Sample records for alkyne cycloaddition cuaac

  1. Recent Advances in Recoverable Systems for the Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction (CuAAC).


    Mandoli, Alessandro


    The explosively-growing applications of the Cu-catalyzed Huisgen 1,3-dipolar cycloaddition reaction between organic azides and alkynes (CuAAC) have stimulated an impressive number of reports, in the last years, focusing on recoverable variants of the homogeneous or quasi-homogeneous catalysts. Recent advances in the field are reviewed, with particular emphasis on systems immobilized onto polymeric organic or inorganic supports.

  2. Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides†

    PubMed Central

    Hein, Jason E.


    Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(i) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science. PMID:20309487

  3. Kinetics of bulk photo-initiated copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) polymerizations†

    PubMed Central

    Song, Han Byul; Baranek, Austin; Bowman, Christopher N.


    Photoinitiation of polymerizations based on the copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction enables spatio-temporal control and the formation of mechanically robust, highly glassy photopolymers. Here, we investigated several critical factors influencing photo-CuAAC polymerization kinetics via systematic variation of reaction conditions such as the physicochemical nature of the monomers; the copper salt and photoinitiator types and concentrations; light intensity; exposure time and solvent content. Real time Fourier transform infrared spectroscopy (FTIR) was used to monitor the polymerization kinetics in situ. Six different di-functional azide monomers and four different tri-functional alkyne monomers containing either aliphatic, aromatic, ether and/or carbamate substituents were synthesized and polymerized. Replacing carbamate structures with ether moieties in the monomers enabled an increase in conversion from 65% to 90% under similar irradiation conditions. The carbamate results in stiffer monomers and higher viscosity mixtures indicating that chain mobility and diffusion are key factors that determine the CuAAC network formation kinetics. Photoinitiation rates were manipulated by altering various aspects of the photo-reduction step; ultimately, a loading above 3 mol% per functional group for both the copper catalyst and the photoinitiator showed little or no rate dependence on concentration while a loading below 3 mol% exhibited 1st order rate dependence. Furthermore, a photoinitiating system consisting of camphorquinone resulted in 60% conversion in the dark after only 1 minute of 75 mW cm−2 light exposure at 400–500 nm, highlighting a unique characteristic of the CuAAC photopolymerization enabled by the combination of the copper(i)’s catalytic lifetime and the nature of the step-growth polymerization. PMID:27429650

  4. Au-iClick mirrors the mechanism of copper catalyzed azide–alkyne cycloaddition (CuAAC)


    Powers, Andrew R.; Ghiviriga, Ion; Abboud, Khalil A.; ...


    This report outlines the investigation of the iClick mechanism between gold(I)-azides and gold(I)-acetylides to yield digold triazolates. Isolation of digold triazolate complexes offer compelling support for the role of two copper(I) ions in CuAAC. In addition, a kinetic investigation reveals the reaction is first order in both Au(I)-N3 and Au(I)-C≡C-R equivalent to C-R, thus second order overall. A Hammett plot with a ρ = 1.02(5) signifies electron-withdrawing groups accelerate the cycloaddition by facilitating the coordination of the second gold ion in a π-complex. Rate inhibition by the addition of free triphenylphosphine to the reaction indicates that ligand dissociation is amore » prerequisite for the reaction. The mechanistic conclusions mirror those proposed for the CuAAC reaction.« less

  5. Au-iClick mirrors the mechanism of copper catalyzed azide–alkyne cycloaddition (CuAAC)

    SciTech Connect

    Powers, Andrew R.; Ghiviriga, Ion; Abboud, Khalil A.; Veige, Adam S.


    This report outlines the investigation of the iClick mechanism between gold(I)-azides and gold(I)-acetylides to yield digold triazolates. Isolation of digold triazolate complexes offer compelling support for the role of two copper(I) ions in CuAAC. In addition, a kinetic investigation reveals the reaction is first order in both Au(I)-N3 and Au(I)-C≡C-R equivalent to C-R, thus second order overall. A Hammett plot with a ρ = 1.02(5) signifies electron-withdrawing groups accelerate the cycloaddition by facilitating the coordination of the second gold ion in a π-complex. Rate inhibition by the addition of free triphenylphosphine to the reaction indicates that ligand dissociation is a prerequisite for the reaction. The mechanistic conclusions mirror those proposed for the CuAAC reaction.

  6. Towards understanding the kinetic behaviour and limitations in photo-induced copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reactions

    PubMed Central

    El-Zaatari, Bassil M.; Shete, Abhishek U.; Adzima, Brian J.; Kloxin, Christopher J.


    The kinetic behaviour of the photo-induced copper(I) catalyzed azide—alkyne cycloaddition (CuAAC) reaction was studied in detail using real-time Fourier Transform Infrared Spectroscopy (FTIR) on both a solvent-based monofunctional and a neat polymer network forming system. The results in the solvent-based system showed near first-order kinetics on copper and photoinitiator concentrations up to a threshold value in which the kinetics switch to zeroth-order. This kinetic shift shows that the photo-CuAAC reaction is not suseptible from side reactions such as copper disproportionation, copper(I) reduction, and radical termination at the early stages of the reaction. The overall reaction rate and conversion is highly dependent on the initial concentrations of photoinitiator and copper(II), as well as their relative ratios. The conversion was decreased when an excess of photoinitiator was utilized compared to its threshold value. Interestingly, the reaction showed an induction period at relatively low intensities. The induction period is decreased by increasing light intensity, and photoinitiator concentration. The reaction trends and limitations were further observed in a solventless polymer network forming system, exhibiting a similar copper and photoinitiator threshold behaviour. PMID:27711587

  7. Synthesis of 5-halogenated 1,2,3-triazoles under stoichiometric Cu(I)-mediated azide-alkyne cycloaddition (CuAAC or 'Click Chemistry').


    Goyard, David; Praly, Jean-Pierre; Vidal, Sébastien


    Glucosylated heterocycles have been identified as potent inhibitors of glycogen phosphorylase (GP), a biomolecular target for the treatment of hyperglycemia and therefore type 2 diabetes. Several glucosylated triazoles have been evaluated as GP inhibitors and additional structures are being considered in the present study with the introduction of a substituent at the 5-position of the triazole ring. The 1,3-dipolar cycloaddition of azide and alkyne using stoichiometric amounts of Cu(I) halides favored the formation of the 5-halogenated 1,2,3-triazoles. The influence of the copper halide introduced (CuI, CuBr, or CuCl) provided different results and more specifically for the CuCl system which afforded a dimeric 5,5'-bistriazole in good yield (56%) as evidenced by crystallographic data.

  8. Structural Determinants of Alkyne Reactivity in Copper-Catalyzed Azide-Alkyne Cycloadditions.


    Zhang, Xiaoguang; Liu, Peiye; Zhu, Lei


    This work represents our initial effort in identifying azide/alkyne pairs for optimal reactivity in copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. In previous works, we have identified chelating azides, in particular 2-picolyl azide, as "privileged" azide substrates with high CuAAC reactivity. In the current work, two types of alkynes are shown to undergo rapid CuAAC reactions under both copper(II)- (via an induction period) and copper(I)-catalyzed conditions. The first type of the alkynes bears relatively acidic ethynyl C-H bonds, while the second type contains an N-(triazolylmethyl)propargylic moiety that produces a self-accelerating effect. The rankings of reactivity under both copper(II)- and copper(I)-catalyzed conditions are provided. The observations on how other reaction parameters such as accelerating ligand, reducing agent, or identity of azide alter the relative reactivity of alkynes are described and, to the best of our ability, explained.

  9. On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition.


    Zhu, Lei; Brassard, Christopher J; Zhang, Xiaoguang; Guha, P M; Clark, Ronald J


    The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4-disubstituted-1,2,3-triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring-formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pKa values and an inclination to engage in π-backbonding with copper(I), azides with ancillary copper-binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne-involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.

  10. Copper-catalyzed azide alkyne cycloaddition polymer networks

    NASA Astrophysics Data System (ADS)

    Alzahrani, Abeer Ahmed

    The click reaction concept, introduced in 2001, has since spurred the rapid development and reexamination of efficient, high yield reactions which proceed rapidly under mild conditions. Prior to the discovery of facile copper catalysis in 2002, the thermally activated azide-alkyne or Huisgen cycloaddition reaction was largely ignored following its discovery in large part due to its slow kinetics, requirement for elevated temperature and limited selectivity. Now, arguably, the most prolific and capable of the click reactions, the copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction is extremely efficient and affords exquisite control of the reaction. The orthogonally and chemoselectivity of this reaction enable its wide utility across varied scientific fields. Despite numerous inherent advantages and widespread use for small molecule synthesis and solution-based polymer chemistry, it has only recently and rarely been utilized to form polymer networks. This work focuses on the synthesis, mechanisms, and unique attributes of the CuAAC reaction for the fabrication of functional polymer networks. The photo-reduction of a series of copper(II)/amine complexes via ligand metal charge transfer was examined to determine their relative efficiency and selectivity in catalyzing the CuAAC reaction. The aliphatic amine ligands were used as an electron transfer species to reduce Cu(II) upon irradiation with 365 nm light while also functioning as an accelerating agent and as protecting ligands for the Cu(I) that was formed. Among the aliphatic amines studied, tertiary amines such as triethylamine (TEA), tetramethyldiamine (TMDA), N,N,N',N",N"-pentamethyldiethylenetriamine (PMDTA), and hexamethylenetetramine (HMTETA) were found to be the most effective. The reaction kinetics were accelerated by increasing the PMDETA : Cu(II) ratio with a ratio of ligand to Cu(II) of 4:1 yielding the maximum conversion in the shortest time. The sequential and orthogonal nature of the photo

  11. Diversity-Oriented Peptide Stapling: A Third Generation Copper-Catalysed Azide-Alkyne Cycloaddition Stapling and Functionalisation Strategy.


    Tran, Phuong Thu; Larsen, Christian Ørnbøl; Røndbjerg, Tobias; De Foresta, Martina; Kunze, Micha B A; Marek, Ales; Løper, Jacob Hartvig; Boyhus, Lotte-Emilie; Knuhtsen, Astrid; Lindorff-Larsen, Kresten; Pedersen, Daniel Sejer


    The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide-alkyne cycloaddition (CuAAC) has emerged as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i+7)- and (i, i+9)-stapled peptides with a single free alkyne positioned on the staple, which can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access to radiolabelled stapled peptides by catalytic tritiation of the alkyne positioned on the staple.

  12. Electrochemically protected copper(I)-catalyzed azide-alkyne cycloaddition.


    Hong, Vu; Udit, Andrew K; Evans, Richard A; Finn, M G


    The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has found broad application in myriad fields. For the most demanding applications that require high yields at low substrate concentrations, highly active but air-sensitive copper complexes must be used. We describe here the use of an electrochemical potential to maintain catalysts in the active Cu(I) oxidation state in the presence of air. This simple procedure efficiently achieves excellent yields of CuAAC products from both small-molecule and protein substrates without the use of potentially damaging chemical reducing agents. A new water-soluble carboxylated version of the popular tris(benzyltriazolylmethyl)amine (TBTA) ligand is also described. Cyclic voltammetry revealed reversible or quasi-reversible electrochemical redox behavior of copper complexes of the TBTA derivative (2; E(1/2)=60 mV vs. Ag/AgCl), sulfonated bathophenanthroline (3; E(1/2)=-60 mV), and sulfonated tris(benzimidazoylmethyl)amine (4; E(1/2) approximately -70 mV), and showed catalytic turnover to be rapid relative to the voltammetry time scale. Under the influence of a -200 mV potential that was established by using a reticulated vitreous carbon working electrode, CuSO4 and 3 formed a superior catalyst. Electrochemically protected bioconjugations in air were performed by using bacteriophage Qbeta that was derivatized with azide moieties at surface lysine residues. Complete derivatization of more than 600 reactive sites per particle was demonstrated within 12 h of electrolysis with substoichiometric quantities of Cu3.

  13. Advancements in the mechanistic understanding of the copper-catalyzed azide-alkyne cycloaddition.


    Berg, Regina; Straub, Bernd F


    The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC's catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates.

  14. Highly-Efficient and Versatile Fluorous-Tagged Cu(I)-Catalyzed Azide-Alkyne Cycloaddition Ligand for Preparing Bioconjugates

    PubMed Central

    Sun, Lingyi; Gai, Yongkang; Anderson, Carolyn J.


    A novel ligand (FBTTBE) for Cu(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) has been developed, which demonstrates not only superior catalytic efficiency but also the ease of removing toxic copper species. FBTTBE has also been successfully applied in the synthesis of radiometal-labeled peptide and antibody without observable transchelation with the non-radioactive Cu(I) catalyst. PMID:26426419

  15. Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

    PubMed Central


    Summary The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC’s catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates. PMID:24367437

  16. A highly active and magnetically recoverable tris(triazolyl)-Cu(I) catalyst for alkyne-azide cycloaddition reactions.


    Wang, Dong; Etienne, Laetitia; Echeverria, María; Moya, Sergio; Astruc, Didier


    Nanoparticle-supported tris(triazolyl)-CuBr, with a diameter of approximately 25 nm measured by TEM spectroscopy, has been easily prepared, and its catalytic activity was evaluated in the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In initial experiments, 0.5 mol % loading successfully promoted the CuAAC reaction between benzyl azide and phenylacetylene, in water at room temperature (25 °C). During this process, the iron oxide nanoparticle-supported tris(triazolyl)-CuBr displayed good monodispersity, excellent recoverability, and outstanding reusability. Indeed, it was simply collected and separated from the reaction medium by using an external magnet, then used for another five catalytic cycles without significant loss of catalytic activity. Inductively coupled plasma (ICP) analysis for the first cycle revealed that the amount of copper leached from the catalyst into the reaction medium is negligible (1.5 ppm). The substrate scope has been examined, and it was found that the procedure can be successfully extended to various organic azides and alkynes and can also be applied to the one-pot synthesis of triazoles, through a cascade reaction involving benzyl bromides, alkynes, and sodium azide. In addition, the catalyst was shown to be an efficient CuAAC catalyst for the synthesis of allyl- and TEG-ended (TEG=triethylene glycol) 27-branch dendrimers.

  17. Photoinduced Vesicle Formation via the Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction.


    Konetski, Danielle; Gong, Tao; Bowman, Christopher N


    Synthetic vesicles have a wide range of applications from drug and cosmetic delivery to artificial cell and membrane studies, making simple and controlled formation of vesicles a large focus of the field today. Here, we report the use of the photoinitiated copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using visible light to introduce spatiotemporal control into the formation of vesicles. Upon the establishment of the spatiotemporal control over vesicle formation, it became possible to adjust initiation conditions to modulate vesicle sizes resulting in the formation of controllably small or large vesicles based on light intensity or giant vesicles when the formation was initiated in flow-free conditions. Additionally, this photoinitiated method enables vesicle formation at a density 400-fold higher than initiation using sodium ascorbate as the catalyst. Together, these advances enable the formation of high-density, controlled size vesicles using low-energy wavelengths while producing enhanced control over the formation characteristics of the vesicle.

  18. Accelerating Strain-Promoted Azide-Alkyne Cycloaddition Using Micellar Catalysis.


    Anderton, Grant I; Bangerter, Alyssa S; Davis, Tyson C; Feng, Zhiyuan; Furtak, Aric J; Larsen, Jared O; Scroggin, Triniti L; Heemstra, Jennifer M


    Bioorthogonal conjugation reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have become increasingly popular in recent years, as they enable site-specific labeling of complex biomolecules. However, despite a number of improvements to cyclooctyne design, reaction rates for SPAAC remain significantly lower than those of the related copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Here we explore micellar catalysis as a means to increase reaction rate between a cyclooctyne and hydrophobic azide. We find that anionic and cationic surfactants provide the most efficient catalysis, with rate enhancements of up to 179-fold for reaction of benzyl azide with DIBAC cyclooctyne. Additionally, we find that the presence of surfactant can provide up to 51-fold selectivity for reaction with a hydrophobic over hydrophilic azide. A more modest, but still substantial, 11-fold rate enhancement is observed for micellar catalysis of the reaction between benzyl azide and a DIBAC-functionalized DNA sequence, demonstrating that micellar catalysis can be successfully applied to hydrophilic biomolecules. Together, these results demonstrate that micellar catalysis can provide higher conjugation yields in reduced time when using hydrophobic SPAAC reagents.

  19. Apparent copper(II)-accelerated azide-alkyne cycloaddition.


    Brotherton, Wendy S; Michaels, Heather A; Simmons, J Tyler; Clark, Ronald J; Dalal, Naresh S; Zhu, Lei


    Cu(II) salts accelerate azide-alkyne cycloaddition reactions in alcoholic solvents without reductants such as sodium ascorbate. Spectroscopic observations suggest that Cu(II) undergoes reduction to catalytic Cu(I) species via either alcohol oxidation or alkyne homocoupling, or both, during an induction period. The reactions involving 2-picolylazide are likely facilitated by its chelation to Cu(II). The highly exothermic reaction between 2-picolylazide and propargyl alcohol completes within 1-2 min in the presence of as low as 1 mol % Cu(OAc)(2).

  20. Cyclic Multiblock Copolymers via Combination of Iterative Cu(0)-Mediated Radical Polymerization and Cu(I)-Catalyzed Azide-Alkyne Cycloaddition Reaction.


    Xiao, Lifen; Zhu, Wen; Chen, Jiqiang; Zhang, Ke


    Cyclic multiblock polymers with high-order blocks are synthesized via the combination of single-electron transfer living radical polymerization (SET-LRP) and copper-catalyzed azide-alkyne cycloaddition (CuAAC). The linear α,ω-telechelic multiblock copolymer is prepared via SET-LRP by sequential addition of different monomers. The SET-LRP approach allows well control of the block length and sequence as A-B-C-D-E, etc. The CuAAC is then performed to intramolecularly couple the azide and alkyne end groups of the linear copolymer and produce the corresponding cyclic copolymer. The block sequence and the cyclic topology of the resultant cyclic copolymer are confirmed by the characterization of (1) H nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

  1. Meeting the Challenge of Intermolecular Gold(I)-Catalyzed Cycloadditions of Alkynes and Allenes

    PubMed Central

    Muratore, Michael E; Homs, Anna; Obradors, Carla; Echavarren, Antonio M


    The development of gold(I)-catalyzed intermolecular carbo- and hetero-cycloadditions of alkynes and allenes has been more challenging than their intramolecular counterparts. Here we review, with a mechanistic perspective, the most fundamental intermolecular cycloadditions of alkynes and allenes with alkenes. PMID:25048645

  2. Fluorescent labelling of in situ hybridisation probes through the copper-catalysed azide-alkyne cycloaddition reaction.


    Hesse, Susann; Manetto, Antonio; Cassinelli, Valentina; Fuchs, Jörg; Ma, Lu; Raddaoui, Nada; Houben, Andreas


    In situ hybridisation is a powerful tool to investigate the genome and chromosome architecture. Nick translation (NT) is widely used to label DNA probes for fluorescence in situ hybridisation (FISH). However, NT is limited to the use of long double-stranded DNA and does not allow the labelling of single-stranded and short DNA, e.g. oligonucleotides. An alternative technique is the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC), at which azide and alkyne functional groups react in a multistep process catalysed by copper(I) ions to give 1,4-distributed 1,2,3-triazoles at a high yield (also called 'click reaction'). We successfully applied this technique to label short single-stranded DNA probes as well as long PCR-derived double-stranded probes and tested them by FISH on plant chromosomes and nuclei. The hybridisation efficiency of differently labelled probes was compared to those obtained by conventional labelling techniques. We show that copper(I)-catalysed azide-alkyne cycloaddition-labelled probes are reliable tools to detect different types of repetitive sequences on chromosomes opening new promising routes for the detection of single copy gene. Moreover, a combination of FISH using such probes with other techniques, e.g. immunohistochemistry (IHC) and cell proliferation assays using 5-ethynyl-deoxyuridine, is herein shown to be easily feasible.

  3. Preventing Alkyne-Alkyne (i.e., Glaser) Coupling Associated with the ATRP Synthesis of Alkyne-Functional Polymers/Macromonomers and for Alkynes under Click (i.e., CuAAC) Reaction Conditions.


    Leophairatana, Porakrit; Samanta, Sanjoy; De Silva, Chathuranga C; Koberstein, Jeffrey T


    Alkyne-functional polymers synthesized by ATRP exhibit bimodal molecular weight distributions indicating the occurrence of some undesirable side reaction. By modeling the molecular weight distributions obtained under various reaction conditions, we show that the side reaction is alkyne-alkyne (i.e., Glaser) coupling. Glaser coupling accounts for as much as 20% of the polymer produced, significantly compromising the polymer functionality and undermining the success of subsequent click reactions in which they are used. Glaser coupling does not occur during ATRP but during postpolymerization workup upon first exposure to air. Two strategies are reported that effectively eliminate these coupling reactions without the need for a protecting group for the alkyne-functional initiator: (1) maintaining low temperature post-ATRP upon exposure to air followed by immediate removal of copper catalyst; (2) adding excess reducing agents post-ATRP which prevent the oxidation of Cu(I) catalyst required by the Glaser coupling mechanism. Post-ATRP Glaser coupling was also influenced by the ATRP synthesis ligand used. The order of ligand activity for catalyzing Glaser coupling was: linear bidentate > tridentate > tetradentate. We find that Glaser coupling is not problematic in ARGET-ATRP of alkyne-terminated polymers because a reducing agent is present during polymerization, however the molecular weight distribution is broadened compared to ATRP due to the presence of oxygen. Glaser coupling can also occur for alkynes held under CuAAC reaction conditions but again can be eliminated by adding appropriate reducing agents.

  4. Silver-catalysed azide-alkyne cycloaddition (AgAAC): assessing the mechanism by density functional theory calculations

    NASA Astrophysics Data System (ADS)

    Banerji, Biswadip; Chandrasekhar, K.; Killi, Sunil Kumar; Pramanik, Sumit Kumar; Uttam, Pal; Sen, Sudeshna; Maiti, Nakul Chandra


    `Click reactions' are the copper catalysed dipolar cycloaddition reaction of azides and alkynes to incorporate nitrogens into a cyclic hydrocarbon scaffold forming a triazole ring. Owing to its efficiency and versatility, this reaction and the products, triazole-containing heterocycles, have immense importance in medicinal chemistry. Copper is the only known catalyst to carry out this reaction, the mechanism of which remains unclear. We report here that the `click reactions' can also be catalysed by silver halides in non-aqueous medium. It constitutes an alternative to the well-known CuAAC click reaction. The yield of the reaction varies on the type of counter ion present in the silver salt. This reaction exhibits significant features, such as high regioselectivity, mild reaction conditions, easy availability of substrates and reasonably good yields. In this communication, the findings of a new catalyst along with the effect of solvent and counter ions will help to decipher the still obscure mechanism of this important reaction.

  5. Silver-catalysed azide-alkyne cycloaddition (AgAAC): assessing the mechanism by density functional theory calculations.


    Banerji, Biswadip; Chandrasekhar, K; Killi, Sunil Kumar; Pramanik, Sumit Kumar; Uttam, Pal; Sen, Sudeshna; Maiti, Nakul Chandra


    'Click reactions' are the copper catalysed dipolar cycloaddition reaction of azides and alkynes to incorporate nitrogens into a cyclic hydrocarbon scaffold forming a triazole ring. Owing to its efficiency and versatility, this reaction and the products, triazole-containing heterocycles, have immense importance in medicinal chemistry. Copper is the only known catalyst to carry out this reaction, the mechanism of which remains unclear. We report here that the 'click reactions' can also be catalysed by silver halides in non-aqueous medium. It constitutes an alternative to the well-known CuAAC click reaction. The yield of the reaction varies on the type of counter ion present in the silver salt. This reaction exhibits significant features, such as high regioselectivity, mild reaction conditions, easy availability of substrates and reasonably good yields. In this communication, the findings of a new catalyst along with the effect of solvent and counter ions will help to decipher the still obscure mechanism of this important reaction.

  6. Thermomechanical Formation–Structure–Property Relationships in Photopolymerized Copper-Catalyzed Azide–Alkyne (CuAAC) Networks

    PubMed Central

    Baranek, Austin; Song, Han Byul; McBride, Mathew; Finnegan, Patricia; Bowman, Christopher N.


    Bulk photopolymerization of a library of synthesized multifunctional azides and alkynes was carried out toward developing structure–property relationships for CuAAC-based polymer networks. Multifunctional azides and alkynes were formulated with a copper catalyst and a photoinitiator, cured, and analyzed for their mechanical properties. Material properties such as the glass transition temperatures (Tg) show a strong dependence on monomer structure with Tg values ranging from 41 to 90 °C for the series of CuAAC monomers synthesized in this study. Compared to the triazoles, analogous thioether-based polymer networks exhibit a 45–49 °C lower Tg whereas analogous monomers composed of ethers in place of carbamates exhibit a 40 °C lower Tg. Here, the formation of the triazole moiety during the polymerization represents a critical component in dictating the material properties of the ultimate polymer network where material properties such as the rubbery modulus, cross-link density, and Tg all exhibit strong dependence on polymerization conversion, monomer composition, and structure postgelation. PMID:27867223

  7. Squish and CuAAC: Additive-Free Covalent Monolayers of Discrete Molecules in Seconds

    PubMed Central

    Pellow, Matthew A.


    A terminal alkyne is immobilized rapidly into a full monolayer by squishing a small volume of a solution of the alkyne between an azide-modified surface and a copper plate. The monolayer is covalently attached to the surface through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction, and the coverages of the immobilized electroactive alkyne species are quantified by cyclic voltammetry. A reaction time of less than twenty seconds is possible with no other reagents required. The procedure is effective in aerobic conditions using either an aqueous or aprotic organic solution of the alkyne (1–100 mM). PMID:23551032

  8. Copper and silver complexes of tris(triazole)amine and tris(benzimidazole)amine ligands: evidence that catalysis of an azide-alkyne cycloaddition ("click") reaction by a silver tris(triazole)amine complex arises from copper impurities.


    Connell, Timothy U; Schieber, Christine; Silvestri, Ilaria Proietti; White, Jonathan M; Williams, Spencer J; Donnelly, Paul S


    The synthesis and characterization of a silver complex of the tripodal triazole ligand, tris(benzyltriazolylmethyl)amine (TBTA, L(1)), that is used as promoter to enhance Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions is reported. X-ray analysis of the silver(I) complex with L(1) reveals a dinuclear cation, [Ag2(L(1))2](2+), that is essentially isostructural to the copper(I) analogue. While the [Ag2(L(1))2](BF4)2 complex provides catalysis for the azide-alkyne cycloaddition process, evidence is presented that this arises from trace copper contamination. The synthesis of silver(I), copper(II), and copper(I) complexes of a second tripodal ligand, tris(2-benzimidazolymethyl)amine (L(2)), which is used to enhance the rate of CuAAC reactions, is also reported. X-ray crystallography of the Cu(I) complex [Cu(I)3(L(2))2(CH3CN)2](BF4)3 offers structural insight into previous mechanistic speculation about the role of this ligand in the CuAAC reaction.

  9. Copper on Chitosan: A Recyclable Heterogeneous Catalyst for Azide-alkyne Cycloaddition Reactions in Water

    EPA Science Inventory

    Copper sulfate is immobilized over chitosan by simply stirring an aqueous suspension of chitosan in water with copper sulfate; the ensuing catalyst has been utilized for the azide-alkyne cycloaddition in aqueous media and it can be recycled and reused many time without loosing it...

  10. CuAAC: An Efficient Click Chemistry Reaction on Solid Phase.


    Castro, Vida; Rodríguez, Hortensia; Albericio, Fernando


    Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry.

  11. Silver-catalysed azide–alkyne cycloaddition (AgAAC): assessing the mechanism by density functional theory calculations

    PubMed Central

    Chandrasekhar, K.; Killi, Sunil Kumar; Pramanik, Sumit Kumar; Uttam, Pal; Sen, Sudeshna; Maiti, Nakul Chandra


    ‘Click reactions’ are the copper catalysed dipolar cycloaddition reaction of azides and alkynes to incorporate nitrogens into a cyclic hydrocarbon scaffold forming a triazole ring. Owing to its efficiency and versatility, this reaction and the products, triazole-containing heterocycles, have immense importance in medicinal chemistry. Copper is the only known catalyst to carry out this reaction, the mechanism of which remains unclear. We report here that the ‘click reactions’ can also be catalysed by silver halides in non-aqueous medium. It constitutes an alternative to the well-known CuAAC click reaction. The yield of the reaction varies on the type of counter ion present in the silver salt. This reaction exhibits significant features, such as high regioselectivity, mild reaction conditions, easy availability of substrates and reasonably good yields. In this communication, the findings of a new catalyst along with the effect of solvent and counter ions will help to decipher the still obscure mechanism of this important reaction. PMID:27703683

  12. Development of protein-cage-based delivery nanoplatforms by polyvalently displaying β-cyclodextrins on the surface of ferritins through copper(I)-catalyzed azide/alkyne cycloaddition.


    Kwon, Chanho; Kang, Young Ji; Jeon, Sangbin; Jung, Seunho; Hong, Sung You; Kang, Sebyung


    Protein cages are spherical hollow macromolecules that are attractive platforms for the construction of nanoscale cargo delivery vehicles. Human heavy-chain ferritin (HHFn) is modified genetically to control the number and position of functional groups per cage. 24 β-CDs are conjugated precisely to the modified HHFn in specific locations through thiol-maleimide Michael-type addition followed by copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC). The resulting human ferritins displaying β-CDs (β-CD-C90 HHFn) can form inclusion complexes with FITC-AD, which can slowly release the guest molecule reversibly in a buffer solution via non-covalent β-CD/AD interactions. β-CD-C90 HHFn can potentially be used as delivery vehicles for insoluble drugs.

  13. Solvent-free copper-catalyzed azide-alkyne cycloaddition under mechanochemical activation.


    Rinaldi, Laura; Martina, Katia; Baricco, Francesca; Rotolo, Laura; Cravotto, Giancarlo


    The ball-mill-based mechanochemical activation of metallic copper powder facilitates solvent-free alkyne-azide click reactions (CuAAC). All parameters that affect reaction rate (i.e., milling time, revolutions/min, size and milling ball number) have been optimized. This new, efficient, facile and eco-friendly procedure has been tested on a number of different substrates and in all cases afforded the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in high yields and purities. The final compounds were isolated in almost quantitative overall yields after simple filtration, making this procedure facile and rapid. The optimized CuAAC protocol was efficiently applied even with bulky functionalized β-cyclodextrins (β-CD) and scaled-up to 10 g of isolated product.

  14. Pressure-accelerated azide-alkyne cycloaddition: micro capillary versus autoclave reactor performance.


    Borukhova, Svetlana; Seeger, Andreas D; Noël, Timothy; Wang, Qi; Busch, Markus; Hessel, Volker


    Pressure effects on regioselectivity and yield of cycloaddition reactions have been shown to exist. Nevertheless, high pressure synthetic applications with subsequent benefits in the production of natural products are limited by the general availability of the equipment. In addition, the virtues and limitations of microflow equipment under standard conditions are well established. Herein, we apply novel-process-window (NPWs) principles, such as intensification of intrinsic kinetics of a reaction using high temperature, pressure, and concentration, on azide-alkyne cycloaddition towards synthesis of Rufinamide precursor. We applied three main activation methods (i.e., uncatalyzed batch, uncatalyzed flow, and catalyzed flow) on uncatalyzed and catalyzed azide-alkyne cycloaddition. We compare the performance of two reactors, a specialized autoclave batch reactor for high-pressure operation up to 1800 bar and a capillary flow reactor (up to 400 bar). A differentiated and comprehensive picture is given for the two reactors and the three methods of activation. Reaction speedup and consequent increases in space-time yields is achieved, while the process window for favorable operation to selectively produce Rufinamide precursor in good yields is widened. The best conditions thus determined are applied to several azide-alkyne cycloadditions to widen the scope of the presented methodology.

  15. Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines.


    Saunthwal, Rakesh K; Patel, Monika; Verma, Akhilesh K


    A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)methanol, and 1,4-bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies.

  16. The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights

    PubMed Central

    Moldoveanu, Costel; Zbancioc, Gheorghita; Mantu, Dorina; Maftei, Dan; Mangalagiu, Ionel


    New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-yl)anilines and to pyrrolo[1,2-a]quinoxalin-4(5H)-ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate. PMID:27224656

  17. Investigation of the Pyridinium Ylide--Alkyne Cycloaddition as a Fluorogenic Coupling Reaction.


    Bonte, Simon; Ghinea, Ioana Otilia; Dinica, Rodica; Baussanne, Isabelle; Demeunynck, Martine


    The cycloaddition of pyridinium ylides with alkynes was investigated under mild conditions. A series of 13 pyridinium salts was prepared by alkylation of 4-substituted pyridines. Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures, solvents, added bases) was studied, and 11 indolizines, with three points of structural variation, were, thus, isolated and characterized. The highest yields were obtained when electron-withdrawing groups were present on both the pyridinium ylide, generated in situ from the corresponding pyridinium salt, and the alkyne (X, Z = ester, amide, CN, carbonyl, etc.). Electron-withdrawing substituents, lowering the acid dissociation constant (pKa) of the pyridinium salts, allow the cycloaddition to proceed at pH 7.5 in aqueous buffers at room temperature.

  18. Novel colorimetric molecular switch based on copper(I)-catalyzed azide-alkyne cycloaddition reaction and its application for flumioxazin detection.


    Xie, Lidan; Zheng, Hanye; Ye, Wenmei; Qiu, Suyan; Lin, Zhenyu; Guo, Longhua; Qiu, Bin; Chen, Guonan


    A novel colorimetric switch based on the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been developed. G-quadruplex-hemin DNAzyme catalyzes the oxidation of 2,2'-azinobis(3-ethylbenzothiozoline)-6-sulfonic acid (ABTS) to form ABTS˙(+), the UV absorbance of the solution increased greatly and the color of the solution changed to dark green. However, in the presence of an azide complex, the absorbance signal decreased and the solution became light green since the catalytic ability of the hemin was inhibited by the azide groups. However, once propargylamine has been added into the above reaction system, which would react with azide groups through the CuAAC reaction, the solution becomes dark green again and the absorption intensity of the system is also increased. The proposed switch allows a good reversibility and can be identified clearly by the naked eye. In addition, the method has been applied to detect some pesticides, which have alkynyl groups (flumioxazin), with high sensitivity and selectivity, where the UV absorbance has a direct linear relationship with the logarithm of flumioxazin concentrations in the range of 0.14-14 nM, and the limit of detection was 0.056 nM (S/N = 3), which can meet the requirement of the maximum residue limits (MRLs) of United States of America (56 nM).

  19. 1,3-Dipolar cycloaddition of organic azides to alkynes by a dicopper-substituted silicotungstate.


    Kamata, Keigo; Nakagawa, Yoshinao; Yamaguchi, Kazuya; Mizuno, Noritaka


    The dicopper-substituted gamma-Keggin silicotungstate TBA 4[gamma-H2SiW10O36Cu2(mu-1,1-N3)2] (I, TBA = tetra- n-butylammonium) could act as an efficient precatalyst for the regioselective 1,3-dipolar cycloaddition of organic azides to alkynes. Various combinations of substrates (four azides and eight alkynes) were efficiently converted to the corresponding 1,2,3-triazole derivatives in excellent yields without any additives. The present system was applicable to a larger-scale cycloaddition of benzyl azide to phenylacetylene under solvent-free conditions (100 mmol scale) in which 21.5 g of the analytically pure corresponding triazole could be isolated. In this case, the turnover frequency and the turnover number reached up to 14,800 h(-1) and 91,500, respectively, and these values were the highest among those reported for the copper-mediated systems so far. In addition, I could be applied to the one-pot synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole from benzyl chloride, sodium azide, and phenylacetylene. The catalyst effect, kinetic, mechanistic, and computational studies show that the reduced dicopper core plays an important role in the present 1,3-dipolar cycloaddition.

  20. Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications.


    Johansson, Johan R; Beke-Somfai, Tamás; Said Stålsmeden, Anna; Kann, Nina


    The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years.

  1. CuAAC click reactions for the design of multifunctional luminescent ruthenium complexes.


    Zabarska, Natalia; Stumper, Anne; Rau, Sven


    CuAAC (Cu(i) catalyzed azide-alkyne cycloaddition) click chemistry has emerged as a versatile tool in the development of photoactive ruthenium complexes with multilateral potential applicability. In this contribution we discuss possible synthetic approaches towards CuAAC reactions with ruthenium(ii) polypyridine complexes and their differences with respect to possible applications. We focus on two main application possibilities of the click-coupled ruthenium assemblies. New results within the development of ruthenium based photosensitizers for the field of renewable energy supply, i.e. DSSCs (dye-sensitized solar cells) and artificial photocatalysis for the production of hydrogen, or for anticancer photodynamic therapeutic applications are reviewed.

  2. 1,3-Dipolar cycloadditions of ruthenium(II) azido complexes with alkynes and nitriles.


    Miguel-Fernández, S; Martínez de Salinas, S; Díez, J; Gamasa, M P; Lastra, E


    The diazido complex [Na][Ru(N3)2{κ(3)(N,N,N)-Tpms}(PPh3)] (1) (Tpms = tris(pyrazolyl)methanesulfonate) has been synthesized, and its reactivity toward dipolarophiles has been investigated. Thus, the reaction of 1 with alkynes leads to complexes with one or two triazolate ligands depending on the alkyne and the reaction conditions. Complex 1 also reacts with nitriles. Thus, the reaction with RCN (R = Me, Ph) leads to the substitution products [Ru(N3)(NCR){κ(3)(N,N,N)-Tpms}(PPh3)]. However, when fumaronitrile is used, a complex containing a new κ(2)(N(1),N(3))-5-(1,2,3-triazol-4-yl)-1,2,3,4-tetrazolate ligand is obtained as the result of two consecutive cycloaddition reactions. The mechanism for this unusual reaction has been unambiguously established through the isolation of the intermediate complex resulting from a first cycloaddition between a coordinated azide and the C═C double bond.

  3. Cleavable Biotin Probes for Labeling of Biomolecules via the Azide – Alkyne Cycloaddition

    PubMed Central

    Szychowski, Janek; Mahdavi, Alborz; Hodas, Jennifer J. L.; Bagert, John D.; Ngo, John T.; Landgraf, Peter; Dieterich, Daniela C.; Schuman, Erin M.; Tirrell, David A.


    The azide-alkyne cycloaddition provides a powerful tool for bio-orthogonal labeling of proteins, nucleic acids, glycans, and lipids. In some labeling experiments, e.g., in proteomic studies involving affinity purification and mass spectrometry, it is convenient to use cleavable probes that allow release of labeled biomolecules under mild conditions. Five cleavable biotin probes are described for use in labeling of proteins and other biomolecules via the azide – alkyne cycloaddition. Subsequent to conjugation with metabolically labeled protein, these probes are subject to cleavage with either 50 mM Na2S2O4, 2% HOCH2CH2SH, 10% HCO2H, 95% CF3CO2H, or irradiation at 365 nm. Most strikingly, a probe constructed around a dialkoxydiphenylsilane (DADPS) linker was found to be cleaved efficiently when treated with 10% HCO2H for 0.5 h. A model GFP protein was used to demonstrate that the DADPS probe undergoes highly selective conjugation and leaves a small (143 Da) mass tag on the labeled protein after cleavage. These features make the DADPS probe especially attractive for use in biomolecular labeling and proteomic studies. PMID:21141861

  4. Interfacial strain-promoted alkyne-azide cycloaddition (I-SPAAC) for the synthesis of nanomaterial hybrids.


    Gobbo, Pierangelo; Novoa, Samantha; Biesinger, Mark C; Workentin, Mark S


    An interfacial strain promoted azide-alkyne cycloaddition (I-SPACC) is introduced as a method to prepare robust nanomaterial hybrids. This is demonstrated with a reaction between a novel dibenzocyclooctyne-modified single walled carbon nanotubes (DBCO-SWCNT) and a versatile water-soluble azide modified gold nanoparticle (N3-EG4-AuNP).

  5. Site-specific conjugation of ScFvs antibodies to nanoparticles by bioorthogonal strain-promoted alkyne-nitrone cycloaddition.


    Colombo, Miriam; Sommaruga, Silvia; Mazzucchelli, Serena; Polito, Laura; Verderio, Paolo; Galeffi, Patrizia; Corsi, Fabio; Tortora, Paolo; Prosperi, Davide


    Particularly suitable: An N-terminal serine mutant of anti-HER2 scFv antibody was conjugated to polymer-coated magnetofluorescent nanoparticles by strain-promoted alkyne-nitrone cycloaddition. The resulting nanoparticles (see scheme) proved effective in targeting and labeling HER2-positive breast cancer cells.

  6. Covalent attachment of diphosphine ligands to glassy carbon electrodes via Cu-catalyzed alkyne-azide cycloaddition. Metallation with Ni(II).


    Das, Atanu K; Engelhard, Mark H; Lense, Sheri; Roberts, John A S; Bullock, R Morris


    Covalent tethering of P(Ph)2N(C6H4C≡CH)2 ligands (P(Ph)2N(C6H4C≡CH)2 = 1,5-di-(4-ethynylphenyl)-3,7-diphenyl-1,5-diaza-3,7-diphosphacyclooctane) to planar, azide-terminated glassy carbon electrode surfaces has been accomplished using a Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) coupling reaction, using a BH3←P protection-deprotection strategy. Deprotected, surface-confined ligands were metallated using [Ni(II)(MeCN)6](BF4)2. X-ray photoelectron spectroscopic measurements demonstrate that metallation introduced 1.3 equivalents Ni(II) per diphosphine onto the electrode surface. Exposure of the surface to a second diphosphine ligand, P(Ph)2N(Ph)2, resulted in the removal of Ni from the surface. Protection, coupling, deprotection, and metallation conditions were optimized using solution-phase model systems, with benzyl azide as a model for the azide-terminated carbon surface; these reactions generate a [Ni(II)(diphosphine)2](2+) complex.

  7. Hybrid NS ligands supported Cu(I)/(II) complexes for azide-alkyne cycloaddition reactions.


    Bai, Shi-Qiang; Jiang, Lu; Zuo, Jing-Lin; Hor, T S Andy


    Three copper complexes of nitrogen-sulfur donor ligands, [CuBr₂(L1)] (1), [CuCl₂(L2)₂] (2) and [Cu₂I₂(L3)]n (3) (L1 = bis(2-cyclohexylsulfanylethyl)amine, L2 = 2-(benzylsulfanylmethyl)pyridine and L3 = 2-(4-pyridylsulfanylmethyl)pyridine), have been synthesized and characterized by single-crystal X-ray diffraction (XRD), powder XRD and TGA analysis. Complexes 1 and 2 are mononuclear Cu(II) complexes and are EPR active with distorted square-pyramidal and octahedral geometry, respectively. Complex 3 is a two-dimensional tetrahedral Cu(I) coordination polymer with 16- and 20-membered metallocycles. These complexes show good catalytic activities for one-pot azide-alkyne cycloaddition reactions in CH₃OH-H₂O.

  8. Sequential one-pot ruthenium-catalyzed azide-alkyne cycloaddition from primary alkyl halides and sodium azide.


    Johansson, Johan R; Lincoln, Per; Nordén, Bengt; Kann, Nina


    An experimentally simple sequential one-pot RuAAC reaction, affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields starting from an alkyl halide, sodium azide, and an alkyne, is reported. The organic azide is formed in situ by treating the primary alkyl halide with sodium azide in DMA under microwave heating. Subsequent addition of [RuClCp*(PPh(3))(2)] and the alkyne yielded the desired cycloaddition product after further microwave irradiation.

  9. The "click" reaction involving metal azides, metal alkynes, or both: an exploration into multimetal structures.


    Casarrubios, Luis; de la Torre, María C; Sierra, Miguel A


    Cu(I) -catalyzed 1,3-cycloaddition of azides and alkynes (CuAAC) is one of the most powerful synthetic methodologies known. However, its use to prepare well-defined multimetallic structures is underdeveloped. Apart from the applications of this reaction to anchor different organometallic reagents to surfaces, polymers, and dendrimers, only isolated examples of CuAAC with metal-η(1) -alkyne and metal-azide complexes to prepare multimetal entities have been reported. This concept sketches the potential of these reactions not only to prepare "a la carte" multimetal 1,2,3-triazole derivatives, but also to discover new and unprecedented reactions.

  10. Synthesis of ferrocene-labeled steroids via copper-catalyzed azide-alkyne cycloaddition. Reactivity difference between 2β-, 6β- and 16β-azido-androstanes.


    Fehér, Klaudia; Balogh, János; Csók, Zsolt; Kégl, Tamás; Kollár, László; Skoda-Földes, Rita


    Copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes were found to be an efficient methodology for the synthesis of ferrocene-labeled steroids. At the same time, a great difference between the reactivity of 2β- or 16β-azido-androstanes and a sterically hindered 6β-azido steroid toward both ferrocenyl-alkynes and simple alkynes, such as phenylacetylene, 1-octyne, propargyl acetate and methyl propiolate, was observed.

  11. The cobalt-mediated [2+2+2]cycloaddition of thiophenes and benzofurans to alkynes

    SciTech Connect

    Malaska, M.J.


    The cobalt-mediated [2+2+2]cycloaddition of thiophenes and benzofurans to alkynes was investigated. The cocyclization of 2-propynyloxymethylthiophenes provided two types of cyclohexadiene complexes. It was found that one of these complexes could be converted to the other by a thermal rearrangement. This novel transformation was investigated by deuterium-labelling and kinetic studies, and a mechanism was proposed. The complexes could be oxidatively demetallated to provide the liberated organic framework. Further reorganization of these dienes were observed during the decomplexation process and in the presence of CpCo(C[sub 2]H[sub 4])[sub 2]. In this manner several new heterocyclic ring systems could be constructed from 2-substituted thiophenes. Following the success of the thiophene cyclizations, the cocyclization of the benzofuran nucleus was examined. Reagents and conditions were developed that provide an efficient synthesis of alkynols from carboxylic acids; other functional group interconversions of the alkynols were briefly studied. The synthesis and cyclization of 1-[7-methoxy-4-benzofuranyl]-3-butyn-2-ol produced a cobalt complex containing the A,B,C, and D rings of the morphine skeleton. A synthetic advantage of this methodology would be the ease of substitution at pharmaco-logically relevant C-6 and C-7 positions of the morphine framework. Synthetic routes using a cobalt cyclization strategy were proposed.

  12. Antifouling coatings based on covalently cross-linked agarose film via thermal azide-alkyne cycloaddition.


    Xu, Li Qun; Pranantyo, Dicky; Neoh, Koon-Gee; Kang, En-Tang; Teo, Serena Lay-Ming; Fu, Guo Dong


    Coatings based on thin films of agarose-poly(ethylene glycol) (Agr-PEG) cross-linked systems are developed as environmentally-friendly and fouling-resistant marine coatings. The Agr-PEG cross-linked systems were prepared via thermal azide-alkyne cycloaddition (AAC) using azido-functionalized Agr (AgrAz) and activated alkynyl-containing poly(2-propiolamidoethyl methacrylate-co-poly(ethylene glycol)methyl ether methacrylate) P(PEMA-co-PEGMEMA) random copolymers as the precursors. The Agr-PEG cross-linked systems were further deposited onto a SS surface, pre-functionalized with an alkynyl-containing biomimetic anchor, dopamine propiolamide, to form a thin film after thermal treatment. The thin film-coated SS surfaces can effectively reduce the adhesion of marine algae and the settlement of barnacle cyprids. Upon covalent cross-linking, the covalently cross-linked Agr-PEG films coated SS surfaces exhibit good stability in flowing artificial seawater, and enhanced resistance to the settlement of barnacle cyprids, in comparison to that of the surfaces coated with physically cross-linked AgrAz films.

  13. Cycloadditions in modern polymer chemistry.


    Delaittre, Guillaume; Guimard, Nathalie K; Barner-Kowollik, Christopher


    Synthetic polymer chemistry has undergone two major developments in the last two decades. About 20 years ago, reversible-deactivation radical polymerization processes started to give access to a wide range of polymeric architectures made from an almost infinite reservoir of functional building blocks. A few years later, the concept of click chemistry revolutionized the way polymer chemists approached synthetic routes. Among the few reactions that could qualify as click, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) initially stood out. Soon, many old and new reactions, including cycloadditions, would further enrich the synthetic macromolecular chemistry toolbox. Whether click or not, cycloadditions are in any case powerful tools for designing polymeric materials in a modular fashion, with a high level of functionality and, sometimes, responsiveness. Here, we wish to describe cycloaddition methodologies that have been reported in the last 10 years in the context of macromolecular engineering, with a focus on those developed in our laboratories. The overarching structure of this Account is based on the three most commonly encountered cycloaddition subclasses in organic and macromolecular chemistry: 1,3-dipolar cycloadditions, (hetero-)Diels-Alder cycloadditions ((H)DAC), and [2+2] cycloadditions. Our goal is to briefly describe the relevant reaction conditions, the advantages and disadvantages, and the realized polymer applications. Furthermore, the orthogonality of most of these reactions is highlighted because it has proven highly beneficial for generating unique, multifunctional polymers in a one-pot reaction. The overview on 1,3-dipolar cycloadditions is mostly centered on the application of CuAAC as the most travelled route, by far. Besides illustrating the capacity of CuAAC to generate complex polymeric architectures, alternative 1,3-dipolar cycloadditions operating without the need for a catalyst are described. In the area of (H)DA cycloadditions

  14. Cascade intermolecular Michael addition-intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction in one pot.


    Arigela, Rajesh K; Mandadapu, Anil K; Sharma, Sudhir K; Kumar, Brijesh; Kundu, Bijoy


    A rapid one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction has been described. The generality of the method has been demonstrated by treating a series of aromatic/aliphatic 2-alkynyl indoles with substituted (E)-1-azido-2-(2-nitrovinyl)benzenes to furnish annulated tetracyclic indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields.

  15. Cycloaddition of zirconacyclopent adienes to alkynes: Selective formation of benzene derivatives

    SciTech Connect

    Takahashi, Tamotsu; Kotora, M.; Xi, Zhenfeng


    Metallacyclopentadienes containing transition metals such as cobalt, rhodium and titanium have been known to react with one equiv of alkynes to give benzene derivatives. This type of reaction is very attractive and very useful, since metallacyclopentadienes can be easily prepared from two equiv of alkynes. One of the major problem of this reaction concerns the control of combination of alkynes. It has been difficult to prepare cleanly the unsymmetrical metallacyclopentadienes using these metals by the intermolecular coupling of two different alkynes. This is the reason why there is no report for the selective formation of benzene derivatives from three different alkynes in high yields. Here, the authors would like to report a selective benzene formation from three different alkynes and related reactions using zirconocene compounds.

  16. Cycloaddition reactivity studies of first-row transition metal-azide complexes and alkynes: an inorganic click reaction for metalloenzyme inhibitor synthesis.


    Evangelio, Emi; Rath, Nigam P; Mirica, Liviu M


    The studies described herein focus on the 1,3-dipolar cycloaddition reaction between first-row transition metal-azide complexes and alkyne reagents, i.e. an inorganic variant of the extensively used "click reaction". The reaction between the azide complexes of biologically-relevant metals (e.g., Fe, Co and Ni) found in metalloenzyme active sites and alkyne reagents has been investigated as a proof-of-principle for a novel method of developing metalloenzyme triazole-based inhibitors. Six Fe, Co and Ni mono-azide complexes employing salen- and cyclam-type ligands have been synthesized and characterized. The scope of the targeted inorganic azide-alkyne click reaction was investigated using the electron-deficient alkyne dimethyl acetylenedicarboxylate. Of the six metal-azide complexes tested, the Co and Ni complexes of the 1,4,8,11-tetrametyl-1,4,8,11-tetraazacyclotetradecane (Me(4)cyclam) ligand showed a successful cycloaddition reaction and formation of the corresponding metal-triazolate products, which were crystallographically characterized. Moreover, use of less electron deficient alkynes resulted in a loss of cycloaddition reactivity. Analysis of the structural parameters of the investigated metal-azide complexes suggests that a more symmetric structure and charge distribution within the azide moiety is needed for the formation of a metal-triazolate product. Overall, these results suggest that a successful cycloaddition reaction between a metal-azide complex and an alkyne substrate is dependent both on the ligand and metal oxidation state, that determine the electronic properties of the bound azide, as well as the electron deficient nature of the alkyne employed.

  17. Labeling live cells by copper-catalyzed alkyne--azide click chemistry.


    Hong, Vu; Steinmetz, Nicole F; Manchester, Marianne; Finn, M G


    The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, optimized for biological molecules in aqueous buffers, has been shown to rapidly label mammalian cells in culture with no loss in cell viability. Metabolic uptake and display of the azide derivative of N-acetylmannosamine developed by Bertozzi, followed by CuAAC ligation using sodium ascorbate and the ligand tris(hydroxypropyltriazolyl)methylamine (THPTA), gave rise to abundant covalent attachment of dye-alkyne reactants. THPTA serves both to accelerate the CuAAC reaction and to protect the cells from damage by oxidative agents produced by the Cu-catalyzed reduction of oxygen by ascorbate, which is required to maintain the metal in the active +1 oxidation state. This procedure extends the application of this fastest of azide-based bioorthogonal reactions to the exterior of living cells.

  18. A highly active and reusable copper(I)-tren catalyst for the "click" 1,3-dipolar cycloaddition of azides and alkynes.


    Candelon, Nicolas; Lastécouères, Dominique; Diallo, Abdou Khadri; Aranzaes, Jaime Ruiz; Astruc, Didier; Vincent, Jean-Marc


    The copper(I) complex [Cu(C18(6)tren)]Br 1 (C18(6)tren = tris(2-dioctadecylaminoethyl)amine) which exhibits a good stability towards aerobic conditions is a versatile, highly reactive and recyclable catalyst for the Huisgen cycloaddition of azides with terminal or internal alkynes and is a useful catalyst for the preparation of "click" dendrimers.

  19. One-pot synthesis of 1,4-disubstituted pyrazoles from arylglycines via copper-catalyzed sydnone-alkyne cycloaddition reaction.


    Specklin, Simon; Decuypere, Elodie; Plougastel, Lucie; Aliani, Soifia; Taran, Frédéric


    A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

  20. Recent applications of the Cu(I)-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry.


    Dedola, Simone; Nepogodiev, Sergey A; Field, Robert A


    This article surveys recent applications of Cu(I)-catalysed 1,3-dipolar cycloaddition of azides and alkynes in carbohydrate chemistry, highlighting developments in the preparation of simple glycoside and oligosaccharide mimetics, glyco-macrocycles, glycopeptides, glyco-clusters and carbohydrate arrays.

  1. Synthesis and structural characterisation of (aryl-BIAN)copper(I) complexes and their application as catalysts for the cycloaddition of azides and alkynes.


    Li, Lidong; Lopes, Patrícia S; Rosa, Vitor; Figueira, Cláudia A; Lemos, M Amélia N D A; Duarte, M Teresa; Avilés, Teresa; Gomes, Pedro T


    A series of Ar-BIAN-based copper(I) complexes (where Ar-BIAN = bis(aryl)acenaphthenequinonediimine) were synthesised and characterised by (1)H and (13)C NMR spectroscopies, FT-IR spectroscopy, MALDI-TOF-MS spectrometry, cyclic voltammetry and single crystal X-ray diffraction. The bis-chelated complexes of general formula [Cu(Ar-BIAN)(2)]BF(4) (where Ar = C(6)H(5) (1), 4-iPrC(6)H(4) (3), 2-iPrC(6)H(4) (4)) were prepared by reaction of [Cu(NCMe)(4)]BF(4) with two equivalents of the corresponding Ar-BIAN ligands, in dichloromethane, while the mono-chelated complexes of the type [Cu(Ar-BIAN)L(2)]BF(4) (where Ar = 2,6-iPr(2)C(6)H(3), L = PhCN (6); Ar = 4-iPrC(6)H(4), L = PPh(3) (7)) were readily accessible by treatment of [Cu(NCR)(4)]BF(4) (R = Me, Ph) with one equivalent of the corresponding Ar-BIAN ligands in the absence or presence of two equivalents of PPh(3), in the same solvent. The structures of complexes 3, 4, 6 and 7 were obtained by single crystal X-ray diffraction, showing distorted tetrahedral geometries around the copper centres in all cases. The electrochemical studies of these complexes and of the already reported [Cu(2,4,6-Me(3)C(6)H(2)-BIAN)(2)]BF(4) (2) and [Cu(2,6-iPr(2)C(6)H(3)-BIAN)(NCMe)(2)] (5), demonstrated that the bis-chelated complexes 1-4 undergo a reversible one-electron reduction or oxidation processes on copper, while the mono-chelated complexes 5-7 show a partially reversible oxidation and an irreversible reduction feature. Both kinds of (Ar-BIAN)copper(I) complexes are active catalysts for the copper(I)-catalysed azide-alkyne cycloaddition reaction (CuAAC). Complex 7, bearing PPh(3) ligands, exhibits the highest catalytic activity, which is comparable with that of the typical CuSO(4)-sodium ascorbate catalyst system.

  2. Carbohydrate CuAAC click chemistry for therapy and diagnosis.


    He, Xiao-Peng; Zeng, Ya-Li; Zang, Yi; Li, Jia; Field, Robert A; Chen, Guo-Rong


    Carbohydrates are important as signaling molecules and for cellular recognition events, therefore offering scope for the development of carbohydrate-mimetic diagnostics and drug candidates. As a consequence, the construction of carbohydrate-based bioactive compounds and sensors has become an active research area. While the advent of click chemistry has greatly accelerated the progress of medicinal chemistry and chemical biology, recent literature has seen an extensive use of such approaches to construct functionally diverse carbohydrate derivatives. Here we summarize some of the progress, covering the period 2010 to mid-2015, in Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition CuAAC "click chemistry" of carbohydrate derivatives, in the context of potential therapeutic and diagnostic tool development.

  3. Regioselective Synthesis of C-3-Functionalized Quinolines via Hetero-Diels-Alder Cycloaddition of Azadienes with Terminal Alkynes.


    Saunthwal, Rakesh K; Patel, Monika; Verma, Akhilesh K


    A highly efficient metal and protection-free approach for the regioselective synthesis of C-3-functionalized quinolines from azadienes (in situ generated from 2-aminobenzyl alcohol) and terminal alkynes through [4 + 2] cycloaddition has been developed. An unprecedented reaction of 2-aminobenzyl alcohol with 1,3- and 1,4-diethynylbenzene provided the C-3 tolylquinolines via [4 + 2] HDA and oxidative decarboxylation. The -NH2 group directed mechanistic approach was well supported by the control experiments and deuterium-labeling studies and by isolating the azadiene intermediate. The reactivity and selectivity of unprotected azadiene in metal-free base-assisted hetero-Diels-Alder reaction is exploited to quickly assemble an important class of C-3-functionalized quinolines, which are difficult to access.

  4. Experimental Investigation on the Mechanism of Chelation-Assisted, Copper(II) Acetate-Accelerated Azide-Alkyne Cycloaddition

    PubMed Central

    Kuang, Gui-Chao; Guha, Pampa M.; Brotherton, Wendy S.; Simmons, J. Tyler; Stankee, Lisa A.; Nguyen, Brian T.; Clark, Ronald J.; Zhu, Lei


    A mechanistic model is formulated to account for the high reactivity of chelating azides (organic azides capable of chelation-assisted metal coordination at the alkylated azido nitrogen position) and copper(II) acetate (Cu(OAc)2) in copper(II)-mediated azide-alkyne cycloaddition (AAC) reactions. Fluorescence and 1H NMR assays are developed for monitoring the reaction progress in two different solvents – methanol and acetonitrile. Solvent kinetic isotopic effect and pre-mixing experiments give credence to the proposed different induction reactions for converting copper(II) to catalytic copper(I) species in methanol (methanol oxidation) and acetonitrile (alkyne oxidative homocoupling), respectively. The kinetic orders of individual components in a chelation-assisted, copper(II)-accelerated AAC reaction are determined in both methanol and acetonitrile. Key conclusions resulting from the kinetic studies include (1) the interaction between copper ion (either in +1 or +2 oxidation state) and a chelating azide occurs in a fast, pre-equilibrium step prior to the formation of the in-cycle copper(I)-acetylide, (2) alkyne deprotonation is involved in several kinetically significant steps, and (3) consistent with prior experimental and computational results by other groups, two copper centers are involved in the catalysis. The X-ray crystal structures of chelating azides with Cu(OAc)2 suggest a mechanistic synergy between alkyne oxidative homocoupling and copper(II)-accelerated AAC reactions, in which both a bimetallic catalytic pathway and a base are involved. The different roles of the two copper centers (a Lewis acid to enhance the electrophilicity of the azido group and a two-electron reducing agent in oxidative metallacycle formation, respectively) in the proposed catalytic cycle suggest that a mixed valency (+2 and +1) dinuclear copper species be a highly efficient catalyst. This proposition is supported by the higher activity of the partially reduced Cu(OAc)2 in

  5. Properties of Poly(ethylene glycol) Hydrogels Cross-Linked via Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC).


    Hodgson, Sabrina M; Bakaic, Emilia; Stewart, S Alison; Hoare, Todd; Adronov, Alex


    A series of poly(ethylene glycol) (PEG) hydrogels was synthesized using strain-promoted alkyne-azide cycloaddition (SPAAC) between PEG chains terminated with either aza-dibenzocyclooctynes or azide functionalities. The gelation process was found to occur rapidly upon mixing the two components in aqueous solution without the need for external stimuli or catalysts, making the system a candidate for use as an injectable hydrogel. The mechanical and rheological properties of these hydrogels were found to be tunable by varying the polymer molecular weight and the number of cross-linking groups per chain. The gelation times of these hydrogels ranged from 10 to 60 s at room temperature. The mass-based swelling ratios varied from 45 to 76 at maximum swelling (relative to the dry state), while the weight percent of polymer in these hydrogels ranged from 1.31 to 2.05%, demonstrating the variations in amount of polymer required to maintain the structural integrity of the gel. Each hydrogel degraded at a different rate in PBS at pH = 7.4, with degradation times ranging from 1 to 35 days. By changing the composition of the two starting components, it was found that the Young's modulus of each hydrogel could be varied from 1 to 18 kPa. Hydrogel incubation with bovine serum albumin showed minimal protein adsorption. Finally, a cell cytotoxicity study of the precursor polymers with 3T3 fibroblasts demonstrated that the azide- and strained alkyne-functionalized PEGs are noncytotoxic.

  6. Site-Specific Antibody Labeling by Covalent Photoconjugation of Z Domains Functionalized for Alkyne-Azide Cycloaddition Reactions.


    Perols, Anna; Arcos Famme, Melina; Eriksson Karlström, Amelie


    Antibodies are extensively used in research, diagnostics, and therapy, and for many applications the antibodies need to be labeled. Labeling is typically performed by using amine-reactive probes that target surface-exposed lysine residues, resulting in heterogeneously labeled antibodies. An alternative labeling strategy is based on the immunoglobulin G (IgG)-binding protein domain Z, which binds to the Fc region of IgG. Introducing the photoactivable amino acid benzoylphenylalanine (BPA) into the Z domain makes it possible for a covalent bond to be be formed between the Z domain and the antibody on UV irradiation, to produce a site-specifically labeled product. Z32 BPA was synthesized by solid-phase peptide synthesis and further functionalized to give alkyne-Z32 BPA and azide-Z32 BPA for Cu(I) -catalyzed cycloaddition, as well as DBCO-Z32 BPA for Cu-free strain-promoted cycloaddition. The Z32 BPA variants were conjugated to the human IgG1 antibody trastuzumab and site-specifically labeled with biotin or fluorescein. The fluorescently labeled trastuzumab showed specific staining of the membranes of HER2-expressing cells in immunofluorescence microscopy.

  7. Topochemical Azide-Alkyne Cycloaddition Reaction in Gels: Size-Tunable Synthesis of Triazole-Linked Polypeptides.


    Krishnan, Baiju P; Sureshan, Kana M


    Though topochemical reactions are attractive, the difficulty associated with crystallization such as low yield, unsuitability for large-scale synthesis, etc. warranted the exploitation of other self-assembled media for topochemical reactions. We synthesized a dipeptide gelator decorated with azide and alkyne at its termini, N3-Ala-Val-NHCH2-C≡CH, which is designed to self-assemble through intermolecular hydrogen bonds to β-sheets thereby placing the azide and alkyne motifs in proximity. As anticipated, this peptide forms gels in organic solvents and water via hydrogen-bonded β-sheet assembly as evidenced from IR spectroscopy and PXRD profiling. The microscopic fibers present in organogel and hydrogel have different morphology as was evident from scanning electron microscopy (SEM) imaging of their xerogels, XGh (xerogel made from hydrogel) and XGo (xerogel made from organogel). Heating of xerogels at 80 °C resulted in the topochemical azide-alkyne cycloaddition (TAAC) polymerization to 1,4-triazole-linked oligopeptides. Under identical conditions, XGo produced larger oligopeptides, and XGh produced smaller peptides, as evidenced from MALDI-TOF spectrometry. We have also shown that degree of TAAC polymerization can be controlled by changing gel fiber thickness, which in turn can be controlled by concentration. SEM studies suggested the morphological intactness of the fibers even after the reaction, and their PXRD profiles revealed that both XGh and XGo undergo fiber-to-fiber oligomerization without losing their crystallinity. In contrast to crystals, the xerogels undergo TAAC polymerization in two distinct stages as shown by DSC analyses. Interestingly, XGh and XGo undergo spontaneous TAAC polymerization at room temperature; the latter shows faster kinetics. This is not only the first demonstration of the use of xerogels for thermally induced topochemical polymerization but also the first report on a spontaneous topochemical reaction in xerogels.

  8. Crystal-to-Crystal Synthesis of Triazole-Linked Pseudo-proteins via Topochemical Azide-Alkyne Cycloaddition Reaction.


    Krishnan, Baiju P; Rai, Rishika; Asokan, Aromal; Sureshan, Kana M


    Isosteric replacement of amide bond(s) of peptides with surrogate groups is an important strategy for the synthesis of peptidomimetics (pseudo-peptides). Triazole is a well-recognized bio-isostere for peptide bonds, and peptides with one or more triazole units are of great interest for different applications. We have used a catalyst-free and solvent-free method, viz., topochemical azide-alkyne cycloaddition (TAAC) reaction, to synthesize pseudo-proteins with repeating sequences. A designed β-sheet-forming l-Ala-l-Val dipeptide containing azide and alkyne at its termini (N3-Ala-Val-NHCH2C≡CH, 1) was synthesized. Single-crystal XRD analysis of the dipeptide 1 showed parallel β-sheet arrangement along the b-direction and head-to-tail arrangement of such β-sheets along the c-direction. This head-to-tail arrangement along the c-direction places the complementary reacting motifs, viz., azide and alkyne, of adjacent molecules in proximity. The crystals of dipeptide 1, upon heating at 85 °C, underwent crystal-to-crystal polymerization, giving 1,4-triazole-linked pseudo-proteins. This TAAC polymerization was investigated by various time-dependent techniques, such as NMR, IR, DSC, and PXRD. The crystal-to-crystal nature of this transformation was revealed from polarizing microscopy and PXRD experiments, and the regiospecificity of triazole formation was evidenced from various NMR techniques. The MALDI-TOF spectrum showed the presence of pseudo-proteins >7 kDa.

  9. Moderating strain without sacrificing reactivity: design of fast and tunable noncatalyzed alkyne-azide cycloadditions via stereoelectronically controlled transition state stabilization.


    Gold, Brian; Dudley, Gregory B; Alabugin, Igor V


    Recently, we have identified two strategies for selective transition state (TS) stabilization in catalyst-free azide/alkyne cycloadditions. In particular, the transition states for the formation of both 1,4- and 1,5-isomers can be stabilized via hyperconjugative assistance for the C···N bond formation, whereas the 1,5-TS can be stabilized via C-H···X H-bonding interactions. When the hyperconjugative assistance is maximized by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, the combination of these TS-stabilizing effects was predicted to lead to ~1 million fold acceleration of the cycloaddition with methyl azide. The present work investigated whether hyperconjugative assistance and H-bonding can be combined with strain activation for the design of even more reactive alkynes and whether reactivity can be turned "on demand." When stereoelectronic amplification is achieved by optimal positioning of σ-acceptors at the endocyclic bonds antiperiplanar to the breaking alkyne π-bonds, the stabilization of the bent alkyne geometry leads to a significant decrease in strain in cyclic alkynes without compromising their reactivity in alkyne-azide cycloadditions. The approach can be used in a modular fashion where the TS stabilizing effects are introduced sequentially until the desired level of reactivity is achieved. A significant increase in reactivity upon the protonation of an endocyclic NH-group suggests a new strategy for the design of click reactions triggered by a pH-change or introduction of an external Lewis acid.

  10. Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides.


    Spahn, Nathan A; Nguyen, Minh H; Renner, Jonas; Lane, Timothy K; Louie, Janis


    Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands.

  11. Efficient microwave assisted synthesis of novel 1,2,3-triazole-sucrose derivatives by cycloaddition reaction of sucrose azides and terminal alkynes.


    Potewar, Taterao M; Petrova, Krasimira T; Barros, M Teresa


    Novel 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-4-substituted-1,2,3-triazoles were synthesized by microwave assisted copper catalyzed 1,3-dipolar cycloaddition of sucrose derived azides with terminal alkynes in excellent yields and in short reaction times. The compound 1',2,3,3',4,4',6-hepta-O-acetyl-6'-azido-6'-deoxy-sucrose was regioselectively synthesized from sucrose by improved procedure and used for the cycloadditions. By combining carbohydrate and 1,2,3-triazole structural motifs, a library of 1,2,3-triazole-sucrose conjugates have been obtained.

  12. [2 + 2] Cycloaddition of fullerenes with electron-rich alkenes and alkynes

    SciTech Connect

    Zhang, Xiaojun; Fan, A.; Foote, C.S.


    [2+2] Cycloaddition between C{sub 60} and N,N-diethyl-4-methyl-3-penten-1-yn-1-amine (1) yields a C{sub 60}-fused cyclobutenamine under photochemical stimulation. Further photooxidation results in dihydrofullerenone amide. C{sub 60} and C{sub 70} react with tetraalkoxyethylenes to yield diketals which were unsuccessfully hydrolyzed. 68 refs., 1 fig.

  13. Azide-alkyne cycloaddition for universal post-synthetic modifications of nucleic acids and effective synthesis of bioactive nucleic acid conjugates.


    Su, Yu-Chih; Lo, Yu-Lun; Hwang, Chi-Ching; Wang, Li-Fang; Wu, Min Hui; Wang, Eng-Chi; Wang, Yun-Ming; Wang, Tzu-Pin


    The regioselective post-synthetic modifications of nucleic acids are essential to studies of these molecules for science and applications. Here we report a facile universal approach by harnessing versatile phosphoramidation reactions to regioselectively incorporate alkynyl/azido groups into post-synthetic nucleic acids primed with phosphate at the 5' termini. With and without the presence of copper, the modified nucleic acids were subjected to azide-alkyne cycloaddition to afford various nucleic acid conjugates including a peptide-oligonucleotide conjugate (POC) with high yield. The POC was inoculated with human A549 cells and demonstrated excellent cell-penetrating ability despite cell deformation caused by a small amount of residual copper chelated to the POC. The combination of phosphoramidation and azide-alkyne cycloaddition reactions thus provides a universal regioselective strategy to post-synthetically modify nucleic acids. This study also explicated the toxicity of residual copper in synthesized bioconjugates destined for biological systems.

  14. Total synthesis of (-)-(α)-kainic acid via a diastereoselective intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne.


    Luo, Zhi; Zhou, Bing; Li, Yuanchao


    An enantioselective synthesis of (-)-(α)-kainic acid in 15 steps with an overall yield of 24% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with complete diastereoselectivity via an unprecedented SmI2-catalyzed intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone and an alkyne. Double bond isomerization was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.

  15. [2+2+2] Cycloadditions of Siloxy Alkynes with 1,2-Diazines: From Reaction Discovery to Identification of an Antiglycolytic Chemotype**

    PubMed Central

    Montavon, Timothy J.; Türkmen, Yunus E.; Shamsi, Noumaan A.; Miller, Christopher; Sumaria, Chintan S.


    A newly uncovered Brønsted acid-promoted [2+2+2] cycloaddition between siloxy alkynes and 1,2-diazines produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under exceedingly mild conditions. A small-molecule library synthesized using this reaction yielded a novel chemotype, which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells. PMID:24346942

  16. Preparation of 18F-labeled peptides using the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition.


    Gill, Herman S; Marik, Jan


    An optimized procedure for preparing fluorine-18 ((18)F)-labeled peptides by the copper-catalyzed azide-alkyne 1,3-dipolar cyloaddition (CuAAC) is presented here. The two-step radiosynthesis begins with the microwave-assisted nucleophilic (18)F-fluorination of a precursor containing a terminal p-toluenesulfonyl, terminal azide and polyethylene glycol backbone. The resulting (18)F-fluorinated azide-containing building block is coupled to an alkyne-decorated peptide by the CuAAC. The reaction is accelerated by the copper(I)-stabilizing ligand bathophenanthroline disulfonate and can be performed in either reducing or nonreducing conditions (e.g., to preserve disulfide bonds). After an HPLC purification, (18)F-labeled peptide can be obtained with a 31 ± 6% radiochemical yield (n = 4, decay-corrected from (18)F-fluoride elution) and a specific activity of 39.0 ± 12.4 Ci μmol(-1) within 77 ± 4 min.

  17. Synthesis and characterization of cyclic polystyrene using copper-catalyzed alkyne-azide cycloaddition coupling - evaluation of physical properties and optimization of cyclization conditions

    NASA Astrophysics Data System (ADS)

    Elupula, Ravinder

    . Whereas, anionically prepared A-PS had much higher reliance on the molecular weight changes for its glass transition temperature. However, in thin films, c-PS films have, within error, no confinement effect. In contrast, A-PS has seen large T g reduction with confinement. Ellipsometry analysis suggests that this invariance of the Tg-confinement effect in c-PS is a result of the weak perturbation to Tg near the free surface (i.e. the polymer-air interface). These weak perturbations are the result of the high packing efficiency of cyclic PS segments. The copper-catalyzed alkyne/azide cycloaddition (CuAAC) click reaction has been used to cyclize many linear polymers with complementary azide and alkyne end groups via unimolecular heterodifunctional approach. Cyclic polymers exhibit unique and potentially useful physical properties compared to their linear analogs, hence increasing interest in techniques for preparing this class of polymers. However, a general route for producing high purity cyclic polymers remained elusive. Prior to the discovery of "click" chemistry, it was difficult to produce highly pure cyclic polymers via the ring-closure approach, requiring extensive post-cyclization purification. However, even minor amounts of linear impurities can influence the physical properties of cyclic polymers. Thermal gradient interaction chromatography (TGIC) coupled with Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-ToF MS) allows the fractionation of cyclic polymer samples and produce valuable data for determining both the quantity and identity of linear impurities. This understanding further enables us to optimize cyclization conditions towards the goal of and efficient, general methodology for producing highly pure cyclic polymers. To solve the ever-growing energy needs of the world and capture the renewable energy that is generated sporadically, we need to create devices that can store high amounts of energy and discharge power at

  18. Simple plate-based, parallel synthesis of disulfide fragments using the CuAAC click reaction.


    Turner, David M; Tom, Christopher T M B; Renslo, Adam R


    Disulfide exchange screening is a site-directed approach to fragment-based lead discovery that requires a bespoke library of disulfide-containing fragments. Previously, we described a simple one-pot, two-step synthesis of disulfide fragments from amine- or acid-bearing starting materials. Here, we describe the synthesis of disulfide fragments that bear a 1,4-substituted-1,2,3-triazole linkage between disulfide and molecular diversity element. This work establishes the compatibility of copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry with a one-pot, two-step reaction sequence that can be readily parallelized. We performed 96 reactions in a single deep-well microtiter plate, employing 48 alkynes and two different azide linker reagents. From this effort, a total of 81 triazole-containing disulfide fragments were obtained in useful isolated yields. Thus, CuAAC chemistry offers an experimentally convenient method to rapidly prepare disulfide fragments that are structurally distinct from fragments accessed via amide, sulfonamide, or isocyanate chemistries.

  19. Tailoring the hydrophilic/lipophilic balance of clickable mesoporous organosilicas by the copper-catalyzed azide-alkyne cycloaddition click-functionalization.


    Noureddine, Achraf; Trens, Philippe; Toquer, Guillaume; Cattoën, Xavier; Man, Michel Wong Chi


    We have designed and synthesized a clickable bridged silsesquioxane material featuring pendant alkyne chains as an aggregate of golf-ball-like nanoparticles, as evidenced by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and small- and wide-angle X-ray scattering (SWAXS). Using the copper-catalyzed azide-alkyne cycloaddition reaction with a range of organic azides of variable characteristics, we transformed this parent bridged silsesquioxane into new materials with tunable hydrophilic/lipophilic balance in high conversions while preserving the original morphology. N2, cyclohexane, and water sorption experiments were used to quantify the affinity of these materials toward the sorbates through the determination of their Henry's constants. This resulted in the following hydrophilic scale: M-OH > M-PEG > M-C6 > M-Ph > M-F > M-C16, which was mostly confirmed by SWAXS measurements.

  20. Cycloaddition and cycloreversion reactions of a monomeric Ti(IV) oxo complex with terminal and internal alkynes. A reversible oxametallacyclobutene/hydroxoacetylide interconversion

    SciTech Connect

    Polse, J.L.; Andersen, R.A.; Bergman, R.G. |


    The synthesis and structure of Cp{sup *}{sub 2}Ti(O)(pry) (Cp{sup *}={eta}{sup 5}-C{sub 5}Me{sub 5}; pyr=pyridine) (1) were described recently. We report here on the [2 + 2] cycloaddition of 1 with terminal alkynes and the novel rearrangement of the resulting oxametallacyclobutenes to hydroxoacetylide complexes. In at least one case the arrangement is reversible, and we have obtained information on its mechanism. We have carried out experiments designed to investigate the mechanism of the oxametallacycle-to-hydroxoacetylide rearrangement. 17 refs., 1 fig.

  1. Mechanism of [3+2] cycloaddition of alkynes to the [Mo3 S4 (acac)3 (py)3 ][PF6 ] cluster.


    Pino-Chamorro, Jose Ángel; Gushchin, Artem L; Fernández-Trujillo, M Jesús; Hernández-Molina, Rita; Vicent, Cristian; Algarra, Andrés G; Basallote, Manuel G


    A study, involving kinetic measurements on the stopped-flow and conventional UV/Vis timescales, ESI-MS, NMR spectroscopy and DFT calculations, has been carried out to understand the mechanism of the reaction of [Mo3 S4 (acac)3 (py)3 ][PF6 ] ([1]PF6 ; acac=acetylacetonate, py=pyridine) with two RCCR alkynes (R=CH2 OH (btd), COOH (adc)) in CH3 CN. Both reactions show polyphasic kinetics, but experimental and computational data indicate that alkyne activation occurs in a single kinetic step through a concerted mechanism similar to that of organic [3+2] cycloaddition reactions, in this case through the interaction with one Mo(μ-S)2 moiety of [1](+) . The rate of this step is three orders of magnitude faster for adc than that for btd, and the products initially formed evolve in subsequent steps into compounds that result from substitution of py ligands or from reorganization to give species with different structures. Activation strain analysis of the [3+2] cycloaddition step reveals that the deformation of the two reactants has a small contribution to the difference in the computed activation barriers, which is mainly associated with the change in the extent of their interaction at the transition-state structures. Subsequent frontier molecular orbital analysis shows that the carboxylic acid substituents on adc stabilize its HOMO and LUMO orbitals with respect to those on btd due to better electron-withdrawing properties. As a result, the frontier molecular orbitals of the cluster and alkyne become closer in energy; this allows a stronger interaction.

  2. A density functional theory investigation of the cobalt-mediated η5-pentadienyl/alkyne [5+2] cycloaddition reaction: mechanistic insight and substituent effects.


    Ylijoki, Kai E O; Budzelaar, Peter H M; Stryker, Jeffrey M


    Alkyl-substituted η(5)-pentadienyl half-sandwich complexes of cobalt have been reported to undergo [5+2] cycloaddition reactions with alkynes to provide η(2),η(3)-cycloheptadienyl complexes under kinetic control. DFT studies have been used to elucidate the mechanism of the cyclization reaction as well as that of the subsequent isomerization to the final η(5)-cycloheptadienyl product. The initial cyclization is a stepwise process of olefin decoordination/alkyne capture, C-C bond formation, olefin arm capture, and a second C-C bond formation; the initial decoordination/capture step is rate-limiting. Once the η(2),η(3)-cycloheptadienyl complex has been formed, isomerization to η(5)-cycloheptadienyl again involves several steps: olefin decoordination, β-hydride elimination, reinsertion, and olefin coordination; also here the initial decoordination step is rate limiting. Substituents strongly affect the ease of reaction. Pentadienyl substituents in the 1- and 5-positions assist pentadienyl opening and hence accelerate the reaction, while substituents at the 3-position have a strongly retarding effect on the same step. Substituents at the alkyne (2-butyne vs. ethyne) result in much faster isomerization due to easier olefin decoordination. Paths involving triplet states do not appear to be competitive.

  3. Citrus Peel Additives for One-Pot Triazole Formation by Decarboxylation, Nucleophilic Substitution, and Azide-Alkyne Cycloaddition Reactions

    ERIC Educational Resources Information Center

    Mendes, Desiree E.; Schoffstall, Allen M.


    This undergraduate organic laboratory experiment consists of three different reactions occurring in the same flask: a cycloaddition reaction, preceded by decarboxylation and nucleophilic substitution reactions. The decarboxylation and cycloaddition reactions occur using identical Cu(I) catalyst and conditions. Orange, lemon, and other citrus fruit…

  4. Synthesis of steroid-ferrocene conjugates of steroidal 17-carboxamides via a palladium-catalyzed aminocarbonylation--copper-catalyzed azide-alkyne cycloaddition reaction sequence.


    Szánti-Pintér, Eszter; Balogh, János; Csók, Zsolt; Kollár, László; Gömöry, Agnes; Skoda-Földes, Rita


    Steroids with the 17-iodo-16-ene functionality were converted to ferrocene labeled steroidal 17-carboxamides via a two step reaction sequence. The first step involved the palladium-catalyzed aminocarbonylation of the alkenyl iodides with prop-2-yn-1-amine as the nucleophile in the presence of the Pd(OAc)(2)/PPh(3) catalyst system. In the second step, the product N-(prop-2-ynyl)-carboxamides underwent a facile azide-alkyne cycloaddition with ferrocenyl azides in the presence of CuSO(4)/sodium ascorbate to produce the steroid-ferrocene conjugates. The new compounds were obtained in good yield and were characterized by (1)H and (13)C NMR, IR, MS and elemental analysis.

  5. Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction".


    Jin, Liqun; Tolentino, Daniel R; Melaimi, Mohand; Bertrand, Guy


    The copper-catalyzed 1,3-dipolar cycloaddition of an azide to a terminal alkyne (CuAAC) is one of the most popular chemical transformations, with applications ranging from material to life sciences. However, despite many mechanistic studies, direct observation of key components of the catalytic cycle is still missing. Initially, mononuclear species were thought to be the active catalysts, but later on, dinuclear complexes came to the front. We report the isolation of both a previously postulated π,σ-bis(copper) acetylide and a hitherto never-mentioned bis(metallated) triazole complex. We also demonstrate that although mono- and bis-copper complexes promote the CuAAC reaction, the dinuclear species are involved in the kinetically favored pathway.

  6. Magnetite nanoparticles coated with alkyne-containing polyacrylates for click chemistry

    NASA Astrophysics Data System (ADS)

    Socaci, Crina; Rybka, Miriam; Magerusan, Lidia; Nan, Alexandrina; Turcu, Rodica; Liebscher, Jürgen


    New magnetic core shell nanoparticles were synthesized consisting of magnetite cores and poly-( O-propargyl acrylate) shells. Strong fixing of the shells was achieved by primary anchoring phosphates or α-dihydroxydiphosphonates containing acrylate or methacrylate functionalities. The magnetic nanoparticles are attractive as supports for a variety of function which can be easily introduced by Cu-catalyzed alkyne azide cycloaddition (CuAAC, a click reaction). In this way, also the loading of the magnetic nanoparticles with propargyl units was determined by reaction with 4-azidoacetophenone and analysis of the supernatant. In order to demonstrate the attractiveness of the magnetic nanoparticles a novel azido-containing conjugate with biotin as recognition function and dansyl as fluorescence marker was introduced by CuAAC reaction. All NP show superparamagnetic behavior with high-saturation magnetization values and were further characterized by FTIR, photoelectron spectroscopy and TEM.

  7. The use of azide-alkyne click chemistry in recent syntheses and applications of polytriazole-based nanostructured polymers

    NASA Astrophysics Data System (ADS)

    Shi, Yi; Cao, Xiaosong; Gao, Haifeng


    The rapid development of efficient organic click coupling reactions has significantly facilitated the construction of synthetic polymers with sophisticated branched nanostructures. This Feature Article summarizes the recent progress in the application of efficient copper-catalyzed and copper-free azide-alkyne cycloaddition (CuAAC and CuFAAC) reactions in the syntheses of dendrimers, hyperbranched polymers, star polymers, graft polymers, molecular brushes, and cyclic graft polymers. Literature reports on the interesting properties and functions of these polytriazole-based nanostructured polymers are also discussed to illustrate their potential applications as self-healing polymers, adhesives, polymer catalysts, opto-electronic polymer materials and polymer carriers for drug and imaging molecules.

  8. 18F-Labeling Using Click Cycloadditions

    PubMed Central

    Ross, Tobias L.


    Due to expanding applications of positron emission tomography (PET) there is a demand for developing new techniques to introduce fluorine-18 (t1/2 = 109.8 min). Considering that most novel PET tracers are sensitive biomolecules and that direct introduction of fluorine-18 often needs harsh conditions, the insertion of 18F in those molecules poses an exceeding challenge. Two major challenges during 18F-labeling are a regioselective introduction and a fast and high yielding way under mild conditions. Furthermore, attention has to be paid to functionalities, which are usually present in complex structures of the target molecule. The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) and several copper-free click reactions represent such methods for radiolabeling of sensitive molecules under the above-mentioned criteria. This minireview will provide a quick overview about the development of novel 18F-labeled prosthetic groups for click cycloadditions and will summarize recent trends in copper-catalyzed and copper-free click 18F-cycloadditions. PMID:25003110

  9. Alkyne-Azide Cycloaddition Catalyzed by Silver Chloride and “Abnormal” Silver N-Heterocyclic Carbene Complex

    PubMed Central

    Ortega-Arizmendi, Aldo I.; Aldeco-Pérez, Eugenia; Cuevas-Yañez, Erick


    A library of 1,2,3-triazoles was synthesized from diverse alkynes and azides using catalytic amounts of silver chloride instead of copper compounds. In addition, a novel “abnormal” silver N-heterocyclic carbene complex was tested as catalyst in this process. The results suggest that the reaction requires only 0.5% of silver complex, affording 1,2,3-triazoles in good yields. PMID:24307866

  10. Ribosome-templated azide–alkyne cycloadditions: synthesis of potent macrolide antibiotics by in situ click chemistry

    PubMed Central

    Glassford, Ian; Teijaro, Christiana N.; Daher, Samer S.; Weil, Amy; Small, Meagan C.; Redhu, Shiv K.; Colussi, Dennis J.; Jacobson, Marlene A.; Childers, Wayne E.; Buttaro, Bettina; Nicholson, Allen W.; MacKerell, Alexander D.; Cooperman, Barry S.; Andrade, Rodrigo B.


    Over half of all antibiotics target the bacterial ribosome—Nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semi-synthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolidefunctionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a six-component reaction (i.e., azide 2 and five alkynes) and ultimately to a sixteen-component reaction (i.e., azide 2 and fifteen alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured Kd values. Computational analysis using the Site-Identification by Ligand Competitive Saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine-ribosome interactions caused by the different alkynes. Protein synthesis inhibition experiments confirmed the mechanism of action. Evaluation of the minimal inhibitory concentrations (MIC) quantified the potency of the in situ click products and demonstrated the efficacy of this method in the triaging and prioritization of potent antibiotics that target the bacterial ribosome. Cell viability assays in human fibroblasts confirmed 2 and four analogs with therapeutic indices for bactericidal activity over in vitro mammalian cytotoxicity as essentially identical to solithromycin (1). PMID:26878192

  11. Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry.


    Glassford, Ian; Teijaro, Christiana N; Daher, Samer S; Weil, Amy; Small, Meagan C; Redhu, Shiv K; Colussi, Dennis J; Jacobson, Marlene A; Childers, Wayne E; Buttaro, Bettina; Nicholson, Allen W; MacKerell, Alexander D; Cooperman, Barry S; Andrade, Rodrigo B


    Over half of all antibiotics target the bacterial ribosome-nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolide-functionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a six-component reaction (i.e., azide 2 and five alkynes) and ultimately to a 16-component reaction (i.e., azide 2 and 15 alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured Kd values. Computational analysis using the site-identification by ligand competitive saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine-ribosome interactions caused by the different alkynes. Protein synthesis inhibition experiments confirmed the mechanism of action. Evaluation of the minimal inhibitory concentrations (MIC) quantified the potency of the in situ click products and demonstrated the efficacy of this method in the triaging and prioritization of potent antibiotics that target the bacterial ribosome. Cell viability assays in human fibroblasts confirmed 2 and four analogues with therapeutic indices for bactericidal activity over in vitro mammalian cytotoxicity as essentially identical to solithromycin (1).

  12. On the Critical Effect of the Metal (Mo vs. W) on the [3+2] Cycloaddition Reaction of M3 S4 Clusters with Alkynes: Insights from Experiment and Theory.


    Bustelo, Emilio; Gushchin, Artem L; Fernández-Trujillo, M Jesús; Basallote, Manuel G; Algarra, Andrés G


    Whereas the cluster [Mo3 S4 (acac)3 (py)3 ](+) ([1](+) , acac=acetylacetonate, py=pyridine) reacts with a variety of alkynes, the cluster [W3 S4 (acac)3 (py)3 ](+) ([2](+) ) remains unaffected under the same conditions. The reactions of cluster [1](+) show polyphasic kinetics, and in all cases clusters bearing a bridging dithiolene moiety are formed in the first step through the concerted [3+2] cycloaddition between the C≡C atoms of the alkyne and a Mo(μ-S)2 moiety of the cluster. A computational study has been conducted to analyze the effect of the metal on these concerted [3+2] cycloaddition reactions. The calculations suggest that the reactions of cluster [2](+) with alkynes feature ΔG(≠) values only slightly larger than its molybdenum analogue, however, the differences in the reaction free energies between both metal clusters and the same alkyne reach up to approximately 10 kcal mol(-1) , therefore indicating that the differences in the reactivity are essentially thermodynamic. The activation strain model (ASM) has been used to get more insights into the critical effect of the metal center in these cycloadditions, and the results reveal that the change in reactivity is entirely explained on the basis of the differences in the interaction energies Eint between the cluster and the alkyne. Further decomposition of the Eint values through the localized molecular orbital-energy decomposition analysis (LMO-EDA) indicates that substitution of the Mo atoms in cluster [1](+) by W induces changes in the electronic structure of the cluster that result in weaker intra- and inter-fragment orbital interactions.

  13. Cysteine as a Monothiol Reducing Agent to Prevent Copper-Mediated Oxidation of Interferon Beta During PEGylation by CuAAC.


    Nairn, Natalie W; Bariola, Pauline A; Graddis, Thomas J; VanBrunt, Michael Pete; Wang, Aijun; Li, Gary; Grabstein, Kenneth


    Bioconjugation by copper-catalyzed azide-alkyne cycloaddition (CuAAC) provides a powerful means to produce site-specifically modified proteins. However, the use of a copper catalyst brings about the possible generation of reactive oxygen species that could cause degradation of vulnerable amino acid residues. We investigated whether PEGylation by CuAAC caused any modifications to the therapeutic protein interferon beta-1b, which was produced via global amino acid substitution with azidohomo-alanine at the N-terminus and contains no methionine residues. Using previously reported reaction conditions, LC-MS peptide mapping detected +32 Da and +48 Da oxidation modifications of tryptic peptides 28-33 (LEYCLK) and 137-147 (EYSHCAWTIVR) in the protein post-PEGylation. The oxidative degradation increased with reaction time, whereas reducing the copper concentration slowed the PEGylation rate as well as the oxidation rate. Replacing dithiothreitol (DTT) with any of five different monothiol reducing agents in anaerobic conditions allowed efficient PEGylation in 2-4 h and abrogated oxidative degradation. Free cysteine provided reproducible reaction results as a reducing agent in this system and has been successfully applied to other protein conjugations. Monothiol reducing agents, such as cysteine, may be useful tools as protective reducing agents for CuAAC in some bioconjugation systems.

  14. Application of strain-promoted azide-alkyne cycloaddition and tetrazine ligation to targeted Fc-drug conjugates.


    Thomas, Joshua D; Cui, Huiting; North, Patrick J; Hofer, Thomas; Rader, Christoph; Burke, Terrence R


    We have previously described an approach whereby antibody Fc fragments harboring a single C-terminal selenocysteine residue (Fc-Sec) are directed against a variety of targets by changing the peptide or small molecule to which they are conjugated. In the present work, we describe methodology for improving the efficacy of these Fc-Sec conjugates by incorporating cytotoxic drugs. The Fc-Sec protein is first programmed to target specific tumor cell types by attachment of a bifunctional linker that contains a "clickable" handle (e.g., cyclobutane or cyclooctyne) in addition to a tumor cell-binding peptide or small molecule. Following Fc-Sec conjugation, a cytotoxic warhead is then attached by cycloaddition reactions of tetrazine or azide-containing linker. To validate this approach, we used a model system in which folic acid (FA) is the targeting moiety and a disulfide-linked biotin moiety serves as a cytotoxic drug surrogate. We demonstrated successful targeting of Fc-Sec proteins to folate-receptor expressing tumor cells. Tetrazine ligation was found to be an efficient method for biotin "arming" of the folate-targeted Fc-Sec proteins. We also report novel bioconjugation methodologies that use [4 + 2] cycloaddition reactions between tetrazines and cyclooctynes.

  15. Steering the azido-tetrazole equilibrium of 4-azidopyrimidines via substituent variation - implications for drug design and azide-alkyne cycloadditions.


    Thomann, A; Zapp, J; Hutter, M; Empting, M; Hartmann, R W


    This paper focuses on an interesting constitutional isomerism called azido-tetrazole equilibrium which is observed in azido-substituted N-heterocycles. We present a systematic investigation of substituent effects on the isomer ratio within a 2-substituted 4-azidopyrimidine model scaffold. NMR- and IR-spectroscopy as well as X-ray crystallography were employed for thorough analysis and characterization of synthesized derivatives. On the basis of this data, we demonstrate the possibility to steer this valence tautomerism towards the isomer of choice by means of substituent variation. We show that the tetrazole form can act as an efficient disguise for the corresponding azido group masking its well known reactivity in azide-alkyne cycloadditions (ACCs). In copper(I)-catalyzed AAC reactions, substituent-stabilized tetrazoles displayed a highly decreased or even abolished reactivity whereas azides and compounds in the equilibrium were directly converted. By use of an acid sensitive derivative, we provide, to our knowledge, the first experimental basis for a possible exploitation of this dynamic isomerism as a pH-dependent azide-protecting motif for selective SPAAC conjugations in aqueous media. Finally, we demonstrate the applicability and efficiency of stabilized tetrazolo[1,5-c]pyrimidines for Fragment-Based Drug Design (FBDD) in the field of quorum sensing inhibitors.

  16. An injectable and fast-degradable poly(ethylene glycol) hydrogel fabricated via bioorthogonal strain-promoted azide-alkyne cycloaddition click chemistry.


    Jiang, Huafang; Qin, Siyong; Dong, Hui; Lei, Qi; Su, Xin; Zhuo, Renxi; Zhong, Zhenlin


    Biocompatible and degradable injectable materials prepared via bioorthogonal reactions are highly promising for biomedical applications because they can be formed in situ and administered in a minimally invasive way. In this work, a PEG-based injectable hydrogel was fabricated via a copper-free, strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry. Azide and cyclooctyne moieties on the PEG backbones underwent a rapid click reaction to trigger the formation of the hydrogel within several minutes. Resulting from the introduction of ester groups into the cross-linked network, the hydrogel presented pH-dependent hydrolysis and biological fast degradability. Good biocompatibility of the hydrogel was verified by in vitro cytotoxicity assay and in vivo studies. The hydrogel formed in situ after subcutaneously injecting the gel precursors into Kungming (KM) mice. The implanted hydrogel caused a mild inflammatory response in vivo, and the surrounding tissues fully recovered a week after the injection. The injectable and fast-degradable hydrogel fabricated by the bioorthogonal click reaction may be useful as biomaterials such as embolic agents for interventional therapy.

  17. Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition: A family of valuable products by click chemistry.


    Zheng, Zhan-Jiang; Wang, Ding; Xu, Zheng; Xu, Li-Wen


    The Cu(I)-catalyzed azide-alkyne cycloaddition reaction, also known as click chemistry, has become a useful tool for the facile formation of 1,2,3-triazoles. Specifically, the utility of this reaction has been demonstrated by the synthesis of structurally diverse bi- and bis-1,2,3-triazoles. The present review focuses on the synthesis of such bi- and bistriazoles and the importance of using copper-promoted click chemistry (CuAAC) for such transformations. In addition, the application of bitriazoles and the related CuAAAC reaction in different fields, including medicinal chemistry, coordination chemistry, biochemistry, and supramolecular chemistry, have been highlighted.

  18. Unprecedented coordination modes and demetalation pathways for unbridged polyenyl ligands. Ruthenium eta1,eta4-cycloheptadienyl complexes from allyl/alkyne cycloaddition.


    Older, Christina M; McDonald, Robert; Stryker, Jeffrey M


    Cationic (eta6-hexamethylbenzene)ruthenium(II) mediates the [3 + 2 + 2] cycloaddition of allyl and alkyne ligands, leading to the unexpected isolation of eta1,eta4-cycloheptadienyl complexes, an unprecedented coordination mode for transition metal complexes of simple organic rings. The nonconjugated, eta1,eta4-coordinated complex is obtained as the kinetic reaction product from treatment of the unsubstituted allyl complex with excess ethyne; this complex rearranges slowly at 80 degrees C to the thermodynamically more stable conjugated eta5-cycloheptadienyl isomer. The eta1,eta4-coordinated isomer is fluxional at room temperature, undergoing rapid and reversible equilibration with a cycloheptatriene hydride intermediate via facile beta-hydride elimination/reinsertion. The reinsertion process is remarkably regioselective, returning the nonconjugated eta1,eta4-cycloheptadienyl isomer exclusively at room temperature. For reactions incorporating dimethylacetylene dicarboxylate (DMAD) as one or both of the alkyne components, eta1,eta4-coordination appears to be both kinetically and thermodynamically favored, despite undergoing equilibration among all possible eta1,eta4-cycloheptadienyl and cycloheptatriene hydride isomers prior to arriving at one observed eta1,eta4-isomer. For this series, no isomerization to eta5-coordination is observed even upon prolonged heating. In contrast, the cyclization incorporating both DMAD and phenylacetylene proceeds directly to the eta5-cycloheptadienyl isomer at or below room temperature, indicating that eta5-coordination remains energetically accessible to this system. The DMAD-based cyclization reactions produce structurally diverse minor byproducts, including both eta1,eta4-methanocyclohexadiene and acyclic eta3,eta2-heptadienyl isomers, which have been isolated and rigorously characterized. The unusual eta1,eta4-coordination of the seven-membered ring leads to unique new organic products upon oxidative demetalation by iodinolysis

  19. Rare-earth metal complexes stabilized by amino-phosphine ligand. Reaction with mesityl azide and catalysis of the cycloaddition of organic azides and aromatic alkynes.


    Liu, Bo; Cui, Dongmei


    Stoichiometric reactions between mesityl azide (MesN3, Mes = 2,4,6-C6H2Me3) and amino-phosphine ligated rare-earth metal alkyl, LLn(CH2SiMe3)2(THF) (L = (2,6-C6H3Me2)NCH2C6H4P(C6H5)2; Ln = Lu (1a), Sc (1b)), amide, LLu(NH(2,6-C6H3iPr2))2(THF) (2) and acetylide at room temperature gave the amino-phosphazide ligated rare-earth metal bis(triazenyl) complexes, [L(MesN3)]Ln[(MesN3)(CH2SiMe3)]2 (Ln = Lu (3a); Sc (3b)), bis(amido) complex [L(MesN3)]Lu[NH(2,6-C6H3iPr2)]2 (4), and bis(alkynyl) complex (5) (L(MesN3)Lu (C[triple bond, length as m-dash]CPh)2)2, respectively. The triazenyl group in coordinates to the metal ion in a rare eta2-mode via N(beta) and N(gamma) atoms, generating a triangular metallocycle. The amino-phosphazide ligand, L(MesN3), in , and chelates to the metal ion in a eta3-mode via N(alpha) and N(gamma) atoms. In the presence of excess phenylacetylene, complex isomerized to , where the triazenyl group coordinates to the metal ion in a eta3 mode via N(alpha) and N(gamma) atoms. Complexes , , and have shown an unprecedented catalytic activity towards the cycloaddition of organic azides and aromatic alkynes to afford 1,5-disubstituted 1,2,3-triazoles selectively.

  20. The [2 + 2] Cycloaddition-Retroelectrocyclization and [4 + 2] Hetero-Diels-Alder Reactions of 2-(Dicyanomethylene)indan-1,3-dione with Electron-Rich Alkynes: Influence of Lewis Acids on Reactivity.


    Donckele, Etienne J; Finke, Aaron D; Ruhlmann, Laurent; Boudon, Corinne; Trapp, Nils; Diederich, François


    The reaction of electrophilic 2-(dicyanomethylene)indan-1,3-dione (DCID) with substituted, electron-rich alkynes provides two classes of push-pull chromophores with interesting optoelectronic properties. The formal [2 + 2] cycloaddition-retroelectrocyclization reaction at the exocyclic double bond of DCID gives cyanobuta-1,3-dienes, and the formal [4 + 2] hetero-Diels-Alder (HDA) reaction at an enone moiety of DCID generates fused 4H-pyran heterocycles. Both products can be obtained in good yield and excellent selectivity by carefully tuning the reaction conditions; in particular, the use of Lewis acids dramatically enhances formation of the HDA adduct.

  1. Tethering antimicrobial peptides onto chitosan: Optimization of azide-alkyne "click" reaction conditions.


    Barbosa, Mariana; Vale, Nuno; Costa, Fabíola M T A; Martins, M Cristina L; Gomes, Paula


    Antimicrobial peptides (AMP) are promising alternatives to classical antibiotics, due to their high specificity and potency at low concentrations, and low propensity to elicit pathogen resistance. Immobilization of AMP onto biomaterials is an emergent field of research, towards creation of novel antimicrobial materials able to avoid formation of biofilms on the surfaces of medical devices. Herein, we report the chemical route towards one such material, where chitosan was used as biocompatible carrier for the covalent grafting of Dhvar-5, a well-known potent AMP, via the chemoselective ("click") Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The material's structure, as well as peptide loading, were confirmed by Fourier-transformed infra-red (FT-IR) and X-ray photoelectron (XPS) spectroscopies, and by Amino Acid Analysis (AAA), respectively. Results herein reported demonstrate that, with proper optimization, the "click" CuAAC is an attractive approach for the tethering of AMP onto chitosan, in order to create novel antimicrobial materials potentially valuable for biomedical applications.

  2. Multi‐Pathway Consequent Chemoselectivities of CpRuCl(PPh3)2/MeI‐Catalysed Norbornadiene Alkyne Cycloadditions

    PubMed Central

    Fang, De‐Cai; Xia, Shu‐Ya; Cheng, Rui‐Jiao


    Abstract Chemoselectivities of five experimentally realised CpRuCl(PPh3)2/MeI‐catalysed couplings of 7‐azabenzo‐norbornadienes with selected alkynes were successfully resolved from multiple reaction pathway models. Density functional theory calculations showed the following mechanistic succession to be energetically plausible: (1) CpRuI catalyst activation; (2) formation of crucial metallacyclopentene intermediate; (3) cyclobutene product (P2) elimination (ΔG Rel(RDS)≈11.9–17.6 kcal mol−1). Alternative formation of dihydrobenzoindole products (P1) by isomerisation to azametalla‐cyclohexene followed by subsequent CpRuI release was much less favourable (ΔG Rel(RDS)≈26.5–29.8 kcal mol−1). Emergent stereoselectivities were in close agreement with experimental results for reactions a, b, e. Consequent investigations employing dispersion corrections similarly support the empirical findings of P1 dominating in reactions c and d through P2→P1 product transformations as being probable (ΔG≈25.3–30.1 kcal mol−1). PMID:27620274

  3. Assessment of the Full Compatibility of Copper(I)-Catalyzed Alkyne-Azide Cycloaddition and Oxime Click Reactions for bis-Labelling of Oligonucleotides

    PubMed Central

    Estalayo-Adriàn, Sandra; Lartia, Rémy; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, François; Defrancq, Eric


    The conjugation of oligonucleotides with reporters is of great interest for improving their intrinsic properties or endowing new ones. In this context, we report herein a new procedure for the bis-labelling of oligonucleotides through oxime ligation (Click-O) and copper(I)-catalyzed alkyne–azide cycloaddition (Click-H). 5′-Azido and 3′-aldehyde precursors were incorporated into oligonucleotides, and subsequent coupling reactions through Click-O and Click-H (or vice versa) were successfully achieved. In particular, we exhaustively investigated the full compatibility of each required step for both tethering strategies. The results demonstrate that click Huisgen and click oxime reactions are fully compatible. However, whilst both approaches can deliver the targeted doubly conjugated oligonucleotide, the route involving click oxime ligation prior to click Huisgen is significantly more successful. Thus the reactions investigated here can be considered to be key elements of the chemical toolbox for the synthesis of highly sophisticated bioconjugates. PMID:25969815

  4. Characterization of non-specific protein adsorption induced by triazole groups on the chromatography media using Cu (I)-catalyzed alkyne-azide cycloaddition reaction for ligand immobilization.


    Gao, Ming; Ren, Jun; Tian, Kaikai; Jia, Lingyun


    As an efficient and facile reaction, click chemistry has been growingly used in the preparation of chromatography media for immobilizing varying types of ligands. For the widely used Cu (I)-catalyzed alkyne-azide click reaction, a 1, 2, 3-triazole group will be inevitably introduced in the molecular linkage, which could give rise to unexpected non-specific adsorption especially for the media employing small compound ligands or high ligand density. Triazole-induced non-specific protein adsorption on sepharose resins was evaluated systematically in this work, by considering the effects of triazole content, length of spacer arm, and solution conditions. We found that triazole content of a resin played the key role. Protein adsorption became significant when the media was coupled with triazole at a medium density (about 60μmol/mL gel), and the binding amount further increased with triazole density. The resin with triazole content of about 100μmol/mL gel could adsorb human IgG, bovine serum albumin and lysozyme at the amount of 13.6, 30.0, and 5.1mg/mL respectively. Proteins tended to be adsorbed at higher amount as the pH of solution approached their isoelectric points, and increasing salt concentration could reduce triazole-induced adsorption but only within limited extent. This study can facilitate reasonable application of click chemistry in the synthesis of chromatography media, by providing some basic principles for optimizing structural properties of separation media and choosing suitable solution conditions.

  5. Synthesis of well-defined alkyne terminated poly(N-vinyl caprolactam) with stringent control over the LCST by RAFT

    PubMed Central

    Góis, Joana R.; Costa, João R. C.; Popov, Anatoliy V.; Serra, Arménio C.; Coelho, Jorge F. J.


    The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using two new xanthates with alkyne functionalities is reported. The kinetic data obtained for polymerization of this non-activated monomer using a protected alkyne-terminated RAFT agent (PAT-X1) revealed a linear increase of the polymer molecular weight with the monomer conversion as well as low dispersity (Đ) during the entire course of the polymerization. The system reported here allowed us to enhance the final conversion, diminish Đ and reduce the polymerization temperature compared to the typical values reported in the scarce literature available for the RAFT polymerization of NVCL. The resulting PNVCL was fully characterized using 1H nuclear magnetic resonance (1H NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), Fourier-transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC) techniques. The temperature-responsive features of PNVCL in aqueous solutions were fully investigated under different conditions using turbidimetry. The presented strategy allows the synthesis of well-defined PNVCL with sharp and reversible phase transition temperatures around 37 °C. By manipulating the polymer molecular weight, or the solution properties, it is possible to tune the PNVCL phase transition. As a proof-of concept, the alkyne functionalized PNVCL was used to afford new linear block copolymers, by reacting with an azide-terminated poly(ethylene glycol) (N3-PEG) through the copper catalyzed azide-alkyne [3+2] dipolar cycloaddition (CuAAC) reaction. The results presented establish a robust system to afford the synthesis of PNCVL with fine tuned characteristics that will enable more efficient exploration of the remarkable potential of this polymer in biomedical applications. PMID:27019706

  6. Heterogeneous catalysis for azide-alkyne bioconjugation in solution via spin column: Attachment of dyes and saccharides to peptides and DNA.


    Kallick, Jeremy; Harris, Sarah; Udit, Andrew K; Hill, Michael G


    Copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry is widely used and has demonstrated particular utility for bio-orthogonal conjugation reactions. Here we describe a one-pot, heterogeneous bioconjugation and purification method for selectively activated CuAAC. A Cu(II) precursor, with either the neutral ligand 1,10-phenanthroline-5,6-dione or the anionic ligand 4,7-diphenyl-1,10-phenanthroline-disulfonic acid, is converted to the active Cu(I) species within an ion-exchange matrix using zinc amalgam as the reducing agent. The Cu(I) complexes are then layered on top of a size-exclusion matrix within a commercial microcentrifuge spin column; passing a mixture of an ethynyl-labeled biomolecule and an azide-bearing ligand through the column results in clean and efficient coupling. The methodology is demonstrated by glycosylating a DNA oligonucleotide as well as by labeling a membrane-penetrating peptide (octa-arginine) with a coumarin dye.

  7. Conjugates of phosphorylated zalcitabine and lamivudine with SiO2 nanoparticles: Synthesis by CuAAC click chemistry and preliminary assessment of anti-HIV and antiproliferative activity.


    Vasilyeva, Svetlana V; Shtil, Alexander A; Petrova, Albina S; Balakhnin, Sergei M; Achigecheva, Polina Y; Stetsenko, Dmitry A; Silnikov, Vladimir N


    Conjugates of phosphorylated dideoxynucleoside antiviral drugs dideoxycytidine (zalcitabine) and lamivudine with SiO2 nanoparticles were obtained via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry between a nucleoside triphosphate containing an alkynyl group at the γ-phosphate or azidothymidine triphosphate and SiO2 nanoparticles containing alkyl azide or alkynyl groups, respectively. 4-(Prop-2-yn-1-yloxy)butylamino group has been attached to the γ-phosphate group of dideoxycytidine (zalcitabine) and lamivudine 5'-triphosphates via the phosphoramidate linkage. New compounds were shown to be potent killers of human colon carcinoma cells. Anti-HIV activity of the conjugates was demonstrated as well. The conjugates of phosphorylated lamivudine and dideoxycytidine (zalcitabine) showed higher potency than the parent nucleosides. The conjugate of phosphorylated azidothymidine was less active against HIV-1 than the parent nucleoside probably because of the replacement of its 3'-azido group by 1,2,3-triazole ring. These results show an opportunity for using SiO2 nanoparticles as a transport for delivering phosphorylated nucleosides to cells in order to increase their efficiency as antiviral and anticancer drugs.

  8. Preparation of new alkyne-modified ansamitocins by mutasynthesis

    PubMed Central

    Harmrolfs, Kirsten; Mancuso, Lena; Drung, Binia; Sasse, Florenz


    Summary The preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3. PMID:24605171

  9. Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition.


    Arrowsmith, Merle; Böhnke, Julian; Braunschweig, Holger; Celik, Mehmet Ali; Claes, Christina; Ewing, William C; Krummenacher, Ivo; Lubitz, Katharina; Schneider, Christoph


    Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaromatic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient conditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6 π-aromatic diborabenzene compound, a 2 π-aromatic triplet biradical 1,3-diborete, and a phosphine-stabilized 2 π-homoaromatic 1,3-dihydro-1,3-diborete. DFT calculations suggest that all three compounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6 H6 and C4 H4 (2+) , and homoaromatic C4 H5 (+) .

  10. Synthesis of Cycloparaphenyleneacetylene via Alkyne Metathesis: C70 Complexation and Copper-Free Triple Click Reaction.


    Lee, Semin; Chénard, Etienne; Gray, Danielle L; Moore, Jeffrey S


    Alkyne metathesis provided an efficient macrocyclization route to a cycloparaphenyleneacetylene derivative in high yield. The cavity size was suitably matched for C70 which was tightly bound in an induced-fit fashion. The strain on the alkynyl bonds enabled a copper-free, three-fold azide-alkyne cycloaddi-tion at 50 °C.

  11. Multi-component Cycloaddition Approaches in the Catalytic Asymmetric Synthesis of Alkaloid Targets†

    PubMed Central

    Perreault, Stéphane; Rovis, Tomislav


    Cycloaddition reactions are attractive strategies for rapid formation of molecular complexity in organic synthesis as multiple bonds are formed in a single process. To this end, several research groups have been actively involved in the development of catalytic methods to activate readily accessible π-components to achieve cycloadditions. However, the use of C-N π-components for the formation of heterocycles by these processes is less well developed. It has been previously demonstrated that the combination of different isocyanates with two alkynes yields pyridones of several types by metal-catalyzed [2+2+2] cycloadditions. The potential of this chemistry has been extended to alkenes as C-C π-components, allowing the formation of sp3-stereocenters. In this tutorial review directed towards [n+2+2] cycloaddition of heterocumulenes, alkynes and alkenes, the recent advances in catalytic asymmetric synthesis of indolizidine, quinolizidine and azocine skeletons are discussed. PMID:19847348

  12. Cu/Pd-Catalyzed, Three-Component Click Reaction of Azide, Alkyne, and Aryl Halide: One-Pot Strategy toward Trisubstituted Triazoles.


    Wei, Fang; Li, Haoyu; Song, Chuanling; Ma, Yudao; Zhou, Ling; Tung, Chen-Ho; Xu, Zhenghu


    A Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide has been developed. By using this Cu/Pd transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-triazoles were quickly assembled in one step in high yields with complete regioselectivity, just like assembling Lego bricks. Notably, different from the well-established CuAAC click reactions only working on terminal alkynes, this reaction offers an alternative solution for the problem of the click reaction of internal alkynes.

  13. CuAAC click chemistry accelerates the discovery of novel chemical scaffolds as promising protein tyrosine phosphatases inhibitors.


    He, X-P; Xie, J; Tang, Y; Li, J; Chen, G-R


    Protein tyrosine phosphatases (PTPs) are crucial regulators for numerous biological processes in nature. The dysfunction and overexpression of many PTP members have been demonstrated to cause fatal human diseases such as cancers, diabetes, obesity, neurodegenerative diseases and autoimmune disorders. In the past decade, considerable efforts have been devoted to the production of PTPs inhibitors by both academia and the pharmaceutical industry. However, there are only limited drug candidates in clinical trials and no commercial drugs have been approved, implying that further efficient discovery of novel chemical entities competent for inhibition of the specific PTP target in vivo remains yet a challenge. In light of the click-chemistry paradigm which advocates the utilization of concise and selective carbon-heteroatom ligation reactions for the modular construction of useful compound libraries, the Cu(I)-catalyzed azidealkyne 1,3-dipolar cycloaddition reaction (CuAAC) has fueled enormous energy into the modern drug discovery. Recently, this ingenious chemical ligation tool has also revealed efficacious and expeditious in establishing large combinatorial libraries for the acquisition of novel PTPs inhibitors with promising pharmacological profiles. We thus offer here a comprehensive review highlighting the development of PTPs inhibitors accelerated by the CuAAC click chemistry.

  14. Resin-supported catalysts for CuAAC click reactions in aqueous or organic solvents.


    Presolski, Stanislav I; Mamidyala, Sreeman K; Manzenrieder, Florian; Finn, M G


    The copper-catalyzed azide-alkyne cycloaddition click reaction is a valuable process for the synthesis of libraries of drug candidates, derivatized polymers and materials, and a wide variety of other functional molecules. In some circumstances, the removal of the copper catalyst is both necessary and inconvenient. We describe here two immobilized forms of a Cu-binding ligand that has been shown to accelerate triazole formation under many different conditions, using different resin supports that are appropriate for aqueous or organic solvents. Copper leaching from these resins was modest, allowing them to be reused in many reaction/filtration cycles without recharging with metal ion. The utility of this catalyst form was demonstrated in the convenient synthesis of 20 N-acetylgalactosamine derivatives for biological testing.

  15. Ligand-guided pathway selection in nickel-catalyzed couplings of enals and alkynes.


    Li, Wei; Montgomery, John


    Nickel-catalyzed couplings of enals and alkynes utilizing triethylborane as the reducing agent illustrate a significant dependence on ligand structure. Simple variation of monodentate phosphines allows selective access to alkylative couplings or reductive cycloadditions, while further variation of reaction conditions provides clean access to reductive couplings and redox-neutral couplings.

  16. Synthesis of quinolones by nickel-catalyzed cycloaddition via elimination of nitrile.


    Nakai, Kenichiro; Kurahashi, Takuya; Matsubara, Seijiro


    Substituted quinolones were efficiently synthesized via the nickel-catalyzed cycloaddition of o-cyanophenylbenzamide derivatives with alkynes. The reaction involves elimination of a nitrile group by cleavage of the two independent aryl-cyano and aryl-carbonyl C-C bonds of the amides.

  17. Cycloaddition reactions of ICNO

    NASA Astrophysics Data System (ADS)

    Pasinszki, Tibor; Krebsz, Melinda; Hajgató, Balázs


    The mechanism and selectivity of cycloaddition reactions of iodonitrile oxide, ICNO, have been studied with theoretical methods for the first time using MR-AQCC coupled-cluster and B3LYP DFT methods. Calculations have predicted that the favoured ICNO dimerisation process is a multi-step reaction to diiodofuroxan involving dinitrosoethylene-like intermediates. The ICNO cycloaddition with nitriles and ethynyl derivatives is a synchronous process favouring the formation of 1,2,4-oxadiazole and 1,2-oxazole derivatives, respectively. The cycloaddition reactions of ICNO have been studied experimentally by generating ICNO from AgCNO and iodine. Diiodofuroxan is obtained, however, even at the presence of nitriles.

  18. Copper-Catalyzed Azide–Alkyne Click Chemistry for Bioconjugation

    PubMed Central

    Presolski, Stanislav I.; Hong, Vu Phong; Finn, M.G.


    The copper-catalyzed azide-alkyne cycloaddition reaction is widely used for the connection of molecular entities of all sizes. A protocol is provided here for the process with biomolecules. Ascorbate is used as reducing agent to maintain the required cuprous oxidation state. Since these convenient conditions produce reactive oxygen species, five equivalents of a copper-binding ligand is used with respect to metal. The ligand both accelerates the reaction and serves as a sacrificial reductant, protecting the biomolecules from oxidation. A procedure is also described for testing the efficiency of the reaction under desired conditions for purposes of optimization, before expensive biological reagents are used. PMID:22844652

  19. Cycloaddition reactions of allenes with N-phenylmaleimide. A two-step, diradical-intermediate process

    SciTech Connect

    Pasto, D.J.; Heid, P.F.; Warren, S.E.


    The stereoselectivities, chemoselectivities, relative reactivities, and kinetic isotope effects have been determined in the cycloaddition reactions of substituted allenes with N-phenylmaleimide. The comparison of these results with those derived from the studies of the cycloaddition of 1,1-dichloro-2,2-difluoroethene and the radical-chain addition of benzenethiol to allenes strongly indicates that the cycloadditions with N-phenylmaleimide occur via a two-step, diradical-intermediate process. The stereochemical features controlling the formation of the stereoisomeric diradical intermediates and their ring closures are discussed. In addition to the cycloaddition processes, competitive ene reactions occur to produce intermediate dienes, which react further to produce 1:2 adducts or nonreactive alkyne-containing 1:1 adducts. These ene reactions also appear to proceed via diradical intermediates.

  20. Chiral bis(imidazolidine)pyridine-cu complex-catalyzed enantioselective [3+2]-cycloaddition of azomethine imines with propiolates.


    Arai, Takayoshi; Ogino, Yuta


    [3+2] Cycloaddition of azomethine imines with electron-deficient terminal alkynes was smoothly catalyzed by a chiral bis(imidazolidine)pyridine-CuOAc complex to give bicyclic pyrazolo[1,2-a]pyrazolone derivatives with up to 74% ee.

  1. Dissecting Anion Effects in Gold(I)-Catalyzed Intermolecular Cycloadditions

    PubMed Central

    Homs, Anna; Obradors, Carla; Lebœuf, David; Echavarren, Antonio M


    From a series of gold complexes of the type [t-BuXPhosAu(MeCN)]X (X=anion), the best results in intermolecular gold(I)-catalyzed reactions are obtained with the complex with the bulky and soft anion BAr4F− [BAr4F−=3,5-bis(trifluoromethyl)phenylborate] improving the original protocols by 10–30% yield. A kinetic study on the [2+2] cycloaddition reaction of alkynes with alkenes is consistent with an scenario in which the rate-determining step is the ligand exchange to generate the (η2-phenylacetylene)gold(I) complex. We have studied in detail the subtle differences that can be attributed to the anion in this formation, which result in a substantial decrease in the formation of unproductive σ,π-(alkyne)digold(I) complexes by destabilizing the conjugated acid formed. PMID:26190958

  2. Synthesis of Main Chain Poly(carbazole)s via CuAAC

    SciTech Connect

    Chen, Zheng; Dreyer, Daniel R; Wu, Zong-Quan; Wiggins, Kelly M; Bielawski, Christopher W.


    The synthesis and characterization of a novel family of main-chain carbazole-containing polymers using copper-catalyzed azide-alkyne cycloaddition chemistry is reported. The reactions were performed under mild conditions using readily available copper catalysts and ligands, which afforded polymeric products with Mws up to 18 kDa. Using a range of techniques, the polymers were found to exhibit a glass transition temperature (Tg) of 85 °C, high thermal stability (Td = 274 °C), and high photoluminescent quantum efficiency (Φf = 0.29; λem = 448 nm), which underscore their potential for use in organic light-emitting diodes or other emissive devices, particularly where efficient blue emission is of value. The approach described offers practical advantages over other synthetic methods used to prepare main-chain carbazole-containing polymers, especially with regard to the lack of need for rigorously inert conditions and the absence of byproducts generated during the polymerization reaction.

  3. Iron-catalyzed cycloaddition reaction of diynes and cyanamides at room temperature.


    Wang, Chunxiang; Wang, Dongping; Xu, Fen; Pan, Bin; Wan, Boshun


    An iron-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and cyanamides at room temperature is reported. Highly substituted 2-aminopyridines were obtained in good to excellent yields with high regioselectivity. Insights toward the reaction process were investigated through in situ IR spectra and control experiments. In this iron-catalyzed cycloaddition reaction, the active iron species was generated only in the presence of both alkynes and nitriles. The lower reaction temperature, broad substrates scope, and inversed regioselectivity make it a complementary method to the previously developed iron catalytic system.

  4. Click chemistry grafting of poly(ethylene glycol) brushes to alkyne-functionalized pseudobrushes.


    Ostaci, Roxana-Viorela; Damiron, Denis; Grohens, Yves; Léger, Liliane; Drockenmuller, Eric


    A versatile method for the grafting of azide-terminated polymer chains to alkyne-functionalized pseudobrushes by the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition has been developed. First, poly[(propargyl methacrylate)-r-(glycidyl methacrylate)-r-(methyl methacrylate)] random copolymers with monomer ratios of respectively 27/27/46, 41/31/28, and 45/55/0 were synthesized by RAFT polymerization. Then, dense alkyne-functionalized pseudobrushes were grafted in melt by thermal ring-opening of the glycidyl groups by the silanols from the silicon substrate. Finally, the grafting of tailor-made alpha-methoxy-omega-azido-poly(ethylene glycol)s (M(w) approximately 5000, 20,000, and 50,000 g/mol) by Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition was performed in sealed reactors at 60 degrees C for 72 h using a polymer weight fraction of 10% in tetrahydrofuran and Cu(PPh(3))(3)Br/DIPEA as the catalytic system. Alkyne-functionalized pseudobrushes and poly(ethylene glycol) brushes were characterized by ellipsometry, scanning probe microscopy, and water contact angle measurements. This "grafting-to" approach represents a fast and versatile method to provide thick and homogeneous polymer brushes with a high surface coverage. A major benefit of this strategy is the tunable and versatile tethering of alkyne functionalities to silicon substrates using a straightforward spin-coating procedure.

  5. Cyclic polymers from alkynes

    NASA Astrophysics Data System (ADS)

    Roland, Christopher D.; Li, Hong; Abboud, Khalil A.; Wagener, Kenneth B.; Veige, Adam S.


    Cyclic polymers have dramatically different physical properties compared with those of their equivalent linear counterparts. However, the exploration of cyclic polymers is limited because of the inherent challenges associated with their synthesis. Conjugated linear polyacetylenes are important materials for electrical conductivity, paramagnetic susceptibility, optical nonlinearity, photoconductivity, gas permeability, liquid crystallinity and chain helicity. However, their cyclic analogues are unknown, and therefore the ability to examine how a cyclic topology influences their properties is currently not possible. We have solved this challenge and now report a tungsten catalyst supported by a tetraanionic pincer ligand that can rapidly polymerize alkynes to form conjugated macrocycles in high yield. The catalyst works by tethering the ends of the polymer to the metal centre to overcome the inherent entropic penalty of cyclization. Gel-permeation chromatography, dynamic and static light scattering, viscometry and chemical tests are all consistent with theoretical predictions and provide unambiguous confirmation of a cyclic topology. Access to a wide variety of new cyclic polymers is now possible by simply choosing the appropriate alkyne monomer.

  6. Advanced hybrid fluoropolymers from the cycloaddition of aryl trifluorovinyl ethers

    NASA Astrophysics Data System (ADS)

    Ligon, S. Clark, Jr.

    This dissertation discusses the synthesis of aryl trifluorovinyl ethers and their cycloaddition polymerization to give perfluorocyclobutyl (PFCB) polymers. To explore the stereochemistry of these polymers, simple monomfunctional aryl trifluorovinyl ethers were dimerized and the resultant cis and trans isomers were separated. Differences in structure help to improve understanding of the amorphous nature of the bulk PFCB polymeric material. To apply this knowledge, crown ether containing perfluorocyclobutyl (PFCB) polymers were synthesized for use in lithium ion battery applications. While poor solubility has hindered further development of these materials, slight modifications to structure may provide a solution. Also described is a fluorinated aryl vinyl ether and its attempted copolymerization with chlorotrifluoroethylene. While this copolymerization did not yield the desired materials, novel semifluorinated phenol precursors have been utilized in reactions with carboxylic acids to give polyesters and most recently with phosgene like species to give polycarbonates. Next, PFCB polymers were post functionalized with fluoroalkyl tethers to improve oleophobicity and hydrophobicity without decreasing thermal stability or optical clarity. In addition, various silica nanostructures were functionalized with aryl trifluorovinyl ethers. This includes the reaction of aryl silanes to give trifluorovinyl ether functional POSS and their polymerization to provide PFCB hybrid materials. Silane coupling agents were also used to functionalize colloidal silica and fumed silica nanoparticles. These procedures allow excellent dispersion of the silica nanoparticles throughout the fluoropolymer matrix. Finally, the reaction of aryl trifluorovinyl ether with nonfluorinated alkenes and alkynes was explored. In these reactions, the fluorinated olefin adds with the hydrocarbon olefin to give semifluorinated cyclobutanes (SFCB) and with the alkyne to give semifluorinated cyclobutene. The

  7. Low-valent niobium-catalyzed intermolecular [2 + 2 + 2] cycloaddition of tert-butylacetylene and arylnitriles to form 2,3,6-trisubstituted pyridine derivatives.


    Satoh, Yasushi; Obora, Yasushi


    A catalytic system based on low-valent niobium has been developed, consisting of NbCl5, Zn, and an alkoxysilane. This combination has been shown to be an efficient catalyst for the synthesis of pyridine derivatives from the intermolecular cycloaddition of alkynes and nitriles via a niobacyclopentadiene intermediate.

  8. Reactivity and Chemoselectivity of Allenes in Rh(I)-Catalyzed Intermolecular (5 + 2) Cycloadditions with Vinylcyclopropanes: Allene-Mediated Rhodacycle Formation Can Poison Rh(I)-Catalyzed Cycloadditions

    PubMed Central


    Allenes are important 2π building blocks in organic synthesis and engage as 2-carbon components in many metal-catalyzed reactions. Wender and co-workers discovered that methyl substituents on the terminal allene double bond counterintuitively change the reactivities of allenes in [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) cycloadditions with vinylcyclopropanes (VCPs). More sterically encumbered allenes afford higher cycloadduct yields, and such effects are also observed in other Rh(I)-catalyzed intermolecular cycloadditions. Through density functional theory calculations (B3LYP and M06) and experiment, we explored this enigmatic reactivity and selectivity of allenes in [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) cycloadditions with VCPs. The apparent low reactivity of terminally unsubstituted allenes is associated with a competing allene dimerization that irreversibly sequesters rhodium. With terminally substituted allenes, steric repulsion between the terminal substituents significantly increases the barrier of allene dimerization while the barrier of the (5 + 2) cycloaddition is not affected, and thus the cycloaddition prevails. Computation has also revealed the origin of chemoselectivity in (5 + 2) cycloadditions with allene-ynes. Although simple allene and acetylene have similar reaction barriers, intermolecular (5 + 2) cycloadditions of allene-ynes occur exclusively at the terminal allene double bond. The terminal double bond is more reactive due to the enhanced d−π* backdonation. At the same time, insertion of the internal double bond of an allene-yne has a higher barrier as it would break π conjugation. Substituted alkynes are more difficult to insert compared with acetylene, because of the steric repulsion from the additional substituents. This leads to the greater reactivity of the allene double bond relative to the alkynyl group in allene-ynes. PMID:25379606

  9. N-heterocyclic carbene-catalyzed 1,3-dipolar cycloaddition reactions: a facile synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles.


    Kankala, Shravankumar; Vadde, Ravinder; Vasam, Chandra Sekhar


    A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with alkynes was developed for the regioselective synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles. Triethylamine (Et(3)N) was employed as an effective base to generate both nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety of substituents, including other biologically active fragments, onto the isoxazole ring to selectively design multinucleus structures. Further, we have also optimized the conditions for Cu(I)-free Sonogashira cross-coupling to obtain internal alkynes in high yields, which were subsequently used in cycloaddition. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of isoxazoles was ascribed to a beneficial zwitterion intermediate developed by the interaction of the strongly nucleophilic organo-NHC catalyst with alkyne followed by nitrile oxide.

  10. Dynamics of carbene cycloadditions.


    Xu, Lai; Doubleday, Charles E; Houk, K N


    Quasiclassical trajectory calculations using quantum mechanical energies and forces generated by the Venus and Gaussian programs provide for the first time a detailed dynamical picture of singlet carbene, CCl(2) and CF(2), cycloadditions to alkenes on the B3LYP/6-31G* surface. For CF(2), B3LYP/6-31G* with exact exchange reduced to 12% HF was also employed to better mimic the high accuracy surface. The range of geometries sampled in reactive trajectories and the timing of bond formation were explored. All trajectories follow the nonlinear approach proposed by Moore and Hoffmann. The reaction of CCl(2) with ethylene is a dynamically concerted reaction, with an average time gap between formation of the two bonds of 50 fs. The reaction of CF(2) with ethylene is dynamically complex with biexponential decay of the diradical species formed from the first bond formation. A general quantitative dynamical classification of cycloaddition mechanisms is proposed, based on the timing of bond formation.

  11. Modular, Concise, and Efficient Synthesis of Highly Functionalized 5-Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence.


    Tran, Gaël; Gomez Pardo, Domingo; Tsuchiya, Tomoki; Hillebrand, Stefan; Vors, Jean-Pierre; Cossy, Janine


    An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.

  12. Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC "click" chemistry as potential anticancer agents.


    Jin, Xin; Yan, Tian-Hua; Yan, Lan; Li, Qian; Wang, Rui-Lian; Hu, Zhen-Lin; Jiang, Yuan-Ying; Sun, Qing-Yan; Cao, Yong-Bing


    A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC.

  13. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries.


    Wang, Xueshun; Huang, Boshi; Liu, Xinyong; Zhan, Peng


    The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chemistry is a highly robust and efficient strategy for establishing SAR and for discovering bioactive molecules. This review outlines the current status of this methodology in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.

  14. Alkyne metathesis on the rise.


    Fürstner, Alois


    The early years of alkyne metathesis were marked by a somewhat ironic state of affairs: the proposed mechanism was swiftly validated and more than one effective catalyst became available shortly after the discovery of this transformation; surprisingly, however, the impact on synthesis remained very limited for a long period of time. Recent advances, however, suggest that this situation is about to change: the remarkable activity, functional-group tolerance, and reliability of the latest generation of catalysts open the door for highly advanced applications. The resulting (cyclo)alkynes are amenable to numerous postmetathetic transformations, which diversify the product portfolio and bring many different structural motifs into reach. Since the catalysts have also evolved from the glovebox to the benchtop, there should be little barrier left for a wider use of this reaction in organic synthesis.

  15. An efficient bioorthogonal strategy using CuAAC click chemistry for radiofluorinations of SNEW peptides and the role of copper depletion.


    Pretze, Marc; Kuchar, Manuela; Bergmann, Ralf; Steinbach, Jörg; Pietzsch, Jens; Mamat, Constantin


    The EphB2 receptor is known to be overexpressed in various types of cancer and is therefore a promising target for tumor cell imaging by positron emission tomography (PET). In this regard, imaging could facilitate the early detection of EphB2-overexpressing tumors, monitoring responses to therapy directed toward EphB2, and thus improvement in patient outcomes. We report the synthesis and evaluation of several fluorine-18-labeled peptides containing the SNEW amino acid motif, with high affinity for the EphB2 receptor, for their potential as radiotracers in the non-invasive imaging of cancer using PET. For the purposes of radiofluorination, EphB2-antagonistic SNEW peptides were varied at the C terminus by the introduction of L-cysteine, and further by alkyne- or azide-modified amino acids. In addition, two novel bifunctional and bioorthogonal labeling building blocks [(18)F]AFP and [(18)F]BFP were applied, and their capacity to introduce fluorine-18 was compared with that of the established building block [(18)F]FBAM. Copper-assisted Huisgen 1,3-dipolar cycloaddition, which belongs to the set of bioorthogonal click chemistry reactions, was used to introduce both novel building blocks into azide- or alkyne-modified SNEW peptides under mild conditions. Finally, the depletion of copper immediately after radiolabeling is a highly important step of this novel methodology.

  16. Clickable degradable aliphatic polyesters via copolymerization with alkyne epoxy esters: synthesis and postfunctionalization with organic dyes.


    Teske, Nele S; Voigt, Julia; Shastri, V Prasad


    Degradable aliphatic polyesters are the cornerstones of nanoparticle (NP)-based therapeutics. In this paradigm, covalent modification of the NP with cell-targeting motifs and dyes can aid in guiding the NP to its destination and gaining visual confirmation. Therefore, strategies to impart chemistries along the polymer backbone that are amenable to easy modification, such as 1,3-dipolar cycloaddition of an azide to an alkyne (the "click reaction"), could be significant. Here we present a simple and efficient way to introduce alkyne groups at high density in aliphatic polyesters without compromising their crystallinity via the copolymerization of cyclic lactones with propargyl 3-methylpentenoate oxide (PMPO). Copolymers of lactic acid and ε-caprolactone with PMPO were synthesized with up to 9 mol % alkyne content, and accessibility of the alkyne groups to the click reaction was demonstrated using several dyes commonly employed in fluorescence microscopy and imaging (Cy3, ATTO-740, and coumarin 343). In order to establish the suitability of these copolymers as nanocarriers, copolymers were formulated into NPs, and cytocompatibility, cellular uptake, and visualization studies undertaken in HeLa cells. Dye-modified NPs exhibited no quenching, remained stable in solution for at least 10 days, showed no cytotoxicity, and were readily taken up by HeLa cells. Furthermore, in addition to enabling the incorporation of multiple fluorophores within the same NP through blending of individual dye-modified copolymers, dye-modified polyesters offer advantages over physical entrapment of dye, including improved signal to noise ratio and localization of the fluorescence signal within cells, and possess the necessary prerequisites for drug delivery and imaging.

  17. Effect of the metal fragment in the thermal cycloaddition between alkynyl metal(0) Fischer carbene complexes and nitrones.


    Fernandez, Israel; Sierra, Miguel A; Cossío, Fernando P


    The thermal cycloaddition between alkynyl metal(0) Fischer carbenes and nitrones has been studied computationally within the Density Functional Theory framework. It is found that the [3 + 2] cycloaddition takes place via transition structures that are more asynchronous and less aromatic than their nonorganometallic analogues. These reactions are also found to be completely regioselective in favor of the cycloadduct possessing the Fischer carbene moiety and the oxygen atom of the nitrone in a 1,3-relative disposition. These results are consistent with the role of the Fischer carbene moiety as an electron withdrawing group that enhances the electrophilic character of the alkyne group acting as a Michael acceptor as a dipolarophile. In terms of the isolobal analogy model, it can be concluded that alkynylalkoxy metal(0) carbene complexes act in this reaction as organometallic analogues of organic alkyl-propiolates with enhanced electrophilic character.

  18. Preparation and Characterization of Macro- & Monomers for Azide & Alkyne Cycloaddition Polyerization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In 1970 Robert Harper and colleagues, showed that poly(ethylene oxide)s and Poly(propylene oxide)s (PEOs and PPOs, respectively) are effective softeners for cotton fabrics (Textile Chemist and Colorist, 1970, 2(1), 37-41. Using this information, we developed PEO and PPO dibromides and diepoxides to ...

  19. Structural Complexity Through Multicomponent Cycloaddition Cascades Enabled by Dual-Purpose, Reactivity Regenerating 1,2,3-Triene Equivalents

    PubMed Central

    Wender, Paul A.; Fournogerakis, Dennis N.; Jeffreys, Matthew S.; Quiroz, Ryan V.; Inagaki, Fuyuhiko; Pfaffenbach, Magnus


    Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step and time economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalyzed [5+2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalyzed or thermal [4+2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions - the homologous Diels-Alder and Diels-Alder cycloadditions - through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles. PMID:24755598

  20. Cycloaddition model for fullerene formation

    SciTech Connect

    Strout, D.L.; Scuseria, G.E.


    Since their discovery, the fullerenes have challenged scientists with a wide array of problems concerning their properties, behavior, and potential applications. One such fundamental question is that of the assembly of these carbon cages. Much effort has been directed at obtaining an understanding of the process whereby graphite is transformed into fullerenes. In a previous work, we introduced a novel interpretation of the ion chromatography results from fullerene generation experiments. In this work, that interpretation is expanded and ab initio calculations are performed to illustrate how the model explains the experimental results. This `cycloaddition model` is then used to develop a plausible fullerene assembly mechanism. 19 refs., 12 figs., 10 tabs.

  1. Catalyst-Free Cycloaddition Reaction for the Synthesis of Glyconanoparticles.


    Kong, Na; Xie, Sheng; Zhou, Juan; Menéndez, Margarita; Solís, Dolores; Park, JaeHyeung; Proietti, Giampiero; Ramström, Olof; Yan, Mingdi


    A new conjugation method for the immobilization of carbohydrates on nanomaterials was demonstrated simply by mixing perfluorophenyl azide-functionalized silica nanoparticles (SNPs), an amine-derivatized carbohydrate, and phenylacetaldehyde under ambient conditions without any catalyst. The density of carbohydrates on the glyconanoparticles was determined using the quantitative (19)F NMR ((19)F qNMR) technique; for example, the density of d-mannose (Man) on Man-SNPs was 2.5 ± 0.2 × 10(-16) nmol/nm(2). The glyconanoparticles retained their binding affinity and selectivity toward cognate lectins. The apparent dissociation constant of the glyconanoparticles was measured by a fluorescence competition assay, where the binding affinity of Man-SNPs was almost 4 orders of magnitude higher than that of Man with concanavalin A. Moreover, even with a ligand density of 2.6 times lower than Man-SNPs synthesized by the copper-catalyzed azide-alkyne cycloaddition, the binding affinity of Man-SNPs prepared by the current method was more than 4 times higher.

  2. Carbon-rich "Click" 1,2,3-triazoles: hexaphenylbenzene and hexa-peri-hexabenzocoronene-based ligands for Suzuki-Miyaura catalysts.


    Wright, James R; Crowley, James D; Lucas, Nigel T


    Hexaphenylbenzene (HPB) and hexa-peri-hexabenzocoronene-(HBC) functionalised 1,2,3-triazoles have been synthesised using an optimised copper(i)-catalysed azide-alkyne cycloaddition (CuAAC) reaction. The coordination chemistry of these ligands was explored through the synthesis of the respective palladium(ii) complexes and their activity as catalysts in the Suzuki-Miyaura reaction assessed.

  3. Glucose selective bis-boronic acid click-fluor.


    Zhai, Wenlei; Male, Louise; Fossey, John S


    Four novel bis-boronic acid compounds were synthesised via copper catalysed azide-alkyne cycloaddition (CuAAC) reactions. Glucose selectivity was observed for a particular structural motif. Moreover, a new glucose selective fluorescent sensor was designed and synthesised as a result.

  4. Novel porphyrin-psoralen conjugates: synthesis, DNA interaction and cytotoxicity studies.


    Kumar, Dalip; Mishra, Bhupendra A; Chandra Shekar, K P; Kumar, Anil; Akamatsu, Kanako; Kurihara, Ryohsuke; Ito, Takeo


    A Cu(i)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) has been utilized to prepare novel triazole-linked cationic porphyrin-psoralen conjugates that exhibited significant photocytotoxicity against A549 cancer cells (IC50 = 84 nM).

  5. Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC “click” chemistry as potential anticancer agents

    PubMed Central

    Jin, Xin; Yan, Tian-Hua; Yan, Lan; Li, Qian; Wang, Rui-Lian; Hu, Zhen-Lin; Jiang, Yuan-Ying; Sun, Qing-Yan; Cao, Yong-Bing


    A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC. PMID:25120353

  6. Sweet graphene I: toward hydrophilic graphene nanosheets via click grafting alkyne-saccharides onto azide-functionalized graphene oxide.


    Namvari, Mina; Namazi, Hassan


    Water-soluble graphene nanosheets (GNS) were fabricated via functionalization of graphene oxide (GO) with mono and disaccharides on the basal plane and edges using Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes (Click chemistry). To graft saccharides onto the plane of GO, it was reacted with sodium azide to introduce azide groups on the plane. Then, it was treated with alkyne-modified glucose, mannose, galactose, and maltose. In the next approach, we attached 1,3-diazideoprop-2-ol onto the edges of GO and it was subsequently clicked with alkyne-glucose. The products were analyzed by Fourier-transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy, thermogravimetric analysis (TGA), and X-ray diffraction spectrometry. FTIR and TGA results showed both sugar-grafted GO sheets were reduced by sodium ascorbate during click-coupling reaction which is an advantage for this reaction. Besides, glycoside-grafted GNS were easily dispersed in water and stable for two weeks.

  7. Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

    PubMed Central

    Matassini, Camilla; Mirabella, Stefania; Goti, Andrea; Robina, Inmaculada; Moreno-Vargas, Antonio J


    Summary The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases. PMID:26734108

  8. One-step ligand exchange reaction as an efficient way for functionalization of magnetic nanoparticles

    NASA Astrophysics Data System (ADS)

    Mrówczyński, Radosław; Rednic, Lidia; Turcu, Rodica; Liebscher, Jürgen


    Novel magnetic Fe3O4 nanoparticles (NPs) covered by one layer of functionalized fatty acids, bearing entities (Hayashi catalyst, biotin, quinine, proline, and galactose) of high interest for practical application in nanomedicine or organocatalysis, were synthesized. The functionalized fatty acids were obtained by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of azido fatty acids with alkynes. All the magnetic NPs show superparamagnetic behavior with high values of magnetization and high colloidal stability in DCM solution.

  9. Synthesis of chitosan-PEO hydrogels via mesylation and regioselective Cu(I)-catalyzed cycloaddition.


    Tirino, Pasquale; Laurino, Rosaria; Maglio, Giovanni; Malinconico, Mario; d'Ayala, Giovanna Gomez; Laurienzo, Paola


    In this work, a well-defined hydrogel was developed by coupling chitosan with PEO through "click chemistry". Azide functionalities were introduced onto chitosan, through mesylation of C-6 hydroxyl groups, and reacted with a di-alkyne PEO by a regioselective Cu(I)-catalyzed cycloaddition. This synthetic approach allowed us to obtain a hydrogel with a controlled crosslinking degree. In fact, the extent of coupling is strictly dependent on the amount of azido groups on chitosan, which in turn can be easily modulated. The obtained hydrogel, with a crosslinking degree of around 90%, showed interesting swelling properties. With respect to chitosan hydrogels reported in literature, a considerably higher equilibrium uptake was reached (940%). The possibility to control the crosslinking degree of hydrogel and its capability to rapidly absorb high amounts of water make this material suitable for several applications, such as controlled drug release and wound healing.

  10. Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold.


    Werkhoven, P R; Elwakiel, M; Meuleman, T J; Quarles van Ufford, H C; Kruijtzer, J A W; Liskamp, R M J


    Mimics of discontinuous epitopes of for example bacterial or viral proteins may have considerable potential for the development of synthetic vaccines, especially if conserved epitopes can be mimicked. However, due to the structural complexity and size of discontinuous epitopes molecular construction of these mimics remains challeging. We present here a convergent route for the assembly of discontinuous epitope mimics by successive azide alkyne cycloaddition on an orthogonal alkyne functionalized scaffold. Here the synthesis of mimics of the HIV gp120 discontinuous epitope that interacts with the CD4 receptor is described. The resulting protein mimics are capable of inhibition of the gp120-CD4 interaction. The route is convergent, robust and should be applicable to other discontinuous epitopes.

  11. Protein stapling via azide-alkyne ligation.


    Abdeljabbar, Diya M; Piscotta, Frank J; Zhang, Siyan; James Link, A


    Here we demonstrate a methodology, termed protein stapling, for the introduction of covalent constraints into recombinant proteins. Using the azide-alkyne click reaction as the stapling chemistry, we have improved the thermostability of a model leucine zipper protein. Additionally, stapling the core of the small, globular protein G resulted in improved binding to its target, immunoglobulin G.

  12. Hydrophosphorylation of alkynes with phosphinous acids

    SciTech Connect

    Nifant'ev, E.E.; Solovetskaya, L.A.; Magdeeva, R.K.


    A feature of the homolytic hydrophosphorylation of alkynes, as compared with alkenes, is more ready addition of phosphinous acids in presence of benzoyl peroxides. A difference was found in the hydrophosphorylation of acetylenes with dibutylphosphinous acid and with diarylphosphinous acids: the latter tend to form diaddition products.

  13. Cu-free 1,3-dipolar cycloaddition click reactions to form isoxazole linkers in chelating ligands for fac-[M(I)(CO)3]+ centers (M = Re, 99mTc).


    Bottorff, Shalina C; Kasten, Benjamin B; Stojakovic, Jelena; Moore, Adam L; MacGillivray, Leonard R; Benny, Paul D


    Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to Cu(I)-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (click, then chelate and chelate, then click) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective fac-[M(I)(CO)3](+) complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. (99m)Tc experiments demonstrate efficient radiolabeling with click, then chelate; however, the chelate, then click approach led to faster product formation, but lower yields compared to the Re analogues.

  14. Biomedical applications of tetrazine cycloadditions.


    Devaraj, Neal K; Weissleder, Ralph


    use more sterically hindered biotin-avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clinical samples for biomarker profiling to predict malignancy and patient outcome. Finally, we discuss recent results with tetrazine reactions used for in vivo molecular imaging applications. Rapid tetrazine cycloadditions allow modular labeling of small molecules with the most commonly used positron emission tomography isotope, (18)F. Additionally, recent work has applied this reaction directly in vivo for the pretargeted imaging of solid tumors. Future work with tetrazine cycloadditions will undoubtedly lead to optimized protocols, improved probes, and additional biomedical applications.

  15. Reactions of isocyanide-substituted dimanganese carbonyl complexes with alkynes. Alkyne-isocyanide coupling and the synthesis of metalated n-substituted pyridines

    SciTech Connect

    Adams, R.D.; Huang, M. )


    When activated by Me[sub 3]NO in the presence of MeCN, the compounds Mn[sub 2](CO)[sub 9](CNR) (la,b; R = Me, Ph) react with MeO[sub 2]O[sub 2]CC[triple bond]CCO[sub 2]Me to yield the new compounds Mn[sub 2](CO)[sub 8][[mu]-(MeO[sub 2]C)C=C(CO[sub 2]Me)C=NR] (2a,b; R = Me, Ph) in yields of 40% and 32%, respectively. Minor products, Mn[sub 2](CO)[sub 7](CNR)[[mu]-(MeO[sub 2]C)C=C(CO[sub 2]Me)-C=O] (3a,b; R = Me, Ph) were also formed. Compound 2a was characterized crystallographically. The structure shows that the isocyanide ligand was coupled to the alkyne, and the nitrogen atom is coordinated to one of the manganese atoms to form a five-membered cyclo-mangana enimine ring. One of the carboxylate groups is coordinated to the other manganese atom. The compounds (4a), (4b), and (4c) were prepared in yields of 27%, 32%, and 31%, respectively, by treatment of 2a,b with C[sub 2]H[sub 2], and of 2a with HC[sub 2](CO[sub 2]Me) in the presence of UV irradiation. Compound 4a was characterized crystallographically. This compound contains a metalated N-methylpyridine ring formed by a 1,4-cycloaddition of the alkyne to the enimine grouping in compound 2a. One of the metal atoms was shifted to a n-bonding coordination involving four of the carbon atoms of the pyridine ring. 14 refs., 2 figs., 7 tabs.

  16. Direct Synthesis of Poly(dimethylsiloxane) Copolymers with TPE-Properties via CuAAC (Click Chemistry).


    Schmidt, Udo; Zehetmaier, Philip C; Rieger, Bernhard


    Poly(dimethylsiloxane) copolymers were synthesized directly from AA/BB monomers employing a CuAAC reaction (click chemistry) in a polyaddition approach. Using organic dialkynes and oligo(siloxane)s end-functionalized with azide moieties it was possible to obtain siloxane-based copolymers with TPE properties by click chemistry for the first time. As seen from DSC experiments, properties were strongly dependent on the incorporated organic comonomer.

  17. "Click chemistry" in zeolites: copper(I) zeolites as new heterogeneous and ligand-free catalysts for the Huisgen [3+2] cycloaddition.


    Chassaing, Stefan; Sani Souna Sido, Abdelkarim; Alix, Aurélien; Kumarraja, Mayilvasagam; Pale, Patrick; Sommer, Jean


    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.

  18. The Electrophilic Addition to Alkynes Revisited

    NASA Astrophysics Data System (ADS)

    Tidwell, Thomas T.


    A recent claim (Weiss, H. J. Chem. Ed. 1993, 70, 873 - 874) that vinyl cations are not the predominant intermediates in the electrophilic addition to alkynes in disputed on the following grounds: (1) these is a linear free energy correlation between the rates of acid-catalyzed hydration of alkenes and alkynes, and since carbocations are accepted as intermediates in the former reaction, they are implicated in the latter as well; (2) rearrangements are known to be energetically less favorable in vinyl cations compared to alkyl cations, and so the lesser observed tendency for rearrangement in the former case does not argue for the absence of vinyl cation intermediates; (3) there is evidence that alkenes and alkynes react with HBr and HCl in some cases with anti addition and a kinetic term in [HX]2, but this is not an argument for a difference in behavior between the two, or for a pi-complex mechanism; (4) thermochemical calculations show that vinyl cations are not prohbitively destabilized compared to analogous alkyl cations; (5) the observation of an HCl/acetylene pi-complex in the gas phase is not an argument that this represents a rate-limiting transition state in solution.

  19. Bivalent alkyne-bisphosphonate as clickable and solid anchor to elaborate multifunctional iron oxide nanoparticles with microwave enhancement

    NASA Astrophysics Data System (ADS)

    Guénin, Erwann; Hardouin, Julie; Lalatonne, Yoann; Motte, Laurence


    We report the elaboration of clickable superparamagnetic nanoparticles that act as a scaffold for further modifications by click chemistry. This nano platform is easily obtained by coating iron oxide nanoparticle γ-Fe2O3, with a new bifunctional molecule (1-hydroxy-1-phosphonopent-4-ynyl)phosphonic acid (HMBPyne). The HMBP and the alkyne functions act respectively as anchoring surface group and click chemistry functionality. We evaluate the functionalization of this new "clickable" nanoplateform using Huisgen 1,3-cycloaddition as model reaction and demonstrate the potential of microwave irradiation to increase the grafting yield. The effectiveness of click chemistry for the modification of mNPs is explored with a diverse array of functional species.

  20. Concertedness of 1,3-Dipolar Cycloadditions.

    ERIC Educational Resources Information Center

    Haque, M. Serajul


    There are two conflicting views about the mechanism of 1,3-dipolar cycloadditions to multibonds. To reconcile these viewpoints a concerted, spin-paired, diradical mechanism, based on valence bond theory, is proposed. Each of these three mechanisms is discussed. (JN)

  1. Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions

    PubMed Central


    New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels–Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels–Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described. PMID:25961416

  2. Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions.


    Wender, Paul A; Jeffreys, Matthew S; Raub, Andrew G


    New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.

  3. Hydrophosphorylation of substituted alkynes by phosphonic acids

    SciTech Connect

    Nifant'ev, E.F.; Solovetskaya, L.A.; Maslennikova, V.I.; Sergeev, N.M.


    Hydrophosphorylation of functionally substituted alkynes by phosphonic acids can be a convenient method for synthesis of functionally substituted mono- and diphosphine oxides. The ease of hydrophosphorylation is determined by the strength of the negative inductive effect of the substituents on the triple bond and the steric factor. The structure of the bis-adducts was confirmed by elementary analysis and the /sup 31/P and /sup 13/C NMR spectra. The /sup 31/P NMR spectrum is an AB two-spin system. The values of the chemical shifts and spin-spin interaction constants /sup 3/J/sub PP/ are in agreement with the data in the literature for similar compounds.

  4. Nickel-catalyzed decarboxylative carboamination of alkynes with isatoic anhydrides.


    Yoshino, Yasufumi; Kurahashi, Takuya; Matsubara, Seijiro


    An intermolecular nickel-catalyzed addition reaction in which isatoic anhydrides react with alkynes to afford substituted quinolones has been developed. A mechanistic rationale is proposed, implying oxidative addition of Ni(0) to a carbamate, which allows intermolecular addition to alkynes via decarboxylation.

  5. Enantiopure 1,2,3-triazolyl-β-amino acids via click cycloaddition reaction on racemic alkynyl precursors followed by separation of stereoisomers.


    Escudero-Casao, Margarita; Vega-Penaloza, Alberto; Juaristi, Eusebio


    In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, β-peptides incorporating β2- and β3-amino acids (the higher homologs of natural α-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to β-amino acids were prepared selectively from the corresponding alkynyl-β2-amino acids according to Huisgen's copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating α-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation.

  6. Metabolic Labeling with an Alkyne-modified Isoprenoid Analog Facilitates Imaging and Quantification of the Prenylome in Cells.


    Palsuledesai, Charuta C; Ochocki, Joshua D; Kuhns, Michelle M; Wang, Yen-Chih; Warmka, Janel K; Chernick, Dustin S; Wattenberg, Elizabeth V; Li, Ling; Arriaga, Edgar A; Distefano, Mark D


    Protein prenylation is a post-translational modification that is responsible for membrane association and protein-protein interactions. The oncogenic protein Ras, which is prenylated, has been the subject of intense study in the past 20 years as a therapeutic target. Several studies have shown a correlation between neurodegenerative diseases including Alzheimer's disease and Parkinson's disease and protein prenylation. Here, a method for imaging and quantification of the prenylome using microscopy and flow cytometry is described. We show that metabolically incorporating an alkyne isoprenoid into mammalian cells, followed by a Cu(I)-catalyzed alkyne azide cycloaddition reaction to a fluorophore, allows for detection of prenylated proteins in several cell lines and that different cell types vary significantly in their levels of prenylated proteins. The addition of a prenyltransferase inhibitor or the precursors to the native isoprenoid substrates lowers the levels of labeled prenylated proteins. Finally, we demonstrate that there is a significantly higher (22%) level of prenylated proteins in a cellular model of compromised autophagy as compared to normal cells, supporting the hypothesis of a potential involvement of protein prenylation in abrogated autophagy. These results highlight the utility of total prenylome labeling for studies on the role of protein prenylation in various diseases including aging-related disorders.

  7. Alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes: a carboalkynylation route to alkyl-substituted alkynes.


    Zhou, Ming-Bo; Huang, Xiao-Cheng; Liu, Yan-Yun; Song, Ren-Jie; Li, Jin-Heng


    A mild and general alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes for assembling alkyl-substituted alkynes is described. This method represents a new way to the use of transient σ-alkylpalladium(II) complexes in organic synthesis through 1,2-carboalkynylation of alkenes.

  8. Hydrazones as substrates for cycloaddition reactions

    NASA Astrophysics Data System (ADS)

    Belskaya, N. P.; Eliseeva, A. I.; Bakulev, V. A.


    The [2+2]-, [4+2]- and [3+2]-cycloaddition reactions of hydrazones and 1,2-diazabuta-1,3-dienes, azomethine imines, nitrile imines and azomethine ylides formed upon hydrazone transformations with dienophiles, dipolarophiles and dienes are considered. The principal issues of structure and reactivity of active substrates and the influence of the reaction conditions and catalysts on the reaction regioselectivity and efficiency are discussed. The bibliography includes 288 references.

  9. All kinds of reactivity: recent breakthroughs in metal-catalyzed alkyne chemistry.


    Anaya de Parrodi, Cecilia; Walsh, Patrick J


    Alkynes of reactions: Recent breakthroughs in metal-catalyzed alkyne reactions, which expand the synthetic utility of alkynes, have been achieved. These approaches broaden the range of alkynes that are accessible by C--N and C--C bond-forming reactions and demonstrate that the use of bifunctional heterobimetallic catalysts can lead to new reactivity and excellent enantioselectivity (see scheme).

  10. Recyclable porous polymer-supported copper catalysts for Glaser and Huisgen 1,3-diolar cycloaddition reactions.


    Sun, Qi; Lv, Zhonfei; Du, Yuyang; Wu, Qinming; Wang, Liang; Zhu, Longfeng; Meng, Xiangju; Chen, Wanzhi; Xiao, Feng-Shou


    A family of polymer-attached phenanthrolines was prepared from solvothermal copolymerization of divinylbenzene with N-(1,10-phenanthroline-5-yl)acrylamide in different ratios. The polymer-supported copper catalysts were obtained through typical impregnation with copper(II) salts. The polymers and supported copper catalysts have been characterized by N2 adsortion, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermogravimetric analysis (TG); they exhibit a high surface area, hierarchical porosity, large pore volume, and high thermal and chemical stabilities. The copper catalyst has proved to be highly active for Glaser homocoupling of alkynes and Huisgen 1,3-diolar cycloaddition of alkynes with benzyl azide under mild conditions at low catalyst loading. The heterogeneous copper catalyst is more active than commonly used homogeneous and nonporous polystyrene-supported copper catalysts. In particular, the catalyst is easily recovered and can be recycled at least ten times without any obvious loss in catalytic activity. Metal leaching was prevented due to the strong binding ability of phenanthroline and products were not contaminated with copper, as determined by ICP analysis.

  11. Polyaddition of Azide-Containing Norbornene-Based Monomer through Strain-Promoted 1,3-Dipolar Cycloaddition Reaction.


    Zhang, Xiaojuan; Zhang, Qian; Wu, Yuzhen; Feng, Chao; Xie, Chao; Fan, Xiaodong; Li, Pengfei


    The azide-alkyne "click" reaction has been well known in the past decade, however, another kind of 1,3-dipolar cycloaddition, the azide-alkene reaction is not fully explored in polymer science to date. This contribution reports, for the first time, the discovery of a polyaddition of norbornene based monomer (NC11N3 ) containing both strained double bond and azide moieties. The reaction product is characterized by Fourier transform infrared spectroscopy (FTIR), NMR, gel permeation chromatography (GPC), and mass spectrometry (MS), which confirmed the mechanism that is through cycloaddition of azide to strained double bond on norbornene ring to form triazoline linkage. The reaction can proceed at room temperature as indicated by the increase of molecular weight and viscosity during storage. Monomer, dimer, trimer, tetramer, etc., and species with loss of N2 due to lability of triazoline moiety are identified in the mixture of reaction product. As a unique feature, elimination of N2 in the five-membered ring of triazoline affords a chance to form highly reactive materials, such as with aziridine, which can be a very powerful tool in chemical functionalizations, and find promising applications in reactive polymer resin industries.

  12. Synthesis of 1,3-bis(tetracyano-2-azulenyl-3-butadienyl)azulenes by the [2+2] cycloaddition-retroelectrocyclization of 1,3-bis(azulenylethynyl)azulenes with tetracyanoethylene.


    Shoji, Taku; Maruyama, Mitsuhisa; Maruyama, Akifumi; Ito, Shunji; Okujima, Tetsuo; Toyota, Kozo


    1,3-Bis(azulenylethynyl)azulene derivatives 9-14 have been prepared by palladium-catalyzed alkynylation of 1-ethynylazulene 8 with 1,3-diiodoazulene 1 or 1,3-diethynylazulene 2 with the corresponding haloazulenes 3-7 under Sonogashira-Hagihara conditions. Bis(alkynes) 9-14 reacted with tetracyanoethylene (TCNE) in a formal [2+2] cycloaddition-retroelectrocyclization reaction to afford the corresponding new bis(tetracyanobutadiene)s (bis(TCBDs)) 15-20 in excellent yields. The redox behavior of bis(TCBD)s 15-20 was examined by using CV and differential pulse voltammetry (DPV), which revealed their reversible multistage reduction properties under the electrochemical conditions. Moreover, a significant color change of alkynes 9-14 and TCBDs 15-20 was observed by visible spectroscopy under the electrochemical reduction conditions.

  13. Vicinal Difluoroalkylation and Aminosulfonylation of Alkynes under Photoinduced Conditions.


    Xiang, Yuanchao; Li, Yuewen; Kuang, Yunyan; Wu, Jie


    A photoinduced vicinal difluoroalkylation and aminosulfonylation of alkynes under photocatalysis was realized. The combination of ethyl 2-bromo-2,2-difluoroacetate, alkynes, and DABCO⋅(SO2 )2 with hydrazines, catalyzed by 9-mes-10-methyl acridinium perchlorate in the presence of visible light, afforded (E)-ethyl 2,2-difluoro-4-aryl-4-sulfamoylbut-3-enoates in good yields with high stereoselectivity. This four-component reaction proceeds through radical addition with the insertion of sulfur dioxide.

  14. De Novo proteome analysis of genetically modified tumor cells by a metabolic labeling/azide-alkyne cycloaddition approach.


    Ballikaya, Seda; Lee, Jennifer; Warnken, Uwe; Schnölzer, Martina; Gebert, Johannes; Kopitz, Jürgen


    Activin receptor type II (ACVR2) is a member of the transforming growth factor type II receptor family and controls cell growth and differentiation, thereby acting as a tumor suppressor. ACVR2 inactivation is known to drive colorectal tumorigenesis. We used an ACVR2-deficient microsatellite unstable colon cancer cell line (HCT116) to set up a novel experimental design for comprehensive analysis of proteomic changes associated with such functional loss of a tumor suppressor. To this end we combined two existing technologies. First, the ACVR2 gene was reconstituted in an ACVR2-deficient colorectal cancer (CRC) cell line by means of recombinase-mediated cassette exchange, resulting in the generation of an inducible expression system that allowed the regulation of ACVR2 gene expression in a doxycycline-dependent manner. Functional expression in the induced cells was explicitly proven. Second, we used the methionine analog azidohomoalanine for metabolic labeling of newly synthesized proteins in our cell line model. Labeled proteins were tagged with biotin via a Click-iT chemistry approach enabling specific extraction of labeled proteins by streptavidin-coated beads. Tryptic on-bead digestion of captured proteins and subsequent ultra-high-performance LC coupled to LTQ Orbitrap XL mass spectrometry identified 513 proteins, with 25 of them differentially expressed between ACVR2-deficient and -proficient cells. Among these, several candidates that had already been linked to colorectal cancer or were known to play a key role in cell growth or apoptosis control were identified, proving the utility of the presented experimental approach. In principle, this strategy can be adapted to analyze any gene of interest and its effect on the cellular de novo proteome.

  15. Click Triazoles for Bioconjugation

    PubMed Central

    Zheng, Tianqing; Rouhanifard, Sara H.; Jalloh, Abubakar S.


    Click Chemistry is a set of rapid, selective and robust reactions that give near-quantitative yield of the desired product in aqueous solutions. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) that forms 1,4-disubstituted triazoles is a prototypical example of click chemistry that features exquisite selectivity and bioorthogonality—that is, non-interacting with biological components while proceeding under physiological conditions. Over the past ten years, CuAAC has found extensive applications in the field of chemical biology. In this chapter, we describe the discovery of Cu(I) catalysts for this transformation and the recent development of the strain-promoted azide-alkyne cycloaddition that eliminate the use of copper. We also highlight several recent applications toward conjugating biomolecules, including proteins, nucleic acids, lipids and glycans, with biophysical probes for both in vitro and in vivo studies. PMID:25431628

  16. Branched Polyhedral Oligomeric Silsesquioxane Nanoparticles Prepared via Strain-Promoted 1,3-Dipolar Cycloadditions

    PubMed Central

    Ledin, Petr A.; Xu, Weinan; Friscourt, Frédéric; Boons, Geert-Jan; Tsukruk, Vladimir V.


    Conjugation of small organic molecules and polymers to polyhedral oligosilsesquioxane (POSS) cores results in novel hybrid materials with unique physical characteristics. We report here an approach in which star-shaped organic–inorganic scaffolds bearing eight cyclooctyne moieties can be rapidly functionalized via strain-promoted azide–alkyne cycloaddition (SPAAC) to synthesize a series of nearly monodisperse branched core–shell nanoparticles with hydrophobic POSS cores and hydrophilic arms. We established that SPAAC is a robust method for POSS core octafunctionalization with the reaction rate constant of 1.9 × 10−2 M−1 s−1. Functionalization with poly(ethylene glycol) (PEG) azide, fluorescein azide, and unprotected lactose azide gave conjugates which represent different classes of compounds: polymer conjugates, fluorescent dots, and bioconjugates. These resulting hybrid compounds were preliminarily tested for their ability to self-assemble in solution and at the air–water interface. We observed the formation of robust smooth Langmuir monolayers with diverse morphologies. We found that polar lactose moieties are completely submerged into the subphase whereas the relatively hydrophobic fluorescein arms had extended conformation at the interface, and PEG arms were partially submerged. Finally, we observed the formation of stable micelles with sizes between 70 and 160 nm in aqueous solutions with size and morphology of the structures dependent on the molecular weight and the type of the peripheral hydrophilic moieties. PMID:26131712

  17. Anionic surfactants enhance click reaction-mediated protein conjugation with ubiquitin.


    Schneider, Daniel; Schneider, Tatjana; Aschenbrenner, Joos; Mortensen, Franziska; Scheffner, Martin; Marx, Andreas


    The Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has become increasingly important in the conjugation chemistry of biomolecules. For example, it is an efficient and convenient method to generate defined ubiquitin-protein conjugates. Here, we investigate the effect of surfactants on the efficiency of CuAAC for chemical protein ubiquitylation. We found that anionic surfactants enhance conjugate formation by up to 10-fold resulting in high yields even at low (i.e., micromolar) concentrations of the reactants. Notably, the herein investigated conjugates are functional and thus properly folded.

  18. Cu(I)-assisted click chemistry strategy for conjugation of non-protected cross-bridged macrocyclic chelators to tumour-targeting peptides.


    Cai, Zhengxin; Li, Barbara T Y; Wong, Edward H; Weisman, Gary R; Anderson, Carolyn J


    Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry has inherent challenges for copper-labeled radiopharmaceuticals. An azide-modified phosphonate-based cross-bridged macrocyclic chelator was synthesized for click chemistry conjugation with azide-modified Y3-TATE (a somatostatin analogue) on resin, without the need for protecting the chelator. The (64)Cu-labeled bioconjugate shows favourable in vitro and in vivo behaviour.

  19. A "clickable" titanium surface platform.


    Watson, Matthew A; Lyskawa, Joël; Zobrist, Cédric; Fournier, David; Jimenez, Maude; Traisnel, Michel; Gengembre, Léon; Woisel, Patrice


    A straightforward functionalization of a titanium surface using "click" chemistry is reported. A "clickable" titanium surface platform was prepared by the immobilization of an azide-functionalized electroactive catechol anchor and was subsequently derivatized with an electroactive or fluorinated probe via the CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction. The course of the reaction was investigated by contact angle, XPS, and electrochemical measurements.

  20. Type III-B rotaxane dendrimers.


    Ho, Watson K-W; Lee, Siu-Fung; Wong, Chi-Hin; Zhu, Xiao-Ming; Kwan, Chak-Shing; Chak, Chun-Pong; Mendes, Paula M; Cheng, Christopher H K; Leung, Ken Cham-Fai


    Type III-B first generation [3]rotaxane and second generation [4]rotaxane dendrimers have been synthesized via (1) a modified copper-catalyzed alkyne-azide cycloaddition (CuAAC), (2) Glaser-Hay's acetylenic oxidative homo-coupling, and (3) amide formation. The dendron does not reveal obvious cytotoxicities in L929 fibroblast cells. The rotaxane dendrimers can capture ammonia and are switchable both in solution and on surfaces.

  1. Bacterial genome mining of enzymatic tools for alkyne biosynthesis

    PubMed Central

    Zhu, Xuejun; Su, Michael; Manickam, Kadhirvel; Zhang, Wenjun


    The alkyne is an important functionality widely used in material science, pharmaceutical science, and chemical biology, but the importance of this functionality is contrasted by the very limited number of enzymes known to be involved in alkyne biosynthesis. We recently reported the first known carrier protein-dependent pathway for terminal alkyne formation, and in silico analysis suggested that this mechanism could be widespread in bacteria. In this paper, we screened additional homologous gene cassettes presumed to be involved in alkyne biosynthesis using both in vitro biochemical study and an E. coli-polyketide synthase (PKS) reporting system for in vivo analysis. We discovered and characterized a new terminal alkyne biosynthetic pathway comprised of TtuA, B, and C from Teredinibacter turnerae T7901. While the acyl-CoA ligase homolog (TtuA) demonstrated promiscuity in the activation and loading of medium-chain fatty acids onto the carrier protein (TtuC), the desaturase homolog (TtuB) showed stringent substrate specificity towards C10 fatty acyl moieties. In addition, TtuB was demonstrated to be a bifunctional desaturase/acetylenase that efficiently catalyzed two sequential O2-dependent dehydrogenation reactions. A novel terminal-alkyne bearing polyketide was further produced upon co-expression of ttuABC and a PKS gene in E. coli. The discovery and characterization of TtuA, B, and C provides us with a new bifunctional desaturase/acetylenase for mechanistic and structural study and expands the scarce enzyme inventory for the biosynthesis of the alkyne functionality, which has important applications in synthetic and chemical biology. PMID:26441143

  2. Cycloadditions of Noncomplementary Substituted 1,2,3-Triazines

    PubMed Central


    The scope of the [4 + 2] cycloaddition reactions of substituted 1,2,3-triazines, bearing noncomplementary substitution with electron-withdrawing groups at C4 and/or C6, is described. The studies define key electronic and steric effects of substituents impacting the reactivity, mode (C4/N1 vs C5/N2), and regioselectivity of the cycloaddition reactions of 1,2,3-triazines with amidines, enamines, and ynamines, providing access to highly functionalized heterocycles. PMID:25222918

  3. Difluorocarbene Addition to Alkenes and Alkynes in Continuous Flow.


    Rullière, Pauline; Cyr, Patrick; Charette, André B


    The first in-flow difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The in situ generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes, allowing the synthesis of the corresponding difluorocyclopropanes and difluorocyclopropenes. The reaction is complete within a 10 min residence time at high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this process in a green, atom-economic, and safe manner.

  4. Cobalt-Catalyzed Z-Selective Hydrosilylation of Terminal Alkynes.


    Teo, Wei Jie; Wang, Chao; Tan, Ye Wei; Ge, Shaozhong


    A cobalt-catalyzed Z-selective hydrosilylation of alkynes has been developed relying on catalysts generated from bench-stable Co(OAc)2 and pyridine-2,6-diimine (PDI) ligands. A variety of functionalized aromatic and aliphatic alkynes undergo this transformation, yielding Z-vinylsilanes in high yields with excellent selectivities (Z/E ratio ranges from 90:10 to >99:1). The addition of a catalytic amount of phenol effectively suppressed the Z/E-isomerization of the Z-vinylsilanes that formed under catalytic conditions.

  5. Stereo‐ and Regioselective Alkyne Hydrometallation with Gold(III) Hydrides

    PubMed Central

    Pintus, Anna; Rocchigiani, Luca; Fernandez‐Cestau, Julio


    Abstract The hydroauration of internal and terminal alkynes by gold(III) hydride complexes [(C^N^C)AuH] was found to be mediated by radicals and proceeds by an unexpected binuclear outer‐sphere mechanism to cleanly form trans‐insertion products. Radical precursors such as azobisisobutyronitrile lead to a drastic rate enhancement. DFT calculations support the proposed radical mechanism, with very low activation barriers, and rule out mononuclear mechanistic alternatives. These alkyne hydroaurations are highly regio‐ and stereospecific for the formation of Z‐vinyl isomers, with Z/E ratios of >99:1 in most cases. PMID:27592697

  6. A Hydration of an Alkyne Illustrating Steam and Vacuum Distillation.

    ERIC Educational Resources Information Center

    Wasacz, J. P.; Badding, V. G.


    Reports on the conversion 2,5-dimethylhexyne-2,5-diol(I) to 2,2,5,5-tetramethyltetrahydrofuran-3-one(II) using aqueous mercuric sulfate without the use of acid. The experiment has been successfully performed in introductory organic chemistry laboratories demonstrating alkyne hydration, steam distillation, vacuum distillation, drying of organic…

  7. Orthogonal Synthesis of Xeno Nucleic Acids.


    Fiers, Guillaume; Chouikhi, Dalila; Oswald, Laurence; Al Ouahabi, Abdelaziz; Chan-Seng, Delphine; Charles, Laurence; Lutz, Jean-François


    Sequence-defined peptide triazole nucleic acids (PTzNA) were synthesized by means of a solid-phase orthogonal "AB+CD" iterative strategy. In this approach, AB and CD building blocks containing carboxylic acid (A), azide (B), alkyne (C), and primary amine (D) functions are assembled together by successive copper-catalyzed azide-alkyne cycloaddition (CuAAC) and acid-amine coupling steps. Different PTzNA genetic sequences were prepared using a library of eight building blocks (i.e., four AB and four CD building blocks).

  8. Adhesion of photon-driven molecular motors to surfaces via 1,3-dipolar cycloadditions: effect of interfacial interactions on molecular motion.


    Carroll, Gregory T; London, Gábor; Landaluce, Tatiana Fernández; Rudolf, Petra; Feringa, Ben L


    We report the attachment of altitudinal light-driven molecular motors to surfaces using 1,3-dipolar cycloaddition reactions. Molecular motors were designed containing azide or alkyne groups for attachment to alkyne- or azide-modified surfaces. Surface attachment was characterized by UV-vis, IR, XPS, and ellipsometry measurements. Surface-bound motors were found to undergo photochemical and thermal isomerizations consistent with unidirectional rotation in solution. Confinement at a surface was found to reduce the rate of the thermal isomerization process. The rate of thermal isomerization was also dependent on the surface coverage of the motors. In solution, changes in the UV-vis signal that accompany thermal isomerization can be fit with a single monoexponential decay. In contrast, thermal isomerization of the surface-bound motors does not follow a single monoexponential decay and was found to fit a biexponential decay. Both one- and two-legged motors were attached to surfaces. The kinetics of thermal isomerization was not affected by the valency of attachment, indicating that the changes in kinetics from solution to surface systems are related to interactions between the surface-bound motors.

  9. Tandem dienone photorearrangement-cycloaddition for the rapid generation of molecular complexity.


    Bos, Pieter H; Antalek, Mitchell T; Porco, John A; Stephenson, Corey R J


    A tandem dienone photorearrangement-cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2π and 4π reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tethered substrates led to (3 + 2) cycloaddition to afford strained alkenes which could be further elaborated by intra- and intermolecular cycloaddition chemistry to produce complex, polycyclic chemotypes.

  10. Glycerol as Precursor of Organoselanyl and Organotellanyl Alkynes.


    Lenardão, Eder J; Borges, Elton L; Stach, Guilherme; Soares, Liane K; Alves, Diego; Schumacher, Ricardo F; Bagnoli, Luana; Marini, Francesca; Perin, Gelson


    Herein we describe the synthesis of organoselanyl and organotellanyl alkynes by the addition of lithium alkynylchalcogenolate (Se and Te) to tosyl solketal, easily obtained from glycerol. The alkynylchalcogenolate anions were generated in situ and added to tosyl solketal in short reaction times, furnishing in all cases the respective products of substitution in good yields. Some of the prepared compounds were deprotected using an acidic resin to afford new water-soluble 3-organotellanylpropane-1,2-diols. The synthetic versatility of the new chalcogenyl alkynes was demonstrated in the iodocyclization of 2,2-dimethyl-1,3-dioxolanylmethyl(2-methoxyphenylethynyl)selane 3f, which afforded 3-iodo-2-(2,2-dimethyl-1,3-dioxolanylmethyl) selenanylbenzo[b]furan in 85% yield, opening a new way to access water-soluble Se-functionalized benzo[b]furanes.

  11. Utilization of alkyne bioconjugations to modulate protein function.


    Maza, Johnathan C; Howard, Christina A; Vipani, Megha A; Travis, Christopher R; Young, Douglas D


    The ability to introduce or modify protein function has widespread application to multiple scientific disciplines. The introduction of unique unnatural amino acids represents an excellent mechanism to incorporate new functionality; however, this approach is limited by ability of the translational machinery to recognize and incorporate the chemical moiety. To overcome this potential limitation, we aimed to exploit the functionality of existing unnatural amino acids to perform bioorthogonal reactions to introduce the desired protein modification, altering its function. Specifically, via the introduction of a terminal alkyne containing unnatural amino acid, we demonstrated chemically programmable protein modification through the Glaser-Hay coupling to other terminal alkynes, altering the function of a protein. In a proof-of-concept experiment, this approach has been utilized to modify the fluorescence spectrum of green fluorescent protein.

  12. Iron-Catalyzed gem-Specific Dimerization of Terminal Alkynes.


    Liang, Qiuming; Osten, Kimberly M; Song, Datong


    We report a gem-specific homo- and cross-dimerization of terminal alkynes catalyzed by a well-defined iron(II) complex containing Cp* and picolyl N-heterocyclic carbene (NHC) ligands, and featuring a piano-stool structure. This catalytic system requires no additives and is compatible with a broad range of substrates, including those with polar functional groups such as NH and OH.

  13. Ru-catalyzed stereoselective addition of imides to alkynes.


    Goossen, Lukas J; Blanchot, Mathieu; Brinkmann, Claus; Goossen, Käthe; Karch, Ralph; Rivas-Nass, Andreas


    A catalyst system formed in situ from bis(2-methylallyl)cycloocta-1,5-dieneruthenium(II) ((cod)Ru[met]2), a phosphine, and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) was found to efficiently catalyze the anti-Markovnikov addition of imides to terminal alkynes, allowing mild and atom-economic synthesis of enimides. Depending on the phosphine employed, both the (E)- and the (Z)-isomer can be accessed stereoselectively.

  14. Stereoselective silylcupration of conjugated alkynes in water at room temperature.


    Linstadt, Roscoe T H; Peterson, Carl A; Lippincott, Daniel J; Jette, Carina I; Lipshutz, Bruce H


    Micellar catalysis enables copper-catalyzed silylcupration of a variety of electron-deficient alkynes, thereby providing access to isomerically pure E- or Z-β-silyl-substituted carbonyl derivatives. These reactions take place in minutes, afford high yields and stereoselectivity, and are especially tolerant of functional groups present in the substrates. The aqueous reaction medium has been successfully recycled several times, and a substrate/catalyst ratio of 10,000:1 has been documented for this methodology.

  15. Mechanism of Pd(NHC)-catalyzed transfer hydrogenation of alkynes.


    Hauwert, Peter; Boerleider, Romilda; Warsink, Stefan; Weigand, Jan J; Elsevier, Cornelis J


    The transfer semihydrogenation of alkynes to (Z)-alkenes shows excellent chemo- and stereoselectivity when using a zerovalent palladium(NHC)(maleic anhydride)-complex as precatalyst and triethylammonium formate as hydrogen donor. Studies on the kinetics under reaction conditions showed a broken positive order in substrate and first order in catalyst and hydrogen donor. Deuterium-labeling studies on the hydrogen donor showed that both hydrogens of formic acid display a primary kinetic isotope effect, indicating that proton and hydride transfers are separate rate-determining steps. By monitoring the reaction with NMR, we observed the presence of a coordinated formate anion and found that part of the maleic anhydride remains coordinated during the reaction. From these observations, we propose a mechanism in which hydrogen transfer from coordinated formate anion to zerovalent palladium(NHC)(MA)(alkyne)-complex is followed by migratory insertion of hydride, after which the product alkene is liberated by proton transfer from the triethylammonium cation. The explanation for the high selectivity observed lies in the competition between strongly coordinating solvent and alkyne for a Pd(alkene)-intermediate.

  16. Highly enantioselective intramolecular 1,3-dipolar cycloaddition: a route to piperidino-pyrrolizidines.


    Vidadala, Srinivasa Rao; Golz, Christopher; Strohmann, Carsten; Daniliuc, Constantin-G; Waldmann, Herbert


    Enantioselective catalytic intermolecular 1,3-dipolar cycloadditions are powerful methods for the synthesis of heterocycles. In contrast, intramolecular enantioselective 1,3-dipolar cycloadditions are virtually unexplored. A highly enantioselective synthesis of natural-product-inspired pyrrolidino-piperidines by means of an intramolecular 1,3-dipolar cycloaddition with azomethine ylides is now reported. The method has a wide scope and yields the desired cycloadducts with four tertiary stereogenic centers with up to 99% ee. Combining the enantioselective catalytic intramolecular 1,3-dipolar cycloaddition with a subsequent diastereoselective intermolecular 1,3-dipolar cycloaddition yielded complex piperidino-pyrrolizidines with very high stereoselectivity in a one-pot tandem reaction.

  17. Alkyne-tag Raman imaging of bio-active small molecules in live cells

    NASA Astrophysics Data System (ADS)

    Ando, Jun; Palonpon, Almar F.; Yamakoshi, Hiroyuki; Dodo, Kosuke; Kawata, Satoshi; Sodeoka, Mikiko; Fujita, Katsumasa


    Raman microscopy is useful for molecular imaging and analysis of biological specimens. Here, we used alkyne containing a carbon-carbon triple bond as a Raman tag for observing small molecules in live cells. Alkyne tags can maintain original properties of target molecules with providing high chemical specificity owing to its distinct peak in a Raman-silent window of biomolecules. For demonstrations, alkyne-tagged thymidine and coenzyme Q analogue in live cells were visualized with high-spatial resolution. We extended the application of alkyne-tag imaging to visualize cell organelles and specific lipid components in artificial monolayer membranes.

  18. The reversible cycloaddition of isomuechnones to C{sub 60}

    SciTech Connect

    Gonzalez, R.; Knight, B.W.; Wudl, F.


    Among the large number of functionalization reactions of buckminster fullerenes, the cycloadditions stand out as the cleanest and most useful. The Rh(II)-catalyzed reaction of diazo imides with buckminsterfullerene C{sub 60} gives rise to dipolar cycloadducts which readily undergo thermal cycloreversion. 1 tab.

  19. An Enamide-Benzyne-[2 + 2] Cycloaddition: Stereoselective Tandem [2 + 2]–Pericyclic Ring-Opening–Intramolecular N-Tethered [4 + 2] Cycloadditions

    PubMed Central

    Feltenberger, John B.; Hayashi, Ryuji; Tang, Yu; Babiash, Eric S. C.


    Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition–pericyclic ring-opening–intramolecular-N-tethered- [4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles. PMID:19624104

  20. Postsynthetic Modification of an Alkyne-Tagged Zirconium Metal-Organic Framework via a "Click" Reaction.


    Li, Bijian; Gui, Bo; Hu, Guiping; Yuan, Daqiang; Wang, Cheng


    Herein, we report the synthesis and postsynthetic modification of a novel alkyne-tagged zirconium metal-organic framework, UiO-68-alkyne. The alkynyl groups in the pore surface were subjected to a "click" reaction, achieving quantitative conversion and maintaining the crystallinity of the framework.

  1. Transient protection of strained alkynes from click reaction via complexation with copper.


    Yoshida, Suguru; Hatakeyama, Yasutomo; Johmoto, Kohei; Uekusa, Hidehiro; Hosoya, Takamitsu


    A transient protection method of cyclooctynes from a click reaction with an azide through 1:1 complexation with a cationic copper(I) salt is reported. The application of the method to a cyclooctyne bearing a terminal alkyne enabled the selective copper-catalyzed click conjugation with an azide at the terminal alkyne moiety, which made cyclooctyne derivatives readily accessible.

  2. Assessment of electrophile damage in a human brain endothelial cell line utilizing a clickable alkyne analog of 2-chlorohexadecanal.


    Nusshold, Christoph; Üllen, Andreas; Kogelnik, Nora; Bernhart, Eva; Reicher, Helga; Plastira, Ioanna; Glasnov, Toma; Zangger, Klaus; Rechberger, Gerald; Kollroser, Manfred; Fauler, Günter; Wolinski, Heimo; Weksler, Babette B; Romero, Ignacio A; Kohlwein, Sepp D; Couraud, Pierre-Olivier; Malle, Ernst; Sattler, Wolfgang


    Peripheral leukocytes aggravate brain damage by releasing cytotoxic mediators that compromise blood-brain barrier function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system. The reaction of HOCl with the endogenous plasmalogen pool of brain endothelial cells results in the generation of 2-chlorohexadecanal (2-ClHDA), a toxic, lipid-derived electrophile that induces blood-brain barrier dysfunction in vivo. Here, we synthesized an alkynyl-analog of 2-ClHDA, 2-chlorohexadec-15-yn-1-al (2-ClHDyA) to identify potential protein targets in the human brain endothelial cell line hCMEC/D3. Similar to 2-ClHDA, 2-ClHDyA administration reduced cell viability/metabolic activity, induced processing of pro-caspase-3 and PARP, and led to endothelial barrier dysfunction at low micromolar concentrations. Protein-2-ClHDyA adducts were fluorescently labeled with tetramethylrhodamine azide (N3-TAMRA) by 1,3-dipolar cycloaddition in situ, which unveiled a preferential accumulation of 2-ClHDyA adducts in mitochondria, the Golgi, endoplasmic reticulum, and endosomes. Thirty-three proteins that are subject to 2-ClHDyA-modification in hCMEC/D3 cells were identified by mass spectrometry. Identified proteins include cytoskeletal components that are central to tight junction patterning, metabolic enzymes, induction of the oxidative stress response, and electrophile damage to the caveolar/endosomal Rab machinery. A subset of the targets was validated by a combination of N3-TAMRA click chemistry and specific antibodies by fluorescence microscopy. This novel alkyne analog is a valuable chemical tool to identify cellular organelles and protein targets of 2-ClHDA-mediated damage in settings where myeloperoxidase-derived oxidants may play a disease-propagating role.

  3. Alkyne-tag Raman imaging for visualization of mobile small molecules in live cells.


    Yamakoshi, Hiroyuki; Dodo, Kosuke; Palonpon, Almar; Ando, Jun; Fujita, Katsumasa; Kawata, Satoshi; Sodeoka, Mikiko


    Alkyne has a unique Raman band that does not overlap with Raman scattering from any endogenous molecule in live cells. Here, we show that alkyne-tag Raman imaging (ATRI) is a promising approach for visualizing nonimmobilized small molecules in live cells. An examination of structure-Raman shift/intensity relationships revealed that alkynes conjugated to an aromatic ring and/or to a second alkyne (conjugated diynes) have strong Raman signals in the cellular silent region and can be excellent tags. Using these design guidelines, we synthesized and imaged a series of alkyne-tagged coenzyme Q (CoQ) analogues in live cells. Cellular concentrations of diyne-tagged CoQ analogues could be semiquantitatively estimated. Finally, simultaneous imaging of two small molecules, 5-ethynyl-2'-deoxyuridine (EdU) and a CoQ analogue, with distinct Raman tags was demonstrated.

  4. Development of Benzophenone-Alkyne Bifunctional Sigma Receptor Ligands

    PubMed Central

    Guo, Lian-Wang; Hajipour, Abdol R.; Karaoglu, Kerim; Mavlyutov, Timur A.; Ruoho, Arnold E.


    Sigma (σ) receptors represent unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been identified to contain σ2 receptor-like binding properties, highlighting the need to understand the biological function of an 18-kDa protein that exhibits σ2-like photoaffinity labeling (herein denoted as σ2-18k) but the amino acid sequence of which is not known. In order to provide novel tools for the study of the σ2-18k protein, we have developed bifunctional sigma receptor ligands that bear a benzophenone photo-crosslinking moiety and an alkyne group, to which an azide-containing biotin affinity tag can be covalently attached via click chemistry following photo-crosslink. While several compounds showed favorable σ2 binding properties, compound 22 exhibited the highest affinity (2 nM) and the greatest potency in blocking photolabeling of the σ2-18k by a radioactive photoaffinity ligand. Thus, these benzophenone-alkyne sigma receptor ligands may be amenable for studying the σ2-18k protein via chemical biology approaches. To our knowledge, these compounds represent the first reported benzophenone-containing clickable sigma receptor ligands, which may potentially serve broad applications by “plugging” in various tags. PMID:23001760

  5. Chiral bifunctional ferrocenylphosphine catalyzed highly enantioselective [3 + 2] cycloaddition reaction.


    Hu, Haiwen; Yu, Shuxian; Zhu, Linglong; Zhou, Lingxiu; Zhong, Weihui


    A series of air-stable ferrocenylphosphines LB1-LB8 were designed and prepared in high yields. (R,SFc)-ferrocenylphosphine LB5 was found to efficiently promote the asymmetric [3 + 2] cycloaddition of Morita-Baylis-Hillman carbonates with maleimides to afford the corresponding bicyclic imides with 84-99% ee and 67-99% yield. Interestingly, the configuration of these products was contrary to those reported in the literature.

  6. Enantioselective Dearomative [3+2] Cycloaddition Reactions of Benzothiazoles.


    Wang, Dong-Chao; Xie, Ming-Sheng; Guo, Hai-Ming; Qu, Gui-Rong; Zhang, Meng-Cheng; You, Shu-Li


    A highly enantioselective dearomative [3+2] cycloaddition of benzothiazole has been successfully developed. A wide range of benzothiazoles and cyclopropane-1,1-dicarboxylates are suitable substrates for this reaction. The desired hydropyrrolo[2,1-b]thiazole compounds were obtained in excellent enantioselectivity and yields (up to 97 % ee and 97 % yield). With the same catalytic system, a highly efficient kinetic resolution of 2-substituted cyclopropane-1,1-dicarboxylates was also realized.

  7. ORGANIC CHEMISTRY. Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes.


    Hoyt, Jordan M; Schmidt, Valerie A; Tondreau, Aaron M; Chirik, Paul J


    Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal-catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks.

  8. Versatility of Alkyne-Modified Poly(Glycidyl Methacrylate) Layers for Click Reactions

    SciTech Connect

    Soto-Cantu, Dr. Erick; Lokitz, Bradley S; Hinestrosa Salazar, Juan Pablo; Deodhar, Chaitra; Messman, Jamie M; Ankner, John Francis; Kilbey, II, S Michael


    Functional soft interfaces are of interest for a variety of technologies. We describe three methods for preparing substrates with alkyne groups, which show versatility for 'click' chemistry reactions. Two of the methods have the same root: formation of thin, covalently attached, reactive interfacial layers of poly(glycidyl methacrylate) (PGMA) via spin coating onto silicon wafers followed by reactive modification with either propargylamine or 5-hexynoic acid. The amine or the carboxylic acid moieties react with the epoxy groups of PGMA, creating interfacial polymer layers decorated with alkyne groups. The third method consists of using copolymers comprising glycidyl methacrylate and propargyl methacrylate (pGP). The pGP copolymers are spin coated and covalently attached on silicon wafers. For each method, we investigate the factors that control film thickness and content of alkyne groups using ellipsometry, and study the nanophase structure of the films using neutron reflectometry. Azide-terminated polymers of methacrylic acid and 2-vinyl-4,4-dimethylazlactone synthesized via reversible addition-fragmentation chain transfer polymerization were attached to the alkyne-modified substrates using 'click' chemistry, and grafting densities in the range of 0.007-0.95 chains nm{sup -2} were attained. The maximum density of alkyne groups attained by functionalization of PGMA with propargylamine or 5-hexynoic acid was approximately 2 alkynes nm{sup -3}. The alkyne content obtained by the three decorating approaches was sufficiently high that it was not the limiting factor for the click reaction of azide-capped polymers.

  9. The development of catalytic nucleophilic additions of terminal alkynes in water.


    Li, Chao-Jun


    One of the major research endeavors in synthetic chemistry over the past two decades is the exploration of synthetic methods that work under ambient atmosphere with benign solvents, that maximize atom utilization, and that directly transform natural resources, such as renewable biomass, from their native states into useful chemical products, thus avoiding the need for protecting groups. The nucleophilic addition of terminal alkynes to various unsaturated electrophiles is a classical (textbook) reaction in organic chemistry, allowing the formation of a C-C bond while simultaneously introducing the alkyne functionality. A prerequisite of this classical reaction is the stoichiometric generation of highly reactive metal acetylides. Over the past decade, our laboratory and others have been exploring an alternative, the catalytic and direct nucleophilic addition of terminal alkynes to unsaturated electrophiles in water. We found that various terminal alkynes can react efficiently with a wide range of such electrophiles in water (or organic solvent) in the presence of simple and readily available catalysts, such as copper, silver, gold, iron, palladium, and others. In this Account, we describe the development of these synthetic methods, focusing primarily on results from our laboratory. Our studies include the following: (i) catalytic reaction of terminal alkynes with acid chloride, (ii) catalytic addition of terminal alkynes to aldehydes and ketones, (iii) catalytic addition of alkynes to C=N bonds, and (iv) catalytic conjugate additions. Most importantly, these reactions can tolerate various functional groups and, in many cases, perform better in water than in organic solvents, clearly defying classical reactivities predicated on the relative acidities of water, alcohols, and terminal alkynes. We further discuss multicomponent and enantioselective reactions that were developed. These methods provide an alternative to the traditional requirement of separate steps in

  10. Selenide-Catalyzed Stereoselective Construction of Tetrasubstituted Trifluoromethylthiolated Alkenes with Alkynes.


    Wu, Jin-Ji; Xu, Jia; Zhao, Xiaodan


    The efficient regio- and stereoselective construction of tetrasubstituted alkenes is challenging and very important. For this purpose, we have developed an efficient approach to synthesize tetrasubstituted trifluoromethylthiolated alkenes from simple alkynes in excellent regio- and stereoselectivities by selenide-catalyzed multicomponent coupling. Using this method, trifluoromethylthiolated alkenyl triflates and arenes were achieved. In particular, the triflates could be further converted into carbofunctionalized alkenes by palladium-catalyzed cross-coupling reactions. Our method provides a new pathway for the construction of trifluoromethylthiolated tricarboalkenes. This work presents the first example of selenide-catalyzed trifluoromethylthiolation of alkynes and enables the challenging functionalizations of alkynes.

  11. Live-cell stimulated Raman scattering imaging of alkyne-tagged biomolecules.


    Hong, Senlian; Chen, Tao; Zhu, Yuntao; Li, Ang; Huang, Yanyi; Chen, Xing


    Alkynes can be metabolically incorporated into biomolecules including nucleic acids, proteins, lipids, and glycans. In addition to the clickable chemical reactivity, alkynes possess a unique Raman scattering within the Raman-silent region of a cell. Coupling this spectroscopic signature with Raman microscopy yields a new imaging modality beyond fluorescence and label-free microscopies. The bioorthogonal Raman imaging of various biomolecules tagged with an alkyne by a state-of-the-art Raman imaging technique, stimulated Raman scattering (SRS) microscopy, is reported. This imaging method affords non-invasiveness, high sensitivity, and molecular specificity and therefore should find broad applications in live-cell imaging.

  12. Copper-catalyzed selective hydroamination reactions of alkynes

    PubMed Central

    Shi, Shi-Liang; Buchwald, Stephen L.


    The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a longstanding goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective, and step-efficient synthesis of amines is still needed. In this work we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines, and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio-, and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine, and tolterodine. PMID:25515888

  13. Copper-catalysed selective hydroamination reactions of alkynes

    NASA Astrophysics Data System (ADS)

    Shi, Shi-Liang; Buchwald, Stephen L.


    The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

  14. Copper-catalysed selective hydroamination reactions of alkynes.


    Shi, Shi-Liang; Buchwald, Stephen L


    The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

  15. Stereodivergent Silylzincation of α-Heteroatom-Substituted Alkynes.


    Fopp, Carolin; Romain, Elise; Isaac, Kevin; Chemla, Fabrice; Ferreira, Franck; Jackowski, Olivier; Oestreich, Martin; Perez-Luna, Alejandro


    Zinc reagents (Me2PhSi)2Zn and [(Me3Si)3Si]2Zn undergo highly regio- and stereoselective addition across the carbon-carbon triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal alkynes in the absence of copper or any other catalyst. Both reagents yield exclusively β-isomers, and the stereoselectivity is determined by the silyl group: Me2PhSi for cis or (Me3Si)3Si for trans. These stereodivergent silylzincation protocols offer an efficient access to heteroatom-substituted vinylsilanes with either double bond geometry, including trisubstituted vinylsilanes by one-pot electrophilic substitution of the intermediate C(sp(2))-Zn bond by copper(I)-mediated carbon-carbon bond formation.

  16. Site-specific protein labeling with PRIME and chelation-assisted Click chemistry

    PubMed Central

    Uttamapinant, Chayasith; Sanchez, Mateo I.; Liu, Daniel S.; Yao, Jennifer Z.; White, Katharine A.; Grecian, Scott; Clarke, Scott; Gee, Kyle R.; Ting, Alice Y.


    This protocol describes an efficient method to site-specifically label cell-surface or purified proteins with chemical probes in two steps: PRobe Incorporation Mediated by Enzymes (PRIME) followed by chelation-assisted copper-catalyzed azide-alkyne cycloaddition (CuAAC). In the PRIME step, Escherichia coli lipoic acid ligase site-specifically attaches a picolyl azide derivative to a 13-amino acid recognition sequence that has been genetically fused onto the protein of interest. Proteins bearing picolyl azide are chemoselectively derivatized with an alkyne-probe conjugate by chelation-assisted CuAAC in the second step. We describe herein the optimized protocols to synthesize picolyl azide, perform PRIME labeling, and achieve CuAAC derivatization of picolyl azide on live cells, fixed cells, and purified proteins. Reagent preparations, including synthesis of picolyl azide probes and expression of lipoic acid ligase, take 12 d, while the procedure to perform site-specific picolyl azide ligation and CuAAC on cells or on purified proteins takes 40 min-3 h. PMID:23887180

  17. Total synthesis of ceratopicanol through tandem cycloaddition reaction of a linear substrate.


    Lee, Sang-Shin; Kim, Won-Yeob; Lee, Hee-Yoon


    Total synthesis of ceratopicanol (1) was achieved with a tandem cycloaddition reaction of allenyl diazo compound 6 via a trimethylenemethane (TMM) diyl intermediate. The TMM diyl mediated [2+3] cycloaddition reaction furnished the consecutive quaternary carbon centers and showed an unusual diastereoselectivity.

  18. Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction.


    Patouret, Remi; Kamenecka, Theodore M


    A regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane is reported. A series of 2-aryltetrazoles were obtained in good to moderate yields with wide functional group compatibility. Furthermore, this cycloaddition reaction opens the way to build up the versatile intermediate 2-aryl-5-bromotetrazole.

  19. Regioselective de novo synthesis of cyanohydroxypyridines with a concerted cycloaddition mechanism.


    Lu, Jin-Yong; Keith, John A; Shen, Wei-Zheng; Schürmann, Markus; Preut, Hans; Jacob, Timo; Arndt, Hans-Dieter


    An efficient cycloaddition reaction of 1-alkoxy-1-azadienes with alpha,alpha-dicyanoalkenes is described, which gives facile access to highly substituted 3-hydroxypyridines in very good yields and with complete regiocontrol and chemoselectivity. The reaction path was investigated in detail by quantum mechanics calculations, reporting that a concerted cycloaddition mechanism and thermodynamic control synergistically contribute to the observed selectivity.

  20. Isocyanide based [4+1] cycloaddition reactions: an indispensable tool in multi-component reactions (MCRs).


    Kaur, Tanpreet; Wadhwa, Preeti; Bagchi, Sourav; Sharma, Anuj


    The advent of cycloaddition reactions in the synthesis of heterocycles and their ever burgeoning applications in the fields of material chemistry, catalysis and drugs have been a profound scientific development. In particular, isocyanide based cycloaddition reactions have been harbingers of an exciting new chapter in the realms of organic synthesis. The emergence of numerous synthetic protocols utilizing formal cycloaddition of isocyanides with conjugated heterodienes has unleashed countless opportunities to design and synthesize diverse heterocyclic scaffolds. To date, there has not been any exclusive review on a formal [4+1] cycloaddition involving isocyanides. The present review highlights the journey of formal [4+1] cycloaddition reactions of isocyanides with diverse electrophilic substrates viz. oxadienes, azadienes, thioacyl imines, alkylidene amides, alkylidene hydrazines, α,β-unsaturated nitro compounds, α-thioxothioamides, nitroso alkenes, acyl imines, vinyl ketenes, vinyl isocyanates, etc. to afford functionalized pyrroles, imidazoles, furans, oxazoles, pyrazoles, etc.

  1. Nickel-Catalyzed Stereoselective Alkenylation of C(sp(3))-H Bonds with Terminal Alkynes.


    Lin, Cong; Chen, Zhengkai; Liu, Zhanxiang; Zhang, Yuhong


    A nickel-catalyzed stereoselective alkenylation of an unactivated β-C(sp(3))-H bond in aliphatic amide with terminal alkynes using 8-aminoquinoline auxiliary is reported for the first time. This reaction displays excellent functional group tolerance with respect to both aliphatic amides and terminal alkynes and features a cheap nickel catalytic system. The 8-aminoquinolyl directing group could be smoothly removed, and the resultant β-styrylcarboxylic acid derivatives could serve as versatile building blocks for further transformation.

  2. Fundamental Flame Velocities of Pure Hydrocarbons I : Alkanes, Alkenes, Alkynes Benzene, and Cyclohexane

    NASA Technical Reports Server (NTRS)

    Gerstein, Melvin; Levine, Oscar; Wong, Edgar L


    The flame velocities of 37 pure hydrocarbons including normal and branched alkanes, alkenes, and alkynes; as well as benzene and cyclohexane, together with the experimental technique employed are presented. The normal alkanes have about the same flame velocity from ethane through heptane with methane being about 16 percent lower. Unsaturation increases the flame velocity in the order of alkanes, alkenes, and alkynes. Branching reduces the flame velocity.

  3. Nickel-catalyzed reductive arylation of activated alkynes with aryl iodides

    PubMed Central

    Dorn, Stephanie C. M.; Olsen, Andrew K; Kelemen, Rachel E.; Shrestha, Ruja; Weix, Daniel J.


    The direct, regioselective, and stereoselective arylation of activated alkynes with aryl iodides using a nickel catalyst and manganese reductant is described. The reaction conditions are mild (40 °C in MeOH, no acid or base) and an intermediate organomanganese reagent is unlikely. Functional groups tolerated include halides and pseudohalides, free and protected anilines, and a benzyl alcohol. Other activated alkynes including an amide and a ketone also reacted to form arylated products in good yields. PMID:26028781

  4. Azide-alkyne cycloaddition en route to 1H-1,2,3-triazole-tethered 7-chloroquinoline-isatin chimeras: synthesis and antimalarial evaluation.


    Raj, Raghu; Singh, Pardeep; Singh, Parvesh; Gut, Jiri; Rosenthal, Philip J; Kumar, Vipan


    We describe the synthesis and antimalarial activities of 1H-1,2,3-triazole tethered 7-chloroquinoline-isatin hybrids. Activity against cultured parasites was dependent on the C-5 substituent of the isatin ring as well as the alkyl chain length between the isatin and 7-chloroquinoline moieties. Compound 8h, with an optimum alkyl chain length (n = 3) and a chloro substituent at the C-5 position of the isatin ring, displayed the best activity among the test compounds, with IC50 value of 1.21 μM against cultured W2-strain Plasmodium falciparum.

  5. Copper-catalyzed azide-alkyne cycloaddition (click chemistry)-based Detection of Global Pathogen-host AMPylation on Self-assembled Human Protein Microarrays*

    PubMed Central

    Yu, Xiaobo; Woolery, Andrew R.; Luong, Phi; Hao, Yi Heng; Grammel, Markus; Westcott, Nathan; Park, Jin; Wang, Jie; Bian, Xiaofang; Demirkan, Gokhan; Hang, Howard C.; Orth, Kim; LaBaer, Joshua


    AMPylation (adenylylation) is a recently discovered mechanism employed by infectious bacteria to regulate host cell signaling. However, despite significant effort, only a few host targets have been identified, limiting our understanding of how these pathogens exploit this mechanism to control host cells. Accordingly, we developed a novel nonradioactive AMPylation screening platform using high-density cell-free protein microarrays displaying human proteins produced by human translational machinery. We screened 10,000 unique human proteins with Vibrio parahaemolyticus VopS and Histophilus somni IbpAFic2, and identified many new AMPylation substrates. Two of these, Rac2, and Rac3, were confirmed in vivo as bona fide substrates during infection with Vibrio parahaemolyticus. We also mapped the site of AMPylation of a non-GTPase substrate, LyGDI, to threonine 51, in a region regulated by Src kinase, and demonstrated that AMPylation prevented its phosphorylation by Src. Our results greatly expanded the repertoire of potential host substrates for bacterial AMPylators, determined their recognition motif, and revealed the first pathogen-host interaction AMPylation network. This approach can be extended to identify novel substrates of AMPylators with different domains or in different species and readily adapted for other post-translational modifications. PMID:25073739

  6. Post-Synthesis Modification of the Aurivillius Phase Bi2SrTa2O9 via In Situ Microwave-Assisted "Click Reaction".


    Wang, Yanhui; Delahaye, Emilie; Leuvrey, Cédric; Leroux, Fabrice; Rabu, Pierre; Rogez, Guillaume


    A new strategy for the functionalization of layered perovskites is presented, based on the in situ post-synthesis modification of a prefunctionalized phase by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). The microwave-assisted protonation and grafting of an alkyne alcohol provides the alkyne-functionalized precursor within a few hours, starting from Bi2SrTa2O9. The subsequent microwave-assisted in situ "click reaction" allows the post-synthesis modification of the precursor within ∼2 h, providing a layered perovskite functionalized by an alcohol-grafted 1,4-disubstituted-1H-1,2,3-triazole. Two compounds are described here, bearing an aliphatic and an aromatic substituent, which illustrates the general application of the method. This work opens new perspectives for the functionalization of layered perovskites, going beyond mere insertion/grafting reactions, and thus broadens the design possibilities and the range of applications of these hybrid systems.

  7. Click Chemistry Immobilization of Antibodies on Polymer Coated Gold Nanoparticles.


    Finetti, Chiara; Sola, Laura; Pezzullo, Margherita; Prosperi, Davide; Colombo, Miriam; Riva, Benedetta; Avvakumova, Svetlana; Morasso, Carlo; Picciolini, Silvia; Chiari, Marcella


    The goal of this work is to develop an innovative approach for the coating of gold nanoparticles (AuNPs) with a synthetic functional copolymer. This stable coating with a thickness of few nanometers provides, at the same time, stabilization and functionalization of the particles. The polymeric coating consists of a backbone of polydimethylacrylamide (DMA) functionalized with an alkyne monomer that allows the binding of azido modified molecules by Cu(I)-catalyzed azide/alkyne 1,3-dipolar cycloaddition (CuAAC, click chemistry). The thin polymer layer on the surface stabilizes the colloidal suspension whereas the alkyne functions pending from the backbone are available for the reaction with azido-modified proteins. The reactivity of the coating is demonstrated by immobilizing an azido modified anti-mouse IgG antibody on the particle surface. This approach for the covalent binding of antibody to a gold-NPs is applied to the development of gold labels in biosensing techniques.

  8. Asymmetric Brønsted Base Catalyzed and Directed [3+2] Cycloaddition of 2-Acyl Cycloheptatrienes with Azomethine Ylides.


    Lauridsen, Vibeke H; Ibsen, Lise; Blom, Jakob; Jørgensen, Karl Anker


    Conjugated cyclic trienes have the potential for different types of cycloaddition reactions. In the present work, we will, in a novel asymmetric cycloaddition reaction, demonstrate that the organocatalytic reaction of 2-acyl cycloheptatrienes with azomethine ylides proceeds as a [3+2] cycloaddition, which is in contrast to the Lewis acid-catalyzed reaction, in which a [3+6] cycloaddition takes place. In the presence of a chiral organosuperbase, 2-acyl cycloheptatrienes react in a highly enantioselective manner in the [3+2] cycloaddition with azomethine ylides, providing the 1,3-dipolar cycloaddition product in high yields and up to 99 % ee. It is also shown that the diene formed by the reaction can undergo stereoselective dihydroxylation, bromination, and cycloaddition reactions. Finally, based on experimental observations, some mechanistic considerations are discussed.

  9. Click on silica: systematic immobilization of Co(II) Schiff bases to the mesoporous silica via click reaction and their catalytic activity for aerobic oxidation of alcohols.


    Rana, Bharat S; Jain, Suman L; Singh, Bhawan; Bhaumik, Asim; Sain, Bir; Sinha, Anil K


    The systematic immobilization of cobalt(II) Schiff base complexes on SBA-15 mesoporous silica via copper catalyzed [3 + 2] azide-alkyne cycloaddition (CuAAC) "click reaction" involving either step-wise synthesis of silica-bound Schiff base ligand followed by its subsequent complexation with cobalt ions, or by the direct immobilization of preformed Co(II) Schiff base complex to the silica support is described. The catalytic activity of the prepared complexes was studied for the oxidation of alcohols to carbonyl compounds using molecular oxygen as oxidant. The immobilized complexes were recycled for several runs without loss in catalytic activity and no leaching was observed during this course.

  10. The click reaction as an efficient tool for the construction of macrocyclic structures.


    Pasini, Dario


    The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC, known as the click reaction) is an established tool used for the construction of complex molecular architectures. Given its efficiency it has been widely applied for bioconjugation, polymer and dendrimer synthesis. More recently, this reaction has been utilized for the efficient formation of rigid or shape-persistent, preorganized macrocyclic species. This strategy also allows the installment of useful functionalities, in the form of polar and function-rich 1,2,3-triazole moieties, directly embedded in the macrocyclic structures. This review analyzes the state of the art in this context, and provides some elements of perspective for future applications.

  11. 2'-Alkynylnucleotides: A Sequence- and Spin Label-Flexible Strategy for EPR Spectroscopy in DNA.


    Haugland, Marius M; El-Sagheer, Afaf H; Porter, Rachel J; Peña, Javier; Brown, Tom; Anderson, Edward A; Lovett, Janet E


    Electron paramagnetic resonance (EPR) spectroscopy is a powerful method to elucidate molecular structure through the measurement of distances between conformationally well-defined spin labels. Here we report a sequence-flexible approach to the synthesis of double spin-labeled DNA duplexes, where 2'-alkynylnucleosides are incorporated at terminal and internal positions on complementary strands. Post-DNA synthesis copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions with a variety of spin labels enable the use of double electron-electron resonance experiments to measure a number of distances on the duplex, affording a high level of detailed structural information.

  12. Polystyrene or Magnetic Nanoparticles as Support in Enantioselective Organocatalysis? A Case Study in Friedel-Crafts Chemistry.


    Ranjbar, Sara; Riente, Paola; Rodríguez-Escrich, Carles; Yadav, Jagjit; Ramineni, Kishore; Pericàs, Miquel A


    Heterogenized versions of the second-generation MacMillan imidazolidin-4-one are described for the first time. This versatile organocatalyst has been supported on 1% DVB Merrifield resin and Fe3O4 magnetic nanoparticles through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The resulting catalytic materials have been successfully applied to the asymmetric Friedel-Crafts alkylation of indoles with α,β-unsaturated aldehydes. While both catalytic systems can be easily recovered and admit repeated recycling, the polystyrene-based catalyst shows higher stability and provides better stereoselectivities.

  13. Silica-based 2-(N,N-dimethylamino)-1,3-propanediol hydrophilic interaction liquid chromatography stationary phase for separating cephalosporins and carbapenems.


    Yin, Wei; Cheng, Lingping; Chai, Huihui; Guo, Ruiqiang; Liu, Renhua; Chu, Changhu; Palasota, John A; Cai, Xiaohui


    A silica-based stationary phase bearing both hydrophilic hydroxyl and amino groups was developed by covalently bonding a small molecular N,N-dimethylamino 1,3-propanediol moiety onto silica beads via copper(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC). This new stationary phase showed good HILIC characteristics and high column efficiency (the theoretical plate number is up to 37000 plates m(-1) in the case of inosine) in the separation of polar compounds, such as nucleosides and bases, organic acids, cephalosporins, and carbapenems.

  14. Self-Assembly of Disorazole C1 through a One-Pot Alkyne Metathesis Homodimerization Strategy**

    PubMed Central

    Ralston, Kevin J; Ramstadius, H Clinton; Brewster, Richard C; Niblock, Helen S; Hulme, Alison N


    Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne-metathesis-based homodimerization approach to natural products. In this approach to the cytotoxic C2-symmetric marine-derived bis(lactone) disorazole C1, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one-pot alkyne cross-metathesis/ring-closing metathesis self-assembly process. PMID:25926364

  15. Ru(ii)-Catalyzed C-H activation and annulation of salicylaldehydes with monosubstituted and disubstituted alkynes.


    Baruah, Swagata; Kaishap, Partha Pratim; Gogoi, Sanjib


    The Ru(ii)-catalyzed C-H activation and annulation reaction of salicylaldehydes and disubstituted alkynes affords chromones in high yields. This reaction also works with terminal alkynes and tolerates a wide range of sensitive functional groups. The selectivity pattern of this Ru(ii)-catalyzed annulation reaction is different from the known Au(i), Rh(iii)-catalyzed annulation reactions of salicylaldehydes and terminal alkynes.

  16. Alkyne-functionalized superstable graphitic silver nanoparticles for Raman imaging.


    Song, Zhi-Ling; Chen, Zhuo; Bian, Xia; Zhou, Li-Yi; Ding, Ding; Liang, Hao; Zou, Yu-Xiu; Wang, Shan-Shan; Chen, Long; Yang, Chao; Zhang, Xiao-Bing; Tan, Weihong


    Noble metals, especially gold, have been widely used in plasmon resonance applications. Although silver has a larger optical cross section and lower cost than gold, it has attracted much less attention because of its easy corrosion, thereby degrading plasmonic signals and limiting its applications. To circumvent this problem, we report the facile synthesis of superstable AgCu@graphene (ACG) nanoparticles (NPs). The growth of several layers of graphene onto the surface of AgCu alloy NPs effectively protects the Ag surface from contamination, even in the presence of hydrogen peroxide, hydrogen sulfide, and nitric acid. The ACG NPs have been utilized to enhance the unique Raman signals from the graphitic shell, making ACG an ideal candidate for cell labeling, rapid Raman imaging, and SERS detection. ACG is further functionalized with alkyne-polyethylene glycol, which has strong Raman vibrations in the Raman-silent region of the cell, leading to more accurate colocalization inside cells. In sum, this work provides a simple approach to fabricate corrosion-resistant, water-soluble, and graphene-protected AgCu NPs having a strong surface plasmon resonance effect suitable for sensing and imaging.

  17. Inactivation of Toluene 2-Monooxygenase in Burkholderia cepacia G4 by Alkynes

    PubMed Central

    Yeager, Chris M.; Bottomley, Peter J.; Arp, Daniel J.; Hyman, Michael R.


    High concentrations of acetylene (10 to 50% [vol/vol] gas phase) were required to inhibit the growth of Burkholderia cepacia G4 on toluene, while 1% (vol/vol) (gas phase) propyne or 1-butyne completely inhibited growth. Low concentrations of longer-chain alkynes (C5 to C10) were also effective inhibitors of toluene-dependent growth, and 2- and 3-alkynes were more potent inhibitors than their 1-alkyne counterparts. Exposure of toluene-grown B. cepacia G4 to alkynes resulted in the irreversible loss of toluene- and o-cresol-dependent O2 uptake activities, while acetate- and 3-methylcatechol-dependent O2 uptake activities were unaffected. Toluene-dependent O2 uptake decreased upon the addition of 1-butyne in a concentration- and time-dependent manner. The loss of activity followed first-order kinetics, with apparent rate constants ranging from 0.25 min−1 to 2.45 min−1. Increasing concentrations of toluene afforded protection from the inhibitory effects of 1-butyne. Furthermore, oxygen, supplied as H2O2, was required for inhibition by 1-butyne. These results suggest that alkynes are specific, mechanism-based inactivators of toluene 2-monooxygenase in B. cepacia G4, although the simplest alkyne, acetylene, was relatively ineffective compared to longer alkynes. Alkene analogs of acetylene and propyne—ethylene and propylene—were not inactivators of toluene 2-monooxygenase activity in B. cepacia G4 but were oxidized to their respective epoxides, with apparent Ks and Vmax values of 39.7 μM and 112.3 nmol min−1 mg of protein−1 for ethylene and 32.3 μM and 89.2 nmol min−1 mg of protein−1 for propylene. PMID:9925593

  18. 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with Carbonyl Dipolarophiles Yielding Oxazolidine Derivatives.


    Meyer, Adam G; Ryan, John H


    We provide a comprehensive account of the 1,3-dipolar cycloaddition reactions of azomethine ylides with carbonyl dipolarophiles. Many different azomethine ylides have been studied, including stabilized and non-stabilized ylides. Of the carbonyl dipolarophiles, aldehydes including formaldehyde are the most studied, although there are now examples of cycloadditions with ketones, ketenes and carboxyl systems, in particular isatoic anhydrides and phthalic anhydrides. Intramolecular cycloadditions with esters can also occur under certain circumstances. The oxazolidine cycloadducts undergo a range of reactions triggered by the ring-opening of the oxazolidine ring system.

  19. Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating Substituents: Robust Pyrimidine Synthesis

    PubMed Central

    Glinkerman, Christopher M.; Boger, Dale L.


    The examination of the cycloaddition reactions of 1,2,3-triazines 17–19, bearing electron-donating substituents at C5, are described. Despite the noncomplementary 1,2,3-triazine C5 substituents, amidines were found to undergo a powerful cycloaddition to provide 2,5-disubstituted pyrimidines in excellent yields (42–99%; EDG = SMe > OMe > NHAc). Even select ynamines and enamines were capable of cycloadditions with 17, but not 18 or 19, to provide trisubstituted pyridines in modest yields (37–40% and 33% respectively). PMID:26172042

  20. Regioselective Sequential Modification of Chitosan via Azide-Alkyne Click Reaction: Synthesis, Characterization, and Antimicrobial Activity of Chitosan Derivatives and Nanoparticles

    PubMed Central

    Sarwar, Atif; Katas, Haliza; Samsudin, Siti Noradila; Zin, Noraziah Mohamad


    Recently, the attention of researchers has been drawn toward the synthesis of chitosan derivatives and their nanoparticles with enhanced antimicrobial activities. In this study, chitosan derivatives with different azides and alkyne groups were synthesized using click chemistry, and these were further transformed into nanoparticles by using the ionotropic gelation method. A series of chitosan derivatives was successfully synthesized by regioselective modification of chitosan via an azide-alkyne click reaction. The amino moieties of chitosan were protected during derivatization by pthaloylation and subsequently unblocked at the end to restore their functionality. Nanoparticles of synthesized derivatives were fabricated by ionic gelation to form complexes of polyanionic penta-sodium tripolyphosphate (TPP) and cationic chitosan derivatives. Particle size analysis showed that nanoparticle size ranged from 181.03 ± 12.73 nm to 236.50 ± 14.32 nm and had narrow polydispersity index and positive surface charge. The derivatives and corresponding nanoparticles were evaluated in vitro for antibacterial and antifungal activities against three gram-positive and gram-negative bacteria and three fungal strains, respectively. The minimum inhibitory concentration (MIC) of all derivatives ranged from 31.3 to 250 µg/mL for bacteria and 188 to1500 µg/mL for fungi and was lower than that of native chitosan. The nanoparticles with MIC ranging from 1.56 to 25 µg/mLfor bacteria and 94 to 750 µg/mL for fungi exhibited higher activity than the chitosan derivatives. Chitosan O-(1-methylbenzene) triazolyl carbamate and chitosan O-(1-methyl phenyl sulfide) triazolyl carbamate were the most active against the tested bacterial and fungal strains. The hemolytic assay on erythrocytes and cell viability test on two different cell lines (Chinese hamster lung fibroblast cells V79 and Human hepatic cell line WRL68) demonstrated the safety; suggesting that these derivatives could be used in future

  1. Regioselective Sequential Modification of Chitosan via Azide-Alkyne Click Reaction: Synthesis, Characterization, and Antimicrobial Activity of Chitosan Derivatives and Nanoparticles.


    Sarwar, Atif; Katas, Haliza; Samsudin, Siti Noradila; Zin, Noraziah Mohamad


    Recently, the attention of researchers has been drawn toward the synthesis of chitosan derivatives and their nanoparticles with enhanced antimicrobial activities. In this study, chitosan derivatives with different azides and alkyne groups were synthesized using click chemistry, and these were further transformed into nanoparticles by using the ionotropic gelation method. A series of chitosan derivatives was successfully synthesized by regioselective modification of chitosan via an azide-alkyne click reaction. The amino moieties of chitosan were protected during derivatization by pthaloylation and subsequently unblocked at the end to restore their functionality. Nanoparticles of synthesized derivatives were fabricated by ionic gelation to form complexes of polyanionic penta-sodium tripolyphosphate (TPP) and cationic chitosan derivatives. Particle size analysis showed that nanoparticle size ranged from 181.03 ± 12.73 nm to 236.50 ± 14.32 nm and had narrow polydispersity index and positive surface charge. The derivatives and corresponding nanoparticles were evaluated in vitro for antibacterial and antifungal activities against three gram-positive and gram-negative bacteria and three fungal strains, respectively. The minimum inhibitory concentration (MIC) of all derivatives ranged from 31.3 to 250 µg/mL for bacteria and 188 to1500 µg/mL for fungi and was lower than that of native chitosan. The nanoparticles with MIC ranging from 1.56 to 25 µg/mLfor bacteria and 94 to 750 µg/mL for fungi exhibited higher activity than the chitosan derivatives. Chitosan O-(1-methylbenzene) triazolyl carbamate and chitosan O-(1-methyl phenyl sulfide) triazolyl carbamate were the most active against the tested bacterial and fungal strains. The hemolytic assay on erythrocytes and cell viability test on two different cell lines (Chinese hamster lung fibroblast cells V79 and Human hepatic cell line WRL68) demonstrated the safety; suggesting that these derivatives could be used in future

  2. Phase emerging from intramonolayer cycloaddition on micro-patterned monolayer

    SciTech Connect

    Tajuddin, Hairul A.; Manning, Robert J.; Leggett, Graham J.; Williams, Nicholas H.


    Cu(I)-catalyzed cycloaddition between azide and acetylene, followed by hydrolysis of ester were performed on micro-patterned self-assembled monolayer to produce smaller features. The reactions were initially performed on mixed monolayers and analysed by water contact angle (CA) and confirmed by X-ray Photoelectron Spectroscopy (XPS). The contact angle measurement has shown a drastic wetting of water on the surface of mixed monolayer indicating that the terminal groups on mixed monolayer has changed into carboxylic acid and hydroxyl terminals. The reactions work in a similar way on micro-patterned SAM and analyzed by using friction force microscope. The emerging of the new lines with high friction force on the border suggested a successful intramonolayer reactions on the border of the patterned SAM.

  3. Cycloadditions of 2-azaallyllithium species with conjugated polyenes.


    Pearson, William H; Mans, Douglas M; Kampf, Jeff W


    2-Azaallyllithium species [R(1)CH(-)N=C(X)R(2)Li(+), where R(1) and R(2) are alkyl and X = OMe] were generated by tin-lithium exchange of (2-azaallyl)stannanes and underwent [pi4s+pi2s] and [pi6s+pi4s] cycloadditions with cyclic dienes and trienes, respectively, to generate novel bridged azabicyclic compounds in a highly diastereoselective endo fashion. The periselectivity using cycloheptatriene was modest, producing a 1:1 mixture of [pi6s+pi4s] and [pi4s+pi2s] adducts. The reactions of 2-azaallyllithium species with dienes proceeded by a [pi4s+pi2s] pathway. The cycloadducts derived from cyclic 2-azaallyllithium species possess the 7-azabicyclo[2.2.1]heptane (tropane) or 8-azabicyclo[3.2.1]octane ring system and have been elaborated into cocaine-like analogues.

  4. Synthesis of heterocycles by formal cycloadditions of isocyanides.


    Kruithof, Art; Ruijter, Eelco; Orru, Romano V A


    Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one-pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.

  5. Chemically-activatable alkyne-tagged probe for imaging microdomains in lipid bilayer membranes

    PubMed Central

    Yamaguchi, Satoshi; Matsushita, Taku; Izuta, Shin; Katada, Sumika; Ura, Manami; Ikeda, Taro; Hayashi, Gosuke; Suzuki, Yuta; Kobayashi, Koya; Tokunaga, Kyoya; Ozeki, Yasuyuki; Okamoto, Akimitsu


    A chemically-activatable alkynyl steroid analogue probe has been synthesized for visualizing the lipid raft membrane domains by Raman microscopy. The Raman probe, in which ring A of its steroid backbone is replaced with an alkynyl group, was designed to enable activation of the alkyne signal through the Eschenmoser-Tanabe fragmentation reaction of the oxidized cholesterol precursor in lipid bilayer membranes. The alkynyl steroid analogue was observed to form liquid-ordered raft-like domains on a model giant-liposome system in a similar manner as cholesterol, and the large alkyne signal of the accumulated probe at 2120 cm−1 was mapped on the microdomains with a Raman microscope. The alkyne moiety of the probe was confirmed to be converted from the α,β-epoxy ketone group of its precursor by reaction with p-toluensulfonyl hydrazine under a mild condition. Through the reaction, the alkyne signal of the probe was activated on the lipid bilayer membrane of liposomes. Furthermore, the signal activation of the probe was also detected on living cells by stimulated Raman scattering microscopy. The ring-A-opened alkyne steroid analogue, thus, provides a first chemically-activatable Raman probe as a promising tool for potentially unravelling the intracellular formation and trafficking of cholesterol-rich microdomains. PMID:28117375

  6. Sensitive SERS glucose sensing in biological media using alkyne functionalized boronic acid on planar substrates.


    Kong, Kien Voon; Ho, Chris Jun Hui; Gong, Tianxun; Lau, Weber Kam On; Olivo, Malini


    In this work, we propose a novel glucose binding mechanism on a highly sensitive SERS substrate, in order to overcome challenges in specific glucose detection in bio-fluids. We make use of phenylboronic acid as a receptor for saccharide capture onto the substrate and the ability of the captured glucose molecule to undergo secondary binding with an alkyne-functionalized boronic acid to form a glucose-alkyne-boronic acid complex. The formation of this complex shows high selectivity for glucose, over other saccharides. In addition, the alkyne group of the alkyne-functionalized boronic acid exhibits a distinct Raman peak at 1996 cm(-1) in a biological silent region (1800-2800 cm(-1)) where most endogenous molecules, including glucose, show no Raman scattering, thus offering a high sensitivity over other SERS glucose sensing. The substrate offers long-term stability, as well as high SERS enhancement to the glucose-alkyne boronic acid complex on substrate. In addition, the reversibility of SERS signals at various incubation stages also shows reusability capabilities, whereas positive results in clinical urine samples demonstrate clinical feasibility. All these strongly suggest that this newly developed SERS-based assay offers great potential in glucose sensing.

  7. Computational study of a model system of enzyme-mediated [4+2] cycloaddition reaction.


    Gordeev, Evgeniy G; Ananikov, Valentine P


    A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system. The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally. In the present study it was demonstrated that the [4+2] cycloaddition reaction may benefit from moving along the energetically balanced reaction coordinate, which enabled the catalytic rate enhancement of the [4+2] cycloaddition pathway involving a single transition state. Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

  8. Cycloaddition reaction of 2-vinylazetidines with benzyne: a facile access to 1-benzazocine derivatives.


    Aoki, Takashi; Koya, Shunsuke; Yamasaki, Ryu; Saito, Shinichi


    The cycloaddition reaction of 2-vinylazetidines with benzyne proceeded smoothly without a catalyst, and various benzazocine derivatives were isolated in good to high yields. The scope of the reaction, as well as the reactions of other arynes, has been studied.

  9. Thermal 1,3-dipolar cycloaddition reaction of azomethine imines with active esters.


    He, Liwenze; Liu, Lin; Han, Runfeng; Zhang, Weiwei; Xie, Xingang; She, Xuegong


    An efficient method for the 1,3-dipolar cycloaddition of azomethine imines with active esters under thermal conditions has been described in good to high yields. This method offers a straightforward pathway to synthesize bioactive pyrazolidinones.

  10. Concerted Ring Opening and Cycloaddition of Chiral Epoxy Enolsilanes with Dienes.


    Krenske, Elizabeth H; Lam, Sarah; Ng, Jerome P L; Lo, Brian; Lam, Sze Kui; Chiu, Pauline; Houk, Kendall N


    Silyl-triflate-catalyzed (4+3) cycloadditions of epoxy enolsilanes with dienes provide a mild and chemoselective synthetic route to seven-membered carbocycles. Epoxy enolsilanes containing a terminal enolsilane and a single stereocenter undergo cycloaddition with almost complete conservation of enantiomeric purity, a finding that argues against the involvement of oxyallyl cation intermediates which have been previously proposed for these types of reactions. Reported are theoretical and experimental investigations of the cycloaddition mechanism. The major enantiomers of the cycloadducts are derived from S(N)2-like reactions of the silylated epoxide with the diene, in which stereospecific ring opening and formation of the two new C-C bonds occur in a single step. Calculations predict, and experiments confirm, that the observed small losses of enantiomeric purity are traced to a triflate-mediated double S(N)2 cycloaddition pathway.

  11. The Copper-nicotinamide complex: sustainable applications in coupling and cycloaddition reactions

    EPA Science Inventory

    Crystalline copper (II)-nicotinamide complex, synthesized via simple mixing of copper chloride and nicotinamide solution at room temperature, catalyzes the C-S, C-N bond forming and cycloaddition reactions under a variety of sustainable reaction conditions.

  12. Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles

    PubMed Central

    Elliott, Gregory I.; Fuchs, James R.; Blagg, Brian S. J.; Ishikawa, Hayato; Tao, Houchao; Yuan, Z.-Q.; Boger, Dale L.


    Full details of a systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined. PMID:16895427

  13. Synthesis of 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones.


    Wu, Chunrui; Fang, Yuesi; Larock, Richard C; Shi, Feng


    A rapid and efficient synthesis of 2H-indazoles has been developed, which involves the [3 + 2] dipolar cycloaddition of arynes and sydnones. The process proceeds under mild reaction conditions in good to excellent yields.

  14. A multicomponent formal [1+2+1+2]-cycloaddition for the synthesis of dihydropyridines.


    Girling, P Ricardo; Batsanov, Andrei S; Shen, Hong C; Whiting, Andrew


    Reaction of methoxyvinylmethylketone with different amines and aldehydes under Lewis-acid catalysed conditions results in a novel, formal, step-wise [1+2+1+2]-cycloaddition to give dihydropyridine products.

  15. Click chemistry-based functionalization on non-oxidized silicon substrates.


    Li, Yan; Cai, Chengzhi


    Copper-catalyzed azide-alkyne cycloaddition (CuAAC), combined with the chemical stability of the Si-C-bound organic layer, serves as an efficient tool for the modification of silicon substrates, particularly for the immobilization of complex biomolecules. This review covers recent advances in the preparation of alkynyl- or azido-terminated "clickable" platforms on non-oxidized silicon and their further derivatization by means of the CuAAC reaction. The exploitation of these "click"-functionalized organic thin films as model surfaces to study many biological events was also addressed, as they are directly relevant to the on-going effort of creating silicon-based molecular electronics and chemical/biomolecular sensors.

  16. Water-soluble NHC-Cu catalysts: applications in click chemistry, bioconjugation and mechanistic analysis.


    Díaz Velázquez, Heriberto; Ruiz García, Yara; Vandichel, Matthias; Madder, Annemieke; Verpoort, Francis


    Copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC), better known as "click" reaction, has triggered the use of 1,2,3-triazoles in bioconjugation, drug discovery, materials science and combinatorial chemistry. Here we report a new series of water-soluble catalysts based on N-heterocyclic carbene (NHC)-Cu complexes which are additionally functionalized with a sulfonate group. The complexes show superior activity towards CuAAC reactions and display a high versatility, enabling the production of triazoles with different substitution patterns. Additionally, successful application of these complexes in bioconjugation using unprotected peptides acting as DNA binding domains was achieved for the first time. Mechanistic insight into the reaction mechanism is obtained by means of state-of-the-art first principles calculations.

  17. Fluorinated alcohol-mediated [4 + 3] cycloaddition reaction of indolyl alcohols with cyclopentadiene.


    Liu, Jian; Wang, Liang; Wang, Xiaoxiao; Xu, Lubin; Hao, Zhihui; Xiao, Jian


    This paper describes an efficient [4 + 3] cycloaddition reaction of 3-indolylmethanols with cyclopentadiene in hexafluoroisopropanol (HFIP), which is catalyst-free and inexpensive, and offers mild reaction conditions, wide substrate scope and convenient workup. This methodology provides the first catalyst- and additive-free [4 + 3] cycloaddition reactions of indolyl alcohols, offering a green and efficient method for the synthesis of cyclohepta[b]indole derivatives.

  18. First diastereoselective [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and maleimides.


    Arróniz, Carlos; Molina, Juan; Abás, Sonia; Molins, Elies; Campanera, Josep M; Luque, F Javier; Escolano, Carmen


    Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of . The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.

  19. Expanding the scope of strained-alkyne chemistry: a protection-deprotection strategy via the formation of a dicobalt-hexacarbonyl complex.


    Gobbo, Pierangelo; Romagnoli, Tommaso; Barbon, Stephanie M; Price, Jacquelyn T; Keir, Jennifer; Gilroy, Joe B; Workentin, Mark S


    A protection-deprotection strategy for strained alkynes used for bioorthogonal chemistry is reported. A strained alkyne can be protected with dicobalt-octacarbonyl and we demonstrate for the first time that a strained alkyne can be re-formed and isolated under mild reaction conditions for further bioorthogonal reactivity. The protection-deprotection strategy herein reported will expand the versatility of strained alkynes for the preparation of substrates in chemical biology and materials applications.

  20. A Genetically Encoded Alkyne Directs Palladium-Mediated Protein Labeling on Live Mammalian Cell Surface

    PubMed Central


    The merging of site-specific incorporation of small bioorthogonal functional groups into proteins via amber codon suppression with bioorthogonal chemistry has created exciting opportunities to extend the power of organic reactions to living systems. Here we show that a new alkyne amino acid can be site-selectively incorporated into mammalian proteins via a known orthogonal pyrrolysyl-tRNA synthetase/tRNACUA pair and directs an unprecedented, palladium-mediated cross-coupling reaction-driven protein labeling on live mammalian cell surface. A comparison study with the alkyne-encoded proteins in vitro indicated that this terminal alkyne is better suited for the palladium-mediated cross-coupling reaction than the copper-catalyzed click chemistry. PMID:25347611

  1. Evaluating the Effect of Catalyst Nuclearity in Ni-Catalyzed Alkyne Cyclotrimerizations.


    Pal, Sudipta; Uyeda, Christopher


    An evaluation of catalyst nuclearity effects in Ni-catalyzed alkyne oligomerization reactions is presented. A dinuclear complex, featuring a Ni-Ni bond supported by a naphthyridine-diimine (NDI) ligand, promotes rapid and selective cyclotrimerization to form 1,2,4-substituted arene products. Mononickel congeners bearing related N-donor chelates (2-iminopyridines, 2,2'-bipyridines, or 1,4,-diazadienes) are significantly less active and yield complex product mixtures. Stoichiometric reactions of the dinickel catalyst with hindered silyl acetylenes enable characterization of the alkyne complex and the metallacycle that are implicated as catalytic intermediates. Based on these experiments and supporting DFT calculations, the role of the dinuclear active site in promoting regioselective alkyne coupling is discussed. Together, these results demonstrate the utility of exploring nuclearity as a parameter for catalyst optimization.

  2. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    PubMed Central

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming


    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  3. Recent Developments in Metal-Catalyzed Additions of Oxygen Nucleophiles to Alkenes and Alkynes

    NASA Astrophysics Data System (ADS)

    Hintermann, Lukas

    Progress in the field of metal-catalyzed redox-neutral additions of oxygen nucleophiles (water, alcohols, carboxylic acids, and others) to alkenes, alkynes, and allenes between 2001 and 2009 is critically reviewed. Major advances in reaction chemistry include development of chiral Lewis acid catalyzed asymmetric oxa-Michael additions and Lewis-acid catalyzed hydro-alkoxylations of nonactivated olefins, as well as further development of Markovnikov-selective cationic gold complex-catalyzed additions of alcohols or water to alkynes and allenes.

  4. Site- and Regioselective Monoalkenylation of Pyrroles with Alkynes via Cp*Co(III) Catalysis.


    Tanaka, Ryo; Ikemoto, Hideya; Kanai, Motomu; Yoshino, Tatsuhiko; Matsunaga, Shigeki


    A site-, regio-, syn-, and monoselective alkenylation of dimethylcarbamoyl-protected pyrroles proceeded using a catalytic amount of [Cp*Co(CH3CN)3](SbF6)2 and KOAc. A variety of internal alkynes with several functional groups and a terminal alkyne afforded hydropyrrolation products in a selective manner in good to excellent yield. The site-selectivity (C2/C5 selectivity) observed for C3-substituted pyrroles is noteworthy because Cp*Rh(III)-catalyzed conditions afforded only a moderate yield and low selectivity. The conditions described here provide general and straightforward access to unsymmetrically mono- and disubstituted pyrrole derivatives.

  5. Bis(amidate)bis(amido) titanium complex: a regioselective intermolecular alkyne hydroamination catalyst.


    Yim, Jacky C-H; Bexrud, Jason A; Ayinla, Rashidat O; Leitch, David C; Schafer, Laurel L


    An efficient and selective bis(amidate)bis(amido) titanium precatalyst for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination of terminal and internal alkynes with primary alkylamines, arylamines, and hydrazines is promoted by 5-10 mol % of Ti catalyst. Various functional groups are tolerated including esters, protected alcohols, and imines. The in situ generated complex shows comparable catalytic activity, demonstrating its synthetic versatility for benchtop application. Applications of this catalyst for the synthesis of amino alcohols and a one-pot procedure for indole synthesis are described. A mechanistic proposal that invokes turnover-limiting protonolysis is presented to rationalize the observed regioselectivities.

  6. The [3 + 3]-Cycloaddition Alternative for Heterocycle Syntheses: Catalytically Generated Metalloenolcarbenes as Dipolar Adducts

    PubMed Central


    Conspectus The combination of two or more unsaturated structural units to form cyclic organic compounds is commonly referred to as cycloaddition, and the combination of two unsaturated structural units that forms a six-membered ring is formally either a [5 + 1]-, [4 + 2]-, [2 + 2 + 2]-, or [3 + 3]-cycloaddition. Occurring as concerted or stepwise processes, cycloaddition reactions are among the most useful synthetic constructions in organic chemistry. Of these transformations, the concerted [4 + 2]-cycloaddition, the Diels–Alder reaction, is by far the best known and most widely applied. However, although symmetry disallowed as a concerted process and lacking certifiable examples until recently, stepwise [3 + 3]-cycloadditions offer advantages for the synthesis of a substantial variety of heterocyclic compounds, and they are receiving considerable attention. In this Account, we present the development of stepwise [3 + 3]-cycloaddition reactions from virtual invisibility in the 1990s to a rapidly growing synthetic methodology today, involving organocatalysis or transition metal catalysis. With origins in organometallic or vinyliminium ion chemistry, this area has blossomed into a viable synthetic transformation for the construction of six-membered heterocyclic compounds containing one or more heteroatoms. The development of [3 + 3]-cycloaddition transformations has been achieved through identification of suitable and compatible reactive dipolar adducts and stable dipoles. The reactive dipolar species is an energetic dipolar intermediate that is optimally formed catalytically in the reaction. The stepwise process occurs with the reactive dipolar adduct reacting as an electrophile or as a nucleophile to form the first covalent bond, and this association provides entropic assistance for the construction of the second covalent bond and the overall formal [3 + 3]-cycloaddition. Organocatalysis is well developed for both inter- and intramolecular synthetic

  7. The [3 + 3]-cycloaddition alternative for heterocycle syntheses: catalytically generated metalloenolcarbenes as dipolar adducts.


    Xu, Xinfang; Doyle, Michael P


    The combination of two or more unsaturated structural units to form cyclic organic compounds is commonly referred to as cycloaddition, and the combination of two unsaturated structural units that forms a six-membered ring is formally either a [5 + 1]-, [4 + 2]-, [2 + 2 + 2]-, or [3 + 3]-cycloaddition. Occurring as concerted or stepwise processes, cycloaddition reactions are among the most useful synthetic constructions in organic chemistry. Of these transformations, the concerted [4 + 2]-cycloaddition, the Diels-Alder reaction, is by far the best known and most widely applied. However, although symmetry disallowed as a concerted process and lacking certifiable examples until recently, stepwise [3 + 3]-cycloadditions offer advantages for the synthesis of a substantial variety of heterocyclic compounds, and they are receiving considerable attention. In this Account, we present the development of stepwise [3 + 3]-cycloaddition reactions from virtual invisibility in the 1990s to a rapidly growing synthetic methodology today, involving organocatalysis or transition metal catalysis. With origins in organometallic or vinyliminium ion chemistry, this area has blossomed into a viable synthetic transformation for the construction of six-membered heterocyclic compounds containing one or more heteroatoms. The development of [3 + 3]-cycloaddition transformations has been achieved through identification of suitable and compatible reactive dipolar adducts and stable dipoles. The reactive dipolar species is an energetic dipolar intermediate that is optimally formed catalytically in the reaction. The stepwise process occurs with the reactive dipolar adduct reacting as an electrophile or as a nucleophile to form the first covalent bond, and this association provides entropic assistance for the construction of the second covalent bond and the overall formal [3 + 3]-cycloaddition. Organocatalysis is well developed for both inter- and intramolecular synthetic transformations, but the

  8. Pyrrolidine synthesis via palladium-catalyzed trimethylenemethane cycloaddition and related studies

    SciTech Connect

    Marrs, C.M.


    The palladium catalyzed trimethylenemethane cycloaddition has been extended to the synthesis of pyrrolidines and azepines. In contrast to previous attempts with N-alkyl and N-aryl imine, successful cycloadditions were recorded with several aromatic and aliphatic electron-deficient imines. Sulfonimines were found to be excellent acceptors, yielding pyrrolidine cycloadducts in excellent yields. Aromatic sulfonimines were observed to undergo cycloaddition very rapidly at or below room temperature. Some aliphatic nitrimine and N-phenyl, C-carbalkoxy imines were also found to be useful acceptors. Azepines were obtained from the cycloaddition of cisoid lockeed [alpha],[beta] unsaturated sulfonimines. In order to support the cycloaddition studies, a novel synthetic method was developed for the synthesis of sulfonimines. bis(Toluene-sulfonylimido)tellurium, Te(=N-Ts)[sub 2], generated from tellurium metal and anhydrous chloramine-t, was found to convert both aromatic and aliphatic aldehydes into the corresponding sulfonimines. Chiral ligands were examined in this cyclization and an enantiomeric excess of 35% was achieved with Hayashi's bidentate ferrocenyl ligand (BPFA). In support of this effort, the total synthesis of [+-] nicotine was accomplished in seven steps starting from pyridine 3-carboxaldehyde using these methodologies in order to verify the enantiomeric excess. Finally, the trimethylenemethane cycloaddition was examined with tropone irontricarbonyl complex. A novel [5+3] cycloaddition was observed to proceed in good yield, which upon decomplexation from the iron tricarbonyl moiety yielded the tricyclo[3.2.0] system. The scope and generality were briefly examined. Extended Huekel calculations were performed in order to help rationalize the unexpected regiochemistry.

  9. Stereodivergent Coupling of Aldehydes and Alkynes via Synergistic Catalysis Using Rh and Jacobsen's Amine.


    Cruz, Faben A; Dong, Vy M


    We report an enantioselective coupling between α-branched aldehydes and alkynes to generate vicinal quaternary and tertiary carbon stereocenters. The choice of Rh and organocatalyst combination allows for access to all possible stereoisomers with high enantio-, diastereo-, and regioselectivity. Our study highlights the power of catalysis to activate two common functional groups and provide access to divergent stereoisomers and constitutional structures.

  10. Transition-metal-free Sonogashira-type cross-coupling of alkynes with fluoroarenes.


    Jin, Guanyi; Zhang, Xuxue; Cao, Song


    A novel, inexpensive, and efficient palladium-, copper-, ligand-, and amine-free Sonogashira-type cross-coupling reaction of terminal alkynes with unreactive aryl fluorides in the presence of sodium, sodium methoxide, and calcium hydroxide under the assistance of a Grignard reagent was developed. A plausible mechanism was also suggested.

  11. Parallel synthesis of terminal alkynes using a ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate.


    Barrett, Anthony G M; Hopkins, Brian T; Love, Andrew C; Tedeschi, Livio


    ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate has been prepared, and the supported reagent has been effectively employed in the conversion of a variety of aldehydes into terminal alkynes under mild reaction conditions. The influence of cross-link structure, comonomers, and polymer structure on reaction efficiency has been examined. [structure: see text

  12. Electrocatalytic activities of alkyne-functionalized copper nanoparticles in oxygen reduction in alkaline media

    NASA Astrophysics Data System (ADS)

    Liu, Ke; Song, Yang; Chen, Shaowei


    Stable alkyne-capped copper nanoparticles were prepared by chemical reduction of copper acetate with sodium borohydride in the presence of alkyne ligands. Transmission electron microscopic measurements showed that nanoparticles were well dispersed with a diameter in the range of 4-6 nm. FTIR and photoluminescence spectroscopic measurements confirmed the successful attachment of the alkyne ligands onto the nanoparticle surface most likely forming Cu-Ctbnd interfacial bonds. XPS measurements indicated the formation of a small amount of CuO in the nanoparticles with a satellite peak where the binding energy red-shifted with increasing Cu(II) concentration. Cu2O was also detected in the nanoparticles. Similar results were observed with commercial CuO nanoparticles. Electrochemical studies showed that the as-prepared alkyne-capped copper nanoparticles exhibited apparent electrocatalytic activity in oxygen reduction in alkaline media, a performance that was markedly better than those reported earlier with poly- or single-crystalline copper electrodes; and the fraction of peroxides in the final products decreased with decreasing concentration of oxide components in the nanoparticles.

  13. Ammonium catalyzed cyclitive additions: evidence for a cation-π interaction with alkynes.


    Nagy, Edith; St Germain, Elijah; Cosme, Patrick; Maity, Pradip; Terentis, Andrew C; Lepore, Salvatore D


    The addition of carbamate nitrogen to a non-conjugated carbon-carbon triple bond is catalyzed by an ammonium salt leading to a cyclic product. Studies in homogeneous systems suggest that the ammonium agent facilitates nitrogen-carbon bond formation through a cation-π interaction with the alkyne unit that, for the first time, is directly observed by Raman spectroscopy.

  14. Palladium‐Catalyzed Oxidative Synthesis of α‐Acetoxylated Enones from Alkynes

    PubMed Central

    Jiang, Tuo; Quan, Xu; Zhu, Can; Andersson, Pher G.


    Abstract We report a palladium‐catalyzed oxidative functionalization of alkynes to generate α‐acetoxylated enones in one step. A range of functional groups are well‐tolerated in this reaction. Mechanistic studies, including the use of 18O‐labeled DMSO, revealed that the ketone oxygen atom in the product originates from DMSO. PMID:27060476


    EPA Science Inventory

    In the presence of indium triflate or gallium chloride, a novel coupling between internal alkynes and aldehydes occurred to give unsaturated ketones and [4+1] annulation products.

    Graphical Abstrac...

  16. Rhodium-catalyzed direct coupling of biaryl pyridine derivatives with internal alkynes.


    Zheng, Jun; You, Shu-Li


    Axially chiral biaryls were synthesized by an isoquinoline or 2-pyridine-directed Rh(III)-catalyzed dual C-H cleavage and coupling with internal alkynes in good to excellent yields. Oxidation of isoquinoline derivatives with m-CPBA furnished their corresponding N-oxides, which could be utilized as Lewis base catalysts in asymmetric reactions.

  17. Magnetically Recoverable Supported Ruthenium Catalyst for Hydrogenation of Alkynes and Transfer Hydrogenation of Carbonyl Compounds

    EPA Science Inventory

    A ruthenium (Ru) catalyst supported on magnetic nanoparticles (NiFe2O4) has been successfully synthesized and used for hydrogenation of alkynes at room temperature as well as transfer hydrogenation of a number of carbonyl compounds under microwave irradiation conditions. The cata...

  18. Catalytic B-H Bond Insertion Reactions Using Alkynes as Carbene Precursors.


    Yang, Ji-Min; Li, Zi-Qi; Li, Mao-Lin; He, Qiao; Zhu, Shou-Fei; Zhou, Qi-Lin


    Herein, we report transition-metal-catalyzed B-H bond insertion reactions between borane adducts and alkynes to afford organoboron compounds in excellent yields under mild reaction conditions. This successful use of alkynes as carbene precursors in these reactions constitutes a new route to organoboron compounds. The starting materials are safe and readily available, and the reaction exhibits 100% atom-economy. Moreover, an asymmetric version catalyzed by chiral dirhodium complexes produced chiral boranes with excellent enantioselectivity (up to 96% ee). This is the first report of highly enantioselective heteroatom-hydrogen bond insertion reactions of metal carbenes generated in situ from alkynes. The chiral products of the reaction could be easily transformed to widely used borates and diaryl methanol compounds without loss of optical purity, which demonstrates its potential utility in organic synthesis. A kinetics study indicated that the Cu-catalyzed B-H bond insertion reaction is first order with respect to the catalyst and the alkyne and zero order with respect to the borane adduct, and no kinetic isotopic effect was observed in the reaction of the adduct. These results, along with density functional theory calculations, suggest that the formation of the Cu carbene is the rate-limiting step and that the B-H bond insertion is a fast, concerted process.

  19. Formation of six-membered rings via alkyne insertion into four-membered rings

    NASA Astrophysics Data System (ADS)

    Matsuda, Takanori; Miura, Norio; Matsumoto, Takeshi


    Alkyne insertion into four-membered carbocyclic rings was achieved through rhodium(I)-catalyzed C-C bond cleavage. The reaction of (2-pyridylmethylene)cyclobutenes proceeded via C-C oxidative addition, and that of cyclobutenols involved β-carbon elimination. In both the cases, multiply substituted benzenes were obtained through the aromatization of the initially formed 1,4-cyclohexadienes.

  20. Copper-catalyzed oxidative alkynylation of diaryl imines with terminal alkynes: a facile synthesis of ynimines.


    Laouiti, Anouar; Rammah, Mohamed M; Rammah, Mohamed B; Marrot, Jérome; Couty, François; Evano, Gwilherm


    An efficient copper-mediated method for the oxidative alkynylation of diaryl imines with terminal alkynes is reported. This reaction provides the first catalytic and general synthesis of ynimines and allows for an easy preparation of these useful building blocks. An improved copper-catalyzed oxidative dimerization of imines to azines and the synthesis of dienes and azadienes from ynimines are also described.

  1. Palladium-catalyzed addition of disulfides and diselenides to alkynes under solvent free conditions.


    Ananikov, Valentine P; Beletskaya, Irina P


    An efficient methodology was developed for performing palladium-catalyzed E-E (E = S, Se) bond addition to alkynes under solvent free conditions. Compared to reaction in solvent significant enhancement of reaction rate, improved efficiency and remarkable catalyst stability were observed under solvent free conditions. The addition reactions were carried out with high stereoselectivity and yields in a short reaction time.

  2. Ancillary ligand-free copper catalysed hydrohydrazination of terminal alkynes with NH2NH2.


    Peltier, Jesse L; Jazzar, Rodolphe; Melaimi, Mohand; Bertrand, Guy


    An efficient and selective Cu-catalysed hydrohydrazination of terminal alkynes with parent hydrazine is reported. The methodology tolerates a broad range of functional groups, allows for the synthesis of symmetrical and unsymmetrical azines, and can be extended to hydrazine derivatives and amines.

  3. Chemical functionalization of graphene via aryne cycloaddition: a theoretical study.


    Zhao, Jing-xiang; Wang, Hong-xia; Gao, Bo; Wang, Xiao-guang; Cai, Qing-hai; Wang, Xuan-zhang


    Chemical functionalization of graphene provides a promising route to improve its solubility in water and organic solvents as well as modify its electronic properties, thus significantly expanding its potential applications. In this article, by using density functional theory (DFT) methods, we have studied the effects of the chemical functionalization of graphenes via aryne cycloaddition on its properties. We found that the adsorption of an isolated aryne group on the graphene sheet is very weak with the adsorption energy of -0.204 eV, even though two new single C-C interactions are formed between the aryne group and the graphene. However, the interaction of graphene with the aryne group can be greatly strengthened by (i) substituting the H-atoms in aryne group with F-, Cl-, -NO(2) (electron-withdrawing capability), or CH(3)-group (electron-donating capability), and (ii) increasing the coverage of the adsorbed aryne groups on the graphene sheet. As expected, the strongest bonding is found on the graphene edges, in which the adsorbed aryne groups prefer to be far away from each other. Interestingly, chemical functionalization with aryne groups leads to an opening of the band gap of graphene, which is dependent on the coverage of the adsorbed aryne groups. The present work provides an insight into the modifications of graphene with aryne groups in experiment.

  4. Catalytic oligomerization of terminal alkynes promoted by organo-f-complexes

    SciTech Connect

    Straub, T.; Haskel, A.; Eisen, M.S.


    Organoactinides of the type Cp*{sub 2}AcMe{sub 2} (Cp*=C{sub 5}Me{sub 5}; Ac=Th, U) are active catalyst precursors for the oligomerization of terminal alkynes HC{triple_bond}CR (R=alkyl, aryl, SiMe{sub 3}). The regioselectivity and the extent of oligomerization strongly depend on the alkyne substituent R, whereas the catalytic reactivity is similar for 1 and 2. In the presence of one of these organoactinides, for example, HCCSiMe{sub 3} regioselectively oligomerizes to the head-to-tail dimer 3 (5%) and the trimer 4 (95%). 1 and 2 react with the terminal alkynes, releasing methane, to the corresponding bisacetylide complexes which are active species and in the catalytic reactions. The bisacetylide complex ({eta}{sup 5}-C{sub 5}Me{sub 5}){sub 2}U(CCPh){sub 2} was identified by proton NMR spectroscopy. Subsequent insertion of alkyne molecules in the actinide-carbon {sigma}-bonds leads to the formation of actinide-alkenyl complexes. The turnover limiting step is the release of the organic oligomer from the actinide-organyl complex. A species of the latter has been spectroscopically characterized in the trimerization reaction of HCCSiMe{sub 3}. In this poster, the catalytic reactivity of the actinide alkyls 1 and 2 with various mono-substituted alkynes as well as the spectroscopic characterization of the key organometallic intermediate complexes in the catalytic cycle and a detailed mechanistic discussion are given.

  5. Intramolecular cycloaddition reactions of furo[3,4-b]indoles for alkaloid synthesis.


    Padwa, Albert; Zou, Yan; Cheng, Bo; Li, Hao; Downer-Riley, Nadale; Straub, Christopher S


    Model studies dealing with the Cu(II)- or Rh(II)-catalyzed carbenoid cyclization/cycloaddition cascade of several α-diazo indolo amido esters have been carried out as an approach to the alkaloid scandine. The Cu(II)-catalyzed reaction of an α-diazo indolo diester that contains a tethered oxa-pentenyl side chain was found to give rise to a reactive benzo[c]furan which undergoes a subsequent [4 + 2]-cycloaddition across the tethered π-bond. The reaction proceeds by the initial generation of a copper carbenoid intermediate which cyclizes onto the adjacent carbonyl group to give a reactive benzo[c]furan which in certain cases can be isolated. Disappointingly, the analogous reaction with the related amido indolo ester failed to take place, even when the tethered π-bond contained an electron-withdrawing carbomethoxy group. It would seem that the geometric requirements for the intramolecular cycloaddition of the furo[3,4-b]indole system with the tethered π-bond imposes distinct restrictions upon the bond angles of the reacting centers to prevent the cycloaddition reaction from occurring. However, the incorporation of another carbonyl group on the nitrogen atom of the tethered alkenyl diazo amido indolo ester seemingly provides better orbital overlap between the reacting π-systems and allows the desired cycloaddition reaction to occur.

  6. Unprecedented Intramolecular [4 + 2]-Cycloaddition between a 1,3-Diene and a Diazo Ester.


    Qiu, Huang; Srinivas, Harathi D; Zavalij, Peter Y; Doyle, Michael P


    Diazo compounds that are well-known to undergo [3 + 2]-cycloaddition provide the first examples of the previously unknown [4 + 2]-cycloaddition with dienes that occur thermally under mild conditions and in high yields. Reactions are initiated from reactants prepared from propargyl aryldiazoacetates that undergo gold(I)-catalyzed rearrangement to activated 1,3-dienyl aryldiazoacetates. These reactions proceed to mixtures of both [4 + 2]-cycloaddition and the 1,3-dienyl aryldiazoacetate after long reaction times. At short reaction times, however, both E- and Z-1,3-dienyl aryldiazoacetates are formed and, after isolation, thermal reactions with the E-isomers form the products from [4 + 2]-cycloaddition with ΔH(‡)298 = 15.6 kcal/mol and ΔS(‡)298 = -27.3 cal/(mol·°C). The Z-isomer is inert to [4 + 2]-cycloaddition under these conditions. The Hammett relationships from aryl-substituted diazo esters (ρ = +0.89) and aryl-substituted dienes (ρ = -1.65) are consistent with the dipolar nature of this transformation.

  7. Dimerization of propargyl and homopropargyl 6-azido-6-deoxy-glycosides upon 1,3-dipolar cycloaddition

    PubMed Central

    Pietrzik, Nikolas; Schmollinger, Daniel


    Summary Copper-catalyzed, thermal or microwave promoted 1,3-dipolar cycloaddition (Click Reaction) of 2-propynyl and 3-butynyl 2,3,4-tri-O-acetyl-6-azido-6-deoxy-glycopyranosides in the D-gluco, D-galacto and D-manno series afford the corresponding dimeric cycloaddition products. PMID:18941499

  8. Conversion of unsaturated alcohols into functionalized tetrahydrofurans and tetrahydropyrans via nitrile oxide dipolar cycloadditions

    SciTech Connect

    Hassner, A.; Murthy, K.S.K. ); Padwa, A.; Dean, D.C.; Schoffstall, A.M. ); Chiacchio, U. )


    The intramolecular nitrile oxide cycloaddition (INOC) of a series of unsaturated oximino ethers has been investigated. The synthesis of the olefinic nitrile oxides involves treating an unsaturated alcohol with a {alpha}-bromoalkanal O-(trimethylsilyl)oxime in the presence of fluoride ion followed by subsequent sodium hypochlorite oxidation. The nitrile oxides were not isolated but spontaneously underwent intramolecular cycloaddition to give fused five- and six-membered ring ethers. The preferred stereoisomer in the formation of the five-membered ring ethers is trans, whereas in the six-membered ring ethers the cis isomer predominates. MM2 calculations help rationalize the observed stereoselectivity. The ratio of diastereomeric products from the INOC reaction appears to correlate with product stabilities. Simple heating of some of the oximino ethers led to intramolecular cycloaddition. The ring closure apparently proceeds subsequent to a tautomeric equilibration of the oxime with a transient nitrone which is trapped by the neighboring {pi}-bond.

  9. Click-to-Chelate: development of technetium and rhenium-tricarbonyl labeled radiopharmaceuticals.


    Kluba, Christiane A; Mindt, Thomas L


    The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction) enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (bio)molecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications.

  10. Solvent-Free Click-Mechanochemistry for the Preparation of Cancer Cell Targeting Graphene Oxide

    PubMed Central


    Polyethylene glycol-functionalized nanographene oxide (PEGylated n-GO) was synthesized from alkyne-modified n-GO, using solvent-free click-mechanochemistry, i.e., copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC). The modified n-GO was subsequently conjugated to a mucin 1 receptor immunoglobulin G antibody (anti-MUC1 IgG) via thiol–ene coupling reaction. n-GO derivatives were characterized with Fourier-transformed infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), Bradford assay, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and atomic force microscopy (AFM). Cell targeting was confirmed in vitro in MDA-MB-231 cells, either expressing or lacking MUC1 receptors, using flow cytometry, confocal laser scanning microscopy (CLSM) and multiphoton (MP) fluorescence microscopy. Biocompatibility was assessed using the modified lactate dehydrongenase (mLDH) assay. PMID:26278410

  11. Synthesis of double-clickable functionalised graphene oxide for biological applications† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc05412e Click here for additional data file.

    PubMed Central

    Mei, Kuo-Ching; Rubio, Noelia; Costa, Pedro M.; Kafa, Houmam; Abbate, Vincenzo; Festy, Frederic; Bansal, Sukhvinder S.; Hider, Robert C.


    Azide- and alkyne-double functionalised graphene oxide (Click2 GO) was synthesised and characterised with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), thermogravimetric analysis (TGA) and Raman spectroscopy. Fourteen-percentage increase in azide content was found, after pre-treatment of GO with meta-chloroperoxybenzoic acid (mCPBA), determined with elemental analysis. No effect on A549 cell viability was found, up to 100 μg mL–1 and 72 h of incubation, determined with the modified lactate dehydrogenase (mLDH) assay. Two sequential copper(i) catalysed azide–alkyne cycloaddition (CuAAC) reactions were performed to conjugate the propargyl-modified blood–brain barrier targeting peptide Angiopep-2, and a bis-azide polyethylene glycol (M W = 3500), to the Click2 GO. The final conjugate was characterised with ATR-FTIR and TGA. PMID:26295072

  12. Design, synthesis, and evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors.


    Jeong, Yunkyung; Lee, Jooyeon; Ryu, Jae-Sang


    A series of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives were designed, synthesized, and evaluated for the Aurora kinase inhibitory activities. The novel hinge-binder tethered 1,2,3-triazolylsalicylamide scaffold was effectively assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). A variety of alkynes with hinge binders were used to search proper structures-binding relationship to the hinge region. The synthesized 1,2,3-triazolylsalicylamide derivatives showed significant Aurora kinase inhibitory activity. In particular, 8a inhibited Aurora A kinase with an IC50 value of 0.284 μM, whereas 8m inhibited Aurora B kinase with an IC50 value of 0.364 μM.

  13. Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles.


    Thakur, Ashish; Louie, Janis


    Transition-metal catalysis has revolutionized the field of organic synthesis by facilitating the construction of complex organic molecules in a highly efficient manner. Although these catalysts are typically based on precious metals, researchers have made great strides in discovering new base metal catalysts over the past decade. This Account describes our efforts in this area and details the development of versatile Ni complexes that catalyze a variety of cycloaddition reactions to afford interesting carbocycles and heterocycles. First, we describe our early work in investigating the efficacy of N-heterocyclic carbene (NHC) ligands in Ni-catalyzed cycloaddition reactions with carbon dioxide and isocyanate. The use of sterically hindered, electron donating NHC ligands in these reactions significantly improved the substrate scope as well as reaction conditions in the syntheses of a variety of pyrones and pyridones. The high reactivity and versatility of these unique Ni(NHC) catalytic systems allowed us to develop unprecedented Ni-catalyzed cycloadditions that were unexplored due to the inefficacy of early Ni catalysts to promote hetero-oxidative coupling steps. We describe the development and mechanistic analysis of Ni/NHC catalysts that couple diynes and nitriles to form pyridines. Kinetic studies and stoichiometric reactions confirmed a hetero-oxidative coupling pathway associated with this Ni-catalyzed cycloaddition. We then describe a series of new substrates for Ni-catalyzed cycloaddition reactions such as vinylcyclopropanes, aldehydes, ketones, tropones, 3-azetidinones, and 3-oxetanones. In reactions with vinycyclopropanes and tropones, DFT calculations reveal noteworthy mechanistic steps such as a C-C σ-bond activation and an 8π-insertion of vinylcyclopropane and tropone, respectively. Similarly, the cycloaddition of 3-azetidinones and 3-oxetanones also requires Ni-catalyzed C-C σ-bond activation to form N- and O-containing heterocycles.

  14. Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition

    PubMed Central

    Palchak, Zachary L; Nguyen, Paula T


    Summary Propargylamines are popular substrates for triazole formation, but tetrasubstituted variants have required multistep syntheses involving stoichiometric amounts of metal. A recent cyclohexanone–amine–silylacetylene coupling forms silyl-protected tetrasubstituted propargylamines in a single copper-catalyzed step. The development of the tandem silyl deprotection–triazole formation reported herein offers rapid access to alpha-tetrasubstituted triazoles. A streamlined two-step approach to this uncommon class of hindered triazoles will accelerate exploration of their therapeutic potential. The superior activity of copper(II) triflate in the formation of triazoles from sensitive alkyne substrates extends to simple terminal alkynes. PMID:26425198

  15. Formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes: stereoselective access to substituted tetrahydropyrans.


    Parsons, Andrew T; Johnson, Jeffrey S


    A highly diastereoselective synthesis of 2,6-cis-disubstituted tetrahydropyrans (THPs) via Lewis acid-catalyzed formal [4 + 2] cycloaddition of donor-acceptor cyclobutanes and aldehydes has been developed. THP products are formed in up to 96% yield and 99:1 diastereoselectivity. Aromatic, cinnamyl, and aliphatic aldehydes are competent dipolarophiles in this system. This methodology was extended to a [[2 + 2] + 2] cycloaddition of 4-methoxystyrene, dimethyl methylidene malonate, and an aldehyde to furnish THPs directly without prior isolation of the cyclobutane.

  16. Application of cycloaddition reactions to the syntheses of novel boron compounds.


    Zhu, Yinghuai; Siwei, Xiao; Maguire, John A; Hosmane, Narayan S


    This review covers the application of cycloaddition reactions in forming the boron-containing compounds such as symmetric star-shaped boron-enriched dendritic molecules, nano-structured boron materials and aromatic boronic esters. The resulting boron compounds are potentially important reagents for both materials science and medical applications such as in boron neutron capture therapy (BNCT) in cancer treatment and as drug delivery agents and synthetic intermediates for carbon-carbon cross-coupling reactions. In addition, the use of boron cage compounds in a number of cycloaddition reactions to synthesize unique aromatic species will be reviewed briefly.

  17. Photochemical [2 + 2] cycloaddition of N,N-diethylpropynylamine to C[sub 60

    SciTech Connect

    Zhang, X.; Romero, A.; Foote, C.S. )


    We report an efficient photochemical [2 + 2] cycloaddition route to a C[sub 60] adduct and its subsequent reaction to give a very high yield of a difunctional dihydrofullerene in one pot. These preliminary studies demonstrate a potentially versatile, high-yield photochemical functionalization of C[sub 60]. The moderately stable cyclobutenamine undergoes interesting chemical changes that lead to useful functionalized dihydrofullerenes that should be easily converted to a wide variety of derivatives. The mechanism of the photochemical [2 + 2] cycloaddition of C[sub 60] with electron-rich compounds is under investigation. 38 refs.

  18. Computational analysis of the stereochemical outcome in the imidazolidinone-catalyzed enantioselective (4 + 3)-cycloaddition reaction.


    Krenske, Elizabeth H; Houk, K N; Harmata, Michael


    Computations show why the catalytic, asymmetric (4 + 3)-cycloaddition reaction developed in the Harmata laboratories proceeds with facial selectivity opposite to that for models proposed for related catalyzed Diels-Alder reactions. Computations with M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) show that iminium ions derived from MacMillan's chiral 2-tert-butyl-5-benzylimidazolidinone and siloxypentadienals undergo (4 + 3)-cycloadditions with furans preferentially on the more crowded face. Conformational reorganization of the benzyl group, to avoid intramolecular interaction with the silyl group, is responsible for differentiating the activation barriers of top- and bottom-face attack.

  19. Functionalization of carbon nanotubes via Cu(I)-catalyzed Huisgen [3+2] cycloaddition "click chemistry".


    Rana, Sravendra; Cho, Jae Whan


    Functionalization of carbon nanotubes is essential for achieving their mechanical, electrical, and biological functions and enhancing their dispersion in a polymer matrix. Cycloaddition reactions can play a significant role as an emerging route in this direction. This minireview focuses on covalent functionalization of carbon nanotubes using a facile approach via a Cu(I)-catalyzed Huisgen [3+2] cycloaddition reaction. Through this reaction, an enormous variety of molecules can be coupled onto carbon nanotubes in a very controlled manner, and may be utilized for many potential applications from nanoelectronics to bio-applications.

  20. Double hydrophosphination of alkynes promoted by rhodium: the key role of an N-heterocyclic carbene ligand.


    Di Giuseppe, Andrea; De Luca, Roberto; Castarlenas, Ricardo; Pérez-Torrente, Jesús J; Crucianelli, Marcello; Oro, Luis A


    The regioselective double hydrophosphination of alkynes mediated by rhodium catalysts is presented. The distinctive stereoelectronic properties of the NHC ligand prevent the catalyst deactivation by diphosphine coordination thereby allowing for the closing of a productive catalytic cycle.

  1. Nickel-catalyzed enantioselective alkylative coupling of alkynes and aldehydes: synthesis of chiral allylic alcohols with tetrasubstituted olefins.


    Yang, Yun; Zhu, Shou-Fei; Zhou, Chang-Yue; Zhou, Qi-Lin


    A highly efficient nickel-catalyzed asymmetric alkylative coupling of alkynes, aldehydes, and dimethylzinc has been realized by using bulky spirobiindane phosphoramidite ligands, affording allylic alcohols with a tetrasubstituted olefin functionality in high yields, high regioselectivities, and excellent enantioselectivities.

  2. Ruthenium-catalyzed decarbonylative addition reaction of anhydrides with alkynes: a facile synthesis of isocoumarins and α-pyrones.


    Prakash, Rashmi; Shekarrao, Kommuri; Gogoi, Sanjib; Boruah, Romesh C


    A novel ruthenium catalyzed straightforward and efficient synthesis of isocoumarin and α-pyrone derivatives has been accomplished by the decarbonylative addition reaction of anhydrides with alkynes under thermal conditions.

  3. New approach to phosphinoalkynes based on Pd- and Ni-catalyzed cross-coupling of terminal alkynes with chlorophosphanes.


    Beletskaya, Irina P; Afanasiev, Vladimir V; Kazankova, Marina A; Efimova, Irina V


    [reaction: see text] The first example of direct phosphination of terminal alkynes with chlorophosphanes catalyzed by Ni or Pd complexes is described. Both aromatic and aliphatic terminal acetylenes undergo the coupling reaction to give corresponding coupling product in high yield.

  4. Self‐Assembly of Disorazole C1 through a One‐Pot Alkyne Metathesis Homodimerization Strategy†

    PubMed Central

    Ralston, Kevin J.; Ramstadius, H. Clinton; Brewster, Richard C.; Niblock, Helen S.


    Abstract Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne‐metathesis‐based homodimerization approach to natural products. In this approach to the cytotoxic C2‐symmetric marine‐derived bis(lactone) disorazole C1, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one‐pot alkyne cross‐metathesis/ring‐closing metathesis self‐assembly process. PMID:27346897

  5. Preparation of a boronate-functionalized affinity hybrid monolith for specific capture of glycoproteins.


    Yang, F; Mao, J; He, X W; Chen, L X; Zhang, Y K


    A novel strategy for preparation of a boronate affinity hybrid monolith was developed using a Cu(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) reaction of an alkyne-boronate ligand with an azide-functionalized monolithic intermediate. An azide-functionalized hybrid monolith was first synthesized via a single-step procedure to provide reactive sites for click chemistry; then the alkyne-boronate ligands were covalently immobilized on the azide-functionalized hybrid monolith via an in-column CuAAC reaction to form a boronate affinity hybrid monolith under mild conditions. The boronate affinity monolith was characterized and evaluated by means of elemental analysis, Fourier transform infrared spectroscopy, and scanning electron microscopy. The boronate affinity hybrid monolith exhibited excellent specificity toward nucleosides and glycoproteins, which were chosen as test cis-diol-containing compounds under neutral conditions. The binding capacity of the monolith for the glycoprotein ovalbumin was 2.36 mg · g(-1) at pH 7.0. The practicability of the boronate affinity hybrid monolithic material was demonstrated by specific capture of the glycoproteins ovalbumin and ovotransferrin from an egg sample.

  6. Clickable and Antifouling Platform of Poly[(propargyl methacrylate)-ran-(2-methacryloyloxyethyl phosphorylcholine)] for Biosensing Applications.


    Wiarachai, Oraphan; Vilaivan, Tirayut; Iwasaki, Yasuhiko; Hoven, Voravee P


    A functional copolymer platform, namely, poly[(propargyl methacrylate)-ran-(2-methacryloyloxyethyl phosphorylcholine)] (PPgMAMPC), was synthesized by reversible addition-fragmentation chain-transfer polymerization. In principle, the alkyne moiety of propargyl methacrylate (PgMA) should serve as an active site for binding azide-containing molecules via a click reaction, i.e., Cu-catalyzed azide/alkyne cycloaddition (CuAAC), and 2-methacryloyloxyethyl phosphorylcholine (MPC), the hydrophilic monomeric unit, should enable the copolymer to suppress nonspecific adsorption. The copolymers were characterized using Fourier transform infrared (FTIR) and (1)H NMR spectroscopies. Thiol-terminated, PPgMAMPC-SH, obtained by aminolysis of PPgMAMPC, was immobilized on a gold-coated substrate using a "grafting to" approach via self-assembly. Azide-containing species, namely, biotin and peptide nucleic acid (PNA), were then immobilized on the alkyne-containing copolymeric platform via CuAAC. The potential use of surface-attached PPgMAMPC in biosensing applications was shown by detection of specific target molecules, i.e., streptavidin (SA) and DNA, by the developed sensing platform using a surface plasmon resonance technique. The copolymer composition strongly influenced the performance of the developed sensing platform in terms of signal-to-noise ratio in the case of the biotin-SA system and hybridization efficiency and mismatch discrimination for the PNA-DNA system.

  7. Covalently crosslinked diels-alder polymer networks.

    SciTech Connect

    Bowman, Christopher; Adzima, Brian J.; Anderson, Benjamin John


    This project examines the utility of cycloaddition reactions for the synthesis of polymer networks. Cycloaddition reactions are desirable because they produce no unwanted side reactions or small molecules, allowing for the formation of high molecular weight species and glassy crosslinked networks. Both the Diels-Alder reaction and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) were studied. Accomplishments include externally triggered healing of a thermoreversible covalent network via self-limited hysteresis heating, the creation of Diels-Alder based photoresists, and the successful photochemical catalysis of CuAAC as an alternative to the use of ascorbic acid for the generation of Cu(I) in click reactions. An analysis of the results reveals that these new methods offer the promise of efficiently creating robust, high molecular weight species and delicate three dimensional structures that incorporate chemical functionality in the patterned material. This work was performed under a Strategic Partnerships LDRD during FY10 and FY11 as part of a Sandia National Laboratories/University of Colorado-Boulder Excellence in Science and Engineering Fellowship awarded to Brian J. Adzima, a graduate student at UC-Boulder. Benjamin J. Anderson (Org. 1833) was the Sandia National Laboratories point-of-contact for this fellowship.

  8. Further studies on hydration of alkynes by the PtCl4-CO catalyst

    SciTech Connect

    Israelsohn, Osnat; Vollhardt, K. Peter C.; Blum, Jochanan


    Under CO atmosphere, between 80 and 120 C, a glyme solution of PtCl{sub 4} forms a carbonyl compound that promotes hydration of internal as well as terminal alkynes to give aldehyde-free ketones. The catalytic process depends strongly on the electronic and steric nature of the substrates. Part of the carbonyl functions of the catalyst can be replaced by phosphine ligands. Chiral DIOP reacts with the PtCl{sub 4}-CO compound to give a catalyst that promotes partial kinetic resolution of a racemic alkyne. Replacement of part of the CO by polystyrene-bound diphenylphosphine enables to attach the catalyst to the polymeric support. Upon entrapment of the platinum compound in a silica sol-gel matrix, it reacts as a partially recyclable catalyst. A reformulated mechanism for the PdCl{sub 4}-CO catalyzed hydration is suggested on the basis of the present study.

  9. Cobalt catalyzed z-selective hydroboration of terminal alkynes and elucidation of the origin of selectivity.


    Obligacion, Jennifer V; Neely, Jamie M; Yazdani, Aliza N; Pappas, Iraklis; Chirik, Paul J


    A bis(imino)pyridine cobalt-catalyzed hydroboration of terminal alkynes with HBPin (Pin = pinacolate) with high yield and (Z)-selectivity for synthetically valuable vinylboronate esters is described. Deuterium labeling studies, stoichiometric experiments, and isolation of catalytically relevant intermediates support a mechanism involving selective insertion of an alkynylboronate ester into a Co-H bond, a pathway distinct from known precious metal catalysts where metal vinylidene intermediates have been proposed to account for the observed (Z) selectivity. The identity of the imine substituents dictates the relative rates of activation of the cobalt precatalyst with HBPin or the terminal alkyne and, as a consequence, is responsible for the stereochemical outcome of the catalytic reaction.

  10. Copper-catalyzed 1,2-addition of α-carbonyl iodides to alkynes.


    Xu, Tao; Hu, Xile


    β,γ-Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β-γ-unsaturated ketones through 1,2-addition of α-carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)-trichostatin A, a histone deacetylase inhibitor.

  11. Gold(i)-catalyzed addition of carboxylic acids to internal alkynes in aqueous medium.


    González-Liste, Pedro J; García-Garrido, Sergio E; Cadierno, Victorio


    We report herein the efficient hydro-oxycarbonylation of symmetrical and unsymmetrical internal alkynes with carboxylic acids in water at 60 °C, employing the catalytic system [AuCl(PPh3)]/AgOAc (5 mol%). This simple and eco-friendly protocol allows for the synthesis of a wide variety of trisubstituted enol esters (37 examples) in high yields and with complete Z-stereoselectivity. The use of microwave irradiation as an alternative energy source has also been evaluated.

  12. Synthesis of axially chiral heterobiaryl alkynes via dynamic kinetic asymmetric alkynylation.


    Hornillos, Valentín; Ros, Abel; Ramírez-López, Pedro; Iglesias-Sigüenza, Javier; Fernández, Rosario; Lassaletta, José M


    The dynamic kinetic Pd(0)-catalyzed alkynylation of racemic heterobiaryl sulfonates was used for the asymmetric synthesis of axially chiral heterobiaryl alkynes with a broad scope. The use of Pd(OAc)2/(S)-QUINAP as the precatalyst provides products in excellent yields and enantioselectivities under mild conditions (DMSO, 40 °C). Semireduction, 1,3-dipolar cycladdition or N-oxidation served to illustrate the synthetic potential of the methodology.

  13. Iron-catalyzed 1,2-addition of perfluoroalkyl iodides to alkynes and alkenes.


    Xu, Tao; Cheung, Chi Wai; Hu, Xile


    Iron catalysis has been developed for the intermolecular 1,2-addition of perfluoroalkyl iodides to alkynes and alkenes. The catalysis has a wide substrate scope and high functional-group tolerance. A variety of perfluoroalkyl iodides including CF3 I can be employed. The resulting perfluoroalkylated alkyl and alkenyl iodides can be further functionalized by cross-coupling reactions. This methodology provides a straightforward and streamlined access to perfluoroalkylated organic molecules.

  14. Preparation of Partially Poisoned Alkanethiolate-Capped Platinum Nanoparticles for Hydrogenation of Activated Terminal Alkynes.


    San, Khin Aye; Chen, Vivian; Shon, Young-Seok


    Stable and isolable alkanethiolate-stabilized Pt nanoparticles (PtNP) were synthesized using the two-phase thiosulfate method with sodium S-alkylthiosulfate as ligand precursor. The mechanistic formation of octanethiolate-capped PtNP (Pt-SC8) from both sodium S-octylthiosulfate and 1-octanethiol ligands was investigated by using (1)H NMR and UV-vis spectroscopies, which revealed the formation of different Pt complexes as the reaction intermediates. The synthesis using S-octylthiosulfate ligand precursor produced Pt-SC8 in higher yields than that using 1-octanethiol ligand. The obtained nanoparticles were characterized by (1)H NMR, UV-vis spectroscopy, infrared spectroscopy (IR), thermogravimetric analysis, and transmission electron microscopy (TEM). The results obtained from (1)H NMR, IR, and UV-vis spectroscopy were consistent with the formation of stable and pure alkanethiolate-capped PtNP. TEM images of PtNP confirmed their small average core size (∼1.5 nm) and high monodispersity. The partially poisoned PtNP with thiolate monolayer ligands were further investigated for the hydrogenation of various alkynes to understand the organic ligands-induced geometric and electronic surface properties of colloidal Pt nanoparticle catalysts. The high catalytic activity of activated terminal alkynes, but the significantly low activity of internal alkynes and unactivated terminal alkynes, were observed under the mild reaction conditions (room temperature and atmospheric pressure). These results indicated that the presence of alkanethiolate ligands could decrease the coordination activity of PtNP surface especially for the bulkier and unactivated substrates.

  15. Carbon dioxide mediated stereoselective copper-catalyzed reductive coupling of alkynes and thiols.


    Riduan, Siti Nurhanna; Ying, Jackie Y; Zhang, Yugen


    A simple protocol for the stereoselective copper-catalyzed hydrothiolation of alkynes under a CO(2) atmosphere has been developed. The stereoselectivity is determined by the presence/absence of a CO(2) atmosphere. The reaction system is robust and utilizes inexpensive, readily available substrates. A cyclic alkene/carboxylate copper complex intermediate is proposed as the key step in determining the stereoselectivity, and an equivalent amount of water is found to play an active role as a proton donor.

  16. Visible-Light-Promoted Vinylation of Tetrahydrofuran with Alkynes through Direct C-H Bond Functionalization.


    Li, Jing; Zhang, Jing; Tan, Haibo; Wang, David Zhigang


    Mild and direct C-H bond functionalizations and vinylations of tetrahydrofuran with alkynes have been accomplished through visible light photocatalysis, yielding a range of vinyl tetrahydrofurans under the synergistic actions of organic dye-type photocatalyst eosin Y, tert-butyl hydroperoxide (t-BuOOH), and a 45 W household lightbulb. A significant kinetic isotope effect (KIE) was recorded, which helps shed light on the mechanistic course.

  17. Lewis Acid Promoted Oxonium Ion Driven Carboamination of Alkynes for the Synthesis of 4-Alkoxy Quinolines.


    Gharpure, Santosh J; Nanda, Santosh K; Adate, Priyanka A; Shelke, Yogesh G


    Lewis acid mediated multisegment coupling cascade is designed for the synthesis of densely substituted 4-alkoxy quinolines via an oxonium ion triggered alkyne carboamination sequence involving C-C and C-N bond formations. Cyclic ether fused-quinolines could also be accessed using this fast, operationally simple, high yielding, chemoselective and functional group tolerant method. Versatility and utility of this methodology is demonstrated by postfunctionalization of products obtained and its use in synthesis of potent drug molecules.

  18. Regioselective reductive hydration of alkynes to form branched or linear alcohols.


    Li, Le; Herzon, Seth B


    The regioselective reductive hydration of terminal alkynes using two complementary dual catalytic systems is described. Branched or linear alcohols are obtained in 75-96% yield with ≥25:1 regioselectivity from the same starting materials. The method is compatible with terminal, di-, and trisubstituted alkenes. This reductive hydration constitutes a strategic surrogate to alkene oxyfunctionalization and may be of utility in multistep settings.

  19. A versatile route to polythiophenes with functional pendant groups using alkyne chemistry

    PubMed Central

    Yang, Li; Emanuelsson, Rikard; Bergquist, Jonas; Strømme, Maria; Sjödin, Martin


    A new versatile polythiophene building block, 3-(3,4-ethylenedioxythiophene)prop-1-yne (pyEDOT) (3), is prepared from glycidol in four steps in 28% overall yield. pyEDOT features an ethynyl group on its ethylenedioxy bridge, allowing further functionalization by alkyne chemistry. Its usefulness is demonstrated by a series of functionalized polythiophene derivatives that were obtained by pre- and post-electropolymerization transformations, provided by the synthetic ease of the Sonogashira coupling and click chemistry. PMID:28144339

  20. Synthesis of Fluorescent Indazoles by Palladium-Catalyzed Benzannulation of Pyrazoles with Alkynes.


    Kim, Og Soon; Jang, Jin Hyeok; Kim, Hyun Tae; Han, Su Jin; Tsui, Gavin Chit; Joo, Jung Min


    The synthesis of indazoles from pyrazoles and internal alkynes is described. Instead of complex benzenoid compounds, readily available pyrazoles were used for the preparation of indazoles by reaction of the C-H bonds of the heterocyclic ring. Oxidative benzannulation was also applied to imidazoles, providing benzimidazoles. This convergent strategy enabled alteration of the photochemical properties of benzo-fused diazoles by varying the substituents at the benzene ring, thus leading to the development of tetraarylindazoles as new fluorophores.

  1. Facile entry into triazole fused heterocycles via sulfamidate derived azido-alkynes.


    Sai Sudhir, V; Phani Kumar, N Y; Nasir Baig, R B; Chandrasekaran, Srinivasan


    Direct synthesis of condensed triazoles from diverse sulfamidates by ring opening of sulfamidates with sodium azide followed by one-pot propargylation and cycloaddition furnished title compounds. The methodology in general has been demonstrated on diverse sulfamidates derived from amino acids, amino acid derivatives, and carbohydrates to obtain diverse triazole fused scaffolds. In one example, a condensed triazole containing amino acid has been synthesized by ring opening of a sulfamidate derivative with propargyl amine.

  2. A novel alkyne cholesterol to trace cellular cholesterol metabolism and localization[S

    PubMed Central

    Hofmann, Kristina; Thiele, Christoph; Schött, Hans-Frieder; Gaebler, Anne; Schoene, Mario; Kiver, Yuriy; Friedrichs, Silvia; Lütjohann, Dieter; Kuerschner, Lars


    Cholesterol is an important lipid of mammalian cells and plays a fundamental role in many biological processes. Its concentration in the various cellular membranes differs and is tightly regulated. Here, we present a novel alkyne cholesterol analog suitable for tracing both cholesterol metabolism and localization. This probe can be detected by click chemistry employing various reporter azides. Alkyne cholesterol is accepted by cellular enzymes from different biological species (Brevibacterium, yeast, rat, human) and these enzymes include cholesterol oxidases, hydroxylases, and acyl transferases that generate the expected metabolites in in vitro and in vivo assays. Using fluorescence microscopy, we studied the distribution of cholesterol at subcellular resolution, detecting the lipid in the Golgi and at the plasma membrane, but also in the endoplasmic reticulum and mitochondria. In summary, alkyne cholesterol represents a versatile, sensitive, and easy-to-use tool for tracking cellular cholesterol metabolism and localization as it allows for manifold detection methods including mass spectrometry, thin-layer chromatography/fluorography, and fluorescence microscopy. PMID:24334219

  3. Ru Catalyzed Alkene-Alkyne Coupling. Total Synthesis of Amphidinolide P

    PubMed Central

    Trost, Barry M.; Papillon, Julien P. N.; Nussbaumer, Thomas


    A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo- and regioselective fashion, in spite of the significant degree of unsaturation of the substrates. The resulting 1,4-diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne partner made use of an unusual anti-selective addition under chelation control conditions of an allyltin reagent derived from tiglic acid. In addition, a remarkably E-selective E2 process using the azodicarboxylate-triphenylphosphine system is featured. Also featured is the first example of the use of a β-lactone as a thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity to further probe the scope of the ruthenium-catalyzed alkene-alkyne coupling, in particular using enynes, and studies using various functionalized substrates are described. PMID:16351124

  4. Evaluation of alkyne-modified isoprenoids as chemical reporters of protein prenylation.


    DeGraw, Amanda J; Palsuledesai, Charuta; Ochocki, Joshua D; Dozier, Jonathan K; Lenevich, Stepan; Rashidian, Mohammad; Distefano, Mark D


    Protein prenyltransferases catalyze the attachment of C15 (farnesyl) and C20 (geranylgeranyl) groups to proteins at specific sequences localized at or near the C-termini of specific proteins. Determination of the specific protein prenyltransferase substrates affected by the inhibition of these enzymes is critical for enhancing knowledge of the mechanism of such potential drugs. Here, we investigate the utility of alkyne-containing isoprenoid analogs for chemical proteomics experiments by showing that these compounds readily penetrate mammalian cells in culture and become incorporated into proteins that are normally prenylated. Derivatization via Cu(I) catalyzed click reaction with a fluorescent azide reagent allows the proteins to be visualized and their relative levels to be analyzed. Simultaneous treatment of cells with these probes and inhibitors of prenylation reveals decreases in the levels of some but not all of the labeled proteins. Two-dimensional electrophoretic separation of these labeled proteins followed by mass spectrometric analysis allowed several labeled proteins to be unambiguously identified. Docking experiments and density functional theory calculations suggest that the substrate specificity of protein farnesyl transferase may vary depending on whether azide- or alkyne-based isoprenoid analogs is employed. These results demonstrate the utility of alkyne-containing analogs for chemical proteomic applications.

  5. Evaluation of alkyne-modified isoprenoids as chemical reporters of protein prenylation

    PubMed Central

    DeGraw, Amanda J.; Palsuledesai, Charuta; Ochocki, Joshua D.; Dozier, Jonathan K.; Lenevich, Stepan; Rashidian, Mohammad; Distefano, Mark D.


    Protein prenyltransferases catalyze the attachment of C15 (farnesyl) and C20 (geranylgeranyl) groups to proteins at specific sequences localized at or near the C-termini of specific proteins. Determination of the specific protein prenyltransferase substrates affected by the inhibition of these enzymes is critical for enhancing knowledge of the mechanism of such potential drugs. Here we investigate the utility of alkyne-containing isoprenoid analogues for chemical proteomics experiments by showing that these compounds readily penetrate mammalian cells in culture and become incorporated into proteins that are normally prenylated. Derivatization via Cu(I) catalyzed Click reaction with a fluorescent azide reagent allows the proteins to be visualized and their relative levels to be analyzed. Simultaneous treatment of cells with these probes and inhibitors of prenylation reveals decreases in the levels of some but not all of the labeled proteins. Two-dimensional electrophoretic separation of these labeled proteins followed by mass spectrometric analysis allowed several labeled proteins to be unambiguously identified. Docking experiments and DFT calculations suggest that the substrate specificity of PFTase may vary depending on whether azide- or alkyne-based isoprenoid analogues are employed. These results demonstrate the utility of alkyne-containing analogues for chemical proteomic applications. PMID:21040496

  6. Construction of Nine-Membered Heterocycles through Palladium-Catalyzed Formal [5+4] Cycloaddition.


    Yang, Li-Cheng; Rong, Zi-Qiang; Wang, Ya-Nong; Tan, Zher Yin; Wang, Min; Zhao, Yu


    The first catalytic formal [5+4] cycloaddition to prepare nine-membered heterocycles is presented. Under palladium catalysis, the reaction of N-tosyl azadienes and substituted vinylethylene carbonates (VECs) proceeds smoothly to produce benzofuran-fused heterocycles in uniformly high efficiency. Highly diastereoselective functionalization of the nine-membered heterocycles through peripheral attack is also demonstrated.

  7. Synthesis and Diels-Alder cycloaddition reaction of norbornadiene and benzonorbornadiene dimers.


    Nişanci, Bilal; Dalkiliç, Erdin; Güney, Murat; Daştan, Arif


    Dimeric forms of norbornadiene and benzonorbornadiene were synthesized starting with known monobromide derivatives. The Diels-Alder cycloaddition reaction of dimers with TCNE and PTAD was investigated and new norbornenoid polycyclics were obtained. All compounds were characterized properly using NMR spectroscopy.

  8. Catalyst-controlled formal [4 + 3] cycloaddition applied to the total synthesis of (+)-barekoxide and (-)-barekol.


    Lian, Yajing; Miller, Laura C; Born, Stephen; Sarpong, Richmond; Davies, Huw M L


    The tandem cyclopropanation/Cope rearrangement between bicyclic dienes and siloxyvinyldiazoacetate, catalyzed by the dirhodium catalyst Rh(2)(R-PTAD)(4), effectively accomplishes enantiodivergent [4 + 3] cycloadditions. The reaction proceeds by a cyclopropanation followed by a Cope rearrangement of the resulting divinylcyclopropane. This methodology was applied to the synthesis of (+)-barekoxide (1) and (-)-barekol (2).

  9. Stepwise cycloadditions of mesoionic systems: thionation of thioisomünchnones by isothiocyanates.


    Cantillo, David; Avalos, Martín; Babiano, Reyes; Cintas, Pedro; Jiménez, José L; Light, Mark E; Palacios, Juan C


    An unusual thionation strategy of mesoionic compounds with aryl isothiocyanates enables a facile synthesis of 1,3-thiazolium-4-thiolate systems. The mechanistic pathway of such a transformation most likely involves a stepwise 1,3-dipolar cycloaddition, which is supported by theoretical calculations performed with a two-layer hybrid method (B3LYP/6-31G(d):PM3).

  10. Torsional Control of Stereoselectivities in Electrophilic Additions and Cycloadditions to Alkenes

    PubMed Central

    Wang, Hao; Houk, K. N.


    Torsional effects control the π-facial stereoselectivities of a variety of synthetically important organic reactions. This review surveys theoretical calculations that have led to the understanding of the influence of the torsional effects on several types of stereoselective organic reactions, especially electrophilic additions and cycloadditions to alkenes. PMID:24409340

  11. Asymmetric 1,3-Dipolar Cycloaddition Reactions Catalyzed by Heterocycle-Based Metal Complexes

    NASA Astrophysics Data System (ADS)

    Suga, Hiroyuki

    Highly enantioselective 1,3-dipolar cycloaddition reactions of several 1,3-dipoles, such as nitrones, nitrile oxides, nitrile imines, diazoalkanes, azomethine imines and carbonyl ylides, catalyzed by heterocyclic supramolecular type of metal complexes consisting of chiral heterocyclic compounds and metal salts were described in terms of their ability of asymmetric induction and enantioface differentiation. The scope and limitations of each cycloaddition reactions were also briefly described. Of the chiral hererocycle-based ligands, chiral bisoxazoline, 2,6-bis(oxazolinyl)pyridine, and related oxazoline ligands are shown to be quite effective in obtaining high levels of asymmtric induction. The combination of the bisoxazoline ligand derived from (1S,2R)-cis-1-amino-2-indanol and metal salts was especially efficient for asymmetric cycloaddition reactions of a number of 1,3-dipoles, such as nitrones, nitrile oxide, nitrile imines, diazoacetates and azomethine imines. The metals utilized for the heterocycle-based complexes show a crucial role for degree of asymmetric induction depending upon the 1,3-dipole used. High levels of enantioselectivity were achieved in 1,3-dipolar cycloaddition reactions of unstable carbonyl ylides with benzyloxyacetaldehyde derivatives, α-keto esters, 3-(2-alkenoyl)-2-oxazolidinones, and even vinyl ethers, which were catalyzed by Pybox-lanthanoid metal complexes.

  12. Theoretical study of the cycloaddition reaction of a tungsten-containing carbonyl ylide.


    Ito, Kazuta; Hara, Yoshihiro; Mori, Seiji; Kusama, Hiroyuki; Iwasawa, Nobuharu


    The [3+2] cycloaddition reaction of a tungsten-containing carbonyl ylide with methyl vinyl ether and the insertion reactions of the nonstabilized carbene complex intermediates produced have been investigated through the use of B3LYP density functional theory. The [3+2] cycloaddition reaction of the tungsten-containing carbonyl ylide has been proven to proceed concertedly, reversibly, and with high endo selectivity. The intermolecular Si-H insertion reactions of the carbene complex intermediates have been proven to be favored over the intramolecular C-H insertion, in good agreement with experimental results. Moreover, the kinetic endo/exo ratio of the [3+2] cycloaddition reaction has been shown to determine the endo/exo selectivity of the Si-H insertion products. In addition, secondary orbital interactions involving the benzene ring and the carbonyl ligand on the metal center have turned out to strongly influence the high endo selectivity of the [3+2] cycloaddition reaction with methyl vinyl ether.

  13. 3+2-Dipolar cycloaddition of dianhydrohexitol azidoderivatives with N-arylmaleimides

    NASA Astrophysics Data System (ADS)

    Gella, I. M.; Babak, N. L.; Drushlyak, T. G.; Shishkina, S. V.; Musatov, V. I.; Lipson, V. V.


    Dianhydrohexitol azides dipolar 3+2 cycloaddition with N-arylmaleimides has been studied with NMR (1H and 13C, COSY, NOESY and HSQC) and X-ray analysis. In spite of low asymmetrical induction in this reaction, diastereomerically pure products have been obtained. These products are interesting over their structural similarity to griseolic acid derivatives and dihydropyrrolotriazoles, significant for pharmaceutics.

  14. Regiospecific and stereospecific palladium-catalyzed cycloaddition of azetidines and carbodiimides

    SciTech Connect

    Baeg, Jin-Ook; Bensimon, C.; Alper, H.


    Acetidines react with carbodiimides in the presence of bis(benzonitrile)palladium dischloride to form tetrahydrophyrimidin-2-imines in 64-97% yields. The reaction is both regio- and stereospecific, the cycloaddition occurring with retention of configuration of the carbon centers bearing the substitutent groups. 2 figs.

  15. Asymmetric Synthesis of α-Trifluoromethyl Pyrrolidines through Organocatalyzed 1,3-Dipolar Cycloaddition Reaction.


    Dong, Zhenghao; Zhu, Yuanyuan; Li, Boyu; Wang, Cui; Yan, Wenjin; Wang, Kairong; Wang, Rui


    The optically active α-trifluoromethyl pyrrolidines have been achieved through organocatalyzed 1, 3-dipolar cycloaddition reaction firstly. With diphenyl- prolinol trimethylsilyl ether as catalyst and in the presence of 3, 5-dinitrobenzoic acid, the reaction of trifluoroethylamine-derived ketimine with 2-enals gave α-trifluoro-methyl pyrrolidines bearing three contiguous stereogenic centers in excellent diastereoselectivies, stereoselectivities and yields.

  16. Nickel(0)-catalyzed cycloaddition copolymerization involving two diynes and carbon dioxide to poly(2-pyrone)

    SciTech Connect

    Tsuda, Tetsuo; Ooi, Osamu; Maruta, Ken-ichi )


    A copolymerizability order of five diynes, i.e., 3,11-tetradecadiyne (A), 2,6-octadiyne (B), 1,4-di(2-hexynyl)benzene (C), 1,3-di(2-hexynyl)benzene (D), and 1,7-cyclotridecadiyne (E), in the nickel(0)-catalyzed 1:1 cycloaddition copolymerization of the diyne with CO[sub 2] to the poly(2-pyrone) was determined by the nickel(0)-catalyzed copolymerization involving two diynes and CO[sub 2]. The copolymerizability order obtained by analyzing the copolymer composition using [sup 1]H NMR spectroscopy was A [gt] E [gt] B [gt] C [gt] D. This order was explained in terms of the steric hindrance exerted by the substituent on the terminal C[triple bond]C bond of the cooligomer or the copolymer to its cycloaddition along with mobility of its terminal C[triple bond]C bond moiety for the cycloaddition. An order of cycloaddition reactivity of the diyne, which is related to formation of the cooligomer, was determined by measuring the unreacted diyne in the copolymerization involving five diynes and CO[sub 2] using gas chromatography. The result was E [gt] B [gt] C [gt] D [gt] A. Thus high copolymerizability of diyne A is noteworthy.

  17. Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction.


    Haddad, Saoussen; Boudriga, Sarra; Porzio, François; Soldera, Armand; Askri, Moheddine; Knorr, Michael; Rousselin, Yoann; Kubicki, Marek M; Golz, Christopher; Strohmann, Carsten


    A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control.

  18. Development of chiral metal amides as highly reactive catalysts for asymmetric [3 + 2] cycloadditions

    PubMed Central

    Yamashita, Yasuhiro; Yoshimoto, Susumu; Dutton, Mark J


    Summary Highly efficient catalytic asymmetric [3 + 2] cycloadditions using a chiral copper amide are reported. Compared with the chiral CuOTf/Et3N system, the CuHMDS system showed higher reactivity, and the desired reactions proceeded in high yields and high selectivities with catalyst loadings as low as 0.01 mol %. PMID:27559396

  19. Computational Study of a Model System of Enzyme-Mediated [4+2] Cycloaddition Reaction

    PubMed Central


    A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reac-tion was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system. The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally. In the present study it was demonstrated that the [4+2] cycloaddition reaction may benefit from moving along the energetically balanced reaction coordinate, which enabled the catalytic rate enhancement of the [4+2] cycloaddition pathway involving a single transition state. Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation. PMID:25853669

  20. Extensions of a Basic Laboratory Experiment: [4+2] and [2+2] Cycloadditions

    ERIC Educational Resources Information Center

    Amarne, Hazem Y.; Bain, Alex D.; Neumann, Karen; Zelisko, Paul M.


    We describe an extended third-year undergraduate chemistry laboratory exercise in which a number of techniques and concepts are applied to the same set of chemical reactions. The reactions are the photochemical and thermal cycloadditions of [beta]-nitrostyrene and 2,3-dimethylbutadiene. This can be viewed as a single long lab or a series of…

  1. Reaction of phosphinylated nitrosoalkenes with electron-rich heterocycles. Electrophilic aromatic substitution vs. cycloaddition.


    de Los Santos, Jesús M; Rubiales, Gloria; Sbai, Zouhair Es; Ochoa de Retana, Ana M; Palacios, Francisco


    The behavior of phosphinyl nitrosoalkenes with indole, pyrrole and 2,5-dimethylpyrrole is described. The reaction of nitrosoalkenes with indole leads to the formation of 3-substituted indoles. While a concerted asynchronous [4 + 2] cycloaddition process may explain the formation of 3-substituted indole when a methyl group is present at the 3-position of nitrosoalkene, the presence of a 3-methoxycarbonyl group at the same position of nitrosoalkene increases its electrophilic character, and both mechanisms, an electrophilic aromatic substitution and a [4 + 2] cycloaddition process, are predicted to be competitive, although thermodynamically the cycloaddition is favoured. Phosphinyl nitrosoalkenes react with pyrrole leading to the corresponding 2-substituted pyrroles, while the treatment of 2,5-dimethylpyrrole with these nitrosoalkenes gives rise to the formation of bicyclic 1,2-oxazines. The mechanism of the reaction of phosphinyl nitrosoalkenes with pyrrole and 2,5-dimethylppyrrole may be explained by an initial hetero-Diels-Alder cycloaddition in both cases, but only subsequent rearomatization in the case of pyrrole. Theoretical studies show very good agreement with the experimental findings and the proposed mechanisms.

  2. Synthesis of pyrroles by consecutive multicomponent reaction/[4 + 1] cycloaddition of alpha-iminonitriles with isocyanides.


    Fontaine, Patrice; Masson, Géraldine; Zhu, Jieping


    [4 + 1] Cycloaddition of alpha,beta-unsaturated imidoyl cyanide (2-cyano-1-azadienes) with isocyanides in the presence of a catalytic amount of AlCl(3) afforded polysubstituted 2-amino-5-cyanopyrroles in good to excellent yields. In combination with the IBX/TBAB-mediated oxidative Strecker reaction, this important heterocycle is readily synthesized in two steps from simple starting materials.

  3. Total Synthesis of (±)-Strychnine via a [4+2]-Cycloaddition/Rearrangement Cascade

    PubMed Central

    Zhang, Hongjun; Boonsombat, Jutatip


    A new strategy for the synthesis of the Strychnos alkaloid (±)-strychnine has been developed and is based on an intramolecular [4+2]-cycloaddition/rearrangement cascade of an indolyl substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide. PMID:17217284

  4. Functionalized azabicycloalkane amino acids by nitrone 1,3-dipolar intramolecular cycloaddition.


    Manzoni, Leonardo; Arosio, Daniela; Belvisi, Laura; Bracci, Antonio; Colombo, Matteo; Invernizzi, Donatella; Scolastico, Carlo


    [reaction: see text] An efficient and operationally simple method for the synthesis of functionalized azaoxobicyclo[X.3.0]alkane amino acids has been devised. The key step is an intramolecular nitrone cycloaddition on 5-allyl- or 5-homoallylproline that was found to be completely regio- and stereoselective.

  5. Synthesis of 2H-indazoles by the [3 + 2] dipolar cycloaddition of sydnones with arynes.


    Fang, Yuesi; Wu, Chunrui; Larock, Richard C; Shi, Feng


    A rapid and efficient synthesis of 2H-indazoles has been developed using a [3 + 2] dipolar cycloaddition of sydnones and arynes. A series of 2H-indazoles have been prepared in good to excellent yields using this protocol, and subsequent Pd-catalyzed coupling reactions can be applied to the halogenated products to generate a structurally diverse library of indazoles.

  6. Quantum Chemistry Study of Cycloaddition Pathways for the Reaction of o-Benzyne with Fullerenes and Carbon Nanotubes

    NASA Technical Reports Server (NTRS)

    Jaffe, Richard; Han, Jie; Langhoff, Stephen R. (Technical Monitor)


    Functionalization of fullerenes via the [2+2] cycloaddition reaction with o-benzyne has been demonstrated in the laboratory. In contrast, [2+4) cycloaddition products are formed when benzyne reacts with planar polycyclic aromatic hydrocarbons. Using density functional theory (DFT) calculations with Becke's hybrid functional and small contracted gaussian basis sets, we are able to reproduce these product preferences. The objective of this work is to explore the functionalization of carbon nanotubes. We have studied o-benzyne cycloaddition products with a [14,0] single-walled nanotube. We find both the [2+2] and [2+4] adducts to be stable, with the latter product being somewhat favored.

  7. Non-Precious Metals Catalyze Formal [4 + 2] Cycloaddition Reactions of 1,2-Diazines and Siloxyalkynes under Ambient Conditions

    PubMed Central


    Copper(I) and nickel(0) complexes catalyze the formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes, a reaction hitherto best catalyzed by silver salts. These catalysts based on earth abundant metals are not only competent, but the copper catalyst, in particular, promotes cycloadditions of pyrido[2,3-d]pyridazine and pyrido[3,4-d]pyridazine, enabling a new synthesis of quinoline and isoquinoline derivatives, as well as the formal [2 + 2] cycloaddition reaction of cyclohexenone with a siloxyalkyne. PMID:24911346

  8. A general and regioselective synthesis of cyclopentenone derivatives through nickel(0)-mediated [3 + 2] cyclization of alkenyl Fischer carbene complexes and internal alkynes.


    Barluenga, José; Barrio, Pablo; Riesgo, Lorena; López, Luis A; Tomás, Miguel


    A broad range of substituted 2-cyclopentenone derivatives 3-6 are synthesized by the nickel(0)-mediated [3 + 2] cyclization reaction of chromium alkenyl(methoxy)carbene complexes 1 and internal alkynes 2. The reaction takes place with complete regioselectivity with both unactivated alkynes and activated alkynes (electron-withdrawing and electron-donating substituted alkynes). Representative cycloadducts containing boron and tin substituents are further demonstrated to be active partners in classical Pd-catalyzed C-C coupling processes to allow the production of 2-aryl- and 2-alkynyl-substituted cyclopentenones 9-13.

  9. Site-directed spin-labeling of DNA by the azide-alkyne 'click' reaction: nanometer distance measurements on 7-deaza-2'-deoxyadenosine and 2'-deoxyuridine nitroxide conjugates spatially separated or linked to a 'dA-dT' base pair.


    Ding, Ping; Wunnicke, Dorith; Steinhoff, Heinz-Jürgen; Seela, Frank


    Nucleobase-directed spin-labeling by the azide-alkyne 'click' (CuAAC) reaction has been performed for the first time with oligonucleotides. 7-Deaza-7-ethynyl-2'-deoxyadenosine (1) and 5-ethynyl-2'-deoxyuridine (2) were chosen to incorporate terminal triple bonds into DNA. Oligonucleotides containing 1 or 2 were synthesized on a solid phase and spin labeling with 4-azido-2,2,6,6-tetramethylpiperidine 1-oxyl (4-azido-TEMPO, 3) was performed by post-modification in solution. Two spin labels (3) were incorporated with high efficiency into the DNA duplex at spatially separated positions or into a 'dA-dT' base pair. Modification at the 5-position of the pyrimidine base or at the 7-position of the 7-deazapurine residue gave steric freedom to the spin label in the major groove of duplex DNA. By applying cw and pulse EPR spectroscopy, very accurate distances between spin labels, within the range of 1-2 nm, were measured. The spin-spin distance was 1.8±0.2 nm for DNA duplex 17(dA*(7,10))⋅11 containing two spin labels that are separated by two nucleotides within one individual strand. A distance of 1.4±0.2 nm was found for the spin-labeled 'dA-dT' base pair 15(dA*(7))⋅16(dT*(6)). The 'click' approach has the potential to be applied to all four constituents of DNA, which indicates the universal applicability of the method. New insights into the structural changes of canonical or modified DNA are expected to provide additional information on novel DNA structures, protein interaction, DNA architecture, and synthetic biology.

  10. Biofunctionalization on alkylated silicon substrate surfaces via "click" chemistry.


    Qin, Guoting; Santos, Catherine; Zhang, Wen; Li, Yan; Kumar, Amit; Erasquin, Uriel J; Liu, Kai; Muradov, Pavel; Trautner, Barbara Wells; Cai, Chengzhi


    Biofunctionalization of silicon substrates is important to the development of silicon-based biosensors and devices. Compared to conventional organosiloxane films on silicon oxide intermediate layers, organic monolayers directly bound to the nonoxidized silicon substrates via Si-C bonds enhance the sensitivity of detection and the stability against hydrolytic cleavage. Such monolayers presenting a high density of terminal alkynyl groups for bioconjugation via copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC, a "click" reaction) were reported. However, yields of the CuAAC reactions on these monolayer platforms were low. Also, the nonspecific adsorption of proteins on the resultant surfaces remained a major obstacle for many potential biological applications. Herein, we report a new type of "clickable" monolayers grown by selective, photoactivated surface hydrosilylation of α,ω-alkenynes, where the alkynyl terminal is protected with a trimethylgermanyl (TMG) group, on hydrogen-terminated silicon substrates. The TMG groups on the film are readily removed in aqueous solutions in the presence of Cu(I). Significantly, the degermanylation and the subsequent CuAAC reaction with various azides could be combined into a single step in good yields. Thus, oligo(ethylene glycol) (OEG) with an azido tag was attached to the TMG-alkyne surfaces, leading to OEG-terminated surfaces that reduced the nonspecific adsorption of protein (fibrinogen) by >98%. The CuAAC reaction could be performed in microarray format to generate arrays of mannose and biotin with varied densities on the protein-resistant OEG background. We also demonstrated that the monolayer platform could be functionalized with mannose for highly specific capturing of living targets (Escherichia coli expressing fimbriae) onto the silicon substrates.

  11. Sunlight induced cycloaddition and host-guest property of self-assembled organometallic macrocycles based on a versatile building block.


    Wu, Tong; Weng, Lin-Hong; Jin, Guo-Xin


    Organometallic rectangle 1 which undergoes [2+2] cycloaddition upon irradiation with sunlight and organometallic prism 3 which displayed interesting host-guest property were self-assembled based on a versatile building block.

  12. Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

    PubMed Central

    Narayanarao, Manjunatha; Koodlur, Lokesh; Revanasiddappa, Vijayakumar G; Gopal, Subramanya


    A new series of spiropyrrolidine compounds containing indole/indazole moieties as side chains have been accomplished via a one-pot multicomponent synthesis. The method uses the 1,3-dipolar cycloaddition reaction between N-alkylvinylindole/indazole and azomethine ylides, prepared in situ from cyclic/acyclic amino acids. The 1,3-dipolar cycloaddition proceeds efficiently under thermal conditions to afford the regio- and stereospecific cyclic adducts. PMID:28144362

  13. Photoinduced [4 + 4], [4 + 2], and [2 + 2] cycloadditions of o-quinones with oxazoles: chemo-, regio-, and diastereoselectivity.


    Wang, Lei; Huang, Yu-Cheng; Liu, Yang; Fun, Hoong-Kun; Zhang, Yan; Xu, Jian-Hua


    Photoinduced reactions of the 1,2-dicarbonyl compounds phenanthrenequinone (PQ), 1-acetylisatin (IS), and benzil (BZ) with the oxazoles 1a-j have been investigated. In photoreactions of PQ with the oxazoles, in addition to the 1,4-dioxins derived from [4 + 2] cycloaddition and the oxetanes from the Paternó-Büchi [2 + 2] reactions, [4 + 4] cycloaddition products are formed in the reactions with 1a, 1c, 1g, 1i, and 1j, with the quinone's dicarbonyl unit (O═C-C═O) and the oxazole's C═N-C═C moiety as two 4π addends. Photoreactions of IS with the oxazoles 1f and 1g give the [4 + 4] cycloaddition products exclusively, while in photoreactions of IS with 1a, 1c, 1e, 1h, and 1i, [4 + 4] products are formed together with the [2 + 2] products. Reaction pathway partitioning in these photocycloaddtions strongly depends on the substitution pattern on the oxazole ring. The presence of a substituent at the oxazole's C2 atom hampers the [4 + 4] pathway by causing steric hindrance to radical pair recombination in the corresponding 1,7-diradical intermediate to form the [4 + 4] cycloaddition products. A substituent at the C4 atom results in steric hindrance for ring closure of the 1,4-diradicals in the [2 + 2] cycloaddition pathway, therefore favoring the [4 + 4] and [4 + 2] cycloaddition pathways. Regio- and diastereoselectivity in the [2 + 2] and [4 + 4] cycloadditions have been discussed based on the thermodynamic stability of the relevant triplet diradical intermediates and the conformations of these diradicals suitable for the intersystem crossing process. Photoreactions of BZ with the oxazoles afford only [2 + 2] cycloaddition products.

  14. Development of a bioorthogonal and highly efficient conjugation method for quantum dots using tetrazine-norbornene cycloaddition.


    Han, Hee-Sun; Devaraj, Neal K; Lee, Jungmin; Hilderbrand, Scott A; Weissleder, Ralph; Bawendi, Moungi G


    We present a bioorthogonal and modular conjugation method for efficient coupling of organic dyes and biomolecules to quantum dots (QDs) using a norbornene-tetrazine cycloaddition. The use of noncoordinating functional groups combined with the rapid rate of the cycloaddition leads to highly efficient conjugation. We have applied this method to the in situ targeting of norbornene-coated QDs to live cancer cells labeled with tetrazine-modified proteins.

  15. Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction.


    Narayanarao, Manjunatha; Koodlur, Lokesh; Revanasiddappa, Vijayakumar G; Gopal, Subramanya; Kamila, Susmita


    A new series of spiropyrrolidine compounds containing indole/indazole moieties as side chains have been accomplished via a one-pot multicomponent synthesis. The method uses the 1,3-dipolar cycloaddition reaction between N-alkylvinylindole/indazole and azomethine ylides, prepared in situ from cyclic/acyclic amino acids. The 1,3-dipolar cycloaddition proceeds efficiently under thermal conditions to afford the regio- and stereospecific cyclic adducts.

  16. Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes.


    Tsubogo, Tetsu; Saito, Susumu; Seki, Kazutaka; Yamashita, Yasuhiro; Kobayashi, Shu


    Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

  17. Counteranion and solvent assistance in ruthenium-mediated alkyne to vinylidene isomerizations.


    Jiménez-Tenorio, Manuel; Puerta, M Carmen; Valerga, Pedro; Ortuño, Manuel A; Ujaque, Gregori; Lledós, Agustí


    The complex [Cp*RuCl((i)Pr2PNHPy)] (1) reacts with 1-alkynes HC≡CR (R = COOMe, C6H4CF3) in dichloromethane furnishing the corresponding vinylidene complexes [Cp*Ru═C═CHR((i)Pr2PNHPy)]Cl (R = COOMe (2a-Cl), C6H4CF3 (2b-Cl)), whereas reaction of 1 with NaBPh4 in MeOH followed by addition of HC≡CR (R = COOMe, C6H4CF3) yields the metastable π-alkyne complexes [Cp*Ru(η(2)-HC≡CR)((i)Pr2PNHPy)][BPh4] (R = COOMe (3a-BPh4), C6H4CF3 (3b-BPh4)). The transformation of 3a-BPh4/3b-BPh4 into their respective vinylidene isomers in dichloromethane is very slow and requires hours to its completion. However, this process is accelerated by addition of LiCl in methanol solution. Reaction of 1 with HC≡CR (R = COOMe, C6H4CF3) in MeOH goes through the intermediacy of the π-alkyne complexes [Cp*Ru(η(2)-HC≡CR)((i)Pr2PNHPy)]Cl (R = COOMe (3a-Cl), C6H4CF3 (3b-Cl)), which rearrange to vinylidenes in minutes, i.e., much faster than their counterparts containing the [BPh4](-) anion. The kinetics of these isomerizations has been studied in solution by NMR. With the help of DFT studies, these observations have been interpreted in terms of chloride- and methanol-assisted hydrogen migrations. Calculations suggest participation of a hydrido-alkynyl intermediate in the process, in which the hydrogen atom can be transferred from the metal to the β-carbon by means of species with weak basic character acting as proton shuttles.

  18. Synthesis of Cyclic Porphyrin Trimers through Alkyne Metathesis Cyclooligomerization and Their Host–Guest Binding Study

    SciTech Connect

    Yu, Chao; Long, Hai; Jin, Yinghua; Zhang, Wei


    Cyclic porphyrin trimers were synthesized through one-step cyclooligomerization via alkyne metathesis from diyne monomers. These macrocycles show interesting host-guest binding interactions with fullerenes, selectively binding C70 (6 x 103 M-1) over C60 and C84 (no binding observed). The fullerene-encapsulated host-guest complex can undergo guest or host exchange in the presence of another guest (2,4,6-tri(4-pyridyl)-1,3,5-triazine) or host (cage COP5) molecule with higher binding affinity.

  19. Silver-Catalyzed Regioselective Fluorination of Carbonyl Directed Alkynes: Synthesis of α-Fluoroketones.


    Li, Fang-Hui; Cai, Zhong-Jian; Yin, Ling; Li, Jian; Wang, Shun-Yi; Ji, Shun-Jun


    A novel silver-catalyzed fluorination reaction of carbonyl directed alkynes in the presence of N-fluorobenzenesulfonimide and water with high regioselectivities has been developed. The established protocol provides an alternative method for rapid assembly of α-fluoroketone derivatives under simple and mild reaction conditions. The reaction pathway involves a ring closure and opening process for the construction of new C-O and C-F bonds. In addition, a fluorine-containing indanone was observed through further N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction of α-fluoroketone.

  20. Selective oxygenation of alkynes: a direct approach to diketones and vinyl acetate.


    Xia, Xiao-Feng; Gu, Zhen; Liu, Wentao; Wang, Ningning; Wang, Haijun; Xia, Yongmei; Gao, Haiyan; Liu, Xiang


    Arylalkynes can be converted into α-diketones with the use of a copper catalyst, and also be transformed into vinyl acetates under metal-free conditions, both in the presence of PhI(OAc)2 as an oxidant at room temperature. A series of substituted α-diketones were prepared in moderate to good yields. A variety of vinyl halides could be regio- and stereo-selectively synthesized under mild conditions, and I, Br and Cl could be all easily embedded into the alkynes.

  1. C-Terminal acetylene derivatized peptides via silyl-based alkyne immobilization.


    Strack, Martin; Metzler-Nolte, Nils; Albada, H Bauke


    A new Silyl-based Alkyne Modifying (SAM)-linker for the synthesis of C-terminal acetylene-derivatized peptides is reported. The broad scope of this SAM2-linker is illustrated by manual synthesis of peptides that are side-chain protected, fully deprotected, and disulfide-bridged. Synthesis of a 14-meric (KLAKLAK)2 derivative by microwave-assisted automated SPPS and a one-pot cleavage click procedure yielding protected 1,2,3-triazole peptide conjugates are also described.

  2. General Method for the Preparation of Alkyne-Functionalized Oligopyridine Building Blocks.


    Ziessel, Raymond; Suffert, Jean; Youinou, Marie-Thérèse


    A large series of alkyne-substituted oligopyridines based on 2,2'-bipyridine, 1,10-phenanthroline, 2,2':6',2"-terpyridine, or 1,8-naphthyridine substrates has been synthesized and fully characterized. The palladium(0)-catalyzed coupling of bromo- or chloro-substituted derivatives with (trimethylsilyl)acetylene proceeds readily in diisopropylamine under ambient conditions giving good yields of the corresponding alkyne-substituted substrates oligoPy(C&tbd1;C)SiMe(3). The terminal monoynes oligoPyC&tbd1;CH become available upon treatment with K(2)CO(3) in methanol. Stepwise homologation of the acetylene function by Cadiot-Chodkiewicz coupling of oligoPyC&tbd1;CH with (bromoethynyl)triethylsilane (BrC&tbd1;CSiEt(3)) affords, in good yield, the silylated diynes oligoPy(C&tbd1;C)(2)SiEt(3), from which the terminal diynes oligoPy(C&tbd1;C)(2)H are formed by treatment with aqueous methanolic alkali. Reaction of oligoPy(C&tbd1;C)(2)H with BrC&tbd1;CSiEt(3) yields the silylated triynes oligoPy(C&tbd1;C)(3)SiEt(3) in modest yield. Further homologation is limited by nucleophilic attack of n-propylamine at the C-2 carbon of the alkyne chain, giving rise to a mixture of cis/cis (48%), cis/trans (33%), and trans/trans (19%) enaminediyne compounds 21a-c. Glaser oxidative self-coupling of the terminal diynes provides access to ditopic bipyridine or terpyridine ligands oligoPy(C&tbd1;C)(4)oligoPy comprising a tetrayne spacer. Quantitative formation of air-stable copper(I) complexes is described for the 6,6'-substituted ligands. A single crystal X-ray structure of complex 22a shows that the two ligands are interlocked around the copper(I) center in a pseudotetrahedral arrangement, similar to the structure deduced from NMR and FAB(+) data. The synthetic methods reported herein represent a valuable approach to the large-scale preparation of alkyne-functionalized oligopyridines.

  3. Ruthenium-catalyzed stereoselective anti-Markovnikov-addition of thioamides to alkynes.


    Goossen, Lukas J; Blanchot, Mathieu; Salih, Kifah S M; Karch, Ralf; Rivas-Nass, Andreas


    A catalyst system generated in situ from bis(2-methallyl)-cycloocta-1,5-diene-ruthenium(II) and a phosphine was found to efficiently catalyze the addition of thioamides to terminal alkynes with exclusive formation of the anti-Markovnikov thioenamide products. The stereoselectivity of the addition is usually high and controlled by the choice of the phosphine ligand, whereas the (E)-isomers are predominantly formed in the presence of tri(n-octyl)phosphine, the use of bis(dicyclohexylphosphino)methane preferentially leads to the formation of the (Z)-configured thioenamides.

  4. Heterocycle synthesis by copper facilitated addition of heteroatoms to alkenes, alkynes and arenes.


    Chemler, Sherry R; Fuller, Peter H


    The de novo synthesis of small organic heterocyclic molecules has benefited from recent protocols for copper-facilitated additions of heteroatoms to alkenes, alkynes and arenes. This tutorial review summarizes a number of these recent contributions. Copper salts can facilitate bond formations due to their ability to serve as Lewis acids, oxidizing agents and transition metal catalysts. The current understanding of the mechanisms of these reactions is presented. This review should be of interest to chemists involved in the synthesis of heterocycles and those investigating transition metal facilitated reactions.

  5. Selective synthesis of indazoles and indoles via triazene-alkyne cyclization switched by different metals.


    Fang, Yan; Wang, Chengming; Su, Shengqin; Yu, Haizhu; Huang, Yong


    We described two orthogonal heterocycle syntheses, where an arene bearing both an alkyne and a triazene functionality underwent two distinct cyclization pathways mediated by different transition metals. Starting from the same substrates, a synthesis of 2H-indazole was accomplished by a Cu(II) salt promoted oxidative cyclization, while 2-substituted indoles could be accessed via a Ag(I) salt mediated N-N bond cleavage. This method represents the first synthesis of indoles from alkynyl triazenes. Computational analysis was performed for both reaction pathways, supporting a Lewis acid role for Cu and a π-acid catalysis for Ag.

  6. Amide-Directed Formation of Five-Coordinate Osmium Alkylidenes from Alkynes

    PubMed Central


    The amide-directed synthesis of five-coordinate osmium alkylidene derivatives from alkynes is reported. These types of complexes, which have been elusive until now because of the tendency of osmium to give hydride alkylidyne species, are prepared by reaction of the dihydride OsH2Cl2(PiPr3)2 (1) with terminal alkynes containing a distal amide group. Complex 1 reacts with N-phenylhex-5-ynamide and N-phenylhepta-6-ynamide to give OsCl2{=C(CH3)(CH2)nNH(CO)Ph}(PiPr3)2 (n = 3 (2), 4 (3)). The relative position of carbonyl and NH groups in the organic substrates has no influence on the reaction. Thus, treatment of 1 with N-(pent-4-yn-1-yl)benzamide leads to OsCl2{=C(CH3)(CH2)3NHC(O)Ph}(PiPr3)2 (4). The new compounds are intermediate species in the cleavage of the C–C triple bond of the alkynes. Under mild conditions, they undergo the rupture of the Cα–CH3 bond of the alkylidene, which comes from the alkyne triple bond, to afford six-coordinate hydride–alkylidyne derivatives. In dichloromethane, complex 2 gives a 10:7 mixture of OsHCl2{≡C(CH2)3C(O)NHPh}(PiPr3)2 (5) and OsHCl2{≡CCH(CH3)(CH2)2C(O)NHPh}(PiPr3)2 (6). The first complex contains a linear separation between the alkylidyne Cα atom and the amide group, whereas the spacer is branched in the second complex. In contrast to the case for 2, complex 4 selectively affords OsHCl2{≡C(CH2)3NHC(O)Ph}(PiPr3)2 (7). In spite of their instability, these compounds give the alkylidene–allene metathesis, being a useful entry to five-coordinate vinylidene complexes, including the dicarbon-disubstituted OsCl2(=C=CMe2)(PiPr3)2 (8) and the monosubstituted OsCl2(=C=CHCy)(PiPr3)2 (9). PMID:26877575

  7. Disorder-to-order transitions induced by alkyne/azide click chemistry in diblock copolymer thin films.

    SciTech Connect

    Wei, X.; Gu, W.; Chen, W.; Shen, X.; Liu, F.; Strzalka, J. W.; Jiang, Z.; Russell, T. P.


    We investigated thin film morphologies of binary blends of alkyne-functionalized diblock copolymer poly(ethylene oxide)-block-poly(n-butyl methacrylate-random-propargyl methacrylate) (PEO-b-P(nBMA-r-PgMA)) and Rhodamine B azide, where the thermal alkyne/azide click reaction between the two components induced a disorder-to-order transition (DOT) of the copolymer. By controlling the composition of the neat copolymers and the mole ratio between the alkyne and azide groups, different microphase separated morphologies were achieved. At higher azide loading ratios, a perpendicular orientation of the microdomains was observed with wide accessible film thickness window. As less azide was incorporated, the microdomains have a stronger tendency to be parallel to the substrate, and the film thickness window for perpendicular orientation also became narrower.

  8. Synthesis of 1,3-Amino Alcohols, 1,3-Diols, Amines, and Carboxylic Acids from Terminal Alkynes.


    Zeng, Mingshuo; Herzon, Seth B


    The half-sandwich ruthenium complexes 1-3 activate terminal alkynes toward anti-Markovnikov hydration and reductive hydration under mild conditions. These reactions are believed to proceed via addition of water to metal vinylidene intermediates (4). The functionalization of propargylic alcohols by metal vinylidene pathways is challenging owing to decomposition of the starting material and catalytic intermediates. Here we show that catalyst 2 can be employed to convert propargylic alcohols to 1,3-diols in high yield and with retention of stereochemistry at the propargylic position. The method is also amenable to propargylic amine derivatives, thereby establishing a route to enantioenriched 1,3-amino alcohol products. We also report the development of formal anti-Markovnikov reductive amination and oxidative hydration reactions to access linear amines and carboxylic acids, respectively, from terminal alkynes. This chemistry expands the scope of products that can be prepared from terminal alkynes by practical and high-yielding metal-catalyzed methods.

  9. 'Click' chemistry synthesis and capillary electrophoresis study of 1,4-linked 1,2,3-triazole AZT-systemin conjugate.


    Dobkowski, Michał; Szychowska, Aleksandra; Pieszko, Małgorzata; Miszka, Anna; Wojciechowska, Monika; Alenowicz, Magdalena; Ruczyński, Jarosław; Rekowski, Piotr; Celewicz, Lech; Barciszewski, Jan; Mucha, Piotr


    The Cu(I) catalyzed Huisgen 1,3-dipolar azide-alkyne cycloaddition (CuAAC) was applied for a nucleoside-peptide bioconjugation. Systemin (Sys), an 18-aa plant signaling peptide naturally produced in response to wounding or pathogen attack, was chemically synthesized as its N-propynoic acid functionalized analog (Prp-Sys) using the SPPS. Next, CuAAC was applied to conjugate Prp-Sys with 3'-azido-2',3'-dideoxythymidine (AZT), a model cargo molecule. 1,4-Linked 1,2,3-triazole AZT-Sys conjugate was designed to characterize the spreading properties and ability to translocate of cargo molecules of systemin. CuAAC allowed the synthesis of the conjugate in a chemoselective and regioselective manner, with high purity and yield. The presence of Cu(I) ions generated in situ drove the CuAAC reaction to completion within a few minutes without any by-products. Under typical separation conditions of phosphate 'buffer' at low pH and uncoated fused bare-silica capillary, an increasing peak intensity assigned to triazole-linked AZT-Sys conjugate was observed using capillary electrophoresis (CE) during CuAAC. CE analysis showed that systemin peptides are stable in tomato leaf extract for up to a few hours. CE-ESI-MS revealed that the native Sys and its conjugate with AZT are translocated through the tomato stem and can be directly detected in stem exudates. The results show potential application of systemin as a transporter of low molecular weight cargo molecules in tomato plant and of CE method to characterize a behavior of plant peptides and its analogs.

  10. Dynamically Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A

    PubMed Central

    Patel, Ashay; Chen, Zhuo; Yang, Zhongyue; Gutiérrez, Osvaldo; Liu, Hung-wen; Houk, K. N.; Singleton, Daniel A.


    SpnF, an enzyme involved in the biosynthesis of spinosyn A, catalyzes a transannular Diels–Alder reaction. Quantum mechanical computations and dynamic simulations now show that this cycloaddition is not well described as either a concerted or stepwise process, and dynamical effects influence the identity and timing of bond formation. The transition state for the reaction is ambimodal and leads directly to both the observed Diels–Alder and an unobserved [6+4] cycloadduct. The potential energy surface bifurcates and the cycloadditions occur by dynamically stepwise modes featuring an “entropic intermediate”. A rapid Cope rearrangement converts the [6+4] adduct into the observed [4+2] adduct. Control of nonstatistical dynamical effects may serve as another way by which enzymes control reactions. PMID:26909570

  11. Mechanistic studies of UV assisted [4 + 2] cycloadditions in synthetic efforts toward vibsanin E.


    Nikolai, Joachim; Loe, Øystein; Dominiak, Paulina M; Gerlitz, Oksana O; Autschbach, Jochen; Davies, Huw M L


    Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the stereochemical course of the photochemical cycloaddition of enone 9 with dienes. The observed products of this photochemically induced cycloaddition showed a stereoselectivity, which is opposite to what would be expected by FMO considerations. The quantum chemical calculations revealed that the unusual stereoselectivity of the reaction can be rationalized by assuming a stereospecific photochemical cis-trans isomerization of enone 9 to trans isomer 9a followed by a thermal Diels-Alder reaction of the diene onto the highly reactive trans enone. The photochemical reaction step involves the selective formation of a twisted triplet intermediate, which accounts for the selectivity of the reaction.

  12. Rhodium-catalyzed acyloxy migration of propargylic esters in cycloadditions, inspiration from the recent "gold rush".


    Shu, Xing-Zhong; Shu, Dongxu; Schienebeck, Casi M; Tang, Weiping


    Transition metal-catalyzed acyloxy migration of propargylic esters offers versatile entries to allene and vinyl carbene intermediates for various fascinating subsequent transformations. Most π-acidic metals (e.g. gold and platinum) are capable of facilitating these acyloxy migration events. However, very few of these processes involve redox chemistry, which are well-known for most other transition metals such as rhodium. The coupling of acyloxy migration of propargylic esters with oxidative addition, migratory insertion, and reductive elimination may lead to ample new opportunities for the design of new reactions. This tutorial review summarizes recent developments in Rh-catalyzed 1,3- and 1,2-acyloxy migration of propargylic esters in a number of cycloaddition reactions. Related Au- and Pt-catalyzed cycloadditions involving acyloxy migration are also discussed.

  13. Trimethylenemethane diyl mediated tandem cycloaddition reactions: mechanism based design of synthetic strategies.


    Lee, Hee-Yoon


    Several criteria for the measure of synthetic strategies toward "ideal synthesis" are available to guide the design and evaluation of the synthetic strategies toward the target molecules. One strategy toward "ideal synthesis" is developing a multistep reaction that involves dramatic change in complexity. Biogenesis of natural products and mechanistic investigation of complicated organic transformation provide good inspiration for design of new synthetic strategies. Trimethylenemethane diradical (TMM diyl), first introduced only as a theoretically interesting structure 60 years ago, gained interests of physical organic chemistry when it was first detected by Dowd. Study of characteristics and properties of TMM diyl was accelerated in a great deal when Koebrich observed dimeric hydrocarbon products from the reaction of 1,1-dibromo-2-methylhexa-1,5-diene with MeLi. Berson followed the mechanistic investigation of the reaction that involved 2-methylenecyclopentane-1,3-diyl, and thoroughly studied physical and chemical properties of the TMM diyl. This lead to the development of intramolecular [2 + 3] TMM diyl cycloaddition reaction for the construction of linearly fused triquinanes by Little. We envisioned that the generation of a TMM diyl through cycloaddition reaction discovered by Koebrich and [2 + 3] cycloaddition reaction of the TMM diyl could be combined together to form polyquinane structures. A cycloaddition reaction sequence of generating a TMM diyl from a alkylidene carbene of 2-methylhexa-1,5-diene structure in the presence of another olefin was designed and executed to produce linearly fused and angularly fused triquinanes depending on the connectivity of the second double bond. The successful transformation also inspired design of a tandem cycloaddition reaction strategy of using unprecedented tetrahydrocyclopentapyrazole to TMM diyl transformation. The new design involves two [2 + 3] cycloaddition reactions of 6-diazohexa-1,2-diene with an olefin attached

  14. Catalysis of Heterocyclic Azadiene Cycloaddition Reactions by Solvent Hydrogen Bonding: Concise Total Synthesis of Methoxatin.


    Glinkerman, Christopher M; Boger, Dale L


    Although it has been examined for decades, no general approach to catalysis of the inverse electron demand Diels-Alder reactions of heterocyclic azadienes has been introduced. Typically, additives such as Lewis acids lead to nonproductive consumption of the electron-rich dienophiles without productive activation of the electron-deficient heterocyclic azadienes. Herein, we report the first general method for catalysis of such cycloaddition reactions by using solvent hydrogen bonding of non-nucleophilic perfluoroalcohols, including hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE), to activate the electron-deficient heterocyclic azadienes. Its use in promoting the cycloaddition of 1,2,3-triazine 4 with enamine 3 as the key step of a concise total synthesis of methoxatin is described.

  15. Recent advances in understanding the enzymatic reactions of [4+2] cycloaddition and spiroketalization.


    Zheng, Qingfei; Tian, Zhenhua; Liu, Wen


    Diels-Alder-like [4+2] cycloaddition and ketalization of dihydroxy ketones are cyclization reactions with different mechanisms that produce characteristic cyclohexene and spiroketal units, respectively. Here, we review newly identified, naturally occurring '[4+2] cycloadditionases' and 'spiroketalases' and reveal several similarities between the two types of enzymes. During catalysis, these enzymes control product stereochemistry or/and enhance the transformation rate. They exhibit convergent evolution of [4+2] cycloaddition or spiroketalization activity, which is likely dependent on interactions of variable protein folds with specialized chemical structures. An understanding of these similarities is expected to allow for establishment of the underlying principles for the application and catalyst design of associated enzymatic reactions in organic chemistry and synthetic biology.

  16. Menthols as Chiral Auxiliaries for Asymmetric Cycloadditive Oligomerization: Syntheses and Studies of β-Proline Hexamers.


    Kudryavtsev, Konstantin V; Ivantcova, Polina M; Muhle-Goll, Claudia; Churakov, Andrei V; Sokolov, Mikhail N; Dyuba, Artem V; Arutyunyan, Alexander M; Howard, Judith A K; Yu, Chia-Chun; Guh, Jih-Hwa; Zefirov, Nikolay S; Bräse, Stefan


    To produce a novel class of structurally ordered poly-β-prolines, an emergent method for synthesizing chiral β-peptide molecular frameworks was developed based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Functionalized short β-peptides with up to six monomeric residues were efficiently synthesized in homochiral forms using a cycloadditive oligomerization approach. X-ray, NMR, and CD structural analyses of the novel β-peptides revealed secondary structure features that were generated primarily by Z/E-β-peptide bond isomerism. Anticancer in cellulo activity of the new β-peptides toward hormone-refractory prostate cancer cells was observed and was dependent on the absolute configuration of the stereogenic centers and the chain length of the β-proline oligomers.

  17. [4 + 2] cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels-Alder reaction sequence.


    Sarkar, Nihar; Banerjee, Abhisek; Nelson, Scott G


    N-Alkenyl iminium ions serve as conduits to three-component [4 + 2] cycloaddition reactions accessing structurally and stereochemically diverse piperidine derivatives. These cationic 2-azadienes participate in endo- or exo-selective [4 + 2] cycloadditions with electron-rich and neutral alkene dienophiles to generate a tetrahydropyridinium ion as the initial cycloadduct. In situ nucleophilic addition to the cycloaddition-derived iminium ion completes the three-component coupling sequence and affords a versatile synthesis of structurally complex piperidines.

  18. Synthesis of 2H-Indazoles by the [3 + 2] Dipolar Cycloaddition of Sydnones with Arynes

    PubMed Central

    Fang, Yuesi; Wu, Chunrui; Larock, Richard C.; Shi, Feng


    A rapid and efficient synthesis of 2H-indazoles has been developed using a [3 + 2] dipolar cycloaddition of sydnones and arynes. A series of 2H-indazoles have been prepared in good to excellent yields using this protocol, and subsequent Pd-catalyzed coupling reactions can be applied to the halogenated products to generate a structurally diverse library of indazoles. PMID:21970468

  19. Click chemistry in CuI-zeolites: the Huisgen [3 + 2]-cycloaddition.


    Chassaing, Stefan; Kumarraja, Mayilvasagam; Souna Sido, Abdelkarim Sani; Pale, Patrick; Sommer, Jean


    [reaction: see text] CuI-exchanged solids based on zeolite materials were investigated for the first time as catalysts in organic synthesis. The catalytic potential of these materials was evaluated in the Huisgen [3 + 2]-cycloaddition. Five CuI-exchanged zeolites were examined and CuI-USY proved to be a novel and efficient heterogeneous ligand-free catalyst for this "click chemistry"-type transformation.

  20. Combining bifunctional chelator with (3 + 2)-cycloaddition approaches: synthesis of dual-function technetium complexes.


    Braband, Henrik; Imstepf, Sebastian; Benz, Michael; Spingler, Bernhard; Alberto, Roger


    A new concept for the synthesis of dual-functionalized technetium (Tc) compounds is presented, on the basis of the reactivity of fac-{Tc(VII)O(3)}(+) complexes. The concept combines the "classical" bifunctional chelator (BFC) approach with the new ligand centered labeling strategy of fac-{TcO(3)}(+) complexes with alkenes ((3 + 2)-cycloaddition approach). To evidence this concept, fac-{(99)TcO(3)}(+) model complexes containing functionalized 1,4,7-triazacyclononane (tacn) derivatives N-benzyl-2-(1,4,7-triazonan-1-yl)acetamide (tacn-ba) and 2,2',2″-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (nota·3H) were synthesized and characterized. Whereas [(99)TcO(3)(tacn-ba)](+) [2](+) can be synthesized following a established oxidation procedure starting from the Tc(V) complex [(99)TcO(glyc)(tacn-ba)](+) [1](+), a new synthetic pathway for the synthesis of [(99)TcO(3)(nota)](2-) [5](2-) had to be developed, starting from [(99)Tc(nota·3H)(CO)(3)](+) [4](+) and using sodium perborate tetrahydrate (NaBO(3)·4H(2)O) as oxidizing reagent. While [(99)TcO(3)(nota)](2-) [5](2-) is a very attractive candidate for the development of trisubstituted novel multifunctional radioprobes, (3 + 2)-cycloaddition reactions of [(99)TcO(3)(tacn-ba)](+) [2](+) with 4-vinylbenzenesulfonate (styrene-SO(3)(-)) demonstrated the suitability of monosubstituted tacn derivatives for the new mixed "BFC-(3 + 2)-cycloaddition" approach. Kinetic studies of this reaction lead to the conclusion that the alteration of the electronic structure of the nitrogen donors by, e.g., alkylation can be used to tune the rate of the (3 + 2)-cycloaddition.

  1. Asymmeric Formal [3+3]-Cycloaddition Reactions of Nitrones with Electrophilic Vinylcarbene Intermediates

    PubMed Central

    Wang, Xiaochen; Xu, Xinfang; Zavalij, Peter Y.; Doyle, Michael P.


    With metal carbene access to dipolar intermediates, 3,6-dihydro-1,2-oxazines are produced in high yields by dirhodium(II) carboxylate catalyzed reactions between nitrones and a β-TBSO-substituted vinyldiazoacetate. High enantiocontrol occurs with catalysis by N-phthaloyl-(S)-(amino acid)-ligated dirhodium carboxylates for [3+3]-cycloaddition reactions with both acyclic and cyclic nitrones. PMID:21932856

  2. Rh2(R-TPCP)4-Catalyzed Enantioselective [3+2]-Cycloaddition between Nitrones and Vinyldiazoacetates

    PubMed Central

    Qin, Changming; Davies, Huw M. L.


    Rhodium-catalyzed reaction of vinyldiazoacetates with nitrones results in a formal [3+2]-cycloaddition to generate 2,5-dihydroisoxazoles with high levels of asymmetric induction. The cascade reaction begins with a vinylogous addition event, followed by an iminium addition ring-closure/hydride migration/alkene isomerization cascade. Dirhodium tetrakis(triarylcyclopropane carboxylates) are the optimum catalysts for this process. PMID:24025195

  3. Catalytic cascade hydroalkoxylation/isomerization/ [4 + 2] cycloaddition using enyne alcohols as latent dienes or dienophiles.


    Guo, Rui; Li, Kang-Nan; Gong, Liu-Zhu


    Enyne alcohols can react as precursors of either dienes or dienophiles with different substrates after hydroxylation and isomerization by gold catalysis. As such, oxa-bridged tricyclo[,6]-undec-8-ene-3,5-dione derivatives have been obtained by the Diels–Alder reaction and tetrahydro-1H-furo[3,4-c]pyran derivatives could be accessed by the hetero-Diels–Alder cycloaddition.

  4. Huisgen cycloaddition reaction of C-alkynyl ribosides under micellar catalysis: synthesis of ribavirin analogues.


    Youcef, Ramzi Aït; Dos Santos, Mickaël; Roussel, Sandrine; Baltaze, Jean-Pierre; Lubin-Germain, Nadège; Uziel, Jacques


    Carbonated analogues of ribavirin were synthesized from ethyl C-ribosylpropiolate obtained by an alkynylation reaction mediated by indium(0). The C-ribosides were then engaged in a Huisgen 1,3-dipolar cycloaddition reaction under a micellar catalysis. In these conditions, formation of 1,2,3-triazoles with control of the regioselectivity was observed. The regiochemistry of the adducts was determined by HMBC 2D-NMR analysis.

  5. Development and applications of Diels-Alder cycloadditions of 2'-hydroxychalcones

    NASA Astrophysics Data System (ADS)

    Cong, Huan

    Single electron transfer (SET)-initiated formal [4+2] cycloadditions of 2'-hydroxychalcones have been achieved employing a combination of Lewis acid and electron donor as catalyst. Mechanistic studies using cyclic voltammetry (CV) and deuterium labeling experiments suggested a radical anion-mediated stepwise mechanism. The utility of this methodology was established in the first total synthesis of natural product nicolaioidesin C. A novel silica-supported silver nanoparticle (AgNP) catalyst has been developed as a highly active, reusable, and user-friendly catalyst for Diels-Alder cycloadditions of 2'-hydroxychalcones, as showcased by the first total synthesis of natural product panduratin A. Our work demonstrates results from an interdisciplinary research project involving synthetic methodology development, nanometric material preparation, heterogeneous catalysis, natural product synthesis, and mechanistic studies using various instrumental techniques. Biomimetic, dehydrogenative cycloadditions of 2'-hydroxychalcones have been achieved using a mixture of platinum on activated carbon (Pt/C) and silica-supported silver nanoparticles (AgNP's) catalysts. This heterogeneous multicatalytic protocol converts a prenyl subunit in situ to diene which subsequently reacts with a 2'-hyroxychalcone dienophile to provide Diels-Alder cycloadducts in a single step. Using this methodology, a concise synthesis of the core structure of the natural product brosimone B has been accomplished. Enantioselective cycloadditions of 2'-hydroxychalcones have been established with excellent yields and enantioselectivity. Two optimized catalytic conditions have been developed: the first method utilizes a catalyst system comprised of chiral rare earth metal complex and electron donor; the second approach involves a chiral borate catalyst. The asymmetric total synthesis of natural product (+)-sorocenol B has been pursued.

  6. The Use of Nitrone Cycloadditions in the Synthesis of Beta-Amino Aldehydes and Unsaturated Amines.

    DTIC Science & Technology


    with alkenes (dipolarophiles) to produce isoxazolidines (2) in a fashion similar to the (4+2] Diels-Alder reaction .’ The cycloaddition results in...occurred under the acidic reaction conditions to produce 84 (Table V, entry 1). N. Alternatively, the reduction-elimination steps can be performed by a...cyclized under the reaction conditions to produce d-lactone 96 (Scheme 27). Although Peterson elimination of the lactone was still possible hypothetically

  7. Regioselective One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes to Ynolates.


    Umezu, Satoshi; Dos Passos Gomes, Gabriel; Yoshinaga, Tatsuro; Sakae, Mikei; Matsumoto, Kenji; Iwata, Takayuki; Alabugin, Igor; Shindo, Mitsuru


    We developed the novel one-pot synthetic method of substituted triptycenes by the reaction of ynolates and arynes. This four-step process involves three cycloadditions and electrocyclic ring opening of the strained Dewar anthracene. Each of the three related but structurally distinct classes of nucleophiles (ynolate, enolate, and anthracenolate) reacts with o-benzyne in the same predictable manner controlled by chelation and negative hyperconjugation. The resulting functionalized C3 -symmetrical triptycenes hold promise in the design of functional materials.

  8. Cycloaddition of C{sub 60} fullerene and stable nitrile oxide, 2-(benzenesulfonyl)benzonitrile oxide

    SciTech Connect

    Drozd, V.N.; Sokolov, V.I.; Stoyanovich, F.M.


    The general features of the reactivity of fullerenes as polyolefins have been well studied over a wide range of cycloadditions. In this study, the stable 2-(benzenesulfonyl)benzonitrile oxide is used to look at the interaction between fullerene and aryl nitrile oxides. Employed were {sup 1}H and {sup 13}C NMR spectroscopy to determine the electronic and molecular structure of the reaction`s monoadduct.

  9. 1,3-Dipolar cycloaddition of diazomethane to element-substituted (Si, Ge, Sn)-alkoxyacetylenes

    SciTech Connect

    Kostyuk, A.S.; Knyaz'kov, K.A.; Ponomarev, S.V.; Lutsenko, I.F.


    1,3-Dipolar cycloaddition of diazomethane to the triple bond of trialkylsilyl-, trialkylgermyl-, and trialkylstannylalkoxyacetylenes proceeds regioselectivity and is a convenient method for synthesis of the previously not described 3(5)-element-substituted 4-alkoxypyrazoles. When heated in methanol in the presence of an acid, 3(5)-silyl(germyl)-4-alkoxypyrazoles are slowly hydrolyzed with cleavage of the element-carbon bond.

  10. Synthesis of α-Benzyloxyamino-γ-butyrolactones via a Polar Radical Crossover Cycloaddition Reaction.


    Cavanaugh, Cortney L; Nicewicz, David A


    A direct catalytic synthesis of substituted α-benzyloxyamino-γ-butyrolactones is reported, starting from simple oxime acids and alkenes. The substituted O-benzyloxime acid starting materials are cyclized with oxidizable alkenes, via Polar Radical Crossover Cycloaddition (PRCC) reactions. The catalytic reaction is carried out using the Fukuzumi acridinium photooxidant and substoichiometric amounts of a redox-active cocatalyst. The utility of this method has been demonstrated through the use of 3 oxime acids and 19 oxidizable olefins.

  11. Chiral phosphoric acid catalyzed enantioselective 1,3-dipolar cycloaddition reaction of azlactones.


    Zhang, Zhenhua; Sun, Wangsheng; Zhu, Gongming; Yang, Junxian; Zhang, Ming; Hong, Liang; Wang, Rui


    The first chiral phosphoric acid catalyzed highly diastereo- and enantioselective 1,3-dipolar cycloaddition reaction of azlactones and methyleneindolinones was disclosed. By using a BINOL-derived chiral phosphoric acid as the catalyst, azlactones were activated as chiral anti N-protonated 1,3-dipoles to react with methyleneindolinones to yield biologically important 3,3'-pyrrolidonyl spirooxindole scaffolds in high yields, with good-to-excellent diastereo- and enantioselectivity.

  12. Synthesis of Dihydrobenzisoxazoles by the [3+2] Cycloaddition of Arynes and Oxaziridines

    PubMed Central

    Kivrak, Arif; Larock, Richard C.


    Dihydrobenzisoxazoles are readily prepared in good yields by the [3+2] cycloaddition of oxaziridines and arynes. The reaction involves an unusual cleavage of the C-O bond of the oxaziridine and tolerates a variety of substituents on the oxaziridine and the o-(trimethylsilyl)aryl triflate to form aryl-, heteroaryl-, alkyl- and naphthyl-substituted dihydrobenzisoxazoles. The resulting halogen-substituted dihydrobenzisoxazoles are readily elaborated to more complex products using palladium-catalyzed crossing-coupling processes. PMID:20936802

  13. Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles

    PubMed Central

    Xie, Lan-Gui; Niyomchon, Supaporn; Mota, Antonio J.; González, Leticia; Maulide, Nuno


    Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry. Herein, we present a family of metal-free intermolecular formal cycloaddition reactions that enable highly selective and orthogonal access to isoquinolines and pyrimidines at will. Applications of the products are complemented by a density functional theory mechanistic analysis that pinpoints the crucial factors responsible for the selectivity observed, including stoichiometry and the nature of the heteroalkyne. PMID:26975182

  14. Direct visualization of a cycloaddition reaction on frozen asymmetric Si dimers at room temperature

    NASA Astrophysics Data System (ADS)

    Baik, Jaeyoon; Ihm, Kyuwook; Ha, Taekyun; An, Ki-Seok; Ahn, Joung Real; Park, Chong-Yun


    We firstly report an experimental visualization of a cycloaddition reaction on RT frozen asymmetric Si dimers. The frozen Si dimers with a local c(4 × 2) order were prepared by pinning flip-flopping Si dimers by using molecules. This RT pristine c(4 × 2) structure was used to determine what Si atom of an asymmetric Si dimer bonds to a molecule at the initial stage of the RT cycloaddition reaction, which has been a long-standing puzzling issue. This made it possible to compare directly experimental cycloaddition reactions with theoretical ones. As a prototype for the experiment, a 1,3-butadiene molecule adsorbed between Si dimer rows was used. The 1,3-butadiene molecule was found to prefer a symmetric Si pair on the frozen Si dimers, i.e., two electrophilic lower atoms of asymmetric Si dimers. This result is consistent with the theoretical prediction that a 1,3-diene molecule prefers a symmetric Si pair on the Si(001)c(4 × 2) surface. This experimental approach can also be applied to other studies for the adsorption of a molecule on a Si(001) surface at room temperature.

  15. Lewis acid catalysis of photochemical reactions. 7. Photodimerization and cross-cycloaddition of cinnamic esters

    SciTech Connect

    Lewis, F.D.; Quillen, S.L.; Hale, P.D.; Oxman, J.D.


    The effects of Lewis acid complexation upon the molecular structure, solid-state photodimerization, and solution dimerization and cross-cycloaddition of cinnamic esters have been investigated. Comparison of crystal structures for free and SnCl/sub 4/-complexed ethyl cinnamate indicates that the enone double bonds are lengthened, the single bonds are shortened, and the enone conformation changes from s-cis to s-trans upon complexation. These changes are consistent with calculated changes in ..pi.. bonding and net charges. Solid-state photodimerization of free and complexed cinnamic esters and related molecules yield syn head-to-tail (..cap alpha..-truxillate) dimers. In most cases the Lewis acid complexes dimerize more efficiently and stereoselectively than the free esters. Photodimerization and cross-cycloaddition of methyl cinnamate in dilute solution is also catalyzed by Lewis acids. The mechanism of these reactions involves electronic excitation of a ground-state ester (dimerization) or simple olefin (cross cycloaddition). The catalytic effect of Lewis acids is attributed to an increase in excited-state lifetime and reactivity.

  16. New cofactor supports α,β-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition.


    Payne, Karl A P; White, Mark D; Fisher, Karl; Khara, Basile; Bailey, Samuel S; Parker, David; Rattray, Nicholas J W; Trivedi, Drupad K; Goodacre, Royston; Beveridge, Rebecca; Barran, Perdita; Rigby, Stephen E J; Scrutton, Nigel S; Hay, Sam; Leys, David


    The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis or microbial biodegradation of aromatic compounds, respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear. Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad1. Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry, we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation.

  17. A New Cycloaddition Process Involving Nitro Group Participation in Polynitroaromatic Chemistry.


    Hallé, Jean-Claude; Vichard, Dominique; Pouet, Marie-José; Terrier, François


    The reaction of ethyl vinyl ether (2 equiv) with 4,6-dinitrobenzofuroxan (DNBF, 1 equiv) in dichloromethane affords a mixture of two diastereomeric dihydrooxazine N-oxide adducts, 5a and 5b, in a 4:1 ratio. Further addition of the enol reagent to this mixture results in a second cycloaddition process with formation of a bis(dihydrooxazine N-oxide) product 6, which can also be obtained directly upon treatment of DNBF with excess ethyl vinyl ether. The observed condensations are accounted for in terms of inverse electron demand Diels-Alder cycloaddition processes between the enol ether dienophile and the heterodienyl moieties of DNBF, constituted first, by the 6-NO(2) group conjugated to the 6,7-double bond and then by the 4-NO(2) group and the 4,5-double bond of the carbocyclic ring. The configurations of the cycloadducts 5a and 5b have been determined on the basis of collected (1)H NMR parameters, as well as NOE experiments. It thus appears that the configuration of the major diastereomer corresponds to the endo product while that of the minor one corresponds to the exo product of the first cycloaddition process. The results obtained emphasize a low aromatic character for the DNBF molecule.

  18. New cofactor supports α,β-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition

    PubMed Central

    Payne, Karl A.P.; White, Mark D.; Fisher, Karl; Khara, Basile; Bailey, Samuel S.; Parker, David; Rattray, Nicholas J.W.; Trivedi, Drupad K.; Goodacre, Royston; Beveridge, Rebecca; Barran, Perdita; Rigby, Stephen E.J.; Scrutton, Nigel S.; Hay, Sam; Leys, David


    The ubiD/ubiX or the homologous fdc/pad genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone biosynthesis1–3 or microbial biodegradation of aromatic compounds4–6 respectively. Despite biochemical studies on individual gene products, the composition and co-factor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear7–9. We show Fdc is solely responsible for (de)carboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesised by the associated UbiX/Pad10. Atomic resolution crystal structures reveal two distinct isomers of the oxidized cofactor can be observed: an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with drastically altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. While 1,3-dipolar cycloaddition is commonly used in organic chemistry11–12, we propose this presents the first example of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation. PMID:26083754

  19. Theoretical Study on the Mechanism of the Thermal Retro-Cycloaddition of Isoxazolinofullerenes.


    Morera-Boado, Cercis; Martínez González, Marco; Miranda-Quintana, Ramón A; Suárez, Margarita; Martínez-Álvarez, Roberto; Martín, Nazario; García de la Vega, José M


    The retro-cycloaddition thermal reaction of isoxazolino[4,5:1,2][60]fullerenes to pristine fullerene seems to be guided by the electronic nature of the substituted nitrile oxide 1,3-dipole in the isoxazoline ring. Trapping experiments proved that the reaction mechanism occurs by thermal removal of the nitrile oxide 1,3-dipole in a process that is favored in the presence of a big excess of a highly efficient dipolarophile such as maleic anhydride. Theoretical gas phase calculations carried out at the B3LYP/6-31G(d) and M06-2X/6-31G(d) levels of theory underpin the experimental findings and predict that compound 1c, bearing the p-(CH3)2N-Ph substituent on the isoxazoline ring and with a remarkable experimental conversion efficiency in just 12 h, showed the lowest activation energy. Solvent calculations have predicted the same behavior in gas phase. Different approaches such as electrostatic natural population analysis and Houk's distortion/interaction model have been applied to understand how the electronic nature of these substituents affects the retro-cycloaddition reaction process. Analysis of the values of the condensed Fukui functions and dual descriptor shed light on the mechanism of the retro-cycloaddition reaction.

  20. Nickel-Catalyzed Insertion of Alkynes and Electron-Deficient Olefins into Unactivated sp(3) C-H Bonds.


    Maity, Soham; Agasti, Soumitra; Earsad, Arif Mahammad; Hazra, Avijit; Maiti, Debabrata


    Insertion of unsaturated systems such as alkynes and olefins into unactivated sp(3) C-H bonds remains an unexplored problem. We herein address this issue by successfully incorporating a wide variety of functionalized alkynes and electron-deficient olefins into the unactivated sp(3) C-H bond of pivalic acid derivatives with excellent syn- and linear- selectivity. A strongly chelating 8-aminoquinoline directing group proved beneficial for these insertion reactions, while an air-stable and inexpensive Ni(II) salt has been employed as the active catalyst.

  1. Copper/silver-mediated direct ortho-ethynylation of unactivated (hetero)aryl C-H bonds with terminal alkyne.


    Liu, Yue-Jin; Liu, Yan-Hua; Yin, Xue-Song; Gu, Wen-Jia; Shi, Bing-Feng


    A copper/silver-mediated oxidative ortho-ethynylation of unactivated aryl C-H bonds with terminal alkyne has been developed. The reaction uses the removable PIP directing group and features broad substrate scope, high functional-group tolerance, and compatibility with a wide range of heterocycles, providing an efficient synthesis of aryl alkynes. This procedure highlights the potential of copper catalysts to promote unique, synthetically enabling C-H functionalization reactions that lie outside of the current scope of precious metal catalysis.

  2. Synthesis of substituted mono- and diindole C-nucleoside analogues from sugar terminal alkynes by sequential sonogashira/heteroannulation reaction.


    Zhang, Fuyi; Mu, Delong; Wang, Liming; Du, Pengfei; Han, Fen; Zhao, Yufen


    The synthesis of substituted mono- and diindole C-nucleoside analogues has been achieved in good to excellent yields by sequential Sonogashira coupling/NaAuCl4-catalyzed heteroannulation reactions of substituted 2-iodoanilines with various sugar terminal alkynes in one pot. The method is general, mild, and efficient and suitable for a wide range of sugar substrates, and 42 examples are given. The amino group of the substituted 2-iodoanilines is unprotected. The sugar terminal alkynes include furanosides, pyranosides, and acyclic glycosides with free hydroxyl groups, sensitive functional subtituents, and various protecting groups having different steric hindrance.

  3. Dynamic Covalent Synthesis of Aryleneethynylene Cages through Alkyne Metathesis: Dimer, Tetramer, or Interlocked Complex?

    SciTech Connect

    Wang, Qi; Yu, Chao; Zhang, Chenxi; Long, Hai; Azarnoush, Setareh; Jin, Yinghua; Zhang, Wei


    A dynamic covalent approach towards rigid aryleneethynylene covalent organic polyhedrons (COPs) was explored. Our study on the relationship of the COP structures and the geometry of their building blocks reveals that the topology of aryleneethynylene COPs strongly depends on the size of the building blocks. A tetramer (D2h symmetric), dimer, or interlocked complex can be formed from monomers with the same face-to-edge angle but in different sizes. As alkyne metathesis is a self-exchange reaction and non-directional, the cyclooligomerization of multi-alkyne monomers involves both intramolecular cyclization and intermolecular metathesis reaction, resulting in complicated thermodynamic process disturbed by kinetic competition. Although a tetrahedron-shaped tetramer (Td symmetric) has comparable thermodynamic stability to a D2h symmetric tetramer, its formation is kinetically disfavored and was not observed experimentally. Aryleneethynylene COPs consist of purely unsaturated carbon backbones and exhibit large internal cavities, which would have interesting applications in host-guest chemistry and development of porous materials.

  4. Magnetic hydrogels from alkyne/cobalt carbonyl-functionalized ABA triblock copolymers


    Jiang, Bingyin; Hom, Wendy L.; Chen, Xianyin; ...


    A series of alkyne-functionalized poly(4-(phenylethynyl)styrene)-block-poly(ethylene oxide)-block-poly(4-(phenylethynyl)styrene) (PPES-b-PEO-b-PPES) ABA triblock copolymers was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. PESn[Co2(CO)6]x-EO800-PESn[Co2(CO)6]x ABA triblock copolymer/cobalt adducts (10–67 wt % PEO) were subsequently prepared by reaction of the alkyne-functionalized PPES block with Co2(CO)8 and their phase behavior was studied by TEM. Heating triblock copolymer/cobalt carbonyl adducts at 120 °C led to cross-linking of the PPES/Co domains and the formation of magnetic cobalt nanoparticles within the PPES/Co domains. Magnetic hydrogels could be prepared by swelling the PEO domains of the cross-linked materials with water. Furthermore, swelling tests, rheological studies and actuation tests demonstrated thatmore » the water capacity and modulus of the hydrogels were dependent upon the composition of the block copolymer precursors.« less

  5. On the cellular metabolism of the click chemistry probe 19-alkyne arachidonic acid.


    Robichaud, Philippe Pierre; Poirier, Samuel J; Boudreau, Luc H; Doiron, Jérémie A; Barnett, David A; Boilard, Eric; Surette, Marc E


    Alkyne and azide analogs of natural compounds that can be coupled to sensitive tags by click chemistry are powerful tools to study biological processes. Arachidonic acid (AA) is a FA precursor to biologically active compounds. 19-Alkyne-AA (AA-alk) is a sensitive clickable AA analog; however, its use as a surrogate to study AA metabolism requires further evaluation. In this study, AA-alk metabolism was compared with that of AA in human cells. Jurkat cell uptake of AA was 2-fold greater than that of AA-alk, but significantly more AA-Alk was elongated to 22:4. AA and AA-alk incorporation into and remodeling between phospholipid (PL) classes was identical indicating equivalent CoA-independent AA-PL remodeling. Platelets stimulated in the pre-sence of AA-alk synthesized significantly less 12-lipoxygenase (12-LOX) and cyclooxygenase products than in the presence of AA. Ionophore-stimulated neutrophils produced significantly more 5-LOX products in the presence of AA-alk than AA. Neutrophils stimulated with only exogenous AA-alk produced significantly less 5-LOX products compared with AA, and leukotriene B4 (LTB4)-alk was 12-fold less potent at stimulating neutrophil migration than LTB4, collectively indicative of weaker leukotriene B4 receptor 1 agonist activity of LTB4-alk. Overall, these results suggest that the use of AA-alk as a surrogate for the study of AA metabolism should be carried out with caution.

  6. Pyridinium substituted tetraphenylethylene entailing alkyne moiety: enhancement of photosensitizing efficiency and antimicrobial activity.


    You, Xue; Ma, Huili; Wang, Yuancheng; Zhang, Guanxin; Peng, Qian; Liu, Libing; Wang, Shu; Zhang, Deqing


    Apart from sensing and imaging, luminogens with aggregation-induced emission are also interesting for photosensitizing. In this paper, we report the photosensitizing behavior and bacteria-killing performance of a new pyridinium substituted tetraphenylethylene with an alkyne group (TPE-A-Py+). Interestingly, TPE-A-Py+ exhibits higher photosensitizing efficiency than TPE-Py+ (without alkyne group) with I- as the counter anion. This is well explained by the fact that the energy gap between the excited singlet state (S1) and triplet state (T1) is lower for TPE-A-Py+ in comparison with that of TPE-Py+ on the basis of theoretical calculations. Moreover, the replacement of I- with other anions (PF6-, N(SO2CF3)2- and BPh4-) leads to the decrease of photosensitizing efficiency for TPE-A-Py+. Notably, TPE-A-Py+ can be utilized as an efficient photosensitizer to photo-inactivate Ampr E. coli at low concentration under white light irradiation for just a few minutes.

  7. Magnetic hydrogels from alkyne/cobalt carbonyl-functionalized ABA triblock copolymers

    SciTech Connect

    Jiang, Bingyin; Hom, Wendy L.; Chen, Xianyin; Yu, Pengqing; Pavelka, Laura C.; Kisslinger, Kim; Parise, John B.; Bhatia, Surita R.; Grubbs, Robert B.


    A series of alkyne-functionalized poly(4-(phenylethynyl)styrene)-block-poly(ethylene oxide)-block-poly(4-(phenylethynyl)styrene) (PPES-b-PEO-b-PPES) ABA triblock copolymers was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. PESn[Co2(CO)6]x-EO800-PESn[Co2(CO)6]x ABA triblock copolymer/cobalt adducts (10–67 wt % PEO) were subsequently prepared by reaction of the alkyne-functionalized PPES block with Co2(CO)8 and their phase behavior was studied by TEM. Heating triblock copolymer/cobalt carbonyl adducts at 120 °C led to cross-linking of the PPES/Co domains and the formation of magnetic cobalt nanoparticles within the PPES/Co domains. Magnetic hydrogels could be prepared by swelling the PEO domains of the cross-linked materials with water. Furthermore, swelling tests, rheological studies and actuation tests demonstrated that the water capacity and modulus of the hydrogels were dependent upon the composition of the block copolymer precursors.

  8. Homo-coupling of terminal alkynes on a noble metal surface.


    Zhang, Yi-Qi; Kepčija, Nenad; Kleinschrodt, Martin; Diller, Katharina; Fischer, Sybille; Papageorgiou, Anthoula C; Allegretti, Francesco; Björk, Jonas; Klyatskaya, Svetlana; Klappenberger, Florian; Ruben, Mario; Barth, Johannes V


    The covalent linking of acetylenes presents an important route for the fabrication of novel carbon-based scaffolds and two-dimensional materials distinct from graphene. To date few attempts have been reported to implement this strategy at well-defined interfaces or monolayer templates. Here we demonstrate through real space direct visualization and manipulation in combination with X-ray photoelectron spectroscopy and density functional theory calculations the Ag surface-mediated terminal alkyne C(sp)-H bond activation and concomitant homo-coupling in a process formally reminiscent of the classical Glaser-Hay type reaction. The alkyne homo-coupling takes place on the Ag(111) noble metal surface in ultrahigh vacuum under soft conditions in the absence of conventionally used transition metal catalysts and with volatile H(2) as the only by-product. With the employed multitopic ethynyl species, we demonstrate a hierarchic reaction pathway that affords discrete compounds or polymeric networks featuring a conjugated backbone. This presents a new approach towards on-surface covalent chemistry and the realization of two-dimensional carbon-rich or all-carbon polymers.

  9. Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities.


    Wang, Changhao; Carter-Cooper, Brandon; Du, Yixuan; Zhou, Jie; Saeed, Musabbir A; Liu, Jinbing; Guo, Min; Roembke, Benjamin; Mikek, Clinton; Lewis, Edwin A; Lapidus, Rena G; Sintim, Herman O


    G-quadruplex ligands have been touted as potential anticancer agents, however, none of the reported G-quadruplex-interactive small molecules have gone past phase II clinical trials. Recently it was revealed that diminazene (berenil, DMZ) actually binds to G-quadruplexes 1000 times better than DNA duplexes, with dissociation constants approaching 1 nM. DMZ however does not have strong anticancer activities. In this paper, using a panel of biophysical tools, including NMR, FRET melting assay and FRET competition assay, we discovered that monoamidine analogues of DMZ bearing alkyne substitutes selectively bind to G-quadruplexes. The lead DMZ analogues were shown to be able to target c-MYC G-quadruplex both in vitro and in vivo. Alkyne DMZ analogues display respectable anticancer activities (single digit micromolar GI50) against ovarian (OVCAR-3), prostate (PC-3) and triple negative breast (MDA-MB-231) cancer cell lines and represent interesting new leads to develop anticancer agents.

  10. Type II Isopentenyl Diphosphate Isomerase: Probing the Mechanism with Alkyne/Allene Diphosphate Substrate Analogues†

    PubMed Central

    Sharma, Nagendra K.; Pan, Jian-Jung; Poulter, C. Dale


    Isopentenyl diphosphate isomerase (IDI) catalyzes the interconversion of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), the basic five-carbon building blocks of isoprenoid molecules. Two structurally unrelated classes of IDI are known. Type I IPP isomerase (IDI-1) utilizes a divalent metal in a protonation-deprotonation reaction. In contrast, the type II enzyme (IDI-2) requires reduced flavin, raising the possibility that the reaction catalyzed by IDI-2 involves the net addition/abstraction of a hydrogen atom. As part of our studies of the mechanism of isomerization for IDI-2, we synthesized allene and alkyne substrate analogues for the enzyme. These molecules are predicted to be substantially less reactive toward proton addition than IPP and DMAPP, but have similar reactivities toward hydrogen atom addition. This prediction was verified by calculations of gas phase heats of reaction for addition of a proton and of a hydrogen atom to 1-butyne (3) and 1,2-butadiene (4) to form the 1-buten-2-yl carbocation and radical, respectively, and related affinities for 2-methyl-1-butene (5) and 2-methyl-2-butene (6) using G3MP2B3 and CBS-QB3 protocols. Alkyne 1-OPP and allene 2-OPP were not substrates for Thermus thermophilus IDI-2 or Escherichia coli IDI-1, but instead were competitive inhibitors. The experimental and computational results are consistent with a protonation-deprotonation mechanism for the enzyme-catalyzed isomerization of IPP and DMAPP. PMID:20560533

  11. Metal Free Azide-Alkyne Click Reaction: Role of Substituents and Heavy Atom Tunneling.


    Karmakar, Sharmistha; Datta, Ayan


    Metal free click reactions provide an excellent noninvasive tool to modify and understand the processes in biological systems. Release of ring strain in cyclooctynes on reaction with azides on the formation of triazoles results in small activation energies for various intermolecular Huisgen reactions (1-9). Substitution of difluoro groups at the α, α' position of the cyclooctyne ring enhances the rates of cycloadditions by 10 and 20 times for methyl azide and benzyl azide respectively at room temperature. The computed rate enhancement on difluoro substitution using direct dynamical calculations using the canonical variational transition state theory (CVT/CAG) with small curvature tunneling (SCT) corrections are in excellent agreement with the experimental results. For the intramolecular click reaction (10) notwithstanding its much higher activation energy, quantum mechanical tunneling (QMT) enhances the rate of cycloaddition significantly and increases the N(14)/N(15) primary kinetic isotope effect at 298 K. QMT is shown to be rather efficient in 10 due to a thin barrier of ∼2.4 Å. The present study shows that tunneling effects can be significant for intramolecular click reactions.

  12. Alkyne-Modulated Surface-Enhanced Raman Scattering-Palette for Optical Interference-Free and Multiplex Cellular Imaging.


    Chen, Yong; Ren, Jia-Qiang; Zhang, Xia-Guang; Wu, De-Yin; Shen, Ai-Guo; Hu, Ji-Ming


    The alkyne tags possess unique interference-free Raman emissions but are still hindered for further application in the field of biochemical labels due to its extremely weak spontaneous Raman scattering. With the aid of computational chemistry, herein, an alkyne-modulated surface-enhanced Raman scattering (SERS) palette is constructed based on rationally designed 4-ethynylbenzenethiol derivatives for spectroscopic signature, Au@Ag core for optical enhancement and an encapsulating polyallylamine shell for protection and conjugation. Even for the pigment rich plant cell (e.g., pollen), the alkyne-coded SERS tag can be highly discerned on two-dimension distribution impervious to strong organic interferences originating from resonance-enhanced Raman scattering or autofluorescence. In addition, the alkynyl-containing Raman reporters contribute especially narrow emission, band shift-tunable (2100-2300 cm(-1)) and tremendously enhanced Raman signals when the alkynyl group locates at para position of mercaptobenzene ring. Depending on only single Raman band, the suggested alkyne-modulated SERS-palette potentially provides a more effective solution for multiplex cellular imaging with vibrant colors, when the hyperspectral and fairly intense optical noises originating from lower wavenumber region (<1800 cm(-1)) are inevitable under complex ambient conditions.

  13. Ruthenium supported on magnetic nanoparticles: An efficient and recoverable catalyst for hydrogenation of alkynes and transfer hydrogenation of carbonyl compounds

    EPA Science Inventory

    Ruthenium supported on surface modified magnetic nanoparticles (NiFe2O4) has been successfully synthesized and applied for hydrogenation of alkynes at room temperature as well as transfer hydrogenation of a number of carbonyl compounds under microwave irradiation conditions. The ...


    EPA Science Inventory

    Direct Grignard type addition of terminal alkynes to in situ generated imines, from aldehydes and amines, occurs under microwave irradiation using CuBr alone in a one-pot operation. This solventless approach provides ready access to propargylamines and is applicable both...

  15. Selective partial hydrogenation of alkynes to (Z)-alkenes with ionic liquid-doped nickel nanocatalysts at near ambient conditions.


    Konnerth, Hannelore; Prechtl, Martin H G


    A selective hydrogenation method for forming (Z)-alkenes from alkynes has been developed using a catalyst system of cheap Ni-NPs in a nitrile functionalised imidazolium based ionic liquid (IL) operating under very mild reaction conditions of 30-50 °C and 1-4 bar H2 pressure.

  16. Silver-Catalyzed Formal Inverse Electron-Demand Diels-Alder Reaction of 1,2-Diazines and Siloxy Alkynes

    PubMed Central

    Türkmen, Yunus E.; Montavon, Timothy J.; Kozmin, Sergey A.; Rawal, Viresh H.


    A highly effective silver-catalyzed formal inverse electron-demand Diels-Alder reaction of 1,2-diazines and siloxy alkynes has been developed. The reactions provide ready access to a wide range of siloxy naphthalenes and anthracenes, which are formed in good to high yields, under mild reaction conditions, using low catalyst loadings. PMID:22607029

  17. Magnetic Fe@g-C3N4: A Photoactive Catalyst for the Hydrogenation of Alkenes and Alkynes

    EPA Science Inventory

    A photoactive catalyst, Fe@g-C3N4, has been developed for the hydrogenation of alkenes and alkynes using hydrazine hydrate as a source of hydrogen. The magnetically separable Fe@g-C3N4 eliminates the use of high pressure hydrogenation and the reaction can be accomplished using vi...

  18. Water-soluble PEGylated silicon nanoparticles and their assembly into swellable nanoparticle aggregates

    NASA Astrophysics Data System (ADS)

    Xu, Zejing; Li, Yejia; Zhang, Boyu; Purkait, Tapas; Alb, Alina; Mitchell, Brian S.; Grayson, Scott M.; Fink, Mark J.


    Water-soluble silicon nanoparticles were synthesized by grafting PEG polymers onto functionalized silicon nanoparticles with distal alkyne or azide moieties. The surface-functionalized silicon nanoparticles were produced in one step from the reactive high-energy ball milling (RHEBM) of silicon wafers with a mixture of either 5-chloro-1-pentyne in 1-pentyne or 1,7 octadiyne in 1-hexyne to afford air and water-stable chloroalkyl or alkynyl-terminated nanoparticles, respectively. Nanoparticles with the ω-chloroalkyl substituents were easily converted to ω-azidoalkyl groups through the reaction of the Si nanoparticles with sodium azide in DMF. The azido-terminated nanoparticles were then grafted with mono-alkynyl-PEG polymers using a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction to afford core-shell silicon nanoparticles with a covalently attached PEG shell. Covalently linked Si nanoparticle clusters were synthesized via the CuAAC "click" reaction of functional Si NPs with α,ω-functional PEG polymers of various lengths. Dynamic light scattering studies show that the flexible globular nanoparticle aggregates undergo a solvent-dependent change in volume (ethanol > dichloromethane > toluene) similar in behavior to hydrogel nanocomposites.

  19. Preparation of reactive fibre interfaces using multifunctional cellulose derivatives.


    Vega, Beatriz; Wondraczek, Holger; Bretschneider, Leonore; Näreoja, Tuomas; Fardim, Pedro; Heinze, Thomas


    Cellulose fibres have poor reactivity and limited potential for surface engineering with advanced chemical functionalization in water. In this work, cellulose fibres were decorated with azide functions by charge-directed self-assembly of a novel water-soluble multifunctional cellulose derivative yielding reactive fibres. Propargylamine and 1-ethynylpyrene were utilized as a proof of concept that alkyne molecules may react with the azide functions of the reactive fibres via copper(I)-catalyzed azide-alkyne Huisgen cycloaddition (CuAAc) reaction in mild conditions. Chemical characterization of the fibres was carried out using classical techniques such as Raman-, fluorescence-, and UV-vis spectroscopy. Among other techniques, time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray spectroscopy (XPS), two-photon microscopy (TPM), and inductively coupled plasma mass spectrometry (ICP-MS) were useful tools for additional characterization of the fibres decorated with amino- or photoactive groups. The information gathered in this work might contribute to the basis for the preparation of reactive cellulose-based interfaces with potential application in CuAAc reactions.

  20. Enhanced Biosensor Platforms for Detecting the Atherosclerotic Biomarker VCAM1 Based on Bioconjugation with Uniformly Oriented VCAM1-Targeting Nanobodies

    PubMed Central

    Ta, Duy Tien; Guedens, Wanda; Vranken, Tom; Vanschoenbeek, Katrijn; Steen Redeker, Erik; Michiels, Luc; Adriaensens, Peter


    Surface bioconjugation of biomolecules has gained enormous attention for developing advanced biomaterials including biosensors. While conventional immobilization (by physisorption or covalent couplings using the functional groups of the endogenous amino acids) usually results in surfaces with low activity, reproducibility and reusability, the application of methods that allow for a covalent and uniformly oriented coupling can circumvent these limitations. In this study, the nanobody targeting Vascular Cell Adhesion Molecule-1 (NbVCAM1), an atherosclerotic biomarker, is engineered with a C-terminal alkyne function via Expressed Protein Ligation (EPL). Conjugation of this nanobody to azidified silicon wafers and Biacore™ C1 sensor chips is achieved via Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” chemistry to detect VCAM1 binding via ellipsometry and surface plasmon resonance (SPR), respectively. The resulting surfaces, covered with uniformly oriented nanobodies, clearly show an increased antigen binding affinity, sensitivity, detection limit, quantitation limit and reusability as compared to surfaces prepared by random conjugation. These findings demonstrate the added value of a combined EPL and CuAAC approach as it results in strong control over the surface orientation of the nanobodies and an improved detecting power of their targets—a must for the development of advanced miniaturized, multi-biomarker biosensor platforms. PMID:27399790

  1. Gas-phase azide functionalization of carbon.


    Stenehjem, Eric D; Ziatdinov, Vadim R; Stack, T Daniel P; Chidsey, Christopher E D


    Tailoring the surface and interfacial properties of inexpensive and abundant carbon materials plays an increasingly important role for innovative applications including those in electrocatalysis, energy storage, gas separations, and composite materials. Described here is the novel preparation and subsequent use of gaseous iodine azide for the azide modification of carbon surfaces. In-line generation of gaseous iodine azide from iodine monochloride vapor and solid sodium azide is safe and convenient. Immediate treatment of carbon surfaces with this gaseous stream of iodine azide provides a highly reproducible, selective, and scalable azide functionalization that minimizes waste and reduces deleterious side reactions. Among the possible uses of azide-modified surfaces, they serve as versatile substrates for the attachment of additional functionality by coupling with terminal alkynes under the mild copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. For instance, coupling ethynylferrocene to azide-modified glassy carbon surfaces achieves ferrocene coverage up to 8 × 10(13) molecules/cm(2) by voltammetric and XPS analyses. The 1,2,3-triazole linker formed during the CuAAC reaction is robust and hydrolytically stable in both aqueous 1 M HClO(4) and 1 M NaOH for at least 12 h at 100 °C.

  2. Chain-growth click polymerization of AB2 monomers for the formation of hyperbranched polymers with low polydispersities in a one-pot process.


    Shi, Yi; Graff, Robert W; Cao, Xiaosong; Wang, Xiaofeng; Gao, Haifeng


    Hyperbranched polymers are important soft nanomaterials but robust synthetic methods with which the polymer structures can be easily controlled have rarely been reported. For the first time, we present a one-pot one-batch synthesis of polytriazole-based hyperbranched polymers with both low polydispersity and a high degree of branching (DB) using a copper-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization. The use of a trifunctional AB2 monomer that contains one alkyne and two azide groups ensures that all Cu catalysts are bound to polytriazole polymers at low monomer conversion. Subsequent CuAAC polymerization displayed the features of a "living" chain-growth mechanism with a linear increase in molecular weight with conversion and clean chain extension for repeated monomer additions. Furthermore, the triazole group in a linear (L) monomer unit complexed Cu(I) , which catalyzed a faster reaction of the second azide group to quickly convert the L unit into a dendritic unit, producing hyperbranched polymers with DB=0.83.

  3. Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed "click" cycloaddition and thio acid/sulfonyl azide "sulfo-click" amidation and their in vivo evaluation.


    Yim, Cheng-Bin; Dijkgraaf, Ingrid; Merkx, Remco; Versluis, Cees; Eek, Annemarie; Mulder, Gwenn E; Rijkers, Dirk T S; Boerman, Otto C; Liskamp, Rob M J


    Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr(3)]octreotide-based analogues as a tool for tumor imaging and/or radionuclide therapy. These compounds were synthesized using a Cu(I)-catalyzed 1,3-dipolar cycloaddition ("click" reaction) between peptidic azides and dendrimer-derived alkynes and a subsequent metal-free introduction of DOTA via the thio acid/sulfonyl azide amidation ("sulfo-click" reaction). In a competitive binding assay using rat pancreatic AR42J tumor cells, the monomeric [Tyr(3)]octreotide conjugate displayed the highest binding affinity (IC(50) = 1.32 nM) followed by dimeric [Tyr(3)]octreotide (2.45 nM), [DOTA(0),Tyr(3)]octreotide (2.45 nM), and tetrameric [Tyr(3)]octreotide (14.0 nM). Biodistribution studies with BALB/c nude mice with subcutaneous AR42J tumors showed that the (111)In-labeled monomeric [Tyr(3)]octreotide conjugate had the highest tumor uptake (42.3 +/- 2.8 %ID/g) at 2 h p.i., which was better than [(111)In-DOTA(0),Tyr(3)]octreotide (19.5 +/- 4.8 %ID/g). The (111)In-labeled dimeric [Tyr(3)]octreotide conjugate showed a long tumor retention (25.3 +/- 5.9 %ID/g at 2 h p.i. and 12.1 +/- 1.3 %ID/g at 24 h p.i.). These promising results can be exploited for therapeutic applications.

  4. Azide-alkyne "click" reaction performed on oligonucleotides with the universal nucleoside 7-octadiynyl-7-deaza-2'-deoxyinosine.


    Ming, Xin; Leonard, Peter; Heindl, Dieter; Seela, Frank


    Oligonucleotides containing 7-substituted 7-deaza-2'- deoxyinosine derivatives bearing alkynyl groups were prepared. The octa-1,7-diynyl derivative was functionalized with the non-fluorescent 3- azidocoumarin by the Huisgen-Sharpless-Meldal cycloaddition to afford a highly fluorescent oligonucleotide conjugate. The ambiguous base pairing character and the clickable side chain allows the incorporation of almost any reporter molecule to DNA.

  5. Carboxylate-assisted ruthenium-catalyzed alkyne annulations by C-H/Het-H bond functionalizations.


    Ackermann, Lutz


    To improve the atom- and step-economy of organic syntheses, researchers would like to capitalize upon the chemistry of otherwise inert carbon-hydrogen (C-H) bonds. During the past decade, remarkable progress in organometallic chemistry has set the stage for the development of increasingly viable metal catalysts for C-H bond activation reactions. Among these methods, oxidative C-H bond functionalizations are particularly attractive because they avoid the use of prefunctionalized starting materials. For example, oxidative annulations that involve sequential C-H and heteroatom-H bond cleavages allow for the modular assembly of regioselectively decorated heterocycles. These structures serve as key scaffolds for natural products, functional materials, crop protecting agents, and drugs. While other researchers have devised rhodium or palladium complexes for oxidative alkyne annulations, my laboratory has focused on the application of significantly less expensive, yet highly selective ruthenium complexes. This Account summarizes the evolution of versatile ruthenium(II) complexes for annulations of alkynes via C-H/N-H, C-H/O-H, or C-H/N-O bond cleavages. To achieve selective C-H bond functionalizations, we needed to understand the detailed mechanism of the crucial C-H bond metalation with ruthenium(II) complexes and particularly the importance of carboxylate assistance in this process. As a consequence, our recent efforts have resulted in widely applicable methods for the versatile preparation of differently decorated arenes and heteroarenes, providing access to among others isoquinolones, 2-pyridones, isoquinolines, indoles, pyrroles, or α-pyrones. Most of these reactions used Cu(OAc)2·H2O, which not only acted as the oxidant but also served as the essential source of acetate for the carboxylate-assisted ruthenation manifold. Notably, the ruthenium(II)-catalyzed oxidative annulations also occurred under an ambient atmosphere of air with cocatalytic amounts of Cu(OAc)2

  6. Gold-catalyzed formal [4π+2π]-cycloadditions of tert-butyl propiolates with aldehydes and ketones to form 4H-1,3-dioxine derivatives.


    Karad, Somnath Narayan; Chung, Wei-Kang; Liu, Rai-Shung


    Gold-catalyzed formal hetero-[4π+2π] cycloadditions of tert-butyl propiolates with carbonyl compounds proceeded efficiently to yield 4H-1,3-dioxine derivatives over a wide scope of substrates. With acetone as a promoter, gold-catalyzed cycloadditions of these propiolate derivatives with enol ethers led to the formation of atypical [4+2]-cycloadducts with skeletal rearrangement.

  7. Formal (4+1) Cycloaddition of Methylenecyclopropanes with 7-Aryl-1,3,5-cycloheptatrienes by Triple Gold(I) Catalysis**

    PubMed Central

    Wang, Yahui; Muratore, Michael E; Rong, Zhouting; Echavarren, Antonio M


    7-Aryl-1,3,5-cycloheptatrienes react intermolecularly with methylenecyclopropanes in a triple gold(I)-catalyzed reaction to form cyclopentenes. The same formal (4+1) cycloaddition occurs with cyclobutenes. Other precursors of gold(I) carbenes can also be used as the C1 component of the cycloaddition. PMID:24898850

  8. Rh-Catalyzed Decarbonylation of Conjugated Ynones via Carbon–Alkyne Bond Activation: Reaction Scope and Mechanistic Exploration via DFT Calculations

    PubMed Central

    Dermenci, Alpay; Whittaker, Rachel E.; Gao, Yang; Cruz, Faben A.; Yu, Zhi-Xiang; Dong, Guangbin


    In this full article, detailed development of a catalytic decarbonylation of conjugated monoynones to synthesize disubstituted alkynes is described. The reaction scope and limitation has been thoroughly investigated, and a broad range of functional groups including heterocycles were compatible under the catalytic conditions. Mechanistic exploration via DFT calculations has also been executed. Through the computational study, a proposed catalytic mechanism has been carefully evaluated. These efforts are expected to serve as an important exploratory study for developing catalytic alkyne-transfer reactions via carbon−alkyne bond activation. PMID:26229587

  9. Rh(III)-Catalyzed Carbocyclization of 3-(Indolin-1-yl)-3-oxopropanenitriles with Alkynes and Alkenes through C-H Activation.


    Zhou, Tao; Wang, Yanwei; Li, Bin; Wang, Baiquan


    Rh(III)-catalyzed carbocyclization reactions of 3-(indolin-1-yl)-3-oxopropanenitriles with alkynes and alkenes have been developed to form 1,7-fused indolines through C-H activation. These reactions have a broad range of substrates and high yields. Unsymmetrical aryl-alkyl substituted alkynes proceeded smoothly with high regioselectivity. Electron-rich alkynes could undergo further oxidative coupling reaction to form polycyclic compounds. For alkenes, 1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-ones were formed via C(sp(2))-H bond alkenylation and C(sp(2))-H, C(sp(3))-H oxidative coupling reactions.

  10. Green Hydroselenation of Aryl Alkynes: Divinyl Selenides as a Precursor of Resveratrol.


    Perin, Gelson; Barcellos, Angelita M; Luz, Eduardo Q; Borges, Elton L; Jacob, Raquel G; Lenardão, Eder J; Sancineto, Luca; Santi, Claudio


    A simple and efficient protocol to prepare divinyl selenides has been developed by the regio- and stereoselective addition of sodium selenide species to aryl alkynes. The nucleophilic species was generates in situ, from the reaction of elemental selenium with NaBH₄, utilizing PEG-400 as the solvent. Several divinyl selenides were obtained in moderate to excellent yields with selectivity for the (Z,Z)-isomer by a one-step procedure that was carried out at 60 °C in short reaction times. The methodology was extended to tellurium, giving the desired divinyl tellurides in good yields. Furthermore, the Fe-catalyzed cross-coupling reaction of bis(3,5-dimethoxystyryl) selenide 3f with (4-methoxyphenyl)magnesium bromide 5 afforded resveratrol trimethyl ether 6 in 57% yield.

  11. Constraining an Irregular Peptide Secondary Structure through Ring‐Closing Alkyne Metathesis

    PubMed Central

    Cromm, Philipp M.; Wallraven, Kerstin; Glas, Adrian; Bier, David; Fürstner, Alois; Ottmann, Christian


    Abstract Macrocyclization can be used to constrain peptides in their bioactive conformations, thereby supporting target affinity and bioactivity. In particular, for the targeting of challenging protein–protein interactions, macrocyclic peptides have proven to be very useful. Available approaches focus on the stabilization of α‐helices, which limits their general applicability. Here we report for the first time on the use of ring‐closing alkyne metathesis for the stabilization of an irregular peptide secondary structure. A small library of alkyne‐crosslinked peptides provided a number of derivatives with improved target affinity relative to the linear parent peptide. In addition, we report the crystal structure of the highest‐affinity derivative in a complex with its protein target 14‐3‐3ζ. It can be expected that the alkyne‐based macrocyclization of irregular binding epitopes should give rise to new scaffolds suitable for targeting of currently intractable proteins. PMID:27596722

  12. Ruthenium-catalyzed oxidation of alkenes, alkynes, and alcohols to organic acids with aqueous hydrogen peroxide.


    Che, Chi-Ming; Yip, Wing-Ping; Yu, Wing-Yiu


    A protocol that adopts aqueous hydrogen peroxide as a terminal oxidant and [(Me3tacn)(CF3CO2)2Ru(III)(OH2)]CF3CO2 (1; Me3tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane) as a catalyst for oxidation of alkenes, alkynes, and alcohols to organic acids in over 80% yield is presented. For the oxidation of cyclohexene to adipic acid, the loading of 1 can be lowered to 0.1 mol %. On the one-mole scale, the oxidation of cyclohexene, cyclooctene, and 1-octanol with 1 mol % of 1 produced adipic acid (124 g, 85% yield), suberic acid (158 g, 91% yield), and 1-octanoic acid (129 g, 90% yield), respectively. The oxidative C=C bond-cleavage reaction proceeded through the formation of cis- and trans-diol intermediates, which were further oxidized to carboxylic acids via C-C bond cleavage.

  13. Synthesis of (α,α-difluoropropargyl)phosphonates via aldehyde-to-alkyne homologation.


    Pajkert, Romana; Röschenthaler, Gerd-Volker


    An efficient synthetic methodology to a series of novel alkynes bearing a difluoromethylenephosphonate function via a Corey-Fuchs-type sequence starting from (diethoxyphosphoryl)difluoroacetic aldehyde is described. Dehydrobromination of the intermediate (3,3-dibromodifluoroallyl)phosphonate with potassium tert-butoxide gave rise to the corresponding bromoalkyne, whereas upon treatment with lithium base, the generation of ((diethoxyphosphoryl)difluoropropynyl)lithium has been achieved for the first time. The synthetic potential of this lithium reagent was further demonstrated by its reactions with selected electrophiles such as aldehydes, ketones, triflates, chlorophosphines, and chlorosilanes, leading to the corresponding propargyl phosphonates in good to excellent yields. However, in the case, of sterically hindered aldehydes, (α-fluoroallenyl)phosphonates were the solely isolated products.

  14. Palladium-Copper Catalyzed Alkyne Activation as an Entry to Multicomponent Syntheses of Heterocycles

    NASA Astrophysics Data System (ADS)

    Müller, Thomas J. J.

    Alkynones and chalcones are of paramount importance in heterocyclic chemistry as three-carbon building blocks. In a very efficient manner, they can be easily generated by palladium-copper catalyzed reactions: ynones are formed from acid chlorides and terminal alkynes, and chalcones are synthesized in the sense of a coupling-isomerization (CI) sequence from (hetero)aryl halides and propargyl alcohols. Mild reaction conditions now open entries to sequential and consecutive transformations to heterocycles, such as furans, 3-halo furans, pyrroles, pyrazoles, substituted and annelated pyridines, annelated thiopyranones, pyridimines, meridianins, benzoheteroazepines and tetrahydro-β-carbolines, by consecutive coupling-cyclocondensation or CI-cyclocondensation sequences, as new diversity oriented routes to heterocycles. Domino reactions based upon the coupling-isomerization reaction (CIR) have been probed in the synthesis of antiparasital 2-substituted quinoline derivatives and highly luminescent spiro-benzofuranones and spiro-indolones.

  15. Polymerization or Cyclic Dimerization: Solvent Dependent Homo-Coupling of Terminal Alkynes at HOPG Surface

    PubMed Central

    Zhang, Xuemei; Liao, Lingyan; Wang, Shuai; Hu, Fangyun; Wang, Chen; Zeng, Qingdao


    Surface reactivity has become one of the most important issues in surface chemistry over the past few years. In this work, we, for the first time, have investigated the homo-coupling of a special terminal alkyne derivative on the highly oriented pyrolitic graphite (HOPG) surface. Using scanning tunneling microscopy (STM) technique, we have found that such coupling reaction seriously depends on the supramolecular assembly of the monomer on the studied substrate, whereas the latter appears an obvious solvent effect. As a result, the reaction in our system undergoes polymerization and cyclic dimerization process in 1-phenyloctane and 1,2,4-trichlorobenzene, respectively. That is to say, the solvent effect can be extended from the two-dimensional (2D) supramolecular self-assembly to surface chemical reactions, and the selective homo-coupling has been successfully achieved at the solid/liquid interface. PMID:24469357

  16. Fabrication of carbon nanotube films from alkyne-transition metal complexes


    Iyer, Vivekanantan S.; Vollhardt, K. Peter C.


    A simple method for the production or synthesis of carbon nanotubes as free-standing films or nanotube mats by the thermal decomposition of transition metal complexed alkynes with aryl, alkyl, alkenyl, or alkynyl substituents. In particular, transition metal (e.g. Co, Ni, Fe, Mo) complexes of diarylacetylenes, e.g. diphenylacetylene, and solid mixtures of these complexes with suitable, additional carbon sources are heated in a vessel. More specifically, the heating of the transition metal complex is completed at a temperature between C. and more particularly C. for between 0.1 to 24 hours and more particularly 0.5-3 hours in a sealed vessel under a partial pressure of argon or helium.

  17. Synthesis of Dihydropyridines and Pyridines from Imines and Alkynes via C-H Activation

    SciTech Connect

    Ellman, Jonathan A.; Colby, Denise; Bergman, Robert


    A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and {alpha},{beta}-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.

  18. Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation.


    Colby, Denise A; Bergman, Robert G; Ellman, Jonathan A


    A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and alpha,beta-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.

  19. Synthesis of functionalized organotrifluoroborates via the 1,3-dipolar cycloaddition of azides.


    Molander, Gary A; Ham, Jungyeob


    [reaction: see text] We have successfully prepared potassium azidoalkyltrifluoroborates from the corresponding halogen compounds in 94-98% yields through a nucleophilic substitution reaction with NaN(3). In the presence of various alkynes and Cu(I) as a catalyst, these azidotrifluoroborates easily formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates in 85-98% yields. This method was then developed into a facile one-pot synthesis for the preparation of various organo-[1,2,3]-triazol-1-yl-trifluoroborates using haloalkyltrifluoroborates as the starting materials.

  20. Triazol-substituted titanocenes by strain-driven 1,3-dipolar cycloadditions

    PubMed Central

    Okkel, Andreas; Schwach, Lukas; Wagner, Laura; Selig, Anja; Prokop, Aram


    Summary An operationally simple, convenient, and mild strategy for the synthesis of triazole-substituted titanocenes via strain-driven 1,3-dipolar cycloadditions between azide-functionalized titanocenes and cyclooctyne has been developed. It features the first synthesis of titanocenes containing azide groups. These compounds constitute ‘second-generation’ functionalized titanocene building blocks for further synthetic elaboration. Our synthesis is modular and large numbers of the complexes can in principle be prepared in short periods of time. Some of the triazole-substituted titanocenes display high cyctotoxic activity against BJAB cells. Comparison of the most active complexes allows the identification of structural features essential for biological activity. PMID:25161720

  1. Nitrile Oxide-Norbornene Cycloaddition as a Bioorthogonal Crosslinking Reaction for the Preparation of Hydrogels.


    Truong, Vinh X; Zhou, Kun; Simon, George P; Forsythe, John S


    This communication describes the first application of cycloaddition between an in situ generated nitrile oxide with norbornene leading to a polymer crosslinking reaction for the preparation of poly(ethylene glycol) hydrogels under physiological conditions. Hydrogels with high water content and robust physical strength are readily formed within 2-5 min by a simple two-solution mixing method which allows 3D encapsulation of neuronal cells. This bioorthogonal crosslinking reaction provides a simple yet highly effective method for preparation of hydrogels to be used in bioengineering.

  2. Prediction of mode specificity in 1,3-dipolar cycloadditions using the Sudden Vector Projection model

    NASA Astrophysics Data System (ADS)

    Li, Anyang; Guo, Hua


    Mode specificity in the cycloaddition of 1,3-dipoles to ethene and ethyne is investigated with the newly proposed Sudden Vector Projection (SVP) model, which attributes the promoting ability of a reactant mode to its projection onto the reaction coordinate at the transition state. The SVP model revealed that dipole bending and translational modes have large components in the reaction coordinate, consistent with the recent direct dynamics studies. It further identified several other promoting modes. The success of the SVP model is encouraging as it requires no dynamics calculations, and as a result it can be applied to many reactions.

  3. Atroposelective [2+2+2] cycloadditions catalyzed by a rhodium(I)-chiral phosphate system.


    Augé, Mylène; Barbazanges, Marion; Tran, Anh Tuan; Simonneau, Antoine; Elley, Paulin; Amouri, Hani; Aubert, Corinne; Fensterbank, Louis; Gandon, Vincent; Malacria, Max; Moussa, Jamal; Ollivier, Cyril


    Enantioselective cationic Rh(I)-catalyzed [2+2+2] cycloaddition reactions between diynes and isocyanates relying on the chiral anion strategy have been devised. In the presence of [Rh(cod)Cl]2, 1,4-bis(diphenylphosphino)butane, and the silver phosphate salt Ag(S)-TRIP as the unique source of chirality, axially chiral pyridones were isolated with ees up to 82%. This approach is novel in the field of chiral anion-mediated asymmetric catalysis since atroposelective transformations have so far remained unprecedented. It also proves to be complementary to the classical strategy based on chiral L-type ligands.

  4. Theoretical Study of 1,3-Dipolar Cycloaddition of Hydrazoic Acid to Substituted Ynamines

    NASA Astrophysics Data System (ADS)

    Chen, Xiao-fang; Yang, Kun; Han, Ke-li


    The 1,3-dipolar cycloaddition reactions of various substituted ynamines with hydrazoic acid were theoretically investigated with the high-accuracy CBS-QB3 method. Two regioisomers, 4-amine, and 5-amine substituted adducts, were obtained, with the former as the preferred yield. This regioselectivity is rationalized by the frontier molecular orbital theory. The reactivity and synchronicity are enhanced with the increase of the electron-withdrawing character of the substitute on ynamine fragment. The calculations also show that the effect of solvent increases the activation energy, and the reaction becomes even harder in polar solvent.

  5. 1-Azadienes in cycloaddition and multicomponent reactions towards N-heterocycles.


    Groenendaal, Bas; Ruijter, Eelco; Orru, Romano V A


    1-Azadienes are versatile building blocks for the efficient construction of various N-heterocycles. Depending on the substitution pattern and reaction partner, they may participate in a range of different reactions. An overview of recent methods for the generation of 1-azadienes is presented, as well as their application in cycloaddition, electrocyclization, and multicomponent reactions. Considering the broad range of reactivities and resulting heterocyclic scaffold structures, 1-azadienes are very useful reactive intermediates for the development of modular reaction sequences in diversity-oriented synthesis.

  6. Carbon-Supported Copper Nanomaterials: Recyclable Catalysts for Huisgen [3+2] Cycloaddition Reactions.


    Shaygan Nia, Ali; Rana, Sravendra; Döhler, Diana; Jirsa, Franz; Meister, Annette; Guadagno, Liberata; Koslowski, Eik; Bron, Michael; Binder, Wolfgang H


    Highly disperse copper nanoparticles immobilized on carbon nanomaterials (CNMs; graphene/carbon nanotubes) were prepared and used as a recyclable and reusable catalyst to achieve Cu(I) -catalyzed [3+2] cycloaddition click chemistry. Carbon nanomaterials with immobilized N-heterocyclic carbene (NHC)-Cu complexes prepared from an imidazolium-based carbene and Cu(I) show excellent stability including high efficiency at low catalyst loading. The catalytic performance evaluated in solution and in bulk shows that both types of Cu-CNMs can function as an effective recyclable catalysts (more than 10 cycles) for click reactions without decomposition and the use of external additives.

  7. Diels-Alder cycloadditions in water for the straightforward preparation of peptide–oligonucleotide conjugates

    PubMed Central

    Marchán, Vicente; Ortega, Samuel; Pulido, Daniel; Pedroso, Enrique; Grandas, Anna


    The Diels-Alder reaction between diene-modified oligonucleotides and maleimide-derivatized peptides afforded peptide–oligonucleotide conjugates with high purity and yield. Synthesis of the reagents was easily accomplished by on-column derivatization of the corresponding peptides and oligonucleotides. The cycloaddition reaction was carried out in mild conditions, in aqueous solution at 37°C. The speed of the reaction was found to vary depending on the size of the reagents, but it can be completed in 8–10 h by reacting the diene-oligonucleotide with a small excess of maleimide-peptide. PMID:16478710

  8. Easy access to heterobimetallic complexes for medical imaging applications via microwave-enhanced cycloaddition

    PubMed Central

    Desbois, Nicolas; Pacquelet, Sandrine; Dubois, Adrien; Michelin, Clément


    Summary The Cu(I)-catalysed Huisgen cycloaddition, known as “click” reaction, has been applied to the synthesis of a range of triazole-linked porphyrin/corrole to DOTA/NOTA derivatives. Microwave irradiation significantly accelerates the reaction. The synthesis of heterobimetallic complexes was easily achieved in up to 60% isolated yield. Heterobimetallic complexes were easily prepared as potential MRI/PET (SPECT) bimodal contrast agents incorporating one metal (Mn, Gd) for the enhancement of contrast for MRI applications and one “cold” metal (Cu, Ga, In) for future radionuclear imaging applications. Preliminary relaxivity measurements showed that the reported complexes are promising contrast agents (CA) in MRI. PMID:26664643

  9. The Structure of SpnF, a Standalone Enzyme that Catalyzes [4+2] Cycloaddition

    PubMed Central

    Fage, Christopher D.; Isiorho, Eta A.; Liu, Yungnan; Wagner, Drew T.; Liu, Hung-wen; Keatinge-Clay, Adrian T.


    In the biosynthetic pathway of the spinosyn insecticides, the tailoring enzyme SpnF performs a [4+2]-cycloaddition on a 22-membered macrolactone to forge an embedded cyclohexene ring. To learn more about this reaction, which could potentially proceed through a Diels-Alder mechanism, the 1.50 Å-resolution crystal structure of SpnF bound to S-adenosylhomocysteine (SAH) was determined. This sets the stage for advanced experimental and computational studies to determine the precise mechanism of SpnF-mediated cyclization. PMID:25730549

  10. Ruthenium-catalyzed intramolecular [2+2+2] cycloaddition and tandem cross-metathesis of triynes and enediynes.


    Yuan, Wei; Wei, Yin; Shi, Min


    [2+2+2] Cycloadditions can be applied to specifically build up derivatives of benzene and cyclohexadiene and, therefore, have attracted much attention. Herein, we present an intramolecular [2+2+2] cycloaddition of triynes catalyzed by the first-generation Grubbs ruthenium complex (Ru gen-1), which can efficiently afford benzene derivatives in good yields under mild conditions. Moreover, we also report on a novel tandem cross-metathesis transformation of intramolecular enediynes also catalyzed by Ru gen-1, which has not been observed previously in related reports. On the basis of deuterium labeling experiments, a possible reaction mechanism is presented.

  11. Rh(I)-catalyzed Pauson-Khand-type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide (CO).


    Yuan, Wei; Dong, Xiang; Shi, Min; McDowell, Patrick; Li, Guigen


    An intramolecular Pauson-Khand type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide has been established by using [Rh(COD)Cl](2) as the catalyst. The reaction was found to be highly efficient in solvents of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane to give excellent yields of 90-99%. The reaction provides easy access to a series of fused 6,5-ring structures containing spiro-cyclopropane units that are useful for drug design and development. A mechanism of this cycloaddition process has been proposed accounting for structures of resulting products that were unambiguously assigned by X-ray diffractional analysis.

  12. Enantioselective Cycloaddition Reactions Catalyzed by BINOL-Derived Phosphoric Acids and N-Triflyl Phosphoramides: Recent Advances.


    Held, Felix E; Grau, Dominik; Tsogoeva, Svetlana B


    Over the last several years there has been a huge increase in the development and applications of new efficient organocatalysts for enantioselective pericyclic reactions, which represent one of the most powerful types of organic transformations. Among these processes are cycloaddition reactions (e.g., [3+2]; formal [3+3]; [4+2]; vinylogous [4+2] and 1,3-dipolar cycloadditions), which belong to the most utilized reactions in organic synthesis of complex nitrogen- and oxygen-containing heterocyclic molecules. This review presents the breakthrough realized in this field using chiral BINOL-derived phosphoric acids and N-triflyl phosphoramide organocatalysts.

  13. Pedagogical Comparison of Five Reactions Performed under Microwave Heating in Multi-Mode versus Mono-Mode Ovens: Diels-Alder Cycloaddition, Wittig Salt Formation, E2 Dehydrohalogenation to Form an Alkyne, Williamson Ether Synthesis, and Fischer Esterification

    ERIC Educational Resources Information Center

    Baar, Marsha R.; Gammerdinger, William; Leap, Jennifer; Morales, Erin; Shikora, Jonathan; Weber, Michael H.


    Five reactions were rate-accelerated relative to the standard reflux workup in both multi-mode and mono-mode microwave ovens, and the results were compared to determine whether the sequential processing of a mono-mode unit could provide for better lab logistics and pedagogy. Conditions were optimized so that yields matched in both types of…

  14. Copper-catalyzed difunctionalization of activated alkynes by radical oxidation-tandem cyclization/dearomatization to synthesize 3-trifluoromethyl spiro[4.5]trienones.


    Hua, Hui-Liang; He, Yu-Tao; Qiu, Yi-Feng; Li, Ying-Xiu; Song, Bo; Gao, Pin; Song, Xian-Rong; Guo, Dong-Hui; Liu, Xue-Yuan; Liang, Yong-Min


    A copper-catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent sodium trifluoromethanesulfinate (NaSO2CF3 or Langlois' reagent) has been developed incorporating a tandem cyclization/dearomatization process. This strategy affords a straightforward route to synthesis of 3-(trifluoromethyl)-spiro[4.5]trienones, and presents an example of difunctionalization of alkynes for simultaneous formation of two carbon-carbon single bonds and one carbon-oxygen double bond.

  15. Revealing Stepwise Mechanisms in Dipolar Cycloaddition Reactions: Computational Study of the Reaction between Nitrones and Isocyanates.


    Darù, Andrea; Roca-López, David; Tejero, Tomás; Merino, Pedro


    The mechanism of cycloaddition reactions of nitrones with isocyanates has been studied using density functional theory (DFT) methods at the M06-2X/cc-pVTZ level of theory. The exploration of the potential energy surfaces associated with two reactive channels leading to 1,2,4-oxadiazolidin-5-ones and 1,4,2-dioxazolidines revealed that the cycloaddition reaction takes place through a concerted mechanism in gas phase and in apolar solvents but a stepwise mechanism in polar solvents. In stepwise mechanisms, the first step of the reaction is a rare case in which the nitrone oxygen acts as a nucleophile by attacking the central carbon atom of the isocyanate (interacting with the π-system of the C═O bond) to give an intermediate. The corresponding transition structure is stabilized by an attractive electrostatic interaction favored in a polar medium. The second step of the reaction is the rate-limiting one in which the formation of 1,2,4-oxadiazolidin-5-ones or 1,4,2-dioxazolidines is decided. Calculations indicate that formation of 1,2,4-oxadiazolidin-5-ones is favored both kinetically and thermodynamically independently of the solvent, in agreement with experimental observations. Noncovalent interactions (NCI) and topological analysis of the gradient field of electron localization function (ELF) bonding confirmed the observed interactions.

  16. Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives

    PubMed Central

    Sidova, Veronika; Zoufaly, Pavel; Pokorny, Jan; Dzubak, Petr; Hajduch, Marian; Popa, Igor


    In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development. PMID:28158265

  17. Theoretical study of the mechanism of cycloaddition reaction between dichloro-germylidene and acetaldehyde

    NASA Astrophysics Data System (ADS)

    Lu, Xiuhui; Han, Junfeng; Xu, Yuehua; Shi, Leyi; Lian, Zhenxia


    The mechanism of the cycloadditional reaction between singlet dichloro-germylidene(R1) and (acetaldehyde(R2) has been investigated with MP2/6-31G* method, including geometry optimization, vibrational analysis and energies for the involved stationary points on the potential energy surface. From the potential energy profile, we predict that the cycloaddition reaction between singlet dichloro-germylidene and acetaldehyde has two competitive dominant reaction pathways. Going with the formation of two side products (INT3 and INT4), simultaneously. The two competitive reactions both consist of two steps: (1) two reactants firstly form a three-membered ring intermediate (INT1) and a twisted four-membered ring intermediate (INT2), respectively, both of which are barrier-free exothermic reactions of 44.5 and 63.0 kJ/mol; (2) then INT1 and INT2 further isomerize to a four-membered ring product (P1) and a chlorine-transfer product (P2) via transitions (TS1 and TS2), respectively, with the barriers of 9.3 and 1.0 kJ/mol; simultaneously, P1 and INT2 react further with acetaldehyde(R2) to give two side products (INT3 and INT4), respectively, which are also barrier-free exothermic reaction of 65.4 and 102.7 kJ/mol.

  18. ARTICLES: Theoretical Study on Mechanism of Cycloadditional Reaction Between Dichloro-Germylidene and Formaldehyde

    NASA Astrophysics Data System (ADS)

    Lu, Xiu-hui; Li, Yong-qing; Xu, Yue-hua; Han, Jun-feng; Shi, Le-yi


    Mechanism of the cycloadditional reaction between singlet dichloro-germylidene and formaldehyde has been investigated with MP2/6-31G* method, including geometry optimization, vibrational analysis and energies for the involved stationary points on the potential energy surface. Prom the potential energy profile, we predict that the cycloaddition reaction between singlet dichloro-germylidene and formaldehyde has two competitive dominant reaction pathways, going with the formation of two side products (INT3 and INT4), simultaneously. Both of the two competitive reactions consist of two steps, two reactants firstly form a three-membered ring intermediate INT1 and a twisted four-membered ring intermediate INT2, respectively, both of which are barrier-free exothermic reactions of 41.5 and 72.3 kJ/mol; then INT1 isomerizes to a four-membered ring product P1 via transition state TS1, and INT2 isomerizes to a chlorine-transfer product P2 via transition state TS2, with the barriers of 2.9 and 0.3 kJ/mol, respectively. Simultaneously, P1 and INT2 further react with formaldehyde to form INT3 and INT4, respectively, which are also barrier-free exothermic reaction of 74.9 and 88.1 kJ/mol.

  19. Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.


    Lozama, Anthony; Cunningham, Christopher W; Caspers, Michael J; Douglas, Justin T; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E


    As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.

  20. Photosensitized [2 + 2] cycloaddition of N-acetylated cytosine affords stereoselective formation of cyclobutane pyrimidine dimer

    PubMed Central

    Yamamoto, Junpei; Nishiguchi, Kosuke; Manabe, Koichiro; Masutani, Chikahide; Hanaoka, Fumio; Iwai, Shigenori


    Photocycloaddition between two adjacent bases in DNA produces a cyclobutane pyrimidine dimer (CPD), which is one of the major UV-induced DNA lesions, with either the cis-syn or trans-syn structure. In this study, we investigated the photosensitized intramolecular cycloaddition of partially-protected thymidylyl-(3′→5′)-N4-acetyl-2′-deoxy-5-methylcytidine, to clarify the effect of the base modification on the cycloaddition reaction. The reaction resulted in the stereoselective formation of the trans-syn CPD, followed by hydrolysis of the acetylamino group. The same result was obtained for the photocycloaddition of thymidylyl-(3′→5′)-N4-acetyl-2′-deoxycytidine, whereas both the cis-syn and trans-syn CPDs were formed from thymidylyl-(3′→5′)-thymidine. Kinetic analyses revealed that the activation energy of the acid-catalyzed hydrolysis is comparable to that reported for the thymine-cytosine CPD. These findings provided a new strategy for the synthesis of oligonucleotides containing the trans-syn CPD. Using the synthesized oligonucleotide, translesion synthesis by human DNA polymerase η was analyzed. PMID:20880992

  1. Cycloadditions on diamond (100) 2 x 1: observation of lowered electron affinity due to hydrocarbon adsorption.


    Ouyang, Ti; Gao, Xingyu; Qi, Dongchen; Wee, Andrew Thye Shen; Loh, Kian Ping


    The adsorption of allyl alcohol, acrylic acid, and allyl chloride, as well as unsaturated organic molecules such as acetylene and 1,3 butadiene, on reconstructed diamond (100) 2 x 1 have been investigated using high-resolution electron energy loss (HREELS) spectroscopy and synchrotron radiation spectroscopy. The cycloadditions of these organic molecules produce chemically adsorbed adlayers with varying degree of coverages on the clean diamond. The organic adsorbed surface has a lowered electron affinity and shows a secondary electron yield that varies between 12 and 40% of the yield obtained from a fully hydrogenated diamond surface. The diamond surface can be functionalized with hydroxyl, carboxylic, and chlorine functionalities by the adsorption of these allyl organics. The [2 + 2] adduct of acetylene on the diamond (100) 2 x 1 surface can be observed. 1,3-butadiene attains a higher coverage as well as forms a thermally more stable adlayer on the diamond surface compared to the other organic molecules, due to its ability to undergo [4 + 2] cycloaddition.

  2. Acceleration of Enantioselective Cycloadditions Catalyzed by Second-Generation Chiral Oxazaborolidinium Triflimidates by Biscoordinating Lewis Acids.


    Thirupathi, Barla; Breitler, Simon; Mahender Reddy, Karla; Corey, E J


    The activation of second-generation fluorinated oxazaborolidines by the strong acid triflimide (Tf2NH) in CH2Cl2 solution leads to highly active chiral Lewis acids that are very effective catalysts for (4 + 2) cycloaddition. We report herein that this catalytic activity can be further enhanced by the use of Tf2NH in combination with the biscoordinating Lewis acid TiCl4 or SnCl4 as a coactivator. The effective increase in acidity of an exceedingly strong protic acid is greater for biscoordinating TiCl4 and SnCl4 than for monocoordinating salts, even the strong Lewis acids AlBr3 and BBr3 in CH2Cl2 or CH2Cl2/toluene. The increase in the effective acidity of Tf2NH can be understood in terms of a stabilized cyclic anionic complex of Tf2N(-) and TiCl4, which implies a broader utility than that described here. The utility of Tf2NH-TiCl4 activation of fluorinated oxazaborolidines is documented by examples including the first enantioselective (4 + 2) cycloaddition to α,β-unsaturated acid chlorides.

  3. Light-induced hetero-Diels-Alder cycloaddition: a facile and selective photoclick reaction.


    Arumugam, Selvanathan; Popik, Vladimir V


    2-Napthoquinone-3-methides (oNQMs) generated by efficient photodehydration (Φ=0.2) of 3-(hydroxymethyl)-2-naphthol undergo facile hetero-Diels-Alder addition (k(D-A)∼ 4×10(4) M(-1) s(-1)) to electron-rich polarized olefins in an aqueous solution. The resulting photostable benzo[g]chromans are produced in high to quantitative yield. The unreacted oNQM is rapidly hydrated (k(H2O) ∼145 s(-1)) to regenerate the starting diol. This competition between hydration and cycloaddition makes oNQMs highly selective, since only vinyl ethers and enamines are reactive enough to form the Diels-Alder adduct in an aqueous solution; no cycloaddition was observed with other types of alkenes. To achieve photolabeling or photoligation of two substrates, one is derivatized with a vinyl ether moiety, while 3-(hydroxymethyl)-2-naphthol is attached to the other via an appropriate linker. The light-induced Diels-Alder "click" strategy permits the formation of either a permanent or hydrolytically labile linkage. Rapid kinetics of this photoclick reaction (k=4×10(4) M(-1) s(-1)) is useful for time-resolved applications. The short lifetime (τ ∼7 ms in H(2)O) of the active form of the photoclick reagent prevents its migration from the site of irradiation, thus, allowing for spatial control of the ligation or labeling.

  4. Z-selective, catalytic internal alkyne semihydrogenation under H2/CO mixtures by a niobium(III) imido complex.


    Gianetti, Thomas L; Tomson, Neil C; Arnold, John; Bergman, Robert G


    The discovery of a Nb(III)-mediated catalytic hydrogenation of internal alkynes to (Z)-alkenes that proceeds through an unprecedented mechanism is reported. The mechanistic proposal involves initial reduction of the alkyne by the Nb(III) complex (BDI)Nb(N(t)Bu)(CO)(2) to provide a Nb(V) metallacyclopropene, itself capable of σ-bond metathesis reactivity with H(2). The resulting alkenyl hydride species then undergoes reductive elimination to provide the (Z)-alkene product and regenerate a metal complex in the Nb(III) oxidation state. Support for the proposed mechanism is derived from (i) the dependence of the product selectivity on the relative concentrations of CO and H(2), (ii) the isolation of complexes closely related to those proposed to be part of the catalytic cycle, (iii) H/D crossover experiments, and (iv) DFT studies of multiple possible reaction pathways.

  5. Boron-mediated sequential alkyne insertion and C-C coupling reactions affording extended π-conjugated molecules

    NASA Astrophysics Data System (ADS)

    Shoji, Yoshiaki; Tanaka, Naoki; Muranaka, Sho; Shigeno, Naoki; Sugiyama, Haruka; Takenouchi, Kumiko; Hajjaj, Fatin; Fukushima, Takanori


    C-C bond coupling reactions illustrate the wealth of organic transformations, which are usually mediated by organotransition metal complexes. Here, we show that a borafluorene with a B-Cl moiety can mediate sequential alkyne insertion (1,2-carboboration) and deborylation/Csp2-Csp2 coupling reactions, leading to aromatic molecules. The first step, which affords a borepin derivative, proceeds very efficiently between the borafluorene and various alkynes by simply mixing these two components. The second step is triggered by a one-electron oxidation of the borepin derivative, which results in the formation of a phenanthrene framework. When an excess amount of oxidant is used in the second step, the phenanthrene derivatives can be further transformed in situ to afford dibenzo[g,p]chrysene derivatives. The results presented herein will substantially expand the understanding of main group chemistry and provide a powerful synthetic tool for the construction of a wide variety of extended π-conjugated systems.

  6. Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

    PubMed Central

    Cromm, Philipp M.; Schaubach, Sebastian; Spiegel, Jochen; Fürstner, Alois; Grossmann, Tom N.; Waldmann, Herbert


    Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets. PMID:27075966

  7. Rhodium/Silver Synergistic Catalysis in Highly Enantioselective Cycloisomerization/Cross Coupling of Keto-Vinylidenecyclopropanes with Terminal Alkynes.


    Yang, Song; Rui, Kang-Hua; Tang, Xiang-Ying; Xu, Qin; Shi, Min


    A rhodium/silver synergistic catalysis has been established, enabling cycloisomerization/cross coupling of keto-vinylidenecyclopropanes with terminal alkynes toward the regio- and enantioselective formation of diversified tetrahydropyridin-3-ol tethered 1,4-enynes in good yields and high ee values. In this synergistic catalysis, Rh(I) and Ag(I) catalysts selectively activate keto-VDCP substrates and terminal alkynes to generate -allyl Rh(III) complex of oxa-rhodacyclic intermediate and Ag alkynyl intermediate, respectively. The rapid transmetalation of alkynyl groups from Ag to Rh is proposed to play a key role to realize the regioselective cleavage of distal bond of the three-membered ring in this transformation.

  8. Discovery of highly selective alkyne semihydrogenation catalysts based on first-row transition-metallated porous organic polymers.


    Tanabe, Kristine K; Ferrandon, Magali S; Siladke, Nathan A; Kraft, Steven J; Zhang, Guanghui; Niklas, Jens; Poluektov, Oleg G; Lopykinski, Susan J; Bunel, Emilio E; Krause, Theodore R; Miller, Jeffrey T; Hock, Adam S; Nguyen, SonBinh T


    Five different first-row transition metal precursors (V(III), Cr(III), Mn(II), Co(II), Ni(II)) were successfully incorporated into a catechol porous organic polymer (POP) and characterized using ATR-IR and XAS analysis. The resulting metallated POPs were then evaluated for catalytic alkyne hydrogenation using high-throughput screening techniques. All POPs were unexpectedly found to be active and selective catalysts for alkyne semihydrogenation. Three of the metallated POPs (V, Cr, Mn) are the first of their kind to be active single-site hydrogenation catalysts. These results highlight the advantages of using a POP platform to develop new catalysts which are otherwise difficult to achieve through traditional heterogeneous and homogeneous routes.

  9. Fluorocarbon compatibilized gold-silica nanocomposites for recyclable regioselective hydroamination of alkynes in a fluorous biphasic system

    NASA Astrophysics Data System (ADS)

    Merican, Zulkifli; Vu, Bao Khanh; Solovyeva, Vera A.; Rodionov, Valentin O.; Khe, Cheng Seong; Rajalingam, Sokkalingam; Vasant, Pandian


    The synthesis and characterization of the mesoporous silica-supported gold (Au@mSiO2) nanoparticles compatibilized with the outer shelled superhydrophobic fluorous (F) "tails" was described. The concept of fluorous biphasic separation was applied in the recycling of the synthesized fluorous material during hydroamination reactions of various alkynes. In the presence of perfluoromethylcyclohexane and heptane as a biphasic liquid system, the F-Au@mSiO2 was found to be a highly active catalyst for hydroamination of various alkynes with anilines, and a near quantitative yield for an imine product and produced a relatively minimal formation of a corresponding hydrolyzed ketone by-product. If perfluoromethylcyclohexane and heptane was used as a biphasic solvent, hydroamination at a lower reaction temperature can also be realized leading to an improved recyclability and conversion.

  10. Ultrasonically improved semi-hydrogenation of alkynes to (Z-)alkenes over novel lead-free Pd/Boehmite catalysts.


    Wu, Zhilin; Cravotto, Giancarlo; Gaudino, Emanuela Calcio; Giacomino, Agnese; Medlock, Jonathan; Bonrath, Werner


    This paper reports the application of ultrasound in the semi-hydrogenation of alkynes over two novel Pd/Boehmite catalysts. The semi-hydrogenations of phenylacetylene, diphenylacetylene and 2-butyne-1,4-diol have either been investigated in an ultrasonic bath under atmospheric hydrogen pressure, or in an ultrasonic horn reactor under 0.1-0.5MPa hydrogen pressure. Alkyne hydrogenation was suppressed by sonication under atmospheric hydrogen pressure, but promoted by sonication under 0.1MPa of hydrogen pressure. Sonication increased selectivity towards the semi-hydrogenated products in both cases. Catalyst loading, hydrogen pressure, temperature and the presence of quinoline, all impacted on hydrogenation rate, activity and selectivity to semi-hydrogenated products. Palladium leaching from the catalyst was evaluated in ethanol and hexane both under plain stirring and sonication.

  11. Magnetic Fe@g??C3N4: A Photoactive Catalyst for the Hydrogenation of Alkenes and Alkynes

    EPA Pesticide Factsheets

    A photoactive catalyst, Fe@g-C3N4, has been developed for the hydrogenation of alkenes and alkynes using hydrazine hydrate as a source of hydrogen. The magnetically separable Fe@g-C3N4 eliminates the use of high pressure hydrogenation, and the reaction can be accomplished using visible light without the need for external sources of energy.This dataset is associated with the following publication:Baig, N., S. Verma, R. Varma , and M. Nadagouda. Magnetic Fe@g-C3N4: A Photoactive Catalyst for the Hydrogenation of Alkenes and Alkynes. ACS Sustainable Chemistry & Engineering. American Chemical Society, Washington, DC, USA, 4(3): 1661-1664, (2016).

  12. Benzimidazole-1,2,3-triazole hybrid molecules: synthesis and evaluation for antibacterial/antifungal activity.


    Ouahrouch, Abdelaaziz; Ighachane, Hana; Taourirte, Moha; Engels, Joachim W; Sedra, My Hassan; Lazrek, Hassan B


    A novel series of hybrid molecules 4a-i and 5a-i were prepared by condensation of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne-azide cycloaddition (CuAAC) to generate the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and the phytopathogenic fungi Verticillium dahliae and Fusarium oxysporum f. sp. albedinis. 2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)methoxy)ethanol 5e showed a moderate inhibition of 30% in the Foa sporulation test.

  13. “Janus” Calixarenes: Double-Sided Molecular Linkers for Facile, Multianchor Point, Multifunctional, Surface Modification

    PubMed Central


    We herein report the synthesis of novel “Janus” calix[4]arenes bearing four “molecular tethering” functional groups on either the upper or lower rims of the calixarene. These enable facile multipoint covalent attachment to electrode surfaces with monolayer coverage. The other rim of the calixarenes bear either four azide or four ethynyl functional groups, which are easily modified by the copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC), either pre- or postsurface modification, enabling these conical, nanocavity reactor sites to be decorated with a wide range of substrates to impart desired chemical properties. Redox active species decorating the peripheral rim are shown to be electrically connected by the calixarene to the electrode surface in either “up” or “down” orientations of the calixarene. PMID:27419844

  14. Synthesis of 1,2,3-triazole derivatives and in vitro antifungal evaluation on Candida strains.


    Lima-Neto, Reginaldo G; Cavalcante, Nery N M; Srivastava, Rajendra M; Mendonça Junior, Francisco J B; Wanderley, Almir G; Neves, Rejane P; dos Anjos, Janaína V


    1,2,3-Triazoles have been extensively studied as compounds possessing important biological activities. In this work, we describe the synthesis of ten 2-(1-aryl-1H-1,2,3-triazol-4-yl)propan-2-ols via copper catalyzed azide alkyne cycloaddition (CuAAc or click chemistry). Next the in vitro antifungal activity of these ten compounds was evaluated using the microdilution broth method against 42 isolates of four different Candida species. Among all tested compounds, the halogen substituted triazole 2-[1-(4-chlorophenyl)-1H-(1,2,3)triazol-4-yl]propan-2-ol, revealed the best antifungal profile, showing that further modifications could be done in the structure to obtain a better drug candidate in the future.

  15. Soluble organic nanotubes for catalytic systems.


    Xiong, Linfeng; Yang, Kunran; Zhang, Hui; Liao, Xiaojuan; Huang, Kun


    In this paper, we report a novel method for constructing a soluble organic nanotube supported catalyst system based on single-molecule templating of core–shell bottlebrush copolymers. Various organic or metal catalysts, such as sodium prop-2-yne-1-sulfonate (SPS), 1-(2-(prop-2-yn-1-yloxy)ethyl)-1H-imidazole (PEI) and Pd(OAc)2 were anchored onto the tube walls to functionalize the organic nanotubes via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Depending on the 'confined effect' and the accessible cavity microenvironments of tubular structures, the organic nanotube catalysts showed high catalytic efficiency and site-isolation features. We believe that the soluble organic nanotubes will be very useful for the development of high performance catalyst systems due to their high stability of support, facile functionalization and attractive textural properties.

  16. Soluble organic nanotubes for catalytic systems

    NASA Astrophysics Data System (ADS)

    Xiong, Linfeng; Yang, Kunran; Zhang, Hui; Liao, Xiaojuan; Huang, Kun


    In this paper, we report a novel method for constructing a soluble organic nanotube supported catalyst system based on single-molecule templating of core-shell bottlebrush copolymers. Various organic or metal catalysts, such as sodium prop-2-yne-1-sulfonate (SPS), 1-(2-(prop-2-yn-1-yloxy)ethyl)-1H-imidazole (PEI) and Pd(OAc)2 were anchored onto the tube walls to functionalize the organic nanotubes via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Depending on the ‘confined effect’ and the accessible cavity microenvironments of tubular structures, the organic nanotube catalysts showed high catalytic efficiency and site-isolation features. We believe that the soluble organic nanotubes will be very useful for the development of high performance catalyst systems due to their high stability of support, facile functionalization and attractive textural properties.

  17. CuAAC-based assembly and characterization of a ruthenium-copper dyad containing a diimine-dioxime ligand framework.


    Queyriaux, Nicolas; Andreiadis, Eugen S; Torelli, Stéphane; Pecaut, Jacques; Veldkamp, Brad S; Margulies, Eric A; Wasielewski, Michael R; Chavarot-Kerlidou, Murielle; Artero, Vincent


    The design of molecular dyads combining a light-harvesting unit with an electroactive centre is highly demanded in the field of artificial photosynthesis. The versatile Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC) procedure was employed to assemble a ruthenium tris-diimine unit to an unprecedented azide-substituted copper diimine-dioxime moiety. The resulting Ru(II)Cu(II) dyad 4 was characterized by electrochemistry, (1)H NMR, EPR, UV-visible absorption, steady-state fluorescence and transient absorption spectroscopies. Photoinduced electron transfer from the ruthenium to the copper centre upon light-activation in the presence of a sacrificial electron donor was established thanks to EPR-monitored photolysis experiments, opening interesting perspectives for photocatalytic applications.

  18. Synthesis and Spectroscopic Evaluation of Two Novel Glycosylated Zinc(II)-Phthalocyanines.


    Bächle, Felix; Hanack, Michael; Ziegler, Thomas


    In continuation of our work on glycoconjugated phthalocyanines, two new water soluble, non-ionic zinc(II) phthalocyanines have been prepared and fully characterized by means of ¹H-NMR, 13C-NMR, MALDI-TOF, ESI-TOF, UV-Vis spectroscopy, emission spectroscopy and fluorescence lifetime measurements. The carbohydrate-containing phthalonitrile precursors were synthesized through a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The 2-methoxyethoxymethyl protecting group (MEM) was used to protect the carbohydrate moieties. It resisted the harsh basic cyclotetramerization conditions and could be easily cleaved under mild acidic conditions. The glycoconjugated zinc(II) phthalocyanines described here have molar extinction coefficents εmax>10⁵ m(-1) cm(-1) and absorption maxima λ>680 nm, which make them attractive photosensitizers for photo-dynamic therapy.

  19. Poly(ethylene glycol) grafted polylactide based copolymers for the preparation of PLA-based nanocarriers and hybrid hydrogels.


    Riva, Raphaël; Schmeits, Stéphanie; Croisier, Florence; Lecomte, Philippe; Jérôme, Christine


    In previous works, poly(D,L-lactide-co-ɛCL-poly(ethylene glycol) (poly(D,L-La-co-αPEGɛCL) amphiphilic graft-copolymers were successfully synthesized according to a copper azide-alkyne cycloaddition (CuAAC) strategy. This paper aims at reporting on the behavior of this amphiphilic copolymer in water, which was not studied in the previous paper. Moreover, the ability of the copolymer to stabilize a PLA nanoparticles aqueous suspension is presented. For this purpose, dynamic light scattering (DLS) and transmission electron microscopy (TEM) are proposed to characterize the nanoparticles in solution. Otherwise, the strategy developed for the synthesis of the amphiphilic copolymers was adapted and extended to the synthesis of PLA-based degradable hydrogel, potentially applicable as drug-loaded degradable polymer implant.

  20. Design, Synthesis, and Antiviral Activity of Novel Ribonucleosides of 1,2,3‐Triazolylbenzyl‐aminophosphonates

    PubMed Central

    Ouahrouch, Abdelaaziz; Taourirte, Moha; Schols, Dominique; Snoeck, Robert; Andrei, Graciela; Lazrek, Hassan B.


    A novel series of ribonucleosides of 1,2,3‐triazolylbenzyl‐aminophosphonates was synthesized through the Kabachnik–Fields reaction using I2 as catalyst followed by copper‐catalyzed cycloaddition of the azide–alkyne reaction (CuAAC). All structures of the newly prepared compounds were characterized by 1H NMR, 13C NMR, and HRMS spectra. The structures of 2e, 2f, 3d, and 3g were further confirmed by X‐ray diffraction analysis. These compounds were tested against various strains of DNA and RNA viruses; compounds 4b and 4c showed a modest inhibitory activity against respiratory syncytial virus (RSV) and compound 4h displayed modest inhibitory activity against Coxsackie virus B4. PMID:26575425

  1. Determination of flumioxazin residue in food samples through a sensitive fluorescent sensor based on click chemistry.


    Lu, Lijun; Yang, Linlin; Cai, Huijian; Zhang, Lan; Lin, Zhenyu; Guo, Longhua; Qiu, Bin; Chen, Guonan


    A sensitive and selective fluorescent sensor for flumioxazin was designed based on the formation of strong fluorescence compound (1,2,3-triazole compounds) via the reaction of the alkynyl group in flumioxazin with 3-azido-7-hydroxycoumarin, a weak-fluorescent compound, through the Cu(+)-catalysed azide-alkyne cycloaddition (CuAAC) reaction. The fluorescence increase factor (represented by F/F0) of the system exhibited a good linear relationship with the concentrations of flumioxazin in the range of 0.25-6.0 μg/L with a detection limit of 0.18 μg/L (S/N=3). Also, the proposed fluorescent sensor demonstrated good selectivity for flumioxazin assay even in the presence of high concentration of other pesticides. Based on such high sensitivity and selectivity, the proposed fluorescent sensor has been applied to test the flumioxazin residue in some vegetable and water samples with satisfied results.

  2. Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel-Crafts alkylations.


    Pecchioli, Tommaso; Muthyala, Manoj Kumar; Haag, Rainer; Christmann, Mathias


    The first immobilization of a MacMillan's first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a-c was tested in the asymmetric Friedel-Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.

  3. Rapid and efficient synthesis of α(1-2)mannobiosides.


    Reina, José J; Di Maio, Antonio; Ramos-Soriano, Javier; Figueiredo, Rute C; Rojo, Javier


    α(1,2)mannobiosides with different substituents at the reducing end have been synthesized by a common strategy using benzoyls as the permanent protecting groups and an acetyl as the orthogonal protecting group at position C2 of the glycosyl acceptor. The new synthetic strategy has been performed remarkably reducing the number of purification steps, the time of synthesis (less than 72 hours) and improving the overall yield at least three times with respect to the best procedure described in the literature at the moment. Additionally, this protecting group strategy is compatible with the presence of azido groups and the use of Cu catalyzed azide alkyne cycloaddition (CuAAC) also called "click chemistry" for conjugating the α(1-2)mannobiosides to different scaffolds for the preparation of mannosyl multivalent systems.

  4. Myristoylation profiling in human cells and zebrafish

    PubMed Central

    Broncel, Malgorzata; Serwa, Remigiusz A; Ciepla, Paulina; Krause, Eberhard; Dallman, Margaret J.; Magee, Anthony I.; Tate, Edward W.


    Human cells (HEK 293, HeLa, MCF-7) and zebrafish embryos were metabolically tagged with an alkynyl myristic acid probe, lysed with an SDS buffer and tagged proteomes ligated to multifunctional capture reagents via copper-catalyzed alkyne azide cycloaddition (CuAAC). This allowed for affinity enrichment and high-confidence identification, by delivering direct MS/MS evidence for the modification site, of 87 and 61 co-translationally myristoylated proteins in human cells and zebrafish, respectively. The data have been deposited to ProteomeXchange Consortium (Vizcaíno et al., 2014 Nat. Biotechnol., 32, 223–6) (PXD001863 and PXD001876) and are described in detail in Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic protein lipidation during vertebrate development׳ by Broncel et al., Angew. Chem. Int. Ed. PMID:26217820

  5. Activation-strain analysis reveals unexpected origin of fast reactivity in heteroaromatic azadiene inverse-electron-demand diels-alder cycloadditions.


    Talbot, Austin; Devarajan, Deepa; Gustafson, Samantha J; Fernández, Israel; Bickelhaupt, F Matthias; Ess, Daniel H


    Heteroaromatic azadienes, especially 1,2,4,5-tetrazines, are extremely reactive partners with alkenes in inverse-electron-demand Diels-Alder reactions. Azadiene cycloaddition reactions are used to construct heterocycles in synthesis and are popular as bioorthogonal reactions. The origin of fast azadiene cycloaddition reactivity is classically attributed to the inverse frontier molecular orbital (FMO) interaction between the azadiene LUMO and alkene HOMO. Here, we use a combination of ab initio, density functional theory, and activation-strain model calculations to analyze physical interactions in heteroaromatic azadiene-alkene cycloaddition transition states. We find that FMO interactions do not control reactivity because, while the inverse FMO interaction becomes more stabilizing, there is a decrease in the forward FMO interaction that is offsetting. Rather, fast cycloadditions are due to a decrease in closed-shell Pauli repulsion between cycloaddition partners. The kinetic-thermodynamic relationship found for these inverse-electron-demand cycloadditions is also due to the trend in closed-shell repulsion in the cycloadducts. Cycloaddition regioselectivity, however, is the result of differences in occupied-unoccupied orbital interactions due to orbital overlap. These results provide a new predictive model and correct physical basis for heteroaromatic azadiene reactivity and regioselectivity with alkene dieneophiles.

  6. Synthesis of Stable Interfaces on SnO2 Surfaces for Charge-Transfer Applications

    NASA Astrophysics Data System (ADS)

    Benson, Michelle C.

    The commercial market for solar harvesting devices as an alternative energy source requires them to be both low-cost and efficient to replace or reduce the dependence on fossil fuel burning. Over the last few decades there has been promising efforts towards improving solar devices by using abundant and non-toxic metal oxide nanomaterials. One particular metal oxide of interest has been SnO2 due to its high electron mobility, wide-band gap, and aqueous stability. However SnO2 based solar cells have yet to reach efficiency values of other metal oxides, like TiO2. The advancement of SnO2 based devices is dependent on many factors, including improved methods of surface functionalization that can yield stable interfaces. This work explores the use of a versatile functionalization method through the use of the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The CuAAC reaction is capable of producing electrochemically, photochemically, and electrocatalytically active surfaces on a variety of SnO2 materials. The resulting charge-transfer characteristics were investigated as well as an emphasis on understanding the stability of the resulting molecular linkage. We determined the CuAAC reaction is able to proceed through both azide-modified and alkyne-modified surfaces. The resulting charge-transfer properties showed that the molecular tether was capable of supporting charge separation at the interface. We also investigated the enhancement of electron injection upon the introduction of an ultra-thin ZrO2 coating on SnO2. Several complexes were used to fully understand the charge-transfer capabilities, including model systems of ferrocene and a ruthenium coordination complex, a ruthenium mononuclear water oxidation catalyst, and a commercial ruthenium based dye.

  7. Microwave-Enhanced Organic Syntheses for the Undergraduate Laboratory: Diels-Alder Cycloaddition, Wittig Reaction, and Williamson Ether Synthesis

    ERIC Educational Resources Information Center

    Baar, Marsha R.; Falcone, Danielle; Gordon, Christopher


    Microwave heating enhanced the rate of three reactions typically performed in our undergraduate organic chemistry laboratory: a Diels-Alder cycloaddition, a Wittig salt formation, and a Williamson ether synthesis. Ninety-minute refluxes were shortened to 10 min using a laboratory-grade microwave oven. In addition, yields improved for the Wittig…

  8. A synthesis of functionalized dihydro-1H-pyrrolizines and spiropyrrolizines via [Formula: see text] cycloaddition reactions.


    Yavari, Issa; Baoosi, Leila; Halvagar, Mohammad R


    A one-pot synthesis of dihydro-1H-pyrrolizine derivatives via [Formula: see text] cycloaddition reaction of azomethine ylides, prepared in situ from proline and ninhydrin, with dialkyl acetylenedicarboxylates, in alcohols, is described. When sarcosine was used instead of proline, functionalized spiropyrrolizines were obtained. Under these conditions, alkyl propiolates produced stable spirans.

  9. Reversal of the Regiochemistry in the Rhodium-Catalyzed [4+3] Cycloaddition Between Vinyldiazoacetates and Dienes

    PubMed Central

    Guzmán, Pablo E.; Lian, Yajing


    A regio-, diastereo- and enantioselective [4+3] cycloaddition between vinylcarbenes and dienes has been achieved using the dirhodium tetracarboxylate catalyst Rh2(S-BTPCP)4. This methodology provides facile access to 1,4-cycloheptadienes that are regioisomers of those formed from the tandem cyclopropanation/Cope rearrangement reaction of vinylcarbenes with dienes. PMID:25266984

  10. Highly Enantioselective Dearomatizing Formal [3+3]-Cycloaddition Reactions of N-Acyliminopyridinium Ylides with Electrophilic Enolcarbene Intermediates

    PubMed Central

    Xu, Xinfang; Zavalij, Peter Y.; Doyle, Michael P.


    A effective dearomatizing formal [3+3]-cycloaddition reaction triggered by Rh(II)-catalyzed dinitrogen extrusion of enoldiazoacetates followed by vinylogous addition of metal enolcarbenes to N-acyliminopyridinium ylides that produces highly substituted 1,2,3,6-tetrahydropyridazines in up to 98% ee and in high yield has been developed. PMID:24123489

  11. Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

    PubMed Central

    Carra, Ryan J.; Epperson, Matthew T.; Gin, David Y.


    An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully-oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in eleven steps from a commercially available starting material. PMID:18443655

  12. Rapid construction of the aza-propellane core of acutumine via a photochemical [2 + 2] cycloaddition reaction.


    Navarro, Raul; Reisman, Sarah E


    Synthetic efforts toward the chlorinated aza-propellane alkaloid acutumine (1) are described. The key vicinal quaternary centers were constructed by a photochemical [2 + 2] cycloaddition reaction of a furanyl-tetrahydroindolone. Dihydroxylation of the [2 + 2] product enabled a tandem retro-aldol/intramolecular ketalization reaction, which revealed the aza-propellane core of 1 while generating an unusual, caged, pentacyclic hemiketal product.

  13. Photochemical Dimerization of Dibenzylideneacetone: A Convenient Exercise in [2+2] Cycloaddition Using Chemical Ionization Mass Spectrometry

    ERIC Educational Resources Information Center

    Rao, G. Nageswara; Janardhana, Chelli; Ramanathan, V.; Rajesh, T.; Kumar, P. Harish


    Chemical reactions induced by light have been utilized for synthesizing highly strained, thermodynamically unstable compounds, which are inaccessible through non-photochemical methods. Photochemical cycloaddition reactions, especially those leading to the formation of four-membered rings, constitute a convenient route to compounds that are…

  14. Synthesis of 2-aminoindolizines by 1,3-dipolar cycloaddition of pyridinium ylides with electron-deficient ynamides.


    Brioche, Julien; Meyer, Christophe; Cossy, Janine


    Electron-deficient ynamides, possessing an ynoate or an ynone moiety, have been successfully involved for the first time in a 1,3-dipolar cycloaddition with stabilized pyridinium ylides. These reactions afford an efficient and general access toward a variety of substituted 2-aminoindolizines which can serve as useful precursors for the synthesis of other more complex nitrogen heterocycles.

  15. Facile Synthesis of Stapled, Structurally Reinforced Peptide Helices via A Photoinduced Intramolecular 1,3-Dipolar Cycloaddition Reaction†

    PubMed Central

    Madden, Michael M.; Vera, Claudia I. Rivera; Song, Wenjiao; Lin, Qing


    We report the first use of a photoinduced 1,3-dipolar cycloaddition reaction in “stapling” peptide side chains to reinforce a model peptide helical structure with moderate to excellent yields. The resulting pyrazoline “staplers” exhibit unique fluorescence useful in a cell permeability study. PMID:19753366

  16. Synthesis of phosphabenzenes by an iron-catalyzed [2+2+2] cycloaddition reaction of diynes with phosphaalkynes.


    Nakajima, Kazunari; Takata, Shohei; Sakata, Ken; Nishibayashi, Yoshiaki


    A method for the synthesis of phosphabenzenes under iron catalysis is described. Thus, the FeI2 -catalyzed [2+2+2] cycloaddition of diynes with phosphaalkynes in m-xylene gave a variety of phosphabenzenes in good to high yields (up to 87 % yield).

  17. Synthesis of novel tryptamine-based macrocycles using an Ugi 4-CR/microwave assisted click-cycloaddition reaction protocol.


    Chavez-Acevedo, Lizbeth; Miranda, Luis D


    A practical synthesis of novel tryptamine-based macrocycles using an Ugi 4-CR/click-cycloaddition sequential reaction protocol is described. The main features of the macrocyclic scaffolds are a peptoid moiety, a 1,3-substituted indole nucleus, and a triazole ring.

  18. Donor-Stabilized Silacyclobutanone: A Precursor of 1-Silaketene via Retro-[2 + 2]-Cycloaddition Reaction at Room Temperature.


    Troadec, Thibault; Lopez Reyes, Morelia; Rodriguez, Ricardo; Baceiredo, Antoine; Saffon-Merceron, Nathalie; Branchadell, Vicenç; Kato, Tsuyoshi


    The synthesis of donor-stabilized silacyclobutanone 2 was successfully realized by the reaction of silacyclopropylidene 1 with benzaldehyde in the presence of a Lewis acid catalyst. Of particular interest, silacyclobutanone 2 evolves at room temperature via a retro-[2 + 2]-cycloaddition reaction, leading to an original NHC-stabilized 1-silaketene 4 and cis-stilbene.

  19. Uncovering the Role of Metal Catalysis in Tetrazole Formation by an In Situ Cycloaddition Reaction: An Experimental Approach.


    Zhong, Di-Chang; Wen, Ya-Qiong; Deng, Ji-Hua; Luo, Xu-Zhong; Gong, Yun-Nan; Lu, Tong-Bu


    Using an experimental approach, the role of metal catalysis has been investigated in the in situ cycloaddition reaction of nitrile with azide to form tetrazoles. It has been shown that metal catalysis serves to activate the cyano group in the nitrile reagent by a coordinative interaction.

  20. Highly Efficient and Stereoselective Construction of Bispirooxindole Derivatives via a Three-Component 1,3-Dipolar Cycloaddition Reaction.


    Xu, Qin; Wang, De; Wei, Yin; Shi, Min


    A highly regio- and stereoselective synthesis of bispirooxindoles by 1,3-dipolar cycloaddition of in situ generated azomethine ylides from isatin and proline to different electron-deficient alkenes has been developed. The synthesis affords the desired bispiro scaffold compounds in excellent yields with high regioselectivity under mild conditions. The stereochemistry was determined by single-crystal X-ray analysis.