Showing papers on "Click chemistry published in 2009"

Analysis and Optimization of Copper-Catalyzed Azide–Alkyne Cycloaddition for Bioconjugation

Abstract: Since its discovery in 2002, the copper-catalyzed azide-alkyne cycloaddition (CuAAC)[1] reaction—the most widely recognized example of click chemistry[2]—has been rapidly embraced for applications in myriad fields.[3] The attractiveness of this procedure (and its copper-free strained-alkyne variant[4]) stems from the selective reactivity of azides and alkynes only with each other. Because of the fragile nature and low concentrations at which biomolecules are often manipulated, bioconjugation presents significant challenges for any ligation methodology. Several different CuAAC procedures have been reported to address specific cases involving peptides, proteins, polynucleotides, and fixed cells, often with excellent results,[5] but also occasionally with somewhat less satisfying outcomes.[6] We describe here a generally applicable procedure that solves the most vexing click bioconjugation problems in our laboratory, and therefore should be of use in many other situations. The CuAAC reaction requires the copper catalyst, usually prepared with an appropriate chelating ligand,[7] to be maintained in the CuI oxidation state. Several years ago we developed a system featuring a sulfonated bathophenanthroline ligand,[8] which was optimized into a useful bioconjugation protocol.[9] A significant drawback was the catalyst’s acute oxygen sensitivity, requiring air-free techniques which can be difficult to execute when an inert-atmosphere glove box is unavailable or when sensitive biomolecules are used in small volumes of aqueous solution. We also introduced an electrochemical method to generate and protect catalytically active CuI–ligand species for CuAAC bioconjugation and synthetic coupling reactions with miminal effort to exclude air.[10] Under these conditions, no hydrogen peroxide was produced in the oxygen-scrubbing process, resulting in protein conjugates that were uncontaminated with oxidative byproducts. However, this solution is also practical only for the specialist with access to the proper equipment. Other protocols have employed copper(I) sources such as CuBr for labeling fixed cells[11] and synthesizing glycoproteins.[12] In these cases, the instability of CuI in air imposes a requirement for large excesses of Cu (greater than 4 mm) and ligand for efficient reactions, which raises concerns about protein damage or precipitation, plus the presence of residual metal after purification. The most convenient CuAAC procedure involves the use of an in situ reducing agent. Sodium ascorbate is the reductant of choice for CuAAC reactions in organic and materials synthesis, but is avoided in bioconjugation with a few exceptions.[13] Copper and sodium ascorbate have been shown to be detrimental to biological[14] and synthetic[15] polymers due to copper-mediated generation of reactive oxygen species.[16] Moreover, dehydroascorbate and other ascorbate byproducts can react with lysine amine and arginine guanidine groups, leading to covalent modification and potential aggregation of proteins.[6a,17] We hoped that solutions to these problems would allow ascorbate to be used in fast and efficient CuAAC reactions using micromolar concentration of copper in the presence of atmospheric oxygen. This has now been achieved, allowing demanding reactions to be performed with biomolecules of all types by the nonspecialist. For purposes of catalyst optimization and reaction screening, the fluorogenic coumarin azide 1 developed by Wang et al. has proven to be invaluable (Scheme 1).[18] The progress of cycloaddition reactions between mid-micromolar concentrations of azide and alkyne in aqueous buffers was followed by the increase in fluorescence at 470 nm upon formation of the triazole 2. Scheme 1 Top: Reaction used for screening CuAAC catalysts and conditions. Below: Accelerating ligand 3 and additive 4 used in these studies. DMSO=dimethylsulfoxide.

Click Chemistry beyond Metal-Catalyzed Cycloaddition

Abstract: 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.

Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments

Abstract: Click chemistry provides extremely selective and orthogonal reactions that proceed with high efficiency and under a variety of mild conditions, the most common example being the copper(I)-catalysed reaction of azides with alkynes. While the versatility of click reactions has been broadly exploited, a major limitation is the intrinsic toxicity of the synthetic schemes and the inability to translate these approaches into biological applications. This manuscript introduces a robust synthetic strategy where macromolecular precursors react through a copper-free click chemistry, allowing for the direct encapsulation of cells within click hydrogels for the first time. Subsequently, an orthogonal thiol-ene photocoupling chemistry is introduced that enables patterning of biological functionalities within the gel in real time and with micrometre-scale resolution. This material system enables us to tailor independently the biophysical and biochemical properties of the cell culture microenvironments in situ. This synthetic approach uniquely allows for the direct fabrication of biologically functionalized gels with ideal structures that can be photopatterned, and all in the presence of cells.

Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in nucleoside, nucleotide, and oligonucleotide chemistry.

Abstract: Pioneered by Huisgen in the 1960’s1, the 1,3-dipolar cycloaddition reaction between acetylenes and azides was brought back into focus by Sharpless and others2 when they developed the concept of “click chemistry”. This approach, based on the joining of smaller units mimics the approach used by nature to generate substances. This concept takes advantage of reactions that are modular, wide in scope, stereospecific, high yielding, and generate only non-offensive by-products to efficiently access new useful compounds. Moreover, to be completely “click”, the process must involve simple reaction conditions, readily available starting materials and reagents, the use of no solvent, or a benign or easily removable solvent.3 At first, the classical Huisgen 1,3-dipolar cycloaddition did not fall into the above definition, but the discovery of copper (I) salts catalyzing the reaction first by Medal and then by Sharpless4 allowed chemists to evolve from harsh reaction conditions that lead to a mixture of 1,4- and 1,5- regio-isomers to a regioselective reaction which can be performed at room temperature in very short reaction times (Scheme 1). The Cu alkyne-azide cycloaddition (CuAAC) fit so well into the above definition that it has become almost synonymous of “click chemistry” itself. Open in a separate window Scheme 1 1,3-Dipolar Cycloaddition Between Azides and Alkynes

Click chemistry and bioorthogonal reactions: unprecedented selectivity in the labeling of biological molecules.

Abstract: In recent years, a number of bioorthogonal reactions have been developed, exemplified by click chemistry, that enable the efficient formation of a specific product, even within a highly complex chemical environment. While the exquisite selectivity and reliability of these transformations have led to their broad application in diverse research areas, they have proven to be particularly beneficial to biological studies. In this regard, the ability to rationally incorporate reactive tags onto a biomolecular target and subsequently achieve high selectivity in tag derivatization within a complex biological sample has revolutionized the toolbox that is available for addressing fundamental issues. Herein, an introduction to the impact of click chemistry and other bioorthogonal reactions on the study of biological systems is presented. This includes discussion of the philosophy behind click chemistry, the details and benefits of bioorthogonal reactions that have been developed, and examples of recent innovative approaches that have effectively exploited these transformations to study cellular processes. For the latter, the impacts of bioorthogonal reactions on drug design (i.e., in situ combinatorial drug design), biomolecule labeling and detection (site-specific derivatization of proteins, viruses, sugars, DNA, RNA, and lipids), and the recent strategy of activity-based protein profiling are highlighted.

Selective Labeling of Living Cells by a Photo-Triggered Click Reaction

Abstract: Phototriggering of the metal-free azide to acetylene cycloaddition reaction was achieved by masking the triple bond of dibenzocyclooctynes as cyclopropenone. Such masked cyclooctynes do not react with azides in the dark. Irradiation of cyclopropenones results in the efficient (Φ355 = 0.33) and clean regeneration of the corresponding dibenzocyclooctynes, which then undergo facile catalyst-free cycloadditions with azides to give corresponding triazoles under ambient conditions. In situ light activation of a cyclopropenone linked to biotin made it possible to label living cells expressing glycoproteins containing N-azidoacetyl-sialic acid. The cyclopropenone-based phototriggered click chemistry offers exciting opportunities to label living organisms in a temporally and spatially controlled manner and may facilitate the preparation of microarrays.

Genetic Encoding and Labeling of Aliphatic Azides and Alkynes in Recombinant Proteins via a Pyrrolysyl-tRNA Synthetase/tRNACUA Pair and Click Chemistry

Abstract: We demonstrate that an orthogonal Methanosarcina barkeri MS pyrrolysyl-tRNA synthetase/tRNA(CUA) pair directs the efficient, site-specific incorporation of N6-[(2-propynyloxy)carbonyl]-L-lysine, containing a carbon-carbon triple bond, and N6-[(2-azidoethoxy)carbonyl]-L-lysine, containing an azido group, into recombinant proteins in Escherichia coli. Proteins containing the alkyne functional group are labeled with an azido biotin and an azido fluorophore, via copper catalyzed [3+2] cycloaddition reactions, to produce the corresponding triazoles in good yield. The methods reported are useful for the site-specific labeling of recombinant proteins and may be combined with mutually orthogonal methods of introducing unnatural amino acids into proteins as well as with chemically orthogonal methods of protein labeling. This should allow the site specific incorporation of multiple distinct probes into proteins and the control of protein topology and structure by intramolecular orthogonal conjugation reactions.

Growing Applications of “Click Chemistry” for Bioconjugation in Contemporary Biomedical Research

Abstract: This update summarizes the growing application of "click" chemistry in diverse areas such as bioconjugation, drug discovery, materials science, and radiochemistry. This update also discusses click chemistry reactions that proceed rapidly with high selectivity, specificity, and yield. Two important characteristics make click chemistry so attractive for assembling compounds, reagents, and biomolecules for preclinical and clinical applications. First, click reactions are bio-orthogonal; neither the reactants nor their product's functional groups interact with functionalized biomolecules. Second, the reactions proceed with ease under mild nontoxic conditions, such as at room temperature and, usually, in water. The copper-catalyzed Huisgen cycloaddition, azide-alkyne [3 + 2] dipolar cycloaddition, Staudinger ligation, and azide-phosphine ligation each possess these unique qualities. These reactions can be used to modify one cellular component while leaving others unharmed or untouched. Click chemistry has found increasing applications in all aspects of drug discovery in medicinal chemistry, such as for generating lead compounds through combinatorial methods. Bioconjugation via click chemistry is rigorously employed in proteomics and nucleic research. In radiochemistry, selective radiolabeling of biomolecules in cells and living organisms for imaging and therapy has been realized by this technology. Bifunctional chelating agents for several radionuclides useful for positron emission tomography and single-photon emission computed tomography imaging have also been prepared by using click chemistry. This review concludes that click chemistry is not the perfect conjugation and assembly technology for all applications, but provides a powerful, attractive alternative to conventional chemistry. This chemistry has proven itself to be superior in satisfying many criteria (e.g., biocompatibility, selectivity, yield, stereospecificity, and so forth); thus, one can expect it will consequently become a more routine strategy in the near future for a wide range of applications.

Polysaccharide‐block‐polypeptide Copolymer Vesicles: Towards Synthetic Viral Capsids

Abstract: Natural inspiration: Amphiphilic polysaccharide-block-polypeptide copolymers were synthesized by click chemistry from dextran end-functionalized with an alkyne group and poly(gamma-benzyl L-glutamate) end-functionalized with an azide group. The ability of these copolymers to self-assemble into small vesicles (see picture) suggests the possibility of a new generation of drug- and gene-delivery systems whose structure mimics that of viruses.

Ultrafast click conjugation of macromolecular building blocks at ambient temperature.

Abstract: Block copolymers in seconds: Catalyst-free, ambient-temperature click conjugation of individual polymer strands becomes possible using novel ATRP-derived cyclopentadienylcapped polymers in an extremely rapid hetero-Diels-Alder cycloaddition with macromolecules equipped with electron-deficient dithioester end groups prepared by the RAFT process. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Selective fluorescence labeling of lipids in living cells.

Abstract: Click chemistry in vivo: Three phosphatidic acid derivatives with alkyne groups in their fatty acid chains were synthesized and incorporated into mammalian cell membranes. Copper(I)-catalyzed and strain-promoted azide–alkyne cycloaddition reactions were used for their visualization (see schematic representation and fluorescence microscopic image).

Polytriazoles with Aggregation-Induced Emission Characteristics: Synthesis by Click Polymerization and Application as Explosive Chemosensors

Abstract: The copper-catalyzed 1,3-dipolar cycloaddition of alkynes with azides is a typical example of “click” reaction. Since the reaction enjoys the advantages of high efficiency and regioselectivity and requires mild reaction conditions and simple purification procedures, it has become a versatile synthetic tool with applicability in diverse areas including bioconjugation and surface modification. The click reaction has also been utilized in polymer science with emphasis on the functionalization of preformed polymers through postpolymerization approaches. The effort of developing the reaction into a new polymerization technique, however, has met with only limited success. The polymerization reactions of arylene diazides and arylene diynes catalyzed by copper(I) species were sluggish, taking as long as 7-10 days to finish. The products often precipitated from the reaction mixtures even at the oligomer stage or became insoluble in common organic solvents after purification, unless very long alkyl chains, such as n-dodecyl groups, were attached to the arylene rings. The prepared polytrizoles were nonluminescent in the solid state, although their dilute solution emitted UV light, suggesting that the polymer emission has been quenched by the aggregate formation. If the polytriazoles are to be utilized as light-emitting materials, this issue must be properly tackled because luminophores are commonly used as solid films in their practical applications. We have recently discovered an intriguing phenomenon of aggregation-induced emission (AIE): a series of nonemissive molecules such as tetraphenylethene (TPE) and hexaphenylsilole as well as their derivatives are induced to emit efficiently by aggregate formation. The AIE effect greatly boosts the fluorescence quantum yields (ΦF) of the molecules by up to 3 orders of magnitude, turning them from faint luminophores into strong emitters. Thanks to their unique AIE characteristics, the molecules have been found to serve as chemosensors, bioprobes, stimuli-responsive nanomaterials, and active layers in the construction of efficient organic light-emitting diodes. Among the AIE luminophores, the TPE system has received much attention because of its facile preparation, ready functionalization, good photostability, and high photoluminescence (PL) efficiency. For practical applications, these low molecular weight luminophores have to be fabricated into solid films by expensive techniques such as vacuum vapor deposition processes, which are not well suited to the manufacture of large-area, flat-panel devices. One way to surmount this processing disadvantage is to synthesize high molecular weight polymers, which can be readily fabricated into large-area films by simple macroscopic processing techniques such as spin coating and static casting. However, polymers with efficient light emissions in the aggregate or solid state are rare because aggregation of the polymer chains commonly quenches light emission. In this paper, we report a group of new TPE-containing polytriazoles (P3) synthesized from the click polymerization of diyne (1) with diazides (2; Scheme 1). The light emission of the polymers is dramatically enhanced, instead of being quenched, by aggregate formation. The diyne and diazide monomers, namely 1,4-bis(propargyloxy)benzene (1), 1,2-bis[4-(azidohexyloxy)phenyl]-1,2-diphenylethene (2a), and 1,2-bis[(4-azidomethyl)phenyl]-1,2-diphenylethene (2b), were synthesized according to Scheme S1. The reactions proceeded smoothly, and the desired monomers were obtained in good yields. The monomer structures were confirmed by spectroscopic analyses (see Supporting Information for detailed characterization data). We attempted to transform the monomers to their polymers by 1,3-dipolar polycycloaddition. We have previously succeeded in the catalyst-free polycycloaddition of bis(aroylacetylene)s with diazides by simple heating. No high molecular weight polymers, however, were obtained when 1 and 2 were refluxed in THF for 110 h (Table 1, no. 1). This is due to the low reactivity of diyne 1 because it contains no election-withdrawing groups. Although the monomers could be polymerized by

"Clicking" polymer brushes with thiol-yne chemistry: indoors and out.

Abstract: Thiol-yne click chemistry is demonstrated as a modular platform for rapid and practical fabrication of highly functional, multicomponent surfaces under ambient conditions. The principle is illustrated using a postmodification strategy in which poly(propargyl methacrylate) brushes were generated via surface-initiated photopolymerization and sequentially functionalized using the radical-mediated thiol-yne reaction. Brush surfaces expressing a three-dimensional configuration of “yne” functionalities were modified with high efficiency and short reaction times using a library of commercially available thiols, including functional thiols that demonstrate applicability for pH responsive surfaces and for bioconjugation. Sequential thiol-yne reactions in conjunction with simple UV photolithography were also applied to afford micropatterned, multicomponent surfaces. The practicality of the platform was further demonstrated by carrying out thiol-yne surface reactions in sunlight, suggesting the possibility of large ...

Synthesis of dendritic macromolecules through divergent iterative thio-bromo “Click” chemistry and SET-LRP

Abstract: The development of a novel nucleophilic thio-bromo “Click” reaction, specifically base-mediated thioetherification of thioglycerol with α-bromoesters was reported in an earlier article. The combination of this thio-bromo click reaction with subsequent acylation with 2-bromopropionyl bromide provides an iterative two-step divergent growth approach to the synthesis of a new class of poly(thioglycerol-2- propionate) (PTP) dendrimers. In this article, the addition of a third step, the single-electron transfer living radical polymerization (SET-LRP) of methyl acrylate (MA), was shown to provides access to a three-step “branch” and “grow” divergent approach to dendritic macromolecules wherein poly(methyl acrylate) (PMA) connects the branching subunits. This facile methodology can provide a diversity of dendritic macromolecular topologies and will ultimately provide the means to the development of self-organizable dendritic macromolecules. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3940–3948, 2009

Selective bifunctional modification of a non-catenated metal-organic framework material via "click" chemistry.

Abstract: A noncatenated, Zn-based metal−organic framework (MOF) material bearing silyl-protected acetylenes was constructed and postsynthetically modified using “click” chemistry. Using a solvent-based, selective deprotection strategy, two different organic azides were “clicked” onto the MOF crystals, resulting in a porous material whose internal and external surfaces are differently functionalized.

Functionalized Chitosan as a Green, Recyclable, Biopolymer‐Supported Catalyst for the [3+2] Huisgen Cycloaddition

Abstract: Owing to increasing concern about environmental impact, tremendous effort has been made towards the development of new processes that minimize pollution in chemical synthesis. For this reason and others (catalyst removal, recovery, and recycling), heterogeneous catalysis is clearly on the rise, including in industry. Of the many systems that have been developed over the past decades, metallic species supported on inorganic materials (e.g. SiO2, Al2O3) or on charcoal are the most common. The immobilization of transition metals on polymer supports derived from petrochemicals (e.g. polystyrenes) has also been the focus of many efforts. Recent developments for cleaner, sustainable chemistry are being driven by a shift from petrochemical-based feedstocks to biological materials. There is considerable interest in exploiting natural polymer macrostructures, and in particular those of polysaccharides, to create high-performance and environmentally friendly catalysts. Indeed, polysaccharides present many advantages that may stimulate their use as polymeric supports for catalysis: 1) They are present in enormous quantity on earth, 2) they contain many functionalities that can be used readily for the anchoring of organometallic species, 3) they contain many stereogenic centers, and 4) they are chemically stable but biodegradable. Surprisingly, although there has been a worldwide realization that nature-derived polysaccharides can provide the raw materials needed for the production of numerous industrial consumer goods, their use as supports for catalysis is still in its infancy. Chitosan (Figure 1 A) is a particularly attractive polysaccharide for application in catalysis owing to the presence of readily functionalizable amino groups and its insolubility in organic solvents. A copolymer of b(1!4)-2-amino-2-deoxyd-glucopyranose and 2-acetamido-2-deoxy-d-glucopyranose, chitosan results from incomplete deacetylation of chitin. At least 10 gigatons of chitin are constantly present in the biosphere; thus, chitosan is a renewable green material. Of

Synthesis of dendrimers through divergent iterative thio-bromo “Click” chemistry

Abstract: The development of a novel nucleophilic thio-bromo “Click” reaction, specifically base-mediated thioetherification of thioglycerol with α-bromoesters, is reported. Combination of this thio-bromo click reaction with subsequent acylation with 2-bromopropionyl bromide provides an iterative two-step divergent growth approach to the synthesis of a new class of poly(thioglycerol-2-propionate) (PTP) dendrimers. This approach is demonstrated in the rapid preparation of four generation (G1–G4) of PTP dendrimers with high-structural fidelity. The isolated G1–G4 bromide-terminated dendrimers can be used directly as dendritic macroinitiators for the synthesis of star-polymers via SET-LRP. Additionally, the intermediate hydroxy-terminated dendrimers are analogs of other water-soluble polyester and polyether dendrimers. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3931–3939, 2009

Click Chemistry for Biotechnology and Materials Science

Abstract: Preface . List of Contributors . Acknowledgments . 1 Click Chemistry: A Universal Ligation Strategy for Biotechnology and Materials Science ( Joerg Lahann). 1.1 Introduction. 1.2 Selected Examples of Click Reactions in Materials Science and Biotechnology. 1.3 Potential Limitations of Click Chemistry. 1.4 Conclusions. References. 2 Common Synthons for Click Chemistry in Biotechnology ( Christine Schilling, Nicole Jung and Stefan Brase). 2.1 Introduction - Click Chemistry. 2.2 Peptides and Derivatives. 2.3 Peptoids. 2.4 Peptidic Dendrimers. 2.5 Oligonucleotides. 2.6 Carbohydrates. 2.7 Conclusion. References. 3 Copper-free Click Chemistry ( Jeremy M. Baskin and Carolyn R. Bertozzi). 3.1 Introduction. 3.2 Bio-orthogonal Ligations. 3.3 Applications of Copper-free Click Chemistries. 3.4 Summary and Outlook. References. 4 Protein and Peptide Conjugation to Polymers and Surfaces Using Oxime Chemistry ( Heather D. Maynard, Rebecca M. Broyer and Christopher M. Kolodziej). 4.1 Introduction. 4.2 Protein/Peptide-Polymer Conjugates. 4.3 Immobilization of Proteins and Peptides on Surfaces. 4.4 Conclusions. References. 5 The Role of Click Chemistry in Polymer Synthesis ( Jean-Francois Lutz and Brent S. Sumerlin). 5.1 Introduction. 5.2 Polymerization via CuAAC. 5.3 Post-polymerization Modification via Click Chemistry. 5.4 Polymer-Biomacromolecule Conjugation. 5.5 Functional Nanomaterials. 5.6 Summary and Outlook. References. 6 Blocks, Stars and Combs: Complex Macromolecular Architecture Polymers via Click Chemistry ( Sebastian Sinnwell, Andrew J. Inglis, Martina H. Stenzel and Christopher Barner-Kowollik). 6.1 Introduction. 6.2 Block Copolymers. 6.3 Star Polymers. 6.4 Graft Copolymers. 6.5 Concluding Remarks. References. 7 Click Chemistry on Supramolecular Materials ( Wolfgang H. Binder and Robert Sachsenhofer). 7.1 Introduction. 7.2 Click Reactions on Rotaxanes, Cyclodextrines and Macrocycles. 7.3 Click Reactions on DNA. 7.4 Click Reactions on Supramolecular Polymers. 7.5 Click Reactions on Membranes. 7.6 Click Reactions on Dendrimers. 7.7 Click Reactions on Gels and Networks. 7.8 Click Reactions on Self-assembled Monolayers. References. 8 Dendrimer Synthesis and Functionalization by Click Chemistry for Biomedical Applications ( Daniel Q. McNerny, Douglas G. Mullen, Istvan J. Majoros, Mark M. Banaszak Holl and James R. Baker Jr). 8.1 Introduction. 8.2 Dendrimer Synthesis. 8.3 Dendrimer Functionalization. 8.4 Conclusions and Future Directions. References. 9 Reversible Diels-Alder Cycloaddition for the Design of Multifunctional Network Polymers ( Amy M. Peterson and Giuseppe R. Palmese). 9.1 Introduction. 9.2 Design of Polymer Networks. 9.3 Application of Diels-Alder Linkages to Polymer Systems. 9.4 Conclusions. References. 10 Click Chemistry in the Preparation of Biohybrid Materials ( Heather J. Kitto, Jan Lauko, Floris P. J. T. Rutjes and Alan E. Rowan). 10.1 Introduction. 10.2 Polymer-containing Biohybrid Materials. 10.3 Biohybrid Structures based on Protein Conjugates. 10.4 Biohybrid Amphiphiles. 10.5 Glycoconjugates. 10.6 Conclusions. References. 11 Functional Nanomaterials using the Cu-catalyzed Huisgen Cycloaddition Reaction ( Sander S. van Berkel, Arnold W.G. Nijhuis, Dennis W.P.M. Lowik and Jan C.M. van Hest). 11.1 Introduction. 11.2 Inorganic Nanoparticles. 11.3 Carbon-based Nanomaterials. 11.4 Self-assembled Organic Structures. 11.5 Virus Particles. 11.6 Conclusions. References. 12 Copper-catalyzed 'Click' Chemistry for Surface Engineering ( Himabindu Nandivada and Joerg Lahann). 12.1 Introduction. 12.2 Synthesis of Alkyne or Azide-functionalized Surfaces. 12.3 Spatially Controlled Click Chemistry. 12.4 Copper-catalyzed Click Chemistry for Bioimmobilization. 12.5 Summary. References. 13 Click Chemistry in Protein Engineering, Design, Detection and Profiling ( Daniela C. Dieterich and A. James Link). 13.1 Introduction. 13.2 Posttranslational Functionalization of Proteins with Azides and Alkynes. 13.3 Cotranslational Functionalization of Proteins with Azides and Alkynes. 13.4 BONCAT: Identification of Newly Synthesized Proteins via Noncanonical Amino Acid Tagging. 13.5 Conclusions and Future Prospects. References. 14 Fluorogenic Copper(I)-catalyzed Azide-Alkyne Cycloaddition Reactions Reactions and their Applications in Bioconjugation ( Celine Le Droumaguet and Qian Wang). 14.1 Click Reaction for Bioconjugation Applications. 14.2 Significance of Fluorogenic Reactions in Bioconjugation. 14.3 CuAAC-based Fluorogenic Reaction. 14.4 Applications of CuAAC in Bioconjugation. 14.5 Conclusions. References. 15 Synthesis and Functionalization of Biomolecules via Click Chemistry ( Christine Schilling, Nicole Jung and Stefan Brase). 15.1 Introduction. 15.2 Labeling of Macromolecular Biomolecules. 15.3 Syntheses of Natural Products and Derivatives. 15.4 Enzymes and Click Chemistry. 15.5 Synthesis of Glycosylated Molecular Architectures. 15.6 Synthesis of Nitrogen-rich Compounds: Polyazides and Triazoles. 15.7 Conclusions. References. 16 Unprecedented Electro-optic Properties in Polymers and Dendrimers Enabled by Click Chemistry Based on the Diels-Alder Reactions ( Jingdong Luo, Tae-Dong Kim and Alex K.-Y. Jen). 16.1 Introduction. 16.2 Diels-Alder Click Chemistry for Highly Efficient Side-chain E-O Polymers. 16.3 Diels-Alder Click Chemistry for Crosslinkable E-O Polymers Containing Binary NLO Chromophores. 16.4 Diels-Alder Click Chemistry for NLO Dendrimers. 16.5 Conclusions. References. Index .

Surface Modification of Poly(divinylbenzene) Microspheres via Thiol-Ene Chemistry and Alkyne-Azide Click Reactions

Abstract: We report the functionalization of cross-linked poly(divinylbenzene) (pDVB) microspheres using both thiol-ene chemistry and azide-alkyne click reactions. The RAFT technique was carried out to synthesize SH-functionalized poly(N-isopropylacrylimide) (pNIPAAm) and utilized to generate pNIPAAm surface-modified microspheres via thiol-ene modification. The accessible double bonds on the surface of the microspheres allow the direct coupling with thiol-end functionalized pNIPAAm. In a second approach, pDVB microspheres were grafted with poly(2-hydroxyethyl methacrylate) (pHEMA). For this purpose, the residual double bonds on the microspheres surface were used to attach azide groups via the thiol-ene approach of 1-azido-undecane-11-thiol. In a second step, alkyne endfunctionalized pHEMA was used to graft pHEMA to the azide-modified surface via click-chemistry (Huisgen 1,3-dipolar cycloaddition). The surface-sensitive characterization methods X-ray photoelectron spectroscopy, scanning-electron microscopy and FT-IR transmission spectroscopy were employed to characterize the successful surface modification of the microspheres. In addition, fluorescence microscopy confirms the presence of grafted pHEMA chains after labeling with Rhodamine B.

“Click Chemistry” in Tailor-Made Polymethacrylates Bearing Reactive Furfuryl Functionality: A New Class of Self-Healing Polymeric Material

Abstract: This investigation reports the effective use of the Diels−Alder (DA) reaction, a “click reaction” in the preparation of thermally amendable and self-healing polymeric materials having reactive furfuryl functionality. In this case, the DA and retro-DA (rDA) reactions were carried out between the tailor-made homo- and copolymer of furfuryl methacrylate prepared by atom-transfer radical polymerization and a bismaleimide (BM). The kinetic studies of DA and rDA reactions were carried out using Fourier transform infrared spectroscopy. The DA polymers were insoluble in toluene at room temperature. When the DA polymers were heated at 100 °C in toluene, it was soluble. This is because of the cleavage between furfuryl functionality and BM. The chemical cross-link density was determined by the Flory−Rehner equation. The cross-linked polymer showed much greater adhesive strength at room temperature, but the adhesive strength was quite low at higher temperature. The self-healing capability was studied by using scannin...

Hydrophilic Interaction Chromatography Based Enrichment of Glycopeptides by Using Click Maltose: A Matrix with High Selectivity and Glycosylation Heterogeneity Coverage

Abstract: Glycosylation analysis based on mass spectrometry (MS) of glycopeptides requires the isolation of glycopeptides from complex glycoprotein digests to facilitate structural determination of the glycopeptides. To this end, hydrophilic interaction chromatography (HILIC)-based methods have been developed to selectively enrich glycopeptides by utilizing the hydrophilicity of the glycans. However, the application of these methods is limited by the medium selectivity of HILIC matrices. To improve the effectiveness of HILIC-based methods, we introduced a customized hydrophilic matrix named "click maltose" and characterized its selectivity and glycosylation heterogeneity coverage. In the selectivity assessment, the non-glycopeptides causing ion suppression to the glycopeptides were effectively removed by click maltose, leading to the identification of 27 glycopeptides in the fractions enriched from human serum immunoglobulin G digest, compared to 13 glycopeptides enriched using Sepharose CL-6B, a commercially available matrix. For the assessment of glycosylation heterogeneity coverage, more than 140 glycopeptides covering all the five glycosites of human serum alpha(1)-acid glycoprotein were captured using click maltose. Click maltose was synthesized by linking alkynyl-derivatized maltose to azide-derivatized silica through click chemistry. The resulting flexible saccharide chain structure remarkably enhances the hydrogen-bonding interactions between the glycans of the glycopeptides and the matrix, which are responsible for the increased selectivity and glycosylation heterogeneity coverage of click maltose.

Sonogashira and "Click" reactions for the N-terminal and side-chain functionalization of peptides with [Mn(CO)3(tpm)]+-based CO releasing molecules (tpm = tris(pyrazolyl)methane).

Abstract: A recently identified photoactivatable CO releasing molecule (CORM) based on [Mn(CO)3(tpm)]+ was conjugated to functionalized amino acids and model peptides using the Pd-catalyzed Sonogashira cross-coupling and the alkyne–azide 1,3-dipolar cycloaddition (“Click reaction”). Both were found to be fully compatible with all functional groups present. The CORM–peptide conjugates were isolated in reasonable yield and high purity, as indicated by IR spectroscopy, ESI mass spectrometry and RP-HPLC. The myoglobin assay was used to demonstrate that they have CO release properties identical those of the parent compound. This work thus opens the way for a targeted delivery of CORMs to cellular systems.

High-efficiency preparation of macrocyclic diblock copolymers via selective click reaction in micellar media

Abstract: We report a novel strategy for the high-efficiency preparation of macrocyclic diblock copolymers at relatively high concentrations via the combination of supramolecular self-assembly and “selective” click reactions, relying on the fine control of spatial accessibility between terminal reactive groups. The linear precursor, α-alkynyl-ω-azido heterodifunctional poly(2-(2-methoxyethoxy)ethyl methacrylate)-b-poly(oligo(ethylene glycol) methyl ether methacrylate), linear-PMEO2MA-b-POEGMA-N3, self-assembles into micelles with PMEO2MA cores and POEGMA coronas at elevated temperatures. The spatial separation between reactive alkynyl and azide groups precludes click reactions within micelle entities. On the other hand, due to the unimer−micelle exchange equilibrium and the fact that unimer concentration is typically low (critical micellization concentration, CMC), click reactions occur exclusively for unimers. This eventually led to complete intramolecular cyclization of all linear precursors.

Has Click Chemistry Lead to a Paradigm Shift in Polymer Material Design

Abstract: Has the introduction of the click chemistry concept by Sharpless and colleagues in 2001 lead to a paradigm shift in how we approach the design of macromolecular materials; or is it simply a relatively inconsequential re-branding exercise of already existing and slightly optimized but well-tried and tested reactions as some critics would have it? The current Trend Article analyses the situation by examining a series of select macromolecular research fields to shed light on this question, providing an unambiguous answer: The focusing of polymer chemists through the click concept on what constitutes a powerful modular chemical transformation to generate a specific polymeric material is a defining element in contemporary synthetic polymer chemistry, transcending a specific reaction. Without the introduction of the click philosophy several classes of innovative materials and polymer designs would not have been realized.

Bifunctional dendrimers: from robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications.

Abstract: Bifunctional Dendrimers : From Robust Synthesis and Accelerated One-Pot Postfunctionalization Strategy to Potential Applications

Orthogonal Transformations on Solid Substrates: Efficient Avenues to Surface Modification

Abstract: The performance of solid substrates is not only governed by their molecular constitution, but is also critically influenced by their surface constitution at the solid/gas or solid/liquid interface In here, we critically review the use of orthogonal chemical transformations (so-called click chemistry) to achieve efficient surface modifications of materials ranging from gold and silica nanoparticles, polymeric films, and microspheres to fullerenes as well as carbon nanotubes In addition, the functionalization of surfaces via click chemistry with biomolecules is explored Although a large host of reactions fulfilling the clicfc-criteria exist, pericyclic reactions are most frequently employed for efficient surface modifications The advent of the click chemistry concept has led-as evident from the current literature-to a paradigm shift in current approaches for materials modification: Away from unspecific and nonselective reactions to highly specific true surface engineering © 2009 WILEY-VCH Verlag GmbH & Co KCaA