Photo‐initiated thiol–ene “click” hydrogels from RAFT‐synthesized poly(N‐isopropylacrylamide)

Despite the efficiency and robustness of the widely used copper‐catalyzed 1,3‐dipolar cycloaddition reaction, the use of copper as a catalyst is often not attractive, particularly for materials intended for biological systems. The use of photo‐initiated thiol‐ene as an alternative “click” reaction to synthesize “model networks” is investigated here. Poly(N‐isopropylacrylamide) precursors were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization and were designed to have trithiocarbonate moieties as end groups. This structure design provides opportunity for subsequent end‐group modifications in preparation for thiol‐ene “click.” Two reaction routes have been proposed and studied to yield thiol and ene moieties. The advantages and disadvantages of each reaction path were investigated to propose a simple but efficient route to prepare copper‐free “click” hydrogels. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4626–4636     

Antibacterial poly(ethylene glycol) hydrogels from combined epoxy‐amine and thiol‐ene click reaction

Antibacterial hydrogels containing quaternary ammonium (QA) groups were prepared via a facile thiol‐ene “click” reaction using multifunctional poly(ethylene glycol) (PEG). The multifunctional PEG polymers were prepared by an epoxy‐amine ring opening reaction. The chemical and physical properties of the hydrogels could be tuned with different crosslinking structures and crosslinking densities. The antibacterial hydrogel structures prepared from PEG Pendant QA were less well‐defined than those from PEG Chain‐End QA. Furthermore, functionalization of the PEG‐type hydrogels with QA groups produced strong antibacterial abilities against Staphylococcus aureus, and therefore has the potential to be used as an anti‐infective material for biomedical devices. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 656–667     

In situ fabrication of paclitaxel‐loaded core‐crosslinked micelles via thiol‐ene “click” chemistry for reduction‐responsive drug release

In this study, a facile method to fabricate reduction‐responsive core‐crosslinked micelles via in situ thiol‐ene “click” reaction was reported. A series of biodegradable poly(ether‐ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4‐butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf)₃] as the catalyst. Then paclitaxel (PTX)‐loaded core‐crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol‐ene “click” chemistry using 2,2′‐dithiodiethanol diacrylate as the crosslinker. These PTX‐loaded CCL micelles with disulfide bonds exhibited reduction‐responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX‐loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK‐8) assays revealed that the reduction‐sensitive PTX‐loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction‐insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 99–107     

Macrocyclization of polymers via ring‐closing metathesis and azide/alkyne‐“click”‐reactions: An approach to cyclic polyisobutylenes

The end‐to‐end cyclization of telechelic polyisobutylenes (PIB's) toward cyclic polyisobutylenes is reported, using either ring‐closing metathesis (RCM) or the azide/alkyne‐“click”‐reaction. The first approach uses bisallyl‐telchelic PIB's (M_n = 1650, 3680, 9770 g mol^?1) and Grubbs 1st‐, 2nd‐, and 3rd‐generation catalyst leading to cyclic PIB's in 60–80% yield, with narrow polydispersities (M_w/M_n = 1.25). Azide/alkyne‐“click”‐reactions of bisalkyne‐telechelic PIB's (M_n = 3840 and 9820 g mol^?1) with excess of 1,11‐diazido‐undecane leads to the formation of mixtures of linear/cyclic PIB's under formation of oligomeric cycles. Subsequent reaction of the residual azide‐moieties in the linear PIB's with excess of alkyne‐telechelic PEO enables the chromatographic removal of the resulting linear PEO‐PIB‐block copolymers by column chromatography. Thus pure cyclic PIB's can be obtained using this double‐“click”‐method, devoid of linear contaminants. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 671–680, 2010     

Dendron–polymer conjugates via the diels–alder “click” reaction of novel anthracene‐based dendrons

Diblock and triblock dendron–polymer conjugates containing biodegradable polyester dendron blocks and polyethylene glycol (PEG) polymer were synthesized using the Diels–Alder “click” cycloaddition reaction. PEG polymers with furan‐protected maleimide functionality were synthesized and reacted with biodegradable polyester dendrons containing an anthracene moiety at their focal point. First through third generations of biodegradable polyester dendrons containing an anthracene unit at their focal point were synthesized using a divergent strategy. Efficient conjugation of the dendrons to polymers was demonstrated using ¹HNMR and size exclusion chromatography. This modular approach provides an easy access to the design of multivalent PEG conjugates. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3191–3201     

Versatile functionalization of aromatic polysulfones via thiol‐ene click chemistry

A facile, efficient approach for preparation of functionalized aromatic polysulfones by postpolymerization modification with thiol‐ene click chemistry is described. The key synthetic strategy is to incorporate a pendant vinyl ether group into polysulfones as a reactive precursor with controlled degrees of functionalization. Synthetic utility of the pendant alkenyl group is demonstrated by generating diverse polymer derivatives using thiol‐ene functionalization including glycosylated polysulfone. The highly reactive alkene platform in the polymer affords convenient, metal‐free, and azide‐free click transformations to create diverse ranges of new functionalized polysulfones that could be applied in various applications. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3237–3243     

Dendronized polymers via Diels–Alder “click” reaction

A modular approach toward the synthesis of polymers containing dendron groups as side chains is developed using the Diels–Alder “click” reaction. For this purpose, a styrene‐based polymer appended with anthracene groups as reactive side chains was synthesized. First through third‐generation polyester dendrons containing furan‐protected maleimide groups at their focal point were synthesized. Facile, reagent‐free, thermal Diels–Alder cycloaddition between the anthracene‐containing polymer and latent‐reactive dendrons leads to quantitative functionalization of the polymer chains to afford dendronized polymers. The efficiency of this functionalization step was monitored using ¹H and ¹³C NMR spectroscopy and FTIR and UV–vis spectrometry. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 410–416, 2010     

Synthesis and characterization of star graft copolymers with asymmetric mixed “V‐shaped” side chains via “click” chemistry on a hyperbranched polyglycerol core

The star graft copolymers composed of hyperbranched polyglycerol (HPG) as core and well defined asymmetric mixed “V‐shaped” identical polystyrene (PS) and poly(tert‐butyl acrylate) as side chains were synthesized via the “click” chemistry. The V‐shaped side chain bearing a “clickable” alkyne group at the conjunction point of two blocks was first prepared through the combination of anionic polymerization of styrene (St) and atom transfer radical polymerization of tert‐butyl acrylate (tBA) monomer, and then “click” chemistry was conducted between the alkyne groups on the side chains and azide groups on HPG core. The obtained star graft copolymers and intermediates were characterized by gel permeation chromatography (GPC), GPC equipped with a multiangle laser‐light scattering detector (GPC‐MALLS), nuclear magnetic resonance spectroscopy and fourier transform infrared. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1308–1316, 2009     

One‐pot preparation of ABA‐type block‐graft copolymers via a combination of “click” chemistry with atom transfer nitroxide radical coupling reaction

A new strategy for the one‐pot preparation of ABA‐type block‐graft copolymers via a combination of Cu‐catalyzed azide‐alkyne cycloaddition (CuAAC) “click” chemistry with atom transfer nitroxide radical coupling (ATNRC) reaction was reported. First, sequential ring‐opening polymerization of 4‐glycidyloxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (GTEMPO) and 1‐ethoxyethyl glycidyl ether provided a backbone with pendant TEMPO and ethoxyethyl‐protected hydroxyl groups, the hydroxyl groups could be recovered by hydrolysis and then esterified with 2‐bromoisobutyryl bromide, the bromide groups were converted into azide groups via treatment with NaN₃. Subsequently, bromine‐containing poly(tert‐butyl acrylate) (PtBA‐Br) was synthesized by atom transfer radical polymerization. Alkyne‐containing polystyrene (PS‐alkyne) was prepared by capping polystyryl‐lithium with ethylene oxide and subsequent modification by propargyl bromide. Finally, the CuAAC and ATNRC reaction proceeded simultaneously between backbone and PtBA‐Br, PS‐alkyne. The effects of catalyst systems on one‐pot reaction were discussed. The block‐graft copolymers and intermediates were characterized by size‐exclusion chromatography, ¹H NMR, and FT‐IR in detail. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Controllable glycosylation of polyphosphazene via radical thiol–yne click chemistry

We describe a versatile approach to synthesize glycosylated polyphosphazenes with controllable density of glycosyl groups. These glycopolymers have been synthesized by the nucleophilic substitution of poly(dichlorophosphazene) with propargylamine and subsequent “thiol–yne” click reaction between poly[di(propargylamine)phosphazene] and 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D ‐glucopyranose (SH‐GlcAc₄). The polymers were characterized with FTIR and ¹H NMR. We found that the high steric hindrance of SH‐GlcAc₄ plays a key role in the overall reaction process, and ～55% of the alkyne groups participate in the “thiol–yne” click reaction. About 8% of the alkyne groups convert to alkene groups at the end of click reaction. The substitution of alkyne/alkane mixture was conducted to reduce the alkyne density in the side groups of polyphosphazenes and minimize the influences of this steric effect. Mixed‐substituent polyphosphazene was synthesized with 2:3 ratio of alkyne and alkane. In this case, almost no alkyne group remains after the “thiol–yne” click reaction, and thus the glycosylated polyphosphazene is able to form into micelles through self‐assembly process. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Orthogonal multifunctionalization of aliphatic polycarbonate via sequential Michael addition and radical‐thiol‐ene click reactions

Aliphatic polycarbonate (PC) copolymer is synthesized by ring opening copolymerization of acrylate‐ and allyl‐functional cyclic carbonate monomers. The post‐polymerization functionalization of the resulting copolymer is performed quantitatively using a variety of thiol compounds via sequential Michael addition and photo‐induced radical thiol‐ene click reactions within relatively short reaction time at ambient temperature. This metal‐free click chemistry methodology affords the synthesis of biocompatible PC copolymer with multifunctional groups. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1581–1587     

Cyclic alkoxyamine‐initiator tethered by azide/alkyne‐“click”‐chemistry enabling ring‐expansion vinyl polymerization providing macrocyclic polymers

A cyclic initiator for the nitroxide‐mediated controlled radical polymerization (NMP) is a powerful tool for the preparation of macrocyclic polymers via a ring‐expansion vinyl polymerization mechanism. For this purpose, we prepared a Hawker‐type NMP‐initiator that includes an azide and a terminal alkyne as an acyclic precursor, which is subsequently tethered via an intramolecular azide/alkyne‐“click”‐reaction, producing the final cyclic NMP‐initiator. The polymerization reactions of styrene with cyclic initiator were demonstrated and the resultant polymers were characterized by the gel permeation chromatography (GPC) and the matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS). These results prove that the ring‐expansion polymerization of styrene occurred together with the radical ring‐crossover reactions originating from the exchange of the inherent nitroxides generating macrocyclic polystyrenes with higher expanded rings. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3402–3416, 2010     

Injectable poly(ethylene glycol) hydrogels for sustained doxorubicin release

Water‐soluble poly(ethylene glycol) derivatives with multiple “clickable” mercapto groups or double bonds were facilely synthesized in a large scale by direct polycondensation of oligo(ethylene glycol) diol with mercaptosuccinic acid or maleic acid catalyzed by scandium trifluoromethanesulfonate under mild conditions. Injectable hydrogels containing doxorubicin hydrochloride (DOX · HCl) could be rapidly formed using these poly(ethylene glycol) derivatives as precursors via in situ thiol‐ene “click” reaction under physiological conditions without light, initiator, or metal catalyst. DOX · HCl could be sustained released from the hydrogels as a result of the hindrance of the three dimensional hydrogel network on the drug molecules, which makes this kind of DOX‐loaded hydrogels a promising candidate for localized tumor chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.     

Photocatalyzed thiol–alkene coupling: Mechanistic study and polymer synthesis

Due to the “click” chemistry characteristics of the thiol–ene reaction, these transformations have been gaining an increasing amount of attention in current chemical research. The high efficiency and selectivity of these transformations have been useful for many areas of study, from small molecule organic synthesis, to polymer synthesis and functionalization, to bio‐conjugation reactions. In this work, a study of a novel method of photochemical thiol–ene reactions using alkyl halides and an tris[2‐phenylpyridinato‐C2,N]iridium(III) (Ir(ppy)₃) photocatalyst is investigated. This process is shown to progress rapidly and has the benefit of low catalyst and initiator concentrations relative to reagents as well as mild conditions associated with photochemical processes. To understand the mechanism of this process, catalyst and initiator concentrations and other reaction conditions are varied. To demonstrate the utility of this process, a step‐growth thiol–ene polymer is synthesized using dithiol and diene monomers and a crosslinked polymer network is synthesized as well. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1931–1937     

Functional aliphatic polyesters and nanoparticles prepared by organocatalysis and orthogonal grafting chemistry

We describe the use of organic catalysis for the ring‐opening polymerization of functionalized lactones and conversion of the resulting aliphatic polyesters into crosslinked nanoparticles that carry additional functional groups amenable to further modification. Specifically, highly functional aliphatic polyester homopolymers, as well as random and block copolymers, were prepared by 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene catalysis, giving polyesters with pendent alkene and alkyne groups. Azide‐alkyne click and thiol‐ene chemistries were used for postpolymerization modification of diblock copolymers possessing alkene groups on one block and alkyne groups on the other block. The polyesters were crosslinked using azide/alkyne cycloaddition, by reaction of α,ω‐diazides with the pendent alkynes on the polyester backbone. This gave polyester nanoparticles possessing alkene functionality, which were subjected to further modification using thiol‐ene reactions to introduce additional functionality. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Copper(0)‐catalyzed one‐pot synthesis of ABC triblock copolymers via the combination of single electron transfer nitroxide radical coupling reaction and “click” chemistry

The synthesis of ABC triblock copolymers were accomplished by Cu(0)‐catalyzed one‐pot strategy combining single electron transfer‐nitroxide radical coupling (SET‐NRC) reaction with “click” chemistry. First, the precursors α,ω‐heterofunctionalized poly(ethylene oxide) (PEO) with a 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) group and an alkyne group, polystyrene (PS), and poly(tert‐butyl acrylate) (PtBA) with bromine or azide end group were designed and synthesized, respectively. Then, the one‐pot coupling reactions between these precursors were carried out in the system of Cu(0)/Me₆TREN: The SET‐NRC reaction between bromine group and nitroxide radical group, subsequently click coupling between azide and alkyne group. It was noticeable that Cu(I) generated from Cu(0) by SET mechanism was utilized to catalyze click chemistry. To estimate the effect of Cu(0) on the one‐pot reaction, a comparative analysis was performed in presence of different Cu(0) species. The result showed that Cu(0) with more active surface area could accelerate the one‐pot reaction significantly. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of a novel graft copolymer with hyperbranched poly(glycerol) as core and “Y”‐shaped polystyrene‐b‐poly(ethylene oxide)2 as side chains

The graft copolymers composed of “Y”‐shaped polystyrene‐b‐poly(ethylene oxide)₂ (PS‐b‐PEO₂) as side chains and hyperbranched poly(glycerol) (HPG) as core were synthesized by a combination of “click” chemistry and atom transfer radical polymerization (ATRP) via “graft from” and “graft onto” strategies. Firstly, macroinitiators HPG‐Br were obtained by esterification of hydroxyl groups on HPG with bromoisobutyryl bromide, and then by “graft from” strategy, graft copolymers HPG‐g‐(PS‐Br) were synthesized by ATRP of St and further HPG‐g‐(PS‐N₃) were prepared by azidation with NaN₃. Then, the precursors (Bz‐PEO)₂‐alkyne with a single alkyne group at the junction point and an inert benzyl group at each end was synthesized by sequentially ring‐opening polymerization (ROP) of EO using 3‐[(1‐ethoxyethyl)‐ethoxyethyl]‐1,2‐propanediol (EEPD) and diphenylmethylpotassium (DPMK) as coinitiator, termination of living polymeric species by benzyl bromide, recovery of protected hydroxyl groups by HCl and modification by propargyl bromide. Finally, the “click” chemistry was conducted between HPG‐g‐(PS‐N₃) and (Bz‐PEO)₂‐alkyne in the presence of N,N,N′,N″,N”‐pentamethyl diethylenetriamine (PMDETA)/CuBr system by “graft onto” strategy, and the graft copolymers were characterized by SEC, ¹H NMR and FTIR in details. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Azide/alkyne‐“click”‐reactions on amino resin materials: An LC‐ESI‐TOF analysis

This article describes the reaction of amino resins with functional molecules using the azide/alkyne‐“click”‐reaction, opening a simple chemical modification of amino resins under aqueous conditions. Alkyne‐modified melamine‐formaldehyde resins are prepared via a direct cocondensation approach using propargylic alcohol (21.6–86.3 mmol) as additive. Subsequently, alkyne‐modified mono‐, bi‐, and trinuclear melamine‐species are identified via LC‐ESI‐TOF methods proving the covalent incorporation of alkyne‐moieties in amounts of up to 3.9 mol %. Subsequent modification of the alkyne‐modified resins was accomplished by reaction of functional azides (octyl azide (1), (azidomethyl)benzene (2), 1‐(6‐azidohexyl) thymine (3), and 4‐azido‐N‐(2,2,6,6‐tetramethylpiperidin‐4‐yl)benzamide (4)) with Cu(I)Br and DIPEA as a base. The formation of triazolyl‐modified MF‐resins was proven by LC‐ESI‐TOF methods, indicating the successful covalent modification of the amino resin with the azides 1 – 4 . © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Postfunctionalization of polyoxanorbornene via sequential Michael addition and radical thiol‐ene click reactions

We demonstrated the successful postfunctionalization of poly(oxanorbornene imide) (PONB) with two types of double bonds using sequential orthogonal reactions, nucleophilic thiol‐ene coupling via Michael addition and radical thiol‐ene click reactions. First, the synthesis of PONB with side chain acrylate groups is carried out via ring‐opening metathesis polymerization and nitroxide radical coupling reaction, respectively. Subsequently, the resulting polymer having two different orthogonal functionalities, main chain vinyl and side chain acrylate, is selectively modified via two sequential thiol‐ene click reactions, nucleophilic thiol‐ene coupling via Michael addition and photoinduced radical thiol‐ene. The orthogonal reactivity of two diverse double bonds, vinyl and acrylate functionalities, for the abovementioned consecutive thiol‐ene click reactions was first demonstrated on the model compound. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis of Novel Core Cross‐Linked Star‐Based Polyrotaxane End‐Capped via “CuAAC” Click Chemistry

The first example of core cross‐linked star (CCS) polyrotaxane was prepared using the poly(ϵ‐caprolactone) (PCL) CCS three‐dimensional (3D) scaffold. The 3D CCS polymer was firstly prepared through the “arm‐first” approach. Then, the “arms” of the resultant PCL CCS polymer were threaded with α‐cyclodextrins (α‐CDs). The threaded α‐CDs were permanently locked by the “click” reaction of terminal alkyne functionalities of the star polymers with the azide‐functionalized end caps to afford the CCS polyrotaxanes. All analytical results confirm the formation of the CCS polyrotaxanes and reveal their characteristics, including fluorescence under UV, a channel‐type crystalline structure, a two‐step thermal decomposition, and a unique core‐shell structure in great contrast to the polymer precursors.