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light at 365 nm (365 does not damage cells) react quickly (so that the UV light does not have to be on for a long time, usually around 1â4 minutes) to make fluorogenic pyrazoline products. This reaction scheme is well suited for the purpose of labeling in live cells, because UV light at 365 nm damages cells minimally. Moreover, the reaction proceeds quickly, so that the UV light can be administered for short durations. Quantum yields for short wavelength UV light can be higher than 0.5. This allows tetrazoles to be used wavelength selectively in combination with another photoligation reaction, where at the short wavelength the tetrazole ligation reaction proceeds nearly exclusively and at longer wavelength another reaction (ligation via o-quinodimethanes) proceeds exclusively. Finally, the non-fluorogenic reactants give rise to a fluorogenic product, equipping the reaction with a built-in spectrometry handle.
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in developing probes specific for these tags. The above reaction occurs between a 1,2-aminothiol and a 2-cyanobenzothiazole to make luciferin, which is fluorescent. This luciferin fluorescence can be then quantified by spectrometry following a wash, and used to determine the relative presence of the molecule bearing the 1,2-aminothiol. If the quantification of non-1,2-aminothiol-bearing protein is desired, the protein of interest can be cleaved to yield a fragment with a N' Cys that is vulnerable to the 2-CBT.
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768:(GFP), on the same genetic sequence as a protein of interest. In this way, the protein can be identified in cells and tissues by the green florescence. However, this approach comes with several difficulties, as the GFP can affect the ability of the protein to achieve its normal shape or hinder its normal expression and functions. Additionally, using this method, GFP can only be attached to proteins, leaving other important
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812:, have been modified and optimized for such reaction conditions. Today, research in the field concerns not only understanding and developing new reactions and repurposing and re-understanding known reactions, but also expanding methods used to incorporate reaction partners into living systems, engineering novel reaction partners, and developing applications for bioconjugation.
2346:(67) (a) van Berkel, S. S.; Dirks, A. T. J.; Meeuwissen, S. A.; Pingen, D. L. L.; Boerman, O. C.; Laverman, P.; van Delft, F. L.; Cornelissen, J. J. L. M.; Rutjes, F. P. J. T. ChemBioChem 2008, 9, 1805. (b) van Berkel, S. S.; Dirks, A. T. J.; Debets, M. F.; van Delft, F. L.; Cornelissen, J. J. L. M.; Nolte, R. J. M.; Rutjes, F. P. J. T. ChemBioChem 2007, 8, 150
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unnatural amino acids. For example, an UAA with an azide side group provides convenient access for cycloalkynes to proteins tagged with this "AHA" unnatural amino acid. In another example, "CpK" has a side group including a cyclopropane alpha to an amide bond that serves as a reaction partner to tetrazine in an inverse diels-alder reaction.
1079:, Aileron, Integrated Diagnostics, and the biotech company baseclick, a BASF spin-off created to sell products made using click chemistry. Moreover, baseclick holds a worldwide exclusive license for the research and diagnostic market for the nucleic acid field. Fluorescent azides and alkynes are also produced by companies such as Cyandye.
303:' wife, Jan Dueser,, who found the simplicity of this approach to chemical synthesis akin to clicking together Lego blocks. In fact, the simplicity of click chemistry represented a paradigm shift in synthetic chemistry, and has had significant impact in many industries, especially pharmaceutical development. In 2022, the
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Valentin, Sencio; Cyril, Robil; François, Trottein; David, Péricat; Emmanuelle, NÀser; Céline, Cougoule; Etienne, Meunier; Anne-Laure, BÚgue; HélÚne, Salmon; Nicolas, Manel; Alain, Puisieux; Sarah, Watson; Mark A., Dawson; Nicolas, Servant; Guido, Kroemer; Djillali, Annane; Raphaël, Rodriguez (2023).
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exemplifies another strategy of isolating reaction partners, which is to take advantage of rarely-occurring, natural groups such as the 1,2-aminothiol, which appears only when a cysteine is the final N' amino acid in a protein. Their natural selectivity and relative bioorthogonality is thus valuable
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Now limitations emerge from the chemistry of the probe to its target. In order for this technique to be useful in biological systems, click chemistry must run at or near biological conditions, produce little and (ideally) non-toxic byproducts, have (preferably) single and stable products at the same
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on solid support, their conditions were far from the true spirit of click chemistry and were overtaken by the publicly more recognized
Sharpless. Meldal and co-workers also chose not to label this reaction type "click chemistry" which allegedly caused their discovery to be largely overlooked by the
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Click chemistry is an approach to chemical synthesis that emphasizes efficiency, simplicity, selectivity, and modularity in chemical processes used to join molecular building blocks. It includes both the development and use of "click reactions", a set of simple, biocompatible chemical reactions that
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Click
Chemistry is a powerful tool to probe for the cellular localization of small molecules. Knowing where a small molecules goes in the cell gives powerful insights into their mechanisms of action. This approach has been used in numerous studies, and discoveries include that salinomycin localizes
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Similar to other cycloadditions, electron-donating substituents on the dienophile and electron-withdrawing substituents on the diene accelerate the inverse-demand Diels-Alder. The diene, the tetrazine, by virtue of having the additional nitrogens, is a good diene for this reaction. The dienophile,
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The first reaction mechanism proposed included one catalytic copper atom; but isotope, kinetic, and other studies have suggested a dicopper mechanism may be more relevant. Even though this reaction proceeds effectively at biological conditions, copper in this range of dosage is cytotoxic. Solutions
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Moreover, this copper-catalyzed "click" does not require ligands on the metal, although accelerating ligands such as tris(triazolyl)methyl amine ligands with various substituents have been reported and used with success in aqueous solution. Other ligands such as PPh3 and TBIA can also be used, even
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Because this reaction is metal-free and proceeds with fast kinetics (k2 as fast as 60 1/Ms, faster than both the CuAAC or the SPAAC) SPANC can be used for live cell labeling. Moreover, substitution on both the carbon and nitrogen atoms of the nitrone dipole, and acyclic and endocyclic nitrones are
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The
Bertozzi group further developed one of Huisgen's copper-free click reactions to overcome the cytotoxicity of the CuAAC reaction. Instead of using Cu(I) to activate the alkyne, the alkyne is instead introduced in a strained difluorooctyne (DIFO), in which the electron-withdrawing, propargylic,
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mainstream chemical society. Fokin and
Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks".
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The tetrazole-alkene "photoclick" reaction is another dipolar addition that
Huisgen first introduced in the late 1960s ChemBioChem 2007, 8, 1504. (68) Clovis, J. S.; Eckell, A.; Huisgen, R.; Sustmann, R. Chem. Ber. 1967, 100, 60.) Tetrazoles with amino or styryl groups that can be activated by UV
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Strained cyclooctenes and other activated alkenes react with tetrazines in an inverse electron-demand Diels-Alder followed by a retro cycloaddition (see figure). Like the other reactions of the trans-cyclooctene, ring strain release is a driving force for this reaction. Thus, three-membered and
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intermediate that subsequently spontaneously undergoes a retro Diels-alder reaction to release furan and give 1,2,3- or 1,4,5-triazoles. Even though this reaction is slow, it is useful because oxabornodiene is relatively simple to synthesize. The reaction is not, however, entirely chemoselective.
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The criteria for click reactions are designed to make the chemistry biocompatible, for applications like isolating and targeting molecules in complex biological environments. In such environments, products accordingly need to be physiologically stable and any byproducts need to be non-toxic (for
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Both tetrazoles and the alkene groups have been incorporated as protein handles as unnatural amino acids, but this benefit is not unique. Instead, the photoinducibility of the reaction makes it a prime candidate for spatiotemporal specificity in living systems. Challenges include the presence of
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Strained alkenes also utilize strain-relief as a driving force that allows for their participation in click reactions. Trans-cycloalkenes (usually cyclooctenes) and other strained alkenes such as oxanorbornadiene react in click reactions with a number of partners including azides, tetrazines and
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2010; 49, 3065. (b) McKay, C. S.; Moran, J.; Pezacki, J. P. Chem. Commun. (Cambridge, U. K.) 2010, 46, 931. (c) Debets, M. F.; van Berkel, S. S.; Dommerholt, J.; Dirks, A. T. J.; Rutjes, F. P. J. T.; van Delft, F. L. Acc. Chem. Res. 2011, 44, 805. (d) McKay, C. S.; Chigrinova, M.; Blake, J. A.;
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to this problem have been presented, such as using water-soluble ligands on the copper to enhance cell penetration of the catalyst and thereby reduce the dosage needed, or to use chelating ligands to further increase the effective concentration of Cu(I) and thereby decreasing the actual dosage.
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Many of the click chemistry criteria are subjective, and even if measurable and objective criteria could be agreed upon, it is unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified that fit the concept better than others:
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This reaction has been used successfully to probe for azides in living systems, even though the reaction rate is somewhat slower than that of the CuAAC. Moreover, because the synthesis of cyclooctynes often gives low yield, probe development for this reaction has not been as rapid as for other
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Mai, Trang Thi; HamaĂŻ, Ahmed; Hienzsch, Antje; Cañeque, Tatiana; MĂŒller, Sebastian; Wicinski, Julien; Cabaud, Olivier; Leroy, Christine; David, Amandine; Acevedo, VerĂłnica; Ryo, Akihide; Ginestier, Christophe; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle; Codogno, Patrice; Mehrpour, Maryam;
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Methods for the incorporation of click reaction partners into systems in and ex vivo contribute to the scope of possible reactions. The development of unnatural amino acid incorporation by ribosomes has allowed for the incorporation of click reaction partners as unnatural side groups on these
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Solier, StĂ©phanie; MĂŒller, Sebastian; Tatiana, Cañeque; Antoine, Versini; Arnaud, Mansart; Fabien, Sindikubwabo; Leeroy, Baron; Laila, Emam; Pierre, Gestraud; G. Dan, PantoÈ; Vincent, Gandon; Christine, Gaillet; Ting-Di, Wu; Florent, Dingli; Damarys, Loew; Sylvain, Baulande; SylvĂšre, Durand;
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Oxanorbornadiene (or another activated alkene) reacts with azides, giving triazoles as a product. However, these product triazoles are not aromatic as they are in the CuAAC or SPAAC reactions, and as a result are not as stable. The activated double bond in oxanobornadiene makes a triazoline
823:. Recently, scientists have adapted click chemistry for use in live cells, for example using small molecule probes that find and attach to their targets by click reactions. Despite challenges of cell permeability, bioorthogonality, background labeling, and reaction efficiency,
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Kashemirov, Boris A.; Bala, Joy L. F.; Chen, Xiaolan; Ebetino, F. H.; Xia, Zhidao; Russell, R. Graham G.; Coxon, Fraser P.; Roelofs, Anke J.; Rogers
Michael J.; McKenna, Charles E. (2008). "Fluorescently labeled risedronate and related analogues: "magic linker" synthesis".
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Wang, Xifan; Schmidt, Franziska; Hanaor, Dorian; Kamm, Paul H.; Li, Shuang; Gurlo, Aleksander (May 6, 2019). "Additive manufacturing of ceramics from preceramic polymers: A versatile stereolithographic approach assisted by thiol-ene click chemistry".
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However, the isoxazoline product is not as stable as the triazole product of the CuAAC and the SpAAC, and can undergo rearrangements at biological conditions. Regardless, this reaction is still very useful as it has notably fast reaction kinetics.
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Liu, Fang; Paton, Robert S.; Kim, Seonah; Liang, Yong; Houk, K. N. (2013). "DielsâAlder
Reactivities of Strained and Unstrained Cycloalkenes with Normal and Inverse-Electron-Demand Dienes: Activation Barriers and Distortion/Interaction Analysis".
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Iacobucci, Claudio; Reale, Samantha; Gal, Jean-François; De
Angelis, Francesco (2015-03-02). "Dinuclear Copper Intermediates in Copper(I)-Catalyzed AzideâAlkyne Cycloaddition Directly Observed by Electrospray Ionization Mass Spectrometry".
564:, Denmark. The copper-catalyzed version of this reaction gives only the 1,4-isomer, whereas Huisgen's non-catalyzed 1,3-dipolar cycloaddition gives both the 1,4- and 1,5-isomers, is slow, and requires a temperature of 100 degrees Celsius.
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molecules as biomolecular probes. A fluorophore can be attached to one of these probes to give a fluorescence signal upon binding of the reporter molecule to the targetâjust as GFP fluoresces when it is expressed with the target.
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in 2001. In this seminal paper, Sharpless argued that synthetic chemistry could emulate the way nature constructs complex molecules, using efficient reactions to join together simple, non-toxic building blocks.
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Rostovtsev, Vsevolod V.; Green, Luke G; Fokin, Valery V.; Sharpless, K. Barry (2002). "A Stepwise
Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective "Ligation" of Azides and Terminal Alkynes".
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reactions. But cyclooctyne derivatives such as DIFO, dibenzylcyclooctyne (DIBO) and biarylazacyclooctynone (BARAC) have all been used successfully in the SPAAC reaction to probe for azides in living systems.
3025:
Ilya A. Osterman; Alexey V. Ustinov; Denis V. Evdokimov; Vladimir A. Korshun; Petr V. Sergiev; Marina V. Serebryakova; Irina A. Demina; Maria A. Galyamina; Vadim M. Govorun; Olga A. Dontsova (January 2013).
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and then converted to nitrone with p-methoxybenzenethiol, N-methylhydroxylamine and p-ansidine, and finally incubated with cyclooctyne to give a click product. The SPANC also allows for multiplex labeling.
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Diaryl-strained-cyclooctynes including dibenzylcyclooctyne (DIBO) have also been used to react with 1,3-nitrones in strain-promoted alkyne-nitrone cycloadditions (SPANC) to yield N-alkylated isoxazolines.
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gem-fluorines act together with the ring strain to greatly destabilize the alkyne. This destabilization increases the reaction driving force, and the desire of the cycloalkyne to relieve its ring strain.
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tetrazoles. These reaction partners can interact specifically with the strained alkene, staying bioorthogonal to endogenous alkenes found in lipids, fatty acids, cofactors and other natural products.
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MacKenzie, DA; Sherratt, AR; Chigrinova, M; Cheung, LL; Pezacki, JP (Aug 2014). "Strain-promoted cycloadditions involving nitrones and alkynesârapid tunable reactions for bioorthogonal labeling".
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An analogous RuAAC reaction catalyzed by ruthenium, instead of copper, was reported by the Jia and Fokin groups in 2005, and allows for the selective production of 1,5-isomers.
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Jean-François Lutz; Zoya
Zarafshani (2008). "Efficient construction of therapeutics, bioconjugates, biomaterials and bioactive surfaces using azideâalkyne "click" chemistry".
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L. Liang and D. Astruc: "The copper(I)-catalysed alkyne-azide cycloaddition (CuAAC) "click" reaction and its applications. An overview", 2011; 255, 23â24, 2933â2045, p. 2934
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is attached to a target of interest and the target quantified or located). More recently, novel methods have been used to incorporate click reaction partners onto and into
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in living systems. In other cases, SPAAC between a cyclooctyne-modified fluorophore and azide-tagged proteins allowed the selection of these proteins in cell lysates.
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Stöckmann, Henning; Neves, Andre; Stairs, Shaun; Brindle, Kevin; Leeper, Finian (2011). "Exploring isonitrile-based click chemistry for ligation with biomolecules".
3015:(a) Liang, G.; Ren, H.; Rao, J. Nat. Chem. 2010, 2, 54. (b) Ren, H.; Xiao, F.; Zhan, K.; Kim, Y.-P.; Xie, H.; Xia, Z.; Rao, J. Angew.Chem., Int. Ed. 2009, 48, 9658.
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in the same mechanism as the Huisgen 1,3-dipolar cycloaddition. Substituents other than fluorines, such as benzene rings, are also allowed on the cyclooctyne.
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the activated alkene, can often be attached to electron-donating alkyl groups on target molecules, thus making the dienophile more suitable for the reaction.
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Dieterich; et al. (2007). "Labeling, detection and identification of newly synthesized proteomes with bioorthogonal non-canonical amino-acid tagging".
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Spiteri, Christian; Moses, John E. (2010). "Copper-Catalyzed AzideâAlkyne Cycloaddition: Regioselective Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles".
1664:"Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides"
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and other reporter molecules has made click chemistry a very powerful tool for identifying, locating, and characterizing both old and new biomolecules..
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Rodionov, Valentin O.; Fokin, Valery V.; Finn, M. G. (2005-04-08). "Mechanism of the Ligand-Free CuI-Catalyzed AzideâAlkyne Cycloaddition Reaction".
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The copper(I)-catalysis of the Huisgen 1,3-dipolar cycloaddition was discovered concurrently and independently by the groups of Valery V. Fokin and
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R. A. Evans (2007). "The Rise of AzideâAlkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification".
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derivatives accumulate in mitochondria to chelate copper(II), affecting metabolism and epigenetic changes downstream in inflammatory macrophages.
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The applications of this reaction include labeling proteins containing serine as the first residue: the serine is oxidized to aldehyde with NaIO
2629:"Adhesion of Photon-Driven Molecular Motors to Surfaces via 1,3-Dipolar Cycloadditions: Effect of Interfacial Interactions on Molecular Motion"
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Zhang, Li; Chen, Xinguo; Xue, Peng; Sun, Herman H. Y.; Williams, Ian D.; Sharpless, K. Barry; Fokin, Valery V.; Jia, Guochen (November 2005).
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Agard, N. J.; Baskin, J. M.; Prescher, J. A.; Lo, A.; Bertozzi, C. R. (2006). "A Comparative Study of Bioorthogonal Reactions with Azides".
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Agard, N. J.; Baskin, J. M.; Prescher, J. A.; Lo, A.; Bertozzi, C. R. (2006). "A Comparative Study of Bioorthogonal Reactions with Azides".
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2267:(64) (a) Ning, X.; Temming, R. P.; Dommerholt, J.; Guo, J.; Ania, D.B.; Debets, M. F.; Wolfert, M. A.; Boons, G.-J.; van Delft, F. L"
1820:Ăzkılıç, Yılmaz; TĂŒzĂŒn, Nurcan Ć. (2016-08-22). "A DFT Study on the Binuclear CuAAC Reaction: Mechanism in Light of New Experiments".
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experiments (in which particular targets can be isolated using, for instance, reporter molecules which bind to a certain column), and
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themed issue highlighting the latest applications of click chemistry, guest edited by M. G. Finn and Valery Fokin. Published by the
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Cox, Courtney L.; Tietz, Jonathan I.; Sokolowski, Karol; Melby, Joel O.; Doroghazi, James R.; Mitchell, Douglas A. (17 June 2014).
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MacKenzie, DA; Pezacki, JP (2014). "Kinetics studies of rapid strain- promoted cycloadditions of nitrones with bicyclononyne".
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meet specific criteria like high yield, fast reaction rates, and minimal byproducts. It was first fully described by Sharpless,
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859:, in which click chemistry plays a fundamental role by intentionally and specifically coupling modular units to various ends.
3340:"Invitrogen Exclusively Licenses Novel Click Chemistry-Based Cell Proliferation Assays from Harvard University (NASDAQ:LIFE)"
1532:. Department of Chemistry. College of Liberal Arts & Sciences, University of Illinois at Urbana-Champaign. Archived from
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B. T. Worrell, J. A. Malik, V. V. Fokin 2013, 340, 457â459 ; J.E. Hein, V.V. Fokin, Chem. Soc. Rev. 39 (2010) 1302.
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H. C. Kolb; M. G. Finn; K. B. Sharpless (2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions".
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3393:"Integrated Diagnostics Licenses "Click Chemistry" from the Scripps Research Institute, Strengthening Partner Network"
2867:"Direct nitric oxide signal transduction via nitrosylation of iron-sulfur centers in the SoxR transcription activator"
364:) to favor a reaction with a single reaction product. A distinct exothermic reaction makes a reactant "spring-loaded".
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2969:"Genetically Encoded Cyclopropene Directs Rapid, Photoclick-Chemistry-Mediated Protein Labeling in Mammalian Cells"
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Menzel, Jan P.; Feist, Florian; Tuten, Bryan; Weil, Tanja; Blinco, James P.; BarnerâKowollik, Christopher (2019).
2134:"Visualizing Metabolically Labeled Glycoconjugates of Living Cells by Copper-Free and Fast Huisgen Cycloadditions"
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One of the earliest and most important methods in bioconjugation was to express a reporter gene, such as the gene
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Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R.J.; Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954.
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3196:"Towards Dynamic Control of Wettability by Using Functionalized Altitudinal Molecular Motors on Solid Surfaces"
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Uttamapinant, C.; Tangpeerachaikul, A.; Grecian, S.; Clarke, S.; Singh, U.; Slade, P.; Gee, K. R.; Ting, A. Y"
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endogenous alkenes, though usually cis (as in fatty acids) they can still react with the activated tetrazole.
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all tolerated. This large allowance provides a lot of flexibility for nitrone handle or probe incorporation.
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Click chemistry is not limited to biological conditions: the concept of a "click" reaction has been used in
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Rieder, Ulrike; Luedtke, Nathan W. (25 August 2014). "Alkene-tetrazine ligation for imaging cellular DNA".
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O in water at room temperature was found also to catalyze the same reaction in 15 minutes with 91% yield.
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Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of
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in 1893. Later, in the middle of the 20th century, this family of 1,3-dipolar cycloadditions took on
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reactions, scientists have opened up the possibility of hitting particular targets in complex cell
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Gordon, C. G.; Mackey, J. L.; Jewett, J. C.; Sletten, E. M.; Houk, K. N.; Bertozzi, C. R. (2012).
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1350:"Tetrazine Ligation: Fast Bioconjugation Based on Inverse-Electron-Demand DielsâAlder Reactivity"
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3143:"Vegetable Oil Derived Solvent, and Catalyst Free "Click Chemistry" Thermoplastic Polytriazoles"
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1857:"Dicopper Cu(I)Cu(I) and Cu(I)Cu(II) Complexes in Copper-Catalyzed AzideâAlkyne Cycloaddition"
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The Scripps Research Institute has a portfolio of click-chemistry patents. Licensees include
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A Tetrazine-Alkene reaction between a generalized tetrazine and a strained, trans-cyclooctene
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For a reaction to be considered a click reaction, it must satisfy certain characteristics:
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four-membered cycloalkenes, due to their high ring strain, make ideal alkene substrates.
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John E. Moses; Adam D. Moorhouse (2007). "The growing applications of click chemistry".
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Carroll, G. T.; London, G.; Fernandez-Landaluce, T.; Rudolf, P.; Feringa, B. L. (2011).
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B. Stump (2022). "Click Bioconjugation: Modifying Proteins Using Click-Like Chemistry".
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To overcome these challenges, chemists have opted to proceed by identifying pairs of
530:
463:
160:
107:
2702:
2678:
2663:
1697:
1013:
clusters and carbohydrate conjugation by Cu(1) catalyzed triazole ligation reactions
4475:
4392:
4047:
3906:
3883:
3836:
3777:
3288:
3251:
3227:
3207:
3166:
3156:
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2194:
2153:
2145:
2104:
2096:
2057:
2021:
1980:
1871:
1829:
1786:
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1677:
1636:
1584:
1499:
1461:
1422:
1414:
1371:
1363:
1300:
1265:
1230:
1144:
1107:
1056:
856:
378:
use no solvent or use a solvent that is benign or easily removed (preferably water)
312:
284:
229:
192:
3440:
2432:"Light-Controlled Orthogonal Covalent Bond Formation at Two Different Wavelengths"
1833:
4333:
4284:
4178:
4154:
3988:
3951:
3804:
3794:
3677:
3243:
1059:, click chemistry has hastened new drug discoveries by making each reaction in a
964:
870:
828:
521:
synthesis, from diethyl acetylenedicarboxylate and phenyl azide, was reported by
471:
382:
2679:"Visualizing biologically active small molecules in cells using click chemistry"
1234:
540:
A comparison of the Huisgen and the copper-catalyzed Azide-Alkyne cycloadditions
4217:
4195:
4190:
4185:
4140:
4136:
4119:
4076:
4007:
3868:
3863:
3848:
3660:
3578:
3292:
2784:
2502:
2246:
1401:"Tetrazine Based Cycloadditions: Application to Pretargeted Live Cell Labeling"
1347:
1291:
Hoyle, Charles E.; Bowman, Christopher N. (2010). "ThiolâEne Click Chemistry".
824:
754:
522:
457:
351:
342:
97:
2818:"Tetrazine-based cycloadditions: application to pretargeted live cell imaging"
2694:
2085:"Second-Generation Difluorinated Cyclooctynes for Copper-Free Click Chemistry"
1162:
4503:
4422:
4311:
4267:
3992:
3826:
3821:
3814:
3692:
3194:
London, GĂĄbor; Chen, Kuang-Yen; Carroll, Gregory T.; Feringa, Ben L. (2013).
1939:
Alder, K.; Stein, G.; Finzenhagen, H. Justus Liebigs Ann.Chem 1931, 485, 211.
1883:
1841:
1798:
1754:
1035:
781:
750:
619:
This reaction proceeds as a concerted cycloaddition to the triple bond in a
557:
536:
514:
429:
405:
102:
35:
2891:
2816:
Devaraj, Neal K.; Weissleder, Ralph; Hilderbrand, Scott A. (December 2008).
2285:
Lang, K.; Chin, J. (2014). "Bioorthogonal Reactions for Labeling Proteins".
1710:
K. Wang, X. Bi, S. Xing, P. Liao, Z. Fang, X. Meng, Q. Zhang, Q. Liu, Y. Ji
923:
697:
4299:
4149:
4064:
4040:
4030:
4022:
3923:
3858:
3757:
3606:
3300:
3263:
3219:
3211:
3180:
3127:
3056:
3048:
3002:
2984:
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2910:
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2802:
2752:
2655:
2557:
2549:
2520:
2467:
2448:
2431:
2416:
2408:
2381:
2306:
2254:
2216:
2167:
2149:
2118:
2069:
2033:
1992:
1891:
1806:
1790:
1762:
1746:
1689:
1648:
1598:
1511:
1473:
1436:
1385:
1312:
1304:
1277:
1269:
1119:
1041:
1010:
773:
769:
526:
393:
386:
357:
155:
132:
3161:
2937:
2333:
1641:
10.1002/1521-3773(20020715)41:14<2596::aid-anie2596>3.0.co;2-4
1112:
10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5
3697:
2536:
1875:
1020:
894:
883:
852:
840:
836:
758:
746:
620:
490:
467:
361:
3520:
911:
567:
4323:
3418:"baseclick GmbH :: We enable nucleic acid labeling bioconjugation"
3140:
2734:
2719:"Salinomycin kills cancer stem cells by sequestering iron in lysosomes"
1465:
1399:
Devaraj, Neal K.; Weissleder Ralph & Hilderbrand, Scott A. (2008).
1290:
1072:
991:
981:
901:
630:
553:
510:
447:
288:
3486:
National Science Foundation: Feature "Going Live with Click Chemistry"
3109:
2833:
2647:
2373:
2298:
2198:
2183:"Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry"
2100:
2061:
2025:
1984:
1681:
1661:
1503:
1418:
1367:
4385:
3687:
3552:
3255:
2354:
2352:
2083:
Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. (2008).
1913:
Kuang, G.-C.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Zhu, L"
1004:
935:
928:
905:
897:
887:
792:
602:
27:
3496:
Chemical and Engineering News: Feature "Copper-free Click Chemistry"
2604:"'Honeymoon-Phase' Chemical Partners Deliver a Toxic Drug to Tumors"
1148:
4407:
1225:
1164:
Nobel Prize lecture: Barry Sharpless, Nobel Prize in Chemistry 2022
1095:
1076:
1016:
999:
995:
953:
848:
518:
2349:
692:
501:
The classic click reaction is the copper-catalyzed reaction of an
4427:
3276:
2232:
1969:"Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides"
801:
738:
639:
381:
provide simple product isolation by non-chromatographic methods (
188:
3491:
Chemical and Engineering News: Feature "In-Situ Click Chemistry"
2769:"A druggable copper-signalling pathway that drives inflammation"
2677:
Cañeque, Tatiana; MĂŒller, Sebastian; Rodriguez, RaphaĂ«l (2018).
1855:
Ziegler, Micah S.; Lakshmi, K. V.; Tilley, T. Don (2017-04-19).
1255:
580:
is liable to Staudinger ligation with the azide substituent. Cu
506:
92:
3240:
3028:"A nascent proteome study combining click chemistry with 2DE"
820:
777:
502:
443:
122:
3417:
2815:
1948:
Alder, K.; Stein, G. Justus Liebigs Ann. Chem. 1933, 501, 1.
1348:
Blackman, Melissa L.; Royzen Maksim; Fox, Joseph M. (2008).
4402:
1775:
713:
453:
3094:"Nucleophilic 1,4-Additions for Natural Product Discovery"
2765:
2082:
973:
macrocyclizations using Cu(I) catalyzed triazole couplings
893:
The commercial potential of click chemistry is great. The
4412:
3456:
2180:
1573:"The growing impact of click chemistry on drug discovery"
977:
112:
3193:
2132:
Ning, X.; Guo, J.; Wolfert, M. A.; Boons, G.-J. (2008).
615:
Scheme of the Strain-promoted Azide-Alkyne Cycloaddition
3091:
2715:
2676:
1898:
491:
Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
2483:"Photoclick chemistry: a fluorogenic light-triggered
2047:
2011:
1209:
571:
The two-copper mechanism of the CuAAC catalytic cycle
375:
use readily available starting materials and reagents
3141:
Michael Floros; Alcides LeĂŁo; Suresh Narine (2014).
2429:
1854:
961:
modification of natural products and pharmaceuticals
855:. These techniques represent a part of the field of
631:
Strain-promoted alkyne-nitrone cycloaddition (SPANC)
3481:
Click Chemistry: Short Review and Recent Literature
2131:
1662:Tornoe, C. W.; Christensen, C.; Meldal, M. (2002).
1570:
866:is a company leveraging click chemistry in humans.
827:have already proven useful in a new generation of
791:reaction partners, thus allowing the use of small
672:
603:Strain-promoted azide-alkyne cycloaddition (SPAAC)
2272:Pezacki, J. P. Org. Biomol. Chem. 2012, 10, 3066.
1732:
1612:
1610:
1608:
1527:"Development and Applications of Click Chemistry"
952:preparative organic synthesis of 1,4-substituted
800:conditions, and proceed quickly to high yield in
299:The term "click chemistry" was coined in 1998 by
4501:
2358:
2319:
1957:Wittig, G.; Krebs, A. Chem. Ber. 1961, 94, 3260.
663:
432:between isonitriles (isocyanides) and tetrazines
3441:http://www.basf.com/group/pressrelease/P-10-427
1966:
958:modification of peptide function with triazoles
693:Alkene and tetrazine inverse-demand Diels-Alder
3365:"Xconomy: Allozyne Licenses Scripps Chemistry"
1933:
1605:
319:, "for the development of click chemistry and
3536:
2394:
2280:
2278:
2228:
2226:
745:In many applications, click reactions join a
263:
1819:
529:'s name after his studies of their reaction
460:type due to low thermodynamic driving force.
425:inverse electron demand Diels-Alder reaction
356:a large thermodynamic driving force (>20
1132:
753:or other molecular probe, a process called
485:
3543:
3529:
2864:
2717:xRodriguez, Raphaël Rodriguez (Oct 2017).
2275:
2223:
1524:
270:
256:
3550:
3170:
3160:
3117:
2992:
2923:
2900:
2890:
2841:
2792:
2742:
2510:
2481:Ramil, Carlo P; Lin, Qing (August 2014).
2457:
2447:
2206:
2157:
2108:
1588:
1426:
1375:
1224:
2533:
2480:
2284:
1973:Journal of the American Chemical Society
1864:Journal of the American Chemical Society
1355:Journal of the American Chemical Society
1089:
922:
910:
815:By developing specific and controllable
696:
638:
610:
566:
535:
3379:"Xconomy: Aileron and Scripps Ink Deal"
2436:Angewandte Chemie International Edition
1779:Angewandte Chemie International Edition
1735:Angewandte Chemie International Edition
1629:Angewandte Chemie International Edition
1525:Gregory C., Patton (November 8, 2004).
1319:
1293:Angewandte Chemie International Edition
1258:Angewandte Chemie International Edition
1099:Angewandte Chemie International Edition
4502:
1205:
1203:
347:insensitivity towards oxygen and water
16:Modular approach to chemical synthesis
3524:
1066:
513:ring: a Cu(I)-catalyzed azide-alkyne
452:carbonyl-chemistry-like formation of
4458:
1571:Kolb, H.C.; Sharpless, B.K. (2003).
1453:Organic & Biomolecular Chemistry
4482:
2491:Current Opinion in Chemical Biology
1200:
1184:"The Nobel Prize in Chemistry 2022"
947:two-dimensional gel electrophoresis
927:Scheme of the synthesis of firefly
338:insensitivity to solvent parameters
13:
2966:
1063:fast, efficient, and predictable.
873:, pharmacological, biomimetic and
497:Azide alkyne Huisgen cycloaddition
14:
4521:
3501:Metal-free click chemistry review
3474:
942:Additional applications include:
843:, including the incorporation of
810:Huisgen 1,3-dipolar cycloaddition
410:Huisgen 1,3-dipolar cycloaddition
4481:
4469:
4457:
4446:
4445:
847:containing reactive groups into
237:
236:
223:
34:
3445:
3434:
3410:
3385:
3371:
3357:
3332:
3307:
3270:
3234:
3187:
3134:
3085:
3018:
3009:
2960:
2917:
2858:
2809:
2759:
2709:
2670:
2620:
2596:
2572:
2527:
2474:
2423:
2388:
2340:
2313:
2261:
2174:
2125:
2076:
2041:
1999:
1960:
1951:
1942:
1920:
1907:
1848:
1813:
1769:
1726:
1717:
1704:
1655:
1619:
1564:
1518:
1480:
1443:
1392:
1136:Australian Journal of Chemistry
757:. The possibility of attaching
730:
673:Alkene and azide cycloaddition
372:have simple reaction conditions
3280:Advanced Drug Delivery Reviews
2580:"The bioorthogonal revolution"
1341:
1284:
1249:
1176:
1155:
1126:
886:in cancer stem cells and that
804:. Existing reactions, such as
368:The process would preferably:
293:The Scripps Research Institute
1:
3810:Interface and colloid science
3564:Glossary of chemical formulae
3200:Chemistry: A European Journal
3148:BioMed Research International
1834:10.1021/acs.organomet.6b00279
1590:10.1016/S1359-6446(03)02933-7
1082:
1034:bioconjugation, for example,
664:Reactions of strained alkenes
481:Sulfur (VI) Fluoride exchange
326:
3455:. 2018-10-03. Archived from
2871:Proc. Natl. Acad. Sci. U.S.A
2865:Ding, H.; Demple, B (2000).
1669:Journal of Organic Chemistry
7:
4087:Bioorganometallic chemistry
3574:List of inorganic compounds
1235:10.1016/j.addma.2019.02.012
643:The SPAAC vs SpANC reaction
10:
4526:
4013:Dynamic covalent chemistry
3984:Enantioselective synthesis
3964:Physical organic chemistry
3917:Organolanthanide chemistry
3516:Royal Society of Chemistry
3293:10.1016/j.addr.2008.02.004
2785:10.1038/s41586-023-06017-4
2503:10.1016/j.cbpa.2014.05.024
2247:10.1016/j.cbpa.2014.05.023
550:Scripps Research Institute
494:
4441:
4344:
4105:
4021:
3942:
3892:
3768:
3711:
3602:Electroanalytical methods
3587:
3559:
2695:10.1038/s41570-018-0030-x
2459:21.11116/0000-0003-99B4-5
1053:high-throughput screening
882:to lysosomes to initiate
833:fluorescence spectrometry
766:green fluorescent protein
456:but not reactions of the
436:nucleophilic substitution
209:List of unsolved problems
4357:Nobel Prize in Chemistry
4273:Supramolecular chemistry
3912:Organometallic chemistry
2967:Yu; et al. (2012).
2683:Nature Reviews Chemistry
988:supramolecular chemistry
851:and the modification of
486:Specific Click Reactions
309:Carolyn R. Bertozzi
305:Nobel Prize in Chemistry
199:List of chemistry awards
4295:Combinatorial chemistry
4206:Food physical chemistry
4169:Environmental chemistry
4053:Bioorthogonal chemistry
3979:Retrosynthetic analysis
3800:Chemical thermodynamics
3783:Spectroelectrochemistry
3726:Computational chemistry
2892:10.1073/pnas.97.10.5146
1049:combinatorial chemistry
321:bioorthogonal chemistry
317:K. Barry Sharpless
307:was jointly awarded to
4367:of element discoveries
4213:Agricultural chemistry
4201:Carbohydrate chemistry
4092:Bioinorganic chemistry
3957:Alkane stereochemistry
3902:Coordination chemistry
3731:Mathematical chemistry
3597:Instrumental chemistry
3212:10.1002/chem.201300500
3049:10.1002/pmic.201200393
2985:10.1002/anie.201205352
2973:Angew Chem Int Ed Engl
2550:10.1002/cbic.202200016
2449:10.1002/anie.201901275
2409:10.1002/anie.201403580
2397:Angew Chem Int Ed Engl
2150:10.1002/anie.200705456
1791:10.1002/anie.201410301
1747:10.1002/anie.200461496
1552:Cite journal requires
1491:Bioconjugate Chemistry
1406:Bioconjugate Chemistry
1305:10.1002/anie.200903924
1270:10.1002/anie.200905322
1213:Additive Manufacturing
931:
916:
900:has been coupled onto
784:, etc.) out of reach.
702:
644:
616:
572:
541:
474:or the alkynes in the
350:regiospecificity and
4362:Timeline of chemistry
4259:Post-mortem chemistry
4244:Clandestine chemistry
4174:Atmospheric chemistry
4097:Biophysical chemistry
3929:Solid-state chemistry
3879:Equilibrium chemistry
3788:Photoelectrochemistry
3508: – a
2938:10.1038/nprot.2007.52
2334:10.1139/cjc-2013-0577
2269:Angew. Chem. Int. Ed.
2007:Angew. Chem. Int. Ed.
1928:Angew. Chem. Int. Ed.
926:
915:Unnatural Amino Acids
914:
845:unnatural amino acids
714:Alkene and tetrazole
700:
642:
614:
570:
539:
509:to form a 5-membered
313:Morten P. Meldal
285:Hartmuth C. Kolb
4352:History of chemistry
4307:Chemical engineering
4082:Bioorganic chemistry
3832:Structural chemistry
3569:List of biomolecules
3098:ACS Chemical Biology
2138:Angew. Chem. Int. Ed
1876:10.1021/jacs.6b13261
1047:In combination with
984:by triazole ligation
562:Carlsberg Laboratory
438:especially to small
421:Diels-Alder reaction
289:M. G. Finn
230:Chemistry portal
151:Analytical chemistry
128:Chemical equilibrium
4375:The central science
4329:Ceramic engineering
4254:Forensic toxicology
4227:Chemistry education
4125:Radiation chemistry
4107:Interdisciplinarity
4060:Medicinal chemistry
3998:Fullerene chemistry
3874:Microwave chemistry
3743:Molecular mechanics
3738:Molecular modelling
3206:(32): 10690â10697.
3162:10.1155/2014/792901
2979:(42): 10600â10604.
2883:2000PNAS...97.5146D
2368:(41): 15642â15649.
2235:Curr Opin Chem Biol
2095:(34): 11486â11493.
1979:(46): 15998â15999.
1714:, 13 (2011), p. 562
1362:(41): 13518â13519.
1061:multistep synthesis
904:, and reacted with
875:molecular machinery
806:Staudinger ligation
677:cycloaddition": -->
517:(CuAAC). The first
166:Inorganic chemistry
22:Part of a series on
4418:Chemical substance
4280:Chemical synthesis
4249:Forensic chemistry
4130:Actinide chemistry
4072:Clinical chemistry
3753:Molecular geometry
3748:Molecular dynamics
3703:Elemental analysis
3656:Separation process
2735:10.1038/nchem.2778
2544:(16): e202200016.
2487:ligation reaction"
2009:Engl. 1963, 2, 565
1466:10.1039/C1OB06424J
1337:10.1039/B9PY00216B
1067:Technology license
1057:chemical libraries
932:
917:
703:
645:
617:
573:
546:K. Barry Sharpless
542:
476:thiol-yne reaction
464:addition reactions
416:Thiol-ene reaction
301:K. Barry Sharpless
171:Physical chemistry
118:Acidâbase reaction
4510:Organic chemistry
4497:
4496:
4433:Quantum mechanics
4398:Chemical compound
4381:Chemical reaction
4319:Materials science
4237:General chemistry
4232:Amateur chemistry
4160:Photogeochemistry
4145:Stellar chemistry
4115:Nuclear chemistry
4036:Molecular biology
4003:Polymer chemistry
3974:Organic synthesis
3969:Organic reactions
3934:Ceramic chemistry
3924:Cluster chemistry
3854:Chemical kinetics
3842:Molecular physics
3721:Quantum chemistry
3634:Mass spectrometry
3459:on 3 October 2018
3315:"Click Chemistry"
3110:10.1021/cb500324n
2877:(10): 5146â5150.
2834:10.1021/bc8004446
2828:(12): 2297â2299.
2822:Bioconjugate Chem
2779:(7960): 386â394.
2729:(10): 1025â1033.
2648:10.1021/nn102876j
2608:Discover Magazine
2442:(22): 7470â7474.
2403:(35): 9168â9172.
2374:10.1021/ja408437u
2299:10.1021/cb4009292
2199:10.1021/ja3000936
2193:(22): 9199â9208.
2144:(12): 2253â2255.
2101:10.1021/ja803086r
2062:10.1021/cb6003228
2026:10.1021/cb6003228
1985:10.1021/ja054114s
1870:(15): 5378â5386.
1828:(16): 2589â2599.
1785:(10): 3065â3068.
1741:(15): 2210â2215.
1682:10.1021/jo011148j
1635:(14): 2596â2599.
1583:(24): 1128â1137.
1577:Drug Discov Today
1504:10.1021/bc800369c
1498:(12): 2308â2310.
1419:10.1021/bc8004446
1413:(12): 2297â2299.
1368:10.1021/ja8053805
1327:Polymer Chemistry
1106:(11): 2004â2021.
934:The synthesis of
751:reporter molecule
466:to carbon-carbon
352:stereospecificity
280:
279:
161:Organic chemistry
108:Chemical reaction
41:Science of matter
4517:
4485:
4484:
4473:
4461:
4460:
4449:
4448:
4393:Chemical element
4048:Chemical biology
3907:Magnetochemistry
3884:Mechanochemistry
3837:Chemical physics
3778:Electrochemistry
3683:Characterization
3545:
3538:
3531:
3522:
3521:
3468:
3467:
3465:
3464:
3449:
3443:
3438:
3432:
3431:
3429:
3428:
3414:
3408:
3407:
3405:
3404:
3395:. Archived from
3389:
3383:
3382:
3375:
3369:
3368:
3361:
3355:
3354:
3352:
3351:
3342:. Archived from
3336:
3330:
3329:
3327:
3326:
3317:. Archived from
3311:
3305:
3304:
3274:
3268:
3267:
3256:10.1039/b613014n
3250:(8): 1249â1262.
3238:
3232:
3231:
3191:
3185:
3184:
3174:
3164:
3138:
3132:
3131:
3121:
3104:(9): 2014â2022.
3089:
3083:
3082:
3080:
3079:
3073:
3067:. Archived from
3032:
3022:
3016:
3013:
3007:
3006:
2996:
2964:
2958:
2957:
2926:Nature Protocols
2921:
2915:
2914:
2904:
2894:
2862:
2856:
2855:
2845:
2813:
2807:
2806:
2796:
2763:
2757:
2756:
2746:
2723:Nature Chemistry
2713:
2707:
2706:
2674:
2668:
2667:
2633:
2624:
2618:
2617:
2615:
2614:
2600:
2594:
2593:
2591:
2590:
2576:
2570:
2569:
2531:
2525:
2524:
2514:
2478:
2472:
2471:
2461:
2451:
2427:
2421:
2420:
2392:
2386:
2385:
2362:J. Am. Chem. Soc
2356:
2347:
2344:
2338:
2337:
2317:
2311:
2310:
2282:
2273:
2265:
2259:
2258:
2230:
2221:
2220:
2210:
2187:J. Am. Chem. Soc
2178:
2172:
2171:
2161:
2129:
2123:
2122:
2112:
2089:J. Am. Chem. Soc
2080:
2074:
2073:
2045:
2039:
2037:
2003:
1997:
1996:
1964:
1958:
1955:
1949:
1946:
1940:
1937:
1931:
1924:
1918:
1911:
1905:
1902:
1896:
1895:
1861:
1852:
1846:
1845:
1817:
1811:
1810:
1773:
1767:
1766:
1730:
1724:
1721:
1715:
1708:
1702:
1701:
1676:(9): 3057â3064.
1659:
1653:
1652:
1623:
1617:
1614:
1603:
1602:
1592:
1568:
1562:
1561:
1555:
1550:
1548:
1540:
1538:
1531:
1522:
1516:
1515:
1484:
1478:
1477:
1447:
1441:
1440:
1430:
1396:
1390:
1389:
1379:
1345:
1339:
1332:, 1 (1), 17â36.
1323:
1317:
1316:
1299:(9): 1540â1573.
1288:
1282:
1281:
1253:
1247:
1246:
1228:
1207:
1198:
1197:
1195:
1194:
1180:
1174:
1173:
1172:
1171:
1159:
1153:
1152:
1130:
1124:
1123:
1093:
1028:material science
976:modification of
862:Biotech company
857:chemical biology
685:
684:
680:
593:peptidotriazoles
533:and conditions.
272:
265:
258:
245:
240:
239:
232:
228:
227:
226:
204:List of journals
38:
19:
18:
4525:
4524:
4520:
4519:
4518:
4516:
4515:
4514:
4500:
4499:
4498:
4493:
4437:
4340:
4334:Polymer science
4290:Click chemistry
4285:Green chemistry
4179:Ocean chemistry
4155:Biogeochemistry
4101:
4017:
3989:Total synthesis
3952:Stereochemistry
3938:
3888:
3805:Surface science
3795:Thermochemistry
3764:
3707:
3678:Crystallography
3583:
3555:
3549:
3506:Click Chemistry
3477:
3472:
3471:
3462:
3460:
3451:
3450:
3446:
3439:
3435:
3426:
3424:
3416:
3415:
3411:
3402:
3400:
3391:
3390:
3386:
3377:
3376:
3372:
3363:
3362:
3358:
3349:
3347:
3338:
3337:
3333:
3324:
3322:
3313:
3312:
3308:
3275:
3271:
3244:Chem. Soc. Rev.
3239:
3235:
3192:
3188:
3139:
3135:
3090:
3086:
3077:
3075:
3071:
3030:
3023:
3019:
3014:
3010:
2965:
2961:
2922:
2918:
2863:
2859:
2814:
2810:
2764:
2760:
2714:
2710:
2675:
2671:
2631:
2625:
2621:
2612:
2610:
2602:
2601:
2597:
2588:
2586:
2584:Chemistry World
2578:
2577:
2573:
2532:
2528:
2479:
2475:
2428:
2424:
2393:
2389:
2357:
2350:
2345:
2341:
2318:
2314:
2283:
2276:
2266:
2262:
2231:
2224:
2179:
2175:
2130:
2126:
2081:
2077:
2056:(10): 644â648.
2046:
2042:
2020:(10): 644â648.
2004:
2000:
1965:
1961:
1956:
1952:
1947:
1943:
1938:
1934:
1925:
1921:
1917:2010; 75, 6540.
1912:
1908:
1903:
1899:
1859:
1853:
1849:
1822:Organometallics
1818:
1814:
1774:
1770:
1731:
1727:
1722:
1718:
1709:
1705:
1660:
1656:
1624:
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1569:
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1553:
1551:
1542:
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1536:
1529:
1523:
1519:
1485:
1481:
1448:
1444:
1397:
1393:
1346:
1342:
1324:
1320:
1289:
1285:
1254:
1250:
1208:
1201:
1192:
1190:
1182:
1181:
1177:
1169:
1167:
1161:
1160:
1156:
1149:10.1071/CH06457
1131:
1127:
1094:
1090:
1085:
1069:
1055:, and building
1031:nanotechnology,
965:natural product
880:
877:applications.
825:click reactions
733:
720:
695:
686:
682:
678:
676:
675:
666:
658:
633:
605:
583:
579:
499:
493:
488:
472:dihydroxylation
383:crystallisation
343:chemical yields
329:
276:
235:
224:
222:
221:
214:
213:
184:
176:
175:
146:
138:
137:
88:
80:
66:
43:
17:
12:
11:
5:
4523:
4513:
4512:
4495:
4494:
4492:
4491:
4479:
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4442:
4439:
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4430:
4425:
4420:
4415:
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4405:
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4390:
4389:
4388:
4378:
4371:
4370:
4369:
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4348:
4346:
4342:
4341:
4339:
4338:
4337:
4336:
4331:
4326:
4316:
4315:
4314:
4304:
4303:
4302:
4297:
4292:
4287:
4277:
4276:
4275:
4264:
4263:
4262:
4261:
4256:
4246:
4241:
4240:
4239:
4234:
4223:
4222:
4221:
4220:
4218:Soil chemistry
4210:
4209:
4208:
4203:
4196:Food chemistry
4193:
4191:Carbochemistry
4188:
4186:Clay chemistry
4183:
4182:
4181:
4176:
4165:
4164:
4163:
4162:
4157:
4147:
4141:Astrochemistry
4137:Cosmochemistry
4134:
4133:
4132:
4127:
4122:
4120:Radiochemistry
4111:
4109:
4103:
4102:
4100:
4099:
4094:
4089:
4084:
4079:
4077:Neurochemistry
4074:
4069:
4068:
4067:
4057:
4056:
4055:
4045:
4044:
4043:
4038:
4027:
4025:
4019:
4018:
4016:
4015:
4010:
4008:Petrochemistry
4005:
4000:
3995:
3986:
3981:
3976:
3971:
3966:
3961:
3960:
3959:
3948:
3946:
3940:
3939:
3937:
3936:
3931:
3926:
3921:
3920:
3919:
3909:
3904:
3898:
3896:
3890:
3889:
3887:
3886:
3881:
3876:
3871:
3869:Spin chemistry
3866:
3864:Photochemistry
3861:
3856:
3851:
3849:Femtochemistry
3846:
3845:
3844:
3834:
3829:
3824:
3819:
3818:
3817:
3807:
3802:
3797:
3792:
3791:
3790:
3785:
3774:
3772:
3766:
3765:
3763:
3762:
3761:
3760:
3750:
3745:
3740:
3735:
3734:
3733:
3723:
3717:
3715:
3709:
3708:
3706:
3705:
3700:
3695:
3690:
3685:
3680:
3675:
3674:
3673:
3668:
3661:Chromatography
3658:
3653:
3652:
3651:
3646:
3641:
3631:
3630:
3629:
3624:
3619:
3614:
3604:
3599:
3593:
3591:
3585:
3584:
3582:
3581:
3579:Periodic table
3576:
3571:
3566:
3560:
3557:
3556:
3548:
3547:
3540:
3533:
3525:
3519:
3518:
3503:
3498:
3493:
3488:
3483:
3476:
3475:External links
3473:
3470:
3469:
3444:
3433:
3422:baseclick GmbH
3409:
3384:
3370:
3356:
3331:
3306:
3287:(9): 958â970.
3269:
3233:
3186:
3133:
3084:
3017:
3008:
2959:
2932:(3): 532â540.
2916:
2857:
2808:
2758:
2708:
2689:(9): 202â215.
2669:
2642:(1): 622â630.
2619:
2595:
2571:
2526:
2473:
2422:
2387:
2348:
2339:
2328:(4): 337â340.
2312:
2287:ACS Chem. Biol
2274:
2260:
2222:
2173:
2124:
2075:
2050:ACS Chem. Biol
2040:
2014:ACS Chem. Biol
1998:
1959:
1950:
1941:
1932:
1930:2012; 51, 5852
1919:
1906:
1897:
1847:
1812:
1768:
1725:
1716:
1703:
1654:
1618:
1604:
1563:
1554:|journal=
1539:on 2010-07-09.
1517:
1479:
1460:(21): 7303â5.
1442:
1391:
1340:
1318:
1283:
1248:
1199:
1188:NobelPrize.org
1175:
1154:
1143:(6): 384â395.
1125:
1087:
1086:
1084:
1081:
1068:
1065:
1045:
1044:
1039:
1032:
1029:
1026:
1023:
1014:
1008:
1002:
985:
974:
971:
970:drug discovery
968:
962:
959:
956:
950:
871:chemoproteomic
835:(in which the
755:bioconjugation
732:
729:
719:
712:
694:
691:
674:
671:
665:
662:
656:
632:
629:
604:
601:
581:
577:
523:Arthur Michael
495:Main article:
492:
489:
487:
484:
483:
482:
479:
461:
450:
433:
430:cycloadditions
427:
418:
413:
408:, such as the
406:cycloadditions
398:
397:
390:
379:
376:
373:
366:
365:
354:
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339:
336:
328:
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233:
216:
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211:
206:
201:
196:
185:
182:
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147:
144:
143:
140:
139:
136:
135:
130:
125:
120:
115:
110:
105:
100:
95:
89:
87:Key components
86:
85:
82:
81:
79:
78:
67:
65:
64:
59:
54:
48:
45:
44:
39:
31:
30:
24:
23:
15:
9:
6:
4:
3:
2:
4522:
4511:
4508:
4507:
4505:
4490:
4489:
4480:
4478:
4477:
4472:
4468:
4466:
4465:
4456:
4454:
4453:
4444:
4443:
4440:
4434:
4431:
4429:
4426:
4424:
4423:Chemical bond
4421:
4419:
4416:
4414:
4411:
4409:
4406:
4404:
4401:
4399:
4396:
4394:
4391:
4387:
4384:
4383:
4382:
4379:
4376:
4372:
4368:
4365:
4364:
4363:
4360:
4358:
4355:
4353:
4350:
4349:
4347:
4343:
4335:
4332:
4330:
4327:
4325:
4322:
4321:
4320:
4317:
4313:
4312:Stoichiometry
4310:
4309:
4308:
4305:
4301:
4298:
4296:
4293:
4291:
4288:
4286:
4283:
4282:
4281:
4278:
4274:
4271:
4270:
4269:
4268:Nanochemistry
4266:
4265:
4260:
4257:
4255:
4252:
4251:
4250:
4247:
4245:
4242:
4238:
4235:
4233:
4230:
4229:
4228:
4225:
4224:
4219:
4216:
4215:
4214:
4211:
4207:
4204:
4202:
4199:
4198:
4197:
4194:
4192:
4189:
4187:
4184:
4180:
4177:
4175:
4172:
4171:
4170:
4167:
4166:
4161:
4158:
4156:
4153:
4152:
4151:
4148:
4146:
4142:
4138:
4135:
4131:
4128:
4126:
4123:
4121:
4118:
4117:
4116:
4113:
4112:
4110:
4108:
4104:
4098:
4095:
4093:
4090:
4088:
4085:
4083:
4080:
4078:
4075:
4073:
4070:
4066:
4063:
4062:
4061:
4058:
4054:
4051:
4050:
4049:
4046:
4042:
4039:
4037:
4034:
4033:
4032:
4029:
4028:
4026:
4024:
4020:
4014:
4011:
4009:
4006:
4004:
4001:
3999:
3996:
3994:
3993:Semisynthesis
3990:
3987:
3985:
3982:
3980:
3977:
3975:
3972:
3970:
3967:
3965:
3962:
3958:
3955:
3954:
3953:
3950:
3949:
3947:
3945:
3941:
3935:
3932:
3930:
3927:
3925:
3922:
3918:
3915:
3914:
3913:
3910:
3908:
3905:
3903:
3900:
3899:
3897:
3895:
3891:
3885:
3882:
3880:
3877:
3875:
3872:
3870:
3867:
3865:
3862:
3860:
3857:
3855:
3852:
3850:
3847:
3843:
3840:
3839:
3838:
3835:
3833:
3830:
3828:
3827:Sonochemistry
3825:
3823:
3822:Cryochemistry
3820:
3816:
3815:Micromeritics
3813:
3812:
3811:
3808:
3806:
3803:
3801:
3798:
3796:
3793:
3789:
3786:
3784:
3781:
3780:
3779:
3776:
3775:
3773:
3771:
3767:
3759:
3756:
3755:
3754:
3751:
3749:
3746:
3744:
3741:
3739:
3736:
3732:
3729:
3728:
3727:
3724:
3722:
3719:
3718:
3716:
3714:
3710:
3704:
3701:
3699:
3696:
3694:
3693:Wet chemistry
3691:
3689:
3686:
3684:
3681:
3679:
3676:
3672:
3669:
3667:
3664:
3663:
3662:
3659:
3657:
3654:
3650:
3647:
3645:
3642:
3640:
3637:
3636:
3635:
3632:
3628:
3625:
3623:
3620:
3618:
3615:
3613:
3610:
3609:
3608:
3605:
3603:
3600:
3598:
3595:
3594:
3592:
3590:
3586:
3580:
3577:
3575:
3572:
3570:
3567:
3565:
3562:
3561:
3558:
3554:
3546:
3541:
3539:
3534:
3532:
3527:
3526:
3523:
3517:
3513:
3512:
3507:
3504:
3502:
3499:
3497:
3494:
3492:
3489:
3487:
3484:
3482:
3479:
3478:
3458:
3454:
3448:
3442:
3437:
3423:
3419:
3413:
3399:on 2012-04-30
3398:
3394:
3388:
3381:. 2010-11-30.
3380:
3374:
3367:. 2010-07-15.
3366:
3360:
3346:on 2012-12-17
3345:
3341:
3335:
3321:on 2012-05-15
3320:
3316:
3310:
3302:
3298:
3294:
3290:
3286:
3282:
3281:
3273:
3265:
3261:
3257:
3253:
3249:
3246:
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3237:
3229:
3225:
3221:
3217:
3213:
3209:
3205:
3201:
3197:
3190:
3182:
3178:
3173:
3168:
3163:
3158:
3154:
3150:
3149:
3144:
3137:
3129:
3125:
3120:
3115:
3111:
3107:
3103:
3099:
3095:
3088:
3074:on 2015-06-30
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2692:
2688:
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2641:
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2204:
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2192:
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2184:
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2169:
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2143:
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2094:
2090:
2086:
2079:
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