Stimuli-responsive amphiphilic (co)polymers via RAFT polymerization
Introduction
Since the advent of polymer science as a discipline, chemists have sought to design and synthesize “smart” macromolecules that respond to external signals such as temperature, pH, electrolytes, light, mechanical stress, etc. Such stimuli-responsive polymers have found a plethora of applications in widely diverse fields including, but not limited to: biomedicine, optics, electronics, diagnostics, and in the formulations of pharmaceuticals and cosmetics. In many cases, synthetic polymers have been constructed to mimic the behavior of an enormously diverse array of biological polymers including proteins, nucleic acids, polysaccharides, and their naturally occurring conjugates.
Prior to the development of controlled radical polymerization (CRP) techniques [1], [2], [3], [4], [5], [6], [7], [8], functional monomer selection, broad polydispersity, and lack of structural and molecular weight control limited synthesis of systems with requisite primary, secondary, and tertiary features for conformational response and assembly featured in stimuli-responsive biomolecules. In this review we focus on developments in the area of stimuli-responsive polymers based on the CRP technique reversible addition–fragmentation chain transfer (RAFT) polymerization. This technique, first reported by the CSIRO group [9], [10] and a French group as MAcromolecular Design via the Interchange of Xanthates (MADIX) [11], [12], has only been in existence for a little over 10 years. In terms of application to all stimuli-responsive systems, and in particular those of biological relevance, RAFT is currently the most versatile of the CRP techniques. It should, however, be noted that the rapid advances in RAFT and aqueous RAFT polymerization technology have been spawned in many cases by predecessor CRP techniques, including stable free radical polymerization (SFRP) [1], [2] and atom transfer radical polymerization (ATRP) [3], [4] as well as classical anionic, ring opening, and group transfer polymerization methods. The powerful synthetic tools developed for RAFT polymerization and subsequent transformations now allow polymerization of highly functional monomers under benign conditions (often in water at ambient temperature without the need of protecting groups) to afford complex, but highly controlled architectures with tailored ranges of response to external stimuli.
The versatility of RAFT polymerization has resulted in rapidly increasing utilization as demonstrated by publications over the last 10 years (Fig. 1). There have been a number of reviews on the RAFT process [5], [6], [13], [14], [15], [16], [17], [18], aqueous RAFT [7], [8], the mechanism of RAFT polymerization [19], RAFT in heterogeneous media [20], [21], and computational studies [22], [23]. Additionally, a book entitled Handbook of RAFT Polymerization containing reviews on all aspects of RAFT technology has recently been published [24].
Our review to follow is organized into sections that first introduce the chain transfer agent (CTA) structures necessary for controlled polymerization and then briefly describe the RAFT mechanism, control of molecular weight, and key issues to successful polymerization in aqueous media. A discussion of those monomers that lead to thermally responsive polymers, pH-responsive copolymers, and polymers responsive to other stimuli follows. In general our discussion of these monomers will not be comprehensive, but rather will present important milestones. For a more detailed discussion of the water-soluble monomers polymerized by RAFT under homogeneous organic and aqueous conditions (including those that are not stimuli-responsive) the reader is directed to our previous review [7]. In the final sections we focus on stimuli-responsive assembly of the block copolymers synthesized via RAFT polymerization and examine the various methods of stabilizing the self-assembled aggregates to prevent dissociation upon removal of external stimuli.
Section snippets
RAFT chain transfer agent structure
The key component in controlled RAFT polymerization (Scheme 1) is the CTA [25], [26]. The CTAs used are thiocrabonylthio compounds and have the general structure RSC(=S)Z. Examples of RAFT agents span all thiocarbonylthio families including dithioesters, xanthates, dithiocarbamates, and trithiocarbonates. Fig. 2 shows generic structures of CTA classes while Fig. 3 illustrates specific examples of CTAs that have been employed in the synthesis of stimuli-responsive polymers. For each monomer to
The RAFT mechanism
Unlike SFRP and ATRP which are based on the reversible deactivation of propagating radical chains, RAFT relies on a series of reversible chain transfer reactions to impart control. Since RAFT is essentially conventional radical polymerization conducted in the presence of a CTA, initiation can be accomplished with traditional initiators such as azo compounds, peroxides, redox initiating systems, photoinitiators, and γ-radiation. Fig. 4 lists some common initiators utilized in RAFT
Molecular weight control by RAFT polymerization
Several conditions must be met in order for a RAFT polymerization to control molecular weight. The two most important criteria are a sufficiently high ratio of CTA to initiator and proper CTA selection for the monomer of choice. According to the RAFT mechanism, there are two potential sources from which polymer chains are derived, initiator fragments and the CTA leaving group (R). As such, the theoretical number-averaged molecular weight (Mn) can be defined as
Considerations for polymerization in aqueous media
While the economic and environmental advantages are obvious, successful RAFT polymerization directly in aqueous media can only be achieved by elimination of competitive reactions during polymerization. First and foremost is the hydrolysis of the thiocarbonylthio moiety of RAFT CTAs. Since CTAs are simply sulfur analogues of esters, it is not surprising that they are susceptible to hydrolysis. Levesque et al. [36] examined the hydrolytic stability of several thiocarbonylthio compounds in mild
Monomers for thermally responsive polymers
Temperature-responsive (co)polymers exhibit a volume phase transition at a critical temperature, which causes a sudden change in the solvation state. Such (co)polymers, which become insoluble upon heating, have a lower critical solution temperature (LCST). Conversely, systems which become soluble upon heating have an upper critical solution temperature (UCST). Thermodynamically, the LCST and UCST behavior of polymers can be explained as a balance between the entropic effects of the dissolution
Assembly induced in aqueous media
Amphiphilic block copolymers are comprised of substituent blocks with varying affinities for a solvent which can induce microphase separation. It is now well established that assembly of polymeric amphiphiles occurs in dilute solutions in a selective solvent above a concentration called the critical micelle concentration (CMC), resembling the behavior of low molecular weight surfactants. Also, the morphology of the resulting assemblies can be influenced by a number of factors including the
Shell/core cross-linked micelles
It is well known that block copolymer assemblies can be used as drug delivery vehicles. However, certain limitations of self-assembled nanostructures preclude the realization of their use in practical applications. One major limitation is the dilution-induced dissociation of the amphiphilic nanostructure into unimers after administration in vivo. When the copolymer concentration falls below the critical micelle concentration (CMC), as it does when administered to a patient, the nanostructure
Summary
Since the initial disclosure over a decade ago, reversible addition fragmentation chain transfer polymerization (RAFT) has proven to be an important tool for the synthesis of stimuli-responsive (co)polymers. In this article we have described the advances in polymerizing water-soluble monomers to yield (co)polymers which undergo reversible assembly in response to changes in temperature, pH, or other external stimuli. The versatility of RAFT has allowed the synthesis of such stimuli-responsive
Added after submission
As proof of the ever growing interest in utilizing RAFT to synthesize stimuli-responsive (co)polymers, a number of related reports have been published since our initial manuscript submission. Several reports have been published detailing the synthesis of temperature-, pH-, and salt-responsive block copolymers capable of self-assembly into spherical micelles [203], [204], [205], [206], [207], [208], [209], [210], [211], worm-like micelles [212], and vesicles [206], [213]. Research efforts have
Acknowledgements
The Department of Energy (DE-FC26-01BC15317), MRSEC program of the National Science Foundation (NSF) (DR-0213883), and the Robert M. Hearin Foundation are gratefully acknowledged for financial support.
References (214)
- et al.
Reversible addition–fragmentation chain transfer (RAFT) radical polymerization and the synthesis of water-soluble (co)polymers under homogeneous conditions in organic and aqueous media
Prog Polym Sci
(2007) - et al.
Radical addition–fragmentation chemistry in polymer synthesis
Polymer
(2008) - et al.
Reversible addition–fragmentation chain transfer polymerization initiated with gamma-radiation at ambient temperature: an overview
Eur Polym J
(2003) - et al.
Thermosensitive and pH-sensitive Au–Pd bimetallic nanocomposites
J Colloid Interface Sci
(2009) - et al.
Coating of gold nanoparticles by thermosensitive poly(N-isopropylacrylamide) end-capped by biotin
Polymer
(2008) - et al.
New polymer synthesis by nitroxide mediated living radical polymerizations
Chem Rev
(2001) - et al.
A novel “stable” radical initiator based on the oxidation adducts of alkyl-9-bbn
J Am Chem Soc
(1996) - et al.
Metal-catalyzed living radical polymerization
Chem Rev
(2001) - et al.
Atom transfer radical polymerization
Chem Rev
(2001) - et al.
Living radical polymerization by the RAFT process
Aust J Chem
(2005)
Living radical polymerization by the RAFT process—a first update
Aust J Chem
Aqueous RAFT polymerization: recent developments in synthesis of functional water-soluble (Co)polymers with controlled structures
Acc Chem Res
Living free-radical polymerization by reversible addition–fragmentation chain transfer: the RAFT process
Macromolecules
Controlled radical polymerization in dispersed media
Macromol Symp
Toward living radical polymerization
Acc Chem Res
Macromolecular design via reversible addition–fragmentation chain transfer (RAFT)/Xanthates (MADIX) polymerization
J Polym Sci Polym Chem
Experimental requirements for an efficient control of free-radical polymerizations via the reversible addition–fragmentation chain transfer (RAFT) process
Macromol Rapid Commun
Complex macromolecular architectures by reversible addition fragmentation chain transfer chemistry: theory and practice
Macromol Rapid Commun
RAFTing down under: tales of missing radicals, fancy architectures, and mysterious holes
J Polym Sci Polym Chem
Mechanism and kinetics of dithiobenzoate-mediated RAFT polymerization. I. The current situation
J Polym Sci Polym Chem
RAFT mediated polymerisation in heterogeneous media
Soft Matter
Controlled radical polymerization in aqueous dispersed media
Aust J Chem
Ab initio kinetic modelling in radical polymerization: a paradigm shift in reaction kinetic analysis
Aust J Chem
Computational studies of RAFT polymerization—mechanistic insights and practical applications
Macromol Rapid Commun
Thiocarbonylthio compounds (S = C(Z)S-R) in free radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization). Effect of the activating group Z
Macromolecules
Thiocarbonylthio compounds [S = C(Ph)S-R] in free radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization). Role of the free-radical leaving group (R)
Macromolecules
Living radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization) using dithiocarbamates as chain transfer agents
Macromolecules
A kinetic study on the rate retardation in radical polymerization of styrene with addition–fragmentation chain transfer
Macromolecules
Kinetic investigations of reversible addition fragmentation chain transfer polymerizations: cumyl phenyldithioacetate mediated homopolymerizations of styrene and methyl methacrylate
Macromolecules
Water-soluble polymers part 85—raft polymerization of N,N-dimethylacrylamide utilizing novel chain transfer agents tailored for high reinitiation efficiency and structural control
Macromolecules
Modeling the reversible addition–fragmentation transfer polymerization process
J Polym Sci Polym Chem
Rate retardation in reversible addition–fragmentation chain transfer (RAFT) polymerization: further evidence for cross-termination producing 3-arm star chain
Macromolecules
Characterization of low-mass model 3-arm stars produced in reversible addition–fragmentation chain transfer (RAFT) process
Macromolecules
Characterization of 3-and 4-arm stars from reactions of poly(butyl acrylate) RAFT and ATRP precursors
Macromolecules
Protein thioacylation: 2. Reagent stability in aqueous media and thioacylation kinetics
Biomacromolecules
Hydrolytic susceptibility of dithioester chain transfer agents and implications in aqueous RAFT polymerizations
Macromolecules
Protein thioacylation: 1. Reagents design and synthesis
Biomacromolecules
Thermally responsive vesicles and their structural “locking” through polyelectrolyte complex formation
Angew Chem Int Ed
Aqueous RAFT synthesis of pH-responsive triblock copolymer mPEO–PAPMA–PDPAEMA and formation of shell cross-linked micelles
Macromolecules
Direct synthesis of controlled-structure primary amine-based methacrylic polymers by living radical polymerization
Macromolecules
Kinetics and molecular weight control of the polymerization of acrylamide via RAFT
Macromolecules
Impact of end-group association and main-chain hydration on the thermosensitive properties of hydrophobically modified telechelic poly(N-isopropylacrylamides) in water
Macromolecules
Thermal response of narrow-disperse poly(N-isopropylacrylamide) prepared by atom transfer radical polymerization
Macromolecules
Molecular weight characterization of poly(N-isopropylacrylamide) prepared by living free-radical polymerization
Macromolecules
Benzyl and cumyl dithiocarbamates as chain transfer agent in the RAFT polymerization of N-isopropylacrylamide. In situ FT-NIR and MALDI-TOF MS investigation
Macromolecules
A new double-responsive block copolymer synthesized via RAFT polymerization: poly(N-isopropylacrylamide)-block-poly(acrylic acid)
Macromolecules
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