Showing papers on "Click chemistry published in 2010"

Thiol–Ene Click Chemistry

Abstract: Following Sharpless' visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical-mediated thiol-ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol-ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed.

Thiol-click chemistry: a multifaceted toolbox for small molecule and polymer synthesis

Abstract: The merits of thiol-click chemistry and its potential for making new forays into chemical synthesis and materials applications are described Since thiols react to high yields under benign conditions with a vast range of chemical species, their utility extends to a large number of applications in the chemical, biological, physical, materials and engineering fields This critical review provides insight into emerging venues for application as well as new mechanistic understanding of this exceptional chemistry in its many forms (81 references)

Cu-free click cycloaddition reactions in chemical biology

Abstract: Bioorthogonal chemical reactions are paving the way for new innovations in biology. These reactions possess extreme selectivity and biocompatibility, such that their participating reagents can form covalent bonds within richly functionalized biological systems—in some cases, living organisms. This tutorial review will summarize the history of this emerging field, as well as recent progress in the development and application of bioorthogonal copper-free click cycloaddition reactions.

Marrying click chemistry with polymerization: expanding the scope of polymeric materials

Abstract: Click chemistry constitutes a class of reactions broadly characterized by efficiency, selectivity, and tolerance to a variety of solvents and functional groups. By far the most widely utilized of these efficient transformation reactions is the CuI-catalyzed azide–alkyne cycloaddition. This reaction has been creatively employed to facilitate the preparation of complex macromolecules, such as multiblock copolymers, shell or core cross-linked micelles, and dendrimers. This critical review highlights the application of click chemistry, in particular the CuI-catalyzed azide-alkyne cycloaddition, to the synthesis of a wide variety of new materials with possible uses as drug delivery agents, tissue engineering scaffolds, and dispersible nanomaterials (83 references).

Macromolecular Engineering through Click Chemistry and Other Efficient Transformations

Abstract: Precision synthesis of advanced polymeric materials requires efficient, robust, and facile chemical reactions. Paradoxically, the synthesis of increasingly intricate macromolecular structures generally benefits from exploitation of the simplest reactions available. This idea, combined with requirements of high efficiency, orthogonality, and simplified purification procedures, has led to the rapid adoption of “click chemistry” strategies in the field of macromolecular engineering. This Perspective provides context as to why these newly developed or recently reinvigorated reactions have been so readily embraced for the preparation of polymers with advanced macromolecular topologies, increased functionality, and unique properties. By highlighting important examples that rely on click chemistry techniques, including copper(I)-catalyzed and strain-promoted azide−alkyne cycloadditions, Diels−Alder cycloadditions, and thiol−ene reactions, among others, we hope to provide a succinct overview of the current state ...

Click chemistry with DNA

Abstract: The advent of click chemistry has led to an influx of new ideas in the nucleic acids field. The copper catalysed alkyne–azide cycloaddition (CuAAC) reaction is the method of choice for DNA click chemistry due to its remarkable efficiency. It has been used to label oligonucleotides with fluorescent dyes, sugars, peptides and other reporter groups, to cyclise DNA, to synthesise DNA catenanes, to join oligonucleotides to PNA, and to produce analogues of DNA with modified nucleobases and backbones. In this critical review we describe some of the pioneering work that has been carried out in this area (78 references).

Rapid Cu-free click chemistry with readily synthesized biarylazacyclooctynones

Abstract: Bioorthogonal chemical reactions, those that do not interact or interfere with biology, have allowed for exploration of numerous biological processes that were previously difficult to study. The reaction of azides with strained alkynes, such as cyclooctynes, readily forms a triazole product without the need for a toxic catalyst. Here we describe a biarylazacyclooctynone (BARAC) that has exceptional reaction kinetics and whose synthesis is designed to be both modular and scalable. We employed BARAC for live cell fluorescence imaging of azide-labeled glycans. The high signal-to-background ratio obtained using nanomolar concentrations of BARAC obviated the need for washing steps. Thus, BARAC is a promising reagent for in vivo imaging.

Copper-free click chemistry in living animals

Abstract: Chemical reactions that enable selective biomolecule labeling in living organisms offer a means to probe biological processes in vivo. Very few reactions possess the requisite bioorthogonality, and, among these, only the Staudinger ligation between azides and triarylphosphines has been employed for direct covalent modification of biomolecules with probes in the mouse, an important model organism for studies of human disease. Here we explore an alternative bioorthogonal reaction, the 1,3-dipolar cycloaddition of azides and cyclooctynes, also known as “Cu-free click chemistry,” for labeling biomolecules in live mice. Mice were administered peracetylated N-azidoacetylmannosamine (Ac4ManNAz) to metabolically label cell-surface sialic acids with azides. After subsequent injection with cyclooctyne reagents, glycoconjugate labeling was observed on isolated splenocytes and in a variety of tissues including the intestines, heart, and liver, with no apparent toxicity. The cyclooctynes tested displayed various labeling efficiencies that likely reflect the combined influence of intrinsic reactivity and bioavailability. These studies establish Cu-free click chemistry as a bioorthogonal reaction that can be executed in the physiologically relevant context of a mouse.

Click chemistry generates privileged CH hydrogen-bonding triazoles: the latest addition to anion supramolecular chemistry

Abstract: The supramolecular chemistry of anions provides a means to sense and manipulate anions in their many chemical and biological roles. For this purpose, Click chemistry facilitated the synthetic creation of new receptors and thus, an opportunity to aid in the recent re-examination of CH⋯anion hydrogen bonding. This tutorial review will focus on the privileged C–H hydrogen bond donor of the 1,2,3-triazole ring systems as elucidated from anion-binding studies with macrocyclic triazolophanes and other receptors. Triazolophanes are shape-persistent and planar macrocycles that direct four triazole and four phenylene CH groups into a 3.7 A cavity. They display strong (log K(Cl−) = 7), size-dependent halide binding (Cl− > Br− ≫ F− ≫ I−) and a rich set of binding equilibria. For instance, the too large iodide (4.4 A) can be sandwiched between two pyridyl-based triazolophanes with extreme positive cooperativity. Computational studies verify the triazole's hydrogen bond strength indicating it approaches the traditional NH donors from pyrrole. These examples, those of transport, sensing (e.g., ion-selective electrodes), templation, and versatile synthesis herald the use of triazoles in anion-receptor chemistry.

Thiol-yne click chemistry: A powerful and versatile methodology for materials synthesis

Abstract: Radical mediated thiol-yne polymerization reactions complement the more well-known thiol-ene radical polymerization processes, with the added advantage of increased functionality. In one system studied, the rate constant for the addition of the thiol to the vinyl sulfide created by the initial reaction of the thiol with the alkyne is three times faster than the initial reaction. When hydrocarbon based dialkynes and dithiols were copolymerized, the resulting thiol-alkyne networks containing only hydrocarbon and sulfide linking groups exhibited refractive index values tunable above 1.65, with the refractive index directly related to the sulfur content. The thiol-yne reaction was also found to be useful in functionalizing thiol-terminated polymer chain ends via sequential Michael thiol-ene addition followed by the thiol-yne reaction: the result is the dual functionalization of the polymer chain end. A thermally responsive polymer hydrogel network was formed when an yne terminated water-soluble homopolymer was polymerized with a tetrafunctional thiol.

In situ click chemistry: probing the binding landscapes of biological molecules

Abstract: Combinatorial approaches to the discovery of new functional molecules are well established among chemists and biologists, inspired in large measure by the modular composition of many systems and molecules in Nature. Many approaches rely on the synthesis and testing of individual members of a candidate combinatorial library, but attention has also been paid to techniques that allow the target to self-assemble its own binding agents. These fragment-based methods, grouped under the general heading of target-guided synthesis (TGS), show great promise in lead discovery applications. In this tutorial review, we review the use of the 1,3-dipolar cycloaddition reaction of organic azides and alkynes in a kinetically-controlled TGS approach, termed in situ click chemistry. The azide–alkyne reaction has several distinct advantages, most notably high chemoselectivity, very low background ligation rates, facile synthetic accessibility, and the stability and properties of the 1,2,3-triazole products. Examples of the discovery of potent inhibitors of acetylcholinesterases, carbonic anhydrase, HIV-protease, and chitinase are described, as are methods for the templated assembly of agents that bind DNA and proteins.

The application of CuAAC ‘click’ chemistry to catenane and rotaxane synthesis

Abstract: The copper(I)-catalysed azide–alkyne cycloaddition (the CuAAC ‘click’ reaction) is proving to be a powerful new tool for the construction of mechanically interlocked molecular-level architectures. The reaction is highly selective for the functional groups involved (terminal alkynes and azides) and the experimental conditions are mild and compatible with the weak and reversible intermolecular interactions generally used to template the assembly of interlocked structures. Since the CuAAC reaction was introduced as a means of making rotaxanes by an ‘active template’ mechanism in 2006, it has proven effective for the synthesis of numerous different types of rotaxanes, catenanes and molecular shuttles by passive as well as active template strategies. Mechanistic insights into the CuAAC reaction itself have been provided by unexpected results encountered during the preparation of rotaxanes. In this tutorial review we highlight the rapidly increasing utility and future potential of the CuAAC reaction in mechanically interlocked molecule synthesis.

Chemical modification of self-assembled silane based monolayers by surface reactions

Abstract: In this critical review, we look at how the functionalization of solid substrates by self-assembly processes provides the possibility to tailor their surface properties in a controllable fashion. One class of molecules, which attracted significant attention during the past decades, are silanes self-assembled on hydroxyl terminated substrates, e.g. silicon and glass. These systems are physically and chemically robust and can be applied in various fields of technology, e.g., electronics, sensors, and others. The introduction of chemical functionalities in such monolayers can be generally obtained via two methods. This involves either the use of pre-functionalized molecules, which can be synthesized by different synthetic routes and subsequent self-assembly of these moieties on the surface. The second method utilizes chemical surface reactions for the modification of the monolayer. The latter method offers the possibility to apply a large variety of different organic reaction pathways on surfaces, which allows the introduction of a wide range of terminal end groups on well-defined base monolayers. In contrast to the first approach an important advantage is that the optimization of the reaction conditions for suitable precursor molecules is circumvented. The following review highlights a selection of chemical surface reactions, i.e., nucleophilic substitution, click chemistry and supramolecular modification, which have been used for the functionalization of solid substrates (80 references).

Metal chelating systems synthesized using the copper(I) catalyzed azide-alkyne cycloaddition.

Abstract: The copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) is the premier example of a click reaction. The reaction is modular, reliable and easy to perform, providing easy access to molecular diversity. The majority of reported applications of the reaction employ the 1,2,3-triazole as a stable linkage to connect two chemical/biological components, while the potential for metal coordination of the heterocycle itself has received much less attention. In fact, 1,4-functionalized 1,2,3-triazoles are versatile ligands offering several donor sites for metal coordination, including N3, N2 and C5. In this article, we summarize the areas in which the CuAAC has been applied to the synthesis of novel triazole-containing ligands for transition metals.

Biocompatible Copper(I) Catalysts for in Vivo Imaging of Glycans

Abstract: The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is the standard method for bioorthogonal conjugation. However, current Cu(I) catalyst formulations are toxic, hindering their use in living systems. Here we report that BTTES, a tris(triazolylmethyl)amine-based ligand for Cu(I), promotes the cycloaddition reaction rapidly in living systems without apparent toxicity. This catalyst allows, for the first time, noninvasive imaging of fucosylated glycans during zebrafish early embryogenesis. We microinjected embryos with alkyne-bearing GDP-fucose at the one-cell stage and detected the metabolically incorporated unnatural sugars using the biocompatible click chemistry. Labeled glycans could be imaged in the enveloping layer of zebrafish embryos between blastula and early larval stages. This new method paves the way for rapid, noninvasive imaging of biomolecules in living organisms.

Click chemistry under non-classical reaction conditions

Abstract: First described almost a decade ago, “click” reactions such as the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) are widely used today in organic and medicinal chemistry, in the polymer and material science field, and in chemical biology. While most click reactions can be performed at room temperature there are instances where some form of process intensification is required. In this tutorial review, aimed at the synthetic chemistry community, examples of click chemistry carried out under non-classical reaction conditions, such as for example applying microwave heating or continuous flow processing will be highlighted.

Fluorogenic click reaction

Abstract: Fluorogenic Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reactions have emerged as a powerful tool for bioconjugation, materials science, organic synthesis and drug discovery. This review highlights the design of the recent development of fluorogenic CuAAC reactions as well as their applications.

Limitations of radical thiol-ene reactions for polymer-polymer conjugation

Abstract: In this work, we report our findings on the use of radical thiol-ene chemistry for polymer–polymer conjugation. The manuscript combines the results from the Preparative Macromolecular Chemistry group from the Karlsruhe Institute of Technology (KIT) and the Polymer Chemistry Research group from Ghent University (UGent), which allowed for an investigation over a very broad range of reaction conditions. In particular, thermal and UV initiation methods for the radical thiol-ene process were compared. In the KIT group, the process was studied as a tool for the synthesis of star polymers by coupling multifunctional thiol core molecules with poly(n-butyl acrylate) macromonomers (MM), employing thermally decomposing initiators. The product purity and thus reaction efficiency was assessed via electrospray ionization mass spectrometry. Although the reactions with 10 or 5 equivalents of thiol with respect to macromonomer were successful, the coupling reaction with a one-to-one ratio of MM to thiol yielded only a fraction of the targeted product, besides a number of side products. A systematic parameter study such as a variation of the concentration and nature of the initiator and the influence of thiol-to-ene ratio was carried out. Further experiments with poly(styrene) and poly(isobornyl acrylate) containing a vinylic end group confirmed that thermal thiol-ene conjugation is far from quantitative in terms of achieving macromolecular star formation. In parallel, the UGent group has been focusing on photo-initiated thiol-ene chemistry for the synthesis of functional polymers on one hand and block copolymers consisting of poly(styrene) (PS) and poly(vinyl acetate) (PVAc) on the other hand. Various functionalization reactions showed an overall efficient thiol-ene process for conjugation reactions of polymers with low molecular weight compounds (∼90% coupling yield). However, while SEC and FT-IR analysis of the conjugated PS-PVAc products indicated qualitative evidence for a successful polymer–polymer conjugation, 1H NMR and elemental analysis revealed a low conjugation efficiency of about 23% for a thiol-to-ene ratio equal to one. Blank reactions using typical thiol-ene conditions indicated that bimolecular termination reactions occur as competitive side reactions explaining why a molecular weight increase is observed even though the thiol-ene reaction was not successful. The extensive study of both research groups indicates that radical thiol-ene chemistry should not be proposed as a straightforward conjugation tool for polymer–polymer conjugation reactions. Head-to-head coupling is a major reaction pathway, which interrupts the propagation cycle of the thiol-ene process. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1699–1713, 2010

Click Polymerization: Progresses, Challenges, and Opportunities

Abstract: Chemical transformations of small molecules have served as a rich source of reactions for the development of new polymerization processes, and “click” reaction has the potential to become a powerful polymerization technique. We herein give a brief account of the research efforts devoted to the development of click reaction into a new polymerization process. Remarkable progresses have been made in recent years in the exploration of metal-mediated and metal-free click polymerization systems and in the syntheses of linear and hyperbranched polytriazoles with regioregular molecular structures and advanced functional properties. We also discuss the existing limitations and challenges as well as the promising opportunities and directions in fostering the click polymerization into a versatile tool for the construction of new macromolecules with well-defined structures and multifaceted functionalities.

Influence of Type of Initiation on Thiol–Ene “Click” Chemistry

Abstract: Thermally and photochemically initiated thiol-ene click reactions using thiol- and allyl- end functionalized linear polystyrenes with various enes (allyl bromide, methyl acrylate, and methyl methacrylate) and thiol (3-mercaptopropionic acid) have been investigated. Allyl- and thiol-end-capped polystyrenes with controlled molecular weight and low polydispersity were prepared by atom transfer radical polymerization (ATRP) of styrene using functional initiator and end group modification approaches, respectively. Thiol-ene reactions can be initiated by both cleavage type photoinitiators such as (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TMDPO) and 2,2-dimethoxy-2-phenyl acetophenone (DMPA) and H-abstraction type photoinitiators such as benzophenone (BP), thioxanthone (TX), camphorquinone (CO), and classical thermal initiator, 2,2'-azobis(isobutyronitrile) (AIBN) at 80 °C. The kinetics of the reactions was monitored online with a real time ATR-FTIR monitoring system and the conversions were determined by 1 H NMR spectroscopy. A comparison of click efficiencies of the studied initiator systems was performed. Compare to the thermal initiators and H-abstraction type photoinitiators, cleavage type photoinitiators were found to induce thiol-ene click reactions with higher efficiency.

Ultrabright and Bioorthogonal Labeling of Cellular Targets Using Semiconducting Polymer Dots and Click Chemistry

Abstract: semiconducting polymer; nanoparticle; click chemistry; bioorthogonal labeling; fluorescenceimagingClick chemistry describes a powerful set of chemical reactions that are rapid, selective, andproduce high yields.[1] The most recognized of these reactions is the copper (I)-catalyzedazide-alkyne cycloaddition, which has been applied to diverse areas, ranging from materialsscience to chemical biology.[2–8] For biological applications, both azido and alkyne groupsare considered to be bioorthogonal chemical reporters because they do not interact with anynative biological functional groups. As a result, these bioorthogonal reporters can beincorporated into a target biomolecule using the cell’s biosynthetic machinery to providechemical handles that can be subsequently tagged with exogenous probes. Thebioorthogonal reporters are complementary to genetically encoded tags, such as greenfluorescent protein (GFP),[9] and provide a powerful approach to tag biomolecules withoutthe need of direct genetic encoding. Bioorthogonal labeling via click chemistry is highlysensitive with low background despite the complex cellular environment. In practice,however, the sensitivity is constrained by the abundance of the target molecules, the labelingefficiency of the chemical reporters, and the performance of the exogenous probes.[7] Inalmost all cases, bright and photostable probes are highly desirable, particularly for long-term tracking and sensitive detection of low-abundance biomolecules.Fluorescent nanoparticles such as quantum dots (Qdots) exhibit improved brightness andphotostability over traditional fluorescent dyes.[10–12] In the context of click chemistry,however, the copper catalyst irreversibly quenches Qdot fluorescence and prevents theirusage in the various applications based on copper-catalyzed click chemistry.[13] Because ofcopper’s cytotoxicity, copper-free bioorthogonal approaches, such as the Staudinger ligationand the strain-promoted azide-alkyne cycloaddition, have been developed for live cell and

Thiol—Ene Click Chemistry

Abstract: Following Sharpless' visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical-mediated thiol-ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol-ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed.

Copper‐Catalyzed Azide–Alkyne Cycloaddition: Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

Abstract: Since Kolb, Finn, and Sharpless laid down the foundations of click chemistry in 2001, there has been an explosive growth in this area of chemistry. The emergence of the coppercatalyzed azide–alkyne cycloaddition reaction (CuAAC) as an entry point to 1,4-triazoles 1 raises a challenge for the discovery of new chemical approaches with equal or even greater fidelity. The CuAAC is second order with respect to copper, although increasing the concentration of copper results in less reactive species such as metal aggregates. These results suggest that a family of Cu species in dynamic equilibrium may exist in solution. However, whether monoor dicuprate species are involved, the observed regioselectivity may be neatly explained through a key complex (5 or 8) between a copper(I) acetylide with the a-nitrogen atom of the organic azide 4 (Scheme 1). Consequently, the CuAAC is limited to terminal alkynes. The recent advent of the ruthenium-catalyzed Huisgen reaction makes available the complementary 1,5-disubstituted 1,2,3-triazoles, although efficiency and reliability does not match the parent reaction. Notably, Ru-catalysis can be extended to internal alkynes, thus giving the corresponding trisubstituted products. However, few reliable methods exist for the synthesis of trisubstituted triazoles with good regiocontrol and functional group tolerance, thus presenting an opportunity for discovery. Several groups have independently taken up this challenge, and sought to discover a general method for the regio-controlled synthesis of substituted 1,2,3triazoles using metal-catalyzed “cycloaddition” reactions. The first example was reported by Wu et al. in 2005, who investigated the possibility of trapping cuprate–triazole intermediates (e.g. see 7, Scheme 1) with electrophiles. Optimal results were obtained when ICl was used in conjunction with a stoichiometric quantity of CuI and five equivalents of triethylamine. The versatility of this protocol was demonstrated by the broad substrate tolerance of the azides, including benzyl, alkyl, and 2,2-dihydropolyfluoroalkyl groups. Meanwhile, the terminal alkyne could carry substituents such as alkyl, ester, amide, and aromatic groups. The corresponding 5-iodo-1,2,3triazole products were amenable to further functionalization, thus making them attractive synthetic intermediates. Trapping cuprate-triazole intermediates with alternative electrophiles such as allyl bromide, benzoyl chloride, and acetyl chloride resulted in lower yields. Major disadvantages include the requirements for stoichiometric quantities of Cu, and prolonged reaction times (20 h). Later in 2005, Rutjes and co-workers reported a catalytic procedure for the formation of 5-bromo-1,2,3-triazoles. By using bromoalkynes and a combination of CuI and Cu(OAc)2, the reaction with organic azides proceeded readily to form the corresponding 5-bromo-1,2,3-triazole derivatives in high yield and with excellent regioselectivity. Nonetheless, this catalytic system often gave small quantities of 5-iodo-1,2,3-triazoles as the by-product, which could be avoided if a combination of CuBr/Cu(OAc)2 was used. In general, the method was robust and had a wide scope—tolerating electron-withdrawing and electron-donating groups, as well as sterically congested alkynes. Interestingly, the reaction was not amenable to iodoalkynes, which appeared to be unstable under the reaction conditions. While investigating the effects of amine ligands on the solubility of Cu salts in CuAAC related work in 2006, Porco and co-workers observed the unexpected formation of 5alkynyl-1,2,3-triazoles. Exploiting this discovery, the group found optimal conditions using a 2:1 ratio of Cu/N-methylmorpholine oxide (NMO) and N,N,N’-trimethylethylenediamine as the ligand under an oxidative atmosphere. 5Substituted triazoles were obtained within 20 min, albeit in low to moderate yields (31–64 %) as a result of competing Glaser coupling. In 2007, Hsung and co-workers reported the use of allyl iodides as suitable electrophiles for trapping cuprate–triazole intermediates 7 derived from ynamides, organic azides, and one equivalent of CuBr in CH3CN. [9] Their plan was to develop a practical entry to 5-allyl-1,2,3-triazoles as substrates [*] C. Spiteri, Dr. J. E. Moses School of Chemistry, University of Nottingham University Park, Nottingham, NG7 2RD (UK) Fax: (+ 44)115-951-3564 E-mail: john.moses@nottingham.ac.uk Homepage: http://moseslabs.com/