Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
  • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent

Definitions

• the invention relates to a process for the preparation of a multiblock , copolymer, the process being carried out in the presence of a multifunctional initiator, said process comprising at least one enzymatically catalyzed homo- or copolymerization reaction chosen from the group comprising a ring opening polymerization (ROP) reaction and a polycondensation reaction, and at least one non- enzymatically catalyzed controlled homo- or copolymerization reaction.
• ROP ring opening polymerization
• the invention also relates to a chiral block copolymer and to a chiral block copolymer obtainable by the process according to the invention.
• a process for the preparation of a block copolymer is disclosed in U. Meyer et al., Macromolecules (2002) 35, 2873. This process combines a lipase- catalyzed ring-opening polymerization of ⁇ -caprolactone ( ⁇ -CL) with atom transfer radical polymerization (ATRP) of styrene in two consecutive steps, in the presence of a bifunctional initiator, yielding diblock copolymers of ⁇ -CL and styrene.
• ⁇ -CL ⁇ -caprolactone
• ATRP atom transfer radical polymerization
• a drawback of the known method is that CuBr is required as a catalyst for the ATRP reaction.
• a catalyst may inhibit the enzymatically catalyzed homo- or copolymerization reaction in the known method. This is particularly the case when the lipase-catalyzed ring-opening polymerization and the ATRP reaction are carried out simultaneously in one pot or when the lipase- catalyzed ring-opening polymerization is carried out after the ATRP reaction in the same reaction medium.
• the presence of such a metal catalyst in the product is undesired. Although removal of the metal catalyst is possible, it requires extra purification steps.
• the aim of the present invention is therefore to provide a process for the preparation of a block copolymer in which at least one enzymatically catalyzed homo- or copolymerization reaction and at least one non-enzymatically catalyzed controlled homo- or copolymerization reaction are applied and in which the use of a metal catalyst is avoided.
• a polymerization reaction chosen from the group comprising a free radical polymerization reaction, an ionic polymerization reaction, a polycondensation reaction, and a ring opening polymerization (ROP) reaction.
• a polymerization reaction chosen from the group comprising a free radical polymerization reaction, an ionic polymerization reaction, a polycondensation reaction, and a ring opening polymerization (ROP) reaction.
• ROP ring opening polymerization
• said non-enzymatically catalyzed controlled polymerization reactions can be performed in the process according to the - invention without inhibiting the enzyme used in the enzymatically catalyzed homo- or copolymerization reaction significantly.
• said non-enzymatically catalyzed polymerization reactions can be used before, during or after the enzymatically catalyzed polymerization reaction, in the same reaction medium, in the presence of a multifunctional initiator, resulting in the formation of a block copolymer.
• a non-enzymatically catalyzed controlled polymerization reaction is understood to be a polymerization reaction which is carried out in the presence of an initiator, i.e. a multifunctional initiator, and in which the initiator is incorporated into the growing polymer chain.
• a non-enzymatically catalyzed free radical polymerization reaction is understood to be a polymerization reaction chosen from the group comprising Reversible Addition Fragmentation Chain Transfer Polymerization (RAFT), nitroxide mediated radical polymerization, and Iniferters polymerization.
• RAFT Reversible Addition Fragmentation Chain Transfer Polymerization
• nitroxide mediated radical polymerization nitroxide mediated radical polymerization
• Iniferters polymerization are described in for example K. Matyjaszewski (Ed.), “Controlled Radical Polymerization", ICS Symposium Series 685, Oxford University Press (1998).
• Such polymerization reactions can be performed in the absence of a metal containing catalyst.
• non-enzymatically catalyzed ionic polymerization reactions can be anionic or cationic polymerization reactions.
• Such polymerization reactions are described in for example WO-A-2000/063256 and WO-A- 96/28487, respectively.
• Non-enzymatically catalyzed polycondensation reactions which can be used in the process according to the present invention, are described in for example G.C. Eastmond et at., Comprehensive Polymer Science, Vol. 5, Pergamon Press (1989).
• Non-enzymatically catalyzed ROP reactions are decribed in for example E.F. Connor et al., J. Am. Chem. Soc, 124 (2002) 914.
• Nitroxide initiators are relatively easy to synthesize, thermally activated and applicable to a wide variety of monomers, resulting in polymers with predictable molecular weight and narrow polydispersity. Suitable examples of nitroxide initiators are mentioned in for example Hawker et al., Chem. Rev. (2001) 101, p. 3661, which is incorporated herein by reference.
• Controlled free radical polymerization reactions in particular nitroxide mediated radical polymerization reactions, generally involves the homo- or copolymerization of a monomer that can stabilize the propagating radicals during the polymerization reaction.
• monomers include those mentioned in Hawker et al., Chem. Rev. (2001) 101, p. 3661, for example (meth)acrylates, styrenes, acrylonitriles, vinyl pyridines, vinyl formamide, (meth)acrylamides, and maleimides.
• (meth)acrylates or styrenes are used as the monomer in the non- enzymatically catalyzed controlled polymerization reaction.
• the enzymatically catalyzed homo- or copolymerization reaction is preferably chosen from the group comprising a enzymatically catalyzed ring opening polymerization (ROP) reaction, and an enzymatically catalyzed polycondensation reaction.
• ROP ring opening polymerization
• polycondensation reaction an enzymatically catalyzed polycondensation reaction.
• an enzymatically catalyzed ROP reaction is applied as the enzymatically catalyzed homo- or copolymerization reaction.
• Enzymatically catalyzed ROP reactions involve the ring opening polymerization of one or more kinds of cyclic compounds.
• lactones cyclic esters
• lactames cyclic amides
• cyclic acid anhydrides cyclic carbonates
• lactides preferably lactones (cyclic esters), lactames (cyclic amides), cyclic acid anhydrides, cyclic carbonates, and lactides are used as a monomer.
• lactones include ⁇ -propiolactone, ⁇ -butyrolactone, ⁇ -valerolactone, ⁇ -butyrolactone, ⁇ -valerolactone, ⁇ - caprylolactone, ⁇ -caprolactone, ⁇ -stearolactone, ⁇ -caprylolactone, and ⁇ - palmitolactone;
• lactams include ⁇ -propiolactam, ⁇ -butyrolactam, ⁇ - valerolactam, ⁇ -valerolactam, ⁇ -caprolactam, and hectolactam;
• examples of cyclic acid anhydrides include succinic anhydride, maleic anhydride, glutamic anhydride, and phtalic anhydride;
• examples of cyclic carbonates include ethylene carbonate, propylene carbonate, and trimethylene carbonate; and examples of lactides include dilactide, diglycollide and diglyceride.
• lactones are used, for example an optionally substituted ⁇ -CL.
• Possible substituents to ⁇ -CL include for example a halogen, an hydroxy group, an amine group, an amide group, a thiol group, an alkoxy group with for example 1 to 20 C atoms, a (hetero)aryl group with for example 1 to 20 C atoms and an aryloxy group with for example 1 to 20 C atoms.
• substituted ⁇ -CL's are 2-bromo- ⁇ - caprolactone, 4-methyl- ⁇ -caprolactone, 4-ethyl- ⁇ -caprolactone, 4-phenyl- ⁇ - caprolactone, and 3,5-dimethyl- ⁇ -caprolactone, as mentioned in for example M.
• the enzyme used in the enzymatically catalyzed homo- or copolymerization reaction may catalyze the polymerization of just one enantiomer of a racemic mixture of such chiral ⁇ -CL's, thereby being capable of selectively polymerizing that enantiomer.
• Lipases are triacylglycerol ester hydrolases classified as EC 3.1.1.3. Particularly suitable lipases are for example Candida antarctica Lipase B, optionally immobilized on for example acrylic resin (Novozyme 435), Pseudomonas cepacia (lipase PS-30), porcine pancreatic lipase (PPL), Candida cylindracea (lipase CCL), Candida Rugosa (lipase CR), Mucor Miehei (lipozyme), Pseudomonas aeruginosa (lipase PA), Pseudomonas fluorescence (lipase PF), and Aspergillus niger (lipase A). Proteases may also be used as the enzyme.
• the process according to the invention comprising at least one enzymatically catalyzed homo- or copolymerization reaction and at least one non- enzymatically catalyzed controlled homo- or copolymerization reaction, may be performed in bulk as well as in the presence of one or more solvents.
• a nitroxide mediated radical polymerization reaction is applied in combination with an enzymatically catalyzed ROP reaction, this reaction may suitably be performed in bulk as well as in the presence of one or more organig solvents.
• Additional cosolvents or surfactants such as glycols or ammonium salts of fatty acids, may be present.
• suitable solvents or mixtures are typically aliphatic hydrocarbons, for example hexane, heptane, octane, or isooctane; aromatic hydrocarbons, for example benzene, toluene, or xylene; halogenated hydrocarbons, for example chlorobenzene, 1,1,2-trichlorotrifluoroethane, chloroform or o-dichlorobenzene; and ethers, for example diethyl ether, dipropyl ether,-' dibutyl ether, diisopropyl ether, or tetrahydrofuran; or mixtures thereof.
• At least one enzymatically catalyzed polymerization reaction and at least one non-enzymatically catalyzed controlled polymerization reaction are preferably both carried out in bulk. As such, the need for removal of solvent after the reaction is avoided.
• Said combination of an enzymatically catalyzed polymerization reaction and a non-enzymatically catalyzed polymerization reaction may be carried out in any order, in a one-pot or a multi-pot reaction set-up, simultaneously or one after the other.
• Preferably said polymerization reactions are performed in one pot. Carrying out the polymerization reactions in one pot avoids intermediate work-up steps and limits the amount of equipment needed. More preferably said polymerization reactions are carried out simultaneously to minimize the reaction time and maximize the output.
• the process according to the invention is generally performed at a reaction temperature between 50 and 200 °C, preferably between 70 and 140 °C, more preferably between 90 and 110 °C.
• the pressure at which the process according to the invention is carried out is not particularly critical and depends on for example the monomers and solvent used and the reaction temperature.
• the reaction time is generally between 0.5 h and 7 days, preferably between 4 and 72 h.
• the reaction conditions may vary between the different polymerization reactions, i.e. the enzymatically catalyzed polymerization reaction and a non-enzymatically catalyzed polymerization reaction, and also within one polymerization reaction.
• the process according to the invention comprising an enzymatically catalyzed polymerization reaction and a non-enzymatically catalyzed polymerization reaction may be carried out in the presence of a multifunctional initiator comprising at least one functional group that initiates an enzymatically catalyzed ROP reaction or an enzymatically catalyzed polycondensation reaction and at least one functional group that initiates a non-enzymatically catalyzed free radical polymerization reaction, a non- enzymatically catalyzed anionic polymerization reaction, or a non-enzymatically catalyzed ROP reaction.
• a multifunctional initiator comprising at least one functional group that initiates an enzymatically catalyzed ROP reaction or an enzymatically catalyzed polycondensation reaction and at least one functional group that initiates a non-enzymatically catalyzed free radical polymerization reaction, a non- enzymatically cat
• the functional group that initiates an enzymatically catalyzed homo- or copolymerization reaction chosen from the group comprising a ring opening polymerization (ROP) reaction and a polycondensation reaction is an hydroxy, amino or carboxylic acid group. More preferably a hydroxy group is applied because of its easy integration into the polymer chain.
• ROP ring opening polymerization
• the functional group that initiates a non-enzymatically catalyzed free radical polymerization reaction, a non-enzymatically catalyzed anionic polymerization reaction, or a non-enzymatically catalyzed ROP reaction is generally group that easily converts to or represents an active initiating species such as a radical, an ion or any other reactive group, which can form a covalent bond with the polymer chain.
• Suitable functional groups include for example halogen, nitroxide, thiol, and alcohol groups.
• the invention also relates to a chiral block copolymer. The term
• block copolymer is generally known in the art and is understood to be a copolymer comprising at least two types of monomers which are arranged in a block structure.
• at least one block comprises at least one substituted ⁇ -CL derivative.
• the substituted ⁇ -CL derivative is chosen from the group comprising 2-bromo- ⁇ -caprolactone, 4-methyl- ⁇ -caprolactone, 4- ethyl- ⁇ -caprolactone, 4-phenyl- ⁇ -caprolactone, and 3,5-dimethyl- ⁇ -caprolactone.
• the chiral block copolymer comprises at least one other block, which may also be chiral, comprising a monomer selected from the group comprising (meth)acrylates, styrenes, acrylonitriles, vinyl pyridines, vinyl formamide, (meth)acrylamides, and maleimides.
• the chiral block copolymer according to the invention comprises at least one other block comprising a (meth)acrylate or a styrene.
• block copolymers comprising at least 2-bromo- ⁇ -caprolactone and a (meth)acrylate, 2-bromo- ⁇ -caprolactone and styrene, 4-methyl- ⁇ -caprolactone and a (meth)acrylate, 4-methyl- ⁇ -caprolactone and styrene, 4-ethyl- ⁇ -caprolactone and a (meth)acrylate, 4-ethyl- ⁇ -caprolactone and styrene, 4-phenyl- ⁇ -caproIactone and a (meth)acrylate, 4-phenyl- ⁇ -caprolactone and styrene, 3,5-dimethyl- ⁇ -caprolactone and a (meth)acrylate, and 3,5-dimethyl- ⁇ -caprolactone and styrene.
• the chiral block copolymer according to the invention preferably has a weight average molecular weight (M w ), measured by Gas Permeation Chromatography (GPC), in the range 500-1000,000 g/mol, more preferably in the range 1000-100,000 g/mol, most preferably in the range 3000-50,000 g/mol, and a molecular weight distribution, measured as the ratio between the weight average molecular weight and the number average molecular weight (M w /M n ) in the range 1.0- 2.5, preferably in the range 1.1-1.8.
• M w weight average molecular weight
• M w number average molecular weight
• Novozym 435 was obtained from NOVO NORDISK. Styrene and ⁇ - CL were distilled before the first reaction. All other chemicals are commercially available and were used without further purification, unless stated otherwise.
• NMR experiments were carried out on a Bruker 300 DPX (300 MHz for 1 H-NMR) and on a Bruker Avance 300 (300 MHz for 1 H-NMR).
• Precipitation of polymers was carried by dropping a concentrated CHCI 3 solution of the polymer in ice-cold methanol and subsequent filtration of the suspension, after which the polymer was dried in vacuo.
• the amount of enzyme used was usually approximately one tenth the weight of ⁇ -CL monomers plus initiator.
• Example I Synthesis of the bifunctional initiator f4-(- ⁇ ftert-butyl(2-methyl-1- phenylpropyDaminoloxylethvDphenvnmethanol (5) Steps 1-3 were carried out according to literature methods, see for example J. Dao et al., J. Pol. Sci. A, Polym. Chem., 30 (1998) 2161-2167.
• Step 1 N-tert-butyl- ⁇ -isopropylnitrone (1)
• 5.0 g (48.5 mmol) of 2-methyl-2-nitropropane 4.4 ml (48.5 mmol) of isobutyraldehyde and 2.9 g (53.3 mmol) of ammonium chloride.
• the resulting solution was cooled to 0°C.
• the solution was added to a mixture of 100 ml of MeOH, 8 ml of aqueous ammonium hydroxide solution and 0.24 g (1.18 mmol) of copper acetate, Cu(OAc) 2 . Air was bubbled through this mixture, while it was stirred, until the colour went green. After this the solution was concentrated and dissolved in a two-phase system of 100 ml of CHCI 3 and 100 ml of water. After separation of the layers the water layer was extracted three times with 20 ml of CHCI 3 and the combined organic layers were washed with 40 ml of an aqueous solution of saturated sodium bicarbonate, dried with MgSO and concentrated.
• Step 3 1-(1- ⁇ [tert-butyl(2-methyl-1-phenylpropyl)amino]oxy ⁇ ethyl)-4- (chloromethyl)benzene (3) To a mixture of 125 ml of toluene and 125 ml of ethanol, which had been bubbled with air for an hour, was added 2.39 g (10.8 mmol) of (2), 2.62 g (17.2 mmol) of 4-vinylbenzylchloride, 2.0 g (2.86 mmol) of (N,N'-bis ⁇ 3,5-di-fet ⁇ - butylsalicylidene ⁇ -1,2-cyclohexanediaminato)manganese(lll)chloride ( ⁇ R,R ⁇ -Jacobsen catalyst) and 1.31 g (34.2 mmol) of NaBH 4 in the mentioned order.
• Example III Two-pot synthesis of a PCL-PS co-polvmer.
• Example VI One-pot one-step synthesis of a PCL-PS co-polymer

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