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Progress in Polymer Science 37 (2012) 38105

Contents lists available at SciVerse ScienceDirect

Progress in Polymer Science


journal homepage: www.elsevier.com/locate/ppolysci

Complex polymer architectures via RAFT polymerization: From


fundamental process to extending the scope using click
chemistry and natures building blocks
Andrew Gregory, Martina H. Stenzel
Centre for Advanced Macromolecular Design, School of Chemical Sciences and Engineering, The University of New South Wales, Sydney, NSW 2052, Australia

a r t i c l e

i n f o

Article history:
Received 20 April 2011
Received in revised form 5 August 2011
Accepted 17 August 2011
Available online 25 August 2011
Keywords:
RAFT polymerisation
Block copolymers
Star polymers
Graft polymers
Hyperbranched polymers
Dendrimer

a b s t r a c t
Reversible addition fragmentation chain transfer (RAFT) polymerization has made a huge
impact in macromolecular design. The rst block copolymers were described early on,
followed by star polymers and then graft polymers. In the last ve years, the types of architectures available have become more and more complex. Star and graft polymers now
have block structures within their branches, or a range of different branches can be found
growing from one core or backbone. Even the synthesis of hyperbranched polymers can
be positively inuenced by RAFT polymerization, allowing end group control or control
over the branching density. The creative combination of RAFT polymerization with other
polymerization techniques, such as ATRP or ring-opening polymerization, has extended the
array of available architectures. In addition, dendrimers were incorporated either as star
core or endfunctionalities. A range of synthetic chemistry pathways have been utilized and
combined with polymer chemistry, pathways such as click chemistry. These combinations
have allowed the creation of novel structures. RAFT processes have been combined with
natural polymers and other naturally occurring building blocks, including carbohydrates,
polysaccharides, cyclodextrins, proteins and peptides. The result from the intertwining
of natural and synthetic materials has resulted in the formation of hybrid biopolymers.
Following these developments over the last few years, it is remarkable to see that RAFT
polymerization has grown from a lab curiosity to a polymerization tool that is now been
used with condence in material design. Most of the described synthetic procedures in the
literature in recent years, which incorporate RAFT polymerization, have been undertaken
in order to design advanced materials.
2011 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +61 2 9385 4344; fax: +61 2 9385 6250.
E-mail address: m.stenzel@unsw.edu.au (M.H. Stenzel).
Abbreviations: 2VP, 2-vinylpyridine; AA, acrylic acid; AAGP, acrylamido glucopyranose; AAm, acrylamide; AcOSty, p-acetoxystyrene; AGA, acryloyl glucosamine; AIG, 3-O-acryloyl-1,2:5,6-di-O-isopropylidene--d-glucofuranose; AN, acrylonitrile; APMA, 2-aminopropyl methacrylamide hydrochloride;
AzA, aziodopropylacrylamide; BA, n-butyl acrylate; BFA, 2-(N-butyl peruorooctaneuorosulfonamido)ethyl acrylate; BIS, methylene bisacrylamide;
BISTRIS, bis(2-hydroxyethyl)aminotris(hydroxymethyl)methane; BMA, n-butyl methacrylate; BzMA, benzyl methacrylate; DEA, N,N-diethylacrylamide;
DEAEMA, 2-(diethylamino) ethyl methacrylate; DIPAMA, N,N-(diisopropylamino)ethyl methacrylate; DMA, N,N-dimethyl acrylamide; DMAEA, 2(dimethylamino)ethyl acrylate; DMAEMA, 2-(dimethylamino)ethyl methacrylate; DMAPMA, 2-(dimethylamino)propyl methacrylate; DTT, dithiothritol;
EA, ethyl acrylate; EGDMA, ethylene glycol dimethacrylate; FDA, 1,1,2,2-tetrahydroperuorodecyl acrylate; FPMA, pentauorophenyl methacrylate; GMA, glycidyl methacrylate; HEA, 2-hydroxyethyl acrylate; HEMA, 2-hydroxyethyl methacrylate; HPA, 2-hydroxypropyl acrylamide; HPMA,
2-hydroxypropyl methacrylamide; iBor, isobornyl acrylate; IP, isoprene; LA, d,l-lactide; LBAM, 2-lactobionamidoethyl methacrylamide; MA, methyl
acrylate; MAA, methacrylic acid; MAGO, 6-O-methacryloyl--d-glucoside; MAGP, methacrylamido glucopyranose; MAn, maleic anhydride; MIGC11, 3 (1 ,2 :5 ,6 -di-O-isopropylidene--d-glucofuranosyl)-11-methacrylamido undecanoate; MIGC5, 3 -(1 ,2 :5 ,6 -di-O-isopropylidene--d-glucofuranosyl)0079-6700/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.progpolymsci.2011.08.004

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

39

Contents
1.
2.

3.

4.
5.

Complex polymer architectures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Block copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
The synthesis of block copolymers via RAFT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1.
Diblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2.
Cross-linked micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.3.
Triblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.4.
Conclusions to 2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
The combination of RAFT with other polymerization techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.
Diblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2.
Triblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3.
Conclusions to 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Block copolymers prepared by RAFT in combination with carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Block copolymers prepared by RAFT in combination with proteins, peptides and DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.1.
Conclusions to 2.3 and 2.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
The combination of RAFT with click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.1.
Block copolymers formed via Cu(I) Huisgen cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.2.
Block copolymers formed via thiol-ene reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.3.
Block copolymers formed via other click reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Branched polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Star polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.
Star polymers via core-rst strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
Star polymers via arm-rst strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3.
Miktoarm star polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Graft and comb polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Graft polymers via the attachment of a RAFT agent to the backbone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.
Graft polymers via the attachment of an initiator to the backbone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.3.
Graft polymers using macro-monomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.4.
Graft polymers via a combination of RAFT and other polymerization techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.5.
Graft polymers via click chemistry and other postfunctionalization techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.6.
Conclusions for 3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Hyperbranched polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.1.
Conclusions to 3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Dendritic polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.1.
Conclusion to 3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other complex architectures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Conclusions to 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Experimental advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Recent developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
The future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Complex polymer architectures


The interest in polymer architectures beyond undened
linear and branched structures, stems from the unique
material properties that can be generated using block
copolymers, star polymers, comb polymers and many other
unusual polymer architectures such as: palm-tree ABn ,

H-shaped B2 AB2 , dumb-bell (pom-pom), ring diblock, starblock (AB)n , amongst many other designs (Fig. 1).
These novel properties arise from the ability of complex architectures to show signicantly different solution
behaviors as well as from their ability to self-assemble

6-methacrylamido hexanoate; MIGP, 3-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose; MMA, methyl methacrylate; NAM, N-acryloyl


morpholine; NAP, N-acryloyl pyrrolidone; NAS, N-acryloxysuccinimide; NEMA, N,N-ethylmethylacrylamide; NIPAAm, N-isopropyl arylamide; NNPA,
N,N-propylacrylamide; NVC, N-vinylcarbazole; NVP, N-vinyl pyrrolidone; P(l-Phe-OMe), poly(N-acryloyl-l-phenylalanine methyl ester); PAcOSty, poly(pacetoxystyrene); PAGP, poly(6-O-acryloyl-R-d-galactopyranose); PBEVB, poly(1-but-3-enyl-4-vinylbenzene); PCL, poly(-caprolactone); PDEA, poly(N,Ndiethyl acrylamide); PDMA, poly(N,N-dimethyl acrylamide); PDMAEMA, poly(2-(dimethylamino)ethyl methacrylate); PDMS, poly(dimethylsiloxane);
PEG, poly(ethylene glycol); PEGA, poly(ethylene glycol)acrylate; PEGMA, poly(ethylene glycol) methacrylate; PFPA, pentauorophenyl acrylate; PHEA,
poly(2-hydroxy acrylate); PiBor, poly(isobornyl acrylate); PLA, poly(d,l-lactide); PMA, poly(methyl acrylate); PMMA, poly(methyl methacrylate); PNIPAAm, poly(N-isopropyl acrylamide); PNVC, poly(N-vinyl carbazole); PNVP, poly(N-vinyl pyrrolidone); PPEGA, poly(poly ethyleneglycol acrylate);
PS, poly(styrene); PtBBPMA, poly(tert-butyl 2-((2-bromopropanoyloxy)methyl)acrylate); PVAc, poly(vinyl acetate); PVAG, poly(6-O-vinyladipoyld-glucopyranose); PVBC, poly(vinylbenzyl chloride); PVND, poly(vinyl dodecanoate); PVP, poly(N-vinyl pyrrolidone); PVPi, poly(vinyl pivalate);
SMDB, N-(3-sulfopropyl)-N-methacrylooxyethyl-N,N-dimethylammonium betaine; STY, styrene; t-BA, tert-butyl acrylate; t-BAm, N-tert-butyl acrylamide; t-BMA, tert-butyl methacrylate; TFT, ,,-triuoro toluene; TMSPMA, trimethylsilyl propargyl methacrylate; VAc, vinyl acetate; VAG,
6-O-vinyladipoyl-d-glucopyranose; VBC, 4-vinylbenzyl chloride; VND, vinyl neodecanoate; VPi, vinyl pivalate; VPr, vinyl propionate; VTEMP, 2 -(4-vinyl[1,2,3]-triazol-1-yl)ethyl-O--d-mannopyranoside; -CL, -caprolactone.

40

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 1. Examples of various complex architectures that can be achieved utilizing two independent blocks (A and B) or segments or a homopolymer structure:
(a) linear; (b) graft; (c) brush or comb; (d) ring; (e) star An Bn ; (f) star-block (AB)n ; (g) AB2 star; (h) palm tree ABn ; (i) dumb-bell (pom-pom); and (j) H-shaped
B2 AB2 .

into structures of higher order. By coordinating the structure and composition of polymers, materials possessing a
diverse array of attributes can be formed and utilized in a
wide range of applications.
With the rise of controlled/living [1] radical polymerization techniques, pathways were created that allowed
access to many polymer architectures, the range of
structures possible only limited by the creativity and imagination of the researcher. Reversible addition fragmentation
chain transfer (RAFT) [2] is one of the very successful
polymerization tools that allows this goal to be achieved
[36]. It should be mentioned here that RAFT polymerization is equivalent to MADIX (macromolecular design

by the interchange of xanthates) polymerization (based


on a similar mechanism, but employs xanthates as controlling agents) [7,8]. In the following we will only use
the term RAFT polymerization, but the contribution of
MADIX polymerization to the development of the eld is
equivalent.
This review will not discuss the background on RAFT
polymerization. The reader is referred to a range of excellent review articles on RAFT polymerization [3,5,6,9,10]. In
this review we want to give a comprehensive overview
on the type of complex architectures available and discuss the different approaches and opportunities open to
the researcher when applying RAFT polymerizations.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

41

Fig. 2. A simple example regarding the formation of a diblock copolymer. Using RAFT polymerization to form a homopolymer and chain extending the
macromolecule with a different monomer to yield the desired block copolymer.

In the following review we focus on a number of areas


including: the synthesis of block copolymers, an area where
RAFT polymerization has made a signicant impact, and
the formation of branched polymers where the emergence
of controlled radical polymerization techniques, such as
the RAFT process, has allowed complicated structures to
be formed via facile experimental steps. According to
IUPAC nomenclature the subclasses of branched polymers
are: comb polymers, dendritic polymers, graft polymers,
hyperbranched polymers and star polymers [11]. RAFT
polymerization made a signicant impact by allowing
the precise control over the main chain (backbone) and
the number and length of the branches. Hyperbranched
polymers and other architectures will briey be summarized. In some examples only the RAFT process (or
the similar (MADIX)), was used, using simple multiple
chain extensions, giving rise to diblock, triblock and higher
order polymer chains. In other sections other chemical
approaches were combined with the RAFT process in order
to achieve the required structures.
In summary, this review looks at the formation of
complex architectures [12] and block copolymers utilizing
various synthetic procedures, using examples seen from
the period, 2007 to early 2011. The tie in feature for all
the examples is that they have used RAFT polymerization
(at least once), in order to produce the nal products. This
article cannot act as a comprehensive review due to the
substantial number of publications, but only looks at different approaches. The reader is referred to the review articles
by the inventors of RAFT polymerization for review articles
listing all publications in 2-year intervals in the Australian
Journal of Chemistry [3,5,6].
2. Block copolymers
Block copolymers, macromolecules that incorporate
two or more sequences (or blocks) of monomer(s), have
been formed from the vast arsenal of monomers that are
commercially available or can be synthesized via facile
methods. The scientic literature shows hundreds of examples of RAFT polymerization techniques being utilized for
the formation of block copolymers, with most papers citing the formation of diblock copolymers, e.g., producing
amphiphilic copolymers to form micelles [1349]. In this
work only block copolymers are examined; alternating,
statistical or gradient copolymers will not be looked into
unless these structures are incorporated as a segment
within the block copolymer, i.e., block copolymers that
have portions of the alternating copolymer of styrene (STY)
and maleic anhydride (MAn) [50].
The applicability and the properties of polymers are tied
to the structure of the macromolecules. Due to the vast
array of techniques at the polymer chemists disposal, the
polymers are not bound to linear chains but can adopt

a range of different structures; the architectures possible


only limited by scientists imaginations. Fig. 1 highlights
examples of structures that can be achieved with the production of block copolymers, ranging from simple chains
to elaborate pom-pom structures.
In the rst section we look at the theoretical aspects
for the formation of block copolymers, moving onto the
simplest and most facile way to produce these materials
with RAFT, utilizing the inherent living characteristics of
the process for chain extension. In the latter sections we see
how RAFT agents can be altered to add additional polymer
chains and how two, or more, homopolymer chains, can
be combined adopting various techniques, including those
encompassed by the click mantra.
2.1. The synthesis of block copolymers via RAFT
Fig. 2 displays a simple example for the formation of a
block copolymer utilizing the RAFT end group on the end of
a homopolymer and performing a second polymerization
with fresh monomer, extending the polymeric chain. What
it does not show are the other potential outcomes, i.e., from
side reactions, which includes the products formed from
termination routes. A full reaction scheme for the synthesis
of a block copolymer can be seen below in Fig. 3.
For the chain extension process to work the prerequisite is the formation of a macro-RAFT agent (a
macromolecule bearing the RAFT end group). Although a
variety of other compounds can be functionalized with
RAFT agents and can act as chain transfer agents (explored
later in the review), in this section the macro-RAFT
agents are homopolymers formed via RAFT. In Fig. 3 the
homopolymer is constructed from the monomer, M1 . This
is then chain extended in the presence of the second
monomer (M2 ), to form the block copolymer. For the chain
extension to occur, a radical source is included. To begin
with the radicals, from an initiator, induce the polymerization of the second monomer. At some point the M2 radical
will undergo chain transfer with the macro-RAFT agent, liberating the M1 chain which acts as the R moiety. It is in
this early stage that two macro-RAFT agents will appear,
one based on the initial M1 polymer, and the other based
on the M2 homopolymer. Block copolymers only begin to
form when the M1 macro-radical begins to polymerize the
free M2 units. With Fig. 3 (step IV a) the block copolymer
continues to grow, consuming all the available monomer.
Undesirable homopolymers will be present in the system
thanks to pathway of Fig. 3 (step IV b), it is impossible for
this to form a diblock copolymer unless it undergoes termination with one of the block copolymer macro-radicals.
What is important here is the concentration of radicals
present in the initial stages, too high and there will be an
abundance of homopolymer side products, too little and
the reaction will take too long to reach completion or be at

42

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 3. The formation of a block copolymer via the chain extension of a macro-RAFT. The various initiation, propagation and termination steps have been
highlighted.
[51] (Copyright, Wiley-VCH, 2008).

higher risk of stalling due to impurities and radical sinks. As


with homopolymerizations, termination events do occur
(Fig. 3, step V).
Temperature, reagent concentrations, time coupled
with the rate of propagation of monomers are all factors which affect the chain extension [52]. One important
consideration is the ability of the leaving group on the
macro-RAFT agent to dissociate and initiate the propagation of the second (third, fourth and so on), monomer. If
the polymer chain will not detach from the RAFT end group
then the chain extension will be unsuccessful. Many studies
have been conducted on the best RAFT agents to use with
the different monomer groups, varying the Z and R moieties [5355]. For example, one group looked at the homoand block co-polymerizations of vinyl acetate (VAc), vinyl
pivalate (VPi), and vinyl benzoate via RAFT. Various chain
transfer agents were examined to elucidate the dependence of the polydispersities of the resulting polymers on
the RAFT agent leaving group, R [56].
When synthesizing the block copolymers a number of
factors need to be considered. As with homopolymerizations, both the R group, in this case the initial polymer
chain, and the Z group must full their roles, favourably
fragmenting from the RAFT group and controlling the chain
transfer, respectively. The Z group must not only control
the propagation of the initial monomer, but all subsequent monomers. For example, if using a dithioester, most
methacrylates will be controlled, but acrylates may not.
As previously mentioned, the macro-RAFT agent must be
able to fragment. When using monomers of varying stability, it is advised to polymerize the monomer which
possesses the higher stability rst, and then repeat the
chain extension with other monomers, with decreasing
stability, this allows the prevalence of Fig. 3 (step IV
a) while reducing (step IV b) to, hopefully, insignicant
levels. For example, if you wanted to produce a poly-

mer incorporating both styrenic and methacrylate based


monomers, it is advisable to polymerize the methacrylate
units rst, followed by the styrenic derivatives (although
this is dependent on the side groups/functionalities present
on the monomers). Going against this would see the rise
of unwanted homopolymer side products, complicating
purication processes, and yield broad molecular weight
distributions for the desired block copolymers. It should
be noted that the stability of radicals cannot always be
successfully estimated, only via experimental studies can
the best, or most favorable, order for the polymerization
sequences be established. Other factors such as the solubility of the products must be looked at. For example,
Sumerlin et al. looked at the formation of block copolymers
of both 2- and 4-vinylpyridine [57]. While the reactivity
of the monomers were similar, block copolymers could
only be formed when 2-vinylpyridine was polymerized,
followed by 4-vinylpyridine. Going the other way, i.e., by
polymerizing 4-vinylpyridine rst, resulted in no copolymer products. In this paper similar monomers, i.e., both
were styrenic derivatives, were used, but the structure of
the monomer played an important role in the physical
properties of the nal polymers formed (in this case the
problem was due to solubility issues). Another example of
where the order of polymerizing monomers was found to
be important is provided by Hu et al. who looked at block
copolymers of N-vinylcarbazole (NVC) and VAc. The desired
products could only be obtained if NVC was polymerized
rst [58].
In order to obtain good control over copolymerizations (obtaining primarily block structures, with narrow
molecular weight distributions), the initial homopolymerization must be well controlled in order to yield welldened macro-RAFT agents. As with any polymerization
the parameters for the reaction (including the aforementioned examples: temperature, concentrations, ratios of

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

RAFT agent and initiator), must allow for the highest yield
of pure homopolymer to be obtained, with minimal termination effects and other side reactions taking place, to
ensure the vast majority of the polymer chains are capped
with the RAFT end group. In order to achieve this desired
outcome, one approach would be to use a high concentration of RAFT agent with minimal initiator present. Although
on the surface this would be the ideal solution, it invariably results in long retardation periods and drawn out (or
minimal) polymerization reactions taking place [59]. As
previously mentioned, using high concentrations of initiator may lead to a prevalence of termination reactions
and dead polymer chains, while too little may see reaction times extended to very long reactions times or, if the
systems are not totally free of contaminants, i.e., oxygen, a
complete loss of radicals, halting propagation in its tracks.
Although termination reactions can never be completely
avoided, by carefully choosing the correct parameters, they
can be severely limited. One way to do this is to stop
the polymerization when only a small percentage of the
available monomer has been polymerized, i.e., stop the
reactions at low conversions. While this can be an advantageous strategy, it may lead to the loss/waste of monomer,
which becomes especially important when a monomer is
not commercially available and/or requires extensive synthesis and purication processes to be made.
Along with radical termination processes, other pathways exist that can cause the destruction of the RAFT agent.
It is widely known that peroxides can destroy the thiocarbonate group due to oxidation [60], these may be found in
a number of common laboratory solvents, e.g., 1,4-dioxane
and THF. Several studies have looked at the removal of the
RAFT agent on purpose, in order to produce desired end
group functionalities [6163], but the RAFT agent can also
be lost inadvertently in an unwanted process. Heat, light
and pH can result in the loss of the RAFT end groups. Caution
not only needs to be taken during RAFT polymerizations to
stop the loss of the RAFT end group functionalities, but also
during the storage of the resulting polymeric products, e.g.,
leaving a RAFT produced polymer exposed to sunlight for
an extended period can remove the end groups due to the
inherent UV radiation [64]. Some speciality RAFT agents
or monomers may also cause unwanted reactions. A good
illustration of this comes from the work completed by the
Davis group where monomers and RAFT agents incorporating disulde moieties (based on pyridyl disulde) were
produced. In this case there is the risk that side reactions
involving disulde exchange could take place, once again
removing the RAFT agent from use [22,6567].
Although the majority of RAFT polymerizations use
additional azo-initiators to form block copolymers, ionizing radiation can also be used to initiate the reaction [68],
be it from a gamma source [69], or a microwave [70,71]. Roy
et al. were able to form well dened block copolymers from
acrylamide and acrylate monomers using a single mode
microwave reactor and with dramatically decreased reaction times (as low as 2 min), when compared to reactions
which relied on conventional heating. Ambient temperature RAFT polymerizations have also been carried out using
mild long-wave radiation and an appropriate photoinitiator [7274].

43

With RAFT, when working with amino-functionalized


monomers, care also needs to be taken to avoid aminolysis (causing the destruction of the RAFT end group).
When performing reactions with alkaline species, there are
tell-tell signs that aminolysis is occurring, for example a
colour change, whereby solutions change from red/pink
to orange/yellow. In order to prevent aminolysis a number of pathways and safeguards are used. One way is to
avoid polymerizing monomers that may hinder the RAFT
process but use monomers with functionalities that can be
later modied to yield amino groups, postpolymerization.
For example, Strube et al. produced ABA and BAB triblock
copolymers of 4-vinylbenzyl chloride (VBC) and STY [75].
The poly(vinylbenzyl chloride) (PVBC), blocks were quantitatively converted into polyamine blocks by a reaction with
diethyl amine. Another route is to use protecting chemistry, e.g., the addition of tert-butyl carbonate (BOC) or
phthalimide [76] groups to contain the amino groups on
the monomer. Postmodication can be advantageous, leading to the desired moieties being installed on a polymeric
structure, but it also means that additional synthetic steps
are required which may complicate the process for forming
the desired material.
Another way to minimize the aminolysis is to modify the
solvent, e.g., via the pH, or increase the rate of polymerization, e.g., by using higher radical concentrations or more
concentrated systems, therefore, increasing the propagation rate so that it competes, favorably, with the aminolysis
pathways. A direct method for the syntheses of primary
aminoalkyl methacrylamides that requires mild reagents
and no protecting group chemistry has been reported [77].
Cationic amino-based block copolymers of reasonably narrow polydispersities (Mw /Mn < 1.30) and predetermined
molecular weights were obtained without recourse to
any protecting group chemistry. The primary amine-based
methacrylamide monomers and polymers were revealed
to be highly stable both with the primary amino group in
the protonated and deprotonated form. Another example
of where protecting chemistry was not required is from
Mori et al. who were able to produce amino acid-based
amphiphilic block copolymers involving poly(N-acryloyll-alanine) using a dithiocarbamate-terminated poly(STY)
(PS) macro-RAFT agent [78].
Protection chemistry is not only used to shield amino
groups in RAFT polymerizations, but it is also applied to
other monomers with reactive groups that might undergo
side reactions during the polymerization steps. These reactions may or may not affect the RAFT group. A good
example is the monomer propargyl methacrylate (or the
acrylate derivative) [7981]. If left unprotected, the alkyne
group can react in the polymerization, creating crosslinking sites within the growing polymer. If, however, the
alkyne group is protected, e.g., with a trimethyl silyl group
[8082], RAFT polymerizations can be used and controlled
homopolymers and block copolymers are obtained. Postmodication is required to remove the protecting groups
(tetra-n-butylammonium uoride hydrate in the presence
of acetic acid is used to remove the trimethyl silyl groups),
but cross-linking is prevented.
Before chain extension is carried out on a homopolymer,
the products must be analyzed to conrm they possess the

44

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

correct RAFT end groups or if dead polymer is present in the


system. Mass spectrometry methods, e.g., matrix assisted
laser desorption ionisation time of ight mass spectrometry (MALDI-TOF), can be utilized to look at chain ends,
while other methods, such as NMR and UV spectroscopy,
can help clarify the presence of dead chains. For the polymer chemist, the primary characterisation method used is
that of gel permeation (or size exclusion) chromatography
(GPC/SEC). Comparisons between initial homopolymers
and the formed block copolymers can be made. After the
block copolymerization, if a peak remains in the same position as for that of the initial homopolymer, this smaller peak
is indicative of dead polymer, formed in the initial reaction.
Another way dead polymer may present itself in the SEC
spectra is with excessive tailing being seen with the block
copolymer peak. For a favorable chain extension, the initial homopolymer peak should shift to consecutively higher
and higher molecular weights as the conversion of the second monomer increases. Typically the molecular weight
distribution broadens, in part due to the formation of dead
polymer, as already discussed.
One method that can be used to determine the purity
of the block copolymer is gradient polymer elution chromatography (GPEC). Although a qualitative system, peaks
for both the block copolymer and the homopolymer components can be compared in order to prove that the
copolymer has been formed [83].
The choice of solvent is also important, especially
when working with disparate monomers and the formation of amphiphilic block copolymers. In some cases,
when polymerizing hydrophilic species, protective chemistry pathways must be invoked in order to allow the
polymerization of both blocks to proceed in the same
medium, i.e., to negate solubility issues [84]. This approach
has been used with the formation of glycopolymers with
protected sugar monomers used (the hydroxyl groups
protected either with either acetyl or isopropylidene
groups) so that polymerizations can take place in organic
media [8590]. Ideally a solvent is found that can accommodate both the initial homopolymer and the second
monomer and associated block copolymer. Solvents such
as dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc)
and dimethylformamide (DMF) allow for the solubilization of a range of monomers and polymers but the latter
two are also highly toxic and all three possess high
boiling points which can make their removal difcult,
although pathways exist to circumvent these problems,
i.e., precipitation of the block copolymer or purication via
dialysis.
One pathway used for the formation of amphiphilic
block copolymers is the application of activated ester
monomers, e.g., pentauoro phenyl methacrylate [9194].
The hydrophobic uorinated monomers can easily be
copolymerized with other equally hydrophobic systems
to yield controlled block copolymers. Facile postmodication involves the addition of an amine which displaces the
pentauorophenol units. A variety of different amines can
be used. For example, Barz et al. synthesized a block copolymer comprised of lauryl methacrylate and pentauoro
phenyl methacrylate. Upon the addition of 1-amino-2propanol, the uorinated units were displaced and the

block copolymer was transformed into a macromolecule


comprised of lauryl methacrylate and the biologically useful N-(2-hydroxypropyl) methacrylamide (HPMA) [91].
In regards to the kinetics of the polymerizations, one
distinct feature when producing block polymers from polymeric macro-RAFT agents is the lack of, or severely reduced,
retardation period at the beginning of the chain extension. The amount of macro-RAFT agent introduced into a
reaction can inuence the rate of polymerization. Akin to
homopolymerizations, a large concentration of RAFT agent,
or macro-RAFT agent, can lead to a decrease in the polymerization rate. The length of the macro-RAFT agent can
also inuence this rate. Wong et al. examined the synthesis of STY and N,N-dimethylacrylamide (DMA) via RAFT in
detail. Two different RAFT agents benzyl dithiobenzoate
and 3-(benzylsulfanylthiocarbonylsufanyl)propionic acid,
were employed to prepare polystyrene macro-RAFT agents
with molecular weights varying between 3000 g mol1 and
62,000 g mol1 and possessing polydispersities between
1.10 and 1.40 [95]. Chain extensions with DMA were carried
out using a constant monomer to RAFT agent concentration
([DMA]/[RAFT] = 500), to compare the rate of polymerization in relation to the PS chain length. A decreasing rate of
polymerization with increasing block length was observed.
Depending on the size of the rst block and type of RAFT
agents used, chain extension polymerization with DMA
was found to be incomplete, leading to signicant low
molecular weight tailing in the SEC analyzes.
There are limitations, although experimental conditions
can be optimized, some polymers have completely disparate reactivities, e.g., methyl methacrylate (MMA) and
VAc, and will not combine. For these, and other odd
combinations to work, a universal RAFT agent is required
[9697]. Theis et al. developed a RAFT agent that contained
a uoride group in the Z-group. The benzyl uoro dithioformate (BFDF) RAFT agent was proposed as a universal RAFT
agent since theoretical calculations suggested that it can be
used for monomers such as vinyl acetate as well as styrene
[96]. Another approach for working with very different
monomers saw the implementaiton of a RAFT agent which
possessed a pyridyl Z-group. Upon protonation, the activity of the RAFT agent changed. This switching behavior
allowed different monomers to be effectively polymerized
[97].
The ability to produce block copolymers either by direct
growth or by combining two more polymer chains together
via other chemical pathways, allows monomers, with very
different properties, to be brought together. The coupling
of hydrophilic and hydrophobic segments gives rise to the
formation of supramolecular structures. Examples of these
structures are: micelles, rods and vesicles.
The following summarizes the paragraph above and can
act as guidelines for block copolymer synthesis:
The order for the polymerization of monomers in the formation of block copolymers cannot be freely chosen. A
rule of thumb is that the methacrylate block needs to be
prepared rst, followed by chain extension with styrene
or acrylate derivatives.
Block copolymers can only be prepared from two
monomers with similar reactivities. Both monomers

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

need to be able to be controlled by one type of RAFT


agent. An alternative option could be the use of a universal RAFT agent, even though this approach has not been
widely tested. Another option is the conjugation of two
polymers via click chemistry (see below).
Care needs to be taken with the amount of radicals generated during the polymerization. An excess amount of
radicals being present can lead to the formation impurities, such as homopolymers and/or dead polymer.
A prerequisite for a successful chain extension is the
careful handling of the polymer, especially during the
purication of the macro-RAFT agent. Heat, light, oxidation agents, high pH values can lead to the depletion of
the RAFT end group.
The presence of the polymer of the macro-RAFT agent can
have a substantial effect on the chain extension. Even if
monomer, initiator and thiocarbonylthio concentrations
are similar to the homopolymerization, using a macroRAFT agent instead of a low molecular weight RAFT agent
often leads to a different rate of polymerization, in most
cases rate retardation is observed.
It is preferred to employ one solvent or solvent mixtures
that can dissolve the macro-RAFT agent, monomer and
the resulting block copolymers. Heterogeneous mixtures
can be successful to generate block copolymers, but conditions need to be carefully chosen, but the reader is then
referred to topics on RAFT polymerization in heterogeneous media.

2.1.1. Diblock copolymers


Figs. 48 illustrate a selection of the vast number of
RAFT agents that can be applied and the diverse array of
monomers that have been used in the formation of block
copolymers (including monomers that are neutral, ionic
and pH and temperature responsive). Although the gures are not exhaustive, they demonstrate the array of
functional groups that can be incorporated in to the polymer chains leading to interesting properties for the bulk
materials. For example, polymers incorporating uorinated
species [98,99] are useful in anti-fog and oil repellent applications. Stimuli responsive systems (e.g. materials which
adapt to changes in pH or heat) are useful in drug delivery
processes [14,100104].
Although block copolymers are required for a number of
applications, e.g., for antifouling surfaces [105], the majority of work has focused on the formation of amphiphilic
block copolymers that can self-assemble into various
structures (depending on the nature of the blocks and
the hydrophilic/hydrophobic ratios), in aqueous environments. Whatever the nal structure, e.g., micelles or rods;
they typically possess a hydrophobic core and a hydrophilic
shell. The hydrophobic cores can act as hosts for a range
of drugs and other biologically important compounds,
including siRNA [49,101,106108]. For example, Luo et al.
synthesized a double-hydrophilic block copolymer composed of N-vinylpyrrolidone (NVP) and poly(STY-alt-MAn)
[109]. In acidic solutions, the block copolymers spontaneously formed polyion complex (PIC) micelles with a
cationic polyelectrolyte, chitosan. Hydrophobic drugs are
usually encapsulated via a hydrophobic core. Fine-tuning

45

of the hydrophobicity of the hydrophobic core can improve


the loading capacity of the nal materials. For example,
Kim et al. focused on different feed ratios of MMA and LMA
during the construction of micelle drug carriers, in order
to maximize the amount of the drug, albendazole being
incorporated into the polymeric structure [108].
Due to the high afnity of sulfur and gold, a number of
block copolymers have been synthesized that utilize the
RAFT end group (or the reduced form, the thiol) to stabilize gold nanoparticles [77,110114]. A variety of polymers
have been used, including pH and temperature responsive
systems [25,111,113117]. Nuopponen and Tenhu utilized
methacrylic acid (MAA) and NIPAAm block copolymers for
the stabilization of gold nanoparticles. pH was observed
to affect the size of the aggregates, whereas the effect of
temperature was moderate [113].
Two different blocks can give rise to various polymeric morphologies forming, with the nal architecture
dependent on the ratio of the blocks [38,114,118120].
Boisse et al. looked at two families of amphiphilic diblock
copolymers, in which the hydrophobic block was a
cholesterol-based smectic liquid-crystalline polymer and
the hydrophilic block was either a neutral polymer with
a lower critical solution temperature (LCST), or a copolymer containing acrylic acid moieties and poly(ethylene
glycol) (PEG) side chains [118]. The morphology of the
nano-assemblies was dependent on the weight fraction
and the nature of the hydrophobic block. The amphiphilic
liquid-crystal (LC) block copolymers with a hydrophobic/hydrophilic weight ratio of 74/26 or 65/35 formed long
nano-bres, whereas the non-LC copolymers, based on PS
with similar ratios, formed vesicles or short cylindrical
micelles. In another interesting paper Tam et al. produced
poly(N-vinylcarbazole)-based block copolymers functionalized with either rhenium diimine complexes or pendant
terpyridine ligands [121]. The copolymers exhibited interesting morphological properties as a result of the phase
separation between different blocks.
A series of well-dened functional gelable diblock
copolymers, poly(3-(triethoxysilyl)propyl methacrylate)b-poly(2VP), were synthesized by a two-step RAFT
mediated procedure [122]. The self-assembly of the
block copolymers in the bulk was studied. By changing
the copolymer composition, three different microphaseseparated morphologies, i.e., lamellae, hexagonally packed
cylinders, and spheres, were obtained. The in situ selfgelation was subsequently carried out under hydrochloric
acid vapour to lock the structures. By dispersing the gelated
bulk materials with ordered structures in an acidic water
solution (pH 3), isolated organic/inorganic hybrid nanoobjects with controlled shapes, including plates, cylinders,
and spheres bearing protonated vinylpyridine hairs, were
prepared.
The beauty of the polymerization process is that almost
any compound can be adapted into a monomer and incorporated into a macromolecule. Sriprom et al. looked at a
range of polymerizable photochromic naphthopyran (NA)
monomers [123]. The monomers obtained were copolymerized with MMA and methyl acrylate (MA) using RAFT
in order to control the number of photochromic molecules
in the chains. Films were prepared with the products and

46

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 4. Various RAFT agents used in the formation of block copolymers as listed in Table 1.

their photochromic properties were assessed. The fading


rate of the photochromic dye was slower in a matrix of
poly(MMA) (PMMA) than in a matrix of poly(MA) (PMA)
(MA having a lower glass transition temperature (Tg )).
Block copolymers of PMMA-b-poly(MA-co-NA) yielded
a faster switching speed, this was enhanced with the
formation of PS-b-poly(MA-co-NA), due to phase separation, which occurred between the poly(MA-co-NA) and PS
blocks. Another example of photoresponsive block copolymers was produced by Zhao et al. [124]. They produced two
water-soluble polymers containing two different photoisomerizable moieties (either azobenzene and spiropyran
or two different azobenzenes), with the two constituting
blocks that, when separated, exhibited a LCST in water and
shift their LCST in opposite directions upon photoisomerisation (decrease of LCST for one polymer and increase for
the other) [124].

Charreyre and co-workers developed block copolymers,


poly(N-decylacrylamide-b-N,N-diethylacrylamide) (PDcAb-PDEA), with a dye molecule as the terminal unit. The dye
was used as a reporter molecule; the uorescence intensity
was a direct indicator for what was occurring in regards to
the self-assembly process [125127].
Finally, very recently a block copolymer with both, UCST
and LCST, was prepared by selective quarternization of N(3-(dimethylamino) propyl) methacrylamide (DMAPMA)
leading to a block with UCST features, while the block based
on oligo(ethylene glycol) methacrylate (OEGMA) undergoes a LCST in aqueous solutions [128].
Table 1 provides some examples of different polymer
systems, utilizing the monomers and RAFT agents shown
in Figs. 48, respectively, along with some of the reaction conditions. The reader is referred to review articles
by the inventors of RAFT polymerization who frequently

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

47

48

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

summarize most of the structures reported in the literature in regular updates [3,5,6]. (Note that some details,
such as concentrations, initiators used, reaction times, etc.,
are absent. This table is only to serve as a guide to the
reader in regards to the different structures that are possible. Should the reader require full experimental details,
they are directed to the complete reference paper.)
2.1.2. Cross-linked micelles
Finally, in the last part of this section we shall look at
a specic architecture of block copolymers, cross-linked
micelles. These are formed from amphiphilic polymers,
that have self-assembled in a micellar structure and,
after cross-linking, the structure has been locked, i.e., the
micelles cannot dissociate into the constituent unimers.
With RAFT polymers the cross-linking can take place either
in the core [23,162165], the shell [43,48,166168] or at
the nexus between the block copolymer blocks [169,170].
A number of different cross-linking techniques exist.
A range of different chemistries have been investigated
[171,172]. Most commonly, micelles are cross-linked via
the addition of a bifunctional reactive agent. Cross-linking
can be carried out using a radical pathway following the
addition of a divinyl cross-linker [48,100,165,173]. The
RAFT polymers undergo chain extension with the addition
of the fresh divinyl monomer creating triblock structures.
The reactions of both vinyl groups introduce crosslinks
between the various chains.
An interesting example of the radical approach was
performed by Zhang et al. who produced a nucleoside containing block copolymer, poly(polyethylene
glycol
methyl
ether
methacrylate)-b-poly(5 -Omethacryloyluridine) and after self-assembly cross-linked
the structure using the degradable compound bis(2methacryloyloxyethyl)disulde [165]. The synthesis
produced coreshell nanoparticles, which could degrade
under reductive conditions. The resulting core-crosslinked micelles readily hydrolyzed into free block copolymers in the presence of dithiothritol (DTT), in less than 1 h.
Another unusual way of cross-linking, presented
by the Wooley group, includes the synthesis of norbonene containing block copolymers. 4-(5 -Norbornene2 -methoxy)-2,3,5,6-tetrauorostyrene was polymerized
via RAFT leading to block copolymers with a polystyrene
blocks and randomly distributed norbonene side groups in
the second block. Ring-opening metathesis polymerization
led to core-cross-linked nanoparticles [176].
Examples of micelles prepared from polymers, formed
via RAFT and cross-linked using bifunctional reactive
agents are the most common structures encountered in

the literature. Lius group used an alternative approach to


cross-link their micelles [164]. The group produced block
copolymers of NIPAAm and N-acryloxysuccinimide (NAS).
When the copolymer was introduced into an aqueous
system and heated, the NIPAAm chains became hydrophobic and the polymers adopted a micelle structure. After
ensuring the micelles had reached equilibrium, cystamine
was injected to produce core cross-linked micelles (the
NAS residues are highly reactive towards primary amines).
Upon the addition of DTT, the cross-liker could be cleaved
and by lowering the temperature, the micelles became
soluble once again in the solution (below the LCST temperature for NIPAAm, 32 C). With heating, the blue tinge,
indicative of colloidal dispersion, could be seen once again.
Similar work was undertaken by Pascual et al. [174].
Other groups have also utilized pendant groups on polymer chains to cross-link the micelles, negating the need
for further polymerization reactions. Xu et al. looked at
the one-pot preparation of reversible, disulde containing shell cross-linked micelles with a triblock copolymer
[42,43]. Initially a PEG based macro-RAFT agent was
synthesized and then utilized for successive polymerizations with N-(3-aminopropyl) methacrylamide (APMA)
and (2-diisopropylamino)ethyl methacrylate (DPAEMA).
The triblock copolymer was soluble in aqueous solution
at low pH (<5.0) due to the protonation of the primary residues on the APMA block and tertiary amine
residues on the DPAEMA block. When the pH was
raised to 6.0 (or above), the copolymer self-assembled
into micelles. These could be locked with the crosslinker dimethyl 3,3 -dithiobispropionimidate (a compound
containing imidoester groups which are highly reactive
to amines). DTT could be used to break the crosslinking, a process that could be revered by exposing the
micelles to air. This work was later extended to introduce crosslinking sites, which can be degraded under acidic
conditions [175].
Jiang et al. produced double hydrophilic diblock copolymers of poly(DMA)-b-poly(NIPAAm-co-AzA), containing
azide moieties in one of the blocks via RAFT [23].
Supramolecular self-assembly into coreshell nanoparticles, consisting of thermoresponsive NIPAAm-co-AzA cores
and water-soluble DMA coronas, occurred above the LCST
of the NIPAAm-co-AzA block. As the micelle cores contained reactive azide residues, core cross-linking was easily
achieved upon the addition of difunctional propargyl ether,
using click chemistry.
Duong et al. used reactive groups on a prodrug for
her cross-linking to work [162]. In a one-pot reaction,
the concurrent incorporation of an anticancer drug and

Fig. 5. Selected examples of neutral monomers: maleic anhydride (MAn), styrene (STY), methyl methacrylate (MMA), 4-vinylpyridine (4VP), 4vinylbenzyl chloride (VBC), pentauorostyrene (PFSty), N-vinylpyrrolidone (NVP), isoprene (IP), methyl acrylate (MA), N,N-dimethylacrylmide (DMA),
2-hydroxypropyl methacrylamide (HPMA), N-acryloylpiperidine (NAP), N-acryloylmorpholine (NAM), 2,5-dibromo-3-vinylthiophene (DBrVT), lauryl
methacrylate (LMA), n-butyl methacrylate (BMA), tert-butyl acrylate (t-BA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (HEA), glycidyl methacrylate (GMA), vinyl chloroacetate (VClAc), vinyl acetate (VAc), pentauorophenyl methacrylate (FPMA), pentauorophenyl acrylate (PFPA)
N-vinylphthalimide (NVPH), polyethylene glycol methyl ether methacrylate (PEGMEMA), polyethylene glycol methyl ether acrylate (PEGEMA), trimethylsilylpropargyl methacrylate (TMSPMA), tert-butyldimethylsilyl methacrylate (tBSiMA) -methacryloxypropyltrimethoxysilane (MASi), aziodopropylacrylamide (AzA), 5-{1,3-dihydro-3,3-dimethyl-6-nitrospiro[2H-1-benzopyran-2,2 -(2H)-indole]}ethyl acrylate (DHNBA), 9-acryloyloxy-[3,3-bis(4methoxyphenyl)]-3H-naphtho[2,1-b]pyran (APNP), N-acryloyl-l-phenylalanine methyl ester (l-Phe-OMe), N-acryloyl-4-trans-hydroxy-l-proline (AHP),
6-acryloylaminohexanoic acid-1-adamantylamide (AAHA), 3-acrylamidophenylboronic acid (APBA) 2-(2-pyridyldisulde)ethylmethacrylate (PDSEMA)
4-(acrylamide)azobenzene (AAzB), vinyltriphenyl amine (p-HT).

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

49

Fig. 6. Examples of ionic monomers: 4-vinylbenzyl(triphenyl-phosphonium)chloride (VBPC), sodium 2-acrylamido-2-methyl-1-propanesulfonate


(SAMPS), N-acryloyl-l-alanine (NALA), sodium 4-styrenesulfonate (S4SS), trioctylammonium p-styrenesulfonate (TAPSS), 2-aminoethyl methacrylamide hydrochloride (AEMA), 2-aminopropyl methacrylamide hydrochloride (APMA), 1-(3-phenylpropyl)-3-vinylimidazolium bromide (PVIBr),
N-(3-sulfopropyl)-N-methacrylooxyethyl-N,N-dimethylammoniumbetaine (SMDB), 2-(methacryloyloxy)ethyl phosphorylcholine (MAPC), {[2(metacryloyloxy)ethoxy]carbonyl}(pyridinium-1-yl)azanide (MCPA), ionic liquid monomer (IL).

Fig. 7. Examples of pH responsive monomers: acrylic acid (AA), acrylamide (AAm), 4-vinylbenzoic acid (4VBA), N,N-(diisopropylamino)ethyl methacrylate (DIPAMA), 2-cinnamoyloxyethyl acrylate (COEA), 2-(dimethylamino)ethyl methacrylate (DMAEMA), 2-(diethylamino)ethyl methacrylate (DEAEMA),
propylacrylic acid (PrAA), N-acryloylvaline (NACV), l-phenylalanine acrylamide (AP).

Fig. 8. Examples of thermoresponsive monomers: N-isopropylacrylamide (NIPAAm), N-(2-methacryloyloxyethyl) pyrrolidone (NAOEP), N,Ndiethylacrylamide (DEA), 2-hydroxypropyl acrylate (HPA), N-acryloyl-l-proline methyl ester (NAPME).

50

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

core cross-linking took place for a self-assembled micelle


system. Highly reactive isocyanate groups, incorporated
into a block copolymer (poly(PEGMEMA)-b-poly(STY-co3-isopropenyl-,-dimethylbenzyl isocyanate)) reacted
with amine groups in a previously prepared platinum(IV)
drug. In the body the platinum was reduced to platinum(II),
degrading the cross-linking sites and leading to the dispersal of the drug and the breakdown of the micelles.
from
poly(trimethylsilyl
propargyl
Micelles
methacrylate)-b-poly(poly(ethylene
glycol)
methyl
ether methacrylate) were cross-linked using a degradable and non-degradable diazide, which were reacted
using Cu(I) click reaction. Excess alkyne functionalities
were then used to coordinate cobalt drugs to the stable
drug carrier [79]. RAFT polymerization was also used as
a tool for the synthesis of well-dened polymers containing imbedded side-chain functionalities. Subsequent
thiol-ene reaction between alkene functional micelle
and thiols resulted either in discrete nanoparticles or
nanoscopically-segregated cross-linked networks [176].
2.1.3. Triblock copolymers
Triblock copolymers can be formed using a number of
approaches. With chain extensions, three different pathways can be envisaged (Fig. 9). The rst (Fig. 9, Pathway
1) is the chain extension of a diblock copolymer. The second (Fig. 9, Pathway 2) utilizes two RAFT agents tethered
together (either through the Z group or R group), while the
third approach (Fig. 9, Pathway 3), introduces a RAFT agent
which possesses two leaving groups (the standard Z group
on the RAFT agent is absent).
Similar problems for the formation of diblock copolymers, exist in the synthesis of the triblock (and higher
order) copolymers, whereby the best experimental conditions need to be discerned, along with the correct,
or optimal order for the polymerizations to occur, i.e.,
overcoming limited re-initiation of the macro-RAFT agent
[177]. In Fig. 3 termination products lead to the formation of triblock and homopolymer impurities. With the
triblock copolymers synthesized through Fig. 9, Pathway
1 the formation of pentablock copolymers is now an issue
(ABCBA systems), along with the inherent homopolymer
formed with the third monomer(s). The sequence of the
polymerizations can become important, not only because
of monomer reactivity but with nal applications. With
amphiphilic systems, the order can affect how the polymers self-assemble and behave in an aqueous environment
[37].
Pathway 1 highlights sequential polymerizations and
can lead to a range of compositions, e.g., ABC or ABA systems, and is one of the most adopted methods of producing
the triblock systems. For example, Germack and Wooley
were able to produce ABC and ACB triblock copolymer
topological isomers comprised of tert-butylacrylate (t-BA),
isoprene (IP) and STY [178]. The triblock copolymers were
isolated with molecular weights on the order of 20,000 Da
and molecular weight distributions between 1.30 and 1.50.
The sequential polymerization process is applicable
to both homogeneous and heterogeneous systems. RAFT
polymerizations have been used in emulsions for the polymerizations of isoprene (IP) and butadiene. The end goal

was the production of latex particles containing block


copolymers of acrylic acid (stabilizer and starting polymer), STY (second polymer) and IP or butadiene (third
polymer) [177]. Emulsion polymerization was also the heterogeneous polymerization of choice for Luo et al. for the
formation of ABA polymers with STY (A blocks) and n-butyl
acrylate (BA) (B block) using an amphiphilic macro-RAFT
agent [179].
et
al.
produced
block
copolymers
of
Xie
poly(N,N-diisopropylacrylamide)-b-PNIPAAm-bpoly(N,N-ethylmethylacrylamide) [180]. The temperature
induced formation and dissociation of terpolymer micelles
in aqueous solutions (via heating/cooling cycles), were
investigated by a combination of static and dynamic laser
light scattering. In the heating process, the folding of
N,N-propylacrylamide (NNPA) at ca. 25 C led to the formation of polymeric micelles with a collapsed hydrophobic
NNPA core and a hydrophilic swollen NIPAAm and N,Nethylmethylacrylamide (NEMA), shell. Results revealed
that when NEMA on the periphery of the micelle was too
short to stabilize the hydrophobic core, individual micelles
tended to aggregate into large micelle clusters. Very
similar studies were undertaken by Cao et al. [181,182].
Yan et al. incorporated the uorescent group Ncarbazole, into their triblock copolymers [44]. Successive
polymerizations involving MAn, STY and NIPAAm were
undertaken. The MAn units were then treated with
N-carbazole ethylamine, opening the ring to allowing conjugation of the uorescent species. Aqueous solutions of
micelles prepared from the novel block copolymers, with
the uorescent group between the STY and NIPAAm units,
displayed logical responsive switches on temperature and
uorescence; at lower temperatures, the stretching of the
NIPAAm chains caused high mobility with the N-carbazole
units, leading to the formation of more excimer species. At
higher temperatures, the shrinking of NIPAAm chains isolated the uorescent groups between the core and shell,
resulting in fewer excimer species.
Linear amphiphilic triblock copolymers were synthesized by three successive steps, using oligo(ethylene oxide)
monomethyl ether acrylate, butyl or 2-ethylhexyl acrylate,
and 1H,1H,2H,2H-peruorodecyl acrylate [37]. The triblock
copolymers consisted of a hydrophilic block, a lipophilic
block, and a uorophilic block and self-assembled in water
into spherical micellar aggregates. Cryogenic transmission
electron microscopy revealed that the cores of the micellar aggregates underwent local phase separation to form
various ultrastructures and found to be highly sensitive in
regards to the sequencing of the constituent blocks. While
the sequence: hydrophiliclipophilicuorophilic resulted
in multicompartment cores with coreshellcorona morphology, the sequence lipophilic-hydrophilicuorophilic
provided new patched double micelle and larger soccer
ball structures.
Lee et al. looked at triblock copolymers for resins, a
major component in a photoresist. Triblock copolymers
of t-BA, p-acetoxystyrene (AcOSty) and STY, with molecular weights around 10,000 and PDI values less than 1.23,
were produced [183]. After hydrolysis, under basic conditions, hydroxystyrene analogs were obtained and these
were constructed into photoresists.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

51

Table 1
Examples for block copolymer structures that can be formed using various monomer units, which can be neutral or ionic in nature and responsive to
changes in pH and temperature. The RAFT agents and monomers may be found in Figs. 48.
Entry Block 1

Block 2

Systems utilizing neutral monomers


STY
4VBCl
1
2
STY
MA and APNP
c
3
AAHA
DMA
TMSPMA
PEGMEMA (n = 7)
4
APBA
NIPAAm
5
NVP
IP
6
LMA
7
FPMAd
HPMA
8
PDSEMA
PFPA
9
STY
STY
DMA
10
11
MMA
tBSiMA
12
NAM
NAP
GMA
PFSty
13
MMA
DBrVT
14
PEGMEA (n = 8)
STY and MAn
15
MMA
TMSPMA
16
17
VAc
VClAc
18
t-BAe
l-Phe-OMe
19f
BMA
GMA
20
NAP
VAc
VAc
VPi
21
p-HT
Fluorinated p-HT
22
Systems utilizing one ionic monomer
MMA
MCPA
23
S4SS
PEGMEMA (n = 9)
24
25
AEMA
HPMA
26
TAPSS
STY
27
NIPAAm
PVIBr
NIPAAm
IL
28
Systems utilizing two ionic monomers
HPMA, APMA
DMAEMA (with HCl)
29
30
MAPC
SMDB
31
AEMA
APMA
32
4VBTCl
4VBA
33
SAMPS
NALA
Thermoresponsive systems
34
DMAEMA
NIPAAm
35
DMA
AZA and NIPAAm
36
DMA and AAzB
NIPAAm and DHNBA
37
NVPH
NIPAAm
STY
NIPAAm
38
GMA
39
NAOEP
40
STY
DEA
HPA
HEA
41
NAPME
AHP
42
Temperature and pH responsive systems
DEAEMA
NIPAAm
43
DMAEMA
MASi
44
DMA
NIPAAm and NACV
45
DEAEMA
NIPAAm
46
NIPAAm
4VBA
47
NIPAAm and MASi DEAEMA
48
MAPC
NIPAAm and DMAEMA
49
pH responsive systems
AA
AAm
50
DIPAMA
PEGMEMA (n = 9)
51
PEG
DEAEMA and COEA
52
DMAEMA
DMAEMA, PAA and BMA
53
l-Phe-OMe
54
DEAEMA
55
DMAEMA
PFSty
PrAA
PDSMA
56
DMAEMA
AP
57
a
b
c
d
e
f

RAFT agent T ( C)a

Solventb

Reference

R18
R1
R5
R2
R19
R19
R3
R3
R10
R14
R1
R9
R1
R2
R5
R4
R20
R21
R22
R20
R25
R26

70
60
40, 50
60
70
80, 125
70
70
65
80
70
90
60, 60/80
60
60
70
70
80, 90
30
70
70/microwave
90/110

Toluene
H2 O
Toluene
DMF:H2 O (95:5)
Dioxane
Dioxane
DMAc
THF
DMF
Toluene
Dioxane
Bulk, dioxane
Dioxane
Acetonitrile, dioxane
Toluene
Dichloroethane
Bulk, dioxane
Benzene
Dioxane
Trioxane
Solvent mixtures

[129]
[123]
[130]
[79]
[131]
[132]
[91]
[22]
[133]
[134]
[135]
[136]
[137]
[138]
[50]
[81]
[139]
[36]
[73]
[140]
[141]
[142]

R3
R3
R3
R19
R16
R16

Various
70
70
80
80, 60
60

Various, N-methyl-2-pyrrolidone
H2 O:EtOH (2:1), H2 O
Acetate buffer (pH 5.2)
Benzene, benzene:NaOH(aq) (1:1)
Dioxane, DMF
Dioxane

[143]
[105]
[144]
[145]
[146]
[147]

R3
R3
R3
R6
R3

70
70, 60
70
80
70

Acetic buffer (pH 5.2), H2 O (pH between 5 and 6)


H2 O, MeOH
H2 O:dioxane (2:1), H2 O
H2 O
H2 O

[107]
[148]
[77]
[149]

R7
R3
R1
R8
R9
R22
R10
R19
R10

70
70
80
60
80, 70
30
110, 90
80
60

Dioxane
Dioxane
Dioxane
DMF
THF
MeOH
Bulk, THF
tert-Butanol
Chlorobenzene, DMF

[114]
[23]
[124]
[76]
[112]
[72]
[16]
[150]
[151]

R3
R1
R12
R1
R6
R6
R3

70, 25
70, 80
70, 30
80
60
70
60

H2 O (pH 4.5)
Dioxane
H2 O (pH 6.5), H2 O (pH 4.8)
THF
DMF
THF
Water/dioxane

[38]
[152]
[30]
[153]
[154]
[104]
[155]

R5
R5
R23
R11
R15
R1
R24
R19

20
70
70
30
80
90, 60
70
60

H2 O:acetone (1:1), H2 O:EtOH (3:2)


1,4-Dioxane
H2 O (pH 7),
DMF
Dioxane
1,4-Dioxane
DMSO
DMF

[156]
[157]
[45]
[101]
[158]
[159]
[160]
[161]

Where two temperatures are shown the former relates to the synthesis of the rst segment, the latter relates to the formation of the second segment.
Where two solvents are shown the former relates to the synthesis of the rst segment, the latter relates to the formation of the second segment.
-Cyclodextrin was also introduced to produce an inclusion complex with the adamantane units.
Later converted into HMPA units.
Later converted into acrylic acid.
Uses a photoinitiator for both reactions.

52

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 9. The formation of triblock copolymers adopting three different chain extension strategies: Pathway 1 sequential chain extensions (the example
yielding a ABC triblock copolymer); Pathway 2 the use of a compound containing two RAFT agents tethered together (the examples given shows two
RAFT agents linked via the Z-groups (left) or the R-groups (right) showing the formation of ABA triblock copolymer) or Pathway 3 RAFT agents possessing
two leaving groups (the example showing the formation of a ABA triblock copolymer).

Various temperature-responsive NIPAAm copolymers


were prepared and used for the stabilization of iron
oxide nanoparticles [184]. Poly(acrylic acid)-b-PNIPAAmb-poly(acrylate methoxy poly(ethylene oxide)) triblock
copolymers were formed with different molecular weights.
A sharp temperature transition was conrmed by particle
size measurements vs. temperature. The stealth properties
of the coated nanoparticles providing the nanoparticles the
ability to remain undetected by the bodys defense system
were assessed in vitro by the haemolytic CH50 test. The
results indicated that the coated particles are particularly
suitable for biomedical applications.
Three different acrylates, oligo(ethylene oxide)
monomethyl ether acrylate, benzyl acrylate, and 1H,1Hperuorobutyl acrylate, were polymerized via RAFT in
different order leading to ABC, ACB, and BAC triblock
copolymers. The resulting polymers were observed to

undergo self-assembly into multi-compartment micelles


[185]. The self-organization of these triblock copolymer were found to be strongly dependent on the block
sequence [186].
While the current range of examples demonstrates the
feasibility of this approach, it was often observed that the
molecular weight distributions broaden with the growth
of each consecutive block. Polydispersity indices of the
nal ABC triblock of more than 1.5 are commonplace
[187].
With Fig. 9, Pathway 2, two RAFT agents are tethered together, either directly or through a linker chain.
This linker can be attached either through the R group
[37,59,188190] or the Z group [189]. In some cases
telechelic polymers can be used whereby the RAFT agents
are attached to the and ends of the macromolecule
(Fig. 10) [17,49,191195].

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

53

Fig. 10. Difunctional RAFT agents which are connected via a linker through either the Z group (R27, R28) or R group (R29, R30, R31) allowing the formation
of ABA (Fig. 9.2a) and BAB (Fig. 9.2b) block copolymers.

In one investigation Bivigou et al. looked at six different


symmetrical RAFT agents for the production of amphiphilic
triblock copolymers with both ABA and BAB structures
[189]. The A blocks were comprised of NIPAAm and the
B blocks were made from STY. As previously mentioned,
the ordering was important, whereas the extension of
poly(NIPAAm) (PNIPAAm) by STY was not effective, PS
macro-RAFT agents could be extended upon the addition
of NIPAAm. The nal products were soluble in aqueous
solutions and self-organised into thermoresponsive micellar aggregates. NIPAAm was also used by Skrabania et al. to
produce ABA triblock copolymers with DMA (which formed
the B block) using R31 [196]. The length of the hydrophilic
middle block was kept constant and the hydrophilic block
was altered. The complex aggregation behavior, driven by
the thermoresponive nature of the NIPAAm, was block
length dependent.
Legge et al. used a difunctional RAFT agent to synthesize
block copolymers of poly(butyl methacrylate)-b-PMMAb-poly(butyl methacrylate) and poly(butyl acrylate)-bPMMA-b-poly-(butyl acrylate) with controlled molecular
weights and polydisperity indices between 1.20 and 1.40
[59]. The authors found the polymerizations of methyl and
butyl methacrylate being more controlled than butyl acrylate.
Triblock copolymers using R29 were formed by
Achilleos et al. for the formation of homopolymer and
copolymer (co)networks. These networks were based
on three monomer types: methacrylates, acrylates, and
styrenics [188]. Amphiphilic block copolymer co-networks

were prepared by RAFT via the cross-linking of linear triblock copolymer precursors possessing two active polymer
ends. These were interconnected via cross-linking to form
three-dimensional networks.
Another co-network was formed using R29,
for the preparation of end-linked semiuorinated
amphiphilic polymer co-networks based on 2,2,2triuoroethyl methacrylate (hydrophobic monomer)
and 2-(dimethylamino)ethyl methacrylate (DMAEMA,
hydrophilic monomer) [190]. Ethylene glycol dimethacrylate (EGDMA) served as the cross-linker. Various ABA
and BAB copolymers were synthesized (where A was
the uorinated block and the B block was comprised of
DMAEMA), with the co-networks characterised in terms of
their degrees of swelling in THF and in water as a function
of the solution pH.
Following on from Fig. 9, Pathway 2, the third route
(Fig. 9, Pathway 3) employs RAFT agents which possess
two leaving groups. A selection of these difunctional RAFT
agents are shown in Fig. 11. The majority of work has used
R32, including Ran et al. who used it in the photopolymerizations of STY and BA [197]. The macro-RAFT agent
of PS successfully controlled the polymerization of BA with
PDI values for the nal products being between 1.12 and
1.14. Liu et al. modied R32 to include two pyridyldisulde
groups [67]. After producing telechelic triblock copolymers
with oligo(ethyleneglycol)acrylate and STY, micelles were
formed and the presence of the disulde groups within the
micelle corona was proven by UVvis spectroscopy. The
pyridyldisulde groups were then used to functionalize the

54

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 11. Difunctional RAFT agents which can be used to produce triblock copolymers according to the procedure in displayed Fig. 9.3.

micelles with a thiol bearing model peptide, reduced glutathione, and a thiol modied uorophore, rhodamine B,
under mild reaction conditions.
As with other synthetic routes designed to produce
block copolymers, amphiphilic copolymers can be formed
using this technique. For example, Vekataraman and Wooley produced ABA and BAB triblock copolymers with
di(ethylene glycol) 2-ethylhexyl ether acrylate and t-BA
[198].
A lot of the amphiphilic systems, based on Fig. 9, Pathway 3, utilize NIPAAm, focussing on its thermoresponsive
behavior (LCST). The aggregation behavior of the thermoresponsive polymers was the primary focus for most
of the studies. For example, Fu et al. used well-dened
naphthalene end-capped STY and NIPAAm amphiphilic
triblock copolymers, coupled with transmission electron
microscopy (TEM), to look at the various aggregates formed
in water and DMF mixtures [199]. Nykaenen et al. described
the synthesis of styrene and NIPAAm triblock copolymers
and their self-assembly and phase behavior in bulk [200].
The self-assembly and phase behavior in bulk of the triblock
copolymers, as well as selected blends with low molecular
weight NIPAAm homopolymers were studied using TEM.
Classical lamellar, cylindrical, spherical, and bicontinuous
double gyroid morphologies were observed in the dried
state. In aqueous solutions, the glassy PS domains act as
physical cross-links, and hydrogels were therefore, formed.
With their ABA triblock copolymers of STY (A block) and
NIPAAm (B block), Zhou et al. formed micelle like aggregates with PS blocks as the cores and PNIPAAm rings as
the coronas [201]. The hydrolysis of the trithiocarbonate
group led the rings in the corona to be cut into open linear
coils.
Qu et al. obtained an unusual structure with their
amphiphilic thermo-responsive ABA triblock copolymer
with MMA (A blocks), and NIPAMM (copolymerized with
PEGMEMA for the B block) [33]. The copolymer dispersed
in water and self-assembled into nanoscaled micelles in
a owerlike arrangement at room temperature. Notably,
there was no copolymer precipitation observed at the LCST,
which is advantageous in regards to the in vivo use of the
micelle. The micelles loaded with folic acid as a model
drug showed a promising thermo-responsive drug release
behavior.

Zhou et al. looked at a series of novel pH and temperature responsive triblock copolymers with stearyl
methacrylate and NIPAAm, the latter as the center block,
using R32 [202]. By varying the organic solvent used in
the self-assembly procedure and adjusting the copolymer
composition, multiple morphologies ranging from vesicles
to coreshell spherical aggregates and pearl-necklace-like
aggregates were obtained.
Kirkland et al. used NIPAAm to form narrowly dispersed,
temperature-responsive BAB block copolymers capable of
forming physical gels under physiological conditions [203].
The NIPAAm (B blocks), was copolymerized in the presence
of R32 with DMA (the A block). At concentrations as low
as 7.5 wt.%, the copolymers formed reversible physical gels
above the phase transition temperature of PNIPPAm. The
mechanical properties of the gel were found to be similar
to those of the naturally occurring collagen.
Nuopponen et al. controlled the tacticity of their
ABA stereoblock polymers with atactic PNIPAAm as a
hydrophilic block (either A or B) and a non-water-soluble
block consisting of isotactic PNIPAAm, using R32 in the
absence, or presence, of yttrium triuoromethanesulfonate, respectively [204]. Both the atactic and isotactic
PNIPAAm macromolecules were successfully used as
macro-RAFT agents.
Xiao et al. produced a functional coilrodcoil triblock
copolymer containing a rigid teruorene unit (rod) and
PNIPAAm for the exible coil using a teruorene-based
dithioester as the RAFT agent [205]. The temperatureresponsive optical properties were investigated with the
aid of dynamic light scattering and uorescence techniques. The copolymers have a potential to be used as
responsive uorescent probes in facile detection of dyelabelled biopolymers.
2.1.4. Conclusions to 2.1
The cornucopia of block copolymers reported so
far shows the versatility of the chain extension of a
macro-RAFT agent to generate these architectures. After
considering suitable experimental conditions, the choices
seem limitless. However, there are still restrictions such as
the order of the preparation, which requires starting the
synthesis with the block that forms the most stable radicals. This can have implications with the position of the

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

RAFT agent, or the ,-position of R- and Z-group of the


RAFT agent, especially when the synthesis of a specic end
functionalized polymer has been targeted. In addition, the
RAFT agent needs to be suitable for both blocks. Although
there are some RAFT agents that are reasonably versatile,
certain pairs of monomers are difcult or impossible to
polymerize. The process works often well for one block,
but leads to broadening or signicant retardation of the
rate of polymerization during the growth of the second
block. Many systems work very well, especially when the
two monomers are of comparable reactivity. However, a
noticeable fraction of block copolymers reported in the
literature does not seem to be as well-dened and molecular weight distributions show noticeable tailing indicative
of terminations reactions. The nature of these side reactions has often not been investigated in detail. It is very
noticeable that in recent years there is a very strong shift
to material design. In these cases the detailed analysis
of the processes involved are often not necessary and
broader molecular weight distributions are acceptable for
the required purpose. However, a more detailed study of
the chain extension process is warranted. Questions such
as how the block length of the rst block, its mobility in
the solvent and its polarity might affect the subsequent
chain extension have not really been addressed in detail.
This might also help to understand why some block copolymers show unnecessary broadening, although the RAFT
agent itself is suitable for the process. This might then help
understand why the synthesis of longer block copolymer
or ABC triblock copolymers is accompanied by an increased
polydispersity.
2.2. The combination of RAFT with other polymerization
techniques
2.2.1. Diblock copolymers
RAFT polymerization has been combined with a range
of other techniques including ring-opening polymerization
(ROP), polycondensation and other radical polymerization techniques such as nitroxide mediated polymerization
(NMP) or atom transfer radical polymerization (ATRP).
A number of routes exist to produce polymers utilizing
two, or more, independent polymerization techniques. The
simplest, and most widely used, is the attachment of a RAFT
agent to the chain end of a polymer and applying the end
product as a macro-RAFT agent. Another viable method is
to incorporate a functional group on a RAFT agent which
is inert and does not play a role in the RAFT process, but
can be utilized in another polymerization technique either
as an initiating entity or a functionality that controls the
growth of a polymer chain via a process which is not RAFT
based. For example, if a RAFT agent possesses a pendent
hydroxyl group, this can be used to initiate ROP with the
appropriate catalyst (enzymatic or metal) [169,206].
Alternatively, two separate polymers can be made, one
via RAFT and the other produced via an alternative technique. In each case the polymers possess functionalities
that are complimentary to one another, e.g., a RAFT polymer possess an azide group and another, e.g., a PEG chain,
has a terminal alkyne group. The two polymers can then
be combined to produce a block copolymer with the center

55

unit consisting of a triazole ring. Examples of this route will


be given later in the review.
Finally, one-pot reactions whereby simultaneous polymerizations (which are mutually exclusive) take place
concurrently. For example, producing a RAFT agent that
has two functionalities (such as the example given above
with the RAFT agents possessing hydroxyl groups that can
initiate ROP), allows for two processes two occur that do
not interfere with one another. Instead of successive polymerizations, both systems are performed at the same time,
yielding block copolymers in a single step.
Taking these examples into account, ve different pathways are envisaged (Fig. 12) [51].
All ve pathways are viable and are used not only
to form block copolymers but other complex architectures as well. For example, pathway four can be used
to form comb copolymers. Wooleys group produced a
norbornenyl-functionalized chain transfer agent for the
formation of polymers with comb architectures [207]. The
norborneyl functionality was inert during the polymerization of either STY or t-BA, but in the presence of a ruthenium
catalyst, ring-opening metathesis polymerization (ROMP)
occurred between the polymer chains giving a comb structure.
With the ve highlighted pathways, the primary concern is the attachment of the RAFT group. The RAFT agent
must either possess a functionality that undergoes a facile
reaction with a complimentary moiety on a non-RAFT controlled polymer chain or the RAFT agent must have a group
attached that can either initiate or control the polymerization of another species (via a non-RAFT process).
The RAFT agent can be functionalized either on the stabilizing (Z) group or the leaving (R) group. The synthesis
of macro-RAFT agents via attachment to either the R or
Z group yields two different chain transfer agents, with
characteristic mechanisms. If a polymer chain is attached
to the R group, it will detach from the RAFT agent after
the initial transfer step (as a macro-leaving group). In
regards to side products, termination products, three structures are possible. The rst is a homopolymer impurity
formed from two homopolymer chains combining. The second is a diblock copolymer formed from a homopolymer
radical and the polymer chain growing from the macroleaving group. The third copolymer impurity is a triblock
copolymer where two growing macro-leaving groups come
together to terminate. With a polymer chain bound to the Z
group, the termination products are composed only of the
second monomer.
With the Z group attachment the RAFT agent is
placed in between the two polymer chains whereas the
attachment via the R group has the RAFT agent as a terminal unit. If the two different products were subject to
aminolysis, the copolymer products from the Z attachment would be cleaved leaving the constituent units (e.g.
two homopolymers), while aminolysis conducted on the
products produced using the R attachment would yield
mercapto terminated copolymers.
2.2.1.1. Pathway 1: covalent attachment of a RAFT agent to
an end functionalized non-RAFT polymer followed by RAFT
polymerization. Most attention has centered on Fig. 12,

56

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 12. The various pathways for producing block copolymers via the combination of RAFT with other, mutually exclusive polymerization techniques. Five
possible pathways are envisaged wherein the polymer blocks are formed using RAFT polymerization (solid spheres) or another technique (blank spheres)
either via successive or concurrent polymerizations.

Pathway 1, whereby a dithioester or trithiocarbonate has


had a polymer chain attached to it (either via the Z or R
group, although the R group is favored) and the resulting
compound is employed as a macro-RAFT agent. The most
frequently encountered example is the PEG-ylation of
a RAFT agent where a commercially available PEG chain
undergoes an esterication reaction with a carboxylic acid
containing RAFT agent. Another way to functionalize a PEG
chain is to install a halogenated functionality and allow this
to react with a Grignard reagent [150,208,209]. Lius group
used an alternative approach to produce their macro-RAFT
agent [164]. Instead of using esterication, they synthesized a RAFT agent by taking a PEG chain and reacting it
with maleic anhydride and subsequently introducing this
to dithiobenzoic acid. The PEG chain then became the R
group on the resulting RAFT agent.
Of great concern during the syntheses of these macroRAFT agents is the completeness of the reaction, i.e.,

ensuring all chains possess RAFT groups on the terminal


units. NMR spectroscopy analysis can usually conrm the
degree of functionalization. Despite the best experimental
controls, after applying the macro-RAFT agents to polymerizations, SEC analyzes can reveal residual macro-RAFT
agent (lower molecular weight peaks). This may be due to
poor chain transfer during the reaction or the remnants
from incomplete functionalization [210].
After attaching a RAFT agent to the end of a polymer
chain, one way to determine the conversion, along with
NMR is to use UV spectroscopy. By generating a calibration curve with known concentrations, the end groups can
be quantied. UV analysis can also be used in conjunction
with other analytical techniques, e.g., with SEC systems, as
additional detectors in dual detection apparatus.
As with polymerizations that use low molecular weight
RAFT agents, care must be taken to ensure the correct compound is attached to the end of a polymer chain, i.e., the

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

correct RAFT agent is used with a particular monomer.


Pound et al. synthesized two xanthate end-functional PEG
macro-RAFT agents and demonstrated how the structure
of the R group played a key role in the synthesis of block
copolymers (using VAc and NVP). The block copolymers
could easily be obtained with PEG macro-RAFT agents
bearing a propionyl ester leaving group whereas when a
macro-RAFT agent with a phenylacetate leaving group was
used, block polymers could not be formed, the polymerization was completely inhibited [211].
From a material perspective, a very interesting PEG
block copolymer has recently been created. Polymerization of the PEG-macro-RAFT agent with N-acryloyl2,2-dimethyl-1,3-oxazolidine led to amphiphilic block
copolymers. However, the presence of acid depleted the
side group leaving a double hydrophilic block copolymer
behind [212].
With polymers formed using Fig. 12, Pathway 1, the
polymerizations are controlled and present the same processes seen in a standard RAFT polymerization (Fig. 3):
initiation, loss of the R group, re-initiation, propagation,
chain transfer and, although minimized, termination. As
with a standard RAFT polymerization, pseudo-rst order
kinetics should be seen, with the molecular weight of the
macromolecules proportional to the respective conversion.
In regards to the PDI of the block copolymer, this can only
be as good as the initial polymer. Commercial polymers
can be obtained with exceptionally low PDI values. The
attachment of a RAFT agent followed by subsequent polymerization can also yield block copolymers yielding very
low PDI values, as long as the optimum conditions are
applied to the reactions [213].
In regards to termination effects, the only differences
are the structures of the termination products. When the
polymer is attached via the R group, ABA block copolymers
can be formed seen as high molecular weight shoulders,
due to combination termination reactions; these will not
be seen when the Z group approach is used.
Although the use of a macro-RAFT agent does not change
the mechanism of the RAFT process, the polymeric chain
can exert an inuence over the kinetics of the propagating
species, due to sterics or a change in polarity. This effect
can be seen when comparing reactions which incorporate
macro-RAFT agents to those which employ low molecular
weight RAFT agents. Shorter inhibition times, attributed to
the slow fragmentation of the intermediate radical in the
pre-equilibrium, can be seen when using the macro-RAFT
agent.
The use of a macro-RAFT agent can alter the microenvironment around the polymer chain. This is the so-called
bootstrap effect [214,215]. In the original paper [215],
four co-monomer pairs (using polar and non-polar
monomers) show a pronounced solvent effect on determined reactivity ratios when the copolymer compositions
versus monomer feed ratios were studied. A copolymer
having the same composition appeared to have the same
microstructure irrespective of the solvent employed during
polymerization. The differences observed in the copolymer composition versus monomer feed plots were due
to this bootstrap effect. This effect means that a growing polymer radical inuences its own environment. The

57

co-monomer ratio available for the growing chain can


therefore differ from the global co-monomer ratio. This
phenomenon has been reported a number of times. It can
be seen with the slow consumption of the macro-RAFT
agent.
In the paragraphs below, some examples of Fig. 12,
Pathway 1, are shown. A number of different RAFT
agents have been functionalized with polymer chains
(primarily PEG chains). The RAFT agents mainly
used are: 4-cyanopentanoic acid dithiobenzoate (R3)
[46,92,216,217] and S-1-dodecyl-S -(,  -dimethyl- acetic acid)trithiocarbonate (R19) [34,218221]. The
acid groups in these RAFT agents allowing for facile
esterication reactions to take place.
The use of a PEG based macro-RAFT agents has allowed
the formation of a range of amphiphilic block copolymers.
The primary use for these has been for the formation of micelles [41,195,222,223], but other structures
have been obtained including vesicles [224], coreshell
polyion complexes [46], lms with dened cylindrical domains for the formation of highly ordered gold
nano-tubes [225], stable copolymer aggregates containing a central oligopeptide segment (based on arginine)
[226], nano-sized uorophores [227], coatings for magnetic
nanoparticles [208,228,229], and quasi-model amphiphilic
polymer co-networks [191]. In some cases, one system can
lead to a variety of morphologies. In the work of Huang
and Pan dispersion polymerizations of styrene in the presence of a PEG macro-RAFT agent were undertaken [218]. By
changing the feed molar ratio and concentration of the STY
in the solvent, methanol, either spherical micelles, nanowires or vesicles could be obtained.
One useful advantage of attaching a RAFT group onto
the end of a hydrophilic polymer chain is that the macroRAFT agent can be used as both a stabilizer and chain
transfer agent in an aqueous environment. Charleuxs
group has focused a lot of attention on emulsion systems utilizing PEG functionalized R19 [34,219,230]. With
Rieger et al. they used an amphiphilic PEG macro-RAFT
agent as a stabilizer and controlling agent in ab initio emulsion polymerizations [219]. They achieved stable
hydrophilichydrophobic, coreshell latex particles composed of polymer chains with controlled molar mass and
narrow molar mass distributions. After polymerizing both
STY and BA, the PEG based RAFT agents displayed their
potential as steric stabilizers. At high conversions the SEC
chromatograms were symmetric and the experimental
molecular weights closely matched the theoretical values.
However, the chromatograms at lower monomer conversion were slightly asymmetric, indicating a heterogeneity
in the chains. In another paper, the same RAFT agent was
used for the surfactant-free controlled polymerizations for
the copolymerizations of BA and MMA in emulsions [230].
Rieger et al. extended the work to look at thermally
responsive block copolymer micelles and nano-gels [34].
Pegylated coreshell nanoparticles were produced in a
minimum number of steps, directly in water. The systems
were based on the RAFT-controlled copolymerization of
N,N-diethylacrylamide (DEA) and N,N -methylene bisacrylamide, the difunctional monomer causing cross-linking
to occur within the polymerization system. The PEG-

58

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

b-poly(DEA) copolymers self-assembled into micelles at


higher temperatures. Triblock copolymers could be formed
using the macro-RAFT with DMA and then extending
with DEA, forming thermoresponsive micelles. The PEG-bpoly(DMA) (PEG-b-PDMA) macro-RAFT agents could also
be used for chain extensions with the DEA and the crosslinker, forming thermoresponsive gel particles.
Similar emulsion work was undertaken by dos Santos et al. but this time R3 was functionalized with PEG.
Hydrophilic (co)polymers carrying a thiocarbonyl thio end
group such as PEG-b-poly(DMAEMA) (PEG-b-PDMAEMA),
were evaluated as precursors of stabilizers in the batch ab
initio emulsion polymerizations of STY under acidic conditions [216]. The block copolymer successfully stabilized
the emulsion to produce electrostatically stabilized latexes.
The same RAFT agent could also be used to simultaneously
stabilize and control the polymerization of STY in mini
emulsion polymerizations [213].
The highly favored thermoresponsive polymer
PNIPAAm has been produced by many groups
PEG
functionalized
macro-RAFT
agents
using
[34,164,195,217,220,221,231], although other thermoresponsive polymers, e.g., 2-hydroxypropyl acrylate
or N-methacryloyl-l--isopropylasparagine benzyl ester
can be used [150,224]. The temperature induced aggregation of the copolymers yielding a range of structures
including micelles [164,195,217], vesicles [217,220],
and thermoresponsive coreshell nanoparticles [34]. Xu
et al. produced triblock copolymers utilizing a PEG-based
RAFT agent and sequentially polymerizing DMAEMA and
NIPAAm [221]. At high temperature, above the LCST of
NIPAAm, the triblock copolymers formed micelles with
a PNIPAAm core, PDMAEMA shell and PEG corona. In
other work, a thermally sensitive ultralong multiblock
copolymer, [PEG23 -b-PNIPAAm124 ]750 , was prepared using
the oxidative coupling of two mercapto groups at the
two ends of ABA block copolymers, from a difunctional
PEG based RAFT agent (forming the B block) and NIPAAm
(forming the A block) [195]. The folding of individual
multiblock copolymer chains in an extremely dilute solution (106 g/mL) was studied. The single-chain folding
underwent two stages, presumably due to the successive
contraction of thermally sensitive PNIPAAm segments in
the middle around each hydrophobic SS coupling point
and near the hydrophilic PEG block.
Another interesting thermoresponsive system was produced by Yokoyamas group, whereby a liquid crystalline
unit was incorporated into temperature sensitive micelles.
A block copolymer was formed from poly(ethylene
glycol)-4-cyano-4-[(thiobenzoyl)sufanyl]pentanoate and
6-[4-(4-pyridylazophenoxy]hexyl methacrylate [232]. The
polymer (PDI = 1.09), assembled into micelles in aqueous
solutions with a weight average diameter of 68 nm. Thermal analysis indicated complex exhibited liquid crystal
phase-transition behavior even in the amphiphilic block
copolymer.
Bartels et al. also used a PEG based RAFT agent [210].
Two RAFT agents were synthesized with molecular weights
of 7600 and 3200 g mol1 (from SEC analysis). The polymerization of IP produced polymers with molecular weights
ranging from 18,000 to 5300 g mol1 and PDI values around

1.30. The copolymers could be assembled into micelles


using solvent-induced micellization procedures, i.e., starting with a good solvent and sequentially adding a poor
solvent.
Although most of the work has focused on using PEG
chains, a number of groups have utilized other polymers,
such as PDMS, for a range of applications, such as thin
lm templates [233]. Well dened PDMS RAFT agents have
been used in the formation of a block copolymer with
styrene [234], for triblock copolymers with 2,2,3,3,4,4,4heptauorobutyl methacrylate and PS [235] and, by using a
difunctional xanthate functionalized PDMS chain, a ABCBA
pentablock copolymer with STY and NVP [236]. Other
inorganic species can be incorporated, a nano-structured,
multifunctional material with mutually exclusive, orthogonal properties was prepared by Lechmann et al. [237].
The hybrid material was obtained in a single step via selfassembly in solution. It consisted of titanium dioxide as a
functional metal oxide and an amphiphilic block copolymer of PEG-b-poly(triphenylamine). The block copolymer
not only acted as a templating agent but added electronic
properties to the resulting hybrid material.
Fig. 12, Pathway 1 was also used by Barz et al. to
produce a block copolymer of poly(d,l-lactide) (PLA) and
HPMA by attaching the d,l-lactide (LA) chains to R3 and
polymerizing pentauorophenyl methacrylate [92]. The
pentauorophenyl groups could be removed by the addition of 2-hydroxypropylamine to give the HPMA units.
Although many PCL containing block copolymers were
prepared via route 2 described in the following, the ringopening polymerization can be carried out via traditional
pathways using alcohols. The hydroxyl terminal group(s)
of PCL can then be directly converted into xanthates [238].
Magenau et al. combined living cationic and RAFT polymerizations for the formation of block copolymers [239].
Poly(isobutylene) was synthesized via quasi-living cationic
polymerization using a TMPCl/TiCl4 initiation system. Postmodication introduced a terminal hydroxyl unit. Site
transformations, via esterication, introduced viable RAFT
agents for either STY or MMA. The nal polymers had
very low PDI values (around 1.04), with high conversions
achieved for both monomers, but in all experiments residual macro-RAFT impurities remained, possibly due to poor
initiation efciency.
Anionic polymerization with butadiene was performed
to generate polyethylene polymers, which were then functionalized with a RAFT agent. After the polymerization of
DMA, disk-like micelles were obtained [240].
Three recent papers describe the formation of block
copolymers incorporating thiophene units and RAFT
based polymers [241244]. In all cases the polythiophenes were formed and the chain ends modied to
include a RAFT group. Yang et al. successfully applied the
macro-RAFT agent to the statistical copolymerization of
8-acryloyloxyoctyl benzoylbutyrate and STY, the former
being able to bind to C60 with the product being applicable
for use in solar cells [242].
2.2.1.2. Pathway 2: initiation of polymerization of non-RAFT
polymer (PA ) using a functional RAFT agent, followed by
RAFT polymerization (PB ). As previously mentioned, one

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

way to form block copolymers it to employ a difunctional compound that can take part in a non-RAFT process.
The product, a macro-RAFT agent, can then be redeployed for the controlled synthesis of a vinyl monomer,
Fig. 12, Pathway 2. The reverse process is also viable
with the RAFT polymerization performed rst, followed
by the mutually exclusive process Fig. 12, Pathway
4. A good example of these routes is the combination
of either ROP [14,17,26,92,102,103,245252] or ROMP
[207,253,254] with RAFT.
The most heavily researched area, using Fig. 12, Pathway 2, is with ROP (using metal catalyzed [170,255,256],
enzymatic [206] or anionic routes [103]). This route allows
for the formation of copolymers incorporating biodegradable polymers such as PCL [17,26,49,102,103,248,257] or
PLA [14,92,169,170,245247,249]. These polymers can act
as templates, e.g., in the formation of nano-cages [170], and
can be easily removed in the correct environment, such as
acidic solutions.
A number of different block copolymers have been
produced using Fig. 12, Pathway 2. Mespouille used 2(benzylsulfanylthiocarbonylsulfanyl)ethanol, the terminal
hydroxyl unit acting as the initiator for the ROP of LA.
The thus formed macro-RAFT agent was then successfully
deployed for the controlled polymerization of NIPAAm. The
process showed high conversions (>99%) and the products
exhibited low PDI values (1.19) [258]. The same process was reported almost simultaneously by Hales et al.,
who further investigated the self-assembly and crosslinking of the aggregates [169]. In a similar approach Ting
et al. were able to produce hollow poly(6-O-acryloyl-Rd-galactopyranose) (PAGP) nano-spheres [170]. Initially,
an amphiphilic block copolymer, PLA-b-PAGP, was synthesized using a PLA macro-RAFT agent. The block copolymers
self-assembled in aqueous solution to form micelles with
pendent galactose moieties covering the surface. The
micelles were cross-linked at the nexus of the copolymer using hexandiol diacrylate, creating stable aggregates.
Aminolysis with hexylamine allowed removal of the lactide
core without any detrimental effect on the glycopolymer
units, to produce hollow nano-cages.
Following in their footsteps, Saeed et al. found a facile
route to biocompatible poly(lactic acid-co-glycolic acid)b-poly(ethylene glycol methacrylate) copolymers utilizing
ROP and applying the polymer as a macro-RAFT agent
for ethylene glycol methacrylate (Fig. 13) [255]. A series
of polymers with various co-monomer content and block
length were synthesized with low polydispersities. All the
block co-polymers formed micelles in aqueous solutions
and were able to encapsulate model drugs (carboxyuorescein and uorescein isothiocyanate).
While most catalytic system employed do not lead
to any regularity within the PLA, the group of OReilly
managed to synthesize recently homochiral PLA using a
functional RAFT agent as initiating species, which was used
to prepare block copolymers [259].
As mentioned in the section above, RAFT and ATRP
can be combined to generate block copolymers with
monomers possessing disparate reactivities. P(t-BA)-bPVAc were obtained by Petruczok et al. in a three step
process [260]. Initially t-BA was polymerized via ATRP, the

59

bromine terminal group on the polymer chain was then


modied via the addition of potassium O-ethyl xanthate to
yield a macro-MADIX agent which successfully controlled
the polymerization of VAc.
Kwak et al., instead of running mutually exclusive
polymerizations, performed concurrent ATRP and RAFT
reactions in order to prepare high molecular weight MMA
and STY polymers the reactions had R2, an azo initiator, copper catalysts and various ligands present (albeit
in various ratios) [261]. They found combining the two
techniques provided a number of advantages. First, the
formation of new chains was suppressed by generating
the initiating radicals directly from the RAFT agent in the
presence of copper catalyst. In the second step, the synthesis of high molecular weight polymers was accomplished
by activators regenerated by electron transfer ATRP, but
low polydispersities required the presence of a minimum
amount of a rapidly deactivating Cu(II) complex.
2.2.1.3. Pathway 3: RAFT polymerization using a functional
RAFT agent (PB ) followed by attachment to non-RAFT polymer
(PA ). This approach is dominated by click chemistry and is
described in more detail in a dedicated click section.
An interesting approach for this pathway is to merge
two polymers together via supramolecular chemistry in
combination with metal complex chemistry. Moughton
et al. produced a RAFT agent with a SCS pincer ligand
that controlled the polymerization of MA to afford chainend pincer-functionalized PMA [262]. Chain extension with
t-BA yielded a block copolymer. The block copolymer
was chain-end-complexed using a palladium(II) precursor, the tert-butyl groups were then removed to yield
an amphiphilic system. The chain-end binding of this
polymer with a second, pyridine-end-functionalized PS
(from NMP) yielded an asymmetric amphiphilic metallotriblock copolymer. The polymers could self-assemble
into monodisperse layered non-covalently connected
micelles and non-covalently connected nanoparticles.
Another route describes the synthesis of H-bonding
polymers via RAFT polymerization. Thymine endfunctionalities interacted with heterocomplementary alphaDAP-functionalized chains to afford supramolecular block
copolymers in solution and in bulk [263].
2.2.1.4. Pathway 4: RAFT polymerization using functional
RAFT agent followed by initiation of polymerization of nonRAFT polymer. Akimoto et al. used Fig. 12, Pathway 4
for their reactions. NIPAAm was copolymerized with
DMA using 2-[N-(2-hydroxyethyl)-carbamoyl]prop-2-yl
dithiobenzoate to produce -hydroxyl, -dithiobenzoate
thermoresponsive polymers. The -hydroxyl group was
then used to produce the PLA blocks [245]. The terminal dithiobenzoate groups were converted into thiols and
reacted with maleimide. By placing the polymers into
water, the chains self-assembled into surface functionalized micelles, which acted as good hosts to the drug
paclitaxel. Similar work was seen in another of their publications, where the cellular uptake of the micelles was
examined [14].
Stimuli-sensitive diblock copolymers consisting of
N-acryloxysuccinimide and NIPAAm were utilized as

60

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 13. The formation of biocompatible micelles using a combination of RAFT and ROP.
[255] (Copyright, Royal Society of Chemistry, 2009).

macro-initiators for the ROP for -CL [220]. The amphiphilic


triblock copolymers were conjugated to biotin to enhance
the internalization of the macromolecules into tumor
cells. The biotinylated chains, self-assembled into micelles
and upon loading with doxorubicin, exhibited thermosensitive drug release.
using
2-(2-carboxyethylsulfanylthiocarbonylBy
sulfanyl)propionic acid, Chang et al. possessed a RAFT
agent whereby both the R and Z group contained a carboxcylic acid group, capable of the ROP of -CL in the presence
of an aluminium catalyst [17]. When the macro-RAFT
agent was applied to the controlled RAFT polymerization
of NIPAAm, ABA triblock copolymers (with NIPAAm as
the B block), were produced, which could self-assemble
into micelles in an aqueous environment. Drug loaded
systems (where the drug was prednisone acetate, an antiinammation drug), displayed thermosensitive controlled
release behaviors.
N-carboxyanhydrides are another group of compounds
that can undergo ROP [264266]. Deng et al. produced a
novel Fmoc-protected RAFT agent and applied it to the
polymerization of NIPAAm that, after hydrolysis, resulted
in amino-end capped PNIPAAm chains. Subsequent ROP
with -benzyl-l-glutamate N-carboxyanhydride yielded
the pH and temperature responsive block copolymers.
Zhang et al. used a modied Pathway 4 for their work
with N-carboxyanhydrides for a novel approach to the
synthesis of polypeptide-based diblock copolymers [266].
DEA was polymerized using RAFT, but the dithioester
end group was removed under selective aminolysis.
The thiol-terminated macro-initiator was applied to the
ROP of either -benzyl-l-glutamate N-carboxyanhydride
or triuoroacetyl-lysine N-carboxyanhydride. A similar

approach was utilized for the ROP of d,l-lactides. PS


macromercaptanes were derived from thiocarbonyl thio
endcapped polymers and used as initiating sites [267].
Alternatively, the thiol group, which is the remnant of
the hydrolysis of the RAFT agent can be converted into
hydroxyl groups [268], which can be directly employed for
ROP [269].
Along with ROP another way to construct block copolymers is to utilize two different radical based polymerization
techniques. Typically one polymerization techniques will
be carried out, e.g., ATRP or NMP, and then a RAFT agent will
either attached directly, e.g., via esterication or a component on the polymer will be modied, such as the halide
groups on ATRP initiators (or macro-initiators), to become
RAFT agents. The most common structures encountered
when ATRP and RAFT are combined are comb or graft
copolymer structures. These can be formed a number of
ways but the tendency is either to polymerize a halogen
containing monomer via RAFT and use the side groups
as initiating sites for ATRP [270272], or to post modify
a RAFT polymer to include ATRP initiating units, e.g., by
reacting a 2-hydroxyethyl methacrylate polymer with 2bromoisobutyryl bromide [273]. Details are discussed in
the section on graft polymers, only the linear structures are
outlined here: Huang et al. produced difunctional haloxanthate inifers that were used for successive reactions, the
RAFT polymerization of NVP and ATRP of either STY, MA
or MMA [274]. In similar work Nicolay et al. used a bromoxanthate iniferter (initiator-transfer agent-terminator)
to produce block copolymers of VAc with either MMA, STY
or MA [275]. This approach was used via the RAFT-rst or
ATRP-rst route hence this method can therefore be listed
under Pathways 2 and 4 (Fig. 14).

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

61

Fig. 14. The combination of RAFT and ATRP to yield block copolymers. Either route can be taken to yield the desired products.
[275] (Copyright, Royal Society of Chemistry, 2008).

2.2.1.5. Pathway 5: simultaneous polymerization. Fig. 12,


Pathway 5 provides an excellent example of where both
a RAFT and another polymerization technique can be
undertaken simultaneously. Thurecht et al. prepared block
copolymers in a one-step process with the RAFT polymerization of STY and the ROP of -caprolactone (-CL) in
supercritical CO2 . The authors used enzymes to catalyze
the ROP, yielding broad PDI values but when the PCL chains
were removed via hydrolysis, the PS segments were found
to be very well controlled [206].
In another simultaneous experiment, ztrk et al.
prepared star copolymers in a one-step process. They synthesized a xanthate, 1,2-propanediol ethyl xanthogenate,
where the R group contained two ROP initiating sites [276].
The concurrent radical polymerization of STY, with the ROP
of -butyrolactone, yielded polymers with three polymer
arms. Two of the arms formed through ROP and the other
via MADIX. The PDI values for the nal polymers were very
broad (between 2.19 and 3.10) suggesting an uncontrolled
reaction.
2.2.2. Triblock copolymers
Commercially available or easily synthesized polymers
can undergo chain end functionalizations to incorporate
the required RAFT agents (becoming macro-RAFT agents)
[17,49,191195]. The synthesis procedure is similar to the
steps outline in Fig. 12, although only Pathways 1 and 2
have been described in the literature.
2.2.2.1. Pathway 1: covalent attachment of a RAFT agent to an
end functionalized non-RAFT polymer, followed by RAFT polymerization. -Caprolactone (-CL) is a useful compound,
as the polymers formed from the ring-opening polymerization (ROP) of the monomers yields biodegradable
materials. Biodegradable cationic micelles were prepared
from DMAEMA and -CL (where the DMAEMA was the
A block), triblock copolymers and applied for the deliv-

ery of siRNA and paclitaxel into cancer cells [49]. The


macro-RAFT agent was formed from the addition of R3 onto
the chain ends of the PCL. Various molecular weights of
triblock copolymers were produced with the products selfassembling into nano-sized micelles in water, possessing
a low cytotoxicity. Some of the micelle solutions exhibited signicantly enhanced gene silencing efciency along
with displaying higher drug efcacy when compared to free
drugs.
PEG, a useful hydrophilic polymer that can easily accommodate RAFT agents on the chain ends, can be acquired
commercially in a variety of different molecular weights.
The stealth properties of the coated nanoparticles, which
are a measure of the ability of nanoparticles to remain
undetected by the bodys defense system, were assessed
in vitro by the haemolytic CH50 test. Achilleos et al. used
PEG for the formation of amphiphilic polymer co-networks
by sequentially functionalizing PEG with two R3 units,
polymerizing a hydrophobic monomer (MMA, STY or BA)
and then introducing a cross-linker [191].
A ,-bis(2-cyanoprop-2-yl dithiobenzoate) PEG
macro-RAFT agent was used by Peng et al. for the synthesis
of triblock copolymers of poly(4-styrenesulfonate)-bPEG-b-poly(4-styrenesulfonate) with narrow molecular
weight distributions (PDI values between 1.28 and 1.40)
in aqueous solutions [193]. The reaction rate was strongly
dependent on the macro-RAFT agent and initiator ratio.
Decreasing the amount of initiator in relation to the
chain transfer agent, slowed the polymerization rate
and improved the molecular weight distribution with a
prolonged induction time.
With their PEG macro-RAFT agent Zhang et al. polymerized NIPAAm and produced thermally sensitive ultralong
multiblock copolymers using the oxidative coupling of
the two mercapto groups at the two ends of the triblock
copolymer chains [195]. The folding of individual multiblock copolymer chains in an extremely dilute solution

62

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

(106 g/mL) was studied by laser light scattering. Each


NIPAAm block collapsed into a small globule (bead) stabilized by the two attached PEG blocks on the chain backbone.
The MADIX approach was also adopted by the use of
novel xanthate end-functionalized PEG chains in order to
control the polymerization of VAc, producing both diblock
and triblock copolymers (utilizing a difunctional PEG chain)
[194].
Other polymers, besides PEG, can also be applied to
the production of triblock structures. Karunakaran and
Kennedy used a ,-functionalized PDMS chain to produce amphiphilic pentablock poly(allyl methacrylate)-bpoly(DMA)-b-PDMS-b-poly(DMA)-b-poly(allyl methacrylate) copolymers [192]. The copolymers were cross-linked
to produce co-networks, swelling in both water and hexanes indicating the existence of cocontinuous hydrophilic
and hydrophobic domains.
An ABC triblock copolymer poly(ethylene-altpropylene)-b-poly(ethylene
oxide)-b-PNIPAAm
was
recently generated by combining anionic polymerization
with RAFT polymerization leading to polymers with
tunable and reversible micellar aggregation behavior
[277].
2.2.2.2. Pathway 2: initiation of polymerization of nonRAFT polymer (PA ) using a functional RAFT agent, followed
by RAFT polymerization (PB ). A series of thermosensitive ABA type triblock PCL-b-PNIPAAm-b-PCL copolymers
with different molecular weights were synthesized by
the combination of ROP with RAFT [17]. The ROP of CL was initiated by a RAFT agent with two hydroxyl
groups followed by RAFT polymerization of NIPAAm.
The products showed thermosensitive controlled release
behavior and characterisations with transmission electron microscopy (TEM) showed micelles with well
dened spherical morphologies, with diameters of around
100 nm.
A ,-bistrithiocarbonyl-end functionalized telechelic
cis-1,4-polyisoprene has been prepared via metathesis
degradation in the presence of a Grubbs catalyst. Subsequent RAFT polymerization of tBA led to ABA triblock
copolymers [278,279].
2.2.3. Conclusions to 2.2
The combination of RAFT polymerization with other
techniques has generated signicant interest over the last
few years. The desire to generate these block copolymers
stems from the opportunity to extend the array of properties and characteristics seen in polymeric systems. So far,
the most common polymerization techniques such as ringopening polymerization, anionic polymerization, ATRP and
metathesis polymerization have been combined with RAFT
polymerization and proven to be successful although occasionally signicant side reaction can be observed. The
interest in material design is reected by the amount of
papers that report on the synthetic approaches taken when
combining the RAFT process with other techniques in order
to provide materials with novel self-assembly characteristics and inherent properties. The degradability of PLA or
the chemical resistance of polyethylene comes to mind.

Fig. 15. Selective end functionalization of dextran by a xanthate for the


polymerization of vinyl acetate.
[290] (Copyright, American Chemical Society, 2009).

It would probably be desirable to investigate the unique


properties of these polymers in more detail to allow drawing conclusions regarding potential superiority of these
novel architectures in comparison to more traditional techniques.
2.3. Block copolymers prepared by RAFT in combination
with carbohydrates
Sugars are of great importance in pharmacology and
all life processes. The majority of polymer research,
based on sugars, has focused on the synthesis of
glycomonomers and the subsequent glycopolymers
[47,85,86,88,170,173,280288]. Despite its importance
[289], the combination of RAFT polymers and polysaccharides has not been attempted in detail to prepare
block copolymers, only for surface modications or to
the synthesis of graft polymers (see below). Bernard et al.
were able to attach a xanthate moiety onto the end of a
dextran chain using Huisgens 1,3-dipolar cycloaddition
to create well dened block copolymers (Fig. 15) [290].
Stable monodisperse poly(VAc) (PVAc) submicron latex
particles were synthesized by ab initio batch emulsion
polymerization using this macro-RAFT agent, which also
functionalized as a viable stabilizer.
The marriage between carbohydrates and RAFT polymerization is dominated by the preparation of glycopolymers, synthetic polymers with carbohydrate pendant
groups. A selection of sugar monomers are shown in Fig. 16.
These have been synthesized using a range of techniques,
including click chemistry [284], and enzymatic routes [32].
Table 2 shows these monomers and how they have been
included in the formation of the block copolymers. Most of
the monomers encountered use protecting groups, e.g., the
isopropylidene groups. Care should be taken when removing these, especially when using acrylate and methacrylate
monomers as the sugar units can be lost during the modications [86,87].

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

63

Fig. 16. Various glycomonomers used for the formation of block copolymers. 3-O-Acryloyl-1,2:5,6-di-O-isopropylidene--d-glucofuranose (AIG)
[88], 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene--d-glucofuranose (MIG) [85,86,88], 3 -(1 ,2 :5 ,6 -di-O-isopropylidene--d-glucofuranosyl)-6methacrylamido hexanoate (MIGC5 when n = 5) [88], 3 -(1 ,2 :5 ,6 -di-O-isopropylidene--d-glucofuranosyl)-11-methacrylamido undecanoate (MIGC11
when n = 10) [88], 6-O-methacryloyl--d-glucoside (MAGO) [281], acrylamidoglucopyranose (AAGP) [47], 2 -(4-vinyl-[1,2,3]-triazol-1-yl)ethyl-O-d-mannpyranoside (VTEMP) [284], 3-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose (MIGP) [87], 6-O-p-Vinylbenzyl-1,2:3,4-di-Oidopropylidene-d-galactopyranose (VDIGP) [291], 2-(-d-galactosyloxy)ethyl methacrylate (GEMA) [281], methacrylamidoglucopyranose (MAGP) [32],
2-(2 ,3 ,4 ,6 -tetra-O-acetyl--d-glucopyranosyloxy)ethyl methacrylate(AGPM) [255], 2-lactobionamidoethyl methacrylamide (LBAM) [292].
[32] (Copyright, John Wiley & Sons, 2009); [85] (Copyright, John Wiley & Sons, 2007); [86] (Copyright, John Wiley & Sons, 2007); [87] (Copyright, Elsevier,
2007); [88] (Copyright, Wiley-VCH, 2007); [255] (Copyright, Royal Society of Chemistry, 2009); [281] (Copyright, Royal Society of Chemistry, 2008); [283]
(Copyright, Wiley-VCH, 2007); [284] (Copyright, Wiley-VCH, 2010); [291] (Copyright, John Wiley & Sons, 2008); [292] (Copyright, American Chemical
Society, 2009).

The glycomonomers can be used to form amphiphilic


polymers, used for the formation of micelles
[47,86,170,173,281,284], rods [32], or vesicles [89].
Cameron et al. used their products to form multivalent
carbohydrate-bearing aggregates in solution with the
capability to solubilize hydrophobic species (a waterinsoluble dye) [281]. Other papers describe the formation
of pH sensitive systems after the removal of the protecting
groups from the MIG monomers in a block copolymer with
DEAEMA [86,87]. Spherical micelles with PDEAEMA as the
hydrophobic cores and PMAGlc as the hydrophilic shells
were formed in alkaline aqueous solutions [86].
Oezyurek et al. synthesized a range of block copolymers
with NIPAAm and four protected glycomonomers (MIG,
AIG, MIGC5 and MAIpGlcC10) [88]. The cloud points of the
aqueous solutions of the copolymers were strongly affected
by the monomer ratios and the spacer chain length of

the glycomonomer. Glycopolymer block copolymers were


formed with LCSTs in the physiologically viable temperature range. NIPAAm was also utilized by Zhang et al. in
conjunction with AAGP for block copolymers. The products
were simultaneously self-assembled and cross-linked in an
aqueous medium via RAFT polymerization to afford corecross-linked micelles exhibiting glycopolymer coronas and
a PNIPAAm stimuli-responsive cores [47].
A novel monomer incorporating a triazole linkage,
based on mannose (VTEMP) was reported by Hetzer et al.
[284]. The monomer was polymerized via RAFT with the
polymer chain extended with NIPAAm in order to generate
thermo-responsive block copolymers, which underwent
reversible micelle formation at elevated temperatures.
Two chiral amphiphilic diblock copolymers with different relative lengths of the hydrophobic and hydrophilic
blocks and containing VDIGP and NIPAAm were syn-

64

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Table 2
The synthesis of sugar containing block copolymers using the glycomonomers shown in Fig. 16, with experimental details and associated references.
Entry

First block

Second block

RAFT agent

T ( C)a

Solventb

Reference

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

NIPAAm
NIPAAm
NIPAAm
NIPAAm
GEMA
GEMA
MAMGIc
DEAEMA
MIG
3-MDF
AAGP
VTEMP
MIGP
VDIGP
AGPM
APMA
MAGP

AIG
MIG
MIGC5
MIGC11
DMAEMA
BA
BMA
MIG
BMA
BMA
NIPAAm
NIPAAm
DMAEMA
NIPAAm
PEGMEMA (n = 2)
LBAM
5 -O-Methacryloyl uridine

R1
R1
R1
R1
R3
R3
R3
R3
R2
R2
R5
R3
R1 or R2
R10
R1
R3
R3

95
95
95
95
70
?
?
70
70
70
60
60
60
90, 60
70, 65
70
60, 70

1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
EtOH:H2 O (9:1)
DMF
DMF
1,4-Dioxane
H2 Oc
H2 Oc
EtOH, H2 O/DMSO
H2 O:MeOH (2:1), DMAC
DMF
Toluene, THF
MeOH, EtOH
H2 O:dioxane (2:1), H2 O:DMF (16:1)
DMAc/H2 O (9:1), DMSO

[88]
[88]
[88]
[88]
[281]
[281]
[281]
[86]
[85]
[85]
[47]
[284]
[87]
[291]
[89]
[292]
[32]

Where two temperatures are quoted the rst is used for the formation of the homopolymer and the second is for the construction of the block copolymer.
Where two solvent systems are shown the rst is in relation to the formation of the homopolymer and the second relates to the construction of the
block copolymer.
c
Mini emulsion systems.
b

thesized by Wang et al. [291]. The copolymers could


self-assemble into micelles in aqueous solution and
showed a higher LCST in comparison to the PNIPAAm
homopolymer. The LCST increased with the relative length
of the poly(VDIPG) block in the copolymer.
Deng et al. reported on the syntheses of diblock
galactose-containing polymers with one galactosecontaining chain segment and one primary aminecontaining segment using LBAM and 3-aminopropyl
methacrylamide, respectively [292]. The primary amine
pendant groups of the copolymer were modied with
biotinyl-N-hydroxysuccinimide ester. Subsequently, multifunctional glyconanoparticles were prepared and used
in the study of biomolecular recognition processes. The
biomolecular recognition of the biotin and galactose
moiety on the surface of the glyconanoparticles towards
avidin and Ricinus communis agglutinin lectin respectively
was conrmed.
Pearson et al. encountered problems with the copolymerization of MAGP and 5 -O-methacryloyl uridine (MAU)
[32]. Homopolymerizations of both monomers proceeded
with pseudo-rst order kinetics although a bimodal molecular weight distribution was observed for poly(MAU) at low
conversions courtesy of hybrid behavior between living
and conventional free radical polymerization. This effect
was more pronounced when a MAGP macro-RAFT agent
was chain extended with MAU, however, in both cases,
good control was attained once the main RAFT equilibrium
was established. Self-assembly of the block copolymers
with increasing hydrophobic (MAU), block lengths produced micelles, with an increased tendency to form rods
as the PMAU block length increased.
2.4. Block copolymers prepared by RAFT in combination
with proteins, peptides and DNA
Natural building blocks that are attracting increased
interest are peptides and proteins. Not only can they be
considered as natures polyamide they also contain a myr-

iad of information in their sequence that is responsible


for many biological functions. There are in general three
approaches to block copolymer-type polymer protein conjugates, which consist of:
(a) Polymerization using a reactive RAFT agent with subsequent conjugation to the biomolecule.
(b) A reaction between the RAFT agent and biomolecule(s),
followed by polymerization.
(c) Conversion of the thiocarbonylthio end group of a RAFT
made polymer to a different functionality, which is suitable for further bioconjugation.
Depending on the functionality of the protein, one
or more polymer chains may be conjugated to the protein. While the attachment of an array of polymer chains
yields structure resembling those of star polymers, a single chain leads to structures, which are closely related
to block copolymers with one protein block and a block
based on a synthetic polymer. The rst report based on a
reactive RAFT agent for bioconjugation focused on pyridyl
disulde (PDS) as an active end group for the conjugation to thiol containing proteins, such as bovine serum
albumin (BSA) [293]. A variety of PDS containing RAFT
agents have since been developed, which were employed to
generate water-soluble polymers of varying chain lengths
[294,295]. Alternatively, conjugation to the thiol groups
of proteins can be carried out via maleimide functionalized polymers. The polymerization needs to be carried out
using a furan-protected maleimide RAFT agent, but the nal
product can be easily deprotected leading to an efcient
maleimide group for site-selective conjugation to free cysteines which exist in proteins [296] Proteins with reactive
amino groups can be modied using polymers prepared
with N-hydroxysuccinimidyl (NHS) ester containing RAFT
agent [297].
Direct modication of a protein with a RAFT agent,
in contrast, can ensure the efcient grafting of the synthetic polymer chain. The growing of a polymer chain is

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

fast and does not require lengthy conjugation reactions


as in the conjunction of a protein and a polymer chain.
The RAFT agent can be immobilized on the protein using
similar techniques such as in postpolymerization conjugation. RAFT agents with pyridyl disulde groups [298,299]
and maleimide groups [300,301] were both used in combination with BSA as the protein building block. Lysozyme
was modied via its amine groups to a RAFT agent with
N-hydroxysuccinimidyl (NHS) ester although the modication of just one amine unit to create a block copolymer
could be more difcult due to the presence of typically
around 7 amine units in lysozyme [302]. In an attempt to
look into renewable sources, soy-protein, which is available in abundance, was modied via its amine groups to
generate a protein macro-RAFT agent for the subsequent
acrylate polymerization [303].
The third approach is the end group modication of
a RAFT made polymer to introduce suitable functional
groups for further conjugation. The replacement of the
RAFT end group using a radical approach was successfully
demonstrated using a furan-protected azo-intiator. After
deprotection, maleimide functional groups were introduced at the chain ends for site-specic conjugation of
V131CT4 lysozyme to the polymers to generate proteinpolymer conjugates [304]. A very gentle technique to
remove the RAFT end group is via aminolysis, which leads
to the formation of polymers with thiol end groups, which
is prone, however, to disulde formation. Addition of
2,2 -dithiodipyridine can prevent this side reaction while
creating a reactive polymer for further reaction with thiol
groups, which are abundant in proteins [305,306]. A very
unusual behavior is observed when using poly(N-vinyl
pyrrolidone) synthesized via RAFT polymerization. When
left in water, the RAFT end group is cleaved. Surprisingly,
the resulting polymer does not carry a thiol group, but a
hydroxyl group instead. Heating of the polymer yields an
aldehyde end group, which undergoes facile bioconjugation with the amine moieties found in proteins [307].
A triblock copolymer based on a peptide block was
prepared by conjugating a polymer with an amine reactive terminal group to a ,-diamino peptide. Wiss et al.
used R3, functionalized with pentauoro phenol, to polymerize diethylethylene glycol methyl ether methacrylate.
These polymers were added to a difunctional collagen-like
peptide with and amino groups. These amino groups
effectively displaced the activated ester groups (the loss of
the uorinated moieties) to yield an ABA block copolymer
(with the peptide as the B block) [308].
Polymerproteins are not discussed in detail here. The
reader is referred to arrange of review articles on this matter that discuss the general approach, but also focus on
RAFT polymerization as one potential avenue [309313].
Similar experimental procedures can be applied when
preparing block copolymers with DNA. PNIPAAm-b-DNA
was prepared through the Michael addition reaction of
thiol-terminated PNIPAAm, which was obtained from RAFT
made PNIPAAm, to 5 -maleimide-modied DNA [314].
2.4.1. Conclusions to 2.3 and 2.4
The combination of RAFT polymerization with natures
building block has probably seen the highest surge in recent

65

years. The interest in this area is not only reected by the


numbers of publications, but also by the number of citations. The focus of these publications is not so much in
the preparation of controlled structures, although this is
always an underlying theme, but to retain the activity of
the biomaterial. A range of approaches have been applied
to generate these architectures and the proof of concept has
been completed. It is now time to apply these procedures
to more complex bioactive molecules such as protein drugs
or vaccines. Also the types of sugars employed are commonly monosaccharides while many sugar molecules with
interesting biological activities are often polysaccharides.
2.5. The combination of RAFT with click chemistry
One drawback with RAFT polymerization is that in order
for a chain extension to work, the monomers must have
similar reactivities. For example, VAc can only be polymerized in the presence of a xanthate, whereas MMA requires
the use of a dithiobenzoate. As previously mentioned, the
use of a universal RAFT agent would be of benet here and
there have already been studies to try and ascertain this
compound, with viable candidates currently under investigation [96,97].
One way to circumvent this problem is two produce
two homopolymers which possess moieties that can be
combined, linking the two disparate chains (Fig. 17). There
are a number of techniques which makes this possible
including: thiol-ene chemistry, 1,3-dipolar cycloaddition,
or the DielsAlder reactions. The latter two examples
are pericyclic [2 + 3] reactions, so called click chemistry
techniques. This term was coined by Sharpless et al. to
encompass all reactions of high yield, modularity and stereospecicity. The most well known and heavily researched
area here is with the copper catalyzed alkyne and azide
1,3-dipolar cycloaddition, which has spawned hundreds of
papers where investigators use the click concept to engineer an array of polymer structures [315317].
Typically the coupling between two macromolecules,
possessing high molecular weights is thermodynamically
unfavorable however, it is achievable using the click
methodologies. In this section a number of techniques will
be examined, the Cu(I) Huisgen cycloaddition, the thiol-ene
reaction and the hetero DielsAlder reaction. Since their
development, click chemistry strategies have been rapidly
integrated into the eld of macromolecular engineering.
Although a vast effort has looked into the modication of
polymers, for example with the attachment of pendent side
groups and chain end modication, this section focuses
on the use of the click chemistry routes to produce block
copolymers, i.e., the nal block copolymers are the result of
the click process. For polymer modications utilizing the
click chemistry techniques, the reader is directed to other
comprehensive reviews regarding these processes (Fig. 18)
[315319].
2.5.1. Block copolymers formed via Cu(I) Huisgen
cycloaddition
Although a plethora of papers have exploited the copper
catalyzed route, this has mainly focused on the synthesis of
polymer backbones containing either alkyne or azide pen-

66

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 17. Two disparate homopolymer chains, possessing complimentary functionalities, which can combine to yield a block copolymer with the functional
groups combined at the nexus between the two chains.

Fig. 18. The coupling of azide and alkyne functionalized homopolymers via the copper catalyzed Huisgencycloaddition to form a block copolymer with a
mid-chain triazole ring.

Fig. 19. Modied compounds that incorporate alkyne groups which can be attached to complimentary azide containing compounds.

dent groups which are later used to attach small molecules,


e.g., a sugar moiety, to the backbone via postmodication
processes. The formation of block polymers with Cu catalyzed click chemistry has primarily relied on the addition
of clickable groups to the RAFT agents (the chain transfer agents possessing either an azide or alkyne group)
(Figs. 19 and 20). Some examples of the copper catalyzed
click approach are shown in Table 3.
The rst example for the power of RAFT being combined
with the copper catalyzed cycloaddition to generate block

copolymers was provided by Quemener et al. [80]. A block


copolymer, PS-b-PVAc, was formed by using two complimentary compounds, a xanthate possessing an azide group
(to polymerize the VAc) and a dithioester with an alkyne
unit (for the STY). The alkyne unit was protected with a
trimethyl silyl group during the polymerization, in order
to ensure that the triple bond remained intact, although
some examples in the literature describe the use of unprotected propargyl groups [320]. This is a good example of
two very different polymers combining effectively (the two

Fig. 20. RAFT agents functionalized with azidegroups which can be attached to complimentary alkyne containing compounds.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

67

Table 3
Examples of block copolymers formed using the Cu(I) Huisgencycloaddition approach. The components used can be seen in Figs. 19 and 20.
Entry
1
2
3
4
5
6
7
8
9
10
11
12

Polymer 1

Polymer 2

Polymer
Azide component
PVAc
C7
1-(3-Azidopropyl)pyrrole-terminated
poly(isobutylene)
PMMA
C8
PMMA
C8
PMMA
C8
Mono azide PEG
(1000 g mol1 )
PBA/PEGMEA/PNIPAAm
C9
PVAc
C10
PVAc
C11
PS capped with azide after ATRP polymerization
P2VP
C6

Polymer
Poly(6-O-methacryloyl mannose)
PNIPAAm

Alkyne component
C1
C2

[288]
[326]

PAA
PDMA
PHEMA
P4VP

C2
C2
C2
C2

[323]
[323]
[323]
[329]

PCL/PLA
PS
Alkyne terminated PCL
Poly(N-acryloyl-l-valineN -methylamide)
Poly(3-(triethoxysilyl)propyl methacrylate)-block-PS

C4
C3

[327]
[324]
[252]
[328]
[325]

homopolymers were clicked together in a facile manner)


to yield block copolymers with narrow macromolecular
weight distributions. Sequential polymerizations would
not have yielded such a favorable result.
In order to ensure the formation of well-dened polymeric material it is essential that either equimolar amounts
of each of the functional homopolymers are employed,
or that excess material can be removed easily, otherwise
homopolymer impurities will remain in the products [288].
It is also important to ensure that all the polymers possess
the desired functionalities. When examining the chromatograms of the click products, a low molecular weight
tail can be indicative of homopolymer present in the system. This homopolymer could be unreactive polymer (from
termination reactions, previously mentioned), in which
case either the alkyne or the azide group is lost. Ladmiral
et al. showed the side reactions that could occur during the
click process, indicating why the process may not always
reach 100% [321]. (Caution: although azides can be handled
safely, they can be explosive so care should be taken with
their use.)
If homopolymer side products are prevalent, they can be
removed using previously mentioned methods, including
dialysis and utilizing the solubility of the nal product, in
relation to the constituent homopolymers. Li et al., in their
click reaction, used an insoluble iodoacetate functionalized
support which would scavenge excess thiol terminated
homopolymer (see the other click reactions section below)
[322].
There are a number of examples of block copolymers
formed utilizing the Cu(I) catalyzed click process. The products can be highly applicable to real-world problems.
Schricker et al. used the click approach for the formation
of materials that could be used as scaffolds for the regeneration of bone [323]. Schricker et al. looked at various block
copolymers using MMA formed from C8 and combined this
with either a polymer of AA, DMA or HEMA with C2. Xue
et al. used the elaborate RAFT agent C3 which, along with an
alkyne group, possessed an azo group that, when exposed
to different wavelengths of light, switched between trans
and cis conrmations (azobenzene polymers exhibit photoor thermal-isomerisation behavior) [324]. C3 controlled
the polymerization of STY while C10 helped to form PVAc.
The clicked products suggested potential applications as
photochromic probes.

Reference

C2
C5

In a similar approach to Quemener et al. [80], Ting et al.


used C6 to polymerize 6-O-methacryloyl mannose and C10
to control the formation of PVAc [288]. The polymers were
successfully clicked together. The resulting system was
believed to be weakly amphiphilic and dilute solutions of
the block copolymers showed aggregates with DLS analysis, with particles roughly 200 20 nm.
A triblock copolymer was formed using two different
RAFT agents. C5 was used to produce a sequential block
copolymer of 3-(triethoxysilyl)propyl methacrylate) and
STY; C6 controlled the synthesis of poly(2-vinylpyridine).
A triblock copolymer able to form gels was obtained
by clicking the two components together [325]. The
supramolecular self-assembly of the triblock copolymer
was examined, whereby the morphology changed, dependent on the addition of small molecules, e.g., stearic acid,
which formed non-covalent interactions with pyridine
units.
Other polymerization techniques can be utilized along
with RAFT and the click process to form block copolymers. The Storey group in Mississippi was able to click
a poly(isobutylene) block, formed through a quasi-living
2-chloro-2,4,4-trimethylpentane initiated polymerization
and then modied to afford an azide terminus, to a NIPAAm
block synthesized with C2 [326]. Voras group combined
ROP, click and RAFT methodologies. C9 was used to polymerize butyl acrylate, NIPAAm and PEGMEA. All three
polymers were obtained with polydispersities 1.10 [327].
In a separate set of reactions C4 was used for the ROP
of -CL and LA. The nal polyesters were produced with
polydispersity values for the PCL and PLA, being 1.28 and
1.24, respectively. The two different polymer systems were
then clicked together to yield copolymers. Liu et al. used PS,
formed via ATRP and with the bromine group modied to
an azide group, and clicked it to poly(N-acryloyl-l-valine
N -methylamide) using C2 to yield polymers with molecular weights around 10,000 and PDI values of 1.121.20
[328].
Alternatively commercially available polymers can be
modied to include either an azide or alkyne group and
then clicked to a RAFT polymer with the complimentary
moiety on the chain ends. Zhang et al. used a PEG functionalized with an azide unit, which was combined with a
polymer of 4VP synthesized using C2 [329]. The copolymers
were then used to stabilize gold nanoparticles. In another

68

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 21. The thiol-ene addition of a homopolymer possessing a single thiol unit to a another chain having free alkene moiety.

approach, Tong et al. clicked -azide, -xanthate PVAc and


biodegradable, alkyne functionalized PCL together [252].
2.5.2. Block copolymers formed via thiol-ene reactions
Old, often well known, chemistries can be re-labelled
as click reactions. The addition of a thiol, RSH, across a
C C bond, i.e., hydrothiolation, commonly referred to as a
thiol-ene reaction, falls into this group [318]. The scope of
the thiol-ene reaction is extremely impressive with virtually any thiol and any ene being capable of undergoing the
reaction under a range of experimental conditions including acid or base catalysis, nucleophilic initiation, and by
a radical process induced either thermally or photochemically. It should be noted that such thiol-ene reactions
are also accurately described as thiol-Michael reactions
and these terms can, and are, used interchangeably
(Fig. 21).
A lot of papers exist where RAFT synthesized polymers
can be modied via the thiol-ene and thiol-yne (whereby
two RSH compounds are added to a triple bond), routes.
The RAFT end groups are reduced to the corresponding
thiols and these are reacted with an alkene containing compound. These papers look at the addition of small molecules
to the and/or chain ends. At the time of writing this
review only two papers are shown to use thiol-ene chemistry to produce a block copolymer. Boyer et al. [305]
produced block copolymers using two thiol-ene reactions.
The rst used a base catalyzed reaction to concurrently
reduce the dithioester group on poly(HPMA) and attach
the resulting terminal thiol to 1,6-hexanediol diacrylate (in
excess). This macro-ene then underwent another thiolene reaction with thiol-terminated poly(ethylene glycol) to
produce the block copolymer. The procedure was repeated
with a thiol modied oligodeoxyribonucleotide to yield a
biohybrid block copolymer containing the synthetic HPMA
and DNA based blocks. In the second paper AAm was polymerized via RAFT and the end group was reduced to a
terminal thiol. In a separate system a 5 -maleimide modied oligodeoxyribonucleotide (ODN) was formed [330].
Block copolymers were produced thanks to the Michael
addition of the thiol-terminated acrylamide to the ODN.
Although producing polymers with terminal thiol
groups is a facile process; the terminal RAFT agent just
needs to be reduced via aminolysis, producing polymers

with a terminal alkene unit is harder. Catalytic Chain


Transfer Polymerization (CCTP), can be used to produce
polymers with terminal ene units but there some drawbacks to its application [331]: there are a limited number of
monomers that can be used (typically methacrylates), and
the polymers formed have broad polydispersity indices.
A recent paper may be able to help here. Soeriyadi et al.
[332] polymerized MMA to produce dithioester terminated
macromolecules. These were then placed back into solution in the presence of AIBN and a CCTP cobalt catalyst,
but no monomer. The CCTP mechanism transformed the
RAFT end group into a terminal alkene unit, mass spectrometry conrming the alteration. In the future these
polymers could be combined with other thiol terminated
polymers for the formation block copolymers. There is
only one problem here. Koo et al. looked at the thiolene approach for polymerpolymer conjugation [333]. Low
yields, for desired block copolymers, were obtained. Blank
reactions using typical thiol-ene conditions indicated that
bimolecular termination reactions occur as competitive
side reactions, explaining why a molecular weight increase
was observed even though the thiol-ene reaction was not
successful. The study (using both thermal and UV methods
for the coupling), indicated that radical thiol-ene chemistry
should not be proposed as a straightforward conjugation
tool for polymerpolymer conjugation reactions.
2.5.3. Block copolymers formed via other click reactions
Although the term click chemistry has recently
become synonymous with the copper catalyzed reaction,
other pathways which can be deemed as click chemistry have also emerged within the literature. Reactions
such as the DielsAlder pathway and the transformation
of strained ring systems can also be deemed as viable click
routes (Table 4).
Li et al. looked at the end-group activation of RAFT synthesized polymers (NIPAAm based), by the reduction of the
Z group into the corresponding thiol and then the subsequent reaction with excess 1,8-bismaleamidodiethyleneglycol led to the formation of maleimido-terminated
macromolecules [322]. Block copolymers of PNIPAAm and
PS were formed, by performing a second thiol-maleimide
Michael addition using a sulfhydryl-terminated PS with
near quantitative coupling.

Table 4
Examples where block copolymers have been synthesized using other click approaches.
Polymer 1

Polymer 2

Polymer

Clickable functionality

Polymer

Clickable functionality

PNIPAM
PiBor
PS
PiBor
PiBor
PiBor
PS

Terminal thiol with bis-maleimide linker


Sulfonyldithioformate
Electron decient RAFT agent
Electron decient RAFT agent
Electron decient RAFT agent
Electron decient RAFT agent
Phosphine

PS
PS
PCL
PCL
PS
PS
PEG

Terminal thiol
Terminal cyclopentadiene
trans,trans-2,4-Hexadien-1-ol
Terminal cyclopentadiene
Terminal cyclopentadiene
Terminal cyclopentadiene
Azide

Click reaction

Reference

Thiol-maleimide Michael addition


Hetero DielsAlder
Hetero DielsAlder
Hetero DielsAlder
Hetero DielsAlder
Hetero DielsAlder
Staudinger-ligation

[322]
[334]
[250]
[335]
[335]
[336]
[337]

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 22. The formation of block copolymers using the hetero-DielsAlder


(HDA) route via the reaction of a polymer formed from the application of
RAFT polymerization with an electron withdrawing Z group and a polymer
functionalized with a diene.

One technique that has been used extensively by the


groups of Barner-Kowollik and Stenzel is the RAFT Hetero DielsAlder reaction, an atom economical approach
to produce a series of block, stars and graft copolymers
[84,257,334,336,338344]. Dithioesters with an electronwithdrawing Z group may be effectively used as controlling
agents in RAFT polymerizations, but also serve as highly
efcient dienophiles in [4 + 2] cycloadditions (Fig. 22). In
this approach the RAFT agent is used to both control the
polymerization and act as the reactive chain end for the
end modication.
Inglis et al. used this approach with the formation
of block copolymers [336]. By using benzyl pyridin-2ylthioformate as the RAFT agent they were able to produce
isobornyl acrylate (iBor) polymers containing an electron
decient chain terminus. This could be readily reacted with
a PS macromolecule, also formed via RAFT but with the
chain end modied via esterication and substitution to
afford a terminal cyclopentadienyl unit. Using facile reaction techniques, the addition to triuoroacetic acid and
ambient temperature, afforded the block copolymers. This
approach was again adopted for the synthesis of other polymers including cyclopentadienyl modied poly(ethylene
glycol) coupled with poly(styrene) and poly(iBor) (PiBor),
formed using electron decient RAFT agents [336]. The
use of the cyclopentadienyl end group means the reaction
was complete in less than 10 min. If macromolecules functionalized with trans,trans-2,4-hexadien-1-ol are used, the
reaction times increased to hours [257,342344].
In another publication, the HDA approach was adopted
to produce block polymers comprising of PCL and
PS [250,257]. The aforementioned benzyl pyridin-2ylthioformate produced controlled molecular weight PS
which was easily coupled to the PCL (synthesized via enzymatic conditions with trans,trans-2,4-hexadien-1-ol as the
initiator). This work was extended with the modication
of the -CL to contain an alkyne moiety on the other
chain end [257]. By adopting the Cu(I) traditional click
chemistry the PS-b-PCL copolymers were transformed
into arms on the tri-azide functionalized 1,3,5-tris((3azidopropoxy)methyl)benzene.
The HDA approach, while efcient, needs to be examined further in order to look at other RAFT agents which

69

are sufciently electron decient, but that are able to control the molecular weights for a large array of monomers.
In the literature the polymers have been limited to STY and
iBor. New agents are currently being developed, including sulfonyldithioformate based RAFT agents [334]. These
were shown to undergo hetero DielsAlder with cyclopentadiene based polymers, although the only examples given
utilized PS and PiBor, so further work is required. Although
there seems to a limitation with the number of viable
monomers for the electron decient RAFT agents, a whole
multitude of polymers can be functionalized with the
appropriate diene, e.g., cyclopentadiene, by performing
facile reactions such as esterications.
A creative approach has been recently reported by Voit
et al. They formed a peptide bond via Staudinger ligation by
reacting two blocks, one with a phosphine-containing ester
functionality and one with a terminal azide group [337].
Although based on older chemistry practices, the use of
the click chemistry processes will continue to grow as the
feasibility of the routes is examined and discussed further.
2.5.3.1. Conclusion to 2.5. In theory, preparations of block
copolymers via click reaction seem to address a lot of
shortcomings of many other reactions. Limitations of block
copolymerization via chain extension of a macro-RAFT
agent include rm rules on the order in which the blocks
are prepared. In addition, block copolymers cannot be
prepared from two monomers with very disparate reactivities. Click reactions can indeed overcome these limitations
and several examples demonstrated the success of such
an approach. The rst prerequisite is the high purity of
both polymers in terms of the functional groups on the
ends of the polymer chains. This means that during the
polymerization with a RAFT agent, which carries, for example an azide group, loss of reactive groups should be
avoided. This might mean that side reactions should be
suppressed by careful selection of reaction conditions and
that the functional group should not react in a radical
process. The latter is often difcult to achieve and it is
known that certain groups such as azides might undergo
reaction with the monomer as highlighted above. Even
if the endfunctionality is high, subsequent click reaction
requires the exact stoichiometry of the two blocks to eliminate the need for further purication. This introduces
an element of uncertainty. It is therefore, not surprising that many click reactions lead to block copolymers
with PDIs higher than the homopolymers prior to reaction. According to the theory, the conjugation of two
polymers should result in a narrowing of the molecular weight distribution. Furthermore, most examples on
block copolymer synthesis via click chemistry deal with
rather short polymers, barely higher than 10,000 g mol1 .
The number of reports on successful synthesis procedures is probably inverse proportional to the molecular
weight of both blocks. Often the reaction is incomplete
at higher molecular weights. This can be understood in
terms of chain mobility and the necessary diffusion of
the two reactive chain ends towards each other. While
this process is already difcult, the actual occurring reaction is hampered by the rate of the click reaction. It is
therefore not surprising that a report on a high-molecular

70

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

R
S

S
Z
S

S
Z

Z
S

S
S

S
Z
R

Z
S

S
R

Fig. 23. Comparison of star synthesis using the core-rst strategy via Z-group (left) and R-group (right) approach.

weight block polymer employs an extremely fast click


reaction, the reaction between cyclopentadiene and a
pyridin-2-yldithioformate, which is complete in less than
10 min [335].

of initiating sites. The attachment of the RAFT agent can be


carried out by covalently binding the RAFT agent to a multifunctional group either via the R-group of the RAFT agent
or the Z-group. This decision has signicant implications
on the outcome of the process as discussed below. The R-

3. Branched polymers
3.1. Star polymers
Similar to other star synthesis techniques, there are
two different avenues to synthesize star polymers: armrst and core rst. The RAFT process however, represents
a unique case since the core-rst method can be further
divided into two processes. Initially, the star synthesis via
core-rst technique was favored but in recent years there is
a stronger focus on arm-rst techniques. This shift in interest may be due to the increasing attention of the end group
chemistry of the RAFT made polymer and the emergence
of efcient click chemistries.
3.1.1. Star polymers via core-rst strategy
RAFT polymerization is unique between all the star
synthesis techniques because the core-rst strategy can
be further subdivided into two strategies: the R-group
approach and the Z-group approach. The core-rst strategy usually refers to the attachment of multiple initiating
sites with the number of arms equivalent to the number

Fig. 24. SEC curve of a polystyrene six-arm star obtained by


the polymerization of styrene at 100 C in the presence of hexakis(thiobenzoylthiomethyl)benzene.
[345] (Copyright, John Wiley & Sons, 2001).

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

group approach has as result that the reactive RAFT group,


the thiocarbonylthio group, grows away from the core with
the growing polymer arm (Fig. 23).
3.1.1.1. Star polymers via the R-group approach. The rst
detailed study on the synthesis of RAFT employed hexakis(thiobenzoylthiomethyl)benzene as a RAFT agent for
the synthesis of a six-arm PS. The RAFT agent together with
STY was heated to 80, 100 or 120 C resulting in reddishcoloured polymer. Surprisingly, the resulting SEC diagram
revealed in all cases a molecular weight distribution far
from the expected value. Although, the molecular weights
increased with conversion, the distribution was always
bimodal and at high conversions even multimodal (Fig. 24)
[345]. However, after detailed inspection of the mechanism
of the RAFT process it became clear that the multimodality
is part of the process.
Like any RAFT synthesis technique, the polymerization is initiated via a radical source. The radical then adds
rapidly to the RAFT agent which is connected via the Rgroup to the core of the star, at least in an ideal RAFT
scenario (Fig. 25). The subsequent fragmentation generates a radical located on the core and in addition a linear
polymer with a thiocarbylthio end group. According to this
mechanism, it seems that indeed a linear macro-RAFT is
created in this project, which is in agreement with the
actual observation in this rst RAFT experiments (Fig. 24).
The radical on the core will then re-initiate the polymerization until a further addition-fragmentation step,
either to the linear macro-RAFT agent or to a RAFT agent
attached to the core, will take place. The array of possible
termination reactions (Fig. 25) highlights the complexity
of the system with the formation of starstar coupling
products and the loss of active arms broadening the
molecular weight distribution, thus leading to multi-modal
distributions.
It seems to be evident that the occurrence of side products is directly related to the amount of radicals in the
system. Like in any other RAFT process, the concentration
of radicals determines the amount of terminated polymers.
But what is even more evident is the presence of the linear
macro-RAFT agent that grows with conversion. The amount
of linear macro-RAFT agent is directly related to the amount
of radicals that have been created via decomposition of
the initiator during the course of reaction. It is therefore
crucial to keep the concentration of free radicals as low
as possible to achieve a small molecular weight distribution. A high radical ux and a long reaction time, which are
common with slowly propagating monomers or in dilute
monomer solutions, should theoretically broaden the distribution increasing the amount of starstar coupling (if
termination by combination occurs) and the fraction of linear macro-RAFT agent.
Barner-Kowollik and co-workers took on the challenge
to predict these side reactions using computational modelling. They employed PREDICI coupled with high level ab
initio quantum chemical calculations to correlate radical
concentration, propagation rate coefcients and additionfragmentation constant of the RAFT equilibrium and other
parameter against the amount of termination reactions. As
a result, they could provide a catalogue of recommenda-

71

tions for a successful star synthesis via R-group approach


[346,347]:
Initiator concentration: The amount of initiator should be
kept small compared to the RAFT agent concentrations,
which allows the suppression of termination reactions.
Number of arms: signicant starstar coupling is more
common with higher number of arms.
RAFT equilibrium: a high addition rate of the macroradical
to the RAFT agent k and a high transfer of the linear
macroradical to a star-bound RAFT group ktrStar are as
benecial for a small molecular weight distribution as is
a strongly retarding RAFT agent.
Propagation rate coefcient: a fast propagating monomers
achieves high conversions in a shorter period of time,
which is equivalent to a smaller amount of radicals generated.
How do these theoretical considerations compare with
actual experiments? Initial inspection of the molecular
weight evolution reveals in most cases reported in the
literature, an increase in molecular weight with conversion. This is often sufcient for applications where the
researcher is interested in the materials without being
too concerned about the ne structure. In fact, many
monomers have been polymerized using a large array
of core structures including: (aromatic) hydrocarbons,
hyperbranched polyesters (ethers), metal complexes and
well-dened dendrimers (Table 5). The resulting number of
arms is determined by the number of RAFT agents attached
to the core. A range of star polymers were synthesized using
monomers such as STY, acrylates, acrylamide, vinyl ester
and NVP (Table 5).
However, as shown in Fig. 24, a detailed analysis of
the results may reveal that the product is not fully well
dened. In agreement with theoretical models, the formation of linear macro-RAFT agents as well as termination
products should broaden the distribution. This is in particular the case with slowly propagating monomers as
demonstrated during the synthesis of PS star polymers
[345,346]. Modelling experiments in contrast predicted
better resolutions with rapidly propagating monomers
since the amount of radicals produced in a short period
of time is signicantly less, which, in turn, keeps the
fraction of termination products low. Indeed, the polymerization of VAc resulted in well-dened star polymers
having a single monomodal molecular weight distribution,
with the absence of observable linear chains or termination
products [348,349]. Other examples of well-dened star
polymers include star polymers based on PNIPAAm [350],
PVP [351] and poly(N-vinylcarbazole) [352], as well as a
range of acrylate stars (Table 5).
As predicted, the number of arms plays a major role
since the likelihood of a star undergoing starstar coupling increases with the number of reactive groups. A PS
four arm star was found to have only negligible amounts
of these side products [353]. With six and more arms,
these side products, but also the formation of linear macroRAFT agent, becomes visible [345]. As seen in Table 5, the
number of arms of the star polymers reported in the literature exceeds barely four arms, highlighting the fact that

72

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

I.

Initiator

2I

II.

I + M

Pn

III.

RAFT process
Z

Z
S
Z

Pn

Pn

S
S

R
S

Z
Z

S
S

S
S

Pn

R
S

Z
S

linear
macroRAFT

S
Z

S
S

An
S

S
Z

S
S

Z
S

S
S

S
Z

S
Z

S
R

Pn

Termination reactions

S
S

S
R

S
Z

S
Z

S
S
S

S
Z

S
R

An

S
Z

S
S

Pn

Z
S

An

S
Z

Pn

Z
S

Pn

Pn

Pn

Z
S

Z
S

An

S
S

S
R

An

S
S

S
An

S
Z

Pn

Z
S

An

targeted product

S
S

IV.

growth of arms

Pn

s
Fig. 25. Schematic drawing of the synthesis of star polymers via R-group approach.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

73

Table 5
Star polymers via R-group approach (N = number of arms).
N

Type of core

1,1,1Tris(hydroxymethyl)ethane,
pentaerythriol

Benzene

RAFT group

Arms

Polymerization T ( C)
solvent

Reference

PVAc

Bulk

60

[349]

Dioxane

65

[359]

110

[353]

PVPi
PVND
PVAG

PS
PEGA

Benzene

PS

Bulk

60

PMA

Benzene

PMA

Toluene

65

[356]

PAcOSty

Toluene

60

[362]

Benzene

PVBC

Bulk

120

[282]

Benzene

PNVP

Bulk

60

[351]

Pentaerythritol

PNIPAAm

DMF

70

[361]

Pentaerythritol

PS
PMMA
PS-b-PDMAEMA

Bulk

80

[363]

Pentaerythritol

PNVC

Dioxane

60

[352]

Pentaerythritol

PtBBPMA

Toluene

70

[358]

Porphyrine

PDEA

Dioxane

70

[364]

Ruthenium
tris(bipyridyl)
complex

PNIPAAm

Chlorobenzene

70

[365,366]

P(Styrylcoumarin)

74

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Table 5 (Continued)
N

Type of core

RAFT group

Arms

Polymerization
solvent

PMMA

Toluene

Europium tris
(-diketenate)
complex

PS-co-PBEVB
PBEVB

Benzene

PS

PS

T ( C)

Reference

70

[367]

Bulk

80
100
120

[345]

Bulk

35

[368]

O
S

Triphenylene

NH O

C H
S

Dendrimer

PtBA

70
110

PNIPAAm

THF

100

[350]

PS

THF

120

[354]

65

[360]

100

[355]

70

[357]

105

[102]

16

Dendrimer

16

16

16

PMA

Hyperbranched
-caprolactone
(-CL)

DMAEMA

Toluene

Dendrimer

PS

THF

PMA

16

19

Dentritic core
with already
existing 16
P(EO-THF)
arms

PMMA

Dioxane

Dendrimer/PCL

PDMAEMA

THF

excessive amount of termination events may be present


otherwise.
However, this should not distract from the fact that it
is possible to obtain stars with high number of arms using
slow propagating monomers. Careful optimization of polymerization conditions can suppress side reactions, which
includes the choice of a small ratio between monomer and
RAFT agent concentration and aiming for arms with smaller
molecular weights [354,355]. Sometime, higher temperatures can be benecial although it is not clear if it is

the faster rate of propagation or maybe even the faster


addition-fragmentation rate to the RAFT agent that narrows the molecular weight distribution [345].
Many experimental ndings conrm the PREDICI
model and therefore the ndings can be used as guidance.
However, the sole attention to the RAFT process as it is
outlined in schematic drawings such as in Fig. 25 neglects
the fact that RAFT polymerization is still a radical process
and that reactions known from free radical polymerization such as other chain transfer reactions are still present.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Barner-Kowollik and co-workers therefore expanded the


mechanism outlined in Fig. 25 and they identied products
that were the result of the formation of mid-chain radicals
[356].
Recent years have seen the addition of more monomers
and RAFT agents used to generate new star architectures,
but there has been little activity in regard to understanding the underpinning mechanism of the R-group approach.
A signicant shift in interest to materials with desired
attributes has drawn focus away from the investigation of
fundamental aspects and questions, such that the actual
number of arms or the molecular weight distribution
of each arm remains unanswered. Application of these
star polymers has dominated the literature in the last
4 years. Interesting developments include the synthesis of
star polymers with mixed arms using a combination of
RAFT polymerization and ROP [102,357]. Star polymers
with reactive functional groups such bromide groups were
prepared for further modication to generate glycopolymers or use the bromide group for further polymerization
[282,358], but also the use of degradable cores has become
popular [359]. A nice example here is the synthesis of
hyperbranched -CL as the core, with end groups then
decorated with RAFT agents [360]. Exclusive to the star
synthesis via R-group approach is also the possibility to
modify the RAFT end group after polymerization to allow
the attachment of proteins [361] or cholesterol [359].
3.1.1.2. Star polymers via the Z-group approach. The occurrence of side reactions, such as the formation of linear
RAFT agents gave the impression that the attachment of the
RAFT agent via the R-group was prone to too many uncertainties and that the attachment via the Z-group might
solve all the problems. This positive outlook was stimulated by the theoretical mechanism of the process. Star
synthesis via the Z-group approach differs from the Rgroup approach by the mode of attachment of the RAFT
agent to the multifunctional core: the RAFT agent is connected to the core via the Z-group. This has the effect
that after the addition-fragmentation step a linear macroradical has been generated. In contrast to the R-group
approach, for which at this step a linear macro-RAFT agent
was generated, no radical is located on the core and a termination reaction resulting in starstar coupling should
therefore, not be possible. As outlined in Figs. 23 and 26, the
RAFT agent will remain close to the core and the additionfragmentation step will take place in the center of the star
polymer. Polymers generated during the star synthesis via
the Z-group approach should theoretically only contain a
small fraction of linear termination products.
A monomodal molecular weight distribution was
indeed observed after the rst few experiments using
STY and a seven-arm star RAFT agent were completed.
However, after the initial ideal correlation between conversion and molecular weight, the star polymers seem to
have stopped growing [369]. The experimental molecular
weight deviates more and more from the theoretical value.
Cleavage of the arms from the core conrms these initial
ndings showing that the growth of each polymer arm is
slowing down with conversion. This delay in growth has
been explained by the shielding effect of the polymer arms,

75

which prevents the diffusion of the macro-radical close the


core where the RAFT agent is located. The macro-radicals
have therefore only one option, which is to terminate
bimolecularly (Fig. 27).
In fact, many examples often describe the same
deviation between measured molecular weight values (disregarding the fact that some SEC systems do not provide
absolute molecular weight values) and the theoretical
molecular weight for the star polymers synthesised in this
manner. Further indication that a shielding effect may prevent efcient chain transfer was the observation that this
behavior was mainly observed at high conversions and low
RAFT agent concentrations, two parameters that contribute
to the length of the polymer arms. Often this deviation
was accompanied by low-molecular weight tailing, which
could be the result of increased occurrences of termination products. In addition, it seems that star RAFT agents
with a high congestion of RAFT agents are more prone to
these unwanted termination reactions, i.e., the RAFT agents
composed with more arms [370]. It is therefore, not surprising that most star polymers reported in the literature
have four or six arms (Table 6). Star polymers with a greater
number of arms have been reported, but the length of each
arm was frequently kept low to assure the formation of a
well-dened star polymer without too many termination
products being present [371]. Also the correlation between
side reactions and type of monomer is remarkable. STY
has often a very pronounced effect while other monomers,
such as VAc, NIPAAm and acrylates seem to result in better
dened polymers with less tailing and better correlation
between theoretical and experimental molecular weights.
Also, high temperature [369] and high pressure [372] were
found to reduce the side reactions.
Vana et al. have made a range of excellent contributions
in recent years to help understand the shielding effect. They
concluded that it is on occasion not the shielding effect
that contributes to a broad molecular weight distribution,
but common radical side reactions or even an ill-planned
experiment in terms of the choice of RAFT agent. In
their experiments using different acrylates they obtained
well-controlled systems with narrow molecular weight
distributions. With proceeding reactions, however, high
molecular weight products emerged, which are more typical for the R-group approach than the Z-group approach.
Detailed studies revealed that the observed starstar coupling was caused by intermolecular chain transfer to the
polymer. Kinetic simulations could indeed correlate the
amount of starstar coupling to the rate coefcient of intermolecular transfer of the radical of several acrylates to the
polymer [373]. Vana and co-workers also highlighted the
importance of a well-planned RAFT experiment with the
optimum choice of RAFT agent structure for the polymer. A
RAFT agent with insufcient ability to fragment may still
result in reasonable distributions when preparing linear
polymers. In the case of star polymer synthesis, it may lead
to the formation of fewer arms than expected. NMR experiments revealed that a benzyl leaving group resulted in the
delayed growth of arms, while a ethylphenyl leaving group
with its more efcient addition-fragmentation rate lead to
the initiation of the growth of all arms [374]. An elegant
way to determine the number of growing arms during the

76

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

I.

Initiator

2I

II.

P1

+ M

III. RAFT process


R
R
S S
S
S

S
S

S
S

Z
S

S
R

R
R

+ Pn
R

Pm
R

S
S

Z
S

S
R

S Pn
R
S
S
S

S
S

S Pn
S
S

Z
S

R
S

S
R

Pm

+ M
R

R
S

R
S

S
S

S
R

S
S

Z
S

Pn

S
S

S
S
S

Z
S

R
S

S
R

Pn

Pm

targeted product

IV. Termination reactions


Pn + Pm

Dn+m
Fig. 26. Schematic drawing of the synthesis of star polymers via Z-group approach.

R
S

S
S
R

Fig. 27. Schematic drawing of the hindered accessibility of the RAFT group during the synthesis of star polymers using the Z-group approach caused by
the shielding effect of the growing polymer arms.
[369] (Copyright, American Chemical Society, 2007).

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

77

Table 6
Star polymers prepared via RAFT process using Z-group approach (N = number of arms).
N

Type of core

Thiourethaneisocyanurate

RAFT group

Arms

Polymerization
solvent

T ( C)

Reference

PS

Bulk

60

[386]

PVAc

Bulk

60

[349]

PS

Bulk

60

[379]

PS
BA
PAGA
PBA
PS

Bulk
Bulk
Water
Bulk
Bulk

60
60
60
60
80

[387]
[387]
[384]
[375]
[372]

VAc

Bulk

60

[388]

PS

Dioxane

75

[382]

PNIPAAm

Dioxane

60

1,1,1-Tris(hydroxy
methyl)ethane

1,1,1-Tris(hydroxy
methyl)ethane

S
O

1,1,1-Tris(hydroxy
methyl)ethane

S
S

1,1,1-Tris(hydroxy
methyl)ethane

1,1,1-Tris(hydroxy
methyl)ethane

PS

Bulk

80

[372]

1,3,5-Triazine

PS

Bulk

115

[389]

PS-b-PNIPAAm

THF

70

VAc

Bulk

60

Pentaerythritol

90

VPr

[390]

Pentaerythritol

PS

Bulk

110

[353]

PMA
PtBA
PS
PNIPAAM
P(l-Phe-OMe)
PBA
PS

Bulk
Toluene
Toluene
DMF
Dioxane
Bulk
Bulk

60
60
60
60
60
60
80

[353]
[391]
[391]
[392]
[383]
[375]
[372]

VAc

Bulk

60

[349]

PNVC

Dioxane

60

[393]

S
O

Pentaerythritol

S
S

Pentaerythritol

78

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Table 6 (Continued)
N

Type of core

RAFT group

Arms

Polymerization
solvent

T ( C)

Reference

PVAc

Bulk

60

[388]

PNVC

Dioxane

60

[352]

S
O

Pentaerythritol

S
S

Pentaerythritol

PNVC

Dioxane

60

[352]

Pentaerythritol

STY

Bulk

80

[372]

Polypseudorotaxanes

PNIPAAm

DMF

60

[385]

BISTRIS-PCL-b-PLA

PDMAEMA

Dioxane

80

[26]

Dendrimer

PS

Bulk

60

[379]

PS
BA

Bulk

60
60

[387]
[387]

P(l-Phe-OMe)

Dioxane

60

[383]

PS
PS

Bulk
Bulk

80
80

[374]
[372]

PBA

Bulk

60

[375]

PMA
PBA
PDA

Bulk
Bulk
Bulk

60
60
60

[373]
[373]
[373]

PS

Bulk

80

[374]

PS

Bulk

80

[372]

PS

Dioxane

75

[381]

PPEGA
PSPPEGA

Dioxane
Dioxane

70
70

PS

Bulk

60

[369]

PS
PS
PEA
PAGA
PHEA

Bulk
Bulk
Bulk
Water
DMSO

100
120
60
65
60

[369]
[369]
[369]
[173]
[173]

Dipentaerythritol

Dipentaerythritol

Dipentaerythritol

Dendrimer

-Cyclodextrin

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

79

Table 6 (Continued)
N

Type of core

12

Hyperbranched
polyester

12

Dendrimer

RAFT group

Arms

Polymerization
solvent

T ( C)

Reference

STY

Bulk

60

[378]

STY

Bulk

110

[394]

PS

Bulk

60

[379]

PBA

Bulk

60

[387]

NIPAAm

Dioxane

65

[395]

S
O
S

12

17

Dendrimer

Hyperbranched
polyglycerol

DMAEA

70

17

Hyperbranched
polyglycerol

EA

Bulk

80

[396]

16/65

Hyperbranched
polyglycerol

STY

Bulk

120

[370]

60/110

Hyperbranched with
PS arms

PBA

Toluene

80

[371]

polymerization is the addition of linear RAFT agent. Assuming an efcient chain-transfer between the macro-radical
and the linear macro-RAFT agent, the molecular weight
was a direct indication of the molecular weight of each
arm and, in return, the number of arms [372,375]. Despite
optimization of all the parameters, some tailing could not
be eliminated and the authors concluded that this must
be solely due to the shielding effect, which hinders the
chain transfer close to the core. Monte Carlo simulations
were used, conrming the presence of the shielding effect,
which becomes more pronounced with larger, or longer
polymer arms [376,377]. The authors also predicted that a
star RAFT agent that has the RAFT groups located a greater
distance from the core may witness less unwanted termination. Indeed, a hyperbranched core [378] with the same
number of arms as a well-dened dendritic core [379] did
prevent further growth of the arm after a monomer conversion of 20% while the dendritic core allowed the controlled
growth of the star polymer to higher conversions. Systems,
such as the star polymer which has been prepared by the
initial ROP followed by the attachment of a RAFT agent on
each PLA arm [26], should then not be affected by shieldingeffects. Shielding effects should therefore, be inuenced by
parameters that might determine chain mobility such as
the solvent present in a reaction [380].
In addition to advancements in terms of understanding
the mechanics involved when synthesizing star polymers,
there has been a clear push to utilize star polymers in var-

ious applications. Star polymers with a degradable core


[381,382] or other degradable parts [26] have received a
lot of attention, as have star polymers which are based on
peptides [383] or carbohydrates [173,384] or star polymers
with supramolecular features [385].
There are currently no guidelines to show that one of the
two approaches, R-group or Z-group, is superior. A direct
comparison of both approaches using 4-arm RAFT agents
may indicate that the R-group approach could be slightly
better, in terms of achieving the desired stars with limited
termination products, although there is not enough data to
fully support this statement [349,352]. In both cases, termination reactions can be responsible for the broadening
of the molecular weight distribution. It is therefore even
more important than in the synthesis of linear polymer to
adjust the radical concentrations to sensible amount since
the fraction of termination products are directly related to
the radical ux. In some cases, it is advisable to correct the
theoretical molecular weight taking the amount of radicals
formed into calculation:
Mntheo =

[M] conversion Mmonomer


+ MRAFT agent
[RAFT] + [I]df (1 ekd t )

with [M], [I] and [RAFT] the initial monomer, initiator and
RAFT agent concentration, respectively, d the number of
chain generated during termination process, f the initiator
efciency, kd the initiator decomposition rate coefcient
and Mmonomer and MRAFT agent are the molecular weights of

80

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

monomer and RAFT agent. The radical ux always needs to


be seen in comparison with the RAFT agent concentration.
High RAFT agent concentrations, especially when the synthesis of short arms has been targeted, always lead to star
polymers with fewer side products. RAFT polymerization
falters, it seems, when star polymers with a large number of arms are targeted. It is therefore, not surprising that
the list of successful synthesis procedures is largely limited to mainly star polymers with fewer than 10 arms, with
four arm stars being the most popular structure. While the
rst star polymers via RAFT polymerization were prepared
from STY, a trend has emerged in recent years, that moves
towards faster propagating monomers, which seem to be
less prone to side reactions, although acrylates are known
to undergo a noticeable fraction of chain transfer to polymer, which can potentially broaden the molecular weight
distribution.
3.1.1.3. Conclusions to 3.1.1. Outlined in detail above were
the mechanisms and the subsequent implications of the
R-group and Z-group approach. Both strategies are prone
to side reactions, which can only be minimized but
not suppressed. It seems therefore, that it is very difcult to generate well-dened star polymers. The R-group
approach is occasionally a slightly better choice although
this depends on the choice of monomer. It seems that
fast propagating monomers such as vinyl acetate or some
acrylates allow better star design. In contrast, stars with
substantial number of arms or made from slow propagating monomers mostly lead to broad molecular weight
distributions and the reader should consider other synthesis strategies. It is therefore not surprising that the interest
in star polymers via core-rst technique has been declining
in the last few years. Opportunities in this area are certainly
in the synthesis of star polymers from monomers that can
only be polymerized with RAFT polymerization.
3.1.2. Star polymers via arm-rst strategy
Star synthesis via arm-rst strategy utilizes functional
linear polymers, which are connected to one another at a
central point, in a subsequent step. The two most common
approaches employ either a multifunctional core, which
reacts with the functional group on the end of the polymer chains, or the further addition of monomer with a
functionality higher than two, a cross-linker.
3.1.2.1. Radical approach: from star polymers to cross-linked
micelles. The rst report on star polymers via the arm-rst
methodology employed a polystyrene macro-RAFT agent,
which was reactivated using divinyl benzene in toluene
[397]. This led to the formation of star-shaped structures,
or microgels, with a branch length determined by the size
of the macro-RAFT agent (Figs. 28a and 29).
The molecular weight typically increased with increasing cross-linker consumption, but although modications
to the reaction conditions were implemented, the molecular weight distribution was found to be broad and often
multimodal. The concentration of DVB and reaction time
had to be carefully adjusted to avoid the formation of a
broad range of PS stars with varying number of branches
[397399]. Recently, PNIPAAm stars were prepared using

this approach with either DVB or EGDMA as the cross-linker


[400]. The reaction with EGDMA led to a large fraction of
uncross-linked PNIPAAm macro-RAFT agent, which shows
that considerations regarding the stability of the second
block, here the cross-linking block, are as valid as they are
in the synthesis of block copolymers. Cross-linking with
DVB was found to be much more successful due to easier
transition from the acrylamidyl radical to the styryl radical. An elegant pathway to introduce further functionalities
is the use of cross-linker with additional reactive groups.
The cross-linking of a PS macro-RAFT agent with 6,6 (ethane-1,2-diylbis(oxy))bis(3-vinylbenzaldehyde) led to
star polymers with an abundance of aldehyde groups in the
core, which were then used for further click reactions after
the polymer was puried to remove unreacted PS macroRAFT agent [401,402]. In addition, degradable cross-linkers
were employed, which allow the degradation of the star
polymers into single polymer chains [403]. However, in all
these approaches conditions needed to be carefully netuned to avoid the formation of broad molecular weight
distributions. The difculty lies in controlling how many
macro-RAFT agents are incorporated into one star polymer. Often unreacted macro-RAFT agent is left behind and
cannot reach the already crowded core of the star.
A smart way to improve the molecular weight distribution is by carefully choosing the solvent. The
polymerization is carried out in a solvent suitable for the
type of macro-RAFT agent being used. In a subsequent step,
cross-linker is mixed with a monomer whose polymer is
insoluble in the chosen solvent. As the reaction progresses
the second block, which consists of cross-linker and comonomer, becomes insoluble, thus a self-assembly process
takes place (Fig. 28b). This self-organization leads to the
assembly of star-like micelles, which are cross-linked into
star polymers once the pendant vinyl groups start taking
place in the polymerization process. For example, a PEO
based poly-RAFT agent was employed to generate a microgel with PEO branches and a cross-linked STY/DVB core.
When ethanol/THF (5:1, v/v) a good solvent for PEO,
but a non-solvent for styrene and divinyl benzene was
utilized, self-assembly facilitated the formation of welldened star-like structures (Fig. 30) [404]. This approach
also provided a suitable pathway to PS stars with narrow molecular weight distributions by cross-linking with
a mixture of cross-linker and AA in benzene [405] or with
a mixture of cross-linker and 4VP in cyclohexane [406].
PNIPAAm stars were also prepared using acrylic acid to
achieve self-assembly prior to the full cross-linking in the
center [407]. This approach was later utilized to generate star polymers with tetraaniline end groups [408]. Most
cases reported in the literature provide narrow molecular
weight distributions as evidence for the superiority of this
approach over the pathway displayed in Fig. 30. Employing
a RAFT agent that has been functionalized with the R-group
has the added benet in that nanoparticles with a reactive
surfaces can be prepared. An example is the azide containing RAFT agent that led to reactive PNIPAAm star polymers
with a styrene/DVB core, which was used for further reactions with biotin [409].
The systems described above use a homogenous reaction mixture and only the proceeding polymerizations

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

81

Fig. 28. Schematic approach to star polymers; (a) macroRAFT and crosslinker are soluble in solvent; (b) macroRAFT is soluble in solvent, but the polymer
of crosslinker and co-monomer are incompatible with solvent causing preassembly into star-shaped structure; (c) pre-assembly prior core-cross-linking
using an amphiphilic block copolymer and subsequent core-crosslinking of star-like micelle.

lead to amphiphilic structures. This approach has been


extended in recent year to heterogeneous systems. An oil in
water emulsion was created using a water soluble macroRAFT agent and oil-droplets consisting of STY and crosslinker. The key to success with this approach was however,
the surface activity of the macro-RAFT agent. A dodecyl
group in the Z-group of the RAFT agent provided enough

crosslinker

amphiphilicity in the macro-RAFT agent (or RAFTstab) to


achieve pre-assembly of the water-soluble block around
the oil-droplets. The PEO RAFTstab [34] or the glycopolymer
RAFTstab [410] were then employed in a one-step ab initio
cross-linking emulsion polymerization of STY with N,N methylene bisacrylamide [34] or with degradable bis(2acryloyloxyethyl) disulde cross-linker [410], respectively.

S
n+1 m

1.2
8 hours
16 hours
24 hours
36 hours
48 hours

1.0

0.8

n+1

S
m

R
X
X
X
X

n+1

S
m

n+1

S
m

S
R

R X

0.6

X R

0.4

X X X X

X X X X

S
Z

X
X
X
X
R

0.2
0.0

-1

log (M/g mol )

Fig. 29. Synthesis of polystyrene star polymers via arm-rst approach and molecular weight distribution after different polymerization times.
[397] (Copyright, Royal Society of Chemistry, 2003).

82

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

R
X
O
O

nO

CN
S

O
S

NC

nO

CN

S
S

soluble in ethanol/THF
soluble in solvent

insoluble in solvent

X
X

X X X X

!
X

X R

X X X X

X
X
X
X
R

Fig. 30. Synthesis of well-dened star polymers via arm-rst strategy facilitated by suitable solvent choice.
[404] (Copyright, John Wiley & Sons, 2006).

A common feature for all the approaches described


so far, is that the star has only been formed after the
polymerization has started. A further development is the
self-assembly of block copolymers into star-like micelles,
followed by crosslinking via chain extension with divinyl
compounds (Fig. 28c). The amphiphilic block copolymer
is self-assembled typically in aqueous solution, with the
cross-linker being now safely encapsulated in the core of
the micelle as an oil-droplet. The size of the star polymer
will then be determined by the aggregation number of
the self-assembled block copolymers. The resulting star
polymers will have a block structure in each arm. The
transition between star polymer and core-cross-linked
micelle therefore becomes indistinguishable. Core-crosslinked star micelles were prepared using PEO-b-PS and
DVB [34], PNIPAAm-b-PS and BIS [411], POEGMA-b-PS
and DVB [163], poly(N-acryloyl glucose)-b-PNIPAAm
and hexan-1,6-diol diacrylate [173], poly(N-acryloyl
glucose)-b-PNIPAAm and the acid labile 3,9-divinyl2,4,8,10-tetraoxaspiro[5.5]-undecane [47]. The radical
initiator was generally water soluble since the attempt
to use oil-soluble initiator resulted only in low monomer
conversion probably because of the conned space inside
the micelle leading to increased termination reactions
[163]. The rate of polymerization with the cross-linker
was found to be highly dependent on the type of core.
The polarity of the core was systematically altered by
employing various feed ratios between styrene and the
reasonably hydrophilic 5 -O-methacryloyluridine. The
more hydrophobic the core, the slower was the crosslinking process. The origin of this effect could not be isolated,
but possible reason was the radical concentration, which
can be signicantly affected in a conned space [412].
The aggregation number of the star-like micelle prior to
crosslinking was maintained in the early stages of the
crosslinking reaction or at low cross-linker concentrations.
Increased crosslinking has been shown to yield bigger
nanogels (the nanogels increasing in size as the degree of
crosslinking rises) [413]. The opposite, the contraction of
the micelles upon crosslinking, has also been reported [47].
The cross-linking in these o/w emulsions was found
to be highly successful although the resulting products
could usually not be investigated using SEC and due to
the size only hydrodynamic diameters were given. This
suggests that these core-cross-linked star micelles are not
star polymers in a traditional sense but rather cross-linked
micelles. Replacing water by a selective organic solvent

such as ethanol was observed to result in similar structures


although the solubility of the cross-linker in the continuous phase as well as the core of the micelles seemed to have
an effect on the product with only a few block copolymers
being cross-linked [414].
3.1.2.2. Star polymers by a combination of the arm-rst strategy and ring-opening polymerization. Very recently, a star
polymer was created by crosslinking the arms via ROP.
The DMAEMA arms were generated with the help of a
hydroxyl functionalized RAFT agent. Subsequently, this
polymer was employed for the ROP copolymerization of
-CL and branching agent 4,4-bioxepanyl-7,7-dione (BOD)
[360].
3.1.2.3. Star polymers by a combination of the arm-rst strategy and click Chemistry. The rise of click chemistry has
affected the synthesis of star polymers only to a modest
extent. The popular Cu(I) catalyzed azide alkyne Huisgen
cycloaddition has not been applied excessively to generate new star architectures. Azide functionalized cyclic
octapeptides were converted into four-arms star polymers
by clicking polymers (prepared by RAFT polymerization)
via the Huisgen 1,3-dipolar cycloaddition reaction. Due to
the high graft density, the efciency of the click chemistry
conjugation reaction was found to be highly dependent on
the size of the polymer [415]. A three- and four-arm PS star
polymer was created by clicking PS-N3 (Mn = 3000 g mol1 ),
which was synthesized using an azide-functionalized RAFT
agent, to a trialkyne coupling reaction [416]. More convenient than having to synthesize a azide containing RAFT
agent is the direct involvement of the thiocarbonylthio
group of the RAFT agent in a hetero-DielsAlder (HDA)
reaction with dienes. A PS macro-RAFT agent with a molecular weight of 3500 g mol1 was directly clicked onto a core
with two to four diene functionalities [339]. However, the
choice of RAFT agents is limited and an electron withdrawing Z-group such as in pyridyl- or diethyoxy phosphoryl
are prerequisite for an efcient click reaction. Both reactions, Cu(I) catalyzed azide alkyne Huisgen cycloaddition
and the hetero-DielsAlder (HDA)-RAFT concept were then
combined to create three-arm stars with PS-PCL block
structures in each arm [257]. Further extension to attempt
the synthesis of 12-arm stars with PiBor-b-PS arms reveals
an average number of arms per star of 9.2 [343].
The masked thiol of every RAFT polymer, which can simply be obtained via aminolysis of the thiocarbonylthio end

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

83

Fig. 31. Synthesis of seven-arm PVP star with lysozyme core.


[420] (Copyright, Wiley-VCH, 2008).

group, can undergo an efcient reaction with alkenes via


the thiol-ene click reaction. The reaction was found to be
complete within a few minutes and well-dened three-arm
star polymers were obtained, subject to the presence of an
effective catalyst [417]. Since free thiols are prone to disulde formation, the RAFT end group can also be converted
into a pyridyl disulde functionality, which protects the
thiol group from further oxidation [305]. Instead of reacting these protected thiols with alkenes, these functional
groups can also be used for conjugation to thiols creating
disulde groups as demonstrated in a three-arm star polymer with degradable disulde bridges between the arm
and core [382].
The approaches described in the literature combining
click and RAFT polymerization focus at the moment only
on star polymers with a limited number of arms while the
molecular weight of the arms barely exceed 5000 g mol1 .
3.1.2.4. Star Polymers by a combination of RAFT polymers
and proteins. Although usually discussed under the term
polymerprotein conjugates, some of the created structures can well be considered as star polymers. Proteins
carry a precise number of amine or thiol groups that are
accessible for functionalization with polymers. For example, lyzosyme, which has up to seven amine functionalities
can be employed as a reactive core. A seven-arm star with
PVP arms was obtained by reacting PVP, which was prepared using a N-succinimidyl functional RAFT agent, to
lysozyme (Fig. 31). It is not even necessary to synthesize a special RAFT agent to achieve the same outcome.
A PVP polymer prepared with a conventional xanthate
RAFT agent can be converted into a hydroxy functionalized polymer when left standing in water, which, over time
and under heat, oxidizes to aldehyde units. The aldehyde
functionalized PVP polymers undergo facile bioconjugation
with the amine moieties found in proteins [307].
While thiols and amines are readily available in many
proteins and some peptides for immediate conjugation
with synthetic polymers, other conjugation techniques
require the pre-functionalization of the biomolecule. For
example, a Boc-protected aminooxy end-functionalized
PNIPAAm was synthesized via RAFT polymerization. At the
same time, BSA was modied with levulinic acid using
its 10 accessible amine groups to create a reactive ketone
functionality on the protein [418]. The Cu(I) catalyzed

azide-alkyne Huisgen cycloaddition requires the modication of proteins in order to introduce alkyne or azides
moieties. BSA has therefore been modied with three
alkyne moieties, which were then linked with PNIPAAm,
which was obtained by polymerization in the presence of
an azide containing RAFT agent [419].
In contrast to star polymer synthesis via click chemistry as described in the section above, the molecular
weight of the polymers that were clicked or reacted
to the core by other efcient synthetic approaches were
usually much higher. For example the PVP arms, which
were reacted with lysozyme, had molecular weights up
to 33,000 g mol1 leading to seven-arms star polymers
with substantial molecular weights [420]. The difference
between these approaches is the spacing between the two
functional groups.
3.1.2.5. Supramolecular star polymers. The interest in noncovalent bonds to create complex molecules has been a
popular topic for many years now for the synthesis of star
polymers. RAFT agents with bypyridyl functionalities were
used for the polymerization of PNIPAAm and PS and upon
mixing the polymers with ruthenium ions, star-shaped
metallopolymers were created with a ruthenium core and
PNIPAAm and PS arms and a combination of both, respectively.
Hetero-complementary H-Bonding RAFT agents, one
with thymine and one with diaminopyridine, were
employed to generate supramolecular PVAc 3-arm stars
(Fig. 32) [421]. Interestingly this supramolecular approach
was sufciently powerful to create a star polymer from
polymers with substantial molecular weights of 6000 and
20,000 g mol1 . Although ionic bonding between a charged
RAFT agent and an oppositely charged core should t into
this category, it has not been utilized yet using the arm rst
strategy, but only the core-rst strategy [368] and as a pathway to introduce an building block to generate miktoarm
stars [422].
3.1.2.6. Conclusion to 3.1.2. The synthesis of star polymers
via arm-rst strategies using radical crosslinking strategies has seen increased activity over the last few years.
The versatility of this technique and the simplicity from
a mechanistic point of view saw a shift in favor from the
core-rst to the arm-rst strategy. Although experimen-

84

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 32. Synthesis of heterocomplementary H-bonding xanthate RAFT agent, followed by polymerization of VAc and the supramolecular assembly of the
blocks to a three-arm star polymer.
[421] (Copyright, Wiley-VCH, 2009).

tal conditions need to be ne-tuned for every approach


to avoid the formation of products with broad molecular weight distributions and to avoid excessive amount of
unreacted polymers, this strategy allows the generation
of stars with signicantly more arms. This pathway has
been applied successfully for various star polymers. However, the number of arms is in most cases is unknown. This
strategy holds huge potential, even if preliminary work is
required for each step. So far, the limits of this approach
are not yet known and questions regarding the maximum
length and maximum number of arms that might be possible are unknown.
Other arm-rst strategies such as the formation of
supramolecular stars or the combination with other techniques such as the outlined example with ROP have just
started to emerge and it is not known yet what the potentials are of such strategies. Some examples on using click
chemistry have emerged, but the limited amount of reports
indicates the difculties of such a pathway. In fact, all the
problems outlined under click and block copolymers are
even more magnied during the star synthesis. The reaction requires entropically unfavorable movements of the
polymer end groups to the small center for the star limiting
the length and number of arms.
3.1.3. Miktoarm star polymers
Star polymers with mixed arms are often referred to as
Miktoarm star polymers and are created via the combination of various polymerization techniques. Star polymers,
such as the A2 B2 polymer, were created by attaching two

RAFT agents to a tetrafunctional core while the remaining two functional groups were used for single-electron
transfer-mediated living radical polymerization (SET-LRP)
[423] or for anionic polymerizations.
Three arm-star polymers were prepared based on
ABC triblock copolymers, in which the second block, B,
consisted of only one reactive repeating unit. Monomers
which cannot undergo homopolymerization such as maleic
anhydride [424] or hydroxyethylene cinnamate [425] were
employed to achieve An B1 Cm structures. The reactive B
block underwent reaction with end functionalized polymers leading to three-arm star polymers [424,425] or can
be used directly as the initiator for the polymerization of
the third arm [28].
Click chemistry was soon utilized to extend the scope
of this approach. Due to the orthogonality of click chemistry, a series of different arms can be grown from the core
without interfering with the polymerization, as shown in
the synthesis of (PS)(PCL)(PMA)(PEO) ABCD 4-miktoarm
star polymer [426] or (PCL)2 (PBA) A2 B three arms stars
[327]. Other type of click reactions employed includes the
aldehydeaminooxy click reaction, which has been used to
prepare An Bn star polymers [401,402].
A very versatile tool to generate miktoarm star polymers
is supramolecular chemistry. Simply by mixing different
arms, a whole library of different types of star polymers
can be created. Non-covalent ligandmetal complexation
between bypyridyl terminated polymers and ruthenium
complex created A2 B type miktoarm stars [427]. An array
of A2 B miktoarm star polymers, with molecular weights up

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

to 20,000 g mol1 , were obtained using heterocomplementary H-bonding RAFT agents [428].
3.1.3.1. Conclusion to 3.1.3. Since the synthesis of
miktoarm-arm star polymers requires the combination of
several techniques, the impact of RAFT polymerization is
not immediately evident although it certainly expanded
the scope of synthetic approaches available to researchers.
3.2. Graft and comb polymers
Graft and comb polymers are closely related to each
other. They both consist of a backbone with branches
attached [11]. Comb polymers have, however, higher
branching density and the chemistry of the backbone
should be similar to that of the branch. The synthesis
of both architectures via RAFT polymerization is equivalent and in the following chapter we will only use the
term graft polymers, not only because most polymers
described in the literature are indeed graft polymers, but
also for convenience. Graft polymers polymers with a
linear backbone and a number of branches along this
chain can be prepared in a similar fashion to star polymers using the attachment of RAFT agents along a linear
polymer chain the backbone. The branches grow from
the RAFT agent anchor points in a controlled fashion.
Branches were also prepared using other polymerization
techniques by combing the RAFT process with a non-RAFT
technique. A one-step approach is the random copolymerization of a macro-monomer with another monomer
forming the branch structure in situ with the growing backbone. In recent years, click chemistry has been utilized
more and more in order to create well-dened graft polymers (Fig. 33).
3.2.1. Graft polymers via the attachment of a RAFT agent
to the backbone
Similar to the synthesis of star polymers, RAFT polymerization is unique regarding the attachment of the chain
transfer agent, which can be carried out via the R-group and
Z-group. Everything discussed earlier regarding the mechanism of the two approaches, advantages and disadvantage,
are valid. Moreover, the presence of usually signicantly
more RAFT agent on one backbone can magnify problems,
such as the increased occurrence of side reactions.
3.2.1.1. Graft polymers via R-group approach. The rst graft
polymer described via RAFT polymerization, in this case
essentially a comb polymer, was based on poly(vinylbenzyl
chloride), which was modied with RAFT functionalities
(Fig. 34) [429]. Similar to star polymers a fraction of linear polymers with RAFT endfunctionalities were observed,
appearing as shoulders in the molecular weight distribution. The event is however, overshadowed by signicant
combcomb termination events, which at high conversions
even led to insoluble network polymers.
These experimental results are in agreement with theoretical predications outlined in the star polymer synthesis
section. The typically higher number of branches in a graft
polymer compared to a star polymer magnies the termi-

85

nation reactions. The RAFT polymerization of STY, a slowly


propagating monomer, was even considered difcult in the
star synthesis and it is even more prone to side reactions
when attempting to prepare graft polymers. In theory, it
should be easier to obtain better dened graft polymers
using fast propagating monomers such as VAc. After all, the
synthesis of PVAc stars with four arms seemed effortless
[349]. Reactive backbones with 20, 100 and 200 dithioxanthate groups were employed for the synthesis of PVAc
graft polymers. As expected, the amount of combcomb
termination increased with increasing number of branches,
but also the amount of linear macro-RAFT agents increased
substantially until the point where the distribution was
dominated by these side products. The vast amount of side
products is now in contradiction to the theory, leading to
the conclusion that chain dynamics and the high concentration of RAFT agents along a backbone introduces additional
obstacles [430].
After these initial results, many lessons have been
learned in recent years and the problems outlined above
were addressed appropriately.
Poly(butyl methacrylate) branches grown from a backbone were observed to lead to better dened products
when keeping the length of the branches small. The
molecular weight distributions were almost monomodal
although it needs to be taken into account that the preferred termination mode of methacrylates is disproportion
and combcomb coupling is naturally absent while there
may still be some dead branches on the polymer [431,432].
The eld of graft polymers via RAFT polymerization
has however been dominated by PNIPAAm branches. The
thermo-responsive character of the polymer in combination with relatively fast propagation made this polymer
interesting from a material perspective but also from a
preparative perspective [433437]. Following the observation that terminations are suppressed at high RAFT agent
concentrations, a range of well-dened PNIPAAm graft
polymers were obtained, all having relatively short PNIPAAm branches (N  100) in common. A range of complex
PNIPAAm graft polymers were obtained by immobilizing
the RAFT agent onto the backbone using Cu(I) click reaction
and then aiming for low monomer to RAFT agent concentration ratios [438]. Using a slightly modied approach,
excess hydroxyl functionalities were created adjacent to
each RAFT agent allowing the immobilization of additional
functionalities at each branching point. Polymerization
of NIPAAm in the presence of high RAFT agent concentrations resulted in well-dened dense graft polymers
with around 30 short PNIPAAm branches [439] or PS-bPNIPAAm branches [440]. The remaining approximately 30
hydroxyl functionalities were modied with pyrene [439]
or PEO [440]. Targeting low molecular weight branches
brought not only success to PNIPAAm graft polymers, but
also to graft polymers with PAA branches [441], with PVAc
branches [442], and, by RAFT polymerization inherently
difcult to synthesize, PS and poly(4-(3-butenyl)styrene)
branches [246,247].
Other pathways to generate graft polymers with small
molecular weight distributions include the reduction of
the radical concentration. Inspired by earlier results on
PVAc graft polymers with broad molecular weight distri-

86

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

R-group approach
S

S S
Z

S S
Z

S S
Z

S
Z
S

S S

S S
Z

S
Z

+ linear polymer with RAFT endgroup + comb-comb termination


Z-group approach

S
S
R

S S
R

S S
R

S S
R

S S

S S

S S

+ linear "dead" polymer


Immobilization of radical initiator on backbone
S

S R
I

S
S

S
Z

S
S R

Macromonomer technique
Z

Grafting onto via click


N
N N

N3
X

S
S

Fig. 33. Synthesis of graft polymers via RAFT.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

87

Fig. 34. Synthetic route to graft polymers (left), and evolution of the molecular weight distribution with time (right) for PS combs (vinylbenzyldithiobenzoate concentration = 55 mol.%; T = 60 C; t = 4, 8, 12, or 16 h; [AIBN] = 1.2 mmol L1 ; benzyl dithiobenzoate moiety concentration = 16.3 mmol L1 ), comb
precursor = 38,600 g mol1 .
[429] (Copyright, John Wiley & Sons, 2002).

butions [430], signicant improvements were achieved by


lowering the radical ux by lowering the reaction temperature. Although the rate of polymerization is now lower, the
reward is PVAc graft polymers with low molecular weight
distributions [443].
Earlier studies have shown that the formation of termination events can be more pronounced than theoretically
expected [430]. One reason could be the high local concentration of RAFT agent on the backbone, while the
surrounding monomer phase is poor in RAFT groups. To
maintain better control, it can be benecial to add sacricial low molecular weight RAFT agent to maintain higher
RAFT agent concentrations. The pathway will lead to more
linear polymer, but also to better dened graft polymers
[436].
It is noticeable that more and more synthesis procedures are tailored towards the nal application of
the polymers. Increasingly popular is the grafting from
polysaccharides [289] such as cellulose [436] and pullulan
(Fig. 35) [437]. Often the R-group approach has been chosen
consciously to generate branches with RAFT end groups.
The type of RAFT groups, or rather the type of Z-group
since this is the determining part of the endfunctionality,
can inuence the LCST of PNIPAAm brushes [434] or the
RAFT groups can be aminolyzed to thiol groups for further
reactions [437,441].

3.2.1.2. Graft polymers via the Z-group approach. The Zgroup approach to graft polymers faces similar difculties
to the star synthesis such as steric shielding leading to
the increased occurrence of termination reactions of two
linear macro radicals. PS branches were grown from cellulose resulting in monomodal distributions. The hydrolysis
of arms however revealed that the growth of each branch
deviates even further from the expected value than during the star synthesis. Some branches already reached a
signicant length, other RAFT agents still remained inactivate [444,445]. Synthesis of graft polymers via Z-group

approach appears to be less popular and only one PNIPAAm


graft polymer prepared from a polycarbonate backbone
was reported [258].
A step forward in understanding the mechanism of the
process was provide in a detailed investigation using a
combination of UV/Vis, HPLC and 2-D chromatography.
Cellulose was modied with xanthates as macro-RAFT
agent for the polymerization with VAc. The presence of terminated polymer next to the PVAc graft polymer could be
visualized [446].
3.2.2. Graft polymers via the attachment of an initiator
to the backbone
Graft polymers have also been obtained by attaching
the initiator to the backbone instead of a RAFT agent. The
length of the grafted chain is then controlled by the added
RAFT agent (Fig. 33). The growth of the branch is subject
to the decomposition rate of the initiator. Potential sideproducts are linear macro-RAFT agents generated from the
leaving group R of the RAFT agent. PEGMA branches have
been generated along a uorinated polyimide [447] and
a poly(vinylidene uoride) backbone [448]. This approach
has been applied early after the discovery of the RAFT process, but has not been further pursued.
3.2.3. Graft polymers using macro-monomers
The use of monomers with long side chains to prepare
graft polymers has frequently been applied: commercially
available PEGMA or PEGMEMA, macro-monomers
with PEO side chains are very popular. The molecular weight of PEGMA/PEGMEMA is typically below
600 g mol1 . The polymerization of such commercial
macro-monomers is now commonplace and references
[105,115,162,163,296,449455] represent only a glimpse
of reports on this very popular class of macro-monomers.
Reports on macro-monomers with longer side chain
or side chains of a different nature are more limited.
PEO based macro-monomers with molecular weights

88

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 35. Grafting of NIPAAm from pullulan via R-group approach (PulSTS: pullulan macroRAFT agent; NgPul: pullulan-graft-PNIPAAm).
[437] (Copyright, American Chemical Society, 2008).

of Mn = 2000 g mol1 were utilized to chain extend a


PS macro-RAFT agent in order to prepare toothbrushlike structures with a PS block forming the handle and
poly(PEO-acrylate) creating the brush [456]. Copolymerization of PDMS based methacrylates (PDMS-MA,
Mn = 2370 g mol1 ) with MMA resulted in graft polymers
with a random branch distributions [457,458]. The reactivity ratios were slightly inuenced by the RAFT process as
well as the reaction temperature [457] probably because
of incompatibility between macro-monomer and macroradical [458]. A methacrylate with a PDMS side chain with
a molecular weight of >4000 g mol1 was copolymerized
with tBMA. The reactivity ratios were determined to be
rtBMA rPDMS-MA 1 [459]. Stimuli-responsive nanostructures were recently prepared from poly(-caprolactone)
methacrylate (Mn = 2370 g mol1 ) copolymerized with
NIPAAm [256] or oligo(2-ethyl-2-oxazoline) methacrylate
(Mn 700 g mol1 ) copolymerized with MAA [460].
3.2.4. Graft polymers via a combination of RAFT and
other polymerization techniques
A substantial body of work over the last few years
deals with the synthesis of graft polymers by combining
RAFT polymerization with other techniques. A commonality between the approaches is the preparation of a reactive
backbone, which is then used to graft polymer chains
via ATRP [249,270,271,273,461465]. RAFT made polymers
with hydroxyl functionalities were frequently utilized as
initiators for ROP. The polymers were prepared from HEMA
[466468] or HEA [469], often copolymerized with other
monomers to control the grafting densities. The hydroxy
groups in the backbone were utilized to initiate the ROP
of -CL [466468] or lactate [469]. A similar approach was
applied to generate poly(tetramethylene oxide) branches
by the ROP of THF, initiated by a well-dened backbone

of randomly copolymerized STY and chloromethyl styrene


[470]. The orthogonality of both polymerization techniques
also allows the simultaneous application of both reactions
demonstrated on the ROP of -CL and the concurrent RAFT
polymerization of HEMA [468].
A very unusual approach to graft polymers is the
direct involvement of the RAFT functionality in a subsequent polymerization procedure. Pyrrolyl-capped PNIPAAm, which was obtained from 1-pyrrolylcarbodithioate,
was oxidized to polypyrrole (Fig. 36) [471].
3.2.5. Graft polymers via click chemistry and other
postfunctionalization techniques
Although the impact of click reaction on material design
is signicant, the inuence on graft polymer design is
rather modest. A reactive vinyl azide monomer, 2-chlorallyl
azide, was copolymerized with MA via RAFT, followed
by the Cu(I) catalyzed Azide-Alkyne Huisgen Cycloaddition (click reaction) with alkyne-functionalized PEG [472].
The opposite approach was carried out by polymerizing
propargyl methacrylate via RAFT polymerization. Azide
terminal PVAc prepared from an azide functional RAFT
agent were clicked onto the backbone forming dense graft
polymers. Full conversion was observed, albeit the grafted
chains were rather short, with a molecular weight of
Mn = 850 g mol1 [80]. Clicking of azide terminal PNIPAAm
onto alkyne functionalized hyaluran led to a thermoresponsive polysaccharide material for tissue engineering.
Click chemistry provided easy access to a broad range of
graft polymers with different grafting densities and different branch lengths in order to identify an ideal candidate
for cell encapsulation [473]. Fibres were prepared by clicking polymers made with an azide containing RAFT agent
onto N-alkyl urea a peptoid sixmer with alkyne functional
groups [474].

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

S
HN

O
S

NH
AgNO3

89

S
n

S
O

HN

Fig. 36. Synthesis of polypyrrole-g-poly(N-isopropylacrylamide).


[471] (Copyright, Royal Society of Chemistry 2011).

Despite the interest in carbohydrates as building blocks,


attempts to functionalize these material by grafting RAFT
made polymers are rare. Only starch has been functionalized with azide functionalities, which were then clicked to
PVAc, prepared using a RAFT agent with carries a ethynyl
group [475].
The hetero-DielsAlder RAFT click concept, the efcient
cycloaddition between dienes and certain RAFT agents
with electron-withdrawing Z-groups, was shown to be an
efcient, metal-free alternative. The diene functionality
could be introduced to the backbone via postmodication
[84] or by direct RAFT polymerization of a HDA reactive
monomer trans, trans-hexa-2,4-dienylacrylate [338]. The
grafting yield varied from 75 to 100% depending on the type
and molecular weight of the monomer [338].
Isocyanate chemistry can be considered a type of
click chemistry due to the high yield of the reaction
with amine and hydroxyl functional groups. This reactive
chemistry was recently employed not only to crosslink
micelles [162,453,476], but also to create PEG graft polymers [477,478].
Beyond click chemistry, traditional postfunctionalization techniques include the modication of PAA with
amino-terminated PEG [167] or the reaction between
maleic anhydride in the backbone and PEG-OH [479,480]
The latter postmodication approach was employed to prepare a perfect graft polymer with controlled backbone
length, grafting sites, and spacing length. Most grafting
techniques lead to a random distribution of branching sites
along the backbone. To control the distribution, a polymer
consisting of several RAFT agents repeating units was rst
polymerized with STY to target a certain distance between
two RAFT agents and therefore two branching sites. Subsequent reaction with maleic anhydride led to a reactive unit
next to a RAFT agent (branching site), which is separated
from the next RAFT agent and branching site by the STY
chain [479,480].
3.2.6. Conclusions for 3.2
Everything that has been discussed for star polymers
is applicable to the formation of graft polymers. Side
reactions such as coupling and formation of single arms
become prevalent, these reactions broadening the molecular weight distribution. Although the grafting of chains
from the backbone, either via R- or Z-group approach,

is now an established technique, researchers are usually


cautious with the number and length of branches. It is
therefore not surprising that this avenue has not been
developed further and only a few applications have been
described. A pathway that has seen more activity is the
grafting from RAFT-made backbones via other techniques
such as ATRP or ROP. The choice of RAFT polymerization
to generate the reactive backbone was obviously due to
the robustness of the RAFT process in the presence of other
functional groups, such as hydroxyl groups. Click chemistry
has also found entry into the realm of graft polymers. Again,
the molecular weight of the branches was limited and the
grafting of high molecular weight branches usually led to
incomplete reactions.
3.3. Hyperbranched polymers
Although hyperbranched polymers are not well-dened
polymer architectures as such, RAFT polymerization
enabled better control over the distance between branching points and often prevents gelation by controlling the
chain length.
RAFT agents were added to traditional copolymerizations of monomer and cross-linker in order to control the
chain length, thus preventing gelation [481,482], but also
to generate branched polymers with RAFT end groups,
which can be used for further end group modication
[483]. (Fig. 37, top) The type of cross-linker usually ranges
from EGDMA [482,483], N,N -methylenebis(acrylamide)
(BisAM) [481], a degradable cross-linker with disulde
bridges [484] to a cross-linker with two different vinyl
functionalities with different reactivity ratios [485]. Gelation was in all cases signicantly reduced, as demonstrated
with DVB, which could be polymerized up to 68% monomer
conversion before gelation occurs, which is in strong contrast to 15%, which is the threshold in case of free radical
polymerization [486].
A monomer with a pendant RAFT agent (inimer) is a
creative way of preparing hyperbranched polymers. The
RAFT group controls the length of the macro-monomer
while the vinyl end group is responsible for the formation
of branching points. These controlling vinyl agents were
copolymerized with STY [487489], NIPAAm [487,490],
MMA [489], MA [489], 1,2 propandiol-3-methacrylate
[491] and DMAEMA [484], but also densely branched

90

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

S
S

R
S
S

AIBN

S
Z

S R

R
R
S

S
Z

Z
S
Z
S R

S
R

S
R

AIBN

S
R

R
R
S

R
S

SB
BS

BS

SB
S
Z
S

BS
B

Aminloysis

SB

BS

BS
BS

SB

SB
BS

BS

BS
BS
BS

SB
Fig. 37. Synthetic strategies to hyperbranched polymers.

BS

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

S
Z

R
S

91

Fig. 38. Approach to dentritic polymer architectures.

polymers were attained via self-condensing vinyl copolymerization [490] (Fig. 37, middle).
Controlling the distance between two branching points
can introduce some regularity to the otherwise broad
molecular weight distribution of the branched polymer.
Telechelic AB2 -polymers with one functionality at one end
that is capable of reacting with two complementary functionalities on the opposite chain end can be employed in
a self-condensing process. Polymers made via the RAFT
process have already an in-built thiol end group, which is
readily available after aminolysis [492]. This thiol group
can then react with two bromide functionalities in the position [493], a -double pyridyl disulde end-groups
[494] or an -alkyne, which can react with two thiol
functionalities [495]. The latter approach was applied to
block copolymers leading to branched polymers with an
amphiphilic structure between two branching points [496]
(Fig. 37, bottom).
3.3.1. Conclusions to 3.3
The use of RAFT agents in the synthesis of hyperbranched polymers is reasonably new, but it made a
signicant impact. The aim of this approach is not so
much the design of a product with narrow molecular
weight distribution. After all, most hyperbranched polymers described here have high PDIs. It is more the
avoidance of gelation, the control over the end groups on
each branch and the control over the distance between two
branching points that sparked the interest in this area. It
would be desirable in the future to see more investigation into the properties of these materials and their use
in different applications.
3.4. Dendritic polymers
The rst dendritic polymer via RAFT polymerization
was described using poly(benzyl ether) monodendrons of
the second generation ([G-2]) or third generation ([G-3]),
which were modied with a RAFT agent in a R-group
approach (Fig. 38). Subsequent polymerization of NIPAAm
led to thermo-responsive micelles [497]. Using a symmet-

ric trithiocarbonate RAFT agent with two dendritic leaving


groups allows the synthesis of dumbbell-shaped dendriticlinear-dendritic structures, where the distance between
the two dendritic portions is determined by the monomer
conversion in the following RAFT polymerization [498].
Dendritic RAFT agents up to G4 with 16 carbazole groups
in the periphery of the structure were successfully used for
the controlled polymerization of STY and MMA yielding
electroactive polymers [499]. Alternatively, the functionality in the periphery of these dendritic groups could be
introduced after polymerization leading to a range of different dendritic structures ranging from phosphonic acid
groups, phosphine oxide endfunctionalities, carboxylic
acid groups to disulde groups [500]. This approach has
also been applied to generate linear polymers with a
dendritic glycopolymer endfunctionality. The dendritic
structures were in that case built using thiol-yne chemistry
[501]. A third strategy involves the synthesis of a polymer
with a functional end group, which is then conjugated to
the focal point of the dendron, demonstrated using PHPMA
with 2-mercaptothiozalidine end-groups, which was
reacted with a dendritic mannose scaffold (Fig. 38) [502].
3.4.1. Conclusion to 3.4
This constitutes a small niche in RAFT polymerisations.
It is not particularly unique to the RAFT process to generate these structures, but this area could have signicant
impact in material design, especially in the biomedical
area. Each of these three approaches seems to have their
own advantages, but it seems that the synthesis of a dendritic RAFT agent may be less challenging in terms of
analysis. Especially the build-up of dendritic structures
onto the chain end face difculties. End group analysis to conrm each addition step to create the dendritic
functionalities of high molecular weight polymers can be
prone to error.
4. Other complex architectures
A range of other architectures were prepared, often from
a combination of RAFT with other techniques such as ATRP,

92

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Fig. 39. Complex polymer architectures prepared by combination of RAFT with other techniques.

ROP and click chemistry. H-shaped polymers based on PS,


PEO and PLA [503] or based on PS and poly(1,3-dioxepane)
(PDOP) [504] were reported as well as -shaped polymers
[505] (Fig. 39). Tadpole-shaped polymer, linear polymers
with an over-dimensional head group, were designed
either with a ring-shaped polymers as head group [506] or
a polyhedral oligomeric silsesquioxanes (POSS) [507,508]
by the combination of click and RAFT chemistry. The simple ring structure was obtained via combination of RAFT
polymerization with Cu(I) click chemistry [509].
4.1. Conclusions to 4
The last chapter makes it evident that only the creativity of the researcher is the limit in architecture design. The
synthesis of these structures is often an imaginative combination of several techniques. Care needs to be taken to
avoid side reactions, often more than in other techniques.
Although the type of complex architectures seems to be
limitless, it would also be interesting to see some applications for these complex polymers.

ular weight distributions. These side reactions are often


directly related to the radical ux. It is therefore advisable
to keep the amount of radicals produced during the course
of the reaction as small as possible. As a rule of thumb, the
initiator should be one tenth of the RAFT agent concentration although this ratio might vary depending on type
of initiator, type of monomer, reaction temperatures and
other polymerization conditions. Often a fast rate of polymerization, either because of fast propagating monomer
has been used or the monomer concentration is reasonably
high, coincides with a narrow molecular weight distribution assuming signicant amounts of other chain transfer
events are absent. These side reactions make it difcult to
generate structures with more and more arms. While termination reactions during block copolymerization led to
dead polymer that is buried under, or at very best visible
as a tail in the SEC curve, coupling of star or graft polymers
lead to very visible high molecular weight products and
they become more and more pronounced with increasing
number of arms. It is not impossible to generate welldened structure, but the more complex the architecture is,
the more attention must be drawn to the right conditions.

5. Conclusions
5.2. Recent developments
5.1. Experimental advice
What advice should be given for a novice in the area
of RAFT polymerization? RAFT polymerization seems to be
robust in the presence of many functional groups, but at
the same time can degenerate quickly in the presence of
other inuences. Heat, light and peroxides, which are often
present in some solvents, as well as alkaline groups such as
amines, can deplete the RAFT agent. However, this sensitivity of RAFT agents bear at the same time the opportunity to
convert the RAFT groups after the polymerization has been
completed. Considering these inuences, the next important step is to keep the radical concentration as low as
possible. Every mechanism discussed above includes side
reactions. These termination reactions often lead to the loss
of the RAFT groups and ultimately result in broader molec-

Despite certain difculties such as the occurrence of termination reactions, RAFT polymerization was shown to be a
versatile tool to access a range of different complex architectures. Especially the broader range of monomers that
can be polymerized in a controlled manner as well as the
robustness of the process in the presence of a range of functional groups makes the RAFT process unique and advantageous. It might have become clear in each chapter that there
are often signicant challenges to overcome. Although
there are some limitations, the power of RAFT polymerization lies certainly in its robustness. The array of monomers
is endless and some monomers can only be polymerized via
RAFT polymerization in a unique manner. This robustness
also allows the creative combination of RAFT polymerization with other materials and other techniques.

A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38105

Therefore, RAFT polymerization is a powerful way to


obtain a range of structures with control over architecture
as well as molecular weight. These complex polymer
architectures were already successfully employed in a
range of applications to generate novel materials. There is
no doubt that the array of polymer architectures prepared
via RAFT polymerization has increased signicantly over
the last 34 years. Although the introduction of click
chemistry and the use of natural polymers have broadened
the scope, it is the creative combination of many different
polymerization techniques with RAFT polymerization and
the introduction of functional monomers have had the
most impact. The opportunities seem limitless although,
after all, potential side reaction may hamper the process
leading to an array for termination products. Despite
certain problems that researcher needs to overcome, RAFT
polymerization has developed into a sophisticated tool in
polymer architecture design.
5.3. The future
It seems that polymer scientists have now developed
a vast array of potential structures. There are still a few
monomers that have not yet been used to make complex
architectures, but most structures have been covered. It
would now be desirable to see the use of these structures
in advanced applications. The question remains: are there
any advantages in making these structures? We believe yes,
but future efforts need to show that this wonderful tool
can indeed broaden the material scope, and perhaps unique
polymer properties will be discovered. It is probably time
for polymer chemist to team up more with scientist of other
elds to test these structures and discover new and better
applications.
References
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[2] Moad G. The emergence of RAFT polymerization. Aust J Chem
2006;59:6612.
[3] Moad G, Rizzardo E, Thang SH. Living radical polymerization by the
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