The Combination of Living Radical Polymerization and Click Chemistry for the Synthesis of Advanced Macromolecular Architectures ⇑ Niels Akeroyd, Bert Klumperman

European Polymer Journal 47 (2011) 1207–1231

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European Polymer Journal

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

Feature Article The combination of living radical polymerization and click chemistry for the synthesis of advanced macromolecular architectures ⇑ Niels Akeroyd, Bert Klumperman

Stellenbosch University, Department of Chemistry and Polymer Science, Private Bag X1, Matieland 7602, South Africa article info abstract

Article history: Since its introduction, click chemistry has received a considerable amount of interest. In Received 17 May 2010 this contribution, the term click chemistry and the reactions that fall under this term are Received in revised form 24 January 2011 briefly explained. The main focus of this review is on the application of click chemistry Accepted 5 February 2011 in conjunction with living radical polymerization for the synthesis of advanced macromo- Available online 12 February 2011 lecular architectures. Therefore the most powerful living radical polymerization (LRP) techniques are discussed and an overview of click chemistry in the different synthetic schemes Keywords: is given. A large number of examples are shown that include the synthesis of block copoly- Click chemistry mers, star-shaped polymers, surface modified particles, and polymer-protein conjugates. Living radical polymerization ATRP The enormous potential of LRP/click chemistry is probably best exemplified by the synthe- RAFT sis of different miktoarm star copolymers, to which a separate section is dedicated. SET-LRP Ó 2011 Elsevier Ltd. Open access under CC BY-NC-ND license. NMP

Contents

1. Introduction ...... 1208 2. Cycloadditions of unsaturated molecules ...... 1208 3. Synthesis of organic azides and alkynes ...... 1210 4. Other examples of click chemistry ...... 1211 4.1. Nucleophilic substitution ...... 1211 4.2. Carbonyl chemistry ...... 1211 4.3. Addition reactions to unsaturated carbon–carbon bonds ...... 1211 5. Living radical polymerization ...... 1211 5.1. RAFT ...... 1212 5.2. ATRP...... 1212 5.3. SET-LRP ...... 1214 5.4. NMP ...... 1214 6. The combination of living radical polymerization and ‘click’ chemistry ...... 1214 6.1. RAFT and click chemistry ...... 1214 6.2. ATRP and click chemistry ...... 1218 6.3. SET-LRP and click chemistry...... 1223 6.4. NMP and click chemistry ...... 1225 7. Miktoarm star polymers ...... 1225 8. Conclusions and Outlook ...... 1227 References ...... 1227

⇑ Corresponding author. E-mail address: [email protected] (B. Klumperman).

0014-3057 Ó 2011 Elsevier Ltd. Open access under CC BY-NC-ND license. doi:10.1016/j.eurpolymj.2011.02.003 1208 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

1. Introduction and out of this reaction type it is considered to be the most reliable (unlike many other starting compounds, azides The term click chemistry was introduced by Sharpless and alkynes are stable towards dimerization and hydroly- and coworkers [1] and is deﬁned as a reaction that is mod- sis) and powerful due to the wide variety, accessibility ular, wide in scope, high in yield, has little side products and relative inertness (towards other organic reactions) that are easily removed by non-chromatographic methods of the starting compounds. The Huisgen reaction using (for example crystallization or distillation), is stereospe- azides as dipoles was reported by Huisgen et al. [2] in ciﬁc but not necessarily enantioselective, uses simple reac- 1965. This reaction gained a boost of interest after the cop- tion conditions, is not sensitive to oxygen or water, uses per-catalyzed version was introduced by Meldal and easily accessible reagents, requires no solvent or a solvent coworkers [3] and by Sharpless and coworkers [4] in 2002. that is easily removed or benign like water, enables simple The CuI catalyst can be introduced in four different product isolation, has a high thermodynamic driving force ways. Firstly, CuI species can be introduced directly in 1 I (greater than 20 kcal mol ) and goes rapidly to comple- the form of Cu salts, for example CuI, CuOTfC6H6 and tion. Most of the click chemistry reactions are carbon– [Cu(NCCH3)4][PF6] have been used. These types of catalysts heteroatom bond forming reactions, for example: require the use of a nitrogen base (e.g. triethylamine, pyr- idine and 2,6-lutidine have been reported). This method Cycloadditions of unsaturated molecules, has one major disadvantage, which is the formation of Nucleophilic substitution, especially ring-opening reac- diacetylenes, bistriazoles and 5-hydroxytriazoles as side tions of heterocyclic electrophiles that have high ring- products [4]. Secondly, a CuII/Cu0 system can be used. In strain, such a system CuI is formed by comproportionation of Carbonyl chemistry, except for the ‘‘aldol’’-type the CuII/Cu0 couple. This is a very useful system when the reactions, substrates cannot be used in the presence of ascorbic acid Oxidizing reactions like aziridination, dihydroxylation or its oxidation products [5]. Thirdly, copper immobilized and epoxidation. on carbon (Cu/C) can be used. This Cu/C catalyst is prepared easily by placing carbon black and Cu(NO3)23H2O 2. Cycloadditions of unsaturated molecules in water and mixing it in an ultrasound bath for 7 h. This catalyst can be activated by the addition of triethylamine, Reports on click chemistry are mostly on the CuI-cata- or by the use of microwave heating, both of which cause lyzed Huisgen 1,3-dipolar cycloaddition reaction (Scheme the reaction time to decrease from hours to minutes. A 1). This reaction is part of the hetero-Diels–Alder family big advantage of this catalyst is that it is easily removed

N CuSO 4 .5H2O, 1 mol% N O Sodium ascorbate , 5 mol% O N + N N N H2O/tBuOH 2:1, RT, 8 h 1

Scheme 1. Example of CuI-catalyzed Huisgen 1,3-dipolar cycloaddition (yield 91%) [4].

R1 1 CuLn R1 R CuLn B-3 N N N R2 N N N N R2 2 N N R C IV

B-2

+ [LnCu] B-direct 1 R CuLn N 2 R R1 H N N A 1 II B-1 R CuLn I

N N N R2

Scheme 2. Proposed mechanism for the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition by Sharpless and coworkers [4]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1209 from the reaction mixture (ﬁltration over Celite) and the ‘‘ligation’’ pathway. Extensive density functional theory catalyst can be recycled (no loss of activity was found after calculations give strong evidence towards the ‘‘ligation’’ recycling the catalyst three times) [6,7]. Finally, CuI can be pathway (12–15 kcal) [4,5]. To optimize the reaction introduced by the reduction of CuII salts by sodium ascor- between azides and alkynes, ligands can be added to the bate or ascorbic acid (5–10 mol%). The fact that CuII salts reaction mixture. These ligands are nitrogen rich com- are relatively cheap (CuSO45H2O can be used) and that pounds (for some examples see Fig. 1). this is a very reliable and simple system makes this the Finn and coworkers [8,9] reported on tris((1-benzyl)-H- preferable route [4]. 1,2,3-triazole-4-yl)methyl)amine (TBTA) (2) and potassium The reaction mechanism proposed by Sharpless and 5,50,500-(2,20,200-nitrilotris(methylene)tris(1H-benzo[d]imid- coworkers (Scheme 2) contains two pathways. The ﬁrst azole-2,1-diyl))tripenta-noate (BimC4A)3 (3) and its proposed pathway is a direct [2+3] cycloaddition and the derivatives as organic and water phase ligands for the second one is a stepwise sequence (B-1?B-2?B-3) or cycloaddition reaction between azides and alkynes. Nolan

KO2C

N N N N N N N N N N N N N N N N NN CO K N 2

KO2C

2 3 4

Fig. 1. Examples of ligands used to optimize alkyne-azide click reactions [8,9].

CuSO4 .5 H2O2mol% Sodium ascorbate 10 mol% OH O KHCO 4,3 equiv N R2 N + R 2 3 1 1 R Cl H2O/tBuOH 1:1 RT, 1-4 h R

Scheme 3. CuI-catalyzed synthesis of 3,5-disubstituted isoxazoles reported by Sharpless and coworkers [5].

OH O N +H2NOH.HCl R H R H

OH OH N N +NCS R H R Cl

NCS = N-chlorosuccinimide

Scheme 4. The synthesis of imidoyl chloride as reported by Howe and coworkers [12].

R" R' R" HO N R' N N or + 3 N or N R" N N HO R 5 R

Scheme 5. Reaction scheme of ring-strain promoted click chemistry with substituted cyclooctynes [14]. 1210 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

3 3 PR 3 R 3P=O

R R OH +HN3 N3 R1 R1

O R2 O O H N O O O O N R2 N N R2 H R2 O

Scheme 6. The Mitsunobu reaction for the synthesis of azides [24]. and coworkers [10] found that 1,3-dicyclohexyl-2,3-dihy- nitrogen in the ring which can be used for probe conjuga- dro-1H-imidazol-2-ide (ICy) (4) is a very effective ligand tion and at the same time it disrupts the hydrophobic sur- for the alkyne-azide click reactions. ICy was reported to face of the cyclooctyne moiety. The two methoxy groups complete the reaction within 90 min with catalyst loadings also make DIMAC more hydrophilic. As a result, DIMAC is as low as 40 ppm. water soluble. (Scheme 6) CuI-catalyzed synthesis of 3,5-disubstituted isoxazoles was also reported by Sharpless and coworkers [5] 3. Synthesis of organic azides and alkynes (Scheme 3). The synthesis of these isoxazoles has been reported to Due to their high reactivity, organic azides have many be faster than the corresponding triazoles. This reaction applications as intermediates in organic reactions. For uses nitrile oxides as reactive intermediates. Nitrile oxides example, azides can be used for the synthesis of heterocy- are easily prepared by the oxidative halogenation/dehy- cles, amines and isocyanates (Curtius rearrangement [19]). drohalogenation of the corresponding aldoximes [11]. Organic azides can be synthesized via five routes [20]: Aldoximes are synthesized readily in high yields from their aldehyde precursors by a reaction with hydroxylamine Insertion of the N3 moiety via substitution or addition, hydrochloride. From these aldoximes, imidoyl chlorides Diazo transfer (insertion of N2), are produced using the procedure reported by Howe and Diazotization (insertion of N), coworkers (Scheme 4) [12]. Degradation of triazines and their analogs, Ring strain has been used as a tool to avoid the use of Rearrangement of azides. CuI catalysis in the synthesis of triazoles (Scheme 5) [13– 15]. This variant of click chemistry is especially interesting Polymer products are difficult to purify, especially from for products that have their applications in biological sys- other polymeric contaminants. Therefore, only reactions tems, because this reaction does not require the use of with extremely high yields are suitable for polymer func- I the toxic Cu catalyst. However, the major drawback of this tionalization. The substitution of halides with sodium route is the synthesis of the cyclooctynes, which is usually azide is used frequently in polymer chemistry. Halide- laborious. functional polymers are readily obtained via atom-transfer Copper-free azide–alkyne cycloadditions were reported radical polymerization (ATRP). The subsequent substitu- 0 with cyclooctynes substituted on the R or R position in tion of the halide with sodium azide yields a polymer with Scheme 5. Electron-withdrawing substituents on the cyc- a high fraction of azide chain-end functionality [21,22]. looctyne ring, like the 1,2:5,6-dibenzo substituent (5) re- Amines can be converted into azides using a two step reac- ported by Boons and coworkers [14] show an increase in tion. First, the amine is reacted with sulphuric acid and so- reaction rate. Bertozzi and coworkers [16] reported a diflu- dium nitrite. After the diazotization the product is reacted orinated cyclooctyne (DIFO) that has a 63 times shorter with sodium azide to form the corresponding azide in high reaction time than cyclooctyne. This DIFO was later ap- yield [23]. The Mitsunobu reaction [24] can be used to sub- plied in live zebrafish embryos [17]. The embryos were ex- stitute primary and secondary alcohols with azides. This posed to an azide-functional sugar which was incorporated reaction uses triphenyl phosphine and diethyl azodicar- in the glycans of the cell membrane. Then, at two different boxylate (DEAD) (or derivatives of DEAD like diisopropyl times, the embryos were exposed to DIFO with two differ- azodicarboxylate (DIAD)) and hydrogen azide. ent fluorescent probes. The images showed the different Due to the hazards of working with DEAD, polymer development stages of glycans in the embryos. This clearly bound DEAD has been used. Lipshutz et al. [25] developed proved that DIFO and other cyclooctynes have applications a stable crystalline azodicarboxylate (di(p-chloroben- in the biomedical field and can be applied even in live zyl)azodicarboxylate (DCAD))(see Fig. 2) that is easily organisms. However the solubility of these cyclooctyne recovered and recycled from the reaction mixture. conjugates in water is very poor. To overcome this problem In one of the examples, DCAD (6) was used to introduce Bertozzi and coworkers developed a hydrophilic azacyc- alkynes. Propargyl alcohol was reacted in the Mitsunobu looctyne derived from a sugar starting compound [18]. reaction with a thiol to quantitatively form the corre- This 6,7-dimethoxyazacyclooct-4-yne (DIMAC) contains a sponding thiolether containing the alkyne moiety [25]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1211

O N N O thiourea, aromatic heterocycles, oxime ethers, hydrazones and amide formation [1]. Fig. 3 shows some examples of O O O O acetal-like products synthesized via carbonyl chemistry, O O N N i.e. the reaction between the relevant diols and hydroxysulfonamides. Cl Cl 6 7 4.3. Addition reactions to unsaturated carbon–carbon bonds

Fig. 2. The structures of DCAD (6) and DEAD (7). Oxidative additions and some Michael additions of Polymers synthesized via RAFT have successfully been Nu–H to carbon–carbon multiple bonds belong to the click modified into azides and alkynes using the Mitsunobu chemistry family as well. The most famous reactions are reaction. Using propargyl alcohol with thiol end-functional the epoxidation and dihydroxylation (Sharpless [32] was awarded the Nobel Prize in chemistry for this type of polymers (obtained via RAFT) as the nucleophile or HN3 as the nucleophile on polymers bearing an alcohol end-group reaction in 2001). The osmium-catalyzed dihydroxylation (obtained via RAFT) [26]. Other ways of making alkynes in- reaction goes to very high yields even for electron-defi- volve the elimination of two hydrogen and two halogen cient olefins when the new ‘‘tricks’’ reported by Sharpless atoms in a double dehydrohalogenation reaction with a and coworkers [33] are used. These tricks include keeping strong base like potassium tert-butoxide [14] or via selen- the pH between 6 and 4 and the addition of citric acid diazoles [27]. together with the frequently used 4-methylmorpholine N-oxide (NMO). Other examples of oxidative additions are aziridination and sulfenyl halide addition [1]. In the 4. Other examples of click chemistry field of synthetic polymer chemistry, thiol-ene chemistry is experiencing a revival. Although the reaction has been 4.1. Nucleophilic substitution used for decades, the present interest in modular, orthogonal and highly efficient reactions has led to its application From the wide range of known nucleophilic substitu- in the synthesis of complex macromolecular architectures. tion reactions, especially the SN2 ring-opening reactions of electrophilic heterocycles that possess a large amount 5. Living radical polymerization of ring strain are considered to be ‘‘click’’ reactions [1]. Substrates for this reaction that are reliable, stereospecific, Free radical polymerization is frequently used in indus- high in regioselectivity and high in yield in this type of try for the production of a wide range of polymers. This is reaction are among others epoxides [28], aziridines mainly due to the robustness of the reaction. A range of dif- [29,30] and episulfonium ions [1,31]. Scheme 7 shows an ferent monomers can be polymerized and the reaction is example of a nucleophilic ring-opening of aziridines. relatively insensitive towards water and oxygen. However, one of the major disadvantages is the lack of control over 4.2. Carbonyl chemistry the polymerization. Since the last years of the 20th cen- tury, a number of controlled or living radical polymeriza- ‘‘Non-aldol’’ type carbonyl reactions also meet the tion (LRP) techniques have been reported. Rizzardo and requirements of click chemistry. Examples here are a, coworkers [34,35] reported on the nitroxide stable radical

Ts Nu NHTs M-Nu N R + R OH OH R OH NHTs Nu

Scheme 7. The nucleophilic ringopening of aziridines as reported by Tanner et al. [30].

N3 O N O O 3 O Ph N 3 H H O N O O Ph Ts 89N3 10

O O N 3 N 3 HO HO O N 3 O N 3 11 12

Fig. 3. Five acetal-like derivatives synthesized by Sharpless and coworkers [1]. 1212 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

Initiation

Monomer I Pn

Chain transfer

S S S S S S Pn R Pn R Pn R M Z Z Z

Reinitiation

Monomer R Pm

Chain equilibration

S S S S S S Pm Pn Pm Pn Pm Pn Z Z Z M M

Scheme 8. The RAFT mechanism as reported by Rizzardo and coworkers [42]. in 1985. Georges et al. [36] reported the first low polydis- to the CTA to form an intermediate radical. The fragmenta- persity index (PDI) polymers synthesized through Nitrox- tion of the intermediate radical produces either a new ide-mediated Polymerization (NMP). After NMP, a radical on the leaving group R, which can re-initiate poly- number of new LRP methods have been reported: merization (chain transfer), or it releases the incoming propagating radical. The chain equilibration step is the Atom Transfer Radical Polymerization (ATRP) [37,38] main equilibrium. This step controls the polymerization Reversible Addition Fragmentation chain Transfer by dynamically exchanging the active polymer chain radi- (RAFT) [39] cal among chains, while keeping most chains in the dor- Single-Electron-Transfer Living Radical Polymerization mant CTA end-capped state due to the stoechiometry (SET-LRP) [40]. between active growing chains (radicals) and (macro) chain transfer agents. RAFT-mediated polymerization is a The introduction of LRP allowed polymer scientists to robust technique that has been used for the LRP of a wide design and build an extended range of macromolecular range of vinyl monomers. architectures based on vinyl monomers [41]. 5.2. ATRP 5.1. RAFT ATRP was first almost simultaneously reported by RAFT-mediated polymerization was first reported in Sawamoto and coworkers [37] and by Matyjaszewski and 1998 by Rizzardo and coworkers [39]. RAFT uses thiocar- coworkers [38]. Sawamoto reported ruthenium-mediated bonyl thio species as chain transfer agent (CTA). The gener- polymerization and Matyjaszewski the nowadays more ally accepted mechanism is shown in Scheme 8. popular copper-catalyzed version of ATRP. The general For a typical RAFT-mediated polymerization, the fol- mechanism of ATRP is shown in Scheme 9. lowing compounds are needed: CTA, monomer and a radi- The following chemicals are needed for a typical ATRP cal source. This radical source is usually a thermally reaction: alkyl halide initiator, monomer, metalI halide decomposing initiator, for example AIBN. However, the (note that other oxidation states than MI or MII can be used use of c and UV radiation has also been reported [43,44]. as long as the oxidation state changes by one electron) and As shown in Scheme 8, an initiator-derived primary radical a ligand. As shown in Scheme 9, the metal complex homo- initiates a polymer chain and this growing chain then adds lytically cleaves the halide from the initiator, generating an

kact n n+1 RX + Mt -Y/Ligand R + XMt -Y/Ligand kdeact kp kt monomer termination

Scheme 9. The ATRP mechanism as reported by Matyjaszewski et al. [45]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1213

kp +M ka I II RX + Cu X/Ligand R + Cu X2/Ligand kda

+ II RR Cu X2/Ligand

Oxidized Agent

Reducing Agent

Scheme 10. The ARGET-ATRP mechanism as proposed by Matyjaszewski and coworkers [46].

kact CuIX/L

kdis

0 II k +nM Pn X Cu + Cu X2/L Pn p

kdis kt

CuIX/L

kdeact

Pn Pn

Scheme 11. The SET-LRP mechanism as proposed by Percec et al. [40]. initiator radical plus a metalII complex. The initiator-de- overcome these problems ARGET-ATRP (activator rived primary radical initiates a propagating chain via regenerated by electron transfer) was introduced by addition to the monomer. The propagating chain is deacti- Matyjaszewski and coworkers [46]. ARGET-ATRP uses a vated by the metalII complex generating a metalI complex reducing agent like stannous 2-ethylhexanoate to reduce II and a Pn –X dormant chain. Since the equilibrium of this the excess Cu that is formed during the polymerization reaction is shifted heavily towards the dormant chains, due to bimolecular termination reactions. This allows for the concentration of propagating radicals present in the the concentration of Cu complex in the reaction mixture reaction mixture is low. This limits termination and control to be lowered to values as low as 10 ppm (the required over the polymerization is obtained. concentration is monomer dependent). ARGET-ATRP is The major drawback of ATRP is the relative sensitivity based on the earlier discovery by Klumperman and of the metal complex towards air and the fact that the ﬁnal coworkers that reducing sugars are able to enhance the product will contain substantial amounts of metal. To rate of an ATRP reaction [47]. 1214 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

O N

O N monomer Pn N O kp Pn monomer kt termination

Scheme 12. The mechanism of NMP.

sisting of a TEMPO molecule bound to an initiator radical or propagating radical. The bond that is formed between a O propagating radical and TEMPO is reversible (Scheme 12). P O However, high temperatures (>120 °C) are required to split O N O N O the alkoxyamine into a persistant TEMPO radical and a transient, propagating radical. 13 14 To overcome the problems presented by the high temperatures needed for TEMPO polymerizations, second gen- Fig. 4. 2,2,5-Trimethyl-4-phenyl-3-azahexane-3-nitroxide (TIPNO) (13) eration alkoxyamines were introduced [51,52]. These [51] and N-tert-butyl-N-(1-diethylphosphono-2,2-dimethyl)-N-oxyl second generation alkoxyamines can be used at tempera- (DEPN or SG1) (14) [53]. tures below 100 °C. In addition, the second generation alkoxyamines can be used to polymerize acrylates and dienes next to styrene. Two examples of second generation alk- ARGET-ATRP follows the same basic mechanism as oxyamines are shown in Fig. 4. ATRP. However, as shown in Scheme 10, the reducing II agent reduces the Cu that is formed, due to termination 6. The combination of living radical polymerization and I I II reactions, back to Cu . The ratio of Cu to Cu can be con- ‘click’ chemistry trolled in this way, which allows the polymerization to proceed at an acceptable rate, while producing a polymer Over the past two decades, a remarkable number of with low PDI [48]. publications were dedicated to the development of new polymerization techniques. The living radical polymeriza- 5.3. SET-LRP tion techniques have been mentioned above, but next to that, several transition metal catalyzed polymerization Single Electron Transfer (SET)-LRP was introduced by reactions were reported, e.g. ring opening metathesis Percec et al. [40]. The authors claim that SET-LRP is cata- polymerization (ROMP), metallocene-catalyzed olefin lyzed by extremely reactive Cu0 that is formed by low acti- polymerization, etc. Apart from the new polymerization vation energy outer-sphere single-electron-transfer. The techniques, there is a tendency of organic chemistry and reaction is controlled or deactivated by CuII species that polymer chemistry approaching each other in the synthe- are formed via the same process (see Scheme 11). It has sis of complex macromolecules [41]. In accordance with been reported that SET-LRP is very effective at room tem- this trend, the number of reports on the combination of perature and that extremely high molecular weights can click chemistry and LRP has been growing rapidly in the be obtained in conjunction with a low PDI. Even in the past few years [54–57]. presence of typical radical inhibitors such as phenol, SET- LRP shows control over the molecular weight distribution 6.1. RAFT and click chemistry and exhibits a high reaction rate [49]. The mechanism of SET-LRP is still under debate. Mat- The combination of RAFT and click chemistry has been yjaszewski and coworkers [50] reported that according to reported in a number of ways. their results the reaction follows the same mechanism as Alkyne and azide-functional polymers were synthesized 0 ARGET-ATRP and the role of Cu is limited to that of the by post-polymerization modification of polymer synthe- reducing agent. sized via RAFT-mediated polymerization by Caruso and coworkers [58]. The polymers obtained after this modifica- 5.4. NMP tion were used to produce an ultrathin polymer multilayer by applying click chemistry to these polymers in combina- NMP is based on the nitroxide radical. The most com- tion with a layer-by-layer assembly technique (Scheme 13). mon first generation nitroxide is TEMPO (2,2,6,6-tetra- A trimethylsilyl (TMS)-protected alkyne RAFT agent methyl-1-piperidinyloxy free radical). When TEMPO is (16) and azide-functional RAFT agents (15 and 17) have added to a styrene polymerization, equilibrium is reached been reported (Fig. 5) [59,60]. The azide and alkyne-func- between the TEMPO free radical and an alkoxyamine con- tionality are introduced in the R group of the RAFT agent. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1215

N3 N3 N3

N N N 3 3 3 N NNNNNNN N N N N N3 N3 N3 N3

Cu I

CuI

N N N N N N N N N

N NNNNNNN N N N N

Scheme 13. Schematic overview for the synthesis of ultrathin polymer multilayers [58].

O O O S O S S S N O O N O 3 S 3 10 S S Si 15 16 17

Fig. 5. Structures of azide (15 and 17) and TMS-protected alkyne (16) functional RAFT agents.

Scheme 14. Polymer–protein conjugates synthesized by Sumerlin and coworkers [63].

These and similar RAFT agents were used to generate longer valid because the degree of functionalization will block copolymers and telechelic polymers [59,60], poly- be limited to the amount of azide left. However the mers with fluorescent end-groups [61], bio-conjugates amount of side reactions can be decreased if short reaction (Scheme 14) [62,63], folate (targeting ligand) functional- times and/or low temperatures are used. ized thermoresponsive block copolymers [64] and Brittain and coworkers [70–72] reported the use of an branched poly(N-isopropyl acrylamide) (PNIPAM) [65–67]. alkyne-functional RAFT agent without the TMS protecting However, the use of azide-functional RAFT agents and group. The obtained polymers were used for surface mod- monomers, under normal free radical polymerization con- ification of silica. This RAFT agent was used in different ditions, is debatable. The groups of Benicewicz [68] and ways. Firstly, the RAFT agent was used in the polymeriza- Perrier [69] reported up to 60% loss of azide functionality tion of styrene. The obtained polymer was ‘‘clicked’’ on during the polymerization. The suggested pathway behind azide-functional silica nanoparticles (Scheme 16). Sec- the loss of azides is shown in Scheme 15. ondly, the RAFT agent was ‘‘clicked’’ on the azide-func- When azide functions are lost, the benefits of click tional silica nanoparticles and styrene was polymerized chemistry, like high yields and little side products, are no onto the RAFT agent functionalized particles. Thirdly, this 1216 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

R N S S O O S HN O N3

O -N NH 2

O O NH R N NH H N N N 2 R N

O R O N HN H NH H NH N N O S S R= O S O

Scheme 15. The side products found by matrix-assisted laser desorption ionization time-of-ﬂight mass spectrometry (MALDI-ToF-MS) by Perrier and coworkers [69].

OH OH HO Cl R O SiO Cl si HO 2 OH + SiO2 O Si Cl Br O HO OH R Br OH

NaN3

R O R SiO2 O Si O CuI O SiO2 O Si R N N O N R N3

O S S O 10 O S n S S N O O 10 n H H S N O H H

Scheme 16. The modiﬁcation of silica particles with alkyne-functional polymers obtained via RAFT [70]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1217

H R Block copolymers of polyisobutylene and NIPAM were H H H N N O obtained when an alkyne-functional trithiocarbonate was O H O HO O HO N N H OH H OH H OH O clicked on an azide-functional polyisobutylene [78]. H H H O The synthesis of cyclic PSTY via RAFT and click chemistry O O O O O O has been reported [79]. The azide function was introduced H H H H H H S via the R group of the RAFT agent and the alkyne was intro- S 18 O duced via the removal of the Z group. The Z group was removed using the addition of radicals formed from azo- bis(4-cyano valeric acid) esteriﬁed with propargyl alcohol Fig. 6. Dextran RAFT agent prepared via click chemistry [75]. using a procedure reported by Perrier and coworkers [80]. Graft copolymers of vinyl acetate have been reported using a TMS-protected propargyl methacrylate monomer S R S [81]. In this case, a backbone was grown via RAFT using al- + R S Z + KBr kyne-functional monomers. These alkyne functions were Br K+ -S Z used for click chemistry with polymers bearing an azide

R1 N3 end-group (obtained from an azide-functional RAFT agent) (Scheme 18). with R = H, CH3 R S Van Hest and coworkers used the Mitsunobu reaction to synthesize an azide functional monomer from HEMA (2- S Z R1 N azidoethyl methacrylate (AzMA)). This AzMA was poly- N N merized via RAFT (homopolymers and co-polymers with HEMA were made), and reacted with diacetylene deriva- Scheme 17. The synthetic route towards the RAFT agents bearing a tives of triethylene glycol yielding stable coatings (normal triazole-based leaving group [77]. acetylene and cyclooctyne derivatives were used) [82]. The cyclooctyne derivatives obviously led to the copper-free RAFT agent was clicked and polymerized in a one-pot syn- version of azide–alkyne click chemistry, which was thus thesis of polystyrene (PSTY) grafted silica nanoparticles. pioneered by van Hest in the polymer ﬁeld. Gold nanoparticles were also modiﬁed via click chemistry Thiols and isocyanates react to form thiocarbamates. and RAFT [73]. Pan and coworkers [74] also reported the When triethylamine is added as a catalyst, this reaction also use of an unprotected alkyne-functional RAFT agent. This falls under the click chemistry domain. Poly(N,N-diethyl- RAFT agent was used to synthesize tadpole-shaped amphi- acrylamide) was synthesized via RAFT-mediated polymeri- philic polymers. zation. The dithiobenzoate end-group was converted into a Charleux and coworkers [75] prepared a xanthate-func- thiol via aminolysis with methylamine. The thiol end- tionalized dextran RAFT agent (18) via click chemistry groups were used in the triethylamine-catalyzed reaction (Fig. 6). The xanthate moiety was linked through the R between different commercially available isocyanates, group via an azide to an alkyne terminated dextran. The yielding thiocarbamate end-functional polymers [83]. obtained RAFT agent was used for surfactant-free emulsion The Diels–Alder reaction between the thiocarbonyl thio polymerization. moiety and polymers functionalized with cyclopentadiene Dendritic polymers were obtained when poly(N-(2- was utilized by Barner-Kowollik and coworkers [84]. This hydroxypropyl) methacrylamide) was clicked onto den- reaction allows for the synthesis of block copolymers in dritic mannose scaffolds [76]. Klumperman and coworkers [77] introduced the triazole leaving group for RAFT. This triazole moiety was intro- R* duced by clicking an alkyne-functional RAFT precursor O S * + R S O onto an azide substrate. Both aromatic and aliphatic sub- OP R O S R S P strates were used. Block copolymers were obtained when O O an oligosaccharide was used as the azide substrate (Scheme 17). The advantage of this methodology is that R = Polymer obtained via RAFT the obtained block copolymer is not linked via an ester R* = PEG or polymer from ATRP but via a triazole, which proved to have excellent stability against hydrolysis. Scheme 19. Scheme of Ultra-fast hetero Diels–Alder click [84].

CuI

THF N N N N NN NN NN NN

Scheme 18. Schematic overview of the synthesis of brushes via click chemistry [81]. 1218 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

R* R* O S O n R* Grubbs 2nd generation OP + S O S P R P O O S R S R S O O O

2 R= 3 R=polystyrene 4 R = polystyrene 1 R=

R*= H R* =H R* =PEG

Scheme 20. General reaction scheme with 1 = the RAFT agent (phenethyl(diethoxyphosphoryl)-dithioformate) and 2 = diethyl 3-(1-phenylethylthio)-2- thiabicyclo[2.2.1]hept-5-en-3-ylphosphonate (DPTHP). 3 and 4 are polystyrene and poly(styrene-block-ethylene glycol) derivatives respectively [85].

N ATRP and click chemistry can both be carried out with the N acid, heat N N N R N 3, N NH same copper catalyst and the halogen terminus of polymer R N R N H chains obtained via ATRP can easily be converted into the corresponding azide derivative [21,22]. The first report on Scheme 21. Tetrazole formation [92]. the combination of click chemistry and ATRP was in 2004 by Matyjaszewski and coworkers [92]. In this paper the seconds (Scheme 19). It also combines RAFT with ATRP be- authors did not use the usual alkyne-azide click chemistry, cause the cyclopentadiene is easily introduced by a reac- but the reaction of sodium azide with a cyanide to form a tion between the halide chain-end of a polymer obtained tetrazole was applied (Scheme 21). via ATRP and the sodium salt of cyclopentadiene. End-group functionalization via click chemistry of poly- The substituted 2-thiabicyclo[2.2.1]hept-5-ene moiety mers (suitable for click chemistry) has been reported. obtained via this reaction can be used in ring-opening Functional groups like carboxylic acids, alkenes, and alco- metathesis polymerization (ROMP) [85]. Grafted copoly- hols have been introduced [93]. Polymer end-group func- mers were obtained in this way (Scheme 20). tionalization allows for the synthesis of macromonomers Thiol-ene click chemistry [86,87] was used for the syn- via ATRP (19, Fig. 7) [94]. This structure would not be thesis of three armed stars of n-butyl acrylate. The thiol accessible through direct synthesis, since the polymeriz- end-functional poly(n-butyl acrylate) was obtained via able end-group of the macromonomer would obviously RAFT-mediated polymerization and subsequent aminoly- interfere with the polymerization of styrene. Copper-free sis. The thiol end-functional polymers were reacted click chemistry was used for the end-group modification in situ via phosphine-catalyzed thiol-ene click chemistry of poly(oligo(ethylene glycol methacrylate) (P(OEGMA)). [88]. End-group modification of p(NIPAM) was also Alkyne-functional P(OEGMA)s were reacted with different achieved via thiol-ene and thiol-yne click chemistry [89]. aromatic oximes without the use of copper. The interesting Recently, a type of click chemistry based on nucleo- feature here is that only the 3,5-isomers were found and philic substitution involving RAFT-moieties was reported. non of the 3,4-isomers, presenting an interesting regiose- The ‘‘thio-bromo’’ click reaction was reported by Davis, lective version of copper free click chemistry [95]. Interest- Lowe and co-workers [90]. After model reactions on low ingly, it was reported that end-group modification may molar mass RAFT agents, they show that a-bromo esters lead to variation in the thermoresponsive properties of can conveniently be used to create a thioether-functional- polyNIPAM [96]. Hence, tuning of the thermoresponsive ized polymer. properties can be conveniently carried out by a post-polymerization process. 6.2. ATRP and click chemistry Telechelic polymers are polymers where both a and x chain-ends have a functional group. Telechelic polymers ATRP and click chemistry have been used together suitable for click chemistry have been reported extensively [91]. This combination is very popular because [21,97,98]. In a typical example, an a,x-dibromo-func-

HO N N N N O N N O n N O N N n OH R O

19 20

Fig. 7. Structure of macromonomer (19) [94] and telechelic polymer (20) [97] synthesized via ATRP and click chemistry. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1219

O O O O O + N3 O 5 n O Br

O Method 1 Method 2 O Click Chemistry ATRP

N O O O O n N O 5 O N O O N N O 3 Br O O p O Br N

ATRP Click chemistry

O O O O N O n N 5 O O N N O O

21 Br O p O

Scheme 22. The synthesis of block copolymers of p-(DMAEMA) and p-(e-carpolactone) (21) via ATRP and click chemistry [102].

tional ATRP initiator is used to synthesize polystyrene. The copolymer is obtained from click chemistry with a propar- two bromine end-groups are subsequently transformed gyl terminated mono-methoxy poly(ethylene glycol) of into azides by reaction with sodium azide. Finally, propar- different chain length. gyl alcohol is clicked on the chain-ends to yield a,x-dihy- Van Hest and coworkers were among the first to report droxy-functional polystyrene (20, Fig. 7) [97]. on the synthesis of block copolymers via a combination of Block copolymers have been prepared from the ob- ATRP and copper-mediated click chemistry [105]. They tained telechelic polymers. First, a-acetylene-x-azido-ter- later reported on the synthesis of ABC triblock copolymers minated PSTY was chain extended via step-growth click via a similar combination of ATRP and click chemistry. polymerization [21,99]. When telechelic polymers were They synthesized sequence-defined oligomers in a stepwise used, multiblocks of polystyrene and poly(ethylene glycol) approach [106]. The oligomers were either synthesized (PEG) were obtained [100]. Ring opening polymerization from an azide-functional Wang resin or using polystyrene (ROP) was also used in combination with ATRP. Poly(e-cap- containing an azide end-group. The azide functionality rolactone) was clicked on a poly(N,N-dimethylamino-2- was reacted with an aliphatic alkyne containing a carboxylic ethyl methacrylate) (p-(DMAEMA)) block [101]. The same acid. Triethylene glycol bearing an amine and an azide as block copolymer was later reported in a one-pot synthesis end-groups was used as the monomer with complementary (Scheme 22) [102]. Block copolymers of acrylic acid and 1- functionality. Click chemistry and DCC coupling were ethoxyethyl acrylate have also been synthesized using this used in one pot to obtain alternating oligomers. Lutz and method [103]. ABA asymmetric triblock copolymers of coworkers further investigated the stepwise synthesis of poly(ethylene oxide) (PEO) and PSTY were reported polymers via living radical polymerization, inspired by [104]. Mono-methoxy poly(ethylene glycol) was converted natural polymers that exhibit perfect sequence control [107]. into an ATRP initiator via the commonly used esterification PSTY, poly(tert-butyl acrylate) and PMMA containing azide with bromo-isobutyryl bromide. A polystyrene block is and triisopropylsilyl-protected alkyne end-groups have synthesized under normal ATRP conditions. Subsequently, been synthesized and clicked together sequentially. First, the terminal bromide is substituted with an azide by stir- the azide-functional PSTY was clicked onto the alkyne- ring with sodium azide. The final asymmetric ABA triblock functional poly(tert-butyl acrylate). The remaining protected 1220 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

was polymerized on this difunctional ATRP macro initiator to yield an ABA block copolymer. Hydrolysis of the solketal methacrylate yielded a polyglycerol monomethacrylate (PGMA) triblock copolymer. The bromine end-groups were replaced by azides and the nonadecafluoro-1-decyl hex-5- ynoate (F9) C blocks were clicked on the obtained diazide end-functional ABA copolymer (Fig. 8) [110]. Grafted copolymers have been synthesized in different approaches. An azide-functional monomer was used to prepare azide-functional backbones [22,111]. Halide-functional e-caprolactone was synthesized and ROP of this monomer yielded a primary halide-functionalized backbone. The halide was substituted with an azide and a bromoisobutyryl group was clicked on the polymer. These bromoisobutyryl groups were used as ATRP initiators for PSTY yielding poly(-caprolactone-graft-STY). Glycidyl methacrylate was polymerized and subsequently reacted Fig. 8. CABAC block copolymer from PPO PGMA and nonadecafluoro-1- with sodium azide to yield azide-functionalized backbones. decyl hex-5-ynoate (F9) synthesized via click chemistry and ATRP [110]. On these backbones, alkyne-functionalized PEO was clicked [112]. Poly(2-hydroxyethyl methacrylate) synthesized via alkyne (on the PSTY) was deprotected and the diblock ATRP was reacted with pentynoic acid to yield an alkyne was clicked onto the azide-functional PMMA [108]. ROP grafted polymer. On these alkyne groups, polymers with was used for the synthesis of ABC-triblock copolymers in azide functionality were clicked so that densely grafted combination with ATRP and click chemistry. A macro-ATRP polymers were obtained [113]. A combination of NMP, click initiator of poly(ethylene oxide) (PEO) was prepared via chemistry and ATRP was used to produce well-defined mul- esterification of PEO with 2-bromo-2-methylpropionyl tifunctional graft copolymers of poly(pentafluorostyrene) bromide and a PSTY block was synthesized via ATRP [114]. Diels–Alder click chemistry between maleimide using this initiator. Then the bromine end-group was and anthracene was used to prepare PSTY-graft-PEO [115]. substituted with an azide. Poly(e-caprolactone) was syn- 3-Acetyl-N-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-5- thesized via ROP using propargyl alcohol as the initiator. ene-2-carboxamide-functional PEG was used for an in situ The poly(e-caprolactone) was clicked on the azide-functional retro Diels–Alder and Diels–Alder reaction with anthra- PEO-block-PSTY. cene-functionalized polymers (Scheme 23). ABC triblock copolymers containing polypeptide seg- Neo-glycopolymers were synthesized via a trimethyl- ments were synthesized using the same combination of silyl-protected alkyne-functional monomer which was ATRP, click chemistry and ROP [109]. polymerized via ATRP. The alkyne functionalities were ABC triblock and CABAC pentablock copolymers have de-protected and sugars containing azide groups were been synthesized using solketal methacrylate, polypropyl- clicked on the backbone (Fig. 9) [116]. In a similar fashion ene oxide (PPO) and alkyne-functional nonadecafluoro-1- phenylpropargyl ether was clicked on azide-functional decyl hex-5-ynoate. To prepare the CABAC pentablock backbones [117]. copolymer, the hydroxyl end-groups of PPO were esterified Cyclic polymers have been reported via alkyne-func- with 2-bromoisobutyryl bromide. Solketal methacrylate tional ATRP initiators where the alkyne functionality was

O O Toluene + N n n m-n m-n m m PEG Reflux O

O O

O N O

PEG

Scheme 23. Grafted copolymers synthesized via anthracene and maleimide Diels–Alder click chemistry [115]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1221

Fig. 9. Neo-glycopolymer (left) [116] and eight-shaped block copolymer (right) [123] synthesized via ATRP and click chemistry.

either trimethylsilyl-protected or unprotected. After polymerization, the bromide terminus was substituted with an azide (and if applicable, the alkyne was de-protected). Br O A click reaction in highly diluted solution yielded cyclic O PSTY and cyclic poly(methyl acrylate)-block-PSTY O [118,119]. A similar approach was followed to synthesize O O cyclic polyNIPAM [120], p(STY-block-PEO) [121] and O grafted PEG [122]. O O O Eight-shaped copolymers were obtained when a difunc- N tional ATRP initiator with two hydroxyl groups was used for ROP and ATRP and subsequent click cyclization (Fig. 9) [123]. H-shaped polymers have been synthesized by a combi- 22 nation of NMP, ATRP and click chemistry [124]. The syn- Fig. 10. The ATRP initiator functionalized with an alkyne and TEMPO thesis started with the difunctional initiator (ATRP and group (22) as reported by Tunca and coworkers [125]. NMP) that carries an alkyne functionality as reported by

Scheme 24. Photocleavable network synthesized via ATRP and click chemistry [127]. 1222 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

N O N N Poly(styrene)

Fig. 12. Polystyrene-grafted carbon nanotube [134].

functional FMOC-amino acid was used to obtain a starting point for solid phase synthesis of polypeptides. Also, an Fig. 11. Grafted copolymer containing a hydrolysable link for non-viral RGD-containing oligopeptide was clicked onto the same gene delivery [128]. azide-functional poly(oligo(ethylene glycol) acrylate) [129]. A biotin conjugate using the same polymer was re- Tunca and coworkers (22, Fig. 10) [125]. PSTY and PMMA ported [130]. Another approach consists of attaching an were synthesized by NMP and ATRP respectively. This cre- ATRP initiator to the biomolecule and polymerizing from ated a block copolymer with an alkyne functionality at the the biomolecule. This technique was reported by Wang junction point. Two such block copolymers were clicked and coworkers [131]. In the same publication, an alkyne together with an a,x-diazide-functional PEG or poly(tert- functionality was introduced on a nanoparticle. To this al- butyl acrylate) to yield the H-shaped polymer. kyne, an azide-functional fluorescent marker was clicked. Amphiphilic networks of poly(e-caprolactone) and Velonia and coworkers [132] reported the polymerization polyDMAEMA have been synthesized via the combination of an alkyne-functional monomer onto a protein. After of ATRP, ROP and click chemistry [101]. Degradable net- the polymerization, a hydrophobe was clicked to the mol- works have been reported from macromonomers synthe- ecule so that a giant amphiphilic conjugate was formed. sized via ATRP. The use of a difunctional initiator Complex bio-conjugates were obtained via ATRP and click containing a C = C double bond yielded a bromide telech- chemistry, up to four different functionalities were at- elic polymer, which was transformed into an azide via tached to a polymer [133]. reaction with sodium azide. This telechelic azide was Conjugates with other molecules have also been re- clicked on a multi alkyne compound, which was tri- or tet- ported. Single-walled carbon nanotubes were functional- ra-ether of pentaerythritol and propargyl alcohol. Degrada- ized with alkynes. Styrene that was polymerized via tion of the network was achieved by ozonolysis of the C = C ATRP was azide-functionalized and clicked onto the carbon double bonds of the ATRP initiator [126]. The same ap- nanotube (Fig. 12) [134]. Fullerenes were modified in a proach was used to synthesize photocleavable hydrogels. similar fashion [135]. In this case the difunctional ATRP initiator used, contained The previously mentioned layer-by-layer technique re- a photocleavable group (Scheme 24) [127]. ported by Caruso and coworkers [58] was also applied on The field of pharmaceutical and biomedical applications carbon nanotubes in combination with ATRP. The surface in polymer science is a growing field of interest. The com- of multiwalled carbon nanotubes (MWNTs) was decorated bination of ATRP and click chemistry has been reported in with alkyne functionalities. The layer-by-layer process was the field of gene delivery. PDMAEMA is a well-known cat- performed to create a thin layer of polymer on the MWNTs. ionic polymer that condenses DNA. In principle, a high At the end of the process, a fluorescent dye or end-func- molecular weight polymer is needed. However, the higher tional PSTY was grafted on the polymer layer [136]. Micro- molecular weight PDMAEMA is very cytotoxic. To over- capsules were obtained in a similar fashion. In this case, come this problem, low molecular weight PDMAEMA was the layer-by-layer deposition and click chemistry were synthesized via ATRP and subsequently azide-functional- performed on the surface of azido-modified silica particles. ized. The azide-functional groups were clicked on a back- After the layer-by-layer assembly, the silica core was dis- bone via a degradable linker to obtain a degradable high solved by treatment with HF to yield the microcapsules molecular weight PDMAEMA with reduced toxicity [137]. (Fig. 11) [128]. Multi-responsive shell cross-linked micelles were also Bioconjugation is another field where the combination produced using ATRP and click chemistry [138]. The shell of ATRP and click chemistry has been reported. The easy of a triblock copolymer micelle was crosslinked by the access to azide end-functional polymer makes ATRP a good reaction of N,N-diethylamino ethyl methacrylate (DEA- candidate for polymer-peptide conjugation. The synthesis EMA) residues with a di-iodo compound to yield bis-qua- of x-azide-functional poly(oligo(ethylene glycol) acrylate) ternary ammonium salt alkyl bridges. Click chemistry at has been reported. Several alkyne-functional compounds the alkyne chain-end functionality of the triblock copoly- were used to click onto the azide end-group. Click chemis- mer was subsequently used to introduce pH- and temper- try between the azide-functional polymer and an alkyne- ature-responsiveness [138]. When block copolymers were N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1223

HO O Br OH HO O O HS OH S O n Et3N, CH3CN n O O "Branch" O O

2 Br Cl 2 O Br Pyr, CH

O O O Br "Grow" Br O O O n O O O O O O O O Br S O O O 0 II S Cu /Cu Br2 Br O n Me -Tren,DMSO O O 6 O O n n O O O O

Scheme 25. The ‘‘Branch’’ and ‘‘Grow’’ thio-bromo click chemistry and subsequent SET-LRP approach used by Percec and coworkers [146,148]. used that respond to different stimuli, like pH and temper- absent from the product, which means that the catalyst ature, the drug release or conformation of these micelles must be totally removed. Koshti and coworkers [145] re- could be influenced [139,140]. ported a self-separating catalyst, which was attached to a Similar to the work of Brittain and coworkers [70–72], polymer synthesized via ATRP. This catalyst can be used silica nanoparticles were modified with ATRP. After the for click chemistry and it separates itself from the product. polymerization of styrene, the bromide end-group was This process is based on the polarity of the ligand. The click transformed into an azide by reaction with sodium azide. reaction was done in a mixture of heptane and ethanol/ Subsequently, different alkynes were clicked on the poly- water (90% ethanol). Upon the addition of an extra 10 % mer chain-ends to yield carboxylic acid, hydroxy, primary (volume) water phase-separation occurs. UV analysis amine and acrylate end-groups [141]. showed that > 99.6% of the copper complex was in the hep- Electrospinning was used to obtain nanofibers of epoxy tane layer. The product could be obtained from the ethanol and chloromethyl-functional polymers. These fibers were phase. modified with sodium azide to have azide functionalities on the surface. After the modification, alkyne end-func- 6.3. SET-LRP and click chemistry tional p(NIPAM) was clicked on the surface and thermoresponsive nanofibers were obtained [142]. So far there have been few reports on SET-LRP com- Grafting of poly(glycidyl methacrylate) from a poly(high bined with click chemistry. Due to the similarity of SET- internal phase emulsion) (poly(HIPE)) surface was achieved LRP and ATRP, the combination of SET-LRP and click chem- using ATRP. The epoxy functionalities were reacted with so- istry is expected to be versatile. Percec and coworkers dium azide to introduce azide functionalities on the surface [146] synthesized dendritic macromolecules via SET-LRP of the poly(HIPE). Click chemistry was used to graft a vari- and thio-bromo click chemistry [147]. In a three step ety of groups on the surface, including a fluorescent dye to ‘‘branch’’ and ‘‘grow’’ mechanism (Scheme 25) dendritic yield fluorescent poly(HIPE) [143]. structures were obtained. Firstly, thioglycerol was used Because of its wide scope, the combination of ATRP and for the base-mediated thioetherification of the a-bromo- click chemistry has received considerable interest. Mat- ester, this is the ‘‘branch’’ step. Secondly, an acylation reac- yjaszewski and coworkers [144] showed that the reaction tion with 2-bromopropionyl bromide was carried out. rate is catalyst dependant. It is important to choose the Thirdly, SET-LRP was used to polymerize methyl acrylate right catalyst for each system. The major disadvantage of onto the branches, this is the ‘‘grow’’ step. For the different these catalysts is that for some applications Cu must be generations dendrimers (generations 1–5 were used) the 1224 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

Scheme 26. Synthesis of ﬂuorescent nanoparticles via NMP and click chemistry [153].

‘‘branch’’ step was repeated an appropriate number of using ATNRC and SET-LRP at room temperature by Huang times before the SET-LRP was carried out. and coworkers [150]. The combination of ATNRC, SET-LRP Atom transfer nitroxide radical coupling (ATNRC) is a and CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reac- reaction in which TEMPO derivatives are used to end-cap tion for the synthesis of chain extended polystyrene and polymer chains. ATNRC also falls under the category of three-armed stars was carried out by Monteiro and click chemistry [149]. Block copolymers were synthesized coworkers [149].

N N N O O Br O N3 O Br O O N NN N NN

MMA ATRP S O

S O = n

=PMMA N N N O

O N NN N NN

Scheme 27. Schematic overview of the preparation of four armed star [166]. N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1225

6.4. NMP and click chemistry the particles. These nanoparticles proved to be a very efficient catalyst for click chemistry [154]. The first article reporting on the combination of NMP Alkoxyamine initiators functionalized with alkyne and and click chemistry was published in 2005 and dealt with azide groups have been reported and used for the synthesis the orthogonal approaches for functionalization of macro- of functionalized polymers and block copolymers [155].As molecules. With the combination of NMP, click chemistry discussed previously, Tunca and coworkers [124,125] re- and other reactions, polymers with multiple functionalities ported the TEMPO-based version of these initiators. were synthesized [151]. There have been multiple reports on the synthesis of functional nanoparticles via the combination of NMP and 7. Miktoarm star polymers click chemistry. Click chemistry has been used in different ways. Firstly, a fluorescent label was clicked on the inside Arguably the most impressive examples of combina- of the hydrophobic core of particles [152]. Secondly, the tions of LRP techniques and click chemistry appear in the fluorescent label was clicked on the outside of the shell field of miktoarm star polymer. Star-shaped polymers have (Scheme 26) [153]. been prepared in a number of ways [98,156–164]. A typical Thirdly, a ligand used for click chemistry was attached core molecule consists of pentaerythritol, esterified with to the inside of the shell of the nanoparticle. Click chemis- pentynoic acid. Polymer chains synthesized via ATRP were try of small molecules was done in the hydrophobic core of azide-functionalized and clicked on the core [165]. To obtain the hetero arms necessary for creating the miktoarm O O architecture, a combination of RAFT and ATRP was used. O O PSTY arms were synthesized via RAFT using an azide-func- Br tional RAFT agent. The obtained polymers were clicked on OH a pentaerythritol center of which three alcohols were converted into the propargyl ether and one was esterified with bromo-isobutyryl bromide. The obtained three-armed 23 PSTY was then used as an ATRP initiator for the polymeri- Fig. 13. The ATRP initiator (23) used by Xu and coworkers for the zation of methyl methacrylate (MMA) (Scheme 27) [166]. synthesis of ABC triblock copolymers via sequential click chemistry, ATRP ABC miktoarm stars were synthesized from a core and ROP [170]. containing an alkyne, a bromide and a TEMPO group (22,

O Br + O O n O m o p q r O O O O

Click r O

Br n O

O O O O O

O N q N N O m p o

Scheme 28. Synthesis of ABCD four armed star copolymers [174]. 1226 N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231

Fig. 10)[125]. First, MMA was polymerized via ATRP using this initiator. In the second step, styrene was polymerized via NMP. The final step consisted of the click reaction with an azide-functionalized PEO. Later, the same initiator was used again, but now chains obtained via ROMP were clicked onto the alkyne [167]. Another approach for the synthesis of an ABC miktoarm star was reported by Fu et al. They synthesized an azide end-functional poly(tert-BA), TEMPO end-functional PEO or poly(e-caprolactone) and alkyne end-functional polystyrene. In a one-pot procedure they then combined click chemistry with atom transfer nitroxide radical coupling (ATNRC) to yield the miktoarm stars [168]. Alternatively, a similar miktoarm star can be made via a combination of azide–alkyne click chemistry and ATRP. Liu et al. started from a three-functional core, 1-azido-3-chloro-2-propanol and created a star consisting of PEG, poly(tert-BA) and poly(DEAE) arms. The micelle formation of these miktoarm stars was investigated under different conditions in terms of temperature and pH [169]. PSTY Miktoarm star polymers of the ABC type were also synthesized via the combination of click chemistry, ATRP and N ROP (23, Fig. 13). Firstly, an azide-functional PEO was N clicked on the initiator. Secondly, ATRP of styrene was pre- N formed. Thirdly the ROP of e-caprolactone was done using N N N the hydroxyl group as initiator [170]. In a slightly different N way, another ABC miktoarm star copolymer was synthe- N sized. In this case the arms consisted of polystyrene, N N HO O O n poly(NIPAAm) and poly(e-caprolactone). The synthesis N took place via a combination of ATRP, ring-opening poly- PAA N N OH N PAA merization and azide–alkyne click chemistry. An alkynyl N and a primary hydroxy moiety were introduced at the N N chain-end of a polystyrene chain via reaction of an azide end-functional PSTY with 3,5-bis(propargyloxy)benzyl N alcohol. Rind-opening polymerization of -caprolactone N e N was initiated from the alcohol functionality and an azide end-functional poly(NIPAAm) chain was clicked onto the PSTY remaining alkynyl functionality at the junction point between the two first arms [171]. 26 AB2, or Y-shaped miktoarm star copolymer with biological relevance were synthesized again by a combination of Fig. 14. Grafted copolymer of glycidyl methacrylate and PEO (25) synthesized via ATRP and click chemistry. First generation dendrimer of ATRP, ring-opening polymerization and click chemistry. polyacrylic acid and polystyrene (26) synthesized via click chemistry and Propargyl amine was used as the initiator for the ring- ATRP. opening polymerization to yield alkynyl end-functional poly(e-benzyloxy-carbonyl-L-lysine). Diazide end-functional poly(NIPAAm) was synthesized with a diazide-func- butyryl groups. Subsequently, ATRP of butyl acrylate was tional ATRP initiator. The click reaction between the two carried out yielding a P(STY-block-polybutyl acrylate) with building blocks led to the AB2 miktoarm star. In a post- a propargyl group at the junction. The polyisoprene was polymerization modification, the benzyloxy protecting functionalized with a hydroxyl group and an ethoxyeth- group could be removed to yield poly(L-lysine) as the func- yl-protected hydroxyl group. The hydroxyl group was used tional arms [172]. for the ROP of ethylene oxide yielding a poly(isoprene- Star block copolymers have been prepared using a block-EO), with the protected hydroxyl group at the junc- three-armed star ATRP initiator to polymerize styrene. tion point. This protected hydroxyl group was de-protected Subsequently, the bromides were substituted with azides and modified in two steps into an azide via a bromoacetyl and an alkyne-functional PEO was clicked on the three intermediate. The two block copolymers were clicked to- armed star [173]. gether to form an ABCD star polymer (Scheme 28) [174]. ABCD miktoarm star polymers were achieved via a Star-shaped polymers with as many as twenty-one arms combination of anionic polymerization, ATRP, ROP and have been reported from the combination of ATRP and click chemistry. PSTY and polyisoprene were anionically click chemistry [175]. polymerized using butyl lithium. Functionalization reac- First generation mikto-dendrimers [176] or dendrimer- tions were conducted on the active lithium chain-ends. like [177] structures have also been synthesized via ATRP PSTY was functionalized with propargyl and 2-bromoiso- and click chemistry (Fig. 14). N. Akeroyd, B. Klumperman / European Polymer Journal 47 (2011) 1207–1231 1227

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amphiphilic ABC miktoarm star terpolymers. J Polym Sci Part A thermoinduced micellization. Macromolecules (Washington, DC, Polym Chem 2009;47:1636–50. US) 2010;43:5699–705. [172] Li L-Y, He W-D, Li J, Zhang B-Y, Pan T-T, Sun X-L, et al. Shell-cross- linked micelles from PNIPAM-b-(PLL)2 Y-shaped miktoarm star copolymer as drug carriers. Biomacromolecules 2010;11:1882–90. [173] Gao H, Min K, Matyjaszewski K. Synthesis of 3-arm star block Niels Akeroyd: Niels Akeroyd obtained his copolymers by combination of ‘‘core-frist’’ and ‘‘coupling-onto’’ MSc from Utrecht University (the Nether- methods using ATRP and click chemistry. Macromol Chem Phys lands) in 2005 after working on polymeric 2007;208. non-viral gene delivery systems and degrad- [174] Wang G, Luo X, Liu G, Huang J. Synthesis of ABCD 4-miktoarm star- able hydrophilic polyesters in the group of shaped quarterpolymers by the combination of the ‘‘click’’ Wim E. Hennink. Subsequently he moved to chemistry with multiple polymerization mechanism. J Polym Sci Stellenbosch University (South Africa) to Part A Polym Chem 2008;46:2154–66. obtain his PhD under the supervision of Bert [175] Xu J, Liu S. Synthesis of well-deﬁned 7-arm and 21-arm poly(N- Klumperman in 2010 for the thesis titled: 6 isopropylacrylamide) star polymers with Œ -cyclodextrin cores Click chemistry for the preparation of via click chemistry and their thermal phase transition behavior in advanced macromolecular architectures. aqueous solution. J Polym Sci Part A Polym Chem 2009;47:404–19. Since March 2010 he has been working as a [176] Whittaker MR, Urbani C, Monteiro MJ. Synthesis of 3-miktoarm postdoctoral fellow at the Radboud University Nijmegen (the Nether- stars and 1st generation mikto dendritic copolymers by ‘‘living’’ radical polymerization and ‘‘click’’ chemistry. J Am Chem Soc lands) with Alan E. Rowan on rotaxanes and processive catalysis. 2006;128:11360–1. [177] Liu Q, Zhao P, Chen Y. Divergent synthesis of dendrimer-like macromolecules through a combination of atom transfer radical Bert Klumperman: Prof. Bert Klumperman is polymerization and click reaction. J Polym Sci Part A Polym Chem currently holder of the South African Research 2006;45:3330–41. Chair on Advanced Macromolecular Architec- [178] Vora A, Singh K, Webster DC. A new approach to 3-miktoarm star tures at Stellenbosch University (South polymers using a combination of reversible addition-fragmentation Africa). He obtained his PhD from Eindhoven chain transfer (RAFT) and ring opening polymerization (ROP) via University of Technology under the joint ‘‘click’’ chemistry. Polymer 2009;50:2768–74. supervision of Profs Ton German and Ken [179] Yang L, Zhou H, Shi G, Wang Y, Pan C-Y. Synthesis of ABCD 4- O’Driscoll. He started his academic career in miktoarm star polymers by combination of RAFT, ROP, and ‘‘click Eindhoven (the Netherlands) in 1995. The chemistry’’. J Polym Sci Part A Polym Chem 2008;46:6641–53. main focus of his research is on synthetic, [180] Wu Z-M, Liang H, Lu J, Deng W-L. Miktoarm star copolymers via mechanistic and kinetic aspects of (living) combination of RAFT arm-ﬁrst technique and aldehyde-aminooxy radical polymerization. He received an A-rat- click reaction. J Polym Sci Part A Polym Chem 2010;48:3323–30. [181] Wu Z, Liang H, Lu J. Synthesis of poly(N-isopropylacrylamide)- ing from the National Research Foundation (South Africa, 2007), was poly(ethylene glycol) miktoarm star copolymers via RAFT elected fellow of the Royal Society of South Africa (2008) and received the polymerization and aldehyde-aminooxy click reaction and their Rector’s Award for Excellent Research (Stellenbosch, 2009).