The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

Department of Chemistry, Department of Radiology, Washington University in Saint Louis, Saint Louis, Missouri 63130, Department of Chemistry, Texas A&M University, College Station, Texas 77842, Cancer Center Karolinska, Department of Oncology-Pathology CCK, R8:03 Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden, and Department of Chemistry and Biochemistry, Department of Materials, and Materials Research Laboratory, University of California, Santa Barbara, California 93106

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Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials

2.1.6. Tacticity and Sequence: Advanced Control 4967 2.2. Transition Metal Catalysts 4967 2.2.1. Overviews of Catalysts 4967 2.2.2. Ruthenium 4967 2.2.3. Copper 4971 2.2.4. Iron 4971 2.2.5. Nickel 4975 2.2.6. Molybdenum 4975 2.2.7. Manganese 4976 2.2.8. Osmium 4976 2.2.9. Cobalt 4976 2.2.10. Other Metals 4976 2.3. Cocatalysts (Additives) 4977 2.3.1. Overview of Cocatalysts 4977 2.3.2. Reducing Agents 4977 2.3.3. Free Radical Initiators 4977 2.3.4. Metal Alkoxides 4977 2.3.5. Amines 4978 2.3.6. Halogen Source 4978 2.4. Initiators 4978 2.4.1. Overview of Initiators: Scope and Design 4978 2.4.2. Alkyl Halides 4978 2.4.3. Arenesulfonyl Halides 4979 2.4.4. N-Chloro Compounds 4979 2.4.5. Halogen-Free Initiators 4979 2.5. Solvents 4980 2.5.1. Overview of Solvents 4980 2.5.2. Catalyst Solubility and Coordination of Solvent 4981 2.5.3. Environmentally Friendly Solvents 4981 2.5.4. Water 4981 2.5.5. Catalytic Solvents: Catalyst Disproportionation 4981

Transition metal-catalyzed living radical polymerization : toward perfection in catalysis and precision polymer synthesis

3.10 - Nitroxide-Mediated Polymerization

No copper needed: In recent years, a large number of metal-free click reactions have been reported based on thiol-ene radical additions, Diels–Alder reactions, and Michael additions. In this Minireview, special attention is given to the advantages and limitations of the different methods to evaluate whether they have the potential to surpass the overwhelming success of the copper(I)-catalyzed azide-alkyne cycloaddition.

The overwhelming success of click chemistry encouraged researchers to develop alternative “spring-loaded” chemical reactions for use in different fields of chemistry. Initially, the copper(I)-catalyzed azide-alkyne cycloaddition was the only click reaction. In recent years, metal-free [3+2] cycloaddition reactions, Diels–Alder reactions, and thiol-alkene radical addition reactions have come to the fore as click reactions because of their simple synthetic procedures and high yields. Furthermore, these metal-free reactions have wide applicability and are physiologically compatible. These and other alternative click reactions expand the opportunities for synthesizing small organic compounds as well as tailor-made macromolecules and bioconjugates. This Minireview discusses the success and applicability of new, in particular metal-free, click reactions.

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Click Chemistry beyond Metal-Catalyzed Cycloaddition

We report a one-pot synthesis of ABC triblock copolymers of poly(ethylene glycol)− (PEG−) polystyrene− (PS−) poly(methyl methacrylate) (PMMA), and poly(e-caprolactone)− (PCL−) PS−PMMA by combining in situ click [3 + 2] and Diels−Alder [4 + 2] reactions. For this purpose, furan-protected maleimide end-functionalized PMMA, PS with α-anthracene and ω-azide end-functionality, and PEG or PCL with an alkyne end-functional group were reacted in N,N-dimehtylformamide (DMF) for 36 h at 120 °C in order to give the corresponding triblock copolymers. All polymeric precursors with narrow molecular weight distribution and well-defined chain-end functionalities were achieved from living polymerization methods, except PEG. The obtained polymers were characterized by 1H NMR (250 MHz), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC) measurements.

One-Pot Synthesis of ABC Type Triblock Copolymers via in situ Click [3 + 2] and Diels−Alder [4 + 2] Reactions

Diels–Alder click reaction was successfully applied for the preparation of 3-arm star polymers (A3) using furan protected maleimide end-functionalized polymers and trianthracene functional linking agent (2) at reflux temperature of toluene for 48 h. Well-defined furan protected maleimide end-functionalized polymers, poly (ethylene glycol), poly(methyl methacrylate), and poly(tert-butyl acrylate) were obtained by esterification or atom transfer radical polymerization. Obtained star polymers were characterized via NMR and GPC (refractive index and triple detector detection). Splitting of GPC traces of the resulting polymer mixture notably displayed that Diels–Alder click reaction was a versatile and a reliable route for the preparation of A3 star polymer. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 302–313, 2008

Preparation of 3‐arm star polymers (A3) via Diels–Alder click reaction

The double click reactions (Cu catalyzed Huisgen and Diels–Alder reactions) were used as a new strategy for the preparation of well-defined heterograft copolymers in one-pot technique. The synthetic strategy to the various stages of this work is outlined: (i) preparing random copolymers of styrene (St) and p-chloromethylstyrene (CMS) (which is a functionalizable monomer) via nitroxide mediated radical polymerization (NMP); (ii) attachment of anthracene functionality to the preformed copolymer by the o-etherification procedure and then conversion of the remaining CH2Cl into azide functionality; (iii) by using double click reactions in one-pot technique, maleimide end-functionalized poly(methyl methacrylate) (PMMA-MI) via atom transfer radical polymerization (ATRP) of MMA and alkyne end-functionalized poly (ethylene glycol) (PEG-alkyne) were introduced onto the copolymer bearing pendant anthryl and azide moieties. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6969–6977, 2008

Heterograft Copolymers via Double Click Reactions Using One-Pot Technique

3-Arm star-block copolymers, (polystyrene-b-poly(methyl methacrylate))3, (PS-b-PMMA)3, and (polystyrene-b-poly(ethylene glycol))3, (PS-b-PEG)3, are prepared using double-click reactions: Huisgen and Diels–Alder, with a one-pot technique. PS and PMMA blocks with α-anthracene-ω-azide- and α-maleimide-end-groups, respectively, are achieved using suitable initiators in ATRP of styrene and MMA, respectively. However, PEG obtained from a commercial source is reacted with 3-acetyl-N-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxamide (7) to give furan-protected maleimide-end-functionalized PEG. Finally, PS/PMMA and PS/PEG blocks are linked efficiently with trialkyne functional linking agent 1,1,1-tris[4-(2-propynyloxy)phenyl]-ethane 2 in the presence of CuBr/N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA) at 120 °C for 48 h to give two samples of 3-arm star-block copolymers. The results of the peak splitting using a Gaussian deconvolution of the obtained GPC traces for (PS-b-PMMA)3 and (PS-b-PEG)3 displayed that the yields of target 3-arm star-block copolymers were found to be 88 and 82%, respectively. © Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7091–7100, 2008

One‐pot synthesis of star‐block copolymers using double click reactions

Two types of multiarm star block copolymers: (polystyrene)m-poly(divinyl- benzene)-poly(methyl methacrylate)n, (PS)m-polyDVB-(PMMA)n and (polystyrene)m- poly(divinylbenzene)-poly(tert-butyl acrylate)k, (PS)m-polyDVB-(PtBA)k were success- fully prepared via a combination of cross-linking and Diels-Alder click reactions based on ''arm-first'' methodology. For this purpose, multiarm star polymer with an- thracene functionality as reactive periphery groups was prepared by a cross-linking reaction of divinyl benzene using a-anthracene end functionalized polystyrene (PS- Anth) as a macroinitiator. Thus, obtained multiarm star polymer was then reacted with furan protected maleimide-end functionalized polymers: PMMA-MI or PtBA-MI at reflux temperature of toluene for 48 h resulting in the corresponding multiarm star block copolymers via Diels-Alder click reaction. The multiarm star and multi- arm star block copolymers were characterized by using 1 H NMR, SEC, Viscotek tri-

Aydan Dag

Papers

One-Pot Synthesis of ABC Type Triblock Copolymers via in situ Click [3 + 2] and Diels−Alder [4 + 2] Reactions

Preparation of 3‐arm star polymers (A3) via Diels–Alder click reaction

Heterograft Copolymers via Double Click Reactions Using One-Pot Technique

One‐pot synthesis of star‐block copolymers using double click reactions

Multiarm Star Block Copolymers via Diels-Alder Click Reaction