Lipase‐catalyzed ring‐opening polymerization of morpholine‐2,5‐dione derivatives: A novel route to the synthesis of poly(ester amide)s

The enzymatic ring‐opening polymerization of 6‐membered cyclic depsipeptides, 3(S)‐isopropyl‐morpholine‐2,5‐dione, 3(R)‐isopropyl‐morpholine‐2,5‐dione, 3(R,S)‐isopropyl‐morpholine‐2,5‐dione, (3S, 6R,S)‐3‐isopropyl‐6‐methyl‐morpholine‐2,5‐dione, 3(S)‐isobutyl‐morpholine‐2,5‐dione, 3(S)‐sec‐butyl‐morpholine‐2,5‐dione, 6(S)‐methyl‐morpholine‐2,5‐dione and 6(R,S)‐methyl‐morpholine‐2,5‐dione in the bulk, was investigated by using the lipase PPL as a catalyst. In the absence of the enzyme, the monomers were recovered, indicating that the present polymerization proceeds through enzymatic catalysis. During the polymerization of morpholine‐2,5‐diones racemization of both the amino acid and the S‐lactic acid moiety takes place. Enzymatic polymerization produces polydepsipeptides with a carboxylic acid group at one end and a hydroxyl group at the other one.     

Synthesis,structure and ring‐opening polymerization of phenolphthalein macrocyclic polyarylates

Phenolphthalein based polyarylate macrocyclic oligomers were selectively synthesized by an interfacial polycondensation reaction of o‐phthaloyl dichloride with phenolphthalein. The high selectivity benefits from the role of phenolphthalein as a color indicator, an efficient phase transfer catalyst, and a preferred conformation of the starting materials as indicated by analyzing a single‐crystal X‐ray structure of an analogous macrocycle. The melt ROP of phenolphthalein polyarylate cyclic dimer was studied using nucleophilic initiators. The molecular weight of the resulting polymers builds up very rapidly at the very early stage of polymerization but decreases with time. During the ROP of cyclic dimer, analogous macrocycles with higher degree of polymerization (n ≥ 3) and linear oligomers were produced by backbiting reaction especially at later stage of polymerization. Conversion of cyclic dimer is very fast at the earlier stage of polymerization and then increases slowly with time as analyzed by gel permeation chromatography. However, the total amount of cyclic oligomers in the ROP system increases with time at the later stage of polymerization because of the formation of larger macrocycles. The resulting polymers are amorphous. Glass transition temperatures (T_gs) of these polymers are influenced by the polymerization time, type of initiator, and initiator concentration.     

Lipase‐catalyzed ring‐opening polymerization and copolymerization of cyclic dicarbonates

Ring‐opening polymerization of cyclic dicarbonates, cyclobis(hexamethylene carbonate) ( 1 a ) and cyclobis‐ (diethylene glycol carbonate) ( 1 b ), and their copolymerization with lactones have been carried out using lipase as catalyst. These carbonates were polymerized by Candida antarctica lipase under mild reaction conditions to give the corresponding polycarbonates. The enzymatic copolymerization with lactones proceeded to produce ester‐carbonate copolymers. The copolymerization of 1 b with 12‐dodecanolide produced the random copolymer, whereas the copolymer from 1 a and 12‐dodecanolide was not statistically random.     

Synthesis of poly[1,1‐bis(trimethylsilyloxy)‐3,3,5,5‐tetramethyltrisiloxane] by anionic ring‐opening polymerization of 1,1‐bis(trimethylsilyloxy)‐3,3,5,5‐tetramethylcyclotrisiloxane

Poly[1,1‐bis(trimethylsilyloxy)‐3,3,5,5‐tetramethyltrisiloxane], the first linear polysiloxane in which each third silicon atom of the polymer backbone is a tetra‐functional SiO₂ (Q) unit, has been prepared by anionic ring‐opening polymerization of 1,1‐bis(trimethylsilyloxy)‐3,3,5,5‐tetramethylcyclotrisiloxane.     

Controlled ring‐opening polymerization of ω‐pentadecalactone with yttrium isopropoxide as an initiator

The ring‐opening polymerization of ω‐pentadecalactone (PDL), a 16‐membered lactone, in the bulk and in solution using yttrium isopropoxide as an initiator was investigated. All isopropoxide groups of yttrium isopropoxide participated in the initiation and the polymerization took place via acyl‐oxygen cleavage of the monomer. The molecular weights of the resulting polymers could be controlled effectively by varying the monomer/initiator ratio. An induction period was observed for the bulk polymerization conducted at 60°C. DSC analyses indicated that poly(ω‐pentadecalactone) is a highly crystalline polymer, having a high crystallization rate.     

“Living” free radical ring‐opening polymerization of 2‐methylene‐4‐phenyl‐1,3‐dioxolane by atom transfer radical polymerization

The “living” free radical ring‐opening polymerization of 2‐methylene‐4‐phenyl‐1,3‐dioxolane (MPDO) in the presence of ethyl α‐bromobutyrate/CuBr/2,2′‐bipyridine at various temperatures has been investigated. In comparison with the conventional ring‐opening polymerization of MPDO, a lower content of ring‐opened unit in the polymer was found. The results of ln[M]₀/[M]) against polymerization time, (M_n)_th and (M_n)_NMR vs conversion, and GPC of the polymers are strongly indicative of the “living” polymerization process. Initiator efficiency was measured. The mechanism of polymerization, and the effect of pyridine on the polymerization mechanism were discussed.     

Biocompatible Poly(D,L‐lactide)‐block‐Poly(2‐methacryloyloxyethylphosphorylcholine) Micelles for Drug Delivery

Well‐defined amphiphilic PLA‐b‐PMPC diblock copolymers were synthesized. Bimimetic micelles were prepared and applied for release of anti‐cancer drugs (DOX). TEM and DLS analysis revealed a regular spherical shape with small diameter (less than 50 nm) of the micelle. The biocompatibility of PLA‐b‐PMPC micelles was studied, and it was found that the micelles possessed excellent cytocompatibility due to the zwitterionic phosphorylcholine group. DOX could be efficiently loaded into the micelles with a loading efficiency of 44–67%. The DOX‐loaded micelles showed lower cytotoxicity than free drugs and efficiently delivered and released the drug into cancer cells. With these properties, the PLA‐b‐PMPC polymer micelles are attractive as drug carriers for pharmaceutical application.

     

Thermodynamics of dimethylene urethane,of its ring‐opening polymerization,and of poly(dimethylene urethane) between 0 and 335 K

In an adiabatic vacuum calorimeter, the temperature dependence of the heat capacity C ⁰_p of dimethylene urethane (DMU) and poly(dimethylene urethane) (PDMU) was studied between 6 and 335 K with an uncertainty of about 0.2%. In a calorimeter with a static bomb and an isothermal shield, the energies of combustion ΔU_comb of the monomer and of the polymer were measured. From the experimental data, the thermodynamic functions C ⁰_p (T), H ⁰ (T)–H ⁰ (0), S ⁰ (T), G ⁰ (T)–H ⁰ (0) were calculated in the range from 0 to 335 K, and enthalpies of combustion ΔH ⁰_comb and thermochemical parameters of formation ΔH ⁰_f, ΔS ⁰_f, ΔG ⁰_f of the substances studied were estimated at T = 298.15 K and standard pressure. The results were used to calculate the thermodynamic characteristics of the ring‐opening polymerization of DMU in bulk (ΔH ⁰_pol, ΔS ⁰_pol, ΔG ⁰_pol) with formation of linear poly(dimethylene urethane) in the range from 0 to 330 K. In addition, the ceiling temperature T ⁰_ceil was determined.     

Synthesis and self‐assembly of polymers containing dicarboximide groups by living ring‐opening metathesis polymerization

Polymers with narrow molecular weight distributions and controlled architectures were generated by living ring‐opening metathesis polymerization of exo‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboximide. The dicarboximide units have been previously shown to exhibit biological activity, can selectively bind to the nucleic acid base adenine by hydrogen‐bonding, and are readily functionalizable. Block copolymers containing these moieties were generated, and underwent self‐assembly into nanoscale spherical aggregates, with surface localized molecular recognition motifs.

     

LCST phase separation in biodegradable polymer blends: poly(D,L‐lactide) and poly(ϵ‐caprolactone)

A lower critical solution temperature (LCST) phase transition is reported for blends of the biodegradable polymers poly(D,L ‐lactide) (PDLA) and poly(ε‐caprolactone) (PCL). From light scattering measurements the cloud point curve is determined to have a critical temperature of 86°C and a critical concentration of mass fraction 36 wt.‐% PCL. Optical microscopy of phase‐separated films indicates a spinodal morphology at the critical concentration, and droplet phases at off‐critical concentrations. After quenching phase separated blends below the melting temperature of PCL (60°C), the crystallization of PCL is used to positively identify PCL‐rich and PDLA‐rich phases. When cystallization of PCL follows LCST phase separation, the size, shape, and distribution of crystalline regions can be adjusted by the degree of PCL/PDLA phase separation. Thus, the LCST phase separation offers a novel method to control microphase structure in biodegradable materials. Applications to control of mechanical and physical properties in tissue engineering scaffolds are discussed in light of the results.     

Cross‐Linked Poly(ε‐caprolactone/D,L‐lactide) Copolymers with Elastic Properties

Cross‐linked ε‐caprolactone (CL) and D ,L ‐lactide (DLLA) copolymers with elastic properties were synthesized in three steps. First, the monomers were copolymerized in ring‐opening polymerization to obtain telechelic star‐shaped oligomers with almost completely random monomer distribution. The oligomers were methacrylated with methacrylic anhydride in the second step and cured in a third. Molar CL/DLLA compositions of 30/70, 50/50, 70/30, 90/10, and 100/0 were used to obtain elastic structures with a wide range of properties. The effect of the average length of the copolymer block on the properties of the networks was evaluated with three different co‐initiator contents (0.5, 1.0, and 2.0/100) in the oligomer synthesis. The oligomers were characterized by ¹³C NMR spectroscopy, size‐exclusion chromatography (SEC), and differential‐scanning calorimetry (DSC). The formation of elastic networks was confirmed by the absence of a flow region in dynamic mechanical analysis (DMA), the increase in T_g in DSC, and the full recovery of the sample dimensions after tensile testing. In addition, gel contents were high and the samples swelled in CH₂Cl₂. The networks possessed break stresses from 0.7–9.7 MPa with elongations from 80–350%. Networks with 100 or 90% of ε‐caprolactone retained their form in vitro for 12 weeks, but an increase in lactide content made the networks more vulnerable to hydrolysis.

Water absorption of the polymers during hydrolysis.     

Highly stereoelective polymerization of rac-(D,L)-lactide with a chiral schiff's base/aluminium alkoxide initiator

A chiral Schiff's base/aluminium alkoxide initiator bearing a ligand derived from R-(+)-1,1′-binaphthyl-2,2′-diamine was synthesized and used for the stereoelective polymerization of rac-(D ,L )-lactide. Rather high stereoelectivity is observed: a polymer with 88% enantiomeric enrichment in D units is obtained at 19% conversion. At high conversions a stereocomplex between D- and L-enriched stereocopolymers is formed. The polymerization reaction shows living type features, and narrow molecular weight distributions (M̄_w/M̄_n = 1,05–1,30) are obtained up to very high conversions. This indicates that transesterification reactions do not occur significantly with this sterically hindered initiator.     

Controlled synthesis of biodegradable lactide polymers and copolymers using novel in situ generated or single-site stereoselective polymerization initiators

Polylactides and their copolymers are key biodegradable polymers used widely in biomedical, pharmaceutical and ecological applications. The development of synthetic pathways and catalyst/initiator systems to produce pre-designed polylactides, as well as the fundamental understanding of the polymerization reactions, has continuously been an important topic. Here, we will address the recent advances in the ring-opening polymerization of lactides, with an emphasis on the highly versatile in situ generated initiator systems and single-site stereoselective initiators. The in situ generated initiators including in situ formed yttrium, calcium and zinc alkoxides all have been shown to bring about a rapid and living polymerization of lactides under mild conditions, which facilitated the preparation of a variety of advanced lactide-based biomaterials. For example, well-defined di- and tri-block copolymers consisting of hydrophilic poly(ethylene glycol) blocks and hydrophobic polyester blocks, which form novel biodegradable polymersomes or biodegradable thermosensitive hydrogels, have been prepared. In the past few years, significant progress has also been made in the area of stereoselective polymerization of lactides. This new generation of initiators has enabled the production of polylactide materials with novel microstructures and/or properties, such as heterotactic (--RRSSRRSSRRSS--) polylactide, crystalline syndiotactic (--RSRSRSRSRSRS--) polylactide and isotactic stereoblock (--Rn Sn Rn Sn--) polylactide, exhibiting a high melting temperature. The recently developed polymerizations using in situ generated initiators and stereoselective polymerizations have no doubt opened a brand-new avenue for the design and exploration of polylactides and their copolymers.     

Polymerizability of cycloalkenes in a living ring‐opening metathesis polymerization initiated by Schrock complexes, 1. Effect of the solvent on the polymerization kinetics

The solvent influence was studied on the polymerizability of norbornene, whereby a Mo‐based Schrock complex was used as the initiator due to its ability to generate a persistent active center. The polymerizations were performed in solvents of differing coordinating power with the aim to look at their effect on the reactivity of the system. Cyclohexane, toluene, and tetrahydrofuran (THF) were chosen as solvents taking into account that cyclohexane has only a diluent effect whereas both toluene and THF should be able to coordinate to the complex. The competitive binding character of both monomer and solvent was established from kinetic data for ring‐opening metathesis polymerization (ROMP) performed in pure and mixed solvents (cyclohexane/THF). Independent of the solvent, first‐order kinetics with respect to the initiator suggest that most organometallic species form monosite propagating species. The kinetic order with respect to the monomer depends on the THF concentration of the reaction medium; the kinetic order is equal to one in pure THF and zero in pure cyclohexane. To explain this behavior, a kinetic scheme of the polymerization process is proposed, considering that the actual active species are monomer‐bonded metala‐alkylidenes. The respective equilibrium constants of monomer and of THF complexation to alkylidenic species were estimated showing the stronger binding of norbornene compared to that of THF and the strong influence on the polymerization kinetics.     

Immiscible Poly(L‐lactide)/Poly(ε‐caprolactone) Blends: Influence of the Addition of a Poly(L‐lactide)‐Poly(oxyethylene) Block Copolymer on Thermal Behavior and Morphology

Summary: A binary blend of poly (L ‐lactide) (PLLA) and poly(ε‐caprolactone) (PCL) of composition 70:30 by weight was prepared using a twin screw miniextruder and investigated by differential scanning calorimetry (DSC), optical microscopy and scanning electron microscopy (SEM). Ternary 70:30:2 blends were also obtained by adding either a diblock copolymer of PLLA and poly(oxyethylene) (PEO) or a triblock PLLA‐PCL‐PLLA copolymer as a third component. Optical microscopy revealed that the domain size of dispersed PCL domains is reduced by one order of magnitude in the presence of both copolymers. SEM confirmed the strong reduction in particle size upon the addition of the copolymers, with an indication of an enhanced emulsifying effect in the case of the PLLA‐PEO copolymer. These results are analyzed on the basis of solubility parameters of the blend components.

Optical micrograph of M3EG2 blend melt quenched at 125 °C.     

Polychloroalkane initiators in copper‐catalyzed atom transfer radical polymerization of (meth)acrylates

A series of polychloroalkanes CCl_nR_4‐n (n = 2, 3, or 4) was tested as initiators for atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) and methyl acrylate (MA) using CuCl/2,2′‐bipyridine as the catalyst. 2,2‐Dichloropropane and 2,2‐dichloroethanol initiate the ATRP of MMA very slowly. 1,1,1‐Trichloroalkanes, RCCl₃, are good initiators. For all the R groups tested, the number‐average molecular weight M_n increases with conversion and polydispersities are low (1.1 < M_w/M_n < 1.3). The initiator efficiency factor increases with electrophilicity of the initiating radical (0.7 < f < 1). CCl₄ is a multifunctional initiator and the final M_n values are lower than targeted. This is explained by the generation of new polymer chains occurring once the third active site is created per chain. ATRP of MA initiated by CCl₃CH₂CF₂Cl or CCl₃C₈H₁₇ results in polymers with M_n values predetermined by the Δ [M]/[Initiator]₀ ratio (f close to 1) and narrow molecular weight distributions (M_w/M_n < 1.3 at high conversion). The polymerization is much slower than that of MMA, but can be considerably accelerated by use of Cu(0) metal while maintaining an excellent control over molecular weights and polydispersities.     

Nanostructures of Stereocomplex Polylactide in Poly(l‐lactide) Doped with Poly(d‐lactide)

Nanostructures of stereocomplex polylactide (sc‐PLA) are obtained and studied in poly(l ‐lactide) (PLLA) doped with a low amount of poly(d ‐lactide) (PDLA) during successive melt‐quenching, extrusion, spinning, and drawing processes corresponding to quiescent, shear flow, elongational flow, and tensioned annealing conditions, respectively. Nanogranules of predominantly sc‐PLA are initially formed with rapid quenching in quiescent and shear flow, which developed into microspheres with slow quenching and uniform nanofibrils in elongational flow. While only amorphous or the α′‐form PLLA is formed with the quenched melts and macroscopic fibers, the embedded nanogranules and nanofibrils are highly crystallized with the coexistence of sc‐PLA and the α‐crystals. A 1D coalescence of nascent sc‐nuclei into nanofibrils in elongational flow is preliminarily proposed to explain the structure evolution and the minor reinforcement of the nanofibrils on the macroscopic fibers.

     

Non‐oxidative Thermal Degradation of Poly(glycidol), Poly(glycidol)‐g‐L‐lactide,and Poly(glycidol)‐g‐glycolide

Three polymers of pharmaceutical/medical relevance are synthesized: poly(glycidol) (PG), poly(glycidol)‐g‐L ‐lactide (PG‐g‐La), and poly(glycidol)‐g‐glycolide (PG‐g‐Gly). Because the thermal stability of these polymers is an essential factor of their processing and practical application, the study focuses on kinetic and mechanistic aspects of non‐oxidative thermal degradation. The study is conducted by combining thermogravimetry, Fourier transform infrared spectroscopy, and isoconversional kinetic analysis. It is found that PG degrades in a single mass loss step, whereas, PG‐g‐La and PG‐g‐Gly in two. It is demonstrated that the first step in degradation of PG‐g‐La and PG‐g‐Gly is associated with decomposition of the pendant groups and the second is due to degradation of the PG backbone.

     

A Novel Bioabsorbable Gel Formed from a Mixed Micelle Solution of Poly(oxyethylene)‐block‐poly(L‐lactide) and Poly(oxyethylene)‐block‐poly(D‐lactide) by Concomitant Stereocomplexation and Chain Extension

Furan‐terminated poly(oxyethylene)‐block‐poly(L‐lactide) (MePEG‐PLLA‐F) and poly(oxyethylene)‐block‐poly(D‐lactide) (MePEG‐PDLA‐F) are synthesized by ring‐opening polymerization of L‐ and D‐lactides, respectively, in the presence of poly(ethylene glycol) monomethyl ether (MePEG) and the following terminal reaction with furfuryl isocyanate. Their mixed micelle solution turns to gel quickly with stereocomplexation of the enantiomeric PLLA and PDLA. When 1,8‐bis(maleimido)diethylene glycol (BMG) is added to the mixed micelle solution, the gelation is promoted by the terminal coupling of the copolymers driven by the Diels–Alder reaction of the furanyl groups and BMG giving a gel having higher strength.

     

Stereocomplex Crystallization Behavior and Physical Properties of Linear 1‐Arm, 2‐Arm,and Branched 4‐Arm Poly(L‐lactide)/Poly(D‐lactide) Blends: Effects of Chain Directional Change and Branching

For number‐average molecular weight (M _n) below 1 × 10⁴ g mol^?1, the comparison of cold crystallization temperature and spherulite growth rate and crystallinity of linear 1‐arm, 2‐arm, and branched 4‐arm poly(L ‐lactide)/poly(D ‐lactide) blends exhibits that the effects of chain directional change and branching significantly disturb stereocomplex crystallization. In contrast, the comparison of glass transition and melting temperatures of linear 1‐arm, 2‐arm, and branched 4‐arm poly(L ‐lactide)/poly(D ‐lactide) blends indicates that the effects of chain directional change and branching insignificantly alter and largely increase the segmental mobility of the blends, respectively, and the crystalline thickness of the blends is determined by M _n per one arm not by M _n and is not affected by the molecular architecture.