due
to the x-terminal vinyl group. It is well known that activated vinyl groups can undergo hetero-Michael reaction
with thiols. This reaction has been termed as ‘‘base catalyzed thiol-ene” click reaction since the process complies
with the typical attributes of a click reaction. Moreover,
the sugar azides can be clicked onto the polymer scaffold
before or after the thiol-ene click chemistry has been performed. This allows a wide array of functionality to be
introduced to the glycopolymers.
Ring opening polymerization (ROP) gives access to a
wider range of cyclic monomers which could not be polymerized by other techniques. This method of polymerization is a chain polymerization; however, the propagating
rate constants are more akin to a step-growth polymerization, making the molecular weight growth small in comparison to chain polymerization of a monomer containing
carbon–carbon double bonds. It is possible to control the
Scheme 3. The synthesis of glycopolymers via Cobalt catalyzed – catalytic chain transfer polymerization and click reactions by Haddleton et al.
440
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
molecular weight of polymers made via ring opening polymerization due to its dependence on conversion and the
ratio of monomer to initiator concentration.
Zi-Chen et al. demonstrated that amphiphilic biodegradable glycopolymers can be successfully synthesized
via a combination of ROP and click chemistry [61]. In this
paper, they synthesize a functional monomer, 2-bromo-ecaprolactone, derived from successive modifications of
cyclohexene. Addition to the alkene with N-bromosuccinimide was carried out to introduce bromine and alcohol
functionalities. The alcohol group was initially converted
to a ketone and then to an ester via Baeyer–Villiger oxidation. The effort devoted to the synthesis and polymerization of this type of monomer is worthwhile since the
resulting glycopolymer is biodegradable. Block copolymerization with poly(e-caprolactone) macroinitiator is
illustrated in Scheme 4. Several more steps were required
to introduce sugars and hence produce an amphiphilic
block copolymer; involving the conversion of bromide
groups to azides and then utilizing the CuAAC click reaction to attach alkyne functional sugars. Proof of aggregation as a result of interaction with lectin Con A was
shown using atomic force microscopy (AFM) and transmission electron microscopy (TEM). When comparing
with other synthetic routes to glycopolymers, the main
drawback of this system is the time and effort required
to produce a well defined polymer. There is a great need
to ensure all reactants are free from water and air to avoid
deactivation of ionic initiators as well as requiring relatively long reaction times and low temperatures due to
the sensitivity of reactants. Nevertheless, it is a beneficial
route to synthesize biodegradable glycopolymers, which
could be of great importance in terms of biomaterial
applications.
RAFT polymerization, used in a number of examples, is
a well established, versatile, route to the synthesis of well
defined polymer architectures [62–67]. In particular, it has
been shown to be an effective route to hyperbranched
polymers [68–70]. It provides control over the molecular
weight, polydispersity and functionality and by changing
the thiocarbonylthio chain transfer agent (RAFT agent), it
is possible to polymerize a wide range of monomers [71].
The RAFT agent has also been shown to be an effective
route to introducing both a and x functionality to polymers made by this technique.
Synthesis of RAFT agents with functionality on the
re-initiating fragment allows the incorporation of a-functionality into a polymer. In addition, modification of the
thiocarbonylthio RAFT end group can be used to easily
introduce x-functionality, summarized in a recent review
by O’Reilly et al. [72]. One issue which should be taken into
consideration is that the introduction of terminal functionality to polymers is usually no greater than 90% efficient at
the a terminus; this is due to initiation from the thermal
initiator. Whilst at the x terminus, termination during
the reaction and loss of the RAFT agent end group can hinder complete end group modification. A review of many aspects of RAFT, including a comprehensive list of RAFT
agents synthesized has been published by Moad and
coworkers [73].
Stenzel et al. have reported the synthesis and RAFT
polymerization of a novel glycomonomer via CuAAC,
belonging to an uncommon monomer class, Scheme 5
[24]. The 4-vinyl-1,2,3-triazole monomers are a relatively
new class of monomers with good thermal properties
[74]. Stenzel et al. show the facile synthesis of
2́-(4-vinyl-1,2,3-triazol-1-yl)ethyl-O-a-D-mannoside, from
2́-azidoethyl-O-a-D-mannoside and 4-trimethylsilyl-1-buten-3-yne. The azide-functional saccharide was easily
synthesised without protecting groups. A disadvantage
to this glycomonomer synthesis, however, is the complex
synthesis of 4-trimethylsilyl-1-buten-3-yne, which requires harsh conditions, and led to low yields. To synthesize the glycomonomer, the deprotection of the alkyne
by tetra-n-butylammonium fluoride (TBAF) and the
CuAAC click reaction were carried out in a one-pot
reaction, where the copper(I) was produced in situ by
the reduction of CuSO4 by sodium ascorbate.
Scheme 4. The synthesis of glycopolymers via ROP of e-caprolactone (CL) and 2-bromo-e-caprolactone (BrCL) blocks, modification of the bromo moieties to
azides, and CuAAC click.
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
441
Scheme 5. The synthesis of a 4-vinyl-1,2,3-triazole glycomonomer (top) and its RAFT polymerization (bottom).
The 4-vinyl-1,2,3-traizole monomer was polymerized
by RAFT in water, with 4,4-azobis(4cyanovaleric acid)
used as the water soluble thermal initiator. The reactions
were carried out in the presence of 3-(benzlsulfanylthiocarbonylsulfanyl) propionic acid (BSPA) as RAFT agent, to
yield high molecular weight polymer with PDI < 1.25.
Poly[20 -(4-vinyl-1,2,3-triazol-1-yl)ethyl-O-a-D-mannoside)] macro RAFT agent was used to synthesize an AB
block copolymer with N-isopropylacrylamide poly(NIPAAm), which reversibly formed micelles above the lower
critical solution temperature of the poly(NIPAAm) block.
The micelles formed were seen to have higher rates of
binding to Con A in comparison to their linear counterparts, which highlights the potential effect that architecture can have on glycopolymers recognition properties.
1.2. Thiol-para fluoro click reaction
Mild reaction conditions are required for the synthesis
of glycopolymers to prevent degradation of the carbohydrates. Thus, nitroxide mediated polymerization (NMP) is
not often used due to the relatively high polymerization
temperatures required. However, NMP has advantages,
which can simplify the overall synthesis of glycopolymers.
For instance, there is no requirement for a metal catalyst or
chain transfer agent. The main requirement for NMP is an
alkoxyamine that is activated by heat, thus it provides colorless and catalyst free polymers without any need for a
purification step. After decomposition of the initiator, a
reactive radical and a stable radical are generated. The stable radical mediates the polymerization by reversibly
deactivating the propagating chain, and hence lowering
the concentration of propagating radicals in the medium
[75,76]. With the advent of click chemistry, it is possible
to use NMP to synthesize well-defined clickable polymeric
scaffolds whilst utilizing the aforementioned advantages of
NMP.
The CuAAC reaction has a copper catalyst that requires a
purification step, negating the benefits of NMP, therefore
metal free click chemistry is a valuable tool for the synthesis of glycopolymers [77]. Schubert et al. have shown a
route to glycopolymers that combines NMP and metal free
click chemistry where well defined homopolymers of
pentafluorostyrene (PFS) were functionalized by thiol-para
fluoro click, as illustrated in Scheme 6 [37,78]. The click
reaction proceeded at ambient temperature in the presence of triethylamine as base and N,N-dimethylformamide
as solvent. Moreover, the kinetics of the substitution reaction was monitored by measuring 19F NMR spectra at 40 "C
and quantitative conversions were observed in less than
1 h.
Although in essence it is a nucleophilic substitution
reaction, the versatility and efficiency of the amine or thiol
substitution to the para position of C6F5 has been demonstrated by Schubert et al. to comply with most of the
‘‘click” chemistry requirements [33] In addition, a wide
range of primary amines and thiols, which can be efficiently reacted with –C6F5 groups, are commercially available. The accessibility of the –C6F5 groups however is
rather limited; obstructing the scope and modularity of
the reaction.
1.3. Thiol-chloro click reaction
Boyer et al. utilized a thio-chloro ‘‘click” reaction to
yield well defined glycopolymers, using the modification
of preformed polymer architectures synthesized by RAFT
[79]. Polymerization of poly(tert-butyl acrylate-co-chloromethylstyrene) was carried out in the presence of 3(benzlsulfanylthiocarbonyl-sulfanyl) propionic acid (BSPA)
as RAFT agent and AIBN to yield well defined polymers
with pendant chloro-functional moieties, Scheme 7. The
reaction of the chloro moieties with thioglucose, in the
presence of triethylamine, proceeded to completion in
16 h to yield glucose functional polymers. The polymer
was purified easily by precipitation into water, to remove
the excess of thioglucose.
An additional approach was utilized by Boyer et al.
through the copolymerization of 2-hydroxyethyl acrylate
with butyl acrylate, however, this approach requires rigorous reaction conditions [79]. For instance, the hydroxyl
groups of poly(2-hydroxyethyl methacrylate) were
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S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
Scheme 6. The synthesis of glycopolymers using nitroxide mediated polymerization (NMP) and thiol-para-fluoro click reaction.
Scheme 7. Synthesis of glycopolymer by RAFT polymerization of tert-butyl acrylate-co-chloromethylstyrene and thiol-chloro click.
converted to tosyl groups and protected galactose was reacted in the presence of sodium hydride. An interesting
application of glycopolymers was highlighted, where gold
nanoparticles were decorated with the acidic glycopolymers and examined for their biological uses, i.e. imaging
or sensing. Glycopolymer incorporated gold nanoparticles
have accessible recognition elements on the surface, which
has also been confirmed by a binding assay with Con A.
1.4. Thiol-ene click reactions
Thiol compounds react either via radical or catalyzed
processes under mild conditions with a multitude of substrates [80]. The radical addition of thiols to vinyl groups
is a highly efficient technique used for polymerizations,
curing reactions and for the modification of polymers
[81]. In 2007 Schlaad and coworkers first demonstrated a
post-polymerization modification of a well-defined
poly[2(-3-isobutenyl)-2-oxazoline] that was synthesized
via cationic ring opening polymerization (CROP) [82]. They
have reacted various thiols including an acetylated
thioglucose (2,3,4,6-tetra-J-acetyl-1-thio-b-D-glucopyranose) with the well-defined polymeric backbone by exposing to UV light, Scheme 8. Photoaddition of thiols were
performed in a 4 wt.% solution of polymer in dry
THF:methanol (1:1) under argon atmosphere, and exposed
to UV light for one day.
A further study was reported by Stenzel et al. on the
synthesis of thiol-linked neoglycopolymers by a combination of RAFT polymerization and thiol-ene click reaction [83]. Block copolymerization of di(ethylene glycol)
methyl ether methacrylate (DEGMA) and 2-hydroxyethyl
methacrylate (HEMA) was performed and followed by a
post-polymerization modification of the hydroxyl groups
of HEMA to clickable vinyl units. They have obtained
thermoresponsive glycomicelles as a potential drug
carrier.
1.5. Thiol-yne click reactions
Perrier et al. have reported the synthesis of hyperbranched glycopolymers using RAFT and a number of
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
443
Scheme 8. Synthesis of glycopolymers by combination of cationic ring opening polymerization of 2-oxazoline and thiol-ene click reaction.
‘‘click” reactions. Propionic acidyl butyl trithiocarbonate
(PABTC), RAFT agent, was used to control the polymerization of a protected alkyne acrylate in the presence of
difunctional monomer, ethylene glycol dimethacrylate
(EGDMA) [84]. This was followed by a deprotection step,
to yield a hyperbranched scaffold with alkyne functionality. The ‘‘clickable” scaffold was modified by two different
routes, Scheme 9. Firstly, by CuAAC of 2-azidoethyl-b-Dgalactopyranoside to the alkyne functionality on the polymer; this reaction reached to 85% conversion. The second
route was via radical addition of the thioglucose to the alkyne to yield bis-glucose functionality. The radical addition
reaction was seen to reach 90% conversion, with a small
amount of C@C bonds visible in the infra-red analysis
and vinyl protons present in the NMR analysis. In
summary, Perrier et al. have shown an effective route to
synthesize hyperbranched glycopolymers, however, optimization of the click reactions are necessary to avoid the
possibility of crosslinking occurring between unreacted
vinyl groups.
A further glycopolymer synthesis utilized unreacted
pendant methacrylate groups present after the polymerization of EGDMA in the absence of a monofunctional
monomer. 2-Cyanoisopropyl dithiobenzoate RAFT agent
was used to control the polymerization, and dimethyl phenyl phosphine (DMPP) was used to catalyze the hetero-Michael addition of thioglucose to the unreacted pendant
methacrylate groups. This reaction yielded a hyperbranched glycopolymer with high conversion of click reaction in a relatively simple manner.
Furthermore, Whittaker et al. demonstrate another efficient route to hyperbranched glycopolymers through the
use of RAFT polymerization and click chemistry, Scheme 10
[85]. They modify the chain transfer agent to incorporate
alkyne groups into the polymer at the a-chain end. The
polymer formed is a statistical copolymer of dimethylaminoethylacrylate (DMAEA) and trifluoroethyl acrylate (tFEA)
with EGDMA as a branching agent to give an alkyne functionalized hyperbranched polymer network. The CuAAC
reaction was implemented to click azide functionalized
Scheme 9. Synthesis of hyperbranched glycopolymers using RAFT polymerization and CuAAC click reactions (left) or thiol-yne click reactions (right).
444
S. Slavin et al. / European Polymer Journal 47 (2011) 435–446
Scheme 10. Synthesis of hyperbranched glycopolymers by RAFT using an alkyne functional RAFT agent and CuAAC click.
sugars onto the polymer network. A nice feature of this
work was the successful incorporation of a 19F magnetic
resonance imaging contrast agent into the glycopolymer.
Another striking feature was that the polymerization was
carried out without protection of the alkyne group on the
RAFT agent. As has been discussed previously in this
review, alkynes are typically protected during polymerization, with trimethylsilyl groups. This is to avoid unwanted
side reactions; however in this work no side reactions were
reported. This enables synthesis of glycopolymers in only
two steps with the added benefit of defined macromolecular properties due to the polymerization method as well as
incorporation of the MRI contrasting agent (tFEA).
2. Conclusions and outlook
The use of click reactions has flourished in all fields of
chemistry since the first introduction of the term by Sharpless [17]. By taking advantage of these reactions in polymer
chemistry it is now easier to synthesize tailor made
macromolecules with functionalities previously difficult
to incorporate. In this review, a selection of routes to
glycopolymers have been discussed which combine the
advantages of click chemistry and controlled polymerization techniques.
The copper catalyzed azide-alkyne cycloaddition
(CuAAC) click reaction has been shown to be a versatile
and effective route to glycopolymers, although the removal
of copper catalyst still remains a challenge for biological
applications. This reaction has been utilized to prepare
polymers with different topologies and carbohydrate content. It has also been demonstrated to be a facile route to
glycomonomers as well as a promising class of monomer
based on vinyltriazole.
Alternatively, thiol based reactions provide a new platform due to their high reactivity with various compounds.
In this review, thiol functional sugars were reacted with alkene, alkyne, chloro and para-pentafluoro groups to yield
glycopolymers. There are still several thiol based reactions,
which have not been employed yet for glycopolymer
synthesis. For instance, thio-bromo, thiol-epoxide, and
thiol-isocyanate reactions could be potentially investigated for their applicability in the glycopolymer field.
The ongoing search for reactions, that meet the criteria
of click chemistry, will present opportunities to polymer
chemists looking for new and simple methods to well defined glycopolymers. Furthermore, these advances in precise glycopolymer synthesis will open up new avenues in
the investigation of carbohydrate–lectin interactions in
biological processes.
Acknowledgment
We thank the European Union Marie Curie fellowship
(proposal number 235999) (C.R.B.), Lubrizol Corporation
Ltd. (JAB), Unilever PLC and EPSRC (SS) for funding.
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Born in Scotland, Stacy Slavin attained an
MSci in Chemistry from the University of
Strathclyde, Glasgow in 2007, which included
an industrial placement at Dupont Teijin
Films , Wilton (2005-2006). Her Masters project was carried out under the supervision of
Professor D. C. Sherrington FRS . Stacy then
undertook a three month IAESTE placement at
RMIT University, Melbourne. Since October
2007 she has been a PhD student at the University of Warwick, under the supervision of
Professor D. M. Haddleton and Dr Ezat
Khoshdel (Unilever PLC). Stacy’s 4 year ChemDoc project (EPSRC and
Unilever funded) investigates the functionalisation of biological surfaces
with polymeric species synthesised via living radical polymerisation
techniques . In 2010 she was awarded the Domino Macro Group UK,
Annual Young Polymer Scientist.
James A. Burns (born 1985) completed his
master’s degree in chemistry at the University
of Warwick in 2008. During this time he
conducted his final year research project in
the area of glycopolymer synthesis, under the
supervision of Professor David M. Haddleton.
Staying within the Haddleton research group,
James began his PhD research in October
2008. He is sponsored by Lubrizol Ltd, and his
research is focused on the investigation of star
polymers synthesised by controlled radical
polymerisation.
David Haddleton is Professor of Chemistry at
the University of Warwick, UK where he
joined in 1993 following 6 years at ICI. His
PhD was in photochemistry of rhodium ethene compounds at 12K with Robin Perutz at
York. He is an ex Editor in Chief of EPJ and is
currently Editor in Chief of the RSC Journal
‘‘Polymer Chemistry”. Professor Haddleton’s
research centres on controlled polymerisation
to give macromolecules of designed, desired
and targeted structure. Work is directed to the
synthesis of polymers one monomer at a time
in an attempt to approach the degree of sophistication exhibited by
natural polymers. An overriding aspect of all the work is the desire to
produce polymers by commercially accessible processes for biosciences
and materials applications.
C. Remzi Becer was born in 1980 in Izmir,
Turkey. He received his BSc degree in 2003 at
the Chemistry Department of the Istanbul
Technical University (ITU). In 2005, he
received his MSc degree in Polymer Science
and Technology at the ITU. He completed his
PhD study titled as ‘‘Controlling Polymer
Architectures” in 2009 under the supervision
of Ulrich S. Schubert at the Eindhoven University of Technology (Netherlands) and the
Friedrich-Schiller-University Jena (Germany).
Since late 2009, he has been a Marie Curie
Research Fellow in the University of Warwick (United Kingdom).
Recently, he received Science City Independent Research Fellowship to
conduct research in the area of magnetic nanomedicines at the University
of Warwick.