Chain‐Growth Click Polymerization of AB2 Monomers for the Formation of Hyperbranched Polymers with Low Polydispersities in a One‐Pot Process

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.     

Copper Catalysis in Living Systems and In Situ Drug Synthesis

The copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction has proven to be a pivotal advance in chemical ligation strategies with applications ranging from polymer fabrication to bioconjugation. However, application in vivo has been limited by the inherent toxicity of the copper catalyst. Herein, we report the application of heterogeneous copper catalysts in azide–alkyne cycloaddition processes in biological systems ranging from cells to zebrafish, with reactions spanning from fluorophore activation to the first reported in situ generation of a triazole‐containing anticancer agent from two benign components, opening up many new avenues of exploration for CuAAC chemistry.     

Chiral Heteroditopic Baskets Designed from Triazolated Calixarenes and Short Peptides

Cone calix[4]arenes and calix[6]arenes bearing two, three, and four short peptide units each having two chiral carbon atoms were prepared. The syntheses were performed by using an efficient modular approach that includes the Ugi preparation of the azido‐peptide followed by its reactions with the propargylated calixarenes under CuAAC (Cu^I‐catalyzed azide–alkyne cycloaddition) conditions. The three novel multitopic hosts were probed for their ability to bind metal ions by UV titration, and showed the highest complexation efficiency towards copper(II) and lead(II). These two cations possessed quite different complexation modes with copper(II) bound predominantly by multiple‐triazole sites, in contrast to lead(II), which is stabilized mainly by multiple interactions with amide groups of the peptide units. Circular dichroism data for the free chiral hosts, their equimolar mixtures with copper(II) perchlorate and lead(II) perchlorate, and for tertiary mixtures of all three compounds showed the formation of mono‐ and binuclear complexes, or a switching behavior, depending on the structure of the host and the addition order of the cations.     

Reaction of Alkynes and Azides: Not Triazoles Through Copper–Acetylides but Oxazoles Through Copper–Nitrene Intermediates

Well‐defined copper(I) complexes of composition [Tpm*^,BrCu(NCMe)]BF₄ (Tpm*^,Br=tris(3,5‐dimethyl‐4‐bromo‐pyrazolyl)methane) or [Tpa^*Cu]PF₆ (Tpa^*=tris(3,5‐dimethyl‐pyrazolylmethyl)amine) catalyze the formation of 2,5‐disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5‐isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper–acyl nitrene species, in contrast to the well‐known mechanism for the copper‐catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper–acetylide complex.     

On the Mechanism of Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition

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 pK_a 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.     

Star polymers by photoinduced copper‐catalyzed azide–alkyne cycloaddition click chemistry

Well‐defined star polymers consisting of tri‐, tetra‐, or octa‐arms have been prepared via coupling‐onto strategy using photoinduced copper(I)‐catalyzed 1,3‐dipolar cycloaddition click reaction. An azide end‐functionalized polystyrene and poly(methyl methacrylate), and an alkyne end‐functionalized poly(ε‐caprolactone) as the integrating arms of the star polymers are prepared by the combination of controlled polymerization and nucleophilic substitution reactions; whereas, multifunctional cores containing either azide or alkyne functionalities were synthesized in quantitatively via etherification and ring‐opening reactions. By using photoinduced copper‐catalyzed azide–alkyne cycloaddition (CuAAC) click reaction, reactive linear polymers are simply attached onto multifunctional cores to form corresponding star polymers via coupling‐onto methodology. The chromatographic, spectroscopic, and thermal analyses have clearly demonstrated that successful star formations can be obtained via photoinduced CuAAC click reaction. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1687–1695     

“Clickable” and Antifouling Block Copolymer Brushes as a Versatile Platform for Peptide‐Specific Cell Attachment

To tailor cell–surface interactions, precise and controlled attachment of cell‐adhesive motifs is required, while any background non‐specific cell and protein adhesion has to be blocked effectively. Herein, a versatile and highly reproducible antifouling surface modification based on “clickable” groups and hierarchically structured diblock copolymer brushes for the controlled attachment of cells is reported. The polymer brush architecture combines an antifouling bottom block of poly(2‐hydroxyethyl methacrylate) poly(HEMA) and an ultrathin azide‐bearing top block, which can participate in well‐established “click” reactions including the highly selective copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction under mild conditions. This straightforward approach allows the rapid conjugation of a cell‐adhesive, alkyne‐bearing cyclic RGD peptide motif, enabling subsequent specific attachment of NIH 3T3 fibroblasts, their extensive proliferation and confluent cell sheet formation after 48 h of incubation. The generally applicable strategy presented in this report can be employed for surface functionalization with diverse alkyne‐bearing biological moieties via CuAAC or copper‐free alkyne‐azide cycloaddition protocols, making it a versatile functionalization approach and a promising tool for tissue engineering, biomaterial implant design, and other applications that require surfaces supporting highly specific cell attachment.     

A reusable polymer‐supported copper(I) catalyst for triazole click reaction on water: An experimental and computational study

In the search for establishing a clickable copper‐catalysed (3 + 2) Huisgen azide–alkyne cycloaddition (CuAAC) reaction under strict conditions, in particular in terms of preventing the presence of copper particles/traces in reaction products and using an environmentally benign medium such as water, we describe here the synthesis of an aminomethyl polystyrene‐supported copper(I) catalyst (Cu(I)‐AMPS) and its characterization by means of Fourier transform infrared and energy‐dispersive X‐ray spectroscopies and scanning electron microscopy. Cu(I)‐AMPS was found to be highly active in the CuAAC reaction of various organic azides with alkynes affording the corresponding 1,4‐disubstituted 1,2,3‐triazoles in a regioselective manner in air at room temperature and using water as solvent. The insolubility and/or partial solubility of the organic azide and alkyne precursors as well as the heterogeneous Cu(I)‐AMPS catalytic system points to the occurrence of the cycloaddition at the organic–water interface ‘on water’ affording quantitative yields of water‐insoluble 1,2,3‐triazoles. A mechanistic study was performed using density functional theory aiming at explaining the observed reactivity and selectivity of the Cu (I)‐AMPS catalyst in CuAAC reactions.     

Copper‐Chelating Azides for Efficient Click Conjugation Reactions in Complex Media

The concept of chelation‐assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)‐catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper‐chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.     

In‐situ Generated and Premade 1‐Copper(I) Alkynes in Cycloadditions

The copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) was discovered in 2002, which has become the most remarkable example for “click chemistry” to date. In CuAAC reaction, 1‐copper(I) alkyne has been recognized to be a key intermediate. However, many contradictory experimental results for this intermediate were reported in literature. For example, only the in‐situ generated 1‐copper(I) alkyne was used, while the premade 1‐copper(I) alkyne proved to be inefficient under the standard conditions. The kinetic studies indicated that CuAAC reaction had a strict second‐order dependence on Cu(I) and the DFT studies demonstrated that 1‐copper(I) alkyne intermediate should be a dinuclear copper(I) complex. But these results were inconsistent with the structure of the premade 1‐copper(I) alkyne. Although hundreds of structurally different ligands were reported to significantly enhance the efficiency of CuAAC reaction, their functions were assigned to prevent the oxidation and the disproportionation of Cu(I) ion. Based on the investigation of the references and our works, we proposed that the in‐situ generated 1‐copper(I) alkyne in CuAAC reaction is not identical with the premade 1‐copper(I) alkyne. The ligands may play dual roles to activate the 1‐copper(I) alkyne by blocking the polymerization of the in‐situ formed 1‐copper(I) alkynes and dissociating the polymeric structures of the premade 1‐copper(I) alkynes. As a result, we first disclosed that carboxylic acids can function as such activators and a novel carboxylic acid‐catalyzed CuAAC strategy was developed, which has been proven to be the most convenient and highly efficient CuAAC method to date. Furthermore, highly efficient and regioselective methods for the syntheses of 1,4,5‐trisubstituted 1,2,3‐triazoles were developed by using the premade 1‐copper(I) alkynes as substrates, in which the novel function of the premade 1‐copper(I) alkynes as excellent dipolarophiles was first disclosed and applied. In this article, a series of works reported by our group for the in‐situ generated and the premade 1‐copper(I) alkynes in cycloadditions are reviewed.     

Synthesis of Lanthanide(III) Chelates by Using ‘Click’ Chemistry

The copper(I)‐catalyzed dipolar [2+3] cycloaddition reaction of an azide and a terminal alkyne is exploited in the preparation of various europium(III), terbium(III), and dysprosium(III) chelates (Schemes 1–3). By changing the nature of the alkyne and the azide, a wide range of chelates and biomolecule‐labeling reactants were obtained. The photophysical properties (Table) of the synthesized chelates are also discussed.     

Following the Azide‐Alkyne Cycloaddition at the Silica/Solvent Interface with Sum Frequency Generation

The Cu^I‐catalyzed 1,3‐dipolar azide‐alkyne cycloaddition (CuAAC) has arisen as one of the most useful chemical transformations for introducing complexity onto surfaces and materials owing to its functional‐group tolerance and high yield. However, methods for monitoring such reactions in situ at the widely used silica/solvent interface are hampered by challenges associated with probing such buried interfaces. Using the surface‐specific technique broadband sum frequency generation (SFG), we monitored the reaction of a benzyl azide monolayer in real time at the silica/methanol interface. A strong peak at 2096 cm^?1 assigned to the azides was observed for the first time by SFG. Using a cyano‐substituted alkyne, the decrease of the azide peak and the increase of the cyano peak (2234 cm^?1) were probed simultaneously. From the kinetic analysis, the reaction order with respect to copper was determined to be 2.1, suggesting that CuAAC on the surface follows a similar mechanism as in solution.     

Spatially Directional Resorcin[4]arene Cavitand Glycoconjugates for Organic Catalysis

The synthesis of novel spatially directional multivalent resorcin[4]arene cavitand glycoconjugates (RCGs) and their ability to catalyze organic reactions is reported. The β‐d ‐glucopyranoside moieties on the upper rim of the “bowl”‐shaped resorcin[4]arene cavitand core are capable of multiple hydrogen‐bond interactions resulting in a pseudo‐cavity, which has been investigated for organic transformations in aqueous media. The RCGs have been demonstrated to catalyze thiazole formation, thiocyanation, copper(I)‐catalyzed azide alkyne cycloaddition (CuAAC), and Mannich reactions; they impart stereoselectivity in the three‐component Mannich reaction. Thermodynamic values obtained from ¹H diffusion‐ordered spectroscopy (DOSY) experiments suggest that the upper saccharide cavity of the RCG and not the resorcin[4]arene cavity is the site of the complexation event.     

‘Clickable’ cyclopentadienyl iron carbonyl complexes for bioorthogonal conjugation of mid‐infrared labels to a model protein and PAMAM dendrimer

Owing to the intrinsic limitations of the conventional bioconjugation methods involving native nucleophilic functions of proteins, we sought to develop alternative approaches to introduce metallocarbonyl infrared labels onto proteins on the basis of the [3 + 2] dipolar azide‐alkyne cycloaddition (AAC). To this end, two cyclopentadienyl iron dicarbonyl (Fp) complexes carrying a terminal or a strained alkyne handle were synthesized. Their reactivity was examined towards a model protein and poly (amidoamine) (PAMAM) dendrimer, both carrying azido groups. While the copper (I)‐catalysed azide‐alkyne cycloaddition (CuAAC) proceeded smoothly with the terminal alkyne metallocarbonyl derivative, labelling by strain‐promoted azide‐alkyne cycloaddition (SPAAC) was less successful in terms of final coupling ratios. Infrared spectral characterization of the bioconjugates showed the presence of two bands in the 2000 cm^?1 region, owing to the stretching vibration modes of the carbonyl ligands of the Fp entities.     

Click Synthesis of Triazolyl Phenylalaninyl and Tyrosinyl Derivatives as New Protein Tyrosine Phosphatase Inhibitors

The efficient construction of triazolyl peptidomimetics via the powerful click chemistry for the discovery of small molecule‐based chemotherapeutic agents represents a promising strategy in drug development today. Herein, the synthesis of novel mono‐triazolyl or bis‐triazolyl amino acid derivatives was rapidly achieved via microwave‐assisted Cu(I)‐catalyzed azide‐alkyne 1,3‐dipolar cycloaddition (CuAAC). Subsequent in vitro enzymatic assay on several homologous protein tyrosine phosphatases (PTPs) identified the triazolyl dimers as new specific inhibitors of Cell Cycle Division 25B (CDC25B) phosphatase and Protein Tyrosine Phosphatase 1B (PTP1B).     

Ultrasound Promoted Step‐Growth Polymerization and Polymer Crosslinking Via Copper Catalyzed Azide–Alkyne “Click” Reaction

Mechano‐activated chemistry is a powerful tool for remodeling of synthetic polymeric materials, however, few reactions are currently available. Here we show that using piezochemical reduction of a Cu^II‐based pre‐catalyst, a step‐growth polymerization occurs via the copper catalyzed azide–alkyne cycloaddition (CuAAC) reaction to form a linear polytriazole. Furthermore, we show that a linear polymer can be crosslinked mechanochemically using the same chemistry to form a solid organogel. We envision that this chemistry can be used to harness mechanical energy for constructive purposes in polymeric materials.     

Screening of Three Transition Metal‐Mediated Reactions Compatible with DNA‐Encoded Chemical Libraries

The construction of DNA‐encoded chemical libraries (DECLs) crucially relies on the availability of chemical reactions, which are DNA‐compatible and which exhibit high conversion rates for a large number of diverse substrates. In this work, we present our optimization and validation procedures for three copper and palladium‐catalyzed reactions (Suzuki cross‐coupling, Sonogashira cross‐coupling, and copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC)), which have been successfully used by our group for the construction of large encoded libraries.     

The Sequential Building of Chiral Macrocyclic Bis‐β‐Lactams by Double Staudinger–Cu‐Catalyzed Azide–Alkyne Cycloadditions

A novel approach for the synthesis of macrocyclic bis‐β‐lactams based on the Cu‐catalyzed alkyne–azide cycloaddition (CuAAC) is reported. The procedure is general and allows access to a full range of diastereomerically or enantiomerically pure macrocyclic cavities in good yields. The incorporation of chiral oxazolidinone fragments at C3 in the β‐lactam rings allows the total enantiocontrol of the process.     

Orthogonal Synthesis of Xeno Nucleic Acids

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).     

Living cationic polymerization of a vinyl ether with an unprotected pendant alkynyl group and their use for the protecting group‐free synthesis of macromonomer‐type glycopolymers via CuAAC with maltosyl azides

An asymmetric bifunctional monomer having both an unprotected alkynyl group and a vinyl ether (VE) group (3‐[2‐(2‐vinyloxyethoxy)‐ethoxy]‐propyne [VEEP]) was newly designed and found that the polymerization of VEEP smoothly proceeded in a controlled manner under a living cationic polymerization condition to give alkyne‐substituted polyVE (polyVEEP) without any protection of the pendant alkynyl function. Next, the use of an initiator with a methacryloyl moiety for the living cationic polymerization of VEEP afforded macromonomer‐type polyVE (MA‐PVEEP) carrying pendant alkynyl groups. The potential ability of the resultant macromonomer as an alkyne‐substituted polymer for the copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) was also confirmed. A novel macromonomer‐type glycopolymer [MA‐P(VE‐Mal)] having pendant maltose residues and a terminal methacryloyl group was successfully synthesized by CuAAC of MA‐PVEEP with maltosyl azide. Thus, a new pathway to the controlled synthesis of macromonomer‐type glycopolymers of free from any protecting/deprotecting processes was demonstrated. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 681–688