Synthesis and Thermosensitive Properties of Poly[(N‐vinylamide)‐co‐(vinyl acetate)]s and Their Hydrogels

Free radical copolymerization of water‐soluble N‐vinylamides such as N‐vinylacetamide (NVA) and N‐vinylformamide (NVF) with hydrophobic vinyl acetate (VAc) gave amphiphilic copolymers. The monomer reactivity ratios were determined as r₁ = 5.8 and r₂ = 0.68 (M₁ = NVA, M₂ = VAc) and r₁ = 6.2 and r₂ = 0.37 (M₁ = NVF, M₂ = VAc), respectively. The growing radical of the terminals of N‐vinylamides propagates more favorably for N‐vinylamide monomers than for VAc monomer, resulting in the possible formation of blocky copolymers. It is found that aqueous solutions of these amphiphilic copolymers exhibited a lower critical solution temperature (LCST), depending on their chemical composition, followed by coacervate formation above the LCST. Furthermore, thermosensitive hydrogels could be prepared by the free radical copolymerization of N‐vinylamide and VAc in the presence of the crosslinker butylenebis(N‐vinylacetamide) (Bis‐NVA). The swelling ratios of these hydrogels decreased with an immediate increase in temperature from 20 to 80 °C, and then reversibly increased with decreasing temperature. These hydrogels showed the same thermosensitive properties as linear copolymers of NVF and VAc.

Relationship between LCST and vinyl acetate content in poly(N‐vinylamide‐co‐VAc)s.     

Copolymers from tert‐Butyl Methacrylate with Trimethylsilyl Methacrylate or Methacrylic Acid: Models for Resist Polymers

Free radical copolymerisation of tert‐butyl methacrylate ( 1 ) with trimethylsilyl methacrylate ( 2 ) and methacrylic acid ( 3 ) has been investigated. Reactivity ratios for methacrylic acid and tert‐butyl methacrylate indicate an azeotropic copolymerisation (r ₁ = 0.476 ± 0.103; r ₃ = 0.300 ± 0.032), whereas the two esters show preferential incorporation of 2 (r ₁ = 0.170 ± 0.050; r ₂ = 1.170 ± 0.124). Thermal cis‐elimination of isobutylene from the tert‐butyl ester and subsequent formation of six‐membered cyclic anhydride moieties has been studied. For poly(methacrylic acid‐co‐tert‐butyl methacrylate) thermogravimetry could be used to determine copolymer composition. Solvolytic desilylation of the trimethylsilyl ester groups has been investigated as an alternative route to poly(methacrylic acid‐co‐tert‐butyl methacrylate). The tert‐butyl ester is not affected under the conditions of desilylation. Sequence distribution of both copolymers has been calculated using the method introduced by Bruns and Motoc.

Copolymer composition diagram for tert‐butyl methacrylate/methacrylic acid.     

Functionalized Biocompatible Poly(N‐vinyl‐2‐caprolactam) With pH‐Dependent Lower Critical Solution Temperature Behaviors

Functionalized temperature‐ and pH‐sensitive poly(N‐vinyl‐2‐caprolactam) (PVCL) polymers are prepared by copolymerizing monomers of N‐vinyl‐2‐caprolactam (VCL) and a VCL derivative, 3‐(tert‐butoxycarbonyl)‐N‐vinyl‐2‐caprolactam (TBVCL). Different molar compositions are studied, with the functional monomer at 9 and 14 mol%, respectively, (COOH‐PVCL9 and COOH‐PVCL14). Sharp, complete, and reversible phase transitions of the copolymers with little hysteresis are shown to be pH‐dependent, with cloud points ranging from 35 to 44 °C for COOH‐PVCL9, and 29 to 64 °C for COOH‐PVCL14, upon pH change from 2.0 to 7.4. Cytotoxicity assay demonstrates that the functionalized PVCL copolymers are biocompatible with NIH/3T3 up to 2 mg mL^?1. Such new PVCL‐based water soluble copolymers with tunable properties could be useful in a variety of biomedical applications.     

Synthesis and characterization of dextran grafted with poly(N‐isopropylacrylamide‐co‐N,N‐dimethyl‐acrylamide)

Graft copolymers consisting of dextran as a main chain and poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) (poly(NIPAAm‐co‐DMAAm)) as graft chains were synthesized. For the synthesis of the graft copolymers, a semitelechelic poly(NIPAAm‐co‐DMAAm) with an amino end‐group was obtained by radical copolymerization with ethanethiol as a chain transfer agent, followed by a coupling reaction of its hydroxyl end‐group with ethylenediamine. Graft copolymers with various length of the grafts were obtained from coupling reactions between carboxymethyl dextran and poly‐(NIPAAm‐co‐DMAAm) in the presence of a water‐soluble carbodiimide. The graft copolymers in phosphate buffer exhibit lower critical solution temperatures due to thermosensitivity of their grafts. There is no significant change in the hydration‐dehydration behavior of the poly(NIPAAm‐co‐DMAAm) chain after the grafting reaction. The existence of such grafts in dextran may play an important role for modulated degradation in synchronization with temperature.     

Syndiospecific Living Block Copolymerization of Styrenic Monomers Containing Functional Groups,and Preparation of Syndiotactic Poly{(4‐hydroxystyrene)‐block‐[(4‐methylstyrene)‐co‐(4‐hydroxystyrene)]}

At –25°C, the sequential block copolymerizations of 4‐(tert‐butyldimethylsilyloxy)styrene (TBDMSS) and 4‐methylstyrene (4MS) were investigated by using a syndiospecific living polymerization catalyst system composed of (trimethyl)pentamethylcyclopentadienyltitanium (Cp*TiMe₃), trioctylaluminum (AlOct₃) and tris(pentafluorophenyl)borane (B(C₆F₅)₃). The number‐average molecular weight (M̄_n) of the poly(TBDMSS)s increased linearly with increasing the polymer yield up to almost 100 wt.‐% consumption of TBDMSS used as 1^st monomer. The M̄_n value of the polymer after the second monomer (4MS) addition continued to increase proportionally to the polymer yield. The molecular weight distributions (MWDs) of the polymers remained constant at around 1.05–1.18 over the entire course of block copolymerization. It was concluded that the block copolymerizations of TBDMSS and 4MS with the Cp*TiMe₃ /B(C₆F₅)₃ /AlOct₃ catalytic system proceeded with a high block efficiency. The ¹³C NMR analysis clarified that the block copolymers obtained in this work had highly syndiotactic structure. By the deprotection reaction of silyl group with conc. hydrochloric acid (HCl), syndiotactic poly{(4‐hydroxystyrene)‐block‐[(4‐methylstyrene)‐co‐(4‐hydroxystyrene)]} (poly[HOST‐b‐(4MS‐co‐HOST)]) was successfully prepared.     

Radical polymerization and copolymerization of bis{3-[tris(trimethylsiloxy)silyl]propyl} fumarate

Radical polymerization and copolymerization of bis{3-[tris(trimethylsiloxy)silyl]propyl} fumarate (BSPF ( 1 )) were investigated. The reactivity of BSPF in homopolymerization was found to be very low, and only low-molecular-weight poly(BSPF) was obtained in low yields. On the other hand, copolymerizations of BSPF with diisopropyl fumarate (DiPF) and di-tert-butyl fumarate (DtBF) proceed with moderate rates to give high-molecular-weight copolymers. The monomer reactivity ratios were determined to be as follows; r₁ = 0,07, r₂ = 0,87 for BSPF (M₁) and DiPF (M₂); r₁ = 0,21, r₂ = 0,67 for BSPF (M₁) and DtBF (M₂). The resulting copolymers are soluble in many common organic solvents. Tough and brittle films were obtained by solution casting of the copolymers of BSPF and DtBF. The copolymers exhibit excellent oxygen permeability.     

Synthesis of Poly(ϵ‐caprolactone‐co‐methacrylic acid) Copolymer via Phosphazene‐Catalyzed Hybrid Copolymerization

Poly(?‐caprolactone‐co‐tert‐butyl methacrylate) (CL‐co‐BMA) random copolymer is synthesized via hybrid copolymerization with 1‐tert‐butyl‐4,4,4‐tris(dimethylamino)‐2,2‐bis[tris(dimethylamino)phophoranylidenamino]‐2Λ5,4Λ5‐catenadi(phosphazene) (t‐BuP₄) as the catalyst. The copolymer is hydrolyzed into poly(?‐caprolactone‐co‐methacrylic acid) (CL‐co‐MAA), a charged copolymer. Nuclear magnetic resonance, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis measurements indicate that cyclic ester and vinyl monomer form a random copolymer. The degradation of the copolymers has also been studied by use of quartz crystal microbalance with dissipation.     

Copolymers of N-vinyl-2-pyrrolidone and 2-(dimethylamino)ethyl methacrylate, 1. Synthesis,characterization, quaternization

2-(Dimethylamino)ethyl methacrylate (DMAEM) — N-vinyl-2-pyrrolidone (VP) copolymers were synthesized and characterized. The copolymerization parameters were determined: r_VP = 0,61, r_DMAEM = 11,41. The tacticity of DMAEM sequences and the distribution of monomer units were estimated. Then, the experimental conditions for the quaternization of the copolymers with alkyl bromides were defined. The modified copolymers were characterized and the mechanism of the quaternization reaction was studied via potentiometry.     

Synthesis,Characterization and In Vitro Cytotoxicity of Poly[(5‐benzyloxy‐trimethylene carbonate)‐co‐(trimethylene carbonate)]

The ring‐opening copolymerization of 5‐benzyloxy‐trimethylene carbonate (BTMC) with trimethylene carbonate (TMC) was described. The polymerization was carried out in bulk at 150°C using stannous octanoate as initiator. The influence of reaction conditions such as polymerization time and initiator concentration on the yield and molecular weight of the copolymers were investigated. The poly(BTMC‐co‐TMC)s obtained were characterized by FT‐IR, ¹H NMR, ¹³C NMR, GPC and DSC. NMR results of copolymer showed no evidence for decarboxylation occurring during the propagation. The relationship between the copolymer glass transition temperature and composition was in agreement with the Fox equation. The in vitro cytotoxicity studies of the poly(BTMC‐co‐TMC) (50 : 50) using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay demonstrated that the copolymer has low cytotoxicity compared to poly[(lactic acid)‐co‐(glycolic acid)] (75 : 25).     

Controlled Anionic Block Copolymerization with N,N‐Dialkylacrylamide as a Second Block

Summary: Novel well‐defined block copolymers composed of polystyrene, poly(2‐vinylpyridine), poly(ethylene oxide), or poly(tert‐butyl methacrylate) as the first block and poly(N,N‐dialkylacrylamide) (PDAlAAm) as the second block were synthesized by ligated anionic polymerization. The latter was carried out in tetrahydrofuran (THF) initiated by 1,1‐diphenyloligostyryllithium in the presence of ZnEt₂ and LiCl. At first the role of the additives LiCl and ZnEt₂ on the mode of the anionic homopolymerization of N,N‐dialkylacrylamide was investigated. Polymerization in the presence of ZnEt₂ resulted in syndiotactic polymers with narrow molecular weight distribution only. In the presence of both additives, the reaction mixture became heterogeneous with a high degree of isotacticity of the polymers. Despite the fact that the polymerizations were performed in heterogeneous phase, the DAlAAm monomers were polymerized in a quantitative yield. The efficiency of the first block of active sites was always higher than 0.71. Preliminary studies using dynamic light scattering of aqueous hydrochloric acid solutions of poly[(2‐vinylpyridine)‐block‐(N,N‐diethylacrylamide)] block copolymers at different temperatures and at pH 2 showed that above 45 °C, micelle‐like aggregates were formed. The heating and cooling cycles were reversible but showed hysteresis, which was obviously due to the isotactic structure of the poly(N,N‐diethylacrylamide) block.

Temperature dependence of the scattering intensity of various poly[(2‐vinylpyridine)‐block‐(N,N‐diethylacrylamide)] block copolymers.     

Combining ATRP of Methacrylates and ROP of L,L‐Dilactide and ε‐Caprolactone

Coupling atom transfer radical polymerization (ATRP) and coordination‐insertion ring‐opening polymerization (ROP) provided a controlled two‐step access to polymethacrylate‐graft‐polyaliphatic ester graft copolymers. In the first step, copolymerization of methyl methacrylate (MMA) and 2‐hydroxyethyl methacrylate (HEMA) was carried out at 80 °C at high MMA concentration by using ethyl 2‐bromoisobutyrate and [NiBr₂(PPh₃)₂] as initiator and catalyst, respectively. Kinetic and molar masses measurements, as well as ¹H NMR spectra analysis of the resulting poly(MMA‐co‐HEMA)s highlighted the controlled character of the radical copolymerization, while the determination of the reactivity ratios attested preferential incorporation of HEMA. The second step consisted of the ROP of ε‐caprolactone or L ,L ‐dilactide, in THF at 80 °C, promoted by tin octoate (Sn(Oct)₂) and coinitiated by poly(MMA‐co‐HEMA)s obtained in the first step. Once again, kinetic, molar mass, and ¹H NMR data demonstrated that the copolymerization was under control and started on the hydroxyl functions available on the poly(MMA‐co‐HEMA) multifunctional macroinitiator.

Comparison of the SEC traces for the poly(MMA‐co‐HEMA) macroinitiator P2 (line only), the polymethacrylate‐g‐PLA copolymer C2 (line marked by ○), and the polymethacrylate‐g‐PLA C3 (line marked by ?).     

Copolymerization of 2-chloro-N,N-dimethylacrylamide

2-Chloro-N,N-dimethylacrylamide (CNA) does not homopolymerize easily (2% after 12 days) in contrast to 2-chloroacrylic esters. Its copolymerization with styrene (St) and methyl methacrylate (MMA) is governed by the following copolymerization parameters: r_CNA = 0,03 and r_MMA = 3,4; r_CNA = 0,2 ± 0,05 and r_St = 1,5 ± 0,2. The very low rates of copolymerization and the low molecular weights of the copolymers are interpreted on the basis of the formation of sterically hindered resonance stabilized radicals, and of high chain transfer constants.     

Glycidyl Cinnamate: Copolymerization with Glycidyl Ethers,In-Situ NMR Kinetics,and Photocrosslinking

The copolymerization of glycidyl cinnamate (GC) as a hitherto non-polymerizable, photoreactive epoxide structure to aliphatic polyether copolymers is described, using the monomer-activated epoxide ring-opening polymerization (MAROP). Ethoxyethyl glycidyl ether (EEGE) and GC are copolymerized employing triisobutylaluminum (i-Bu₃Al) as a catalyst and tetraoctylammonium bromide (NOctBr₄) as an initiator. The amount of GC varies from 3 mol% to 100 mol%, which results in apparent molecular weights in the range of 2600 to 4600 g mol⁻¹ and dispersities (Đ) below 1.34. Studies of the microstructure by in-situ ¹H NMR kinetics indicate a gradient-like distribution of EEGE and GC (reactivity ratios: r_EEGE = 0.28; r_GC = 3.6), applying the ideal copolymerization model for evaluation. A tentative explanation relies on differing bond lengths in the respective epoxide rings, as suggested by density functional theory (DFT) calculations. Mild and selective cleavage of the acetal protecting groups of EEGE is achieved using the acidic ionic resin Dowex, leaving the GC ester bonds intact (M_n = 1900–3700 g mol⁻¹, Đ < 1.34). Thermal properties of the copolymers and the PGC homopolymer are investigated by differential scanning calorimetry (DSC). The crosslinking of P(G-co-GC) copolymers by UV irradiation allows hydrogel formation, which is confirmed by IR spectroscopy.     

Synthetic Route and Characterization of Main Chain Ester‐Containing Hydrolytically Degradable Poly(N,N‐dimethylaminoethyl methacrylate)‐Based Polycations

The possibility of introducing hydrolytically cleavable ester linkages onto the poly(N,N‐dimethylaminoethyl methacrylate) for the formation of less toxic and degradable polycations is shown in this work. For achieving this aim, the copolymerization behavior of 5,6‐benzo‐2‐methylene‐1,3‐dioxepane (BMDO), with N,N‐dimethylaminoethyl methacrylate (DMAEMA) is studied by free radical ring‐opening polymerization. Structural characterization is performed using 1D and 2D NMR techniques. Under optimized reaction conditions, quantitative ring‐opening of BMDO took place during the copolymerizations leading to the formation of poly(DMAEMA‐co‐ester)s. Blocky random copolymers were further quaternized by alkyl bromide to generate degradable cation containing polymers. Cytotoxicity results were highly encouraging and showed less cytotoxicity as compared to polyethyleneimine, which was used as a positive control. The formation and characterization of highly stable copolymer/DNA polyplexes is also shown here.

     

Visible Light–Induced RAFT Polymerization of Methacrylate with 4‐(N,N‐diphenylamino)benzaldehyde as Organophotoredox Catalyst and the Effect of Temperature on the Polymerization

With UV–vis absorption in the range of 270–435 nm, 4‐(N,N‐diphenylamino)benzaldehyde (DPAB) takes efficient photoreduction quench with 4‐cynao‐4‐(phenylcarbonothioylthio)pentanoic acid (CTP). The polymerization rates of methyl methacrylate (MMA) are 0.019, 0.056, and 0.102 h^?1 at 33, 40, and 50 °C, respectively, in the presence of DPAB and CTP under visible‐light irradiation. Dark reaction produces no PMMA at 50 °C for 120 h. The living feature is demonstrated by linearly increasing M_n with the monomer conversions and narrow polydispersity index (PDI), chain extension, and block polymerizations with benzyl methacrylate (BnMA) and poly(ethylene glycol) monomethyl ether methacrylate (PEGMA). With PMMA‐CTP (M_n = 6800, PDI = 1.17), chain extension gives PMMA with M_n = 15 900 and PDI = 1.15. With PMMA‐CTP (M_n = 6000, PDI = 1.21) as macro‐RAFT, PMMA‐b‐PBnMA of M_n = 12 600 (PDI = 1.44) and M_n = 18 500 (PDI = 1.31) are prepared. These results support that there is a positive synergistic effect between polymerization temperature and visible‐light irradiation on the photo‐RAFT without losing the living features.     

Novel Polyesteramide‐Based Diblock Copolymers: Synthesis by Ring‐Opening Copolymerization and Characterization

Block copolymers based on a polyesteramide sequence and a polyether block were synthesized in bulk at 250 °C by ring‐opening copolymerization (ROP) of ε‐caprolactone (CLo) and ε‐caprolactam (CLa) as initiated by Jeffamine® M1000, i.e., ω‐NH₂ copoly[(ethylene oxide)‐co‐(propylene oxide)] copolymer [P(EO‐co‐PO)‐NH₂]. For an initial molar ratio of [CLa]₀/[CLo]₀ = 1, the copolymerization allowed for the formation of a diblock copolymer with a statistical polyesteramide sequence, as evidenced by ¹³C NMR. Investigation of the ROP mechanism highlighted that CLo was first polymerized, leading to the formation of a diblock copolymer P(EO‐co‐PO)‐b‐PCLo‐OH, followed by CLa hydrolysis to aminocaproic acid that inserted into the ester bonds of PCLo via aminolysis and subsequent condensation reactions. The outcome is the selective formation of P(EO‐co‐PO)‐b‐P(CLa‐co‐CLo)‐OH diblock copolymers where the composition and length of the polyesteramide sequence can be fine‐tuned by the [CLa]₀/[CLo]₀ and ([CLa]₀ + [CLo]₀)/[P(EO‐co‐PO)‐NH₂]₀ initial molar ratios.     

Lanthanum Tris(2,6‐di‐tert‐butyl‐4‐methylphenolate) as a Novel,Versatile Initiator for Homo‐ and Copolymerization of Cyclic Carbonates and Lactones

Lanthanum tris(2,6‐di‐tert‐butyl‐4‐methylphenolate) is reported as a highly active initiator for homopolymerizations of DTC, TMC, and CL as well as random copolymerizations of DTC with CL and with TMC, respectively. The monomer insertion occurs via acyl‐oxygen bond cleavage. The random structures of copolymers are identified by GPC, ¹H NMR, and DSC. The reactivity ratios of DTC and CL are measured to be 13.4 (r_DTC) and 0.20 (r_CL), respectively.     

Functional Poly(Dimethyl Aminoethyl Methacrylate) by Combination of Radical Ring‐Opening Polymerization and Click Chemistry for Biomedical Applications

In this work, the macromolecular design and modular synthesis of degradable and biocompatible copolymers via radical polymerization and click chemistry is highlighted and the resulting systems are evaluated as gene delivery carriers. Poly(ethylene glycol) (PEG) grafted poly[2‐methylene‐1,3‐dioxepane (MDO)‐co‐propargyl acrylate (PA)‐co‐2‐(dimethyl aminoethyl methacrylate (DMAEMA)] (MPD) is synthesized using radical polymerization and azide‐alkyne click chemistry. The polymers are less cytotoxic and are able to condense plasmid DNA into nanosized particles. The low transfection efficiency of polyplexes in HepG2 cells is significantly improved by mixing Tat peptide with polyplexes.     

Poly(hydroxyl propyl methacrylate)‐b‐Poly(oligo ethylene glycol methacrylate) Thermoresponsive Block Copolymers by RAFT Polymerization

Thermoresponsive amphiphilic poly(hydroxyl propyl methacrylate)‐b‐poly(oligo ethylene glycol methacrylate) block copolymers (PHPMA‐b‐POEGMA) are synthesized by RAFT polymerization, with different compositions and molecular weights. The copolymers are molecularly characterized by size‐exclusion chromophotography, and ¹H NMR spectroscopy. Dynamic light scattering (DLS) and static light scattering (SLS) experiments in aqueous solutions show that the copolymers respond to temperature variations via formation of self‐organized nanoscale aggregates. Aggregate structural characteristics depend on copolymer composition, molecular weight, and ionic strength of the solution. Fluorescence spectroscopy experiments confirm the presence of less hydrophilic domains within the aggregates at higher temperatures. The thermoresponsive behavior of the PHPMA‐b‐POEGMA block copolymers is attributed to the particular solubility characteristics of the hydrophilic, water insoluble PHPMA block that are modulated by the presence of the water soluble POEGMA block.     

PLLA-Based Block Copolymers via Raft Polymerization—Impact of the Synthetic Route and Activation Mechanism

Designing supramolecular structures with well-defined dimensions and diverse morphologies via the self-assembly of block copolymers is renowned. Specifically, the design of 1D fiber nanostructures is extensively emphasized, due to their unique properties in many areas, such as microelectronics, photonics, and particularly in the biomedical field. Herein, amphiphilic diblock copolymers of P(l -lactide)-b-P(N-t-butoxy-carbonyl-N´-acryloyl-1,2-diaminoethane)-co-P(N-isopropylacrylamide) PLLA_n-b-P(BocAEAm)_m-co- P(NiPAAm)_Ɩ are developed. Two synthetic strategies are investigated to equip PLLA with a chain transfer agent (CTA), either by Steglich esterification of PLLA-OH or via the ring-opening polymerization of l -lactide using a CTA containing a hydroxyl functional group. The second strategy proves to be superior in terms of degree of functionalization. The corona-forming blocks, with degrees of polymerization of 200 and above are achieved in good definition by photo-iniferter RAFT polymerization (Đ ≤ 1.25), while a Đ of 1.75 is obtained by conventional RAFT polymerization. The self-assembly of the developed system leads to the formation of nanofibers with a height of 11 nm and a length of ≈300 nm, which is determined by atomic force microscopy (AFM). These fibers are the basis for new antimicrobial nanomaterials after deprotection, as the subject of upcoming work.