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Showing papers on "Click chemistry published in 2008"


Journal ArticleDOI
TL;DR: The present review will outline the accomplishments of the 1,3‐dipolar cycloaddition (“click‐reaction”) between azides and alkynes catalyzed by copper (I) salts and outline some of medicinal chemistry applications in which click‐chemistry might be relevant in the future.
Abstract: In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chemistry to keep pace with the multitude of information derived from modern biological screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddition ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purification of the resulting products have opened new opportunities in generating vast arrays of compounds with biological potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chemistry applications in which click-chemistry might be relevant in the future.

876 citations


Journal ArticleDOI
TL;DR: Azides, which are extremely rare in biological systems, are emerging as attractive chemical handles for bioconjugation and have been employed for the tagging of a variety of biomolecules, activity-based protein profiling, and the chemical synthesis of microarrays and small molecule libraries.
Abstract: Azides, which are extremely rare in biological systems, are emerging as attractive chemical handles for bioconjugation.[1–5] In particular, the CuI catalyzed 1,3-dipolar cyclization of azides with terminal alkynes to give stable triazoles[6, 7] has been employed for the tagging of a variety of biomolecules,[8–12] activity-based protein profiling,[13] and the chemical synthesis of microarrays and small molecule libraries.[14]

865 citations


Journal ArticleDOI
TL;DR: Dendrimers up to the fourth generation were successfully prepared via the divergent growth strategy using a combination of thiol-ene "click" chemistry and traditional esterification reactions to functionalize with carboxylic acid, pyrene, and Fmoc-protected cysteine moieties via thiol -ene reactions.
Abstract: Dendrimers up to the fourth generation were successfully prepared via the divergent growth strategy using a combination of thiol-ene “click” chemistry and traditional esterification reactions. The thiol-ene reactions were conducted under solvent-free, ambient conditions at room temperature by irradiating with UV light. The fourth-generation dendrimers were subsequently functionalized with carboxylic acid, pyrene, and Fmoc-protected cysteine moieties via thiol-ene reactions.

740 citations


Journal ArticleDOI
TL;DR: The metal catalyzed azide/alkyne "click" reaction as mentioned in this paper has been widely used in the field of polymer science and is one of the few universal, highly efficient functionalization reactions which combines both high efficiency with an enormously high tolerance of functional groups and solvents.
Abstract: The metal catalyzed azide/alkyne ‘click’ reaction (a variation of the Huisgen 1,3-dipolar cycloaddition reaction between terminal acetylenes and azides) has vastly increased in broadness and application in the field of polymer science. Thus, this reaction represents one of the few universal, highly efficient functionalization reactions, which combines both high efficiency with an enormously high tolerance of functional groups and solvents under highly moderate reaction temperatures (25–70 °C). The present review assembles an update of this reaction in the field of polymer science (linear polymers, surfaces) with a focus on the synthesis of functionalized polymeric architectures and surfaces.

724 citations


Journal ArticleDOI
TL;DR: Important aspects of the Huisgen cycloaddition will be reviewed, along with some of its many pharmaceutical applications, including bioconjugation, nanoparticle surface modification, and pharmaceutical-related polymer chemistry will all be covered.
Abstract: Click chemistry refers to a group of reactions that are fast, simple to use, easy to purify, versatile, regiospecific, and give high product yields. While there are a number of reactions that fulfill the criteria, the Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes has emerged as the frontrunner. It has found applications in a wide variety of research areas, including materials sciences, polymer chemistry, and pharmaceutical sciences. In this manuscript, important aspects of the Huisgen cycloaddition will be reviewed, along with some of its many pharmaceutical applications. Bioconjugation, nanoparticle surface modification, and pharmaceutical-related polymer chemistry will all be covered. Limitations of the reaction will also be discussed.

708 citations




Journal ArticleDOI
TL;DR: A novel class of DIFO reagents for copper-free click chemistry that are considerably more synthetically tractable are reported and should expand the use of copper- free click chemistry in the hands of biologists.
Abstract: The 1,3-dipolar cycloaddition of azides and activated alkynes has been used for site-selective labeling of biomolecules in vitro and in vivo. While copper catalysis has been widely employed to activate terminal alkynes for [3 + 2] cycloaddition, this method, often termed “click chemistry”, is currently incompatible with living systems because of the toxicity of the metal. We recently reported a difluorinated cyclooctyne (DIFO) reagent that rapidly reacts with azides in living cells without the need for copper catalysis. Here we report a novel class of DIFO reagents for copper-free click chemistry that are considerably more synthetically tractable. The new analogues maintained the same elevated rates of [3 + 2] cycloaddition as the parent compound and were used for imaging glycans on live cells. These second-generation DIFO reagents should expand the use of copper-free click chemistry in the hands of biologists.

521 citations


Journal ArticleDOI
TL;DR: The advantages and versatility of CuAAC in scientific disciplines as diverse as drug discovery, biochemistry, bioconjugates synthesis, drug-delivery, gene therapy, bioseparation or diagnostics are presented and discussed in detail.

510 citations


Journal ArticleDOI
TL;DR: A pH-responsive nanovalve that relies on the ion–dipole interaction between cucurbit[6]uril (CB[6]) and bisammonium stalks, and operates in water is described, which is imperative to generate ultimately pHresponsive, biocompatible nanovalves capable of executing different missions.
Abstract: The ability to control the release of molecules from mesoporous silica nanoparticles promises to have far-reaching consequences for drug-delivery applications. Both molecular and supramolecular nanovalves, which regulate the release of guest molecules from nanopores of mesostructured silica nanoparticles, and operate under a range of stimuli including pH, competitive binding, light, and redox control, have been designed and their successful operation demonstrated in organic solvents. These systems are based upon the switching of components that have been tethered to the nanoparticle surfaces, such that access to the entrances of the nanopores can be opened and gated on demand. Since most of the traditional nanovalve designs have been based on [2]pseudorotaxanes and bistable [2]rotaxanes that rely upon donor–acceptor and hydrogen-bonding interactions between the ring and stalk components, they are limited largely to use in organic solvents. However, to realize the potential of nanovalves in therapeutic applications, it is imperative that they not only employ biocompatible components but that they also operate under physiological conditions. For nanovalves to be viable in biological environments, a recognition and binding motif which operates in aqueous media has to be identified, and then tried and tested. Herein, we describe a pH-responsive nanovalve that relies on the ion–dipole interaction between cucurbit[6]uril (CB[6]) and bisammonium stalks, and operates in water. CB[6], a pumpkin-shaped polymacrocycle with D6h symmetry consisting of six glycouril units strapped together by pairs of bridging methylene groups between nitrogen atoms, has received considerable attention because of its highly distinctive range of physical and chemical properties. Of particular interest in the field of supramolecular chemistry is the ability of CB[6] to form inclusion complexes with a variety of polymethylene derivatives, especially diaminoalkanes: the stabilities of these 1:1 complexes are highly pHdependent. The pH-dependent complexation/decomplexation behavior of CB[6] with diaminoalkanes has enabled the preparation of dynamic supramolecular entities which can be controlled by pH. Another important characteristic of CB[6] is its ability to catalyze 1,3-dipolar cycloadditions, such that the reaction between an azide-substituted ammonium ion and an alkyne-containing ammonium ion yields a disubstituted 1,2,3-triazole derivative encircled by a CB[6] ring. In view of these particular properties of CB[6], we set about to employ it as a catalyst for the formation of monolayers of [2]pseudorotaxanes on the surfaces of mesoporous silica nanoparticles so as to generate ultimately pHresponsive, biocompatible nanovalves capable of executing different missions. Mesoporous silica has proven to be an excellent support for the formation of dynamic nanosystems, including nanovalves, because it is chemically stable and optically transparent. In this current study, [2]pseudorotaxanes consisting of bisammonium stalks and CB[6] rings were constructed (Figure 1a,b) on the surface of mesoporous silica nanoparticles, and the pH-dependent binding of CB[6] with the bisammonium stalks is exploited to control the release of guest molecules from the pores of the silica nanoparticles. At neutral and acidic pH values, the CB[6] rings encircle the bisammonium stalks tightly, thereby blocking the nanopores efficiently when employing tethers of suitable lengths. Deprotonation of the stalks upon addition of base results in spontaneous dethreading (Figure 1b,c) of the CB[6] rings and unblocking of the silica nanopores. The silica supports employed were approximately 400nm-diameter spherical particles which contain ordered 2D hexagonal arrays of tubular pores (pore diameters of ca. 2 nm with a lattice spacing of ca. 4 nm) prepared by using a basecatalyzed sol–gel method. The nanopores were templated by cetyltrimethylammonium bromide (CTAB) surfactants, and tetraethylorthosilicate (TEOS) was used as the silica precursor. Empty nanopores were obtained by removal of the templating agents by solvent extraction. The ordered structure and particle morphology were confirmed (Figure 2) by X-ray diffraction (XRD) and scanning electron microscopy. This system was designed (Scheme 1a) such that the nanovalve components could be assembled in a stepwise, divergent manner from the nanoparticle surface outwards. Following solvent extraction, the nanoparticles were heated under reflux in an aminopropyltriethoxysilane (APTES) solution, which afforded the amino-modified nanoparticles 1. These nanoparticles were recovered by vacuum filtration [*] S. Angelos, Dr. Y.-W. Yang, K. Patel, Prof. J. F. Stoddart, Prof. J. I. Zink California NanoSystems Institute and Department of Chemistry and Biochemistry University of California, Los Angeles 405 Hilgard Avenue, Los Angeles, CA 90095-1569 (USA) Fax: (+1)310-206-1843 E-mail: stoddart@chem.ucla.edu zink@chem.ucla.edu Homepage: http://stoddart.chem.ucla.edu http://www.chem.ucla.edu/dept/Faculty/jzink/ [] These authors have contributed equally and both should be considered first author.

448 citations


Journal ArticleDOI
TL;DR: This method allows the naked eye, without the aid of any advanced instrument, to assay for the presence of Cu ions by the aggregation of Au NPs as a result of the Cu(I)-catalyzed conjugation between the two functional groups.
Abstract: We report a method for the detection of Cu ions by azideand terminal alkyne-functionalized gold nanoparticles (Au NPs) in aqueous solutions using click chemistry. The catalyst, Cu(I), was conveniently derived from the reduction of Cu(II) in the presence of sodium ascorbate. This method allows the naked eye, without the aid of any advanced instrument, to assay for the presence of Cu ions by the aggregation of Au NPs as a result of the Cu(I)-catalyzed conjugation between the two functional groups. Copper is a transition metal essential for life but also highly toxic to organisms, such as certain algae, fungi and many bacteria and viruses. In recent years, copper has been suspected of causing liver damage in children. The analysis and measurement of copper in environmental and biological samples have become increasingly important. Several methods exist for the detection of Cu ions, for example, those based on organic fluorophores or chromogenic sensors, quantum dots, atomic absorption spectroscopy, inductively coupled plasma mass spectroscopy, absorbance spectro-photometry, peptides and voltammetry. The color changes associated with the aggregation of metal nanoparticles has led to the development of a number of assays for a variety of target species. Colorimetric methods can be convenient and attractive in many applications because they can be easily monitored with the naked eye, without the aid of any advanced instruments. The extinction coefficient of 13 nm-diameter gold nanoparticles is 2.7 4 10m 1 cm , several orders of magnitude more than those of traditional organic chromophores. As a result, colors arising from nanoparticles at nanomolar concentrations can be observed by the naked eye, allowing sensitive detection of small amounts of analytes. Since Cu(I) is used as a catalyst in the cycloaddition reaction between azides and alkynes in click chemistry based on Huisgen6s reaction, the amount of copper needed for its completion is typically small. Therefore, a method that can visualize the progress of the reaction using the aggregation of Au NPs might also be useful for the detection of trace amounts of Cu(II) (by detection of Cu(I)). Because the azide/alkyne functional groups and their conjugation are highly selective and are essentially inert to most biological molecules, oxygen, water, and the majority of common reaction conditions in chemical synthesis, and are tolerant of a wide range of solvents, temperatures, and pH values, we reasoned that an assay based on such chemistry may find myriad uses. Our method for the detection of Cu ions relies on the Cu(I)-catalyzed 1,3-dipolar cycloaddition of alkynes and azides on the surface of functionalized Au NPs, that results in the aggregation of Au NPs (Scheme 1). We synthesized azideand terminal alkyne-functionalized thiols, 1 and 2, and prepared gold NPs coated with these

Journal ArticleDOI
TL;DR: An overview of the use of chemoselective reactions such as Heck, Sonogashira and Suzuki coupling, Diels-Alder cycloaddition, Click chemistry, Staudinger ligation, Michael's addition, reductive alkylation and oxime/hydrazone chemistry for the convergent synthesis of peptide/protein-polymer conjugates is given.

Journal ArticleDOI
TL;DR: In this article, a series of alkene-functional polymers were synthesized by controlled polymerization techniques in order to investigate and compare the efficiency and orthogonality of both photochemically and thermally initiated thiol−ene click coupling reactions.
Abstract: A series of alkene-functional polymers were synthesized by controlled polymerization techniques in order to investigate and compare the efficiency and orthogonality of both photochemically and thermally initiated thiol−ene click coupling reactions. The copolymers were designed to have single or multiple alkene-functional groups along the backbone, and to evaluate the robustness of these procedures, functionalization reactions with a library of mercaptans were studied. In comparing the photoinitiated reaction to its thermal counterpart, the thiol−ene photocoupling was found to proceed with higher efficiency, require shorter reaction times for complete conversion, and displayed a higher tolerance to various backbones and functional groups. To examine the orthogonality of the thiol−ene click reaction, an asymmetric telechelic polymer based on PS was designed with alkene functionality at one end and an azide at the other. The thermally initiated thiol−ene coupling was found to be completely orthogonal with th...

Journal ArticleDOI
TL;DR: The copper(I)-catalyzed Huisgen cycloaddition of azides and alkynes (CuAAC) has recently been added to the repertoire of DNA labeling methods, thus allowing the virtually unlimited functionalization of both small synthetic oligonucleotides and large gene fragments with unprecedented efficiency.
Abstract: The attachment of labels onto DNA is of utmost importance in many areas of biomedical research and is valuable in the construction of DNA-based functional nanomaterials. The copper(I)-catalyzed Huisgen cycloaddition of azides and alkynes (CuAAC) has recently been added to the repertoire of DNA labeling methods, thus allowing the virtually unlimited functionalization of both small synthetic oligonucleotides and large gene fragments with unprecedented efficiency. The CuAAC reaction yields the labeled polynucleotides in very high purity after a simple precipitation step. The reviewed technology is currently changing the way in which functionalized DNA strands are generated cost-efficiently in high quality for their application in molecular diagnostics systems and nanotechnological research.

Journal Article
TL;DR: In this paper, a series of alkene-functional polymers were synthesized by controlled polymerization techniques in order to investigate and compare the efficiency and orthogonality of both photochemically and thermally initiated thiol−ene click coupling reactions.

Journal ArticleDOI
TL;DR: The CuAAC "click" reaction has developed as one of the most useful and widely employed reactions in ligation within polymer chemistry as mentioned in this paper, which is due to the unique properties of the Cu(I) catalysis which renders the reaction quantitative even at low concentrations, orthogonal with other chemistries and extremely robust.
Abstract: The CuAAC "click" reaction has developed as one of the most useful and widely employed reactions in ligation within polymer chemistry. This is due to the unique properties of the Cu(I) catalysis which renders the reaction quantitative even at low concentrations, orthogonal with other chemistries and extremely robust. The formed triazole on the other hand is of intermediate polarity and chemically and biochemically "invisible", and the CuAAC provides the ideal "click" reaction for stitching together polymer architectures of unprecedended complexity as was it molecular LEGO. The CuAAC "clicking" in polymer chemistry is increasing exponentially and lead to highly defined polymer materials with novel properties.

Journal ArticleDOI
TL;DR: A review of the application of CuAAC to the field of materials construction, defined here as the preparation of materials with architectural integrity dependent upon the triazole linkage, is presented in this article.
Abstract: The enrichment of materials synthesis with the diverse chemical building blocks and functional groups of small molecule organic chemistry has been greatly accelerated in recent years by the introduction of the copper-catalyzed azide-alkyne cycloaddition (CuAAC). The efficiency and modular nature of this unique reaction enables materials chemists to prepare novel functional materials of unprecedented complexity. This review summarizes the application of CuAAC to the field of materials construction, defined here as the preparation of materials with architectural integrity dependent upon the triazole linkage. Recent examples, including linear polymers, dendrimers, polymer networks, polymeric nanoparticles, and other polymeric architectures, are described.

Journal ArticleDOI
TL;DR: Inexpensive copper catalysts enabled modular one-pot multicomponent syntheses of fully decorated triazoles through a sustainable "click" reaction/direct arylation sequence.

Journal ArticleDOI
TL;DR: Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes, however, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection.

Journal ArticleDOI
TL;DR: The motivation of this study was the preparation of a nanotube-based platform which allows the facile fabrication of more complex functional nanometer-scale structures, such as a SWNT-ZnPc hybrid.
Abstract: We describe the functionalization of single-wall carbon nanotubes (SWNTs) with 4-(2-trimethylsilyl)ethynylaniline and the subsequent attachment of a zinc-phthalocyanine (ZnPc) derivative using the reliable Huisgen 1,3-dipolar cycloaddition. The motivation of this study was the preparation of a nanotube-based platform which allows the facile fabrication of more complex functional nanometer-scale structures, such as a SWNT-ZnPc hybrid. The nanotube derivatives described here were fully characterized by a combination of analytical techniques such as Raman, absorption and emission spectroscopy, atomic force and scanning electron microscopy (AFM and SEM), and thermogravimetric analysis (TGA). The SWNT-ZnPc nanoconjugate was also investigated with a series of steady-state and time-resolved spectroscopy experiments, and a photoinduced communication between the two photoactive components (i.e., SWNT and ZnPc) was identified. Such beneficial features lead to monochromatic internal photoconversion efficiencies of 17.3% when the SWNT-ZnPc hybrid material was tested as photoactive material in an ITO photoanode.

Journal ArticleDOI
TL;DR: Controlling the organic linkers and incorporation of the azide groups should provide the designer-made MOFs that have controlled molecular cavities with the desired steric dimensions and functionality.
Abstract: We demonstrated the metal−organic framework bearing the azide group in the organic linkers and in situ click reactions with some small alkynes. The XRPD patterns indicated that the click reaction proceeded without any decomposition of the original MOF network. Controlling the organic linkers and incorporation of the azide groups should provide the designer-made MOFs that have controlled molecular cavities with the desired steric dimensions and functionality.


Journal ArticleDOI
TL;DR: The remarkable activity of [(NHC)CuX] complexes (NHC = N-heterocyclic carbene; X = Cl, Br) in this cycloaddition reaction and this catalytic system has already been applied to the preparation of triazole-containing carbanucleosides, porphyrins or platinum-based anticancer drugs.
Abstract: In 2001, Sharpless and co-workers defined the concept of ‘Click Chemistry’ and the criteria for a transformation to be considered as ‘Click’. Since then, the copper-catalyzed reaction of azide and alkyne to produce 1,2,3-triazoles regioselectively (1,3dipolar Huisgen cycloaddition) has become the best Click reaction to date. Thanks to its mild conditions and high efficiency, this reaction has found a myriad of applications in biology and material science. Less attention has been focused on the development of novel copper(I)-based well-defined systems and to the amount of copper used. This last point is extremely important for future industrial applications and it might be one of the last challenges to overcome for this transformation. We recently reported the remarkable activity of [(NHC)CuX] complexes (NHC = N-heterocyclic carbene; X = Cl, Br) in this cycloaddition reaction and this catalytic system has already been applied to the preparation of triazole-containing carbanucleosides, porphyrins or platinum-based anticancer drugs. On the other hand, we have also studied a family of cationic NHC-containing complexes of general formulae [(NHC)2Cu]X (X = PF6, BF4). Interestingly, during the examination of their activity in the hydrosilylation of ketones we observed an enhanced reactivity of these complexes when compared to their neutral analogues [(NHC)CuCl]. This improved activity was rationalized via a more efficient activation pathway of the cationic pre-catalyst. Additionally, the second NHC ligand was found to have an active role in the catalytic cycle. Since under hydrosilylation conditions one NHC ligand is displaced by the base in the reaction mixture, we wondered if an alkyne could play a similar role to produce the active copper acetylide species, from [(NHC)2Cu]X species (Figure 1). Figure 1. Catalyst design

Journal ArticleDOI
TL;DR: A novel convergent route to 3-arm star polymers is described that takes advantage of RAFT-synthesized homopolymers serving as masked macromolecular terminal thiol-containing materials capable of undergoingThiol-ene click reactions.

Journal ArticleDOI
TL;DR: A variety of substituted benzotriazoles have been prepared by the [3 + 2] cycloaddition of azides to benzynes under mild conditions, affording a rapid and easy entry to substituted, functionalized benzotRIazoles under mild circumstances.

Journal ArticleDOI
TL;DR: The copper(I)-catalyzed version of the azide–alkyne reaction to give triazoles, developed by Meldal et al. and Sharpless et al, can be used to functionalize alkyne-modified DNA nucleobases with extremely high efficiency.
Abstract: The attachment of labels such as fluorescent dyes or biotin molecules to DNA is of paramount importance for DNAbased molecular diagnostics and for nanotechnological applications. There is high demand for such modified oligonucleotides, but the chemistry behind the labeling procedures is cumbersome, and the modified oligonucleotides are frequently obtained in only low yields. Presently, the labels are incorporated as the corresponding phosphoramidites during the solid-phase synthesis of oligonucleotides, which frequently reduces the coupling yield significantly. This method is restricted to labels that can withstand the harsh conditions of DNA synthesis and deprotection. Alternatively, the labels are introduced postsynthetically by, for example, reaction of the corresponding activated esters with aminoalkyl-modified oligonucleotides. This method suffers from inefficient coupling yields, making the purification of the labeled oligonucleotides a challenging task. In a world in which the demand for labeled oligonucleotides is rapidly growing, new methods for the efficient incorporation of multiple different labels are required. Seela and Sirivolu and our group have recently discovered that the copper(I)-catalyzed version of the azide–alkyne reaction to give triazoles, developed by Meldal et al. and Sharpless et al. can be used to functionalize alkyne-modified DNA nucleobases with extremely high efficiency. A critical point is the presence of a sufficient amount of a proper copper(I)complexing ligand to prevent the copper-catalyzed cleavage of DNA. Herein we report that this chemistry can be extended to label oligonucleotides with up to three (and possibly more) different labels. These functionalizations can be achieved either directly on the resin or in solution after deprotection of the oligonucleotide. The latter method can be used to incorporate extremely sensitive labels with unprecedented efficiency. The first goal was to establish a method for the introduction of two different labels during the solid-phase synthesis of oligonucleotides. We thought that the best way to achieve this goal would be to introduce one free alkyne for the first click reaction and a second TMS-protected alkyne (Scheme 1) for the second click process after removal of the

Journal ArticleDOI
TL;DR: Investigations withdeuterated alkynes and deuterated zeolites proved that this Cu(I)-zeolite-catalyzed "click" reaction exhibited a mechanism different from that reported for the Meldal-Sharpless version.
Abstract: For the first time, copper(I)-exchanged zeolites were developed as catalysts in organic synthesis. These solid materials proved to be versatile and efficient heterogeneous, ligand-free catalytic systems for the Huisgen [3+2] cycloaddition. These cheap and easy-to-prepare catalysts exhibited a wide scope and compatibility with functional groups. They are very simple to use, easy to remove (by filtration), and are recyclable (up to three times without loss of activity). Investigations with deuterated alkynes and deuterated zeolites proved that this Cu I -zeolite-catalyzed "click" reaction exhibited a mechanism different from that reported for the Meldal-Sharpless version.

Journal ArticleDOI
TL;DR: A wide variety of materials have been examined for soft imprint lithography, many of them suffer from resolution and fidelity issues with synthetic challenges due to thermal expansion mismatch and/or oxygen sensitivity as mentioned in this paper.
Abstract: The drive towards miniaturization and high throughput processing in a wide variety of technologically relevant areas has led to the development of techniques for the rapid fabrication of nanoscale patterns, including imprint lithography using hard and soft patterned substrates. Soft imprint lithography is among themost promising for large scale patterning of nano/microstructures on surfaces and its attractiveness is further enhanced by its simplicity. Although a wide variety of materials have been examined for soft imprint lithography, many of them suffer from resolution and fidelity issues with synthetic challenges due to thermal expansion mismatch and/or oxygen sensitivity. For example, the most widely used formulation is based on a thermally crosslinked poly(dimethyl siloxane) (PDMS, Sylgard 184). While this material is capable of patterning microstructures, the poor mechanical properties (Young’s modulus, E, ca. 2MPa), poor solvent resistance, and thermal curing process leads to complications at dimensions below 1mm and for high aspect ratio systems. To overcome these issues, materials with higher cross-linking densities have been examined, which give rise to hard-PDMS having a modulus of ca. 9MPa. However, a composite stamp with soft PDMS as a flexible backing layer is required, which complicates the fabrication process and the mechanical properties are still not sufficient for many demanding applications. More recently, DeSimone and Rogers have introduced photocurable perfluoropolyether (PFPE) derivatives in a variety of soft lithographic techniques leading to significant improvements in feature fidelity, solvent resistance, and chemical robustness. These

Journal ArticleDOI
TL;DR: The stoichiometric reaction between thiols and maleimide-functional poly(ester)s is demonstrated to be a quantitative, tolerant, mild and efficient method for polymer modification.

Journal ArticleDOI
TL;DR: It is reported that CuAAC reactions can be combined with a diazonium-coupling reaction to quantitatively functionalize tyrosine residues with a wide array of starting materials.
Abstract: Cu-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction, renascent of the well-known Huisgen reaction, has recently flourished with applications in organic synthesis, drug discovery, polymer and materials science, and biotechnology. The high reaction yield, simple reaction and purification conditions, wide range of solvent and pH stabilities, and functional group tolerance make the CuAAC reaction a prototypical “click chemistry”, ideal for incorporating functionalities onto desired scaffolds. Over the years it has been widely employed to construct and functionalize polymeric and polyvalent display systems, including polymers, dendrimers, nanoparticles, and surfaces, where an extremely high reaction efficiency for every unit reaction is desirable. In particular, as organic azides and alkynes are almost unreactive with biomolecules and water, CuAAC reactions have been employed in derivatizing biomacromolecules, viruses, and cells with high efficacy under mild reaction conditions. Recently tyrosine residues have been considered as a particularly attractive target for chemoselective modification of proteins because of its subabundant distribution. Francis and coworkers have reported a number of transformations, ranging from the Mannich-type reaction to a transition metal mediated allylation reaction to a diazonium-coupling reaction, which can efficiently target the phenolic group of tyrosine residues at physiological conditions. To overcome the sluggish reactivity with electron-enriched diazonium salts, a sequential reduction/oxidation/Diels–Alder reaction was developed to break the limitation of functionalities being incorporated. In this communication, we report that CuAAC reactions can be combined with a diazonium-coupling reaction to quantitatively functionalize tyrosine residues with a wide array of starting materials. Tobacco Mosaic Virus (TMV) is a classic example of rodlike plant viruses consisting of 2130 identical protein subunits arranged helically around genomic single RNA strand. The length of TMV, that is, 300 nm, is defined by the encapsulated genomic RNA that stabilizes the coat protein assembly. The polar outer and inner surfaces of TMV have been exploited as templates to grow metal or metal oxide nanowires, and conductive polymers have been coated on 1D assembled TMV to produce conductive nanowires. TMV based materials have recently shown great potential with applications in nanoelectronics and energy harvesting devices. In addition, it has been reported that tyrosine residues (Y139) of TMV are viable for chemical ligation using the electrophilic substitution reaction at the ortho position of the phenol ring with diazonium salts. This reaction is very efficient, yet has two distinct disadvantages for broader applications. First, it is difficult to synthesize desired starting materials; and second, the reaction is not compatible with acid-labile functional groups and suitable for electron-deficient anilines only. To embrace the structural diversity of various starting materials, TMV offers an ideal polyvalent display system which allows us to test the efficiency of CuAAC reaction in combining with the tyrosine ligation reaction. As shown in Scheme 1, TMV was first treated with the diazonium salt generated from 3-ethynylaniline 1 in situ adapted from the protocol reported by Francis and co-workers. MALDI-TOF MS analysis indicated that >95% of the capsid monomers were converted into alkyne derivatives 2 (Figure 1) despite the absence of a strong electron withdrawing group in the diazonium reagent. Encouraged by this result, the CuAAC reactions between 2 and azides were explored. For bioconjugation reactions using CuAAC, the Cu catalysts are either generated directly by addition of Cu salts, or in situ from soluble Cu sources and a reducing agent, such as a copper wire, phosphines, thiols, or ascorbate. Multidentate heterocyclic ligands are often required for enhancing the reaction efficiency. Upon screening a series of reaction conditions, we found that the combination of CuSO4/sodium ascorbate (NaAsc) gave the best results. Whereas it is destructive to most other protein complex systems, ascorbate is evidently benign to TMV and has no impact on its structural integrity. 3-Azido-7-hydroxy-coumarin a was first employed as the ACHTUNGTRENNUNGazido counterpart in the reaction, which could be easily monitored by UV-visible absorption at 340 nm (Figure 1B). As a general protocol, 2 (2 mgmL ) and a (3 mm) were added to a solution of CuSO4 (1 mm) and NaAsc (2 mm) in Tris buffer (10 mm, pH 7.8) with 20% DMSO (used to increase the solubility of the azide component). After incubation for 18 h at room temperature, the viral particles were separated from the small molecules by sucrose gradient sedimentation. The integrity of TMV was confirmed by TEM and size-exclusion chromatography (SEC) analysis (data not shown). A strong absorption at 340 nm indicated the successful attachment of coumarin motifs (Figure 1B). MALDI-TOF MS analysis indicated a near quantitative transformation of surface alkynes to triazoles as shown in Figure 1A. [a] M. A. Bruckman, G. Kaur, L. A. Lee, F. Xie, J. Sepulveda, Dr. Q. Wang Department of Chemistry and Biochemistry and Nanocenter University of South Carolina 631 Sumter Street, Columbia, South Carolina 29208 (USA) Fax: (+1)803-777-9521 E-mail : wang@mail.chem.sc.edu [b] R. Breitenkamp, X. Zhang, M. Joralemon, Dr. T. P. Russell, Dr. T. Emrick Polymer Science and Engineering Department, University of Massachusetts Conte Center for Polymer Research, Massachusetts 01003 (USA)