Combining Oxidative N‐Heterocyclic Carbene Catalysis with Click Chemistry: A Facile One‐Pot Approach to 1,2,3‐Triazole Derivatives

A combination of the oxidative N‐heterocyclic carbene catalysis and click chemistry has been explored for the direct, one‐pot synthesis of 1,2,3‐triazole derivatives from aromatic aldehydes. This procedure was found to be very efficient and a variety of 1,2,3‐triazole derivatives could be accessed through their corresponding propargyl esters in moderate‐to‐good yields under mild conditions.     

A Nucleobase‐Discriminating Pyrrolo‐dC Click Adduct Designed for DNA Fluorescence Mismatch Sensing

New pyrrolo‐dC click adducts ( 4 and 5 ) tethered with a 1,2,3‐triazole skeleton were synthesized and oligonucleotides were prepared. The triazole system was either directly linked to the pyrrolo moiety ( 5 ) or connected via an n‐butyl linker ( 4 ). The quantum yield of nucleoside 5 (Φ=0.32), which is 10 times higher than those of 8‐methylpyrrolo‐dC ( 1 b , Φ=0.026) or the long linker derivative 4 (Φ=0.03), is maintained in oligonucleotides. Compound 5 was used as a nucleobase‐discriminating fluorescence sensor in duplex DNA. Excellent mismatch discrimination was observed when 5 was positioned opposite the four canonical nucleosides. Compound 5 has the potential to be used for SNP detection in long DNA targets when conventional techniques such as high resolution melt analysis fail.     

Click To Bind: Metal Sensors

The copper‐catalyzed azide–alkyne “click” cycloaddition reaction is an efficient coupling reaction that results in the formation of a triazole ring. The wide range of applicable substrates for this reaction allows the construction of a variety of conjugated systems. The additional function of triazoles as metal‐ion ligands has led to the click reaction being used for the construction of optical sensors for metal ions. The triazoles are integral binding elements, which are formed in an efficient modular synthesis. Herein, we review recent examples of triazoles as a metal‐binding element in conjugated metal‐ion sensors.     

Protein‐Sized Bright Fluorogenic Nanoparticles Based on Cross‐Linked Calixarene Micelles with Cyanine Corona

The key challenge in the field of fluorescent nanoparticles (NPs) for biological applications is to achieve superior brightness for sizes equivalent to single proteins (3–7 nm). We propose a concept of shell‐cross‐linked fluorescent micelles, in which PEGylated cyanine 3 and 5 bis‐azides form a covalently attached corona on micelles of amphiphilic calixarene bearing four alkyne groups. The fluorescence quantum yield of the obtained monodisperse NPs, with a size of 7 nm, is a function of viscosity and reached up to 15 % in glycerol. In the on‐state they are circa 2‐fold brighter than quantum dots (QD‐585), which makes them the smallest PEGylated organic NPs of this high brightness. FRET between cyanine 3 and 5 cross‐linkers at the surface of NPs suggests their integrity in physiological media, organic solvents, and living cells, in which the NPs rapidly internalize, showing excellent imaging contrast. Calixarene micelles with a cyanine corona constitute a new platform for the development of protein‐sized ultrabright fluorescent NPs.     

Visible‐Light‐Induced Click Chemistry

A rapid and catalyst‐free cycloaddition system for visible‐light‐induced click chemistry is reported. A readily accessible photoreactive 2H‐azirine moiety was designed to absorb light at wavelengths above 400 nm. Irradiation with low‐energy light sources thus enables efficient small‐molecule synthesis with a diverse range of multiple‐bond‐containing compounds. Moreover, in order to demonstrate the efficiency of the current approach, quantitative ligation of the photoactivatable chromophore with functional polymeric substrates was performed and full conversion with irradiation times of only 1 min at ambient conditions was achieved. The current report thus presents a highly efficient method for applications involving selective cycloaddition to electron‐deficient multiple‐bond‐containing materials.     

Click Chemistry with Polysaccharides

Summary: The copper‐catalyzed Huisgen reaction as a typical example of click chemistry was realized with the polysaccharide cellulose for the first time. The generality, selectivity, and the efficiency of click chemistry perfectly fit the requirements of polysaccharide modification, which is demonstrated by the introduction of triazole‐spacer bound functional groups, i.e., carboxylic ester, thiophene, and aniline moieties. Azide moieties introduced into cellulose via the tosyl derivative were simply transferred with ethynyl compounds under Cu(I) catalysis and mild and easily applicable conditions. Hydrolytically stable cellulose derivatives soluble in organic solvents, e.g., DMSO or DMF with DS up to 0.9 are obtained. The triazole substituted cellulose derivatives were characterized by elemental analysis, FTIR, ¹H NMR, and ¹³C NMR spectroscopies and show no impurities or substructures resulting from side reactions.

6‐Azido‐6‐deoxy cellulose.     

Interfacing Click Chemistry with Automated Oligonucleotide Synthesis for the Preparation of Fluorescent DNA Probes Containing Internal Xanthene and Cyanine Dyes

Double‐labeled oligonucleotide probes containing fluorophores interacting by energy‐transfer mechanisms are essential for modern bioanalysis, molecular diagnostics, and in vivo imaging techniques. Although bright xanthene and cyanine dyes are gaining increased prominence within these fields, little attention has thus far been paid to probes containing these dyes internally attached, a fact which is mainly due to the quite challenging synthesis of such oligonucleotide probes. Herein, by using 2′‐O‐propargyl uridine phosphoramidite and a series of xanthenes and cyanine azide derivatives, we have for the first time performed solid‐phase copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) click labeling during the automated phosphoramidite oligonucleotide synthesis followed by postsynthetic click reactions in solution. We demonstrate that our novel strategy is rapid and efficient for the preparation of novel oligonucleotide probes containing internally positioned xanthene and cyanine dye pairs and thus represents a significant step forward for the preparation of advanced fluorescent oligonucleotide probes. Furthermore, we demonstrate that the novel xanthene and cyanine labeled probes display unusual and very promising photophysical properties resulting from energy‐transfer interactions between the fluorophores controlled by nucleic acid assembly. Potential benefits of using these novel fluorescent probes within, for example, molecular diagnostics and fluorescence microscopy include: Considerable Stokes shifts (40–110 nm), quenched fluorescence of single‐stranded probes accompanied by up to 7.7‐fold light‐up effect of emission upon target DNA/RNA binding, remarkable sensitivity to single‐nucleotide mismatches, generally high fluorescence brightness values (FB up to 26), and hence low limit of target detection values (LOD down to <5 nM ).     

点击化学最新进展

点击化学(click chemistry)是由2001年诺贝尔化学奖获得者美国化学家 Sharpless首次提出。最主要的一类点击化学反应是Cu(Ⅰ)化合物催化叠氮化合物与炔基化合物反应生成1,2,3-三唑五元环化合物,它能够将两种不同物质通过五元环共价结合起来。该方法具备产量高、效率高、副反应少、反应条件温和、分离提纯简单、环境污染小等优点,因此得到了广泛的应用。目前点击化学的发展极为迅速,涉及到了各个领域,特别是在功能聚合物、表面修饰、生物大分子、DNAs,生物与化学传感器等方面取得了瞩目的成就。本文论述了点击化学反应的基本概念、特点及优势,对近几年点击化学的发展状况,以及一些最新研究成果作一简要概述,并展望了点击化学的发展前景。     

Click approach to the three‐component synthesis of novel β‐hydroxy‐1,2,3‐triazoles catalysed by new (Cu/Cu2O) nanostructure as a ligand‐free,green and regioselective nanocatalyst in water

Copper nanostructures were produced as an effective and regioselective catalyst for the synthesis of 1,2,3‐triazoles from a wide range of raw materials, such as sodium azide, epoxides and terminal alkynes, in water via a one‐pot three‐component click reaction. The new heterogeneous catalyst was prepared by a simple ball mill reduction of CuO with NaBH₄ using a ball‐to‐powder weight ratio of 50:1 under air atmosphere at room temperature. The catalyst was fully characterized using scanning electron microscopy, energy‐dispersive X‐ray analysis, Fourier transform infrared spectroscopy and X‐ray diffraction. The copper nanostructures catalysed both ring opening and triazole cyclization steps. Products were obtained in high yields and short reaction times. The reactions were performed at ambient temperature in water as a green solvent. The Cu/Cu₂O nanostructures revealed high reusability and high stability via a simple recycling process.     

Click Chemistry beyond Metal‐Catalyzed Cycloaddition

No copper needed : In recent years, a large number of metal‐free click reactions have been reported based on thiol‐ene radical additions, Diels–Alder reactions, and Michael additions. In this Minireview, special attention is given to the advantages and limitations of the different methods to evaluate whether they have the potential to surpass the overwhelming success of the copper(I)‐catalyzed azide‐alkyne cycloaddition.

     

Neoglycopolymers Based on 4‐Vinyl‐1,2,3‐Triazole Monomers Prepared by Click Chemistry

The synthesis of a new glycomonomer based on mannose, prepared via CuAAC, is reported. The resulting 1,2,3‐triazole linkage between mannose and the polymer backbone ensures the formation of highly stable glycopolymers, which will not undergo hydrolysis. The monomer 2′‐(4‐vinyl‐[1,2,3]‐triazol‐1‐yl)ethyl‐O‐α‐D ‐mannopyranoside was polymerized in the presence of a RAFT agent – 3‐benzylsulfanylthiocarbonylsulfanyl propionic acid – to yield well‐defined polymers with molecular weights up to 51 500 g mol^?1 and a PDI of 1.16. The resulting polymer was employed as a macroRAFT agent in the polymerization of NIPAAm in order to generate thermo‐responsive block copolymers, which undergo reversible micelle formation at elevated temperatures. The rapid interaction between the polymers prepared and ConA confirms the high affinity of these structures to proteins. While the linear glycopolymers already undergo a fast complexation with ConA, the reported rates have found to be exceeded by the micellar glycopolymer structure presented in the current contribution.

     

Modular Synthesis of Thermosensitive P(NIPAAm‐co‐HEMA)/β‐CD Based Hydrogels via Click Chemistry

Two kinds of representative polymers, poly(N‐isopropylacrylamide) (PNIPAAm) and β‐cyclodextrin (β‐CD) were selected and modified with azide and alkyne fucntional groups, respectively. When the solutions of these two modified polymers were mixed together, a cross‐linking reaction, a type of Huisgen's 1,3‐dipolar azide‐alkyne cycloaddition, occurred in the presence of Cu(I) catalyst. The strategy described here provides several advantages for the hydrogel formation including mild reaction conditions and controllable gelation rate. The resulted hydrogels were studied in terms of scanning electric microscopy (SEM), equilibrium swelling ratio and swelling/shrinking kinetics. The data obtained demonstrated the hydrogels had a porous structure as well as favorable thermosensitivity.

     

Preparation of Lanthanide‐Polymer Composite Material via Click Chemistry

Covalently attaching lanthanide complexes to the polymer backbone can effectively reduce the clustering of lanthanides and thus become an important strategy to fully unleash their potential. In this Communication, a metal‐free click reaction is used for the first time to link a lanthanide complex to the polymer matrix. A diene‐bearing copolymer with anthracenylmethyl methacrylate as a monomer and a dienophile‐bearing lanthanide complex with 5‐maleimido‐1,10‐phenanthroline as the second ligand are synthesized and coupled together through a Diels–Alder cycloaddition (DA). A comparative investigation demonstrates that the composite material prepared by DA click reaction shows the highest quantum yields in the same lanthanide concentration as compared to materials prepared by widely used “directly doping” and “in situ coordinating lanthanide ions with macromolecular ligand” approaches. This work suggests that the “metal‐free” DA click reaction can be a promising tool in the synthesis of high efficient lanthanide functionalized polymeric materials.

     

Iterative In Situ Click Chemistry Creates Antibody‐like Protein‐Capture Agents

Special agents for protein capture : Iterative in situ click chemistry (see scheme for the tertiary ligand screen) and the one‐bead–one‐compound method for the creation of a peptide library enable the fragment‐based assembly of selective high‐affinity protein‐capture agents. The resulting ligands are water‐soluble and stable chemically, biochemically, and thermally. They can be produced in gram quantities through copper(I)‐catalyzed cycloaddition.

     

Chiroptical Probing of Lanthanide‐Directed Self‐Assembly Formation Using btp Ligands Formed in One‐Pot Diazo‐Transfer/Deprotection Click Reaction from Chiral Amines

A series of enantiomeric 2,6‐bis(1,2,3‐triazol‐4‐yl)pyridines (btp)‐containing ligands was synthesized by a one‐pot two‐step copper‐catalyzed amine/alkyne click reaction. The Eu^III‐ and Tb^III‐directed self‐assembly formation of these ligands was studied in CH₃CN by monitoring their various photophysical properties, including their emerging circular dichroism and circularly polarized luminescence. The global analysis of the former enabled the determination of both the stoichiometry and the stability constants of the various chiral supramolecular species in solution.     

Mono‐, Di‐, or Triazidated Cyclodextrin‐Based Polyrotaxanes for Facile and Efficient Functionalization via Click Chemistry

As a feasible way for controlling the density of ligands in polyrotaxanes, azidated polyrotaxanes comprising PEG (MW = 3 000 and 20 000 g · mol⁻¹) and mono‐, di‐, or triazidated α‐cyclodextrins are prepared in a water/DMSO solution in a one‐pot synthesis. The azidated polyrotaxanes are then allowed to conjugate with propargyl‐modified mannose as a ligand via click chemistry. As proven by FTIR spectroscopy and ¹H NMR‐spectroscopy, mannose molecules are efficiently introduced into all of the azide moieties of the polyrotaxanes. The results verify the achievement of ligand‐density‐controlled polyrotaxanes. The functionalized polyrotaxanes can be utilized for a variety of biological applications.

     

A Versatile Approach for the Site‐Specific Modification of Recombinant Antibodies Using a Combination of Enzyme‐Mediated Bioconjugation and Click Chemistry

A unique two‐step modular system for site‐specific antibody modification and conjugation is reported. The first step of this approach uses enzymatic bioconjugation with the transpeptidase Sortase A for incorporation of strained cyclooctyne functional groups. The second step of this modular approach involves the azide–alkyne cycloaddition click reaction. The versatility of the two‐step approach has been exemplified by the selective incorporation of fluorescent dyes and a positron‐emitting copper‐64 radiotracer for fluorescence and positron‐emission tomography imaging of activated platelets, platelet aggregates, and thrombi, respectively. This flexible and versatile approach could be readily adapted to incorporate a large array of tailor‐made functional groups using reliable click chemistry whilst preserving the activity of the antibody or other sensitive biological macromolecules.     

Electroactive Tetrathiafulvalenyl‐1,2,3‐triazoles by Click Chemistry: Cu‐ versus Ru‐Catalyzed Azide–Alkyne Cycloaddition Isomers

Two series of 4‐ and 5‐tetrathiafulvalenyl‐1,2,3‐triazoles, as multifunctional ligands and precursors for molecular materials, have been synthesized by copper‐ or ruthenium‐based “click” chemistry. The solid‐state structures of three ligands and two Cu^II complexes were determined. Large differences in the electron‐donating properties between the 1,4‐ and 1,5‐isomers were evidenced by cyclic voltammetry. Theoretical calculations support this observation and allow the assignment of the electronic transitions observed in UV/Vis spectra of the ligands.