The combination of living radical polymerization and ... - CyberLeninka

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

a r t i c l e

i n f o

Article history: Received 17 May 2010 Received in revised form 24 January 2011 Accepted 5 February 2011 Available online 12 February 2011 Keywords: Click chemistry Living radical polymerization ATRP RAFT SET-LRP NMP

a b s t r a c t Since its introduction, click chemistry has received a considerable amount of interest. In this contribution, the term click chemistry and the reactions that fall under this term are briefly explained. The main focus of this review is on the application of click chemistry in conjunction with living radical polymerization for the synthesis of advanced macromolecular architectures. Therefore the most powerful living radical polymerization (LRP) techniques are discussed and an overview of click chemistry in the different synthetic schemes is given. A large number of examples are shown that include the synthesis of block copolymers, star-shaped polymers, surface modified particles, and polymer-protein conjugates. The enormous potential of LRP/click chemistry is probably best exemplified by the synthesis of different miktoarm star copolymers, to which a separate section is dedicated. Ó 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

5.

6.

7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cycloadditions of unsaturated molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of organic azides and alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other examples of click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Nucleophilic substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Carbonyl chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Addition reactions to unsaturated carbon–carbon bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Living radical polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. RAFT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. ATRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. SET-LRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. NMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The combination of living radical polymerization and ‘click’ chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. RAFT and click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. ATRP and click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. SET-LRP and click chemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. NMP and click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miktoarm star polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⇑ Corresponding author. E-mail address: [email protected] (B. Klumperman). 0014-3057/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.eurpolymj.2011.02.003

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and out of this reaction type it is considered to be the most reliable (unlike many other starting compounds, azides and alkynes are stable towards dimerization and hydrolysis) and powerful due to the wide variety, accessibility and relative inertness (towards other organic reactions) of the starting compounds. The Huisgen reaction using azides as dipoles was reported by Huisgen et al. [2] in 1965. This reaction gained a boost of interest after the copper-catalyzed version was introduced by Meldal and coworkers [3] and by Sharpless and coworkers [4] in 2002. The CuI catalyst can be introduced in four different ways. Firstly, CuI species can be introduced directly in the form of CuI salts, for example CuI, CuOTfC6H6 and [Cu(NCCH3)4][PF6] have been used. These types of catalysts require the use of a nitrogen base (e.g. triethylamine, pyridine and 2,6-lutidine have been reported). This method has one major disadvantage, which is the formation of diacetylenes, bistriazoles and 5-hydroxytriazoles as side products [4]. Secondly, a CuII/Cu0 system can be used. In such a system CuI is formed by comproportionation of the CuII/Cu0 couple. This is a very useful system when the substrates cannot be used in the presence of ascorbic acid or its oxidation products [5]. Thirdly, copper immobilized on carbon (Cu/C) can be used. This Cu/C catalyst is prepared easily by placing carbon black and Cu(NO3)23H2O in water and mixing it in an ultrasound bath for 7 h. This catalyst can be activated by the addition of triethylamine, or by the use of microwave heating, both of which cause the reaction time to decrease from hours to minutes. A big advantage of this catalyst is that it is easily removed

1. Introduction The term click chemistry was introduced by Sharpless and coworkers [1] and is defined as a reaction that is modular, wide in scope, high in yield, has little side products that are easily removed by non-chromatographic methods (for example crystallization or distillation), is stereospecific but not necessarily enantioselective, uses simple reaction conditions, is not sensitive to oxygen or water, uses easily accessible reagents, requires no solvent or a solvent that is easily removed or benign like water, enables simple product isolation, has a high thermodynamic driving force (greater than 20 kcal mol1) and goes rapidly to completion. Most of the click chemistry reactions are carbon– heteroatom bond forming reactions, for example: Cycloadditions of unsaturated molecules, Nucleophilic substitution, especially ring-opening reactions of heterocyclic electrophiles that have high ringstrain, Carbonyl chemistry, except for the ‘‘aldol’’-type reactions, Oxidizing reactions like aziridination, dihydroxylation and epoxidation. 2. Cycloadditions of unsaturated molecules Reports on click chemistry are mostly on the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction (Scheme 1). This reaction is part of the hetero-Diels–Alder family

CuSO 4 . 5 H 2O, 1 mol% Sodium ascorbate , 5 mol%

O + N

N

O

N N N

N H 2 O/tBuOH 2:1, RT, 8 h 1

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

R1 R

CuL n

R1

1

N

CuLn N 2 N R

B-3

N N

N IV

N

N R2

N

R2

C

B-2 [L nCu]+ B-direct

R1 N

CuL n N R2 N

R1

H

A II

R1

B-1

CuL n I

N

N N

R2

Scheme 2. Proposed mechanism for the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition by Sharpless and coworkers [4].

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‘‘ligation’’ pathway. Extensive density functional theory calculations give strong evidence towards the ‘‘ligation’’ pathway (12–15 kcal) [4,5]. To optimize the reaction between azides and alkynes, ligands can be added to the reaction mixture. These ligands are nitrogen rich compounds (for some examples see Fig. 1). Finn and coworkers [8,9] reported on tris((1-benzyl)-H1,2,3-triazole-4-yl)methyl)amine (TBTA) (2) and potassium 5,50 ,500 -(2,20 ,200 -nitrilotris(methylene)tris(1H-benzo[d]imidazole-2,1-diyl))tripenta-noate (BimC4A)3 (3) and its derivatives as organic and water phase ligands for the cycloaddition reaction between azides and alkynes. Nolan

from the reaction mixture (filtration over Celite) and the catalyst can be recycled (no loss of activity was found after recycling the catalyst three times) [6,7]. Finally, CuI can be introduced by the reduction of CuII salts by sodium ascorbate or ascorbic acid (5–10 mol%). The fact that CuII salts are relatively cheap (CuSO45H2O can be used) and that this is a very reliable and simple system makes this the preferable route [4]. The reaction mechanism proposed by Sharpless and coworkers (Scheme 2) contains two pathways. The first proposed pathway is a direct [2+3] cycloaddition and the second one is a stepwise sequence (B-1?B-2?B-3) or

KO2C

N N N

N N

N N N N N

N N

N

N

N

N N

N

N

CO2 K

KO2C

3

2

4

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

CuSO 4 .5 H2 O 2 mol% Sodium ascorbate 10 mol% KHCO3 4,3 equiv

OH N R1

+

R2

Cl

H2 O/tBuOH 1:1 RT, 1-4 h

N

O

R2

R1

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

O R

N

H2 N OH .HCl

H

N R

+

H

R

OH +

N

NCS

OH Cl

R

H

OH

NCS = N -chlorosuccinimide Scheme 4. The synthesis of imidoyl chloride as reported by Howe and coworkers [12].

R' or HO

+

N3

HO R"

R" N N N

R" N N N

R' or

R 5 Scheme 5. Reaction scheme of ring-strain promoted click chemistry with substituted cyclooctynes [14].

R

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R 33 P=O

PR3 3

R

R OH

+

HN3

R1

R1 O

O O O R2

N N

O R2

O R2

N H

N3

R2 O

H N O

Scheme 6. The Mitsunobu reaction for the synthesis of azides [24].

and coworkers [10] found that 1,3-dicyclohexyl-2,3-dihydro-1H-imidazol-2-ide (ICy) (4) is a very effective ligand for the alkyne-azide click reactions. ICy was reported to complete the reaction within 90 min with catalyst loadings as low as 40 ppm. CuI-catalyzed synthesis of 3,5-disubstituted isoxazoles was also reported by Sharpless and coworkers [5] (Scheme 3). The synthesis of these isoxazoles has been reported to be faster than the corresponding triazoles. This reaction uses nitrile oxides as reactive intermediates. Nitrile oxides are easily prepared by the oxidative halogenation/dehydrohalogenation of the corresponding aldoximes [11]. Aldoximes are synthesized readily in high yields from their aldehyde precursors by a reaction with hydroxylamine hydrochloride. From these aldoximes, imidoyl chlorides are produced using the procedure reported by Howe and coworkers (Scheme 4) [12]. Ring strain has been used as a tool to avoid the use of CuI catalysis in the synthesis of triazoles (Scheme 5) [13– 15]. This variant of click chemistry is especially interesting for products that have their applications in biological systems, because this reaction does not require the use of the toxic CuI catalyst. However, the major drawback of this route is the synthesis of the cyclooctynes, which is usually laborious. Copper-free azide–alkyne cycloadditions were reported with cyclooctynes substituted on the R or R0 position in Scheme 5. Electron-withdrawing substituents on the cyclooctyne ring, like the 1,2:5,6-dibenzo substituent (5) reported by Boons and coworkers [14] show an increase in reaction rate. Bertozzi and coworkers [16] reported a difluorinated cyclooctyne (DIFO) that has a 63 times shorter reaction time than cyclooctyne. This DIFO was later applied in live zebrafish embryos [17]. The embryos were exposed to an azide-functional sugar which was incorporated in the glycans of the cell membrane. Then, at two different times, the embryos were exposed to DIFO with two different fluorescent probes. The images showed the different development stages of glycans in the embryos. This clearly proved that DIFO and other cyclooctynes have applications in the biomedical field and can be applied even in live organisms. However the solubility of these cyclooctyne conjugates in water is very poor. To overcome this problem Bertozzi and coworkers developed a hydrophilic azacyclooctyne derived from a sugar starting compound [18]. This 6,7-dimethoxyazacyclooct-4-yne (DIMAC) contains a

nitrogen in the ring which can be used for probe conjugation and at the same time it disrupts the hydrophobic surface of the cyclooctyne moiety. The two methoxy groups also make DIMAC more hydrophilic. As a result, DIMAC is water soluble. (Scheme 6) 3. Synthesis of organic azides and alkynes Due to their high reactivity, organic azides have many applications as intermediates in organic reactions. For example, azides can be used for the synthesis of heterocycles, amines and isocyanates (Curtius rearrangement [19]). Organic azides can be synthesized via five routes [20]:

Insertion of the N3 moiety via substitution or addition, Diazo transfer (insertion of N2), Diazotization (insertion of N), Degradation of triazines and their analogs, Rearrangement of azides.

Polymer products are difficult to purify, especially from other polymeric contaminants. Therefore, only reactions with extremely high yields are suitable for polymer functionalization. The substitution of halides with sodium azide is used frequently in polymer chemistry. Halidefunctional polymers are readily obtained via atom-transfer radical polymerization (ATRP). The subsequent substitution of the halide with sodium azide yields a polymer with a high fraction of azide chain-end functionality [21,22]. Amines can be converted into azides using a two step reaction. First, the amine is reacted with sulphuric acid and sodium nitrite. After the diazotization the product is reacted with sodium azide to form the corresponding azide in high yield [23]. The Mitsunobu reaction [24] can be used to substitute primary and secondary alcohols with azides. This reaction uses triphenyl phosphine and diethyl azodicarboxylate (DEAD) (or derivatives of DEAD like diisopropyl azodicarboxylate (DIAD)) and hydrogen azide. Due to the hazards of working with DEAD, polymer bound DEAD has been used. Lipshutz et al. [25] developed a stable crystalline azodicarboxylate (di(p-chlorobenzyl)azodicarboxylate (DCAD))(see Fig. 2) that is easily recovered and recycled from the reaction mixture. In one of the examples, DCAD (6) was used to introduce alkynes. Propargyl alcohol was reacted in the Mitsunobu reaction with a thiol to quantitatively form the corresponding thiolether containing the alkyne moiety [25].

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O

N N O

thiourea, aromatic heterocycles, oxime ethers, hydrazones and amide formation [1]. Fig. 3 shows some examples of acetal-like products synthesized via carbonyl chemistry, i.e. the reaction between the relevant diols and hydroxysulfonamides.

O O O

O O

O N N

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 Nu–H to carbon–carbon multiple bonds belong to the click chemistry family as well. The most famous reactions are the epoxidation and dihydroxylation (Sharpless [32] was awarded the Nobel Prize in chemistry for this type of reaction in 2001). The osmium-catalyzed dihydroxylation reaction goes to very high yields even for electron-deficient olefins when the new ‘‘tricks’’ reported by Sharpless and coworkers [33] are used. These tricks include keeping the pH between 6 and 4 and the addition of citric acid together with the frequently used 4-methylmorpholine N-oxide (NMO). Other examples of oxidative additions are aziridination and sulfenyl halide addition [1]. In the field of synthetic polymer chemistry, thiol-ene chemistry is experiencing a revival. Although the reaction has been used for decades, the present interest in modular, orthogonal and highly efficient reactions has led to its application in the synthesis of complex macromolecular architectures.

Polymers synthesized via RAFT have successfully been modified into azides and alkynes using the Mitsunobu reaction. Using propargyl alcohol with thiol end-functional polymers (obtained via RAFT) as the nucleophile or HN3 as the nucleophile on polymers bearing an alcohol end-group (obtained via RAFT) [26]. Other ways of making alkynes involve the elimination of two hydrogen and two halogen atoms in a double dehydrohalogenation reaction with a strong base like potassium tert-butoxide [14] or via selendiazoles [27]. 4. Other examples of click chemistry 4.1. Nucleophilic substitution From the wide range of known nucleophilic substitution reactions, especially the SN2 ring-opening reactions of electrophilic heterocycles that possess a large amount of ring strain are considered to be ‘‘click’’ reactions [1]. Substrates for this reaction that are reliable, stereospecific, high in regioselectivity and high in yield in this type of reaction are among others epoxides [28], aziridines [29,30] and episulfonium ions [1,31]. Scheme 7 shows an example of a nucleophilic ring-opening of aziridines.

5. Living radical polymerization Free radical polymerization is frequently used in industry for the production of a wide range of polymers. This is mainly due to the robustness of the reaction. A range of different monomers can be polymerized and the reaction is relatively insensitive towards water and oxygen. However, one of the major disadvantages is the lack of control over the polymerization. Since the last years of the 20th century, a number of controlled or living radical polymerization (LRP) techniques have been reported. Rizzardo and coworkers [34,35] reported on the nitroxide stable radical

4.2. Carbonyl chemistry ‘‘Non-aldol’’ type carbonyl reactions also meet the requirements of click chemistry. Examples here are a,

Nu

Ts

M-Nu

N R

R

OH

NHTs OH

NHTs

+

R

OH Nu

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

N3 Ph

N3

O O

Ph

O

O

H

N

N3 H

O

Ts 9

8 O

N3

HO O 11

O

N3

O

10 O

N3

O

N3

HO

N3 12

Fig. 3. Five acetal-like derivatives synthesized by Sharpless and coworkers [1].

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Initiation Monomer I

Pn

Chain transfer S

S

Pn M

R

S

Pn

S

R

Pn

S

R

Z

Z

S Z

Reinitiation Monomer

R

Pm

Chain equilibration S

S

Pm M

Pn

Pm

S

S

Z

Pn

Pm

Z

S

S Pn Z

M

Scheme 8. The RAFT mechanism as reported by Rizzardo and coworkers [42].

in 1985. Georges et al. [36] reported the first low polydispersity index (PDI) polymers synthesized through Nitroxide-mediated Polymerization (NMP). After NMP, a number of new LRP methods have been reported: Atom Transfer Radical Polymerization (ATRP) [37,38] Reversible Addition Fragmentation chain Transfer (RAFT) [39] Single-Electron-Transfer Living Radical Polymerization (SET-LRP) [40]. The introduction of LRP allowed polymer scientists to design and build an extended range of macromolecular architectures based on vinyl monomers [41].

to the CTA to form an intermediate radical. The fragmentation of the intermediate radical produces either a new radical on the leaving group R, which can re-initiate polymerization (chain transfer), or it releases the incoming propagating radical. The chain equilibration step is the main equilibrium. This step controls the polymerization by dynamically exchanging the active polymer chain radical among chains, while keeping most chains in the dormant CTA end-capped state due to the stoechiometry between active growing chains (radicals) and (macro) chain transfer agents. RAFT-mediated polymerization is a robust technique that has been used for the LRP of a wide range of vinyl monomers. 5.2. ATRP

5.1. RAFT RAFT-mediated polymerization was first reported in 1998 by Rizzardo and coworkers [39]. RAFT uses thiocarbonyl thio species as chain transfer agent (CTA). The generally accepted mechanism is shown in Scheme 8. For a typical RAFT-mediated polymerization, the following compounds are needed: CTA, monomer and a radical source. This radical source is usually a thermally decomposing initiator, for example AIBN. However, the use of c and UV radiation has also been reported [43,44]. As shown in Scheme 8, an initiator-derived primary radical initiates a polymer chain and this growing chain then adds

R X

+

M tn -Y/Ligand

k act

ATRP was first almost simultaneously reported by Sawamoto and coworkers [37] and by Matyjaszewski and coworkers [38]. Sawamoto reported ruthenium-mediated polymerization and Matyjaszewski the nowadays more popular copper-catalyzed version of ATRP. The general mechanism of ATRP is shown in Scheme 9. The following chemicals are needed for a typical ATRP reaction: alkyl halide initiator, monomer, metalI halide (note that other oxidation states than MI or MII can be used as long as the oxidation state changes by one electron) and a ligand. As shown in Scheme 9, the metal complex homolytically cleaves the halide from the initiator, generating an

R

+

k deact

X Mtn+1 -Y/Ligand

kp kt monomer

termination

Scheme 9. The ATRP mechanism as reported by Matyjaszewski et al. [45].

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kp +M

ka +

R X

Cu I X/Ligand

+

R

CuII X2 /Ligand

k da

kt

R R

+

CuII X2 /Ligand

Oxidized Agent

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

k act CuIX/L

k dis

Pn X

Cu0

CuIIX2/L

+

Pn

kp

+ nM

k dis kt CuIX/L k deact

Pn Pn Scheme 11. The SET-LRP mechanism as proposed by Percec et al. [40].

initiator radical plus a metalII complex. The initiator-derived primary radical initiates a propagating chain via addition to the monomer. The propagating chain is deactivated by the metalII complex generating a metalI complex and a Pn –X dormant chain. Since the equilibrium of this reaction is shifted heavily towards the dormant chains, the concentration of propagating radicals present in the reaction mixture is low. This limits termination and control over the polymerization is obtained. The major drawback of ATRP is the relative sensitivity of the metal complex towards air and the fact that the final product will contain substantial amounts of metal. To

overcome these problems ARGET-ATRP (activator regenerated by electron transfer) was introduced by Matyjaszewski and coworkers [46]. ARGET-ATRP uses a reducing agent like stannous 2-ethylhexanoate to reduce the excess CuII that is formed during the polymerization due to bimolecular termination reactions. This allows for the concentration of Cu complex in the reaction mixture to be lowered to values as low as 10 ppm (the required concentration is monomer dependent). ARGET-ATRP is based on the earlier discovery by Klumperman and coworkers that reducing sugars are able to enhance the rate of an ATRP reaction [47].

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O N O N

monomer

Pn

N

kp monomer

O Pn

kt termination

Scheme 12. The mechanism of NMP.

O N

O N

13

O P O O

14

Fig. 4. 2,2,5-Trimethyl-4-phenyl-3-azahexane-3-nitroxide (TIPNO) (13) [51] and N-tert-butyl-N-(1-diethylphosphono-2,2-dimethyl)-N-oxyl (DEPN or SG1) (14) [53].

ARGET-ATRP follows the same basic mechanism as ATRP. However, as shown in Scheme 10, the reducing agent reduces the CuII that is formed, due to termination reactions, back to CuI. The ratio of CuI to CuII can be controlled in this way, which allows the polymerization to proceed at an acceptable rate, while producing a polymer with low PDI [48]. 5.3. SET-LRP Single Electron Transfer (SET)-LRP was introduced by Percec et al. [40]. The authors claim that SET-LRP is catalyzed by extremely reactive Cu0 that is formed by low activation energy outer-sphere single-electron-transfer. The reaction is controlled or deactivated by CuII species that are formed via the same process (see Scheme 11). It has been reported that SET-LRP is very effective at room temperature and that extremely high molecular weights can be obtained in conjunction with a low PDI. Even in the presence of typical radical inhibitors such as phenol, SETLRP shows control over the molecular weight distribution and exhibits a high reaction rate [49]. The mechanism of SET-LRP is still under debate. Matyjaszewski and coworkers [50] reported that according to their results the reaction follows the same mechanism as ARGET-ATRP and the role of Cu0 is limited to that of the reducing agent. 5.4. NMP NMP is based on the nitroxide radical. The most common first generation nitroxide is TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical). When TEMPO is added to a styrene polymerization, equilibrium is reached between the TEMPO free radical and an alkoxyamine con-

sisting of a TEMPO molecule bound to an initiator radical or propagating radical. The bond that is formed between a propagating radical and TEMPO is reversible (Scheme 12). However, high temperatures (>120 °C) are required to split the alkoxyamine into a persistant TEMPO radical and a transient, propagating radical. To overcome the problems presented by the high temperatures needed for TEMPO polymerizations, second generation alkoxyamines were introduced [51,52]. These second generation alkoxyamines can be used at temperatures 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 alkoxyamines are shown in Fig. 4. 6. The combination of living radical polymerization and ‘click’ chemistry Over the past two decades, a remarkable number of publications were dedicated to the development of new polymerization techniques. The living radical polymerization techniques have been mentioned above, but next to that, several transition metal catalyzed polymerization reactions were reported, e.g. ring opening metathesis polymerization (ROMP), metallocene-catalyzed olefin polymerization, etc. Apart from the new polymerization techniques, there is a tendency of organic chemistry and polymer chemistry approaching each other in the synthesis of complex macromolecules [41]. In accordance with this trend, the number of reports on the combination of click chemistry and LRP has been growing rapidly in the past few years [54–57]. 6.1. RAFT and click chemistry The combination of RAFT and click chemistry has been reported in a number of ways. Alkyne and azide-functional polymers were synthesized by post-polymerization modification of polymer synthesized via RAFT-mediated polymerization by Caruso and coworkers [58]. The polymers obtained after this modification were used to produce an ultrathin polymer multilayer by applying click chemistry to these polymers in combination with a layer-by-layer assembly technique (Scheme 13). A trimethylsilyl (TMS)-protected alkyne RAFT agent (16) and azide-functional RAFT agents (15 and 17) have been reported (Fig. 5) [59,60]. The azide and alkyne-functionality are introduced in the R group of the RAFT agent.

1215


N3

N3

N3

N3

N3 N3

N3

N3

N3

N3

N N N

N N N

N N N

N N N

Cu I

Cu I

N N N N N N

N N N N N N

N N N N N N

N N N

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

N O N3

O

O S

O

O O

S S

N3

S

O

S

S S

10

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 block copolymers and telechelic polymers [59,60], polymers with fluorescent end-groups [61], bio-conjugates (Scheme 14) [62,63], folate (targeting ligand) functionalized thermoresponsive block copolymers [64] and branched poly(N-isopropyl acrylamide) (PNIPAM) [65–67]. However, the use of azide-functional RAFT agents and monomers, under normal free radical polymerization conditions, is debatable. The groups of Benicewicz [68] and Perrier [69] reported up to 60% loss of azide functionality during the polymerization. The suggested pathway behind the loss of azides is shown in Scheme 15. When azide functions are lost, the benefits of click chemistry, like high yields and little side products, are no

longer valid because the degree of functionalization will be limited to the amount of azide left. However the amount of side reactions can be decreased if short reaction times and/or low temperatures are used. Brittain and coworkers [70–72] reported the use of an alkyne-functional RAFT agent without the TMS protecting group. The obtained polymers were used for surface modification of silica. This RAFT agent was used in different ways. Firstly, the RAFT agent was used in the polymerization of styrene. The obtained polymer was ‘‘clicked’’ on azide-functional silica nanoparticles (Scheme 16). Secondly, the RAFT agent was ‘‘clicked’’ on the azide-functional silica nanoparticles and styrene was polymerized onto the RAFT agent functionalized particles. Thirdly, this

1216


R N S

S

O

S

O

O

HN

N3

O -N 2

NH

O

O NH N

R

R

N H

N

NH N2

N

O R HN

N H

O NH

H N

NH N O

S

S R= S

O 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 SiO2

HO

OH

+

Cl

R

Cl si

SiO2

Cl HO

Br

OH OH

O O Si O R

Br

NaN3

R O O Si O R

SiO2

R I

Cu

SiO2

N N N

O O Si O R

O

S

S

10 S H

O O

n N H

O

S 10

S S H

O

n N

O H

Scheme 16. The modification of silica particles with alkyne-functional polymers obtained via RAFT [70].

N3

1217


H H H H R O HO O HO O HO N H OH H OH H OH H H H OO OO OO HH HH HH

N N N O O S S

18

O

Fig. 6. Dextran RAFT agent prepared via click chemistry [75].

R Br

S

S

+ K+ -S

R

S

Z

+ KBr

Z

R1 N3 with R = H, CH 3 R R1 N N N

S S

Z

Scheme 17. The synthetic route towards the RAFT agents bearing a triazole-based leaving group [77].

RAFT agent was clicked and polymerized in a one-pot synthesis of polystyrene (PSTY) grafted silica nanoparticles. Gold nanoparticles were also modified via click chemistry and RAFT [73]. Pan and coworkers [74] also reported the use of an unprotected alkyne-functional RAFT agent. This RAFT agent was used to synthesize tadpole-shaped amphiphilic polymers. Charleux and coworkers [75] prepared a xanthate-functionalized dextran RAFT agent (18) via click chemistry (Fig. 6). The xanthate moiety was linked through the R group via an azide to an alkyne terminated dextran. The obtained RAFT agent was used for surfactant-free emulsion polymerization. Dendritic polymers were obtained when poly(N-(2hydroxypropyl) methacrylamide) was clicked onto dendritic mannose scaffolds [76]. Klumperman and coworkers [77] introduced the triazole leaving group for RAFT. This triazole moiety was introduced by clicking an alkyne-functional RAFT precursor onto an azide substrate. Both aromatic and aliphatic substrates were used. Block copolymers were obtained when an oligosaccharide was used as the azide substrate (Scheme 17). The advantage of this methodology is that the obtained block copolymer is not linked via an ester but via a triazole, which proved to have excellent stability against hydrolysis.

Block copolymers of polyisobutylene and NIPAM were obtained when an alkyne-functional trithiocarbonate was clicked on an azide-functional polyisobutylene [78]. The synthesis of cyclic PSTY via RAFT and click chemistry has been reported [79]. The azide function was introduced via the R group of the RAFT agent and the alkyne was introduced via the removal of the Z group. The Z group was removed using the addition of radicals formed from azobis(4-cyano valeric acid) esterified with propargyl alcohol using a procedure reported by Perrier and coworkers [80]. Graft copolymers of vinyl acetate have been reported using a TMS-protected propargyl methacrylate monomer [81]. In this case, a backbone was grown via RAFT using alkyne-functional monomers. These alkyne functions were used for click chemistry with polymers bearing an azide end-group (obtained from an azide-functional RAFT agent) (Scheme 18). Van Hest and coworkers used the Mitsunobu reaction to synthesize an azide functional monomer from HEMA (2azidoethyl methacrylate (AzMA)). This AzMA was polymerized via RAFT (homopolymers and co-polymers with HEMA were made), and reacted with diacetylene derivatives of triethylene glycol yielding stable coatings (normal acetylene and cyclooctyne derivatives were used) [82]. The cyclooctyne derivatives obviously led to the copper-free version of azide–alkyne click chemistry, which was thus pioneered by van Hest in the polymer field. Thiols and isocyanates react to form thiocarbamates. When triethylamine is added as a catalyst, this reaction also falls under the click chemistry domain. Poly(N,N-diethylacrylamide) was synthesized via RAFT-mediated polymerization. The dithiobenzoate end-group was converted into a thiol via aminolysis with methylamine. The thiol endgroups were used in the triethylamine-catalyzed reaction between different commercially available isocyanates, yielding thiocarbamate end-functional polymers [83]. The Diels–Alder reaction between the thiocarbonyl thio moiety and polymers functionalized with cyclopentadiene was utilized by Barner-Kowollik and coworkers [84]. This reaction allows for the synthesis of block copolymers in

O O P O

R* S S

R

+

R*

O S R S P O O

R = Polymer obtained via RAFT R* = PEG or polymer from ATRP Scheme 19. Scheme of Ultra-fast hetero Diels–Alder click [84].

CuI THF N N N

N N N

N N N

N3

Scheme 18. Schematic overview of the synthesis of brushes via click chemistry [81].

N N N

1218


O O P O

R*

R* S S

+

R

R*

Grubbs

O R S PO O S

1R=

O n S P O R SO

2nd generation

2R=

3 R = polystyrene

4 R = polystyrene

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)-2thiabicyclo[2.2.1]hept-5-en-3-ylphosphonate (DPTHP). 3 and 4 are polystyrene and poly(styrene-block-ethylene glycol) derivatives respectively [85].

R

N

N N N N R H

N3 , acid, heat

N N NH N R

Scheme 21. Tetrazole formation [92].

seconds (Scheme 19). It also combines RAFT with ATRP because the cyclopentadiene is easily introduced by a reaction between the halide chain-end of a polymer obtained via ATRP and the sodium salt of cyclopentadiene. The substituted 2-thiabicyclo[2.2.1]hept-5-ene moiety obtained via this reaction can be used in ring-opening metathesis polymerization (ROMP) [85]. Grafted copolymers were obtained in this way (Scheme 20). Thiol-ene click chemistry [86,87] was used for the synthesis of three armed stars of n-butyl acrylate. The thiol end-functional poly(n-butyl acrylate) was obtained via RAFT-mediated polymerization and subsequent aminolysis. The thiol end-functional polymers were reacted in situ via phosphine-catalyzed thiol-ene click chemistry [88]. End-group modification of p(NIPAM) was also achieved via thiol-ene and thiol-yne click chemistry [89]. Recently, a type of click chemistry based on nucleophilic substitution involving RAFT-moieties was reported. The ‘‘thio-bromo’’ click reaction was reported by Davis, Lowe and co-workers [90]. After model reactions on low molar mass RAFT agents, they show that a-bromo esters can conveniently be used to create a thioether-functionalized polymer. 6.2. ATRP and click chemistry ATRP and click chemistry have been used together extensively [91]. This combination is very popular because

HO

N N N

O

ATRP and click chemistry can both be carried out with the same copper catalyst and the halogen terminus of polymer chains obtained via ATRP can easily be converted into the corresponding azide derivative [21,22]. The first report on the combination of click chemistry and ATRP was in 2004 by Matyjaszewski and coworkers [92]. In this paper the authors did not use the usual alkyne-azide click chemistry, but the reaction of sodium azide with a cyanide to form a tetrazole was applied (Scheme 21). End-group functionalization via click chemistry of polymers (suitable for click chemistry) has been reported. Functional groups like carboxylic acids, alkenes, and alcohols have been introduced [93]. Polymer end-group functionalization allows for the synthesis of macromonomers via ATRP (19, Fig. 7) [94]. This structure would not be accessible through direct synthesis, since the polymerizable end-group of the macromonomer would obviously interfere with the polymerization of styrene. Copper-free click chemistry was used for the end-group modification of poly(oligo(ethylene glycol methacrylate) (P(OEGMA)). Alkyne-functional P(OEGMA)s were reacted with different aromatic oximes without the use of copper. The interesting feature here is that only the 3,5-isomers were found and non of the 3,4-isomers, presenting an interesting regioselective version of copper free click chemistry [95]. Interestingly, it was reported that end-group modification may lead to variation in the thermoresponsive properties of polyNIPAM [96]. Hence, tuning of the thermoresponsive properties can be conveniently carried out by a post-polymerization process. Telechelic polymers are polymers where both a and x chain-ends have a functional group. Telechelic polymers suitable for click chemistry have been reported [21,97,98]. In a typical example, an a,x-dibromo-func-

O

O

n O

R

19

N

N N

n

N

N N OH

20

Fig. 7. Structure of macromonomer (19) [94] and telechelic polymer (20) [97] synthesized via ATRP and click chemistry.

1219


O O O

O

+

O n 5

O

N3

O Br O

Method 1

O Click Chemistry

Method 2

ATRP N

O O

O O

O n 5

N N N

O

O

N3

O

O

O

O Br

p Br O

N

ATRP

Click chemistry

O O O O N O

O n 5

N N N

O

O O Br p

21 O O

N 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 two bromine end-groups are subsequently transformed into azides by reaction with sodium azide. Finally, propargyl alcohol is clicked on the chain-ends to yield a,x-dihydroxy-functional polystyrene (20, Fig. 7) [97]. Block copolymers have been prepared from the obtained telechelic polymers. First, a-acetylene-x-azido-terminated PSTY was chain extended via step-growth click polymerization [21,99]. When telechelic polymers were used, multiblocks of polystyrene and poly(ethylene glycol) (PEG) were obtained [100]. Ring opening polymerization (ROP) was also used in combination with ATRP. Poly(e-caprolactone) was clicked on a poly(N,N-dimethylamino-2ethyl methacrylate) (p-(DMAEMA)) block [101]. The same block copolymer was later reported in a one-pot synthesis (Scheme 22) [102]. Block copolymers of acrylic acid and 1ethoxyethyl acrylate have also been synthesized using this method [103]. ABA asymmetric triblock copolymers of poly(ethylene oxide) (PEO) and PSTY were reported [104]. Mono-methoxy poly(ethylene glycol) was converted into an ATRP initiator via the commonly used esterification with bromo-isobutyryl bromide. A polystyrene block is synthesized under normal ATRP conditions. Subsequently, the terminal bromide is substituted with an azide by stirring with sodium azide. The final asymmetric ABA triblock

copolymer is obtained from click chemistry with a propargyl terminated mono-methoxy poly(ethylene glycol) of different chain length. Van Hest and coworkers were among the first to report on the synthesis of block copolymers via a combination of ATRP and copper-mediated click chemistry [105]. They later reported on the synthesis of ABC triblock copolymers via a similar combination of ATRP and click chemistry. They synthesized sequence-defined oligomers in a stepwise approach [106]. The oligomers were either synthesized from an azide-functional Wang resin or using polystyrene containing an azide end-group. The azide functionality was reacted with an aliphatic alkyne containing a carboxylic acid. Triethylene glycol bearing an amine and an azide as end-groups was used as the monomer with complementary functionality. Click chemistry and DCC coupling were used in one pot to obtain alternating oligomers. Lutz and coworkers further investigated the stepwise synthesis of polymers via living radical polymerization, inspired by natural polymers that exhibit perfect sequence control [107]. PSTY, poly(tert-butyl acrylate) and PMMA containing azide and triisopropylsilyl-protected alkyne end-groups have been synthesized and clicked together sequentially. First, the azide-functional PSTY was clicked onto the alkynefunctional poly(tert-butyl acrylate). The remaining protected

1220


Fig. 8. CABAC block copolymer from PPO PGMA and nonadecafluoro-1decyl hex-5-ynoate (F9) synthesized via click chemistry and ATRP [110].

alkyne (on the PSTY) was deprotected and the diblock was clicked onto the azide-functional PMMA [108]. ROP was used for the synthesis of ABC-triblock copolymers in combination with ATRP and click chemistry. A macro-ATRP initiator of poly(ethylene oxide) (PEO) was prepared via esterification of PEO with 2-bromo-2-methylpropionyl bromide and a PSTY block was synthesized via ATRP using this initiator. Then the bromine end-group was substituted with an azide. Poly(e-caprolactone) was synthesized via ROP using propargyl alcohol as the initiator. The poly(e-caprolactone) was clicked on the azide-functional PEO-block-PSTY. ABC triblock copolymers containing polypeptide segments were synthesized using the same combination of ATRP, click chemistry and ROP [109]. ABC triblock and CABAC pentablock copolymers have been synthesized using solketal methacrylate, polypropylene oxide (PPO) and alkyne-functional nonadecafluoro-1decyl hex-5-ynoate. To prepare the CABAC pentablock copolymer, the hydroxyl end-groups of PPO were esterified with 2-bromoisobutyryl bromide. Solketal methacrylate

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-5ynoate (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 with sodium azide to yield azide-functionalized backbones. On these backbones, alkyne-functionalized PEO was clicked [112]. Poly(2-hydroxyethyl methacrylate) synthesized via ATRP was reacted with pentynoic acid to yield an alkyne grafted polymer. On these alkyne groups, polymers with azide functionality were clicked so that densely grafted polymers were obtained [113]. A combination of NMP, click chemistry and ATRP was used to produce well-defined multifunctional graft copolymers of poly(pentafluorostyrene) [114]. Diels–Alder click chemistry between maleimide and anthracene was used to prepare PSTY-graft-PEO [115]. 3-Acetyl-N-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-5ene-2-carboxamide-functional PEG was used for an in situ retro Diels–Alder and Diels–Alder reaction with anthracene-functionalized polymers (Scheme 23). Neo-glycopolymers were synthesized via a trimethylsilyl-protected alkyne-functional monomer which was polymerized via ATRP. The alkyne functionalities were de-protected and sugars containing azide groups were clicked on the backbone (Fig. 9) [116]. In a similar fashion phenylpropargyl ether was clicked on azide-functional backbones [117]. Cyclic polymers have been reported via alkyne-functional ATRP initiators where the alkyne functionality was

O O n

m-n m

+

Toluene

N O

PEG

n

Reflux

m-n m

O

O

O N O PEG Scheme 23. Grafted copolymers synthesized via anthracene and maleimide Diels–Alder click chemistry [115].


1221

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

Br

O O O

O

O O

O

O

O N

22 Fig. 10. The ATRP initiator functionalized with an alkyne and TEMPO group (22) as reported by Tunca and coworkers [125].

either trimethylsilyl-protected or unprotected. After polymerization, the bromide terminus was substituted with an azide (and if applicable, the alkyne was de-protected). A click reaction in highly diluted solution yielded cyclic PSTY and cyclic poly(methyl acrylate)-block-PSTY [118,119]. A similar approach was followed to synthesize cyclic polyNIPAM [120], p(STY-block-PEO) [121] and grafted PEG [122]. Eight-shaped copolymers were obtained when a difunctional 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 combination of NMP, ATRP and click chemistry [124]. The synthesis started with the difunctional initiator (ATRP and NMP) that carries an alkyne functionality as reported by

Scheme 24. Photocleavable network synthesized via ATRP and click chemistry [127].

1222


O

N N N

Poly(styrene)

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

Fig. 11. Grafted copolymer containing a hydrolysable link for non-viral gene delivery [128].

Tunca and coworkers (22, Fig. 10) [125]. PSTY and PMMA were synthesized by NMP and ATRP respectively. This created a block copolymer with an alkyne functionality at the junction point. Two such block copolymers were clicked together with an a,x-diazide-functional PEG or poly(tertbutyl acrylate) to yield the H-shaped polymer. Amphiphilic networks of poly(e-caprolactone) and polyDMAEMA have been synthesized via the combination of ATRP, ROP and click chemistry [101]. Degradable networks have been reported from macromonomers synthesized via ATRP. The use of a difunctional initiator containing a C = C double bond yielded a bromide telechelic polymer, which was transformed into an azide via reaction with sodium azide. This telechelic azide was clicked on a multi alkyne compound, which was tri- or tetra-ether of pentaerythritol and propargyl alcohol. Degradation of the network was achieved by ozonolysis of the C = C double bonds of the ATRP initiator [126]. The same approach was used to synthesize photocleavable hydrogels. In this case the difunctional ATRP initiator used, contained a photocleavable group (Scheme 24) [127]. The field of pharmaceutical and biomedical applications in polymer science is a growing field of interest. The combination of ATRP and click chemistry has been reported in the field of gene delivery. PDMAEMA is a well-known cationic polymer that condenses DNA. In principle, a high molecular weight polymer is needed. However, the higher molecular weight PDMAEMA is very cytotoxic. To overcome this problem, low molecular weight PDMAEMA was synthesized via ATRP and subsequently azide-functionalized. The azide-functional groups were clicked on a backbone via a degradable linker to obtain a degradable high molecular weight PDMAEMA with reduced toxicity (Fig. 11) [128]. Bioconjugation is another field where the combination of ATRP and click chemistry has been reported. The easy access to azide end-functional polymer makes ATRP a good candidate for polymer-peptide conjugation. The synthesis of x-azide-functional poly(oligo(ethylene glycol) acrylate) has been reported. Several alkyne-functional compounds were used to click onto the azide end-group. Click chemistry between the azide-functional polymer and an alkyne-

functional FMOC-amino acid was used to obtain a starting point for solid phase synthesis of polypeptides. Also, an RGD-containing oligopeptide was clicked onto the same azide-functional poly(oligo(ethylene glycol) acrylate) [129]. A biotin conjugate using the same polymer was reported [130]. Another approach consists of attaching an ATRP initiator to the biomolecule and polymerizing from the biomolecule. This technique was reported by Wang and coworkers [131]. In the same publication, an alkyne functionality was introduced on a nanoparticle. To this alkyne, an azide-functional fluorescent marker was clicked. Velonia and coworkers [132] reported the polymerization of an alkyne-functional monomer onto a protein. After the polymerization, a hydrophobe was clicked to the molecule so that a giant amphiphilic conjugate was formed. Complex bio-conjugates were obtained via ATRP and click chemistry, up to four different functionalities were attached to a polymer [133]. Conjugates with other molecules have also been reported. Single-walled carbon nanotubes were functionalized with alkynes. Styrene that was polymerized via ATRP was azide-functionalized and clicked onto the carbon nanotube (Fig. 12) [134]. Fullerenes were modified in a similar fashion [135]. The previously mentioned layer-by-layer technique reported by Caruso and coworkers [58] was also applied on carbon nanotubes in combination with ATRP. The surface of multiwalled carbon nanotubes (MWNTs) was decorated with alkyne functionalities. The layer-by-layer process was performed to create a thin layer of polymer on the MWNTs. At the end of the process, a fluorescent dye or end-functional PSTY was grafted on the polymer layer [136]. Microcapsules were obtained in a similar fashion. In this case, the layer-by-layer deposition and click chemistry were performed on the surface of azido-modified silica particles. After the layer-by-layer assembly, the silica core was dissolved by treatment with HF to yield the microcapsules [137]. Multi-responsive shell cross-linked micelles were also produced using ATRP and click chemistry [138]. The shell of a triblock copolymer micelle was crosslinked by the reaction of N,N-diethylamino ethyl methacrylate (DEAEMA) residues with a di-iodo compound to yield bis-quaternary ammonium salt alkyl bridges. Click chemistry at the alkyne chain-end functionality of the triblock copolymer was subsequently used to introduce pH- and temperature-responsiveness [138]. When block copolymers were

1223


HO O OH

Br

O

HS

n O

HO

O

OH

S

Et 3 N, CH 3CN

O

n O

O

Pyr, CH2 Cl2

"Branch"

O

Br O Br

O Br

"Grow"

O n O

O

O

O

O O

Br

O

O n

O

O O

O

Br

S

O

O S

O

O

Br O

O

O

O

n O

Cu0 /Cu IIBr 2 Me 6-Tren,DMSO

n 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 temperature, the drug release or conformation of these micelles could be influenced [139,140]. Similar to the work of Brittain and coworkers [70–72], silica nanoparticles were modified with ATRP. After the polymerization of styrene, the bromide end-group was transformed into an azide by reaction with sodium azide. Subsequently, different alkynes were clicked on the polymer chain-ends to yield carboxylic acid, hydroxy, primary amine and acrylate end-groups [141]. Electrospinning was used to obtain nanofibers of epoxy and chloromethyl-functional polymers. These fibers were modified with sodium azide to have azide functionalities on the surface. After the modification, alkyne end-functional p(NIPAM) was clicked on the surface and thermoresponsive nanofibers were obtained [142]. Grafting of poly(glycidyl methacrylate) from a poly(high internal phase emulsion) (poly(HIPE)) surface was achieved using ATRP. The epoxy functionalities were reacted with sodium azide to introduce azide functionalities on the surface of the poly(HIPE). Click chemistry was used to graft a variety of groups on the surface, including a fluorescent dye to yield fluorescent poly(HIPE) [143]. Because of its wide scope, the combination of ATRP and click chemistry has received considerable interest. Matyjaszewski and coworkers [144] showed that the reaction rate is catalyst dependant. It is important to choose the right catalyst for each system. The major disadvantage of these catalysts is that for some applications Cu must be

absent from the product, which means that the catalyst must be totally removed. Koshti and coworkers [145] reported a self-separating catalyst, which was attached to a polymer synthesized via ATRP. This catalyst can be used for click chemistry and it separates itself from the product. This process is based on the polarity of the ligand. The click reaction was done in a mixture of heptane and ethanol/ water (90% ethanol). Upon the addition of an extra 10 % (volume) water phase-separation occurs. UV analysis showed that > 99.6% of the copper complex was in the heptane layer. The product could be obtained from the ethanol phase. 6.3. SET-LRP and click chemistry So far there have been few reports on SET-LRP combined with click chemistry. Due to the similarity of SETLRP and ATRP, the combination of SET-LRP and click chemistry is expected to be versatile. Percec and coworkers [146] synthesized dendritic macromolecules via SET-LRP and thio-bromo click chemistry [147]. In a three step ‘‘branch’’ and ‘‘grow’’ mechanism (Scheme 25) dendritic structures were obtained. Firstly, thioglycerol was used for the base-mediated thioetherification of the a-bromoester, this is the ‘‘branch’’ step. Secondly, an acylation reaction with 2-bromopropionyl bromide was carried out. Thirdly, SET-LRP was used to polymerize methyl acrylate onto the branches, this is the ‘‘grow’’ step. For the different generations dendrimers (generations 1–5 were used) the

1224


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

using ATNRC and SET-LRP at room temperature by Huang and coworkers [150]. The combination of ATNRC, SET-LRP and CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction for the synthesis of chain extended polystyrene and three-armed stars was carried out by Monteiro and coworkers [149].

‘‘branch’’ step was repeated an appropriate number of times before the SET-LRP was carried out. Atom transfer nitroxide radical coupling (ATNRC) is a reaction in which TEMPO derivatives are used to end-cap polymer chains. ATNRC also falls under the category of click chemistry [149]. Block copolymers were synthesized

N N N O O N3

O

Br O

Br

S

O S

=

= PMMA

O

N N N

O

n

N N N

ATRP

MMA

O

N N N O O N N N

Scheme 27. Schematic overview of the preparation of four armed star [166].

O N N N

1225


the particles. These nanoparticles proved to be a very efficient catalyst for click chemistry [154]. Alkoxyamine initiators functionalized with alkyne and azide groups have been reported and used for the synthesis of functionalized polymers and block copolymers [155]. As discussed previously, Tunca and coworkers [124,125] reported the TEMPO-based version of these initiators.

6.4. NMP and click chemistry The first article reporting on the combination of NMP and click chemistry was published in 2005 and dealt with the orthogonal approaches for functionalization of macromolecules. With the combination of NMP, click chemistry and other reactions, polymers with multiple functionalities were synthesized [151]. There have been multiple reports on the synthesis of functional nanoparticles via the combination of NMP and click chemistry. Click chemistry has been used in different ways. Firstly, a fluorescent label was clicked on the inside of the hydrophobic core of particles [152]. Secondly, the fluorescent label was clicked on the outside of the shell (Scheme 26) [153]. Thirdly, a ligand used for click chemistry was attached to the inside of the shell of the nanoparticle. Click chemistry of small molecules was done in the hydrophobic core of O

7. Miktoarm star polymers Arguably the most impressive examples of combinations of LRP techniques and click chemistry appear in the field of miktoarm star polymer. Star-shaped polymers have been prepared in a number of ways [98,156–164]. A typical core molecule consists of pentaerythritol, esterified with pentynoic acid. Polymer chains synthesized via ATRP were azide-functionalized and clicked on the core [165]. To obtain the hetero arms necessary for creating the miktoarm architecture, a combination of RAFT and ATRP was used. PSTY arms were synthesized via RAFT using an azide-functional RAFT agent. The obtained polymers were clicked on 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 PSTY was then used as an ATRP initiator for the polymerization of methyl methacrylate (MMA) (Scheme 27) [166]. ABC miktoarm stars were synthesized from a core containing an alkyne, a bromide and a TEMPO group (22,

O O

O

Br OH 23 Fig. 13. The ATRP initiator (23) used by Xu and coworkers for the synthesis of ABC triblock copolymers via sequential click chemistry, ATRP and ROP [170].

O Br n

O O

O

+ o

p

q

O

O O N3

r

Click

O O

n

Br

O

O O O O

N N N

o

p

q

O

O

m

m O

24 Scheme 28. Synthesis of ABCD four armed star copolymers [174].

O

r

1226


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]. Miktoarm star polymers of the ABC type were also synthesized via the combination of click chemistry, ATRP and ROP (23, Fig. 13). Firstly, an azide-functional PEO was clicked on the initiator. Secondly, ATRP of styrene was preformed. Thirdly the ROP of e-caprolactone was done using the hydroxyl group as initiator [170]. In a slightly different way, another ABC miktoarm star copolymer was synthesized. In this case the arms consisted of polystyrene, poly(NIPAAm) and poly(e-caprolactone). The synthesis took place via a combination of ATRP, ring-opening polymerization and azide–alkyne click chemistry. An alkynyl and a primary hydroxy moiety were introduced at the chain-end of a polystyrene chain via reaction of an azide end-functional PSTY with 3,5-bis(propargyloxy)benzyl alcohol. Rind-opening polymerization of e-caprolactone was initiated from the alcohol functionality and an azide end-functional poly(NIPAAm) chain was clicked onto the remaining alkynyl functionality at the junction point between the two first arms [171]. AB2, or Y-shaped miktoarm star copolymer with biological relevance were synthesized again by a combination of ATRP, ring-opening polymerization and click chemistry. Propargyl amine was used as the initiator for the ringopening polymerization to yield alkynyl end-functional poly(e-benzyloxy-carbonyl-L-lysine). Diazide end-functional poly(NIPAAm) was synthesized with a diazide-functional ATRP initiator. The click reaction between the two building blocks led to the AB2 miktoarm star. In a postpolymerization modification, the benzyloxy protecting group could be removed to yield poly(L-lysine) as the functional arms [172]. Star block copolymers have been prepared using a three-armed star ATRP initiator to polymerize styrene. Subsequently, the bromides were substituted with azides and an alkyne-functional PEO was clicked on the three armed star [173]. ABCD miktoarm star polymers were achieved via a combination of anionic polymerization, ATRP, ROP and click chemistry. PSTY and polyisoprene were anionically polymerized using butyl lithium. Functionalization reactions were conducted on the active lithium chain-ends. PSTY was functionalized with propargyl and 2-bromoiso-

PSTY N N N N N N PAA

N

N N N HO

n

O

N OH

O

N N N N N

N N N

PAA

N

PSTY 26 Fig. 14. Grafted copolymer of glycidyl methacrylate and PEO (25) synthesized via ATRP and click chemistry. First generation dendrimer of polyacrylic acid and polystyrene (26) synthesized via click chemistry and ATRP.

butyryl groups. Subsequently, ATRP of butyl acrylate was carried out yielding a P(STY-block-polybutyl acrylate) with a propargyl group at the junction. The polyisoprene was functionalized with a hydroxyl group and an ethoxyethyl-protected hydroxyl group. The hydroxyl group was used for the ROP of ethylene oxide yielding a poly(isopreneblock-EO), with the protected hydroxyl group at the junction point. This protected hydroxyl group was de-protected and modified in two steps into an azide via a bromoacetyl intermediate. The two block copolymers were clicked together to form an ABCD star polymer (Scheme 28) [174]. Star-shaped polymers with as many as twenty-one arms have been reported from the combination of ATRP and click chemistry [175]. First generation mikto-dendrimers [176] or dendrimerlike [177] structures have also been synthesized via ATRP and click chemistry (Fig. 14).


From the overview above, it may appear as if the great majority of miktoarm star syntheses are based on ATRP as the living radical polymerization technique. Surely, also RAFT can be used, but the combination with alkyne-azide click chemistry makes ATRP very attractive as shown. Some examples are reported where RAFT is combined with alkyne-azide click chemistry [178,179]. Other approaches are to combine RAFT with the aldehyde-aminoxy click coupling reaction as was reported by Wu et al. [180,181] and obviously the popular approach where the thiocarbonyl thio end-group of a RAFT polymer is aminolyzed to a thiol for subsequent use in thiol-ene chemistry [88].

8. Conclusions and Outlook Since the introduction of the concept of click chemistry in 2001, the research on click type reactions is growing fast. The combination of click chemistry with high fidelity polymerization reactions is a logical consequence. The living radical polymerization techniques that have been developed since the 1990s turn out to be excellent candidates to use in conjunction with click chemistry. High chain-end functionality after polymerization is combined with highly efficient end-group transformation reactions. The subsequent reaction of those end-groups via click chemistry leads to enormous versatility in the construction of macromolecular architectures. Without doubt, the newly developed synthetic routes will find application in a wide variety of fields. Morphological control on the nanometer length scale opens up possibilities in the biomedical field (drug delivery, regenerative medicine, etc.), in electro- and photo-active materials (polymer LED, photovoltaic devices, etc.), and in the broad field of sensors and actuators. Further developments will certainly be seen on the combination of natural components and synthetic polymers. The field of Synthetic Biology is an example of an emerging field where complex natural components are interfaced with well-defined synthetic materials. The complex character of contemporary applications of polymer materials asks for a multidisciplinary approach. Living radical polymerization and click chemistry will play an eminent role. However, chemists will need to interact with disciplines such as biology, physics, engineering, etc. in order to meet future requirements of advanced materials. References [1] Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed 2001;40:2004–21. [2] Huisgen R, Knorr R, Moebius L, Szeimies G. 1,3-Dipolar cycloadditions. XXIII. Addition of organic azides to C–C triple bonds. Chem Ber 1965;98:4014–21. [3] Tornoe CW, Christensen C, Meldal M. Peptidotriazoles on solid phase:[1–3]-triazoles by regiospecific copper(I)-Catalyzed 1,3dipolar cycloadditions of terminal alkynes to azides. J Org Chem 2002;67:3057–64. [4] Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective ‘‘ligation’’ of azides and terminal alkynes. Angew Chem Int Ed 2002;41:2596–9.

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Niels Akeroyd: Niels Akeroyd obtained his MSc from Utrecht University (the Netherlands) in 2005 after working on polymeric non-viral gene delivery systems and degradable hydrophilic polyesters in the group of Wim E. Hennink. Subsequently he moved to Stellenbosch University (South Africa) to obtain his PhD under the supervision of Bert Klumperman in 2010 for the thesis titled: Click chemistry for the preparation of advanced macromolecular architectures. Since March 2010 he has been working as a postdoctoral fellow at the Radboud University Nijmegen (the Netherlands) with Alan E. Rowan on rotaxanes and processive catalysis.

Bert Klumperman: Prof. Bert Klumperman is currently holder of the South African Research Chair on Advanced Macromolecular Architectures at Stellenbosch University (South Africa). He obtained his PhD from Eindhoven University of Technology under the joint supervision of Profs Ton German and Ken O’Driscoll. He started his academic career in Eindhoven (the Netherlands) in 1995. The main focus of his research is on synthetic, mechanistic and kinetic aspects of (living) radical polymerization. He received an A-rating from the National Research Foundation (South Africa, 2007), was elected fellow of the Royal Society of South Africa (2008) and received the Rector’s Award for Excellent Research (Stellenbosch, 2009).