Combining “click” chemistry and step‐growth polymerization for the generation of highly functionalized polyesters

Aliphatic polyesters bearing pendant alkyne groups were successfully prepared by step‐growth polymerization of different building blocks such as adipic acid and succinic acid in combination with an acetylene‐based diol, 2‐methyl‐2‐propargyl‐1,3‐propanediol, besides 1,4‐butanediol and ethylene glycol. It was demonstrated that the alkyne groups survive the high reaction temperatures (200 °C) in the presence of a radical inhibitor. The alkyne loading has been tuned by the ratio of the different monomers used, up to 25 mol % of alkyne groups. Subsequently, the alkyne groups have been reacted with azides by the copper‐catalyzed Huisgen 1,3‐dipolar cycloaddition reaction, a popular type of “click” chemistry. “Click” reactions have been performed quantitatively in the presence of benzyl azide and azide‐terminated poly(ethylene glycol), yielding brush copolymers in the latter case. Kinetic investigations about this click reaction have been performed by means of on‐line Fourier transform mid‐infrared spectroscopy, which was reported for the first time in the field of the click chemistry research. A whole range of functionalized polyesters, based on poly(ethylene succinate) and poly(butylene adipate), is available, the properties of which can be tailored by choosing the appropriate azide compound. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6552–6564, 2008     

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     

Degradable star polymers with high “click” functionality

Degradable polyester‐based star polymers with a high level of functionality in the arms were synthesized via the “arms first” approach using an acetylene‐functional block copolymer macroinitiator. This was achieved by using 2‐hydroxyethyl 2′‐methyl‐2′‐bromopropionate to initiate the ring‐opening polymerization (ROP) of caprolactone monomer followed by an atom transfer radical polymerization (ATRP) of a protected acetylene monomer, (trimethylsilyl)propargyl methacrylate. The hydroxyl end‐group of the resulting block copolymer macroinitiator was subsequently crosslinked under ROP conditions using a bislactone monomer, 4,4′‐bioxepanyl‐7,7′‐dione, to generate a degradable core crosslinked star (CCS) polymer with protected acetylene groups in the corona. The trimethylsilyl‐protecting groups were removed to generate a CCS polymer with an average of 1850 pendent acetylene groups located in the outer block segment of the arms. The increased functionality of this CCS polymer was demonstrated by attaching azide‐functionalized linear polystyrene via a copper (I)‐catalyzed cycloaddition reaction between the azide and acetylene groups. This resulted in a CCS polymer with “brush‐like” arm structures, the grafted segment of which could be liberated via hydrolysis of the polyester star structure to generate molecular brushes. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1485–1498, 2009     

Thiol‐epoxy “click” chemistry: Application in preparation and postpolymerization modification of polymers

Base‐catalyzed reaction between a thiol and an epoxide group is a simple fusion process that leads to the formation of a β‐hydroxythio‐ether linkage. This reaction is efficient, regio‐selective, and fast. In addition, it produces a reactive hydroxyl group upon completion. Therefore, it is of considerable potential in synthesis of reactive and functional soft materials. Here, we discuss the fundamental aspects of this process, the so‐called thiol‐epoxy “click” reaction, and its utility in the preparation and post‐polymerization functionalization of polymers and crosslinked networks. Furthermore, its application in surface modification of solid substrates is also considered. Finally, utility of multifunctional materials created using the thiol‐epoxy reaction is discussed in the biomedical arena. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3057–3070     

Modular synthesis of ABC type block copolymers by “click” chemistry

Heterotelechelic polystyrene (PS), poly(tert‐butyl acrylate) (PtBA), and poly (methyl acrylate) (PMA), containing both azide and triisopropylsilyl (TIPS) protected acetylene end groups, were prepared in good control (M_w/M_n ≤ 1.24) by atom transfer radical polymerization (ATRP). The end groups were independently applied in two successive “click” reactions, that is: first the azide termini were functionalized and, after deprotection, the acetylene moieties were utilized for a second conjugation step. As a proof of concept, PS was consecutively functionalized with propargyl alcohol and azidoacetic acid, as confirmed by MALDI‐ToF MS. In addition, the same methodology was employed to modularly build up an ABC type triblock terpolymer. Size exclusion chromatography measurements demonstrated first coupling of PtBA to PS and, after the deprotection of the acetylene functionality on PS, connection of PMA, yielding a PMA‐b‐PS‐b‐PtBA triblock terpolymer. The reactions were driven to completion using a slight excess of azide functionalized polymers. Reduction of the residual azide groups into amines allowed easy removal of this excess of polymer by column chromatography. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2913–2924, 2007     

Click Polyester: Synthesis of Polyesters Containing Triazole Units in the Main Chain by Click Chemistry and Improved Thermal Property

A “click” polymerization of dialkynes that contain an ester linkages and diazides to has been performed to synthesize various polyesters, termed “click polyesters” with a high of 1.0 × 10⁴ to 7.0 × 10⁴ in an excellent yield. This polymerization accompanied a formation of 1,4‐disubstituted triazoles in the polyester main chain by a Cu^I catalyst. The triazole ring formation in the polyester main chain leads to improved thermal properties and enhancement of the even–odd effect of methylene chain length of the produced click polyesters. This report is the first report of the application of click chemistry to synthesize a series of polyesters under mild conditions.

     

Direct synthesis of terminally “clickable” linear and hyperbranched polyesters

1,3‐Dipolar cycloaddition of an organic azide and an acetylenic unit, often referred to as the “click reaction”, has become an important ligation tool both in the context of materials chemistry and biology. Thus, development of simple approaches to directly generate polymers that bear either an azide or an alkyne unit has gained considerable importance. We describe here a straightforward approach to directly prepare linear and hyperbranched polyesters that carry terminal propargyl groups. To achieve the former, we designed an AB‐type monomer that carries a hydroxyl group and a propargyl ester, which upon self‐condensation under standard transesterification conditions yielded a polyester that carries a single propargyl group at one of its chain‐ends. Similarly, an AB₂ type monomer that carries one hydroxyl group and two propargyl ester groups, when polymerized under the same conditions yielded a hyperbranched polymer with numerous “clickable” propargyl groups at its molecular periphery. These propargyl groups can be readily clicked with different organic azides, such as benzyl azide, ω‐azido heptaethyleneglycol monomethylether or 9‐azidomethyl anthracene. When an anthracene chromophore is clicked, the molecular weight of the linear polyester could be readily estimated using both UV–visible and fluorescence spectroscopic measurements. Furthermore, the reactive propargyl end group could also provide an opportunity to prepare block copolymers in the case of linear polyesters and to generate nanodimensional scaffolds to anchor a variety of functional units, in the case of the hyperbranched polymer. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3200–3208, 2010     

Synthesis and postfunctionalization of well‐defined star polymers via “double” click chemistry

In this article, the synthesis and the functionalization of well‐defined, narrow polydispersity (polydispersity index < 1.2) star polymers via reversible addition‐fragmentation chain transfer polymerization is detailed. In this arm first approach, the initial synthesis of a poly(pentafluorophenyl acrylate) polymer, and subsequent, cross‐linking using bis‐acrylamide to prepare star polymers, has been achieved by reversible addition fragmentation chain transfer polymerization. These star polymers were functionalized using a variety of amino functional groups via nucleophilic substitution of pentafluorophenyl activated ester to yield star polymers with predesigned chemical functionality. This approach has allowed the synthesis of star glycopolymer using a very simple approach. Finally, the core of the stars was modified via thiol‐ene click chemistry reaction using fluorescein‐o‐acrylate and DyLigh 633 Maleimide. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis,characterization, and properties of new thermally curable polyetheresters containing benzoxazine moieties in the main chain

High molecular weight polyetheresters (PEE) containing thermally curable benzoxazine units in the main chain have been synthesized. For this purpose, first the diol functional monomer is synthesized through the Mannich reaction of 4,4′‐isopropylidenediphenol (bisphenol A), formaldehyde, and 2‐(2‐aminoethoxy)ethanol. Polycondensation of the resulting benzoxazine dietherdiol with adipoyl chloride and terephthaloyl dichloride in the presence of triethyl amine yields the corresponding PEE with the molecular weights of 34.000 Da. The structures of the precursor diol monomer and the resulting PEEs are confirmed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy (¹H‐NMR) analysis. Curing behavior of both the monomer and polymers has also been studied by differential scanning calorimetry (DSC). Flexible free standing transparent films of the PEEs are obtained by solvent casting from dichloromethane solution on Teflon plates. The films preserve shape and, to some extent, toughness after thermal curing between 140 and 220 °C. Thermal properties of the cured polymers are also investigated by thermogravimetric analysis (TGA). © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 414–420, 2008     

Synthesis of arborescent polystyrene by “click” grafting

A method was developed for the synthesis of arborescent polystyrene by “click” coupling. Acetylene functionalities were introduced on linear polystyrene (M_n = 5300 g/mol, M_w/M_n = 1.05) by acetylation and reaction with potassium hydroxide, 18‐crown‐6 and propargyl bromide in toluene. Polymerization of styrene with 6‐tert‐butyldimethylsiloxyhexyllithium yielded polystyrene (M_n = 5200 g/mol, M_w/M_n = 1.09) with a protected hydroxyl chain end. Deprotection, followed by conversions to tosyl and azide functionalities, provided the side chain material. Coupling with CuBr and N,N,N′,N″,N″‐pentamethyldiethylenetriamine proceeded in up to 94% yield. Repetition of the grafting cycles led to well‐defined (M_w/M_n ≤ 1.1) polymers of generations G1 and G2 in 84% and 60% yield, respectively, with M_n and branching functionalities reaching 2.8 × 10⁶ g/mol and 460, respectively, for the G2 polymer. Coupling longer (M_n = 45,000 g/mol) side chains with acetylene‐functionalized substrates was also examined. For a linear substrate, a G0 polymer with M_n = 4.6 × 10⁵ g/mol and M_w/M_n = 1.10 was obtained in 87% yield; coupling with the G0 (M_n = 52,000 g/mol) substrate produced a G1 polymer (M_n = 1.4×10⁶ g/mol, M_w/M_n = 1.38) in 28% yield. The complementary approach using azide‐functionalized substrates and acetylene‐terminated side chains was also investigated, but proceeded in lower yield. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1730–1740     

Metal‐free synthesis of responsive polymers: Cloud point tuning by controlled “click” reaction

Nitroxide‐mediated radical polymerization has been used for the preparation of pentafluorostyrene (PFS) homopolymers and random copolymers of PFS and oligo(ethyleneglycol) methacrylate (OEGMA_8.5). The poly(pentafluorostyrene) homopolymers were reacted with thiophenol at different ratios at room temperature in the presence of triethylamine. The “clicked” polymers were characterized by ¹H and ¹⁹F NMR spectroscopy and size exclusion chromatography. Moreover, the copolymerization kinetics of the PFS and OEGMA_8.5 copolymers was followed, and the phase transition behavior of random copolymers with different compositions was discussed. Furthermore, copolymers of PFS and 2‐(dimethylamino) ethyl methacrylate (DMAEMA) were prepared at various mole ratios, and the copolymer with a 10:90 ratio, respectively, was soluble in water at room temperature. Turbidimetry measurements were performed for PFS and OEGMA_8.5 or DMAEMA copolymers to determine their cloud points. Finally, the PFS and OEGMA_8.5 copolymer with a mole ratio of 60:40 was reacted further with thiophenol to increase the hydrophobic part in the copolymer. The cloud points of the obtained copolymers could be tuned from 87 to 33 °C by using not only the controlled radical polymerization but also the “click” reaction in a controlled fashion. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1278–1286, 2010     

“Clickable” polymers via a combination of RAFT polymerization and isocyanate chemistry

We describe a facile, one‐pot, two‐step polymerization towards synthesizing block co‐polymers bearing reactive isocyanate functional groups. Reversible addition fragmentation chain transfer (RAFT) polymerization is used to mediate the co‐polymerization of isocyanate‐bearing monomers dimethyl meta‐isopropenyl benzyl isocyanate (TMI) and 2‐isocyanatoethyl methacrylate (ICEMA) with styrene and methyl methacrylate (MMA), respectively. ICEMA was incorporated into the polymer at a faster rate than TMI and its unhindered isocyanate group was found to be more reactive than the hindered isocyanate group of TMI. Both the TMI/styrene and the MMA/ICEMA systems maintain the reactivity of the isocyanate functionality, which was exploited by attaching representative hydroxyl‐bearing small and large molecules as well as solid substrates to the block co‐polymers. Thus, we demonstrate the versatility of the block co‐polymer system as a basis for forming branched polymers or as grafts for a solid substrate. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of ABCD 4‐Miktoarm star‐shaped quarterpolymers by combination of the “click” chemistry with multiple polymerization mechanism

Well‐defined ABCD 4‐Miktoarm star‐shaped quarterpolymers of [poly(styrene)‐poly(tert‐butyl acrylate)‐poly(ethylene oxide)‐poly(isoprene)] [star(PS‐PtBA‐PEO‐PI)] were successfully synthesized by the combination of the “click” chemistry and multiple polymerization mechanism. First, the poly(styryl)lithium (PS^?Li⁺) and the poly(isoprene)lithium (PI^?Li⁺) were capped by ethoxyethyl glycidyl ether (EEGE) to form the PS and PI with both an active ω‐hydroxyl group and an ω′‐ethoxyethyl‐protected hydroxyl group, respectively. After these two hydroxyl groups were selectively modified to propargyl and 2‐bromoisobutyryl group for PS, the resulted PS was used as macroinitiator for ATRP of tBA monomer and the diblock copolymer PS‐b‐PtBA with a propargyl group at the junction point was achieved. Then, using the functionalized PI as macroinitiator for ROP of EO monomer and bromoethane as blocking agent, the diblock copolymer PI‐b‐PEO with a protected hydroxyl group at the conjunction point was synthesized. After the hydrolysis, the recovered hydroxyl group of PI‐b‐PEO was modified to bromoacetyl and then azide group successively. Finally, the “click” chemistry between them was proceeded smoothly. The obtained star‐shaped quarterpolymers and intermediates were characterized by ¹H NMR, FT‐IR, and SEC in detail. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2154–2166, 2008     

Polymer end group modifications and polymer conjugations via “click” chemistry employing microreactor technology

This study presents the development of microreactor protocols for the successful continuous flow end group modification of atom transfer radical polymerization precursor polymers into azide end‐capped materials and the subsequent copper‐catalyzed azide alkyne click reactions with alkyne polymers, in flow. By using a microreactor, the reaction speed of the azidation of poly(butyl acrylate), poly(methyl acrylate), and polystyrene can be accelerated from hours to seconds and full end group conversion is obtained. Subsequently, copper‐catalyzed click reactions are executed in a flow reactor at 80 °C. Good coupling efficiencies are observed and various block copolymer combinations are prepared. Furthermore, the flow reaction can be carried out in only 40 min, while a batch procedure takes several hours to reach completion. The results indicate that the use of a continuous flow reactor for end group modifications as well as click reactions has clear benefits towards the development and improvement of well‐defined polymer materials. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1263–1274     

Combining Spontaneous Polymerization and Click Reactions for the Synthesis of Polymer Brushes: A “Grafting Onto” Approach

Two novel benzofulvene monomers bearing propargyl or allyl groups have been synthesized by means of readily accessible reactions, and were found to polymerize spontaneously by solvent removal, in the apparent absence of catalysts or initiators, to give the corresponding polybenzofulvene derivatives bearing clickable propargyl or allyl moieties. The clickable propargyl and allyl groups were exploited in appropriate click reactions to develop a powerful and versatile “grafting onto” synthetic methodology for obtaining tailored polymer brushes.     

Synthesis,purification, and characterization of “perfect” star polymers via “Click” coupling

The copper (I)‐catalyzed azide‐alkyne cycloaddition “click” reaction was successfully applied to prepare well‐defined 3, 6, and 12‐arms polystyrene and polyethylene glycol stars. This study focused particularly on making “perfect” star polymers with an exact number of arms, as well as developing techniques for their purification. Various methods of characterization confirmed the star polymers high purity, and the structural uniformity of the generated star polymers. In particular, matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry revealed the quantitative transformation of the end groups on the linear polymer precursors and confirmed their quantitative coupling to the dendritic cores to yield star polymers with an exact number of arms. In addition to preparing well‐defined polystyrene and poly(ethylene glycol)homopolymer stars, this technique was also successfully applied to amphiphilic, PCL‐b‐PEG star polymers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis of anionic carbosilane dendrimers via “click chemistry” and their antiviral properties against HIV

The synthesis and characterization of four families of anionic carbosilane dendrimers bearing carboxylate, phosphonate, naphthylsulfonate, and sulfate terminal groups prepared by cycloaddition of azide–alkyne catalyzed by copper (CuAAC) are presented here. For the preparation of these anionic carbosilane dendrimers, two strategies starting from azide‐terminated carbosilane dendrimers were followed: (i) click coupling of neutral alkynes followed by derivatization into anionic moieties or (ii) click coupling of anionic alkynes. Both strategies require different reaction conditions in order to accommodate the different substrate polarities. These anionic dendrimers, in general, do not present cell toxicity in vitro until concentration up to 20 µM. Therefore, they can be used in inhibition experiments in concentrations below this limit. We have observed that dendrimers bearing phosphonate groups possess poor anti‐HIV capabilities in vitro in PBMCs, while carboxylate dendrimers can reduce HIV infection levels moderately. On the other hand, sulfate and naphthylsulfonate dendrimers are powerful anti‐HIV agents and their antiviral activity is generation and concentration dependent. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1099–1112     

Scalable ambient synthesis of water‐soluble poly(β‐hydroxythio‐ether)s

Proton transfer polymerization through thiol‐epoxy “click” reaction between commercially available and hydrophilic di‐thiol and di‐epoxide monomers is carried out under ambient conditions to furnish water‐soluble polymers. The hydrophilicity of monomers permitted use of aqueous tetrahydrofuran as the reaction medium. A high polarity of this solvent system in turn allowed for using a mild catalyst such as triethylamine for a successful polymerization process. The overall simplicity of the system translated into a simple mixing of monomers and isolation of the reactive polymers in an effortless manner and on any scale required. The structure of the resulting polymers and the extent of di‐sulfide defects are studied with the help of 13C‐ and ¹H‐NMR spectroscopy. Finally, reactivity of the synthesized polymers is examined through post‐polymerization modification reaction at the backbone sulfur atoms through oxidation reaction. The practicality, modularity, further functionalizability, and water solubility aspects of the described family of new poly(β‐hydroxythio‐ether)s is anticipated to accelerate investigations into their potential utility in bio‐relevant applications. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 3381–3386