Cu(I)-catalyzed Azide-alkyne Cycloaddition Reaction Research Articles

Tailored isatin-derived chemosensor immobilized on silica nanoparticles for targeted detection of Ni(II) ion

In this study, we have designed and synthesized a chemosensor, isatin-based triazole-linked silanes (ITS), employing the Cu(I)-catalyzed Azide-Alkyne cycloaddition reaction (CuAAC) and the synthesized silanes has been well characterized through various analytical techniques, including FT-IR, 1H NMR, 13C NMR, and ESI-MS. The developed sensor exhibited the capability to detect Ni2+ ion in a methanol/water solution (9:1, v/v) by manifesting different absorbance changes and fluorescence. In the fluorescence mode, the addition of Ni2+ ion triggers a “Turn-OFF” response in the sensor, demonstrating an ultratrace detection limit of 2.49 × 10−7 M. Successful grafting of organosilane onto silica nanoparticles has been achieved, and these new silane-coated nanoparticles demonstrate enhanced sensing abilities for Ni2+ ions, with a detection limit of 1.56 × 10−8 M. Stoichiometric data reveals a 1:1 coordination between the sensor and Ni2+ ion. Furthermore, both the synthesized alkyne and silane underwent examination for their drug-likeness profiles, providing valuable insights.

Computational studies of the CuAAC reaction mechanism with diimine and phosphorus ligands for the synthesis of 1,4-disubstituted 1,2,3-triazoles

The Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions with diimine and phosphorus ligands have been studied using DFT calculations in order to understand the effect of the nature of the ligands on the catalytic cycle for the formation of the 1,4-regioisomer.

Ultrafast synthesis of dialkyne-functionalized polythioether and post-polymerization modification via click chemistry

Herein, we prepare a polythioether with double “clickable” alkyne groups in each repeating unit via an extremely rapid polymerization method and combine it with Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to construct new topological polymers. A monomer having both electron-deficient and electron-rich dual alkyne functionalities was synthesized and subsequently reacted with 1,6-hexanedithiol (HDT) using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst, and the reaction proceeded at room temperature for 1 min to give polythioether P1. The obtained polymer was then used as a polymer platform and reacted with a variety of azide compounds to modify the pendant alkynes via CuAAC reaction. The post-polymerization modification (PPM) studies have also been shown to be rapid as the reactions reached completion in 1 h. All synthesized polymers were analyzed using various spectroscopic methods and the results confirmed that quantitative “click” reaction efficiency was achieved in each reaction. It is believed the presented strategy not only provides a time-saving approach for both polymer synthesis and PPM, but also brings a new insight to impart the desired functionalities to a polymer chain with CuAAC “click” chemistry. Thus, a new type of polymer structure that can be prepared rapidly and undergoes fast PPM has been introduced to polymer chemistry with this study. • A Polythioether with clickable pendant units has been synthesized extremely rapidly in 1 min. • Post-polymerization modification (PPM) via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction has been successfully carried out. • Quantitative “click” reaction efficiency has been achieved in all cases. • Time- and energy-saving polymerization and PPM method have been developed.

Synthesis and hemagglutination inhibitory properties of mannose-tipped ligands: The effect of terminal phenyl groups and the linker between the mannose residue and the triazole moiety

Two families (A, B) of triazole conjugates derived from d-mannose possessing reversed linkage functionality were easily assembled by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). The mannose precursors were built with either 3-azidopropyl or propargyl aglycones whereas the phenyl moieties were built with terminal azide or propargyl groups, respectively. In a hemagglutination inhibition (HAI) assay, family A (7a-11a), where the linker between the mannose residue and the triazole ring is three carbons displayed a 3–5 fold enhancement in activity compared to family B (13a-17a) having methyl-triazolyl moiety. The representative ligand 7a, where the terminal phenyl ring is substituted with an ester group and Cl atom exhibited the highest inhibitory activity with an HAI titer of 8 μM. This compound could be a good candidate for the further design of potent mannosyl ligands targeting FimH fimbrial lectin.

Development of 3-Acetylcoumarin derived organosilane as potent antioxidant: Selective and sensitive colorimetric and fluorescent sensor for Al3+ ions

The Al3+ intake to the human body was limited by EPA and WHO because it is non-essential for living beings. In the current study, we synthesized 3-Acetylcoumarin derived 1,2,3-triazole linked silane as a chemosensor (CS) through Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). The synthesized probe has been used for colorimetric and fluorimetric detection of Al3+ ions. The sensor exhibits “turn-on” fluorescence due to the synergistic effect of chelation-enhanced fluorescence CHEF. The detection limit can reach as low as 8.1 × 10−7 M. The binding mode exhibits a 1:1 ratio between CS and Al3+ ions confirmed by IR-spectra, 1H NMR titration data, and job’s plot experiment. Meanwhile, CS at low concentration can detect Al3+ with excellent interference resistance to typical disturbing metal ions. It also exhibits good reusability by alternate addition of Al3+ and EDTA to the CS solution. Moreover, the synthesized compounds were investigated for their antioxidant properties.

Synthesis and biological evaluation of mannosyl triazoles and varying the nature of substituents on the terminal phthalimido moiety in the aglycone backbone

In the present study, a facile synthesis of six monovalent α-d-mannoside ligands terminated with phthalimido moiety by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC) has been achieved. All synthesized ligands were tested for their inhibitory activities against E. coli FimH adhesion using hemagglutination inhibition (HAI) assay and showed inhibitory activity in the range of HAI = 4.8–23.5 µM comparing with 2-azidoethyl α-d-mannopyranoside 17 as the standard ligand (HAI = 135 µM). Among them, ligand 21 (R = NO2), displayed the best activity (HAI = 4.8 µM) which was approximately 28 times more potent than the reference ligand 17. Thus confirming the beneficial effect of lipophilic interactions between the aromatic aglycone and the tyrosine gate of FimH. We feel that our lead ligand will be a good platform for identification of more potent FimH inhibitors.

α-d-Mannoside ligands with a valency ranging from one to three: Synthesis and hemagglutination inhibitory properties

Six mono-, di-, and trivalent α-d-mannopyranosyl conjugates built on aromatic scaffolds were synthesized in excellent yields by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). These conjugates were designed to have unique, flexible tails that combine a mid-tail triazole ring, to interact with the tyrosine gate, with a terminal phenyl group armed with benzylic hydroxyl groups to avoid solubility problems as well as to provide options to connect to other supports. Biological evaluation of the prepared conjugates in hemagglutination inhibition (HAI) assay revealed that potency increases with valency and the trivalent ligand 6d (HAI = 0.005 mM) is approximately sevenfold better than the best meta-oriented monovalent analogues 2d and 4d (HAI ≈ 0.033 mM) and so may serve as a good starting point to find new lead ligands.

Near-Infrared Light Dual-Promoted Heterogeneous Copper Nanocatalyst for Highly Efficient Bioorthogonal Chemistry in Vivo

Owing to better stability and biosafety, heterogeneous Cu nanoparticles (CuNPs) have been put forward as a promising candidate to complete the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. However, the inherent poor activity of Cu(0) deterred its wide bioapplication. Herein, we employed near-infrared (NIR) light to dual-promote the CuAAC reaction of a biocompatible heterogeneous copper nanocatalyst through photodynamic and photothermal effects in vitro and in vivo. Specifically, the photodynamic activity could promote the conversion of Cu(0) to Cu(I) to accelerate the catalytic process of CuAAC. The high photothermal conversion efficiency (η = 50.6%) could increase the local temperature, further promoting the whole reaction. Then, a drastically increased reaction rate in a living system ranging from cells to nematodes was achieved in our system. Meanwhile, the better antitumor efficacy has determined with in vivo tumor therapy experiments.

Copper-catalyzed click reactions: quantification of retained copper using 64Cu-spiked Cu(I), exemplified for CuAAC reactions on liposomes

Abstract The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is a powerful, highly reliable and selective reaction which allows for a rapid synthesis in high yields and under mild conditions (pH, temperature). However, the cytotoxicity of copper requires its complete removal prior to an application in vivo. This is an issue especially when it comes to CuAAC reactions on macromolecular structures or drug delivery systems, as copper might be retained by these systems. Thus, a quantification of the final copper content of these systems is inevitable, which we exemplified for a CuAAC reaction on liposomes using 64Cu-spiked Cu(I). In this respect, a Cu(II) nitrate solution was irradiated at the TRIGA Mark II research reactor Mainz to obtain c.a. [64Cu]Cu(II). The irradiated solution was directly used for a CuAAC on liposomes. After purification, their copper content was calculated utilizing γ-ray spectrometry. Only 0.018% of the added 64Cu-activity was still present in the liposome containing fractions after purification. This refers to a total amount of copper of 0.17 ng. The amount of retained copper is so low, that an in vivo application of the liposomes is absolutely reasonable. Besides this particular study, the experimental methodology may be applied to study many other CuAAC reactions, used for the synthesis of radiolabeled or non-radioactive species, which are intended for human applications.

Tuning the functionalization degree of amylose and amylopectin with photochromic spiropyran by CuAAc reaction

Amylose and amylopectin were functionalized with an alkynyl derivative of spiropyran (SPCC) and/or propargyl alcohol by a two step procedure consisting in the derivatization of glucopyranose units with azide at the C6 position followed by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc). Substitution degrees with spiropyran (DSSP) between 0.10 and 0.95 were achieved by simply modulating the molar ratio between alkyne species and polysaccharide in the CuAAc reaction, as it was confirmed by FT-IR and NMR spectroscopy characterizations. The UV–Vis spectra of SPCC-modified amylose in DMF solution kept in the dark exhibited an absorbance band with maximum at ∼346 nm, ascribed to spiropyran units. The intensity of the absorbance was found to increase linearly with DSSP. Upon irradiation with UV light, a band at ∼560 nm appeared, due to the conversion of spiropyran to zwitterionic merocyanine, its intensity linearly increasing with DSSP too. ICP-MS analysis showed the presence of a small amount (<270 ppm) of residual Cu from the catalyst in the functionalized polysaccharides. However, EPR spectroscopy indicated that Cu2+ species are bonded to different moieties and they do not significantly interfere with the optical behaviour. These findings indicate that the proposed synthetic strategy can be exploited to prepare photochromic materials with the desired signal intensity by using natural amylose as raw material.

A potential industrialized fiber-supported copper catalyst for one-pot multicomponent CuAAC reactions in water

Abstract A potential industrialized fiber catalyst for “click chemistry” via the one-pot multicomponent Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) for the synthesis of 1,2,3-triazoles in water, is reported. Detailed characterization by appearance, mechanical properties, elemental analysis, FTIR spectroscopy, and SEM confirmed the rangeability of the fiber catalyst during the preparation and utilization processes. Moreover, the fiber catalyst-mediated reactions proceeded smoothly to afford triazoles with nearly quantitative yields in short time (15 min). Furthermore, the fiber catalyst has shown tandem activities and superior recyclability (over 10 cycles), and the procedure is operationally simple and amenable to the gram-scale on a simple fixed-bed reactor.

Intermediates Stabilized by Tris(triazolylmethyl)amines in the CuAAC Reaction.

Tris(triazolylmethyl)amine ligands (TL) are widely used to accelerate the CuI -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, but its mechanistic role remains unclear. Using electrospray ionization mass spectrometry, we detected for the first time the trinuclear TL-CuI3 -acetylide and the dinuclear TL-CuI2 -acetylide complexes in aqueous solution. The apparent second-order rate constants of their reaction with an azide were 27 and 783 m-1 ⋅s-1 when the alkyne was tethered to TL. In the catalytic system without the tether, the rate constant increased to >146 m-1 ⋅s-1 for the TL-CuI3 -acetylide, but dropped about 14-fold to approximately 55 m-1 ⋅s-1 for the TL-CuI2 -acetylide. The results indicated that TL accelerated the reaction by stabilizing the CuI2 - and CuI3 -acetylide and their azide-adduct intermediates, but this role is largely weakened by excess alkyne and other competing ligands under catalytic conditions.

Recent advances of CuAAC click reaction in building cyclic polymer

Cyclic polymers have attracted more and more attentions in recent years because of their unique topological structures and characteristic properties in both solution and bulk state. There are relatively few reports on cyclic polymers, partly because of the more demanding synthetic procedures. In recent years, “click” reaction, especially Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), has been widely utilized in the synthesis of cyclic polymer materials because of its high efficiency and low susceptibility to side reactions. In this review, we will focus on three aspects: (1) Constructions of monocyclic polymer using CuAAC “click” chemistry; (2) Formation of complex cyclic polymer topologies through CuAAC reactions; (3) Using CuAAC “click” reaction in the precise synthesis of molecularly defined macrocycles. We believe that the CuAAC click reaction is playing an important role in the design and synthesis of functional cyclic polymers.

Synthesis and reaction of block copolymer composed of independently clickable segments via monomer-selective living copolymerization

Living anionic copolymerizations of silyl-protected propargyl acrylate (TMS-PA) and 6-chlorohexyl methacrylate (CHMA) were conducted in the presence of ethylaluminum bis(2,6-di-tert-butylphenoxide) [EtAl(ODBP)2], a bulky aluminum Lewis acid, in toluene at ź60 °C. The polymerization proceeded in a monomer-selective manner, where the acrylate, TMS-PA, was selectively activated by EtAl(ODBP)2 and polymerized preferentially over to the methacrylate, CHMA, and the polymerization of CHMA followed after the complete consumption of TMS-PA to afford a block copolymer with narrow molecular weight distribution. The blocky sequence was confirmed with 1H NMR spectrum, while the peak shift of size exclusion chromatograms (SECs) from low to high molecular weights as well as the progressive monomer consumptions also supported the monomer-selective living copolymerization. The obtained block copolymer could be functionalized with respect to each segment independently via a repeated Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry; the alkynyl (propargyl) group was deprotected with tetrabutylammonium fluoride (TBAF) in acetic acid, and the subsequent CuAAC reaction with benzyl azide allowed quantitative and selective modification of the polyacrylate block. Subsequently, the 6-chlorohexyl group was azidated with sodium azide, and the CuAAC reaction with phenylacetylene resulted in complete modification on the polymethacrylate segment. Since CuAAC reaction is selective, quantitative and tolerant to various functional groups, this procedure, that is a combination of monomer-selective copolymerization of reactive monomers with a click chemistry, can provide a facile pathway for the preparation of a block copolymer with a variety of combination of functional pendants groups.

Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems.

A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars.

ChemInform Abstract: Application of “Click” Chemistry to the Construction of Supramolecular Functional Systems

AbstractReview: [79 refs.

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.

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.

Novel porphyrin–psoralen conjugates: synthesis, DNA interaction and cytotoxicity studies

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).

Identification of diverse 1,2,3-triazole-connected benzyl glycoside-serine/threonine conjugates as potent corrosion inhibitors for mild steel in HCl

The corrosion inhibitive efficiency of diverse 1,2,3-triazolyl benzyl glucoside-, galactoside- and mannoside-serine/threonine conjugates readily synthesized via CuI-catalyzed azide–alkyne cycloaddition reaction (Cue-AAC) for mild steel in HCl was examined via electrochemical impedance spectroscopy. The results indicate that these compounds are potent corrosion inhibitors even in highly concentrated HCl solutions. The potential mechanism of three inhibitors was characterized in detail via polarization and isotherm calculations. This study implies that benzyl glycoside-amino acid hybrids effectively constructed via the Cue-AAC between the highly biocompatible sugars and amino acids may represent a new class of promising and potentially green corrosion inhibitors.

Derivatization of a Bioorthogonal Protected Trisaccharide Linker—Toward Multimodal Tools for Chemical Biology

When cross-linking biomolecules to surfaces or to other biomolecules, the use of appropriate spacer molecules is of great importance. Mimicking the naturally occurring spacer molecules will give further insight into their role and function, possibly unveil important issues regarding the importance of the specificity of carbohydrate-based anchor moieties, in e.g., glycoproteins and glycosylphosphatidylinositols. Herein, we present the synthesis of a lactoside-based trisaccharide, potentially suitable as a heterobifunctional bioorthogonal linker molecule whereon valuable chemical handles have been conjugated. An amino-derivative having thiol functionality shows promise as novel SPR-surfaces. Furthermore, the trisaccharide has been conjugated to a cholesterol moiety in combination with a fluorophore which successfully assemble on the cell surface in lipid microdomains, possibly lipid-rafts. Finally, a Cu(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) confirms the potential use of oligosaccharides as bioorthogonal linkers in chemical biology.