Polymeric nanomaterials from combined click chemistry and controlled radical polymerization

Abstract

This review highlights recent research on the preparation of functional polymeric nanomaterials (nanoparticles, microcapsules, nanofibers, carbon nanotubes) by combined ‘click chemistry’ and controlled radical polymerization (CRP) techniques. In particular, it focuses primarily on combined atom transfer radical polymerization (ATRP), reversible addition-fragmentation transfer polymerization (RAFT), nitroxide-mediated polymerization (NMP), copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene chemistry. These versatile techniques of polymer synthesis allow the preparation of functional polymeric nanomaterials with well-defined nanostructures and desired functionalities.

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Rong Fu

Rong Fu is a graduate student at the School of Chemistry and Chemical Engineering at Southeast University, China. She undertook her undergraduate studies at southeast university and received her B.S. degree in 2008 in the field of chemical engineering. After completing her undergraduate studies, she joined the group of Prof. Guo-Dong Fu to continue her graduate studies. Now her main research interests focus on preparation of well-defined functional hydrogel hybrid with nanoparticles by combined click chemistry and CRP.

Guo-Dong Fu

Guodong Fu received his BSc and MSc degrees in polymer science from Beijing University of Chemical Technology in 1996 and 1999, respectively. In 2005, he received a PhD degree in polymer science from the National University of Singapore. In 2009, he worked at Bayreuth University as an Alexander von Humboldt fellow. Currently he is a professor in the School of Chemistry and Chemical Engineering, Southeast University. His research centers on the preparation of nanostructured, smart and crosslinked polymeric materials by living radical polymerization, click chemistry and electrospinning, as well as exploring their new functions and applications.

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1. Introduction

Polymeric nanomaterials with sizes in the range of 1–1000 nm in at least one dimension, have attracted much attention because of their dramatically increased surface area to volume ratio, leading to a variety of unique properties.¹ The nanosized structures afford polymers unique and supreme properties differing from those of the bulk polymer, such as optical,² magnetic,³ thermal,⁴ and electrical properties.⁵ Polymeric nanomaterials are potentially used in drug delivery, surface coatings, nanoreactors, catalysis and filtration.^6–8

Recent developments in the techniques of polymer synthesis such as controlled radical polymerization (CRP) and ‘click chemistry’ provide a feasible approach to prepare well-defined macromolecules with desired functionalities.^9–17CRP, especially atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization, has been demonstrated to be a powerful tool for synthesizing macromolecules with controlled molecular weight and desired architectures.^12,13 ‘Click chemistry’, termed by Sharpless and co-workers, has been approved to be an efficient and a versatile way to synthesize a range of functional polymers.^18–24 Because of the high specificity, excellent functional group tolerance, and quantitative yields under mild experimental conditions, ‘click chemistry’ is approved to be a powerful tool to prepare functional polymeric architectures.²⁵ The combination of CRP, including nitroxide-medicated radical polymerization (NMP), RAFT, and ATRP and ‘click chemistry’ such as copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and thiol-ene ‘click chemistry’ provides a feasible approach to prepare polymeric architectures with controlled molecular weight and narrow molecular weight distribution.^14–17 The combination of ‘click chemistry’ and CPR could be used to prepare polymeric functional nanomaterials with well-defined nanostructures. Thus, a review summarizing the recent work on the preparation of functional polymeric nanomaterials by combined ‘click chemistry’ and CPR will serve as a useful resource for the future development and application of these materials and structures. This review covers the scientific literature which appeared in recent years concerning the preparation and applications of polymeric nanomaterials from the combination of ‘click chemistry’ and CRP.

2. Preparation of nanomaterials from combined CuAAC and CRP

‘Click chemistry’ is a series of chemical reactions which proceeds with extremely rapidly rate, high yield, high stereospecific selectivity and low by-product under benign conditions.^{23,24,26–32}CuAAC to form a 1,4-disubstituted 1,2,3-triazoles (Fig. 1) is one of most classical ‘click chemistries', which can be conducted in aqueous or organic solvent almost without any side effects.³³ The feasibility of synthesis of chemicals with the alkyne or azide groups also puts CuAAC into the realm of the most popular methodology of ‘click chemistry’.^34,35 Tang and co-workers summarized the recent research on the preparation of linear and hyperbranched poly(triazole)s (PTAs) by CuAAC.³⁶

Fig. 1 An overview of Cu-catalyzed azide/alkyne click (CuAAC).

2.1 Nanomaterials from CuAAC and ATRP

ATRP is one of the most extensively studied CRP methods, due to the simplicity, the wide applicability to monomers, and the ability to prepare well-defined polymeric architectures.³⁷ Polymeric nanomaterials prepared by ATRP have been reviewed by Golas and Matyjaszewski. ³⁸ The polymers from ATRP with dormant species (halogen atoms) on end can be easy converted into azide groups by simple nucleophilic substitution, which can be used starting materials for CuAAC to prepare functional polymers or nanomaterials.^39–41

2.1.1 Self-assembly of block copolymers. Because of the potential applications in pharmaceutics, coatings, rheology modifiers and colloidal stabilizers, the synthesis and self-assembly of amphiphilic block copolymers has received a great deal of attention in the past decades.^42–49 Micelles from self-assembly of amphiphilic polymers are not stable and would be destroyed upon the change of external conditions such as temperature, pH, etc.^50,51 Thus, nanomaterials with cross-linked structure have improved environmental stability and solvent resistance, which greatly expand their applications in various fields. The combination of ‘CuAAC’ and ATRP gives access to the synthesis of block copolymer and the preparation of cross-linked nanomaterials by adding flexibility, diversity, and functionality. Zhang et al.⁵² synthesized oppositely charged polyelectrolyte architectures of poly(methacrylic acid-co-3-azidopropyl methacrylate)-g-poly(N-isopropylacrylamide) (P(MAA-co-AzPMA)-g-PNiPAM) and poly(2-(dimethylamino)ethyl methacrylate-co-AzPMA)-g-PNiPAM) (P(QDMA-co-AzPMA)-g-PNiPAM) by the combination of ATRP and CuAAC. Self-assembly of these polymers in aqueous solution gave rise to micelles consisting of polyion complex cores and thermo-responsive PNiPAM coronas. One more step of ‘CuAAC’ of the prepared micelles and cross-linkers with propargyl groups allows the formation of nanoparticles with a covalently cross-linked core and thermo-responsive coronas. The prepared nanoparticles exhibit solvent resistance against salt, acid and base solutions. (Fig. 2) The PNiPAM coronas afford the nanoparticles thermo-induced dispersion/aggregation properties, which make them applicable to pharmaceutical technology and biotechnology. Wang et al.⁵³ synthesized poly(ethylene glycol)-b-poly(hydroxyethyl methacrylate)-b-poly(methyl methacrylate) (PEG-b-PHEMA-b-PMMA) by ATRP. Subsequent modification of PHEMA block gave rise to the azido-containing amphiphilic triblock copolymer of PEG-b-poly(azidoethyl methacrylate)-b-PMMA (PEG-b-PAzEMA-b-PMMA). Self-assembly of block polymers allows the formation of nanoparticles with azide groups on the surface. Biotin-conjugated nanoparticles were obtained after CuAAC of prepared nanoparticles and alkynated biotin. Li et al.⁵⁴ synthesized poly(ethylene oxide)-b-poly(glycidyl methacrylate) (PEO-b-PGMA) viaATRP from PEO-based macroinitiator. Block copolymers having both ATRP initiator and N₃groups in each repeat unit (PEO-b-[PGMA-(N₃)(Br)]) have been prepared by ring-opening reaction of epoxy groups of PEO-b-PGMA with NaN₃ and followed by esterification with 2-bromoisobutyryl bromide. ATRP of 2-(2-methoxyethoxy)ethyl methacrylate) (MEO₂MA) and CuAAC of alkynyl-terminated poly(2-(diethylamino)ethyl methacrylate) (alkynyl-PDEA) gave rise to block copolymer with double polymer brushes of PDEA and poly MEO₂MA. Varying pH and temperature, nanoparticles with various size and functionalities were obtained from the self-assembly of prepared polymers.

Fig. 2 Schematic illustration of formation of thermosensitive polyion complex (PIC) micelles and their core cross-linking via click chemistry.⁵²

Bioconjugated nanoparticles were prepared by Reynhout et al.⁵⁵ Firstly, amphiphilic block copolymers of polystyrene-b-PEG (PS-b-PEG) were synthesized by ATRP. Conversion of the halogen dominant species in to azido group and one more step of CuAAC gave rise to the biohybrid triblock copolymers myoglobinZn-b-PS-b-PEG (MbZn-b-PS-b-PEG) and horse radish peroxidase-b-PS-b-PEG (HRPZn-b-PS-b-PEG). Lamellae structured nanospheres were obtained from self-assembly of these triblock copolymers. Jiang et al.⁵⁶ presented a simple approach to prepare nanoparticles with two types of inverted structures from a same schizophrenic triblock copolymer. A well-defined ABC triblock copolymer, PMEO₂MA-b-poly(2-(dimethylamino)ethyl methacrylate)-b-PDEA (PMEO₂MA-b-PDMA-b-PDEA), was synthesized via sequential ATRP using ethyl 2-bromoisobutyrate as the initiator. Reacting the triblock precursor with propargyl bromide in anhydrous tetrahydrofuran (THF) gave rise to PMEO₂MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer with ‘clickable’ moieties, where QDMA is quaternized DMA. Self-assembly of PMEO₂MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer generated micelles with three-layer onion-like PMEO₂MA-core or PDEA-core upon proper adjustment of the solution pH and temperature. Subsequent cross-linking of micelles with tetra(ethylene glycol) diazideviaCuAAC led to the formation of two types of shell-cross-linked (SCL) micelles with “inverted” structures. The cores and coronas of SCL micelles exhibited multiresponsive swelling/shrinking and collapse/aggregation behavior, respectively. (Fig. 3)

Fig. 3 Preparation of two types of SCL micelles with inverted structures in aqueous solution.⁵⁶

A simple approach to prepare cross-linked nanoparticlesvia simultaneous ‘click chemistry’ and atom transfer radical emulsion polymerization (ATREP) was developed by our group.⁵⁷ Well-defined cross-linked PS nanoparticles with diameter in the range of 50–150 nm were prepared from a simultaneous ‘click chemistry’ and ATREP of a mixture styrene and 4-vinylbenzyl azide using 4,4-bis((2′-bromo-2′-methylpropionyloxy)methyl)-1,6-heptadiyne (BMP) as initiator (Fig. 4). The size of the nanoparticles can be regulated by changing the monomer/initiator ratio or the amount of the emulsifiers. The cross-linked nanoparticles are uniform and exhibit excellent solvent-resistant properties to THF and N,N-dimethylformamide (DMF). The cross-linked nanoparticles also have an improved thermal stability. In nitrogen, the weight loss of nanoparticles commences at about 320 °C, which is much higher than that (280 °C) of linear PS polymers. The cross-linked nanoparticles could be used in photonic crystals, drug delivery, and fabrication of periodic structures.

Fig. 4 Synthesis of diblock polystyrene (PS) and cross-linked PS nanoparticles by simultaneous “click chemistry” and atom transfer radical emulsion polymerization (ATREP) (DMF = dimethylformamide).⁵⁷

2.1.2 Nanomaterials surface modification. Because the performance of a material is always dependent on its surface properties, surfaces modification provides a feasible approach for constructing materials with desirable molecular structures and tailor-made surface properties.⁵⁸ The combination of ATRP and CuAAC has exhibited the capability on the surface modification to prepare core-shell nanomaterials or nanomaterials with polymer brushes. Tchoul et al. synthesized alkyne-terminated PS (At-PS) by ATRP.⁵⁹ The CuAAC of At-PS and titanium dioxide (TiO₂) nanoparticles with azide groups on surface gave rise to the TiO₂ nanoparticles with PS brushes. The prepared nanoparticles exhibited good dielectric properties. White et al.⁶⁰ also prepared core-shell Fe₂O₃ nanoparticles by combined ATRP and CuAAC. γ-Fe₂O₃ nanoparticles with azide group on surface were firstly prepared from phosphonic acid ligand having azide groups (Fig. 5). ATRP of tert-butyl acrylate from an alkyne-functional initiator gave rise to the alkyne-terminated poly(tert-butyl acrylate) (At-PtBA). One more step of CuAAC γ-Fe₂O₃ nanoparticles and At-PtBA allows the preparation of γ-Fe₂O₃ nanoparticles with PtBA brushes on surface. Ultra thin thermo-responsive microcapsules were also synthesized by Huang and Chang.⁶¹ Initially, poly(NiPAM-co-(trimethylsilyl)propargylacrylamide) (P(NiPAM-c-TMSPA)) and poly(NiPAM-co-3-azideopropylacrylamide) (P(NiPAM-c-APA)) were prepared by ATRP. After de-protection of trimethylsilyl groups, P(NiPAM-c-TMSPA) and P(NiPAM-c-APA) were grafted and cross-linked onto the silica nanoparticles with azide groups on surface in aqueous media by CuAAC. Then removal of the silica core by HF etching gave rise to solvent-resistant thermo-responsive microcapsules. The thickness and surface morphology of the cross-linked PNiPAM microcapsules could be regulated by changing the number of clickable groups. The surfaces of these microcapsules are further functionalized with azido-modified lissamine rhodamin dyesvia one more step of CuAAC. The applications of microcapsules in encapsulation have also been demonstrated (Fig. 6). Bioconjugated Janus nanoparticles were prepared by Zhang et al. via combined ATRP and CuAAC (Fig. 7).⁶² Firstly, a Pickering emulsion was obtained by adding toluene solution of PS into an aqueous solution with dispersed azide modified silica particles. After removal of toluene under a reduced pressure, the silica nanoparticles were frozen on the surfaces of PS particles, which made half of silica nanoparticle be exposed to aqueous phase and another be immersed into PS. Then, biotins were immobilized on the surface of silica nanoparticles exposed to aqueous surface by CuAAC. After removal of PS, the azide groups embedded in PS phase were released out. One more step of CuAAC of biocompatible PEO chains allows the preparation of Janus silica nanoparticles with half surface grafted PEO and another half of biotins.

Fig. 5 A general scheme for functionalizing the surface of iron oxide nanoparticles.⁶⁰

Fig. 6 A schematic representation of the preparation of covalently stabilized thermoresponsive microcapsules through layer-by-layer assembly using click chemistry.⁶¹

Fig. 7 A schematic representation of the preparation of bioconjugated particles.⁶²

The combination of ATRP and CuAAC can also be use to the surface functionalization of carbon nanotubes (CNTs) to tailor the surface properties. Li and co-workers have reported a highly efficient, modular approach to prepare single wall carbon nanotubes (SWNTs) with well-defined PS brushes using the CuAAC and ATRP.⁶³Alkyne-functionalized SWNTs were prepared via a solvent-free diazotization and coupling procedure of p-aminophenyl propargyl ether. A series of well-defined PS polymers was prepared by ATRP. Then the bromine end-groups of PS were conversed into azide groups. SWNTs with well-defined PS brushes on surface were obtained viaCuAAC of alkyne-functionalized SWNTs and azide-terminated PS. This reaction was found to be very efficient in producing organosoluble polymer-nanotube conjugates under relatively low reaction temperatures and short reaction times. (Fig. 8) CNTs with amphiphilic block copolymer brush, such as poly(n-butyl methacrylate), PS, and PEG were prepared by combined ATRP and CuAAC.⁶⁴PGMA were firstly synthesized by ATRP. Then, ring-opening of epoxy groups of PGMA with NaN₃ and esterification by ethyl 2-bromoisobutyrate (EBiB) allows the preparation of the macromolecules, poly(3-azido-2-(2-bromo-2-methylpropanoyloxy)propyl methacrylate) (PBrAzPMA), having both to ATRP initiator and azide group in each repeat unite. The clickable macroinitiators, PBrAzPMA, were then grafted onto the surface of SWNTs viaCuAAC. Subsequent ATRP of n-butyl methacrylate, styrene, and ethylene glycol gave rise to CNTs with amphiphilic polymer brushes on surface. Using a similar strategy, Chang and co-workers prepared polyimide (PI) nanofibers with well defined PMMA by combined ATRP and CuAAC.⁶⁵

Fig. 8 A schematic representation of the preparation of the alkyne-functionalized SWNTs. (i) Isoamyl nitrite, 60 °C; (ii) EBiB, CuBr/BPy, DMF, 110 °C; (iii) NaN₃, DMF, room temperature; (iv) Cu(I), DMF.⁶³

2.2 Combined CuAAC and NMP

Nanomaterials can also be prepared by combined CuAAC and NMP. Cross-linked nanoparticles with either shell functionalized or core functionalized were prepared by O'Reilly and co-workers (Fig. 9).⁶⁶ Initially, amphiphilic diblock copolymer poly(acrylic acid)-b-PS (PAA-b-PS) were synthesized viaNMP. Self-assembly of prepared amphiphilic copolymers produced micelles with PS core and PAA shell. Then modification of the PAA units with either azido or alkynyl groups containing chemicals via amidation chemistry gave rise to the micelles with functional groups on shell. The micelles were then cross-linked using amidation chemistry by activating a fraction of the remaining carboxylic acid groups, with 1-[3′-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide followed by reaction with 2,2′-(ethylenedioxy)bis(ethylamine) overnight at ambient temperature. The nanoparticles carrying clickable groups in the hydrophilic shell were reacted with either an alkynyl- or azido-functionalized fluorescein dye. Finally, cross-linked nanoparticles with fluorescein dye on shell were obtained. Core-functionalized nanoparticles were also prepared by O'Reilly et al.⁶⁶ Firstly, the amphiphilic block copolymer of PAA-b-poly(styrene-c-vinyl benzylchlorize) (PAA-b-P(S-c-VBC)) viaNMP. Self-assembly of amphiphilic block copolymer and displacement of the chloro groups for azides in micelle produced the micelles with core having azido groups. The azide core-functionalized and shell cross-linked nanoparticles were formed by intramicellar cross-linking of approximately 50% of the acrylic acid residues. The subsequent ‘click chemistry’ allows the preparation of nanoparticles with a cross-linked shell and fluorescein cores.

Fig. 9 A schematic representation of the preparation of the click-functionalized nanoparticles.⁶⁶

Binder and co-workers synthesized 2,2,5-tri-methyl-4-phenyl-3-azahexane-3-nitroxide-based (TIPNO-based) NMP initiators with different functional groupsviaCuAAC.⁶⁷ The NMP initiators were firstly immobilized on λ-Fe₂O₃ nanoparticles surface viaCuAAC. The subsequent NPM polymerization of the NiPAM produced the superparamagnetic core/shell nanoparticles with a defined PNiPAM-shell.

2.3 Combined CuAAC and RAFT

Nanomaterials can also be prepared by combined CuAAC and RAFT. In some attempts, chain transfer agents (CTAs) were anchored to silica nanoparticles^68,69 or gold nanoparticles^70,71 by CuAAC. Then, subsequent RAFT polymerization from these nanoparticles allows the preparation of well-defined core-shell nanoparticles. A typical example was reported by Ranjan and Brittain.⁶⁸ Firstly, silica nanoparticles with a bromide group on surface and were converted into azido groups. Then, RAFT CTA with an alkyne group was synthesized. CuAAC between silica nanoparticles and alkyne RAFT CTAs gave rise to silica nanoparticles with RAFT CTAs on surface. RAFT polymerization of styrene and methyl acrylate allows to prepare silica nanoparticles with block copolymer brushes (SiO₂-PS-b-PMA).⁶⁸ Ranjan and Brittain have synthesized functionalized silica nanoparticles based on the combination of CuAAC and RAFT.⁷² Firstly, azide-modified silica nanoparticles were prepared via deposition of 3-bromopropyltrichlorosilane on surfaces and substituted bromo group into N₃ with NaN₃. Then trithiocarbonate CTA with alkyne group were synthesized and used as the CTA to prepare well-defined alkyne-terminated-PNiPAM (PNiPAM_AT) via RAFT. CuAAC of the PNiPAM_AT and silica nanoparticles gave rise the core-shell nanoparticle with a thermo-sensitive shell.

Alexander et al. have successfully prepared cross-linked nanoparticles with encapsulated cobalt carbonyl complexes (Fig. 10).⁷³ Firstly, they synthesized block copolymers of poly(trimethysilyl propargyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (P(TMS-PAMA)-b-P(PEGMA)) by RAFT polymerization. Subsequent removal of the trimethylsiyl protective groups with tetra-n-butylammonium fluoride hydrate gave rise to the polymer with pendant alkyne groups. Self-assembly of the prepared amphiphilic copolymer in water produced nanoparticles with diameters less than 20 nm. The pendant alkyne groups could not only be used as a reactive group for cross-linking viaCuAAC, but also as a ligand for the reaction with Co₂(CO)₈ to produce the Co₂(CO)₆(alkyne) complex. Nanoparticles were further cross-linked by 1,2-bis-(2-azidoethoxy)ethane and bis-(azidoethyl)disulfideviaCuAAC at room temperature. The amount of added cross-linker can be adjusted, leaving a desired amount of alkyne groups that were utilized in the formation of the cobalt complexes. The functionalized nanoparticles were used to reduce the toxicity of tumour cells.

Fig. 10 Core cross-linking of micelles using a click chemistry and reaction with Co₂(CO)₈ using the remaining alkyne groups.⁷³

Smart nanofibers with a photo-responsive surface prepared by combined RAFT polymerization, ‘click chemistry’ and electrospinning were also reported by our group.⁷⁴ By combination of the mechanisms of the host–guest interaction and drug conjugation with cyclodextrin (CD), a smart delivery system based on this cross-linked nanofibers with surface-loaded CD prodrugs has been developed (Fig. 11). Firstly, cross-linked nanofibers with azido groups on the surface were fabricated viaelectrospinning of the block copolymer of VBC and GMA (PVBC-b-PGMA) prepared by consecutive RAFT polymerization and subsequent reaction with sodium azide. Then photosensitive groups were introduced on the nanofiber surface by ‘click chemistry’ with 4-propargyloxyazobenzene (PAB). The α-CD-5-fluorouracil (α-CD-5FU) prodrug were synthesized and loaded on the nanofiber surface viahost–guest interaction. Photo-controlled release of the α-CD-5FU prodrug from the nanofiber surface was realized by UV irradiation. A novel photo-responsive controlled release system has been demonstrated, in which the α-CD-5FU prodrugs are loaded on the photo-responsive and cross-linked nanofiber surface viahost–guest interaction. Differing from the other controlled release systems, in which the drug is loaded inside the carrier and is susceptible to release delays in response to external stimuli, the present system provides a photo-controlled fast “ON-OFF” release characteristic. With the availability of a wide variety of CD prodrugs, stimuli-responsive nanofiber systems with loaded CD prodrugs are expected to provide unique opportunities for the effective and controlled “ON-OFF” release of therapeutic agents.

Fig. 11 A schematic illustration of the preparation of the cross-linked nanofibers of PVBC-b-PGMA with AB groups on the surface (CNFPVBC-b-PGMA-AB), the synthesis of the CD and 5FU prodrug (R-CD-5FU), and the photoresponsive loading and release of the R-CD-5FU prodrug on the CNFPVBC-b-PGMA-AB surface by host–guest interaction.⁷⁴

3. Preparation of nanomaterials combined thiol-ene click chemistry and CRP

As the most popular ‘click chemistry’ technique, the application of CuAAC was restricted by some of its disadvantages such as requirement of an inert environment due to the typical catalysts used for CuAAC, the difficulty in the removal and toxicity of copper-based residues and easy explosion of azide chemicals. In order to get over those unfavorable conditions, thiol-ene chemistry, which is also noted for its efficiency, versatility, and selectivity, becomes more and more popular.^75,76Thiol-ene chemistry represents all the advantages of ‘click chemistry’, including mild reaction conditions, fast reaction rate, high yields, insensitive to moisture. Fig. 12 gives an overview of the mechanism of UV-induced thiol-ene reaction.⁷⁷ The feasibility of conversion of the dithioester or trithioester groups at the end of well-defined polymers from RAFT into thiol group by reducing made it possible to prepared well-defined nanomaterials via combined RAFT polymerization and thiol-ene chemistry.

Fig. 12 The reaction mechanism of UV-induced thiol-ene chemistry.⁷⁷

Kakwere and Perrier⁷⁸ synthesized amphiphilic block copolymers poly[ethyl acrylate-b-(hydroxyethylacrylate-co-N-acryloxysuccinimide)](P[EA-b-(HEA-co-NAS)]) via RAFT. Self-assembly of prepared polymers in water and cross-linking with hexamethylenediamine (HMDA) give rise to the cross-linking soft nanoparticles with thiolcarbonyl groups. The reduction of thiolcarbonyl end groups using sodium borohydride in aqueous solution under mild conditions produced the nanoparticles with thiol end groups on surface. Then, the nanoparticles can be further functionalized by fluorescent tag or the protein with alkenyl groupviathiol-ene click chemistry. Goldmann and co-workers synthesized cross-linked poly(divinylbenzene) (pDVB) microspheres with PNiPAM brushes on surface via combined RAFT and thiol-ene.⁷⁹ Initially, PNiPAM were prepared via RAFT using 3-benzylsulfanylthiocarbonylsulfanyl propionic acid (BPATT) as CTA. Then PNiPAMs with thiol group were obtained after reduction by sodium borohydride. The accessible double bonds on the surface of the pDVB microspheres allow the direct coupling thiol-end functionalized PNiPAMviathiol-ene chemistry. Particles with different functionalities could be prepared by this method by using other functional thiol-ended polymers or proteins.

Hawker and co-workers described a feasible method to prepared inorganic/organic hybrid nanoparticlesvia combined emulsion polymerization, RAFT polymerization and thiol-ene chemistry.⁸⁰ First, MnFe₂O₄ and Au nanoparticles grafted with short polystyrene brushes are dispersed in the monomer, DVB. This monomer/nanoparticle solution is then emulsified with an aqueous solution of surfactant (cetyltrimethylammonium bromide, CTAB), viaultrasonication, to generate an emulsion of submicrometer monomer droplets containing the inorganic nanoparticles. The free radical polymerization of these droplets (using 2,2′-azobis(2-amidinopropane) dihydrochloride, or ‘V-50’, as initiator) yields cross-linked pDVB latex particles with inorganic nanoparticles embedded in the interior. The nanoparticles were further functionalized by the residual vinyl (‘ene’) groups present in the pDVB matrix and thiol-terminated PEG chains. These PEG-grafted composite nanoparticles were found to be completely stable upon redispersion in a variety of solvents, such as DMF, chloroform, water, and THF. These particles exhibit both the properties of magnetic MnFe₂O₄ nanoparticles and the surface plasmon resonance of Au nanoparticles.

4. Multiple/other methods of preparing nanomaterials

To prepare well-defined nanomaterials with multi-functionalities, sometimes the combination of only one or two polymerization techniques is not enough. Thus, more techniques were applied together. Multiple methods of CRP and click chemistry are also pretty efficient when introduced into the field of surface modification to produce functional nanomaterials. Goldmann and co-workers⁷⁹ empolyed two click-techniques (thiol-ene chemistry and CuAAC) to prepare core-shell pDVB nanoparticles (Fig. 13). Initially, pDVB particles were prepared by precipitation polymerization, having diameters of 1.3 μm. These microspheres have a thin surface layer consisting of lightly cross-linked and swellable poly(divinyl benzene) and contain vinyl groups on their surfaces. The residual double bonds on the microsphere surface were converted into azido groupsvia a thiol-click approach using a thiol-azide compound (1-azido-undecane-11-thiol). Then, alkyne end functionalized pHEMA was synthesized viaATRP grafted onto the azide-modified pDVB particle surface viaCuAAC.

Fig. 13 PHEMA grafted microspheres via Huisgen 1,3-dipolar cycloaddition.⁷⁹

Functional CNTs were also prepared by Zhang and co-workers via layer-by-layer deposition, ‘click chemistry’, ATRP and RAFT.⁸¹ Firstly, the clickable polymers, PAMA and poly(propargyl methacrylate) (PPMA) were synthesized by ATRP and RAFT, respectively. Then alternately CuAAC of the PAMA and PPMA on the surfaces of alkyne-modified NTs (MWNTs) gave rise to MWNTs with clickable polymer brushes on surface. Further CuAAC of alkyne-modified rhodamine B or monoalkyne-terminated PS and the prepared MWNTs gave rise to fluorescent CNTs or CNT with PS brushes on surface, respectively.

Solvent-resistant nanofibers with an environmental-responsive surface were prepared by our groupvia the combined technology of ATRP, RAFT, electrospinning, and CuAAC (Fig. 14).⁸² Initially, block copolymers of PVBC-b-PGMA were synthesized via RAFT using 2-cyanoprop-2-yl 1-dithionaphthalate (CPDN) as the CTAs. Electrospinning of PVBC-b-PGMA from a solution in THF gave rise to fibers with diameters in the range of 0.4–1.5 μm. Exposure to a solution of NaN₃ not only affords nanofibers with azido groups on the surface but also leads to a cross-linking structure in the nanofibers. One more step of ‘click chemistry’ between the PVBC-b-PGMA nanofibers with azide groups on the surface (PVBC-b- PGMA(-N₃)) and PNiPAM_AT, which were prepared by ATRP allows the preparation of a PVBC-b-PGMA nanofiber with thermal-sensitive PNiPAM brushes on the surface (PVBC-b-PGMA-g-PNiPAM). PVBC-b-PGMA nanofibers exhibit a good resistance to solvents and thermal-responsive character to the environment having a hydrophobic surface at 45 °C (water contact angle similar to 140°) and having a hydrophilic surface at 20 °C (water contact angle similar to 30°).

Fig. 14 Preparation of solvent-resistant nanofibers with a thermal-sensitive surface by combined ATRP, RAFT polymerization, electrospinning, and ‘click chemistry’.⁸²

5. Conclusion and outlook

The combined technology of ‘click chemistry’ and CRP has been demonstrated to be a powerful tool for preparing well-defined nanomaterials with desired functionalities. Attributable to the simplicity, the wide applicability to monomers, and the ability to prepare well-defined polymeric architectures of ATRP, and the extremely rapidly rate, high yield, high stereospecific selectivity and low by-product under benign conditions of CuAAC, as well as feasible conversion of the combination of the halogen species on the end of polymers from ATRP into azido or alkynyl groups, the combination of ATRP and CuAAC exhibited the strong capabilities in the nanomaterials preparation and the nanomaterials functionalization. Interestingly, ATRP not only shares a number of attractive features with CuAAC, such as good tolerance for a wide range of functional groups, but also the same copper catalyst system. One-pot simultaneous ATRP and CuAAC would become a powerful tool for the preparation of nanomaterials. However, the requirement of an inert environment due to the typical catalysts for CuAAC and ATRP, as well as the difficulty in the removal and toxicity of copper-based residues restrict the application of ATRP and CuAAC in the preparation of nanomaterials. Thiol-ene chemistry represents all the advantages of ‘click chemistry’, including mild reaction conditions, fast reaction rate, high yields, insensitive to moisture. The feasibility of conversion of the dithioester or trithioester groups, at the end of well-defined polymers from RAFT, into thiol groups by reduction made it possible to prepared well-defined nanomaterials via combined RAFT polymerization and thiol-ene chemistry. Sometimes the combination of only one or two polymerization techniques is not enough to prepare well-defined nanomaterials with desired functionalities. Thus, the combination of more than two approaches, including ATRP, CuAAC, RAFT, NMP, emulsion polymerization and electrospinningetc. has been applied to preparation of nanomaterials, and could play an important role in the preparation and functionalization of nanomaterials. Abbreviations

APA	azideopropylacrylamide
At-PS	alkyne-terminated polystyrene
ATRP	atom transfer radical polymerization
ATREP	atom transfer radical emulsion polymerization
AzPMA	3-azidopropyl methacrylate
BMP	4,4-bis((2′-bromo-2′-methylpropionyloxy)methyl)-1,6-heptadiyne
BPATT	3-benzylsulfanylthiocarbonylsulfanyl propionic acid
CD	cyclodextrin
α-CD-5FU	α-cyclodextrin-5-fluorouracil
CNTs	carbon nanotubes
CPDN	2-cyanoprop-2-yl 1-dithionaphthalate
CRP	controlled radical polymerization
CTAB	cetyltrimethylammonium bromide
CTAs	chain transfer agents
CuAAC	copper(I)-catalyzed azide-alkyne cycloaddition
DMF	N,N-dimethylformamide
EA	ethyl acrylate
EBiB	ethyl 2-bromoisobutyrate
GMA	glycidyl methacrylate
HEA	hydroxyethylacrylate
HEMA	hydroxyethyl methacrylate
HF	hydrofluoric acid
HMDA	hexamethylenediamine
HRP	radish peroxidase
MAA	methacrylic acid
Mb	myoglobin
MEO2MA	2-(2-methoxyethoxy)ethyl methacrylate)
MMA	methyl methacrylate
MWNTs	multiwalled carbon nanotubes
NaN3	sodium azide
NAS	N-acryloxysuccinimide
NMP	nitroxide-medicated radical polymerization
PAA	poly(acrylic acid)
PAB	4-propargyloxyazobenzene
PAzEMA	poly(azidoethyl methacrylate)
PBrAzPMA	poly(3-azido-2-(2-bromo-2-methylpropanoyloxy)propyl methacrylate)
PAMA	poly(2-azidothyl methacrylate)
PDEA	poly(2-(diethylamino)ethyl methacrylate
PQDMA	quaternized poly(2-(dimethylamino)ethyl methacrylate
PDMA	poly(2-(dimethylamino)ethyl methacrylate
pDVB	poly(divinylbenzene)
PEG	polyethylene glycol
PEGMA	poly(ethylene glycol) methyl ether methacrylate
PEO	polyethylene oxide
PI	polyimide
PPMA	poly(propargyl methacrylate)
PNiPAM	poly(N-isopropylacrylamide)
PNiPAMAT	alkyne-terminated poly(N–isopropylacrylamide)
PS	polystyrene
PtBA	α-acetylene-poly(tert-butyl acrylate)
P(TMS-PAMA)	poly(trimethysilyl propargyl methacrylate)
RAFT	reversible addition-fragmentation chain transfer
SCL	shell-cross-linked
SWNTs	single wall carbon nanotubes
TIPNO	2,2,5-tri-methyl-4-phenyl-3-azahexane-3-nitroxide
TiO2	titanium dioxide
THF	tetrahydrofuran
TMSPA	(trimethylsilyl)propargylacrylamide
UV	ultraviolet
V-50	2,2′-azobis(2-amidinopropane) dihydrochloride
VBC	4-vinylbenzyl chloride
Zn	zinc

Acknowledgements

This work was supported by National Natural Science Foundation of China under the Grant 20804009 and 21074022, and the Key Project of Chinese Ministry of Education Grant 108062. This work was also supported by the Program for New Century Excellent Talents in University of grant NCET-08-0117.

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