Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • 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
  • C08F2438/00—Living radical polymerisation
  • C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• Subject of this invention is an initiator of controlled radical polymerisation ATRP (Atom Transfer Radical Polimerisation) for synthesis of low-dispersion polymers and block copolymers, including thermosensitive polymers and copolymers, method of its synthesis, and the use of this initiator in polymerisation reactions.
• ATRP Atom Transfer Radical Polimerisation
• Thermosensitive polymers are known, i.e. those that show a change in their chemical and physical properties at a certain temperature (defined as phase transition temperature, PTT) [Prog. Polym. Sci. 32 (2007) 1205].
• PTT phase transition temperature
• One of the most intensively studied thermosensitive polymers is poly(N-isopropylacrylamide) (PNIPAM), due to its biocompatibility, and the fact, that PTT of this polymer is close to human body temperature.
• PNIPAM-containing materials can have many medical applications, among others, as carriers for controlled drug release, base materials in tissue engineering, and new carriers in gene therapies [ Polymers , 3 (2011) 1215].
• PNIPAM-block-PS polystyrene block
• PS polystyrene
• PNIPAM-block-PS polystyrene block
• thermosensitive nanostructures such as micelles, inverted micelles, liposomes and others.
• Systems of this type can be successfully used for controlled drug release and for other biomedical purposes [Prog. Polym. Sci., 34 (2009) 893]. Due to the widespread use of PS as a biocompatible material in cell cultures, PNIPAM-block-PS copolymers may also find applications in this field.
• Controlled radical polymerisation (CRP) methods are known for producing low- dispersion homopolymers as well as copolymers with narrow molecular weight distributions and well-defined architecture, i.e. block, gradient, and star copolymers [Polimery, 56 (2011) 427; "Progress in Controlled Radical Polymerisation: Mechanisms and Techniques” by the American Chemical Society (2012)].
• the most important techniques used in CRP include stable free radical polymerisation (SFRP), reversible addition-fragmentation transfer polymerisation (RAFT), and atom transfer radical polymerisation (ATRP) [Prog. Polym. Sci. 38 (2013) 63; Polym. Chem. 9 (2016) 2532; Chem. Rev. 101 (2001) 2921].
• ATRP due to its applicability for a wide group of monomers and the possibility of obtaining polymers with a very narrow molecular weight distribution (PDI below 1.5), as well as planned- architecture copolymers, i.e. block copolymers.
• ARGET ATRP method Activators Regenerated by Electron Transfer Atom Transfer Radical Polymerisation
• ARGET ATRP method which is a modification of the ATRP method and allows to control polymerisation with a small (several ppm) concentration of a catalytic complex. Due to this, the obtained homopolymers and copolymers do not require a laborious procedure of purification from the used catalytic materials [Chem. Rev. 101 (2001) 2921].
• R-X initiator is not only a source of an initiating radical R* (alkyl or alkylaromatic), but also of a terminal group terminating the polymer chain-the radical X’ (usually a chlorine or bromine, less often iodine atom) [Prog. Polym. Sci. 38 (2013) 63].
• the terminal atom (X) should be quickly and selectively transferred between the active (growing) and inactive (dormant) form of the polymer chain, according to the following scheme:
• ARGET ATRP method is based on a constant regeneration of the Cu(I)X/L catalytic complex by a reducing agent, the amount of which significantly exceeds the amount of initiator in the reaction medium.
• reducer in excess allows the concentration of the catalytic complex to be reduced, it also enables polymerisation in the presence of sm all amounts of oxygen, so that oxygen does not have to be removed entirely from the polymerisation system.
• the obtained copolymers do not require a purification from the catalytic materials used (the content of the catalytic complex in the copolymer is usually at the level of several ppm), which significantly simplifies the synthesis [Langmuir 23 (2007) 4528].
• the reason is probably much higher bond energy between the chlorine atom and the styrene-terminated polymer chain than the bond energy between the chlorine atom and the NIPAM-terminated polymer chain.
• the catalyst system is not able to transfer the chlorine atom and form an active polymer form capable of propagation. Therefore, to initiate ATRP of less active monomers, such as styrene, it is necessary to use more active bromine derivatives instead of chlorine derivatives.
• a method of synthesis of PNIPAM-block-PS copolymer on a silicon substrate using ATRP is known [Langmuir, 26 (2010) 8582]. Modification of the silicon surface makes it biocompatible, i.a. well compatible with blood, and renders properties of an excellent substrate for cell culture [Langmuir, 26 (2010) 8582]. This method assumes construction of the PS block on the previously obtained PNIPAM block anchored on the silicon surface. This involves the need of bromine initiator application in the whole process so that it is possible to construct the PS block on the PNIPAM block.
• An initiator of ATRP radical polymerisation having a functional group with a substituent active in polymerisation process is characterised in that it is a bifunctional initiator of a formula
• the active substituent X is active in ATRP polymerisation process, preferably a halogen substituent, most preferably a chlorine, bromine or iodine substituent.
• the protecting substituent Z is inactive in ATRP polymerisation process, but it is possible to be substituted with other functional groups, preferably -OH, -NH2, -NHP, -COOH, -N 3 , -NCS, -NCO.
• the hydrocarbon moiety Z contains an amide group and a hydrocarbon chain R.
• Initiator according to the invention belongs to the group of organic compounds including functionalised amides of aliphatic and aromatic carboxylic acids, preferably 2-chloro-N-(2-hydroxyethyl)propionamide (NCPAE), N-(2-aminoethyl)-2-chloropropionamide, N-(2-aminoethyl)-2-bromopropionamide or 2-bromo- N-(2-hydroxyethyl)propionamide.
• NPAE 2-chloro-N-(2-hydroxyethyl)propionamide
• N-(2-aminoethyl)-2-chloropropionamide N-(2-aminoethyl)-2-bromopropionamide
• 2-bromo- N-(2-hydroxyethyl)propionamide 2-bromo- N-(2-hydroxyethyl)propionamide
• a method of synthesis of 2-chloro-N-(2-hydroxyethyl)propionamide initiator, NCPAE, is characterised in that ethanolamine is subjected to an acylation reaction with 2-chloropropionyl chloride in presence of triethylamine (TEA), wherein the reaction is carried out under inert atmosphere at room temperature, and the desired compound is obtained with a yield of ca. 90%.
• TAA triethylamine
• a solution of chloride 2-chloropropionyl in methylene chloride is added drop w/ise, preferably maintaining a significant excess of ethanolamine in relation to 2-chloropropionyl chloride, and then the reaction is carried out at room temperature for 15-24 h, preferably 19 , the obtained product is isolated by column chromatography and subjected to recrystallisation.
• a method of synthesis of block copolymers using a radical polymeri sation initiator having a functional group with a substituent active in polymerisation process is characterised in that a bifunctional radical polymerisation initiator as defined above is used, wherein:
• a mixture of reagents including bifunctional initiator, catalyst system, solvent and monomer of the first block is loaded into the reactor, air is removed, e.g. by using an inert gas flow, an inert gas is introduced (nitrogen or argon), the process temperature is set, and then the radical polymerisation reaction of the first block is initiated,
• the active substituent X of the first functional group is deactivated, preferably by its substitution with a hydrogen atom
• the second functional group of the bifunctional initiator is activated by substituting the protecting substituent Z with a functional group having the active substituent X,
• block copolymer BLOCKl-block-BLOCK2 the product of polymerisation, i.e. block copolymer BLOCKl-block-BLOCK2, is separated.
• polymerisation of PNIPAM block is carried out first, followed by polymerisation of PS block, wherein: - PNIPAM block formation is carried out using NIPAM as a monomer, a bifun ctional initiator with an active chloride group, preferably NCPAE, and the reaction is carried out in isopropanol using CuCI/Me 6 TREN as a catalyst system, preferably at room temperature, wherein polymerisation time may vary between a few up to several hours depending on the planned length of the first chain,
• styrene polymerisation is carried out using styrene as a monomer, PNIPAM-Br macroinitiator, CuCl 2 PMDETA as a catalyst system, Sn(EH) 2 as a reducing agent, wherein styrene polymerisation is carried out in DMF at an elevated temperature, preferably 90°C, with polymerisation time may vary between a few up to several hours depending on the planned length of the first chain.
• polymerisation of the PS block is carried out first, followed by polymerisation of the PNIPAM block, wherein:
• - PS block formation is carried out using styrene as a monomer, a bifunctional initiator with an active bromide group, wherein polymerisation reaction is carried out in DMF, using CuBr 2 /PMDETA as a catalyst system, at an elevated temperature, preferably 90°C.
• NIPAM NIPAM polystyrene-maleic anhydride
• PS-CI macroinitiator PS-CI macroinitiator
• CuCI/Me 6 TREN as a catalyst system
• Sn(EH) 2 Sn(EH) 2 as a reducing agent
• NIPAM polymerisation is carried out in DMF at room temperature, wherein polymerisation time may vary between a few up to several hours depending on the planned length of the chain .
• Fig. 1 General structure of a bifunctional polymerisation reaction initiator
• Fig. 3 Diagram of the four-step PNIPAM-block-PS block copolymer synthesis using the NCPAE initiator, wherein the subsequent steps provide:
• FIG. 5 Photograph of an exemplary PNIPAM-block-PS copolymer sample dissolved in water (PNIPAM-b-PSl sample, Table 2);
• Fig. 6 1 H NMR spectrum of an exemplary PNIPAM polymer sample
• Fig. 7 DSC curve obtained for an exemplary PNIPAM homopolymer sample dissolved in water (PNIPAM1 sample, Table 1, concentration 1.5%);
• Fig. 8 Particle size distribution (by number) in the aqueous solution of the PNIPAM homopolymer sample at 25°C and 45°C (PNIPAM1 sample, Table 1, concentration 1.5%); Fig. 9 Molecular weight distributions for PNIPAM polymers obtained, SEC analysis (PNIPAM1, PNIPAM2 and PNIPAM3 samples, Table 1);
• Fig. 11 DSC curve of an exemplary PNIPAM-block-PS copolymer sample in an aqueous solution (PNIPAMPS1 sample);
• Fig. 12 Particle size distributions in aqueous solution, determined by the DLS method, for exemplary PNIPAM-block-PS copolymer samples at 25°C and 45°C (PNIPAM-b-PSl sample).
• Subject of this invention is a bifunctional polymerisation initiator containing a halogen active group and a second active group, allowing subsequent polymerisation of various types of polymer blocks, and a synthetic path leading to block copolymers, which consists of 4 steps: I. Polymerisation leading to BLOCK l by a method using bifunctional initiator
• the invention constitutes a solution to the synthetic problem related to the low yield of initiation and propagation of the (co)polymer chain growth at its end, consisting in the use of a bifunctional initiator enabling an independent growth of two polymer blocks at the two initiator poles, wherein these growths are accomplished in two subsequent processes.
• the invention provides a bifunctional initiator having two terminal moieties: one halogen and the other one, which could be activated in a suitable process.
• the halogen moiety is the initiator of the first polymerization reaction during which the group, e.g. -O H, -NH , -NHP, -COOH, -N 3 , -NCS, -NCO group, preferably the hydroxyl group, remains Inactive.
• the group e.g. -O H, -NH , -NHP, -COOH, -N 3 , -NCS, -NCO group, preferably the hydroxyl group, remains Inactive.
• An exemplary bifunctional initiator is 2-chloro-N-(2-hydroxyethyl)propionamide (NCPAE), a molecule having a chlorine and hydroxyl substituents on opposite poles of the molecule.
• NPAE 2-chloro-N-(2-hydroxyethyl)propionamide
• Other examples of this type of initiators may be N-(2-aminoethyl)-2-chloropropionamide, N-(2-aminoethyl)-2- bromopropionamide, 2-bromo-N-(2-hydroxyethyl)propionamide and others with the general structure depicted in Fig. 1.
• a bifunctional initiator allows polymerisation of one block and constructing it on the halogen pole, while the protecting substituent Z remains inactive. After completion of the first block polymerisation, it is possible to deactivate the halogen moiety and further activate of the hydroxyl moiety to construct the second polymer block at the second pole of the initiator. This allows block polymerisation of polymers of different activities and properties, and the resulting blocks can have different planned lengths/molecular weights.
• An exemplary block copolymer that can be obtained is PNIPAM-block-PS.
• Such copolymer is amphiphilic, biocompatible and shows thermosensitivity. It is also possible to obtain other block copolymers, for example, copolymers made of a block of polyacrylic acid (PAA)/polymethyl methacrylate (PMM)/ polyacrylonitrile (PAN) and a block of poly-4- methylstyrene (P4MeS)/poly-4-tert-butylstyrene (P4-TbS)/poly-3-methylstyrene (P3MeS) in various combinations and sequences.
• PAA polyacrylic acid
• PMM polymethyl methacrylate
• PAN polyacrylonitrile
• P4MeS poly-4- methylstyrene
• P4-TbS poly-4-tert-butylstyrene
• P3MeS poly-3-methylstyrene
• PAA-block-P4MeS PAA-block-P4MeS
• PMM-block-PAMeS PAN-block-P MeS
• PAA-block-P4TbS PAA-block-PNIPAM
• PS-block-PAA PAA-block-P3MeS PAA-block-P4MeS
• PAA-block-P4MeS PAA-block-P4MeS
• PMM-block-PAMeS PAN-block-P MeS
• PAA-block-P4TbS PAA-block-P4TbS
• PS-PNIPAM PS-block-PAA PAA-block-P3MeS.
• the bifunctional polymerisation initiator can also be used to synthesise homopolymers composed of monomers of one type. An initiator having the appropriate active group for one type of polymerisation is then used.
• the polymer materials obtained can find a variety of applications, e.g. medical, as carriers for controlled drug release, base materials in tissue engineering, new carriers in gene therapies, and as materials for "intelligent membrane" construction.
• NCPAE by transesterification
• isobutyl (S)-2-chloropropionate in ethanol and 1,4-dioxane at elevated temperature [Monatshefte fuer Chemie, 119 (1988) 839]. Due to the reversibility of the transesterification reaction and the possibility of ester formation as a by-product, this method does not provide high yields, requires a long reaction time to obtain satisfactory yields (80% yield after 72 h of heating at 60-70°C), which means that the cost of obtaining the right product is high.
• NCPAE 2-chloro-N-(2-hydroxyethyl)propionamide
• TAA triethylamine
• NCPAE synthesis being the subject of the present invention, is carried out at room temperature, using cheap reactants, and leads to the product with a very high yield (90%).
• the bifunctional polymerisation initiator NCPAE is an amide derivative of propionic acid containing two "poles" in the molecule: a chlorine atom and a hydroxyl group. Due to the presence of a chlorine atom in the molecule, NCPAE is able to initiate the polymerisation process using ATRP method, while the hydroxyl group remains inactive during polymerisation. After completion of the first block polymerisation, the terminal chlorine group is deactivated, and the inactive hydroxyl group is activated, which can react with carboxylic acids, their anhydrides, and acid halides, which allows easy modification of the polymer chain after the first polymerisation is completed and enables the construction of the second block at the second "pole" of the initiator. Such modification is possible i.a.
• a-bromoisobutyryl bromide which allows introduction of a moiety with the terminal bromine atom into the molecule already containing the first polymer block, and such a macroinitiator is able to initiate the polymerisation of a second polymer block composed of a less reactive monomer than the first one.
• the dehalogenation process i.e. the deactivation of the active functiona l group, is done by transferring the halogen atom to ATRP catalyst system (PMDETA/CuBr) in t he presence of tributyltin hydride according to a known procedure [Macromol. Rapid Commun. 20 (1999) 66].
• the activation process of the protected functional group is done depending on the protective group used and the planned modification.
• an esterification reaction is carried out using a-bromoisobutyryl bromide and triethylamine in anhydrous THF in a molar ratio of polymer, bromide and triethylamine of 1/1.8/1.3.
• an esterification reaction is carried out using a-chloroisobutyryl chloride and triethylamine in anhydrous THF in a molar ratio of polymer, bromide and triethylamine of 1/1.8/1.3.
• the bifunctional initiator must have two independent functional groups (Fig. 1), of which one active group (e.g. chlorine, bromine, iodine, fluorine) is used for the first block polymerisation, while the second group ⁇ e.g. hydroxyl, amino, carboxyl, azide, cyanate, thiocyanate) remains inactive in the polymerisation reaction.
• the terminal active function group is deactivated (e.g. halogen is substituted with hydrogen)
• the second "pole" of the initiator is activated (e.g. substitution with chlorine, bromine or iodine) in order to obtain the possibility to initiate the reaction of second block formation in the subsequent polymerisation.
• function of a bifunctional polymerisation initiator can have, e.g. N-(2-aminoethyl)-2-chloropropionamide, N-(2-aminoethyl)-2- bromopropionamide, 2-bromo-N-(2-hydroxyethyl)propionamide. It is also possible to design new chemical compounds that could be used as bifunctional initiators of polymerisation reaction, for example: functionalised amides of aliphatic and aromatic carboxylic acids.
• the initiator synthesis is carried out by means of an acylation reaction using ethanolamine (EA) as a substrate, 2-chloropropionyl chloride (CCP) as an acylating agent, in the presence of triethylamine (TEA).
• EA ethanolamine
• CCP 2-chloropropionyl chloride
• TEA triethylamine
• the reaction is then carried out in a molar excess of ethanolamine to CCP (e.g . in a 4.1/1 mola r ratio) so as to prevent double acylation of this compound (via amino and hydroxyl groups).
• a slight molar excess of TEA to CCP e.g.
• the reaction is carried out in a suitably selected solvent, for example, in dichloromethane (DCM) solution, under an ine rt atmosphere, argon, for example.
• DCM dichloromethane
• the mixture is stirred vigorously, and the mixture is cooled (its temperature should be around 0°C) because slowing of the reaction increases its selectivity (the amount of product which is mono-substituted derivative increases).
• the reaction mixture is left at room temperature, and stirring is continued for another 15-24 h, preferably 19 h.
• the proper product is separated from the post-reaction mixture, e.g. by column chromatography. Additional product purification is obtained by crystallisation, for example from a 1/1 ethyl acetate/hexane mixture.
• Polymerisation of each block of the desired block copolymer is carried out separately, by subsequently using each of the polymerisation initiator "poles".
• optimal chemical (terminal active group, e.g. chloride, bromide or iodide) and physical (temperature, pressure, solvent, etc.) conditions for the polymerisation of each block. This enhances process control, which helps to avoid the uncontrolled premature termination of the polymer chains and produces a material with a low polydispersity index and properly selected chain length.
• BLOCKl-block-BLOCK2 block copolymer synthesis consists of 4 steps:
• Step I and IV are steps of BLOCK1 and BLOCK2 formation respectively, while steps II and III are modifications of the initiator "poles" which allow changing the direction of polymerisation.
• steps II and III are modifications of the initiator "poles" which allow changing the direction of polymerisation.
• the method according to the invention could be used with many different block copolymers, for example, copolymers composed of a polyacrylic acid (PAA)/polymethyl methacrylate (PMM)/polyacrylonitrile (PAN) block and a poly-4-methylstyrene (P4MeS)/poly-4- tertbutylstyrene (P4-TbS)/poly-3-methylstyrene (P3MeS) block in various combinations and sequences.
• PAA polyacrylic acid
• PMM polymethyl methacrylate
• PAN polyacrylonitrile
• P4MeS poly-4-methylstyrene
• P4-TbS poly-4-tertbutylstyrene
• P3MeS poly-3-methylstyrene
• block copolymers that can be obtai ned using the bifunctional initiator of the present invention: PAA-block-P4MeS; PMIVl-block-P4MeS; PAN-block-P4MeS; PAA-block-P4TbS; PS-block-PNIPAM; PS-block-PAA; PAA-block -P3MeS.
• the bifunctional polymerisation initiator according to the invention can also be used to synthesise homopolymers composed of monomers of one type. An initiator having the appropriate active group for one type of polymerisation is then used.
• the method according to the invention allows subsequent block polymerisations to be carried out in any order while maintaining the appropriate polymerisation conditions for each block. It is also possible to stop the polymerisation process and resume it again, provided that the active functional group has not been deactivated before.
• Particularly preferred is to use the method of the invention for synthesis of block copolymers with the sequence of PNIPAM-block-PS because the obtained copolymers have properties that allow their full potential to be utilised: thermosensitivity, amphiphilicity and biocompatibility due to the possibility of precise chain length control in both blocks, as well as the use of functional groups that do not affect its biocompatibility.
• PNIPAM block formation is carried out using NIPAM as a monomer, an initiator with an active chloride group, in isopropanol using CuCI/Me 6 TREN as a catalyst system, at room temperature, where the polymerisation time is from a few up to several hours depending on the planned length of the first chain.
• PS block formation is carried out using styrene as a monomer, an initiator with an active bromide group, CuCl 2 /PMDETA as a catalyst system, Sn(EH) 2 as a reducing agent, and the styrene polymerisation is carried out in DMF at a styrene/DMF volume ratio of 1/1, at 80-100°C, preferably 90°C, using molar ratios of PNIPAM reagents to styrene, copper(ll) halide, ligand and Sn(EH)2 of 1/400/0.006/0.1/0.1, where the polymerisation time is from a few up to several hours depending on the planned length of the first chain.
• copolymers obtained by the method of the invention may have amphiphilic and thermosensitive properties, due to which they can have a variety of medical applications as carriers for controlled drug release, base materials in tissue engineering, new carriers in gene therapies, but also as materials for "smart membrane" construction.
• the product was isolated by column chromatography (silica gel packing, chloroform/methanol 95:5 mixture was used as eluent). Separation was monitored by thin layer chromatography (TLC). Solvent contained in the product fractions was evaporated using a rotary evaporator. The product was crystallised from a mixture of ethyl acetate and hexane in a volume ratio of 1:1. 1.4 g of product was obtained. The reaction yield was 90%.
• Polymerisation reactions were carried out which differed in duration, from 2 hours to 22 hours and molar ratio of monomer to initiator, copper(l) chloride and ligand used (Table 1).
• the polymers were isolated and purified as a result of a procedure consisting of several steps: 1) evaporation of isopropanol using a rotary evaporator, 2) dissolution of the resulting precipitate in THF, 3) passing the resulting solution through a column packed with basic alumina, 4) precipitation of polymers from the solution with hexane.
• the resulting polymers were dried in a vacuum dryer for 24 h at 40°C. NIPAM polymerisation yield was determined by gravimetric method.
• Average molecular weights and polydispersity indices for the polymers obtained were determined by the SEC method, using DMF with addition of LiBr (1% by weight) as eluent. For all PNIPAM polymers obtained, the determined polydispersity index values are close to one, which indicates a narrow distribution of their molecular weights.
• PNIPAM polymers obtained in the first block formation reaction were characterised by 1H NMR spectroscopy (Fig. 6), differential scanning calorimetry (DSC) (Fig. 7) and dynamic light scattering (DLS) (Fig. 8).
• NMR measurements confirmed the assumed molecular structures of the polymers obtained: 1 H NMR (300 MHz, CDCI 3 ): d:; 4.01 (bs) -CH(CH 3 ) 2 ; 2.30-1.25 broad signals -CH 2 -CH(R)-; 1.14 (bs) -CH(CH 3 ) 2 ; DSC measurements in aqueous solutions showed an endothermic phase transition of the polymers obtained in a narrow PTT range 42.8-44.0°C with peak minimum at 43°C (PNIPAM1, Table 1).
• PNIPAM (1 g PNIPAM/7 mL THF), CuBr and 1,1,4,7,7-pentamethyldiethylenetriamine (PMDETA) were dissolved in it; after adding the latter the solution turned deep green.
• the mixture was degassed under argon flow for 30 minutes.
• tributyltin hydride was added to the reaction mixture.
• the molar ratio of PNIPAM to copper(l) bromide, PMDETA ligand and tributyltin hydride was 1:0.5:0.5:3.
• reaction was carried out at 60°C for 4 hours, with reaction mixture left on a magnetic stirrer in a thermostatic oil bath. After putting the flask with the reaction mixture into oil bath, a change of colour to light brown was observed, after 20 minutes the mixture turned dark brown. After completing the reaction by flask opening and exposing the reaction mixture to air, its colour became intense green again.
• the post-reaction mixture was passed through a column packed with basic alumina, then concentrated using a rotary evaporator. The reaction product was precipitated with hexane, filtered off and dried in a vacuum dryer (24 h, 40°C).
• Copolymerisation with styrene by ARGET ATRP method was carried out as follows: a 50 mL flask pre-degassed in argon flow and charged with bromine functionalised PNIPAM, styrene and DMF (volume ratio of DMF to styrene 1:1). The mixture was degassed under argon flow for 20 minutes. A previously prepared solution of copper(ll) salt and ligand both dissolved in DMF was then added. The almost colourless mixture was again degassed under argon flow for 10 minutes, after which a previously prepared and degassed solution of tin(ll) 2-ethylhexanoate in DMF was added.
• the molar ratio of PNIPAM to styrene, copper(ll) halide, ligand and Sn(EH)2 was the same for all syntheses 1:400:0.006:0.1:0.1.
• the reaction was carried out at 90°C or 110°C at various times, from 4 hours to 45.7 hours (Table 2).
• the reaction mixture was stirred on magnetic stirrer.
• the copolymer was isolated by evaporation of the solvent followed by dissolution in THF and precipitation with hexane.
• the white precipitate was filtered on G4 Schott funnel.
• the filtrate after precipitation with hexane was concentrated using a rotary evaporator, followed by precipitation with methanol.
• the copolymers obtained directly from step IV contained a small fraction of polystyrene, which was removed by washing the precipitate with toluene until the filtrate did not become cloudy when methanol added (until it was polystyrene free).
• the copolymers obtained were characterised by 1 H NMR spectroscopy, differential calorimetry (DSC) in solid phase (Fig. 10) and aqueous solutions (Fig. 11), and by DLS (Fig. 12).
• the obtained results confirmed the structure of the obtained copolymers and their thermosensitive properties.
• the NMR spectra for the obtained copolymers confirmed the presence of PNIPAM block and PS block (Fig. 4), the 4.01 ppm chemical shift signal corresponds to the proton in PNIPAM isopropyl group, and broad signals in the range of 6.57-7.26 ppm correspond to protons in aromatic ring in PS block and protons from amide groups.
• phase transition temperature of PNIPAM-block-PSl copolymer in the PTT range 30.1-37.5°C. As expected, these values are lower than for PNIPAM1 sample.
• the temperature range in which the phase transition occurs is much wider than for the PNIPAM sample, which is associated with the broader molecular weight distribution of the copolymer in relation to homopolymer used in the second polymerisation step.
• aqueous solution of PNIPAM-block-PSl sample was tested at 25°C and 45°C (Fig. 12).
• DLS dynamic light scattering
• particles with a mean hydrodynamic diameter of 619.5 nm were recorded.
• the average particle size recorded in the sample was 297.4 nm.
• the reduction in particle size at a temperature higher than the phase transition temperature of the copolymer is associated with the shrinkage of PNIPAM block, and thus reduction in the volume of aggregates formed by the copolymer.
• PNIPAM-block-PSl copolymer After dissolving the obtained PNIPAM-block-PSl copolymer in water, a foam appeared (Fig 5) and a decrease in the water surface tension was observed, which indicates copolymer's amphiphilic nature resulting from the presence of a hydrophobic and hydrophilic fragment in its particles. As a result, the obtained product can form micelles in water and behave in a similar way to surfactants.
• ARGET ATRP - Activators regenerated by electron transfer atom transfer radical polymerisation bpy - 2,2'-bipyrine
• NCPAE 2-chloro-N-(2-hydroxyethyl)propionamide

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  • 2019-06-07 PL PL430174A patent/PL243003B1/pl unknown
• 2020
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