Dendronized linear polymers via "click chemistry"

Dendronized linear polymers are prepared from dendritic azides and poly(vinylacetylene) using "click chemistry." The Cu(I)-catalyzed Huisgen [2 + 3] cycloaddition is quantitative up to the third generation.     

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

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.     

In situ Raman monitoring triazole formation from self-assembled monolayers of 1,4-diethynylbenzene on Ag and Au surfaces via "click" cyclization

We prepared acetylenyl-terminated aromatic self-assembled monolayers (SAMs) of 1,4-diethynylbenzene on silver and gold. After the fabrication of pendent acetylenyl SAMs, the formation of triazoles was performed via Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition "click" chemistry. A density functional theory (DFT) calculation of Raman frequencies showed good agreement with our experimental data to provide evidence of the formation of the triazole molecule. Our results indicated that "click" chemistry could be successfully applied to simple aromatic SAMs proximate (<1 nm) to roughened gold surfaces. The reaction process could be monitored in real time by measuring intensity changes of the nu(CC)(free) band in surface-enhanced Raman scattering (SERS) spectra.     

Different functionalization of the internal and external surfaces in mesoporous materials for biosensing applications using "click" chemistry

We report the use of copper(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) to selectively functionalize the internal and external surfaces of mesoporous materials. Porous silicon rugate filters with narrow line width reflectivity peaks were employed to demonstrate this selective surface functionalization approach. Hydrosilylation of a dialkyne species, 1,8-nonadiyne, was performed to stabilize the freshly fabricated porous silicon rugate filters against oxidation and to allow for further chemical derivatization via "click" CuAAC reactions. The external surface was modified through CuAAC reactions performed in the absence of nitrogen-based Cu(I)-stabilizing species (i.e., ligand-free reactions). To subsequently modify the interior pore surface, stabilization of the Cu(I) catalyst was required. Optical reflectivity measurements, water contact angle measurements, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) were used to demonstrate the ability of the derivatization approach to selectively modify mesoporous materials with different surface chemistry on the exterior and interior surfaces. Furthermore, porous silicon rugate filters modified externally with the cell-adhesive peptide Gly-Arg-Gly-Asp-Ser (GRGDS) allowed for cell adhesion via formation of focal adhesion points. Results presented here demonstrate a general approach to selectively modify mesoporous silicon samples with potential applications for cell-based biosensing.     

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

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.     

Chemistry of the heavy group 15 elements with the pyridyl tethered 1,2-bis(imino)acenaphthene "clamshell" ligand

Cobaltocene has been used as a one-electron reductant in a facile route to generate pnictogen(I) (P, As) synthons. These subsequently undergo a formal 4 + 2 cycloaddition with a pyridyl tethered 1,2-bis(imino)acenaphthene "clamshell" ligand to yield N-heterocyclic chlorophosphines and -arsines, which are precursors to the corresponding N-heterocyclic pnictenium cations. In the absence of a reductant the "clamshell" ligand can be used in forming hypervalent donor-acceptor complexes with heavy main group elements (Sn, Sb and Bi).     

"Clickphine": a novel and highly versatile P,N ligand class via click chemistry

[Structure: see text] A novel P,N-type ligand family (ClickPhine) is disclosed that is easily accessible using the Cu(I)-catalyzed azide-alkyne "click" cycloaddition. A diverse set of ligands was made in just three steps from readily available starting materials to give several homogeneous and a heterogeneous catalyst. Preliminary experiments show the efficacy of these ligands in the Pd-catalyzed allylic alkylation reaction.     

Rhodium-catalyzed intra- and intermolecular [5 + 2] cycloaddition of 3-acyloxy-1,4-enyne and alkyne with concomitant 1,2-acyloxy migration

A new type of rhodium-catalyzed [5 + 2] cycloaddition was developed for the synthesis of seven-membered rings with diverse functionalities. The ring formation was accompanied by a 1,2-acyloxy migration event. The five- and two-carbon components of the cycloaddition are 3-acyloxy-1,4-enynes (ACEs) and alkynes, respectively. Cationic rhodium(I) catalysts worked most efficiently for the intramolecular cycloaddition, while only neutral rhodium(I) complexes could facilitate the intermolecular reaction. In both cases, electron-poor phosphite or phosphine ligands often improved the efficiency of the cycloadditions. The scope of ACEs and alkynes was investigated in both the intra- and intermolecular reactions. The resulting seven-membered-ring products have three double bonds that could be selectively functionalized.     

Access to functionalised silver(I) and gold(I) N-heterocyclic carbenes by [2 + 3] dipolar cycloadditions

A new strategy was developed for the modification of silver(I) and gold(I) N-heterocyclic carbenes. Azido groups were grafted and used either by copper-catalysed azide-alkyne cycloaddition before metallation or by thermal and "strain-promoted" 1,3-dipolar cycloaddition after metallation to functionalise the metal-NHCs.     

Polymer brushes grafted to "passivated" silicon substrates using click chemistry

We present herein a versatile method for grafting polymer brushes to passivated silicon surfaces based on the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click chemistry) of omega-azido polymers and alkynyl-functionalized silicon substrates. First, the "passivation" of the silicon substrates toward polymer adsorption was performed by the deposition of an alkyne functionalized self-assembled monolayer (SAM). Then, three tailor-made omega-azido linear brush precursors, i.e., PEG-N3, PMMA-N3, and PS-N3 (Mn approximately 20,000 g/mol), were grafted to alkyne-functionalized SAMs via click chemistry in tetrahydrofuran. The SAM, PEG, PMMA, and PS layers were characterized by ellipsometry, scanning probe microscopy, and water contact angle measurements. Results have shown that the grafting process follows the scaling laws developed for polymer brushes, with a significant dependence over the weight fraction of polymer in the grafting solution and the grafting time. The chemical nature of the brushes has only a weak influence on the click chemistry grafting reaction and morphologies observed, yielding polymer brushes with thickness of ca. 6 nm and grafting densities of ca. 0.2 chains/nm2. The examples developed herein have shown that this highly versatile and tunable approach can be extended to the grafting of a wide range of polymer (pseudo-) brushes to silicon substrates without changing the tethering strategy.     

Selectivity among two lectins: probing the effect of topology, multivalency and flexibility of "clicked" multivalent glycoclusters

The design of multivalent glycoconjugates has been developed over the past decades to obtain high-affinity ligands for lectin receptors. While multivalency frequently increases the affinity of a ligand for its lectin through the so-called "glycoside cluster effect", the binding profiles towards different lectins have been much less investigated. We have designed a series of multivalent galactosylated glycoconjugates and studied their binding properties towards two lectins, from plant and bacterial origins, to determine their potential selectivity. The synthesis was achieved through copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) under microwave activation between propargylated multivalent scaffolds and an azido-functionalised carbohydrate derivative. The interactions of two galactose-binding lectins from Pseudomonas aeruginosa (PA-IL) and Erythrina cristagalli (ECA) with the synthesized glycoclusters were studied by hemagglutination inhibition assays (HIA), surface plasmon resonance (SPR) and isothermal titration microcalorimetry (ITC). The results obtained illustrate the influence of the scaffold's geometry on the affinity towards the lectin and also on the relative potency in comparison with a monovalent galactoside reference probe.     

"Click" immobilization on alkylated silicon substrates: model for the study of surface bound antimicrobial peptides

We describe an effective approach for the covalent immobilization of antimicrobial peptides (AMPs) to bioinert substrates via Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). The bioinert substrates were prepared by surface hydrosilylation of oligo(ethylene glycol) (OEG) terminated alkenes on hydrogen-terminated silicon surfaces. To render the OEG monolayers "clickable", mixed monolayers were prepared using OEG-alkenes with and without a terminal alkyne protected by a trimethylgermanyl (TMG) group. The mixed monolayers were characterized by X-ray photoelectron spectroscopy (XPS), elliposometry and contact angle measurement. The TMG protecting group can be readily removed to yield a free terminal alkyne by catalytic amounts of Cu(I) in an aqueous media. This step can then be combined with the subsequent CuAAC reaction. Thus, the immobilization of an azide modified AMP (N3-IG-25) was achieved in a one-pot deprotection/coupling reaction. Varying the ratio of the two alkenes in the deposition mixture allowed for control over the density of the alkynyl groups in the mixed monolayer, and subsequently the coverage of the AMPs on the monolayer. These samples allowed for study of the dependence of antimicrobial activities on the AMP density. The results show that a relative low coverage of AMPs (～1.6×10(13) molecule per cm(2)) is sufficient to significantly suppress the viability of Pseudomonas aeruginosa, while the surface presenting the highest density of AMPs (～2.8×10(13) molecule per cm(2)) is still cyto-compatible. The remarkable antibacterial activity is attributed to the long and flexible linker and the site-specific "click" immobilization, which may facilitate the covalently attached peptides to interact with and disrupt the bacterial membranes.     

"Click" chemistry in a supramolecular environment: stabilization of organogels by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition

Organogels are thermoreversible, viscoelastic (soft) materials consisting of low molecular weight compounds which self-assemble into fibers, often of micrometer lengths and nanometer diameters. The installation of terminal azide and alkyne functional groups on the end of a standard alkylamide-based organogelator was found to cause a modest disruption in the gelation properties of the molecule. Cross-linking of those groups by the copper(I)-catalyzed azide-alkyne cycloaddition reaction produced thermoreversible materials of substantially greater gelation temperatures and mechanical rigidity. These results highlight the ability of azides and alkynes-participants in the most commonly used "click" reaction-to function as innocuous precursors to meaningful covalent interactions in materials science.     

Transition metal-catalyzed hetero-[5 + 2] cycloadditions of cyclopropyl imines and alkynes: dihydroazepines from simple,readily available starting materials

The first example of a transition metal-catalyzed hetero-[5 + 2] cycloaddition reaction is described. Use of cyclopropyl imines as five-atom components, an alkyne as a two-carbon component, and a Rh(I) catalyst enables a new route to dihydroazepines. This new hetero-[5 + 2] cycloaddition works well with aldimines, ketimines, and with substituted cyclopropanes and affords the desired dihydroazepines in excellent yields as single regioisomers. Use of serial imine formation/aza-[5 + 2] cycloaddition generates the desired dihydroazepines in one operation from three commercially available starting materials. The reaction has been scaled to give gram quantities of dihydroazepine.     

"Dimers" and "trimers" of tetrahydroindenes and hexahydroazulenes, respectively generated from [2-(1-cycloalkenyl)ethynyl]carbene complexes (M = W, Cr) by cascade cyclization/cycloaddition reactions

A cascade of cyclization/cycloaddition reactions was triggered by addition of protic oxygen nucleophiles ROH 2 (RO = CH3CO2, PhCO2, PhO) to [2-(1-cyclohexenyl)ethynyl]carbene complexes 1b and 1c (M=W, Cr, respectively), affording highly strained "dimers" 11/11' and "trimers" 12 of the carbene ligand. The first reaction step involved the formation of 1-metalla1,3,5-hexatrienes 7, which readily gave tetrahydroindenes 8 by pi cyclization and extrusion of the metal unit. "Dimers" 11/11' were generated from tetrahydroindenes 8 by a highly exo selective [4+2] cycloaddition of compounds 1b and 1c to afford 1-metalla-1,3,5-hexatriene intermediates 9, and a spontaneous pi cyclization of the latter compounds involving the disengagement of the metal unit. Propenylidene cyclohexenes 13/13' were formed in "ene"-type side reactions to the pi cyclization of 1-metalla-1,3,5-hexatrienes 7, by loss of the metal unit. "Dimers" 11 were transformed into "trimers" 12 by a [4+2] cycloaddition and subsequent pi-cyclization of the resulting 1-metalla-1,3,5-hexatriene system. The course of the reaction was elucidated by means of model reactions with (2-phenylethynyl)carbene complex 14, in which 1-metalla-1,3,5-hexatriene intermediates 16 and 17 were isolated and characterized. Alkynyl benzene derivatives 19 were obtained by an unprecedented ring-expansion of a cyclopentadiene unit of "dimers" 11a and 11c, involving the insertion of a carbene carbon atom of compound 14 into a C=C bond. A reaction cascade leading to "dimers" 24/24' could also be triggered by treatment of compounds 2 with [2-(1-cycloheptenyl)ethynyl]carbene tungsten complex 1d.     

Catalytic "active-metal" template synthesis of [2]rotaxanes, [3]rotaxanes, and molecular shuttles, and some observations on the mechanism of the cu(i)-catalyzed azide-alkyne 1,3-cycloaddition

A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.     

"Formal" ruthenium-catalyzed [4+2+2] cycloaddition of 1,6-diynes to 1,3-dienes: formation of cyclooctatrienes vs vinylcyclohexadienes

[reaction: see text] A new "formal" Ru-catalyzed [4+2+2] cycloaddition of 1,6-diynes to 1,3-dienes giving conjugated 1,3,5-cyclooctatrienes and vinylcyclohexadienes is described. This formal cycloaddition is really a tandem process, the Ru(II)-catalyzed formation of (Z)-tetraenes or vinyl-(Z)-trienes followed by a pure thermal conrotatory 8 pi- or disrotatory 6 pi-electrocyclization. The proposed mechanism allows the differences in product ratio to be explained in terms of steric and stereochemical considerations.     

Click-chemistry as an efficient synthetic tool for the preparation of novel conjugated polymers

The Cu(I)-catalysed 1,3-dipolar "click" cycloaddition is utilised as an efficient reaction for the preparation of novel fluorene-based conjugated polymers.     

Synthesis of conformationally restricted 1,2,3-triazole-substituted ethyl β- and γ-aminocyclopentanecarboxylate stereoisomers. Multifunctionalized alicyclic amino esters

Stereoisomers of 1,2,3-triazole-functionalized, conformationally restricted β- or γ-amino esters with a cyclopentane skeleton were efficiently synthetized from the bicyclic β-lactam 6-azabicyclo[3.2.0]hept-3-en-7-one (1) and Vince γ-lactam (15) in five or six steps involving the azide-alkyne 1,3-dipolar cycloaddition of azido-substituted amino ester stereoisomers with nonsymmetric acetylenes. The azide-alkyne click reactions were investigated under thermal and Cu(I)-catalyzed conditions. Surprisingly, the thermally induced cycloaddition furnished the corresponding 1,4-triazoles regioselectively, which also took place selectively in response to Cu(I) catalysis.     

Cu(I)-catalyzed intramolecular cyclization of alkynoic acids in aqueous media: a "click side reaction"

Alkynoic acids, in particular, 4-pentynoic acid derivatives, undergo intramolecular cyclizations to enol lactones under reaction conditions typically applied for the Cu(I)-catalyzed cycloaddition of terminal alkynes and azides (click chemistry). Starting from appropriate alkynoic acid derivatives, either enol lactones or 1,2,3-triazole click products can be obtained selectively by Cu(I) catalysis in aqueous media.