Minireview

Click Chemistry and ATRP: A Beneficial Union for the

Preparation of Functional Materials
Patricia L. Golas and Krzysztof Matyjaszewski*
Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA,
E-mail: km3b@andrew.cmu.edu

Keywords: ATRP, Click chemistry, Polymer functionalization

Received: May 24, 2007; Accepted: August 28, 2007

DOI: 10.1002/qsar.200740059

Abstract
Since the concept of highly efficient and selective “click” reactions was put forth by
Sharpless and coworkers, this branch of chemical transformations has been subject to an
astounding degree of applications. Although click chemistry encompasses a wide variety
of reactions, the CuI-catalyzed azide – alkyne cycloaddition has received the most
attention. It has been increasingly employed in polymer functionalization and materials
synthesis, especially in conjunction with controlled radical polymerization methods, such
as Atom Transfer Radical Polymerization (ATRP). The CuI-catalyzed azide – alkyne
cycloaddition is utilized particularly well with ATRP, due to the ease of incorporating
clickable functionality into polymers prepared by ATRP and the use of the same catalyst
in each process. This minireview summarizes and analyzes recent developments in the
field of CuI-click chemistry as applied to ATRP, and how the combination of these two
powerful techniques has greatly expanded the range of available materials and has
contributed to fundamental understanding of this process.

1 Introduction
The development of new polymeric materials for macro-
molecular engineering and biological applications often
requires the use of highly selective and efficient modifica-
tion reactions. To these ends, a broad class of reactions col-
lectively termed “click” chemistry has recently been exten-
sively applied as a polymer modification technique. Click
reactions are characterized by high fidelity, quantitative
yields, tolerance to a variety of functional groups, applica-
bility under mild reaction conditions, and minimal synthet-
ic work-up [1]. This categorization can be applied to a mul-
titude of macromolecular transformations, including the
Lewis acid-catalyzed azide – nitrile cycloaddition [2 – 5],
Diels – Alder cycloaddition [6, 7], thiol-oxidative coupling
[8 – 10], ring-opening of epoxides [11, 12], and atom trans-
fer radical addition [13, 14]. However, the 1,3-dipolar
azide – alkyne cycloaddition [15] has received the most at-
tention since it was demonstrated by Tornoe et al. [16] and
Rostovtsev et al. [17] that this reaction can be regioselec-
tively catalyzed by CuI to yield 1,4-triazoles at room tem-
perature. Since this momentous discovery, the CuI-cata-
lyzed click reaction has been subject to a variety of mecha-
nistic investigations [18 – 21] and has received widespread
application in polymer and materials science [22 – 24]. It
has been utilized for the conjugation of biological poly-
mers to viruses [25 – 27], synthetic polymers [28 – 30], and
solid surfaces; [31 – 33] the preparation of cyclodextrin [34]
and cyclopeptide [35, 36] analogues; polymer functionali-
zation;[37 – 39] and the preparation of macromonomers
[40, 41], block copolymers [7, 42, 43], star polymers [44,
45], dendrimers [46 – 48], brushes [11, 49], mechanically in-
terlocked architectures [50, 51], shell cross-linked nanopar-
ticles [52], and organometallic polymers [53]. The CuI-cat-
alyzed azide – alkyne cycloaddition is generally limited to
terminal alkynes, but it has recently been successfully ex-
tended to internal alkynes after appropriate catalyst selec-
tion [54, 55]. In addition, metals other than CuI have been
demonstrated to catalyze the azide – alkyne cycloaddition,
including RuII [55, 56], PdII, and PtII [57].
The application of click chemistry together with Con-
trolled Radical Polymerization (CRP) has contributed to
rapid development in the available range of polymer archi-
tectures and functional materials due to the ease with
which these two synthetic techniques are combined. CRP
methods allow for the preparation of polymers with prede-
termined molecular weight, narrow molecular weight dis-
tribution, chain end functionality, and complex architec-
ture and composition [58 – 62]. These methods are applica-
ble to a wide range of monomers and solvents, and are tol-
erant to many impurities. The most commonly employed
CRP techniques include Atom Transfer Radical Polymeri-

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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Scheme 1. ATRP mechanism.
zation (ATRP) [63 – 66], stable free radical polymerization
(such as Nitroxide-Mediated Polymerization, NMP) [67 –
69], and Reversible Addition – Fragmentation Transfer
(RAFT) polymerization [70 – 72]. Control over molecular
weight, composition, and topology is accomplished by
maintaining a low concentration of propagating chains
through a fast dynamic equilibrium between active and
dormant state. Since the majority of growing polymer
chains remains in the dormant state [73], termination reac-
tions are suppressed. In ATRP, this equilibrium is estab-
lished between a lower oxidation state transition metal
complex and its higher oxidation state (Scheme 1); this
complex is generally derived from Cu, although a variety
of other metals including Ru [74], Fe [75 – 77], Ni [78], Pd
[79], Mo [80], and Os [81] have all been successfully dem-
onstrated to mediate the process.
Recent years have witnessed an extensive range of ma-
terials prepared by combination of click chemistry with
CRP. The simultaneous and cascade functionalization of a
variety of polymeric scaffolds prepared by NMP was dem-
onstrated using a variety of synthetic transformations, in-
cluding esterification, amidation, and CuI-mediated click
chemistry [82]. This strategy presents an efficient method
of conducting multiple, independent functionalization re-
actions on a polymer backbone in one pot. The prepara-
tion of surface-functionalized shell cross-linked Knedel-
like nanoparticles (SCKs) was demonstrated using sequen-
tial NMP to synthesize amphiphilic block copolymers with
“clickable” functionality, which were then self-assembled
in water and cross-linked within the shell layer to afford
SCKs [83, 84]. Fluorescent dyes containing complementa-
ry click-reactive functional groups were attached to the
surface via CuI-catalyzed azide – alkyne cycloaddition. In
addition, the preparation of photolabile functional poly-
mers for gold surface patterning has recently been report-
ed [85]. In this example, NMP was used to prepare a ran-
dom copolymer of styrene and 4-propargyloxystyrene,
which was then functionalized with disulfide anchoring
units and/or photocleavable amino groups via CuI click
chemistry. A combination of NMP, ring-opening polymeri-
zation, and azide – alkyne cycloaddition was recently em-
ployed for the synthesis of miktoarm star terpolymers in
one pot [86]. RAFT polymerization has also been used in
combination with the azide – alkyne click reaction [87] to
prepare well-defined block copolymers [43] and functional
telechelics [88] by capitalizing on the ability to directly in-
corporate clickable functionality into polymer chains using
an appropriately functionalized chain transfer agent. Thin
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multilayer films have been prepared by a different ap-
proach, namely RAFT copolymerization of acrylic acid
and 3-chloropropyl acrylate followed by postpolymeriza-
tion incorporation of azide groups [89], and direct poly-
merization of propargyl acrylate to introduce alkyne func-
tionality [90]. CuI-click chemistry has been used in con-
junction with non-CRP methods of polymer synthesis as
well. A wide variety of novel materials have been prepared
in this manner, including peptide-grafted aliphatic polyes-
ters [91], functionalized poly(oxazoline)s [92], and derivat-
ized poly(e-caprolactone) (PCL) [93] by ring-opening
polymerization; functionalized poly(oxynorbornenes) by
ring-opening metathesis polymerization; [94, 95] linear
dendronized polymers [96] and phosphorescent iridium-
containing polymers [97] by free radical polymerization;
and functional poly(p-phenyleneethynylene)s by polycon-
densation [98]. The efficiency and selectivity of the CuI-
catalyzed azide – alkyne cycloaddition has even allowed it
to be used as a polycondensation technique for polymer
synthesis [57, 99]. This should by no means be taken as an
exhaustive account of the novel polymeric materials that
have been prepared using click chemistry.
The majority of polymers functionalized using the CuI-
catalyzed azide – alkyne cycloaddition has been prepared
by ATRP. This CRP method lends itself particularly well
to CuI click chemistry. There are a variety of available
methods for incorporating clickable groups into a polymer
chain, including the use of functional monomers or initia-
tors and postpolymerization modification reactions
(Scheme 2). The halogen end groups of polymers prepared
by ATRP are easily converted to azido moieties by simple
nucleophilic substitution [100 – 105]. Additionally, the CuI
catalyst typically used in ATRP is the same that catalyzes
azide – alkyne cycloaddition, and both processes are typi-
cally conducted with similar or the same N-based ligands.
These advantages have allowed for the one-pot synthesis,
azidation, and click coupling [106] or click functionaliza-
tion [107] of telechelic polymers. The judicious use of
ATRP together with click chemistry has yielded a plethora
of new polymeric materials for both biological applications
and macromolecular engineering [108]. This minireview
will summarize and analyze these recent advances and ap-
plications.
2 Catalyst Selection
Although azide – alkyne cycloaddition and ATRP can be
catalyzed by the same Cu-based complexes, the two tech-
niques are mechanistically different. ATRP is a redox pro-
cess that is mediated by the reversible reaction between a
low-oxidation state transition metal complex and an alkyl
halide, which generates propagating radicals and the high-
er-oxidation state metal complex, as outlined earlier. The
activity of an ATRP catalyst has been demonstrated to
correlate linearly with redox potential [109, 110]. The rules
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Minireview
Scheme 2. Incorporating clickable functionality in polymers prepared by ATRP.
for rational selection of the most active and appropriate
catalysts for ATRP have been thoroughly described [111 –
114]. The nitrogen-based ligands used for ATRP include
bidentate bipyridines [115 – 119], and tridentate [120 –
122], tetradentate [64, 123 – 127], and hexadentate [128]
amines.
The mechanism of the CuI-catalyzed azide – alkyne cy-
cloaddition has been recently explained as a stepwise pro-
cess beginning with formation of a CuI-acetylide p-com-
plex, followed by azide complexation and cyclization. Sub-
sequent protonation of the triazole-copper derivative and
dissociation of the product regenerates the catalyst
(Scheme 3). A variety of compounds have been utilized as
ligands for this process [57, 129 – 131], including pyridines,
amines, triazoles, phosphines, and solvents such as water,
DMF, DMSO, and acetonitrile. It has been repeatedly
demonstrated that ligand choice strongly affects the cata-
lytic activity of the copper center. A recent systematic in-
vestigation conducted in organic media [57] revealed that
aliphatic amine ligands consistently led to significantly
faster rates as compared to pyridine-based ligands. This
could be due to a number of factors, including electron
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Patricia L. Golas and Krzysztof Matyjaszewski
back donation from the copper center to the alkyne, and
the stronger basicity and enhanced lability of aliphatic
amine ligands relative to pyridine-based ligands. Faster
rates were also observed with tridentate versus tetraden-
tate ligands. This is presumably due to coordinative satura-
tion of the CuI catalyst by tetradentate ligands, which may
interfere with alkyne complexation. This is so far the only
investigation that has described a systematic correlation
between catalytic activity and ligand structure for CuI-cat-
alyzed azide – alkyne cycloaddition in organic systems. Im-
portant ligand effects have also been demonstrated in a
mixed aqueous/organic system [130]. It should be noted
that it is difficult to compare the ligand effects on catalytic
activity observed during experiments conducted under dif-
ferent conditions, since the order of the reaction with re-
spect to catalyst and alkyne has been reported to vary
based on concentrations and reaction conditions [18 – 20].
Although it is convenient to employ the same catalytic
complex for both ATRP and Cu-based click chemistry
when the two techniques are used together for polymer
synthesis and modification, this is not necessarily the most
efficient approach.
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Scheme 3. Proposed outline of mechanistic pathway in CuI-cat-
alyzed azide – alkyne cycloaddition.
3 Macromolecular Engineering
ATRP has rapidly developed as one of the most powerful
polymerization techniques with unparalleled versatility in
designing functional materials and polymers with complex
architectures and compositions [132 – 134], including stars
[135 – 139], graft copolymers [140 – 144], brushes [145 –
149], block copolymers [150 – 154], and gradient copoly-
mers [61, 133, 155 – 158]. The combination of ATRP with
click chemistry has expanded the range of materials viable
through polymer functionalization and macromolecular
engineering. In addition, ATRP has been previously suc-
cessfully applied in various transformation techniques to-
gether with ionic, coordination, and condensation poly-
merization [140, 159 – 164]. This approach can be further
advanced by using click chemistry.
3.1 Pendant Functionalization and Complex Architectures
A high degree of clickable functionality can be easily in-
troduced into polymers prepared by ATRP by use of an
appropriate monomer. This was first demonstrated by the
polymerization of propargyl methacrylate and 3-azido-
propyl methacrylate (AzPMA) [37]. Propargyl methacry-
late is a commercially available monomer, but its polymer-
ization yielded polymers with high polydispersities, multi-
modal molecular weight distributions, and a cross-linked
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Scheme 4. Pendant functionalization of poly(3-azidopropyl
methacrylate).
network at high conversions, presumably due to some con-
tribution from radical addition to the alkyne groups and
possible coordination of the CuI catalyst to the monomer
[165, 166]. The polymerization of the novel monomer
AzPMA proceeded with good control over molecular
weight and resulted in polymers with low polydispersity
and retention of chain end functionality. The pendant azi-
do groups were then click-coupled with various alkyne-
bearing compounds, including propargyl alcohol, proparg-
yl triphenylphosphonium bromide, propargyl 2-bromoiso-
butyrate, and 4-pentynoic acid (Scheme 4). Quantitative
transformations were confirmed by 1H NMR. In addition,
the rate of azide – alkyne coupling between pAzPMA and
propargyl alcohol was observed to be significantly faster
than the analogous reaction between AzPMA monomer
and propargyl alcohol. This unusual phenomenon was at-
tributed to complexation of CuI to the triazole linkages
[129] formed along the polymer backbone, resulting in an
autocatalytic effect [18].
Although the direct polymerization of an azido-func-
tionalized monomer is a convenient and efficient method
of incorporating pendant clickable functionality, the
shock- and heat-sensitivity of low molecular weight azides
makes this a riskier approach. A recent report [11] demon-
strates that pendant azido functionality can be quantita-
tively introduced along a polymer backbone by ring-open-
ing of an epoxide-containing monomer, in this case glycid-
yl methacrylate, thereby avoiding handling potentially
dangerous compounds. Using this strategy, graft copoly-
mers were prepared by two different consecutive click re-
actions. Random copolymers of glycidyl methacrylate and
methyl methacrylate (MMA) were synthesized by ATRP,
and subsequently functionalized with azide group via ring-
opening of the epoxide moiety with NaN3 in the presence
of ammonium chloride in DMF. 1H NMR and FT-IR spec-
troscopy revealed that the ring-opening was quantitative.
The azido-bearing polymer backbone was reacted with
poly(ethylene oxide) methyl ether pentynoate (MePEO-
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Minireview
Scheme 5. Copolymerization of glycidyl methacrylate and MMA, ring-opening of the epoxide ring in the presence of azide, and syn-
thesis of brush copolymers via a “grafting onto” click technique.
P) in the presence of CuBr/N,N,N’,N’’,N’’-pentamethyldi-
ethylenetriamine (PMDETA) as catalyst in order to pre-
pare loosely grafted brushes with PEO side chains
(Scheme 5). The conversions of MePEO-P were 59 and
75% for copolymers comprised 20 and 44 wt% glycidyl
methacrylate, respectively. Grafting density was limited by
steric crowding of the polymeric side chains.
Pendant functionality can be utilized for the prepara-
tion of molecular brushes by postpolymerization modifi-
cation of the polymer backbone with alkyne moieties.
Poly(2-hydroxyethyl methacrylate) (PHEMA) was deriv-
atized with acetylene groups by reaction of the hydroxyl
groups with pentynoic acid [49]. A number of polymers
displaying azido-end groups were then coupled to the
PHEMA backbone using CuBr/PMDETA as catalyst in
DMF in order to generate a variety of molecular brushes
with low molecular weight side chains. The monoazido-
polymers included PEO, PS, PBA, and PBA-b-PS. It was
found that coupling efficiency depended heavily on the
nature of the side chain polymer. Grafting PEO-N3 to
PHEMA backbone yielded brushes with up to 88% graft-
ing density when a large excess of azido-terminated poly-
mer was used, while grafting density was less than 50%
with PS-N3, PBA-N3, and PBA-b-PS-N3. Molecular
weights of the synthesized brushes reached up to
200 000 g/mol, with Mw/Mn between 1.2 and 1.3, as deter-
mined by triple detection size exclusion chromatography
(SEC). This is a general strategy that can potentially be
used to prepare a variety of molecular brushes, utilizing
any of the strategies for pendant functionalization of po-
lymer backbones outlined in this review. Notably, this re-
port demonstrated the facile preparation of brushes with
block copolymer side chains.
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Patricia L. Golas and Krzysztof Matyjaszewski
3.2 End Group Functionalization and Architectural
Control
Terminal functionality can be easily introduced on poly-
mers prepared via ATRP by substitution of the halogen
end group with azide [101, 102] and subsequent click cou-
pling with alkyne-modified species. This strategy was em-
ployed for the preparation of polymers end-modified with
a variety of functional groups [105]. Low molecular weight
azido-terminated polystyrene (PS) was synthesized by
ATRP followed by reaction with NaN3 in DMF. Click cou-
pling was then utilized for the introduction of alcohol, car-
boxyl, and methyl vinyl functionalities by reaction with
propargyl alcohol, propiolic acid, and 2-methyl-1-buten-3-
yne, respectively (Scheme 6). 1H NMR confirmed the effi-
ciency of each transformation. This is a robust technique
that can potentially be applied to a wide variety of poly-
mers and functional groups.
End-modification of a,w-diazido PS by click chemistry
was used as a model reaction for quantification of the dif-
ferent telechelic species present at various reaction times
and determination of apparent rate constants of consecu-
tive click reactions [38]. The kinetic measurements were
made by gradient polymer elution chromatography-SEC
(GPEC-SEC), a two-dimensional chromatographic tech-
nique that measures both the functionality-type distribu-
tion and molecular weight distribution of polymers. Dibro-
mo-PS was synthesized by ATRP from a difunctional ini-
tiator, dimethyl-2,6-dibromoheptanedioate (DM-2,6-
DBHD), modified with azido groups, and click coupled
with propargyl alcohol (Scheme 7). The concentrations of
non-hydroxyl-PS, monohydroxyl-PS, and dihydroxyl-PS
were monitored by GPEC-SEC as a function of time (Fig-
ure 1). Assuming pseudo-first-order conditions (propargyl
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Scheme 6. Transformation of bromine end-functional PS into various functional polymers. Adapted from Ref. [105] with permission
from John Wiley & Sons, Inc.
alcohol was present in tenfold excess relative to azido
groups), the apparent rate constants of click coupling (k1
and k2) were determined to be (3.2
0.2)  104 and (1.1

0.1)  104 s1, semiquantitatively indicating that the first
click coupling of propargyl alcohol to a PS chain end is
three times faster than the second coupling. The distance
between chain ends and the presence of PMDETA as li-
gand may therefore preclude the autocatalytic effect previ-
ously observed during click reactions. This work demon-
strates that the functionality-type distribution of modified
polymers can be measured using GPEC-SEC, which pres-
ents a significant advantage over analytical techniques
such as NMR and ultraviolet-visible spectroscopy that can
only determine average functionality. A similar methodol-
ogy was also used to separate hydroxyl-telechelic PS pre-
pared by either ATRP and click chemistry, or ATRP and
atom transfer radical coupling [167].
The preparation of a-functional polymers was demon-
strated by ATRP of MMA from azido-functionalized ini-
tiators [107]. Subsequent click coupling with propargyl al-
cohol and alkyne-modified diaza and coumarin dyes was
conducted in one pot by adding alkyne compound to the
polymerization mixture at high conversion (87 – 95%), us-
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ing CuBr/N-alkyl-2-pyridylmethanimine as catalyst for
both ATRP and azide – alkyne cycloaddition. After stir-
ring overnight at 70 8C, each click reaction was revealed by
1
H NMR to be complete. Although the functionalized ini-
tiator approach is an efficient method of incorporating
clickable groups at polymer chain ends, it requires the syn-
thesis of explosive low molecular weight azides.
The facile incorporation of terminal functionality in
polymers prepared by ATRP has been utilized not only
for end functionalization, but also for the generation of
polymeric architectures. One of the earliest examples of
combining ATRP with CuI-catalyzed azide – alkyne cyclo-
addition was for the modular synthesis of block copoly-
mers [42]. Alkyne-functionalized PMMA and PS of vari-
ous molecular weights were synthesized by ATRP from a
trimethylsilyl-protected initiator, 3-(1,1,1-trimethylsilyl)-2-
propynyl 2-bromo-2-methylpropanoate, which was then
quantitatively deprotected by reaction with tetrabutylam-
monium fluoride (TBAF). Mono- and diazido-PS were
prepared by substitution of PS bromine end groups with
azide by reaction with azidotrimethylsilane and TBAF. In
addition, PEG monomethyl ether was modified with al-
kyne or azide moiety. A variety of block copolymers were
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Minireview
Scheme 7. Synthesis of a,w-dihydroxyl-terminated PS.
Figure 1. Fraction of dihydroxyl-, monohydroxyl-, and non-hy-
droxyl-PS as a function of reaction time. Reprinted with permis-
sion from ref.[38]. Copyright 2005 American Chemical Society.
then prepared by click coupling of the various end-func-
tionalized polymers in the presence of CuI and 1,8-Dia-
za[5.4.0]bicycloundec-7-ene (DBU) in THF at 35 8C for
18 h. The synthesized materials included PMMA-b-PEG,
PS-b-PEG, PEG-b-PS-b-PEG, and PMMA-b-PS. In each
case, SEC demonstrated clean block coupling and virtually
no residual starting material, along with retention of low
polydispersity. This methodology provides a convenient
and versatile strategy for preparing block copolymers
comprised of monomers with extremely disparate reactivi-
ties or blocks prepared by different polymerization tech-
niques.
CuI click chemistry has been utilized as a method for the
step-growth click coupling of end-functional polymers syn-
thesized by ATRP [106]. This concept was demonstrated
using homo- and heterotelechelic PS (Scheme 8). Difunc-
tional PS was prepared using two different approaches:
ATRP of styrene from DM-2,6-DBHD and subsequent re-
action with NaN3 in DMF to generate a,w-diazido-PS, and
ATRP of styrene from propargyl 2-bromoisobutyrate fol-
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Patricia L. Golas and Krzysztof Matyjaszewski
lowed by reaction with NaN3 in DMF to generate a-al-
kyne-w-azido-PS. The former material was click coupled
with propargyl ether (Pg2O), and the latter material was
self coupled. A one-pot ATRP-nucleophilic substitution-
click coupling was also demonstrated by ATRP of styrene
from propargyl 2-bromoisobutyrate, followed by addition
of NaN3, ascorbic acid, and DMF in order to displace bro-
mine end group with azide, regenerate the active CuI cata-
lyst, and solubilize the reaction mixture. In each case, SEC
demonstrated that click coupling resulted in PS of higher
molecular weight and broader molecular weight distribu-
tion, as expected for a step-growth process, in addition to
residual low molecular weight material that was not con-
sumed as the coupling proceeded. However, 1H NMR in-
dicated the virtual absence of unreacted azido-chain ends
after 89 h. Due to the higher elution volume of the remain-
ing low molecular weight material relative to parent PS,
this material was attributed to cyclization. Further investi-
gation [168] revealed that as the reaction mixture was di-
luted, larger amounts of low molecular weight material
were formed. During click coupling of diazido-terminated
PS with Pg2O in very dilute solution (2.08  103 M poly-
mer and Pg2O), 22% unreacted azide groups remained af-
ter 192 h, while the fraction of low molecular weight poly-
mer was 67%. This polymer always exhibited lower appar-
ent molecular weight relative to the parent PS. These ob-
servations indicate that a substantial amount of macrocy-
cle can be formed by polymer click coupling in dilute
solution.
The strategy outlined above for synthesis of a-alkyne-w-
azido-PS and subsequent self-click coupling was refined in
order to more efficiently prepare cyclic polymers [169].
The primary determining factor for the occurrence of cyc-
lization versus condensation is polymer concentration, and
it was reported that polymer concentrations below 0.1 mM
favored cyclization. However, since prohibitively excessive
dilution would be required to prepare pure macrocycles in
bulk solution, a technique was devised to ensure an infini-
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Scheme 8. Click coupling reactions using telechelic polymers prepared by ATRP: (a) synthesis of a-acetylene-w-azido-terminated PS
and its homocoupling and (b) synthesis of a,w-diazido-terminated PS and its coupling with Pg2O.
tesimal concentration of linear polymer. A syringe pump
was used for slow addition of polymer into a solution of
CuBr/bpy in DMF over 25 h. The starting polymers includ-
ed PS with Mn of 2200 and 4200 g/mol, and poly(p-acetoxy-
styrene) with Mn of 2700 g/mol. A combination of several
analytical techniques was utilized to support the formation
of macrocycles. MALDI-TOF confirmed that the molecu-
lar weight of the product was nearly identical to that of the
linear polymer, but SEC demonstrated the exclusive pres-
ence of species with higher elution volume. In addition,
FT-IR spectroscopy and 1H NMR revealed the disappear-
ance of azide and alkyne functionalities, indicating quanti-
tative cyclization.
The step growth click coupling of low molecular weight
polymers prepared by ATRP was utilized as a novel strat-
egy for facile screening of appropriate conditions for click
reactions and a systematic investigation into the effects of
ligand, solvent, and metal on catalyst performance [57].
Click coupling of a,w-diazido-terminated PS with Pg2O in
DMF using CuBr as catalyst was used as the model reac-
tion for this investigation. Reactions were monitored by
SEC and semi-quantitatively analyzed by Gaussian multi-
peak fitting and subsequent peak integration. It was dem-
onstrated that aliphatic amine ligands led to significantly
faster reaction rates as compared to pyridine-based li-
gands, and tridentate ligands contributed to faster rates
than tetradentate ligands (Chart 1). Specifically, the click
reaction using CuBr/PMDETA as catalyst in DMF was
nearly three orders of magnitude faster than the reaction
in the presence of CuBr/bpy. An additional rate enhance-
ment was observed when reactions were conducted in a
non-coordinating (toluene) versus a coordinating (DMF)
solvent. The typical susceptibility of CuI to oxidation was
circumvented by employing excess hydrazine as a reducing
agent, which allowed click reactions in organic systems to
be conducted in the presence of limited amounts of air.
The addition of hydrazine resulted in a pronounced rate
enhancement, which could be due to the basicity of hydra-
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zine. Finally, the use of complexes derived from metals
other than CuI as catalysts for click reactions was explored.
These metals included NiII, PdII, and PtII. The PtII catalyst
demonstrated the highest activity relative to the other
metals investigated, although this activity still did not ap-
proach that of CuI. However, the complexes of these met-
als have the advantage of not being air sensitive. Prelimi-
nary investigation revealed that PMDETA is not an ap-
propriate ligand for the PtII catalyst, and therefore addi-
tional ligands and solvents need to be investigated in order
to achieve fast and efficient reactions, and elucidate the
catalytic mechanism.
The click coupling of block copolymers synthesized by
ATRP was utilized for the preparation of multisegmented
block copolymers [170]. A variety of diazido-terminated
block copolymers was prepared via ATRP followed by re-
action with NaN3 in DMF. These materials included poly-
styrene-b-poly(ethylene oxide)-b-polystyrene (N3-PS-
PEO-PS-N3), poly(n-butyl acrylate)-b-poly(methyl metha-
crylate)-b-poly(n-butyl acrylate) (N3-PBA-PMMA-PBA-
N3), and polystyrene-b-poly(n-butyl acrylate)-b-poly-
(methyl methacrylate)-b-poly(n-butyl acrylate)-b-polystyr-
ene (N3-PS-PBA-PMMA-PBA-PS-N3). Multisegmented
block copolymers were then synthesized by click coupling
each of the diazido-terminated block copolymers with Pg2
O in DMF using CuBr/PMDETA as catalyst. Triple detec-
tion-SEC revealed that typically 5 – 7 block copolymer
B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1123
Minireview
Scheme 9. Synthesis of linear, three-arm, and four-arm star PS polymers by click coupling.
molecules were linked during the coupling reactions,
which yielded materials with up to 25 polymer segments in
a single chain. The amphiphilic multisegmented block co-
polymer demonstrated different mechanical properties
from N3-PS-PEO-PS-N3. These properties were character-
ized by dynamic mechanical analysis, which revealed that
the precursor polymer behaves as a viscoelastic fluid,
while the product is a lightly cross-linked elastic material.
Differential Scanning Calorimetry (DSC) indicates that
this cross-linking occurs through the glassy PS domains, as
evidenced by the disappearance of the glass transition of
the PS segments after click coupling of N3-PS-PEO-PS-N3.
The hard/soft materials were also characterized by DSC,
which demonstrated that the single glass transition tem-
perature (Tg) exhibited by each precursor polymer (N3-
PBA-PMMA-PBA-N3 and N3-PS-PBA-PMMA-PBA-PS-
N3) increases upon click coupling. A wide range of multi-
segmented block copolymers can potentially be prepared
using this robust strategy.
ATRP and click chemistry have been recently combined
in a variety of ways to prepare complex polymeric archi-
tectures. The first synthesis of star polymers using this
strategy was accomplished by coupling azido-terminated
PS with compounds bearing multiple alkyne functionali-
ties [44]. The coupling agents included a di-, tri-, and tet-
raalkyne (Scheme 9), to which azido-terminated PS was
attached with 95, 90, and 83% efficiency, respectively. All
coupling reactions were complete within 3 h. The click re-
1124 B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Patricia L. Golas and Krzysztof Matyjaszewski
action between PS and dialkyne was used as a model to in-
vestigate the effects of several parameters on product
yield. It was reported that increasing polymer molecular
weight reduced coupling efficiency. For example, the con-
jugation of PS with Mn ¼ 1400 and 6800 g/mol to dialkyne
coupling agent proceeded with 95 and 89% efficiency, re-
spectively. The effects of additional parameters were in-
vestigated, including the presence of Cu(0) as reducing
agent and molar ratio of azide to alkyne groups. It was
found that a small amount of Cu(0) enhances coupling ef-
ficiency, and the highest product yield was obtained when
the ratio of azide/alkyne groups was close to one. This is a
versatile strategy that can potentially be used to efficiently
prepare numerous different star polymers.
A similar methodology was utilized shortly thereafter to
synthesize 3-miktoarm star polymers and first-generation
polymeric miktodendrimers comprised PS, Poly(t-butyl ac-
rylate) (PtBA), Poly(methyl acrylate) (PMA), and/or
Poly(acrylic acid) (PAA) arms [171]. Star synthesis was ac-
complished by click coupling azido-terminated polymers
to tripropargylamine using CuBr/PMDETA as catalyst in
DMF. Miktoarm stars were typically prepared by first cou-
pling azido-terminated polymer to a large excess of tripro-
pargylamine, followed by addition via syringe pump of the
product to a solution of a different polymer. This strategy
was utilized for the preparation of a variety of miktoarm
star polymers, including P[(MA65)2-(Sty50)1], P[(MA65)2-
(tBA54)1], P[(Sty50)2-(tBA54)1], P[(tBA42)2-(MA65)1], and
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 10. Synthesis of miktoarm star terpolymers poly(methyl methacrylate)-polystyrene-poly(t-butyl acrylate) and poly(methyl
methacrylate)-polystyrene-poly(ethylene glycol). Adapted from Ref. [45] with permission from John Wiley & Sons, Inc.

P[(tBA54)2-(Sty50)1]. Statistical stars were prepared by one-
pot nucleophilic substitution-click coupling reactions,
while well-defined stars were prepared using neat materi-
als for each reaction step. Coupling efficiency was 70 –
92% for the variety of star and dendritic polymers synthe-
sized, as determined by SEC.
Miktoarm star terpolymers have also been prepared by
a combination of ATRP, NMP, and click chemistry [45].
A linker molecule was synthesized that contained an
ATRP initiating moiety, a stable nitroxide, and an alkyne
group. This initiator was first used for the ATRP of
MMA, followed by NMP of styrene, and finally by click
coupling with azido-terminated PtBA or PEG. Two mik-
toarm star terpolymers were thus generated, PMMA-PS-
PtBA (Mn ¼ 11 200 g/mol, Mw/Mn ¼ 1.15) and PMMA-PS-
PEG (Mn ¼ 9700 g/mol, Mw/Mn ¼ 1.21) (Scheme 10). SEC
demonstrated that the molecular weight of the product
cleanly shifted after each step. The thermal transitions of
the two star polymers were then characterized by DSC.
PMMA-PS-PEG exhibited a single Tg at 78 8C, which in-
dicates segment miscibility. Two Tgs were observed at 43
and 96 8C for PMMA-PS-PtBA, the first transition corre-
sponding to PtBA and the second to PS/PMMA. This re-
port demonstrates an efficient way to cleanly prepare
miktoarm star polymers with well-defined composition
and arm length.
A slight modification in this strategy was used by the
same group to prepare heteroarm H-shaped terpolymers
[172], using the trifunctional initiating species described in
the previous publication [45]. Sequential NMP of styrene
followed by ATRP of MMA yielded a PS-PMMA precur-
sor bearing alkyne functionality. This polymer was linked
to diazido-terminated PEG or PtBA in the presence of
CuBr/PMDETA as catalyst in DMF. The resulting H-shap-

QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134 www.qcs.wiley-vch.de B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1125
Minireview
ed terpolymers included (PS)(PMMA)-PEG-
(PMMA)(PS) (Mn ¼ 22 000 g/mol, Mw/Mn ¼ 1.16) and
(PS)(PMMA)-PtBA-(PMMA)(PS) (Mn ¼ 32 000 g/mol,
Mw/Mn ¼ 1.33). These materials were characterized by
DSC, which revealed Tm at 22 8C and Tg at 88 8C for
(PS)(PMMA)-PEG-(PMMA)-PS, and two Tgs at 45 and
100 8C for (PS)(PMMA)-PtBA-(PMMA)(PS). The ther-
mal transitions thus displayed are similar to those ob-
served for PMMA-PS-PEG and PMMA-PS-PtBA mik-
toarm star polymers, although the materials cannot be di-
rectly compared due to their differences in molecular
weight. The H-shaped polymers were further investigated
by AFM, which demonstrated phase separation between
PS and PMMA blocks for each polymer, and self-assembly
into ordered cylinders for (PS)(PMMA)-PEG-
(PMMA)(PS). Heteroarm H-shaped terpolymers were
previously prepared by combination of ATRP, NMP, and
Diels – Alder click chemistry; [173] this report investigated
the efficiency of CuI-catalyzed azide – alkyne cycloaddition
for the synthesis of these materials.
A similar strategy was recently employed for the prepa-
ration of a miktoarm star terpolymer comprised PEO, PS,
and PCL, which was generated by combination of ATRP,
ring-opening polymerization, and CuI-catalyzed azide – al-
kyne cycloaddition [174]. This was accomplished first by
synthesis of a molecule bearing alkyne and hydroxyl func-
tionality as well as an ATRP initiating moiety. The multi-
functional initiator was click coupled with azido-terminat-
ed PEO using CuBr/PMDETA as catalyst in THF for
3.5 h, and subsequently chain extended by consecutive
ATRP of styrene and ring-opening polymerization of CL
in order to prepare the 3-miktoarm star, PEO-PS-PCL
(Mn ¼ 115 700 g/mol, Mw/Mn ¼ 1.10). The transformation of
azide and alkyne functionalities to triazole was confirmed
by 1H NMR and FT-IR spectroscopy, and successful chain
extension after each synthetic step was confirmed by
SEC.
Star block copolymers have recently been prepared by a
combination of ATRP with click chemistry [175]. PS
three-arm star polymers with high azide chain end func-
tionality were synthesized by ATRP from a trifunctional
initiator, followed by displacement of bromine groups with
azide. These materials were subsequently coupled with
monoalkyne-terminated PEO in the presence of CuBr/
PMDETA in DMF to yield the desired three-arm star
block copolymers with 85% efficiency, as determined by
SEC. This is a robust strategy that can potentially be ap-
plied for the synthesis of a wide variety of star copolymers
with multiblock arms.
As outlined earlier, the application of click chemistry to-
gether with ATRP for the generation of complex architec-
tures has been extended to the preparation of molecular
brushes. Polymeric brushes can be prepared using a variety
of strategies, including the macromonomer method. This
technique involves the synthesis of polymers that display a
polymerizable group, which can then be copolymerized to
1126 B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Patricia L. Golas and Krzysztof Matyjaszewski
prepare graft or branch topologies, or homopolymerized
to generate densely grafted molecular brushes. Macromo-
nomer synthesis generally requires specific and efficient
postpolymerization modification strategies of well-defined
polymers, and the combination of ATRP and click chemis-
try lends itself particularly well to this application. Macro-
monomers were prepared by click coupling azido-func-
tionalized PS or PBA with propargyl acrylate or propargyl
methacrylate (Scheme 11) [40]. The w-acryloyloxy- and w-
methacryloyloxy-macromonomers were synthesized by ei-
ther isolation and purification of the azido-functionalized
intermediate, or by one-pot azidation and click coupling.
Each method resulted in macromonomers with high de-
grees of functionalization (> 90%), as confirmed by NMR.
The same methodology was used to prepare a block mac-
romonomer by end group modification of a PS-b-PBA
block copolymer. This material exhibited slightly lower
chain end functionality (81%) than the homopolymer
macromonomers. The w-acryloyloxy-PS and w-methacry-
loyloxy-PBA macromonomers were then homopolymer-
ized via free radical polymerization in order to demon-
strate the successful incorporation of a high degree of
polymerizable groups. This report demonstrates the versa-
tility of click chemistry and ATRP for the efficient prepa-
ration of macromonomers, and the synthesis of block mac-
romonomers can potentially provide a convenient method
of preparing core – shell brushes or stars by simple chemi-
cal linking reactions. A similar methodology was utilized
shortly thereafter to prepare macromonomers composed
of PS, PtBA, and PEO-b-PS [41].
Degradable model networks have been prepared via
ATRP and CuI-catalyzed azide-alkyne cycloaddition by
cross-linking linear polymers with multifunctional com-
pounds [176]. ATRP of tBA was conducted from a difunc-
tional initiator with an ozonizable group at the center of
the molecule. Azide functionality was introduced into the
homotelechelic polymer by reaction with NaN3 in DMF,
and networks were obtained by cross-linking PtBA with
tri- and tetraacetylene molecules in the presence of CuBr/
PMDETA and sodium ascorbate in DMF at 80 8C for
5 min. Different conditions were evaluated in order to ob-
tain the fastest cross-linking, and it was reported that the
use of CuBr/PMDETA/sodium ascorbate yielded signifi-
cantly faster reactions than CuI/diisopropylethylamine
(DIPEA) or CuBr without ligand. The resulting networks
were ozonized in order to obtain soluble products, which
were then analyzed by SEC. The primary product of tri-
functional network degradation exhibited Mn equal to 1.5
times that of the linear polymer precursor (i.e., a three-
arm star), and the product of tetrafunctional network deg-
radation displayed Mn equal to two times that of PtBA
(i.e., a four-arm star). However, SEC reveals that both sys-
tems also contain polymers with molecular weight equal to
one-half that of the parent polymer, which suggests the
presence of unreacted azide or alkyne groups. Degrada-
tion of the tetrafunctional network resulted in a larger
www.qcs.wiley-vch.de QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134
Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Scheme 11. Postpolymerization end group transformations of PS and poly(n-butyl acrylate) during (meth)acrylate macromonomer
preparation. Reprinted with permission from Ref. [40]. Copyright 2006 American Chemical Society.
amount of this unreacted material, which indicates that in-
creased steric congestion limits the extent of cross-linking.
The application of click chemistry to polymer and mate-
rials science has been extended to the functionalization of
notoriously insoluble structures, such as carbon nanotubes.
To these ends, Single-Walled Carbon Nanotubes (SWNTs)
were surface modified with alkyne moieties by reaction
with p-aminophenyl Pg2O [177]. Azido-terminated PS was
prepared via ATRP and subsequent reaction with NaN3 in
DMF. The two materials were then click coupled in the
presence of CuI or CuBr(PPh3)3 and DBU in DMF. The
PS-modified SWNTs displayed significantly enhanced sol-
ubility in THF, CH2Cl2, and CHCl3 relative to both the
pristine and alkyne-functionalized nanotubes (Figure 2).
The PS – SWNT conjugates remained soluble in organic
media for at least 3 weeks. A variety of click reaction con-
Figure 2. Photograph of three separate SWNTs in THF: (a)
pristine SWNTs, (b) alkyne-functionalized SWNTs, and (c) poly-
mer-functionalized SWNTs. Reprinted with permission from
Ref. [177]. Copyright 2005 American Chemical Society.
QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134 www.qcs.wiley-vch.de
ditions were investigated in order to obtain the highest ex-
tent of solubilization. It was found that the conjugation of
PS with Mn equal to 4800 g/mol imparted the greatest solu-
bility on the carbon structures, whereas coupling PS with
Mn equal to 2000 or 8600 g/mol resulted in less soluble ma-
terials. In addition, higher reaction temperatures and lon-
ger times (up to 48 h) improved solubility. Thermogravi-
metric analysis indicated a typical grafting density of one
polymer chain for every 200 – 700 carbons, corresponding
to 45% polymer. A similar methodology was recently used
to prepare water-soluble and pH-responsive SWNTs by at-
tachment of PS chains via click chemistry and subsequent
sulfonation using acetyl sulfate [178]. This technique pro-
vides a strategy for reducing nanotube aggregation by
electrostatic repulsion of the negatively charged SWNTs.
4 Bioconjugation
The development of a broad range of click reactions was
originally inspired by “NatureNs favorite molecules” and
designed to be tolerant of benign solvents, such as water,
and functional groups typically found in biomaterials [1].
Therefore, the use of click chemistry for biomolecule con-
jugation to surfaces, viruses, and synthetic polymers is a
logical extension of this diverse class of transformations.
The utility of ATRP in preparing water-soluble [179 – 181]
and biocompatible [182 – 185] polymers allows these two
synthetic techniques to be easily and beneficially com-
bined.
One of the earliest bioconjugation applications of CuI-
catalyzed azide – alkyne cycloaddition together with
ATRP was the preparation of protein – polymer conju-
gates [28]. Low molecular weight PS was prepared by
ATRP and subsequently end-functionalized with azide
group by reaction of the polymer with azidotrimethylsi-
lane and TBAF in THF. Azido-functionalized PS was then
B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1127
Minireview
Scheme 12. Preparation of polymer – peptide conjugate PS-GlyGlyArg-(7-amino-4-methylcoumarin) (PS-GlyGlyArg-AMC). Adapt-
ed with permission from Ref. [28] with permission from the Royal Society of Chemistry.
coupled with an alkyne-terminated peptide block
(Scheme 12). Successful formation of the coupled product
was demonstrated by SEC, MALDI-TOF mass spectrome-
try, and end group analysis. A similar methodology was
used to prepare a biohybrid amphiphile comprised of PS
and bovin serum albumin. The formation of protein – PS
aggregates of 30 – 70 nm in aqueous solution was demon-
strated by TEM for each bioconjugate.
A recent report described the synthesis of polypeptide-
based rod-coil diblock copolymers via combination of click
chemistry and ATRP [186]. Poly[2-(dimethylamino)ethyl
methacrylate] (PDMAEMA) was synthesized by ATRP
from azide- or alkyne-functionalized initiators and cou-
pled with the corresponding azide- or alkyne-modified
synthetic polypeptide. In this case, the polypeptide
(PBLG) was prepared from ring-opening polymerization
of g-benzyl-l-glutamate N-carboxyanhydride using func-
tionalized initiators. SEC, IR, and NMR analyses demon-
strated that the click reaction was quantitative. A slight ex-
cess of PDMAEMA (1.2 equiv. relative to PBLG) was em-
ployed during the reaction to ensure efficient coupling,
1128 B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Patricia L. Golas and Krzysztof Matyjaszewski
and was subsequently removed by column chromatogra-
phy. The pure diblock copolymers were treated with KOH
to yield poly(glutamic acid)-b-PDMAEMA, which is a wa-
ter-soluble, biocompatible, pH- and temperature-sensitive
material. Interestingly, the authors reported that the al-
kyne-functionalized initiators did not need to be protected
before use in polymerizations, as the alkyne groups did not
appear to interfere with the ATRP of DMAEMA or ring-
opening polymerization of BLG. A previous report has in-
dicated the occurrence of side reactions, such as branching
and catalyst complexation, during the ATRP of monomers
functionalized with unprotected alkyne groups [37].
CuI-catalyzed ATRP and click reactions have also been
used for the synthesis of novel carbohydrate – polymer
conjugates [29]. The preparation of these materials was ap-
proached using an alkyne-functionalized monomer and
well-documented azido-derivatized sugars. Trimethylsilyl-
protected propargyl methacrylate was homopolymerized
and copolymerized with MMA and poly(ethylene glycol)
methacrylate via ATRP. A protected alkyne monomer was
utilized in order to avoid side reactions through the acety-
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
lene group that lead to poor control and cross-linking at
high conversion [37]. Quantitative deprotection and full
retention of alkyne groups was accomplished using TBAF
and acetic acid, as revealed by 1H NMR, FT-IR spectros-
copy, and SEC. The pendant-functionalized polymers were
then conjugated with both protected and unprotected azi-
do-sugar derivatives using CuBr(PPh3)3 as catalyst in the
presence of DIPEA. The addition of a base is well-known
to accelerate click reactions [20]. 1H NMR and FT-IR
spectroscopy confirmed near quantitative transformation
of alkyne groups to triazoles after 3 days. This same syn-
thetic strategy was employed for the conjugation of lectin-
binding sugars. Mannose- and galactose-based sugar azides
were attached to the various alkyne-functionalized poly-
(methacrylates) in different proportions in order to obtain
a variety of multidentate ligands for lectin binding studies.
The molar ratio of the two sugar moieties in the carbohy-
drate – polymer conjugates was essentially the same as the
initial ratio used during the click reaction. Preliminary in-
vestigations revealed that model lectins were able to selec-
tively bind either galactose or mannose residues.
Virus – glycopolymer conjugates have been prepared by
attachment of alkyne-functionalized neoglycopolymers to
an azide-functionalized viral scaffold [26]. Azide function-
ality was initially introduced into the glycopolymer using
an azide-functionalized initiator for the ATRP of metha-
cryloylethyl glucoside. This was then extended to alkyne
functionality by conjugation of the polymer to fluorescein
dialkyne via CuI-catalyzed azide – alkyne cycloaddition, in
order to introduce a spectroscopic label for further deriva-
tizations. The alkyne-terminated polymer was attached to
azide-functionalized cowpea mosaic virus using copper(I)
triflate/sulfonated bathophenanthroline [27] as catalyst.
The attachment was conducted in the presence of 20
equivalents of alkyne-labeled poly(methacryloylethyl glu-
coside). After purification by sucrose-gradient sedimenta-
tion to remove unattached polymer, measurement of the
calibrated dye absorbance indicated that 125
12 polymer
chains were covalently attached to each particle. Consider-
ing that the virus was functionalized at lysine chain ends
(approximately 240 of which are solvent-accessible), the
bioconjugation reaction proceeded with 52% efficiency.
A variety of functional biocompatible materials and po-
lymer bioconjugates can be prepared by combination of
ATRP with CuI-catalyzed azide – alkyne cycloaddition. A
recent report [30] demonstrated the synthesis of well-de-
fined Poly[oligo(ethylene glycol) acrylate] (POEGA) by
ATRP and subsequent substitution of bromine end group
with azide by reaction of the polymer with NaN3 in DMF.
A variety of functional groups was introduced by reaction
of the azide-terminated polymer with low molecular
weight alkynes for 24 h in the presence of CuBr and either
4,4’-Di(5-nonyl)-2,2’-bipyridine (dNbpy) or PMDETA as
catalyst and THF as solvent. The conjugated functional al-
kynes included propargyl alcohol, propargyl amine, the
amino acid N-a-(9-fluoroenylmethyloxycarbonyl)-l-prop-
QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134 www.qcs.wiley-vch.de
argylglycine, and the oligopeptide alkyne-GGRGDG. In
each case, attachment of the various functional groups to
POEGA was confirmed by 1H NMR. The synthesis of
polymers with terminal azide groups by ATRP and subse-
quent derivatization by CuI click chemistry had been pre-
viously demonstrated; [38, 105] this report extended the
concept to functionalization of biocompatible polymers
with bioactive molecules.
The CuI-catalyzed azide – alkyne cycloaddition can also
be used to functionalize polymers grown from surfaces
[187]. Poly[oligo(ethylene glycol) methyl ether methacry-
late] (OEGMA) was grown from a gold substrate using
surface-initiated ATRP [188 – 192] from a disulfide-con-
taining initiator attached to the surface. The polymer coat-
ing was end-functionalized with azide by immersing the
substrate in a DMF solution of NaN3, and then derivatized
with a variety of alkyne-bearing compounds by click reac-
tion in a solution of copper(II) sulfate in water/alcohol
and sodium l-ascorbate as reducing agent to generate the
active CuI catalyst in situ [17, 18, 193, 194]. The attached
molecules include 1-hexyne, 5-hexyn-1-ol, 4-pentynoic
acid, propargyl benzoate, and a biotin derivative
(Scheme 13). Several different functional alkynes were
employed in order to demonstrate the ease with which po-
lymer thin films can be derivatized using click chemistry.
Ellipsometry revealed that surface thickness increases of
no more than 5 O were observed after non-specific protein
adsorption experiments were conducted on the gold sub-
strate modified with either bromo-terminated, azido-ter-
minated, or click-functionalized polymer. This indicates
that the inert character of PEG was retained irrespective
of the functionalities it presented and thus the surface
maintained its non-biofouling property. Interestingly, the
only exception to this observation was the biotin-present-
ing surface which exhibited a thickness decrease of 20 O
upon exposure to streptavidin, which could be due to con-
densation of the polymer layer after interaction between
biotin and streptavidin. The functionalization of various
surfaces by CuI-mediated azide – alkyne cycloaddition had
been previously reported; [31, 195 – 197] this group extend-
ed the methodology to polymeric thin films and demon-
strated the versatility of the synthetic technique when
combined with ATRP.
The concept of surface derivatization via ATRP and
click chemistry was recently extended to chemoselective
derivatization of bionanoparticles [198]. Horse spleen apo-
ferritin, the hollow protein shell derived from ferritin, was
functionalized at its lysine residues with alkyne-modified
or tertiary bromide-modified N-hydroxysuccinimidyl ester.
The alkyne-bearing bionanoparticle was conjugated with a
3-azidocoumarin derivative. Monitoring the fluorescence
emission of the product revealed that one triazolylcoumar-
in was formed per protein subunit, which was the maxi-
mum attachment density anticipated after steric hindrance
considerations. The tertiary bromide-bearing nanoparticle
was utilized as a macroinitiator for the ATRP of oligo-
B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1129
Minireview
Scheme 13. Functionalization of surface-modified gold substrate via click chemistry. Reprinted with permission from Ref. [187].
Copyright 2007 American Chemical Society.
(ethylene glycol) methacrylate. The amphiphilicity thus
imparted onto the ferritin nanoparticle demonstrated the
utility of ATRP in altering the surface affinities of biona-
noparticles via “grafting-from” polymerization.
Amphiphilic block copolymers have been self-assem-
bled into vesicles and functionalized by click chemistry to
yield streptavidin-labeled polymersomes [199]. Azide-ter-
minated PS-b-PAA was synthesized by the controlled
polymerization of styrene and subsequent chain extension
with t-butyl acrylate via ATRP, followed by substitution of
bromine end groups with azide and acidic hydrolysis of t-
butyl acrylate to acrylic acid. The block copolymer was
dissolved in dioxane and self-assembled by slow addition
of water to the polymer solution, followed by dialysis
against water to remove organic solvent. The vesicular na-
ture of the subsequent aggregates was confirmed by TEM.
In order to exploit the surface azide groups as a scaffold
for further modification, alkyne-functionalized biotin was
attached to the vesicles via click chemistry and subse-
quently complexed with streptavidin labeled with colloidal
gold particles. This complexation did not induce a morpho-
logical change in the block copolymer aggregates. Typical-
ly 25% of azide moieties present within the polymersomes
react during click coupling, as evidenced by confocal laser-
1130 B 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Patricia L. Golas and Krzysztof Matyjaszewski
scanning microscopy after attachment of fluorescent
probes to the vesicles.
5 Summary and Outlook
The combination of click chemistry with CRP techniques,
including NMP, RAFT, and in particular ATRP, has pro-
ven to be a powerful and convenient synthetic approach to
a staggering variety of novel polymeric architectures, func-
tional materials, and bioconjugates. The range of materials
available using this methodology has been amply demon-
strated. However, this range can be expanded even further
if fundamental understanding of the reaction pathway con-
tinues to develop. Systematic mechanistic investigations
can provide solutions to the current drawbacks of the CuI-
catalyzed azide – alkyne cycloaddition, such as oxidative
instability of the catalyst, and can elucidate better ap-
proaches to an already robust synthetic technique, includ-
ing new organic substrates, appropriate additives such as
reducing agents and bases, catalyst-stabilizing ligands and
solvents, and alternative metals. In addition, although the
CuI-catalyzed azide – alkyne cycloaddition has been exten-
sively explored, there are only a few reports on the use of
www.qcs.wiley-vch.de QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134
Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
other examples of click chemistry, such as ring-opening of
epoxides and Lewis acid-catalyzed azide – nitrile cycload-
dition. These methods present significant opportunities for
polymer and materials chemistry and should be given
equal consideration as efficient chemical transformation
procedures in the future.
Acknowledgements
The authors are grateful to the members of the CRP Con-
sortium at Carnegie Mellon University and the National
Science Foundation (grant DMR 0549353) for funding.
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