NMR and mass spectral analysis of step-growth polymers from azide alkyne cycloaddition and regioselectivity afforded by copper(I) and ruthenium(II) catalysts

Azide alkyne cycloaddition was applied to step growth polymerization of the diazido monomer, di(3-azido-2-hydroxypropyl) ether of bisphenol-A (DAHP-BPA) with either tetraethyleneglycol dipropargyl ether (TEGDPE) or tetraethyleneglycol dipropiolate (TEGDP). Polymerizations were conducted without catalyst and in the presence of Cu(I) or Ru(II) complex. The resulting oligomers and polymers were characterized using ¹H- and ¹³C-NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), with an emphasis on the relative abundance of 1,4- vs. 1,5-disubstituted regioisomeric 1,2,3-triazoles. Uncatalyzed reaction of DAHP-BPA/TEGDPE at 70°C yielded a 55/45 mixture of 1,4/1,5-disubstituted triazoles; reaction was slow and residual alkyne end groups were observed, suggesting attritional loss of azide. Catalyzed with Cu(PPh₃)₃Br, the same system yielded 93/7, 1,4/1,5-disubstituted triazoles, and few residual end groups were detected, consistent with higher molecular weight and controlled 1:1 depletion of azide and alkyne. Cp*RuCl(COD) catalyst was not soluble in the bulk system, necessitating solution polymerization in THF. Ru(II) yielded 6/94, 1,4/1,5-disubstituted triazoles, and MALDI-TOF-MS showed an end group composition similar to that observed with Cu(I). Uncatalyzed reaction of the DAHP-BPA/TEGDP system, involving the more reactive propiolate, yielded a high proportion (85%) of 1,4-disubstituted triazole linkages, and MALDI-TOF-MS revealed a controlled 1:1 depletion of azide and alkyne groups.     

Cu Nano particles immobilized on silk‐fibroin as a green and biodegradable catalyst for copper catalyzed azide‐terminal,internal alkynes cycloaddition

Copper immobilized on silk fibroin was successfully prepared and fully characterized using powder X‐ray diffraction, scanning electron microscopy–energy‐dispersive X‐ray spectroscopy, Fourier transform‐infrared, CHN elemental analysis, and inductively coupled plasma‐atomic emission spectroscopy. Catalytic activity of this catalyst was examined in the azide‐alkyne cycloaddition reaction with internal and terminal alkynes at room temperature under mild conditions. The reusability of the heterogeneous supported Cu catalyst was examined four times without significant loss of catalytic activity.     

CuII‐Catalyzed Oxidative Formation of 5‐Alkynyltriazoles

In an alcoholic solvent under the catalysis of Cu(OAc)₂?H₂O, organic azide and terminal alkyne could oxidatively couple to afford 5‐alkynyl‐1,2,3‐triazole (alkynyltriazole) at room temperature under an atmosphere of O₂ in a few hours. The involvement of 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) is essential, without which the redox neutral coupling instead proceeds to produce 5‐H‐1,2,3‐triazole (protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between terminal alkyne and organic azide, the copper‐catalyzed “click” reaction to afford protiotriazole, to an oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the copper(II)‐catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity between alkynyl‐ and protiotriazole, and other acetylide or triazolide oxidation products is determined by the competition between copper(I)‐catalyzed redox neutral cycloaddition and copper(II)/O₂‐mediated acetylide oxidation after the formation of copper(I) acetylide.     

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.     

Combining Atom Transfer Radical Polymerization and Click Chemistry: A Versatile Method for the Preparation of End‐Functional Polymers

Summary: The bromine chain ends of well‐defined polystyrene ( = 2 700 g · mol⁻¹, = 1.11) prepared using ATRP were successfully transformed into various functional end groups (ω‐hydroxy, ω‐carboxyl and ω‐methyl‐vinyl) by a two‐step pathway: (1) substitution of the bromine terminal atom by an azide function and (2) 1,3‐dipolar cycloaddition of the terminal azide and functional alkynes (propargyl alcohol, propiolic acid and 2‐methyl‐1‐buten‐3‐yne). The “click” cycloaddition was catalyzed efficiently by the system copper bromide/4,4′‐di‐(5‐nonyl)‐2,2′‐bipyridine. In all cases, ¹H NMR spectra indicated quantitative transformation of the chain ends of polystyrene into the desired function.

Preparation of well‐defined functional polymers possessing diverse chain‐end functionalities by the combination of atom transfer radical polymerization and click chemistry.     

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     

Benedict's solution/ vitamin C: An alternative catalytic protocol for the synthesis of regioselective‐1,4‐disubstituted‐1H‐1,2,3‐triazoles at room temperature

A novel and highly efficient method for the synthesis of 1,4‐disubstituted‐1H‐1,2,3‐triazoles by copper‐catalyzed azide‐alkyne cycloaddition has been developed. This economic and sustainable protocol uses a readily available Benedict's solution/Vitamin C catalyst system affording a wide range of 1,4‐disubstituted‐1H‐1,2,3‐triazoles under mild conditions.     

Quantification of ATRP initiator density on polymer latex particles by fluorescence labeling technique using copper‐catalyzed azide‐alkyne cycloaddition

We developed a novel fluorescence labeling technique for quantification of surface densities of atom transfer radical polymerization (ATRP) initiators on polymer particles. The cationic P(St‐CPEM‐C₄DMAEMA) and anionic P(St‐CPEM) polymer latex particles carrying ATRP‐initiating chlorine groups were prepared by emulsifier‐free emulsion polymerization of styrene (St), 2‐(2‐chloropropionyloxy)ethyl methacrylate (CPEM), and N‐n‐butyl‐N,N‐dimethyl‐N‐(2‐methacryloyloxy)ethylammonium bromide (C₄DMAEMA). ATRP initiators on the surface of polymer particles were converted into azide groups by sodium azide, followed by fluorescent labeling with 5‐(N,N‐dimethylamino)‐N′‐(prop‐2‐yn‐1‐yl)naphthalene‐1‐sulfonamide (Dansyl‐alkyne) by copper‐catalyzed azide‐alkyne cycloaddition (CuAAC). The reaction time required for both azidation of ATRP‐initiating groups and successive fluorescence labeling of azide groups with Dansyl‐alkyne by CuAAC were investigated in detail by FTIR and fluorescence spectral measurement, respectively. The ATRP initiator densities on the cationic P(St‐CPEM‐C₄DMAEMA) and anionic P(St‐CPEM) particle surfaces were estimated to be 0.21 and 0.15 molecules nm^?2, respectively, which gave close agreement with values previously determined by a conductometric titration method. The fluorescence labeling through click chemistry proposed herein is a versatile technique to quantify the surface ATRP initiator density both on anionic and cationic polymer particles. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4042–4051     

Spinel copper ferrite nanoparticles: Preparation,characterization and catalytic activity

The magnetic CuFe₂O₄ nanoparticles have been synthesized and characterized by various spectroscopic methods, including X‐ray diffraction (XRD), O K, Cu and Fe K ‐edge X‐ray absorption near edge structure (XANES), energy dispersive X‐ray analysis (EDX), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The azide‐alkyne cycloaddition by the reaction of various phenylacetylenes with a mixture of benzyl halides and NaN₃ and also three component (A³) coupling reaction of aldehyde, alkyne and amine catalyzed by CuFe₂O₄ nanoparticles under aerobic conditions led to the formation of the 1,4‐disubstituted‐1,2,3‐triazoles and propargylamines in excellent yields. The catalyst can be recovered by applying an external magnetic field for the subsequent cycloaddition reactions and reused without any tangible loss in catalytic efficiency.     

1,4-二取代-1,2,3-三唑衍生物的合成

在超声波辐射下,端基炔与叠氮基(3,3-二甲基-2,4-二氧戊环基)甲烷通过1,3-偶极环加成合成了1-(3,3-二甲基-2,4-二氧戊环基甲基)-4-芳基-1,2,3-三唑(5);5在酸性条件下脱保护得1-(2,3-二羟基丙基)-4-芳基-1,2,3-三唑,其结构经1H NMR,13C NMR,MS和元素分析表征。     

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

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 ¹H nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared spectroscopy, and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry.

     

Claycop/hydrazine: A new and highly efficient recyclable/reusable catalytic system for 1,4‐disubstituted‐1,2,3‐triazole synthesis under solvent‐free conditions

Clay‐supported copper(II) nitrate (claycop) has been used as an efficient catalyst for azide–alkyne cycloaddition reactions leading to 1,4‐disubstituted 1,2,3‐triazoles. The highly efficient claycop/hydrazine hydrate catalytic system affords triazoles in a few minutes (1–20 min) at room temperature, under mild and solvent‐free conditions. High regioselectivity, excellent yields, ease of claycop synthesis and recyclability/reusability of the catalyst are considered as practical merits of the protocol.     

A UV‐Cleavable Bottlebrush Polymer with o‐Nitrobenzyl‐Linked Side Chains

An ultraviolet (UV)‐cleavable bottlebrush polymer is synthesized using the “grafting‐onto” strategy by combining living radical polymerization and copper‐catalyzed azide‐alkyne cycloaddition (CuAAC). In this approach, reversible addition‐fragmentation chain transfer polymerization is used to prepare a poly(methylacrylate) backbone with azide side groups, while atom transfer radical polymerization is employed to prepare polystyrene (PS) side chains end‐functionalized with o‐nitrobenzyl (UV‐cleavable) propargyl groups. CuAAC is then used to graft PS side chains onto the polymer backbone, producing the corresponding bottlebrush polymers with UV‐cleavable PS side chains. The formation of the bottlebrush polymer is characterized by ¹H nuclear magnetic resonance spectroscopy, gel permeation chromatography (GPC), and Fourier transform infrared spectroscopy. The cleavage behavior of the bottlebrush polymer is monitored in tetrahydrofuran solution under UV irradiation by GPC and viscosity measurements.

     

Functional polyisobutylenes via a click chemistry approach

1‐(ω‐Azidoalkyl)pyrrolyl‐terminated polyisobutylene (PIB) was successfully synthesized both by substitution of the terminal halide of 1‐(ω‐haloalkyl)pyrrolyl‐terminated PIB with sodium azide and by in situ quenching of quasiliving PIB with a 1‐(ω‐azidoalkyl)pyrrole. Azide substitution of the terminal halide was carried out in 50/50 heptane/DMF at 90 °C for 24 h using excess azide. The 1‐(ω‐haloalkyl)pyrrolyl‐PIB precursors included 1‐(2‐chloroethyl)pyrrolyl‐PIB, 1‐(2‐bromoethyl)pyrrolyl‐PIB, and 1‐(3‐bromopropyl)pyrrolyl‐PIB. In situ quenching involved direct addition of 1‐(2‐azidoethyl)pyrrole to quasiliving PIB initiated from 5‐tert‐butyl‐1,3‐di(1‐chloro‐1‐methylethyl)benzene (bDCC)/TiCl₄ at ?70 °C in hexane/CH₃Cl (60/40, v/v). ¹H NMR analysis of the quenched product revealed mixed isomeric end groups in which PIB was attached at either C₂ or C₃ of the pyrrole ring (C₂/C₃ = 0.40/0.60). SEC indicated the absence of coupled PIB under optimized conditions, confirming exclusive mono‐substitution on each pyrrole ring. 1‐(3‐Azidopropyl)pyrrolyl‐PIB was reacted in modular fashion with various functional alkynes, propargyl alcohol, propargyl acrylate, glycidyl propargyl ether, and 3‐dimethylamino‐1‐propyne, via a Huisgen 1,3‐dipolar cycloaddition (Click) reaction, using Cu(I)Br/N,N,N′,N″,N″‐pentamethyldiethylenetriamine or bromtris(triphenylphosphine)Cu(I) as catalyst. The reactions were quantitative and produced PIBs bearing terminal hydroxyl, acrylate, glycidyl, or dimethylaminomethyl groups attached via exclusively four‐substituted triazole linkages. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2533–2545, 2010     

Strain‐Promoted Azide–Alkyne Cycloaddition with Ruthenium(II)–Azido Complexes

The reactivity of an exemplary ruthenium(II)–azido complex towards non‐activated, electron‐deficient, and towards strain‐activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non‐activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron‐deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non‐4‐yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X‐ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3‐triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second‐order rate constant for the ADIBO cycloaddition with the azido complex (k₂=6.9 × 10^?2 M ^?1 s^?1) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k₂=4.0 × 10^?1 M ^?1 s^?1). Our results demonstrate that it is possible to transfer the concept of strain‐promoted azide–alkyne cycloaddition (SPAAC) from purely organic azides to metal‐coordinated azido ligands. The favorable reaction kinetics for the ADIBO‐azido‐ligand cycloaddition and the well‐proven bioorthogonality of strain‐activated alkynes should pave the way for applications in living biological systems.     

Synthesis of tadpole polymers via triple click reactions: Copper‐catalyzed azide–alkyne cycloaddition,diels–alder,and nitroxide radical coupling reactions

We designed a trifunctional initiator ( 3 ) containing anthracene, bromide, and OH functionalities and subsequently used as an initiator in atom transfer radical Polymerization (ATRP) of styrene to yield linear polystyrene (PS) with α‐anthracene, OH, and ω‐bromide terminal groups, of which bromide is later transformed into azide to result in the linear anthracene‐, OH‐, and azide‐terminated PS (l‐α‐anthracene‐OH‐ω‐azide‐PS). The copper‐catalyzed azide–alkyne cycloaddition reaction between l‐α‐anthracene‐OH‐ω‐azide‐PS and α‐furan‐protected‐maleimide‐ω‐alkyne linkage, 4 afforded the linear anthracene‐, OH‐, and maleimide‐terminated PS. The cyclization via intramolecular Diels–Alder click reaction of this linear PS and the subsequent conversion of the hydroxyl into bromide resulted in the cyclic PS with one bromide located on the ring, (c‐PS)‐Br. Finally, the c‐PS‐Br was clicked with either well‐defined tetramethylpiperidine‐1‐oxyl‐terminated poly(ethylene glycol) (PEG) or poly(ε‐caprolactone) (PCL) yielding the tadpole polymer, (c‐PS)‐b‐PEG or (c‐PS)‐b‐PCL. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Preparation of Fluorescent Organometallic Porphyrin Complex Nanogels of Controlled Molecular Structure via Reverse‐Emulsion Click Chemistry

Here, we are the first to report a novel approach to preparing well‐defined poly(ethylene glycol) (PEG) fluorescent nanogels, with well‐defined molecular structures and desired functionalities via reverse (mini)emulsion copper(I)‐catalyzed azide‐alkyne cycloaddition (REM‐CuAAC). Nanogels with hydroxyl groups and Ga‐porphyrin complex (Ga‐porphyrin‐OH nanogels), as well as with Ga‐porphyrin complex and folate functional groups (Ga‐porphyrin‐FA), are successfully prepared. Nanogels of 30 and 120 nm in diameter are obtained and they exhibit an emission maxima within the wavelength range 700–800 nm. The nanogels could find uses in near infrared (NIR) imaging attributable to their fluorescence and their functionality for cell affinity.     

Preparation of side‐chain liquid crystalline Azopolymers by CuAAC postfunctionalization using bifunctional azides: Induction of chirality using circularly polarized light

Well‐defined side‐chain liquid crystal azopolymers have been synthesized by click chemistry of poly(propargyl methacrylate) with bifunctional liquid crystalline azides to produce materials with large degrees of functionalization. A polymeric scaffold having pendant alkyne groups was prepared by atom transfer radical polymerization (ATRP) and postfunctionalized by copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) using homo‐ and heterobifunctional azides. The azides are derivatives of 2,2‐bis(hydroxymethyl)propanoic acid (bis‐MPA) containing photoresponsive azobenzene and/or liquid crystalline biphenyl moieties. The approach is a convenient alternative to increase the density of functional units in side‐chain polymers having moderate polymerization degrees and to modulate the properties of the final material. The article describes the synthesis, characterization, and liquid crystalline properties of the obtained polymers. The effect of the chemical structure and the possible cooperative effects between functional units in the photo‐induction of chirality are also evaluated. A switchable photo‐transference of chirality from the circularly polarized light (CPL) to material has been achieved. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Stereoselective Synthesis of 1,2,3‐Triazolooxazine and Fused 1,2,3‐Triazolo‐δ‐Lactone Derivatives

The stereoselective synthesis of 1,2,3‐triazolooxazine and fused 1,2,3‐triazolo‐δ‐lactone by applying chemoenzymatic methods is described. trans‐2‐Azidocyclohexanol was successfully resolved by Novozyme 435 with an ee value of 99%. Installation of the alkyne moiety on the enantiomerically enriched azidoalcohol by O‐alkylation, followed by intramolecular azide? alkyne [3+2] cycloaddition resulted in the desired 1,2,3‐triazolooxazine derivative. Enantiomerically pure azidocyclohexanol was also subjected to the Huisgen 1,3‐dipolar cycloaddition reaction with dimethylacetylene dicarboxylate, followed by intramolecular cyclization of the corresponding cycloadduct, to furnish a fused 1,2,3‐triazolo‐δ‐lactone.     

Preparation of 1H‐1,2,3‐Triazoles by Cuprous Ion Mediated Cycloaddition of Terminal Alkyne and Sodium Azide

1H‐1,2,3‐triazoles can be prepared in good yield by the reaction of terminal alkyne and sodium azide in the presence of cuprous chloride at a temperature higher than 70°C. The alkyne is unactivated and the reaction has to be carried out under inert gas. At room temperature, the reaction first gives a Cu(I)‐azide complex which is converted to a Cu‐alkyne complex when the temperature is raised to higher than 70°C. The reaction of Cu(I)‐alkyne complex and azide ion dissociated from or coordinated to Cu(I) then gives 1H‐1,2,3‐triazoles.