The Combination of Living Radical Polymerization and Click Chemistry for the Synthesis of Advanced Macromolecular Architectures ⇑ Niels Akeroyd, Bert Klumperman
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European Polymer Journal 47 (2011) 1207–1231 Contents lists available at ScienceDirect 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) tech- niques 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 À1 I (greater than 20 kcal mol ) and goes rapidly to comple- the form of Cu salts, for example CuI, CuOTfÁC6H6 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 pre- pared easily by placing carbon black and Cu(NO3)2Á3H2O 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 (CuSO4Á5H2O 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