AU2002244523B2 - A method of treating the surface of a substrate polymer useful for graft polymerization - Google Patents

Description

P\OPER\Rdt2007\12120190 2p doc-2604/2007 -1- A method of treating the surface of a substrate polymer useful for graft polymerisation FIELD OF THE INVENTION The present invention relates generally to polymerization processes and more particularly to modifying the surfaces of solid supports to facilitate polymerization processes. The present invention is predicated in part on the use of radicals generated on functional and/or backbone portions of polymers forming part of a solid phase surface and/or sub-surface to generate a substrate for initiation of polymerization. The polymerization is conducted in the presence of a control agent which induces a dynamic population of anchored growing and dormant polymeric chains each comprising two or more monomers. The polymerization conditions contemplated by the present invention include, therefore, inter alia living polymerization. Consequently, the present invention provides a means for generating a population of anchored polymer chains in a controlled manner. Polymers generated by this process include homopolymers and copolymers (comprising two or more monomers including ter-polymers) such as inter alia block, graft, tapered, cross-linked and branched polymers.

BACKGROUND OF THE INVENTION Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the general common knowledge.

Moderating the influence of a bulk material' surface chemistry, such as imparting hydrophilic nature to a hydrophobic but stable bulk material, is a technique central to many areas of research ranging from biotechnology to microelectronics. The ability to modify the nature of a surface with macromolecules has existed for some time. Methods developed allow the covalent surface attachment of pre-formed macromolecular systems, the grafting of solution initiated macromolecular chains to a suitably functionalized surface, and the surface-initiated polymerization of a variety of monomer formulations. All these methods WO 02/079305 PCT/AU02/00416 -2have resulted in effective graft coating of the substrate with high grafting efficiency.

However, they provide little control of the macromolecular properties (molecular weight, distribution and composition) of the polymer layer. Furthermore, as well as generating a polymer coating on the substrate, the process also results in the formation of non-bound polymer in solution, which can hinder isolation and purification of the coated substrate.

The control of polymer coatings on bulk solid-supports is key to improving the utility of combinatorial solid-phase synthesis, as well as other solid-phase applications. Solid-phase synthesis technologies are used to create large numbers of new chemical compositions across a wide range of chemical disciplines. For example, combinatorial chemical synthesis may be carried out on the solid phase to generate libraries of thousands of new chemical entities that may be evaluated as pharmaceutical lead compounds. One method for generating new useful supports for solid-phase synthesis is by grafting polymers to an underlying bulk solid support. The grafted polymers may be selected to have chemical functional groups, or other physical properties, that provide improved sites for solid-phase synthesis.

The limitations cited above have provided impetus for the development of surfaceconfined methods of grafting substrates of interest with predetermined macromolecular composition and architecture, employing the spectrum of commercially-available monomers susceptible to standard free radical chemistry. More recently, methods to achieve such have been reported utilizing "living"/controlled free radical polymerization (see e.g. Kato, et al., Macromolecules 28: 1721 (1995); Wang Matyjaszewski, J. Am.

Chem. Soc. 117: 5614 (1995); Pattern et al., Science 272: 866 (1996); Percec Barboiu Macromolecules 28: 7970 (1995); Granel et al., Macromolecules 29: 8576 (1996); Hawker et al., J Am. Chem. Soc. 118: 11467 (1996); Ejaz et al., Macromolecules 33: 2870 (2000); Mandal et al., Chem. Mater. 12: 3481 (2000); and Angot et al., Macromolecules 34: 768 (2001)). As these methods work by controlling the growth of polymer chains, the tethered chain ends are active, thus the desired polymer molecular weight and composition can be achieved by varying the nature of the monomer feed and time of polymerization. The continuous approach that these controlled methods of performing free radical WO 02/079305 PCT/AU02/00416 -3polymerization allows, does not result in the generation of steric barriers imposed by crowding of the growing chains at the surface, which hinders the diffusion of chain ends to the monomer interface for further propagation of the bound macromolecules. The ability of the living free radical process to achieve these desired effects is based on the dynamic equilibrium between dormant and active chain ends. The terminology "living"/controlled radical polymerization is discussed in Darling et al., J Polym. Sci. Part A: Polym. Chem.

38: 1706 (2000). The general features of such a polymerization are: the main chain carrier is a carbon centered radical; the control over the reaction is exerted by a reversible capping mechanism so that there is an equilibrium between dormant and active chains; this has the effect of reducing the overall radical concentration, thereby suppressing radical-radical termination events; in reversible-addition-fragmentation transfer (RAFT) polymerizations, this is achieved by a dithioester or related compound; in atom transfer radical polymerization (ATRP), this is achieved by a halogen atom and in nitroxide-mediated polymerizations (NMP) it is achieved with a nitroxide molecule; the molecular weight of the polymer grows in a linear fashion with time/conversion; "living" polymers are distinguished from "dead" polymers by having the ability to grow whenever addition monomer is supplied; and block copolymers can be prepared by sequential monomer addition.

These general features of the state of the art of living/controlled polymerizations may be found in several recent patent publications. WO 98/01480 (Matyjaszewski et al.) describes a solution-phase method of controlled polymerization using Atom Transfer Radical Polymerization (ATRP). The disclosed method uses control agents comprising transition WO 02/079305 PCT/AU02/00416 -4metal-ligand complexes. WO 97/47661 (corresponds to US Patent No. 6,310,149 Bl, Haddleton) discloses additional metal-ligand complexes that are useful as ATRP control agents in solution phase controlled polymerization reactions. WO 99/28352 (Haddleton et al.) discloses solid silica supports chemically modified with ligands that can be used to inmnobilize transition metals capable of acting as control agents for controlled polymerization reactions of the type described in WO 98/01480 and WO 97/47661.

Canadian Patent Application 2,341,387 (Bottcher et al.) discloses the use of a "living"/controlled polymerization method to produce defined layers of polymers on a solid surface. The disclosed "living"/controlled polymerization method requires chemically modifying the solid surface with a compound of the general formula A-L-I, where A represents an active group, I is an ATRP initiating group, and L is a linkage between them.

Canadian Patent Application 2,249,955 (Guillet et al.) discloses a method of graft polymerization on backbone polymers using stable nitroxide-based free-radical generating compounds. The disclosed method is limited to stable free radicals that can exist in solution for at least 24 hours without recombining with one another to any substantial extent. Moreover, the nitroxide-based free radical compounds disclosed by Canadian Patent Application 2,249,955 require high temperatures 110 0 C) to achieve controlled polymerization. High temperatures during polymerization have the disadvantage of increasing the production of unbound polymerization in solution as well as causing increased "in-growth" of the graft polymer into the bulk solid support.

Notwithstanding the partial successes of previous "living"/controlled polymerization processes in the development of a range of polymers, these processes exhibit the disadvantages of requiring a multi-step approach to the attachment of the control agent to the substrate and/or high-temperature nitroxide-based control agents. Consequently, the surface of the bulk solid support must be functionalized prior to polymerization and/or treated to high temperatures that result in non-surface-bound polymers as well as undesirable polymer graft in-growth.

The in-growth, or penetration of grafts into the bulk solid support during the polymerization process is a major limitation of state of the art solid phase grafting WO 02/079305 PCT/AU02/00416 techniques. Ideally, polymerization of grafts occurs on the outer most surface of a solid support with little or no penetration into the bulk solid) so that functional groups on the graft have maximum accessibility to the surrounding solvent environment. The ingrowth of polymer grafts results in poor accessibility to the solvent environment.

Furthermore, this lack of accessibility is exacerbated by the solvent swelling that most polymers undergo during the course of a solid-phase synthesis protocol.

Consequently, the use of the polymer grafts as sites for solid-phase synthesis results in large amounts of impurities. These impurities must be separated from the desired products upon cleavage from the support resulting in lower solid phase synthesis yields and increased costs. Additionally, where solid phase synthesis is used in the context of highthroughput screening applications solid-phase combinatorial synthesis methods), the presence of even small amounts of impurities may create a false positive "hit" that misleads researchers, resulting in lost time, effort and money.

State of the art methods of living/controlled polymerization that generate polymer grafts on solid supports do not allow one to control the depth of penetration in-growth) of grafts. Consequently, substrate polymers for solid-phase synthesis, made using state of the art methods, have unpredictable surface properties. Specifically, the transition (i.e.

boundary layer) between the bulk polymer of the solid support and the polymer of the graft may vary considerably between different preparations. As described above, these differences may greatly affect the usefulness of a substrate polymer in solid-phase synthesis, or any other solid-phase application that requires consistent surface characteristics.

In accordance with the present invention, the inventors have developed more efficacious methods for controlled polymerization on solid supports which facilitate the production of a range of polymers grafted to a solid support. These improved methods allow polymerization to occur directly from the non-functionalized surface of the bulk support.

In addition, these methods may employ the non-nitroxide-based RAFT and ATRP control agents that allow controlled polymerization to proceed at relatively low temperatures WO 02/079305 PCT/AU02/00416 0 Significantly, these improved methods may be controlled so as to provide reproducibly thin layers of graft polymers with decreased levels of "in-growth" of the bulk solid support.

P.OPERRdtU7\!212OI9 2W. dom-26O4/007 -7- SUMMARY OF THE INVENTION Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

The present invention provides a method for generating a substrate polymer useful for graft polymerization comprising: providing a substrate polymer comprising a surface; subjecting the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the substrate polymer; and contacting the substrate polymer with a control agent; whereby the control agent reacts with the generated radicals, or radicals generated therefrom, to modify the surface of the substrate polymer.

The present invention also provides a method of graft polymerization comprising: providing a substrate polymer comprising a surface; subjecting the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the substrate polymer; and contacting the substrate polymer with a solution comprising monomer and a control agent; whereby the control agent reacts with the generated radicals, or radicals generated therefrom, and controlled polymerization of said monomer occurs resulting in a graft polymer on the surface of the substrate polymer.

P XOPERR dt2C7 2120190 2.p. do-2604f00 -8- A method for generating a surface or sub-surface region of a polymer forming at least part of a non-functionalized solid support for use in a living polymerization process is also described herein, said method comprising subjecting said surface and/or sub-surface region of said polymer to radical-forming means for a time and under conditions sufficient to generate radicals wherein said radicals may be capped by a control agent for subsequent use or may participate in a grafting reaction of a monomer or its precursor.

The substrate polymer surfaces modified with control agents may be useful for graft polymerization processes. A method for generating these substrate polymers may comprise: providing a substrate polymer with a non-functionalized surface; subjecting the substrate polymer to a radical-forming agent; and contacting the substrate polymer with a solution comprising solvent and a control agent under conditions wherein the temperature is less than 80'C. The resulting surface of the substrate polymer is modified with the control agent.

Such methods may be conducted at temperatures less than 60'C and preferably less than in order to prevent heat damage to molded plastic substrates. The control agents may be selected from the group of control agent compounds consisting of: RAFT agents, ATRP agents and nitroxide-radical based control agents.

The methods may be used for generating a substrate polymer with a plurality of surface regions modified with control agents useful for graft polymerization.

This method may comprise: providing a substrate polymer with a non-functionalized surface; subjecting a first region of the surface of the substrate polymer to a radicalforming agent; and contacting the substrate polymer with a solution comprising solvent and a first control agent under conditions wherein the temperature is less than 80'C. The method further comprises: subjecting at least a second region of the surface of the substrate polymer to a radical-forming agent; and contacting the substrate polymer with at least a second solution comprising solvent and a second control agent under conditions wherein the temperature is less than 80*C. The above combination of steps results in the first and at P %OPERUR4IUO07\122O01 2s dm.2&M42O07 -9least second regions of the surface of the solid support are modified with the first and second control agents. In a particularly preferred embodiment of this method, at least two regions of the substrate polymer are modified with different control agents. However, the method need not be limited to only two control agents. In another preferred embodiment of this method, the different control agents at the at least two regions on the surface of the substrate polymer utilize chemically orthogonal conditions for subsequent living/controlled polymerization of graft polymers.

Physical stress means may be selectively applied to a substrate polymer to generate a plurality of surface regions useful for graft polymerization. In this case the method may comprise: providing a substrate polymer comprising a surface; subjecting a first region of the surface of the substrate polymer to a physical stress means; subjecting the first region of the surface of the substrate polymer to a radical-forming means; and contacting the substrate polymer with a solution comprising solvent and a first control agent. The method may further comprise: subjecting at least a second region of the surface of the substrate polymer to a physical stress means; subjecting the at least second region of the surface of the substrate polymer to a radical-forming agent; and contacting the substrate polymer with at least a second solution comprising solvent and a second control agent. The method thereby results in a first and at least a second region of the surface of the substrate polymer modified with the first and second control agents. At least two regions of the substrate polymer may be modified with different control agents. The substrate polymer may also be modified with greater than two different control agents in different regions. The different control agents at the at least two regions on the surface of the substrate polymer may utilize chemically orthogonal conditions for subsequent graft polymerization.

Also described herein are methods of graft polymerization on a solid support comprising providing a substrate polymer comprising a non-functionalized surface; subjecting the substrate polymer to a radical-forming agent; and contacting the substrate polymer with a solution comprising monomer, solvent and a control agent under conditions wherein the temperature is less than about 80°C. The method results in a living/controlled P.NOPERdO07\2 120190 2. dC-2604/2007 polymerization of the monomer resulting in a graft polymer on the non-functionalized surface of the substrate polymer.

Also described herein is a method of generating co-polymers on a solid support comprising: providing a substrate polymer comprising a non-functionalized surface; subjecting the substrate polymer to a radical-forming agent; contacting the substrate polymer with a solution comprising monomer, solvent and a control agent under conditions wherein the temperature is less than about 80°C; and contacting the substrate polymer with at least a second solution comprising a second monomer, solvent and a control agent under conditions wherein the temperature is less than 80 0 C. This method results in a controlled polymerization of said second monomer from the end of the first graft polymer on the nonfunctionalized surface resulting in a copolymer graft on the substrate polymer.

The above-described methods of graft polymerization and co-polymerization may be conducted at temperatures less than 60'C and preferably less than 45°C in order to prevent heat damage to molded plastic substrates. The concentration of control agent as a mol% of monomer contacted to the substrate polymer may be increased so as to minimize the depth of penetration or in-growth of the graft polymers. The concentration of control agent in the solution may be between about 0.001 mol% and 1 mol%, and preferably between 0.1 mol% and 0.3 mol% of the monomer concentration.

The invention also provides a method of generating polymer grafts at a plurality of regions on the surface of a substrate polymer. This method comprises: providing a substrate polymer comprising a surface; subjecting a first region of' the surface of the substrate polymer to a physical stress means; subjecting the first region of the surface of the substrate polymer to a radical-forming agent; contacting the substrate polymer with a first solution comprising a monomer, solvent and a control agent; subjecting at least a second region of the surface of the substrate polymer to a physical stress means; subjecting the at least a second region of the surface of the substrate polymer to a radical-forming agent; and contacting the substrate polymer with at least a second solution comprising a monomer, solvent and a control agent. The method thereby results in graft polymerization P \OPER\RdI2U007I 2120190 2 pl d0o.26/4R2007 -11of the monomers in the first and at least second solutions at the first and at least second regions of the surface of the substrate polymer.

Substrate polymers with surfaces modified with control agents may be provided by the methods described above. Solid supports with a plurality of different graft polymers attached in different regions on the surface of the substrate polymer may also be provided by the methods described above. The graft polymers may have an average depth of penetration into the substrate polymer surface less than about 80 gim, preferably less than about 60 jtm, and most preferably less than about 40 pjm.

Also described herein is a process of generating a population of one or more polymers comprising the structure:

Z-Q

wherein: Z is a chemical moiety derived from a radical generated on a surface or subsurface polymer forming part of a solid support and wherein said radical is formed by subjecting said solid support to physical and/or chemically-mediated radical forming means; Q is a chemical moiety that imparts living free radical polymerization to a process and is derived from a compound capable of influencing or exerting control by formation of a reversible bond to the growing polymer chain such that radical radical termination is reduced whilst retaining the ability to grow the polymer chains further when monomer is present; wherein said process comprises subjecting monomeric units or their precursors or oligomeric/macromeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub-surface region of said solid support via a free radical generated on said solid support by radical-forming means.

P\OPERRdt\2007\l 2120190 2p. dc.-2&d 4/2007 12- Yet another process described herein relates to generating a population of one or more chemical species comprising the structure:i1

S

H2C R2

P

nL wherein: RI and R 2 may be the same or different and each is hydrogen, halogen, optionally substituted Ci-Clo alkyl, wherein the substitutions include hydroxy, alkoxy, aryloxy, carboxy, acyloxy, aroyloxy, alkoxy-carbonyl, aryloxy-carbonyl or halogen; X is S, O, NRI or (CRIR 2 )n; P is S, O, NRiR 2 (CRiR 2

R

3 )n or [Y]mR 3 wherein Y, when present, is selected from the same substituents as for P, n is an integer which may be 0, 1 or >1; m is an integer 1 or and

R

3 is hydrogen, halogen bromine, chlorine), optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxyl-carbonyl, optionally substituted aryloxycarbonyl, carboxy, optionally substituted acyloxy, optionally substituted carbamoyl, cyano, dialkyl, diarylphosphonato, heterocycle of ring size 5, 6, 7 or 8, dialkylor diaryl-phosphonato or a polymer chain; wherein said process comprises subjecting monomeric units or their precursors or oligomeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub- P IOPERRtPO07 12120I90 2spa doc-26/42007 13surface region of said solid support via a free radical generated on said solid support by radical-forming means.

Still another method described herein relates to generating a population of polymeric chains each comprising at least one monomeric unit anchored to a polymer on the surface or sub-surface of a solid support, said method comprising generating a surface or subsurface region of a polymer forming at least part of said solid support for use in a polymerization process by subjecting said surface or sub-surface region of said polymer to radical-forming means for a time and under conditions sufficient to generate radicals, optionally capping said radicals by a control agent; simultaneously or sequentially contacting said surface to monomeric units or their precursors or oligomeric polymer units and subjecting same to polymerization means to permit the generation of chains of polymers anchored to said solid support.

The process for generating polymeric chains may be a method of graft polymerization comprising providing a substrate polymer comprising a non-functionalized surface; subjecting the substrate polymer to a radical-forming agent; and contacting the substrate polymer with a solution comprising monomer, solvent and a control agent under conditions wherein the temperature is less than about 80'C; whereby controlled polymerization of said monomer occurs resulting in a graft polymer on the non-functionalized surface of the substrate polymer.

Co-polymeric (or ter-polymeric) chains may also be generated on a substrate polymer by graft polymerization using the method comprising providing a substrate polymer comprising a non-functionalized surface; subjecting the substrate polymer to a radicalforming agent; contacting the substrate polymer with a solution comprising a first monomer, solvent and a control agent under conditions wherein the temperature is less than 80'C; whereby controlled polymerization of said first monomer occurs resulting in a graft polymer on the non-functionalized surface of the substrate polymer. And subsequently, contacting the substrate polymer with a solution comprising a second monomer, solvent and a control agent under conditions wherein the temperature is less P IOPER'Rdi\O077120190 21P. d.26MOD4fl7 -13Athan 80 0 C; whereby controlled polymerization of said second monomer occurs from the end of the first polymer graft resulting in a copolymer graft on the surface of the substrate polymer. The steps of this method of polymerization may be repeated multiple times to generate complex co-polymer and ter-polymer grafts.

Also described herein is a process for the production of a population of two or more polymeric chains on a surface or sub-surface of a solid support, said process comprising subjecting monomeric units or their precursors or oligomeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub-surface region of said solid support via a free radical generated on said solid support by radical-forming means.

WO 02/079305 PCT/AU02/00416 -14- BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graphical representation of substrate polymer mass increase versus control agent concentration for RAFT polymerization of polystyrene grafts on a nonfunctionalized polypropylene.

Figure 2 is a graphical representation of the depth profile determined by Raman microspectroscopy of polystyrene grafts on a non-functionalized polypropylene substrate polymer at two different control agent concentrations.

Figure 3 is a graphical representation of substrate polymer mass increase versus control agent concentration for RAFT polymerization of polystyrene grafts on a nonfunctionalized porous fluorinated polymer.

Figure 4 is a graphical representation of substrate polymer mass increase versus control agent concentration for CBr 4 chain transfer polymerization of polystyrene grafts on molded polypropylene tubes.

Figure 5 shows Raman spectra obtained at three different depths of penetration of the polystyrene-poly(methyl methacrylate) (PS/PMMA) block copolymer grafts generated via re-initiation of polystyrene grafts on polypropylene substrate polymer capped with RAFT control agent.

Figure 6 shows ATR-IR spectra illustrating the generation of polystyrene-poly(methyl methacrylate) (PS/PMMA) block copolymer grafts via re-initiation of polystyrene grafts capped with RAFT control agent on an expanded (porous) fluoropolymer substrate. The top spectrum is of the grafted substrate polymer before the re-initiation reaction. The bottom spectrum is of the grafted substrate polymer after the re-initiation reaction and shows a signal indicating formation of PS/PMMA copolymer grafts.

P\OPERRWt 2007M 2120190 2p. doc.-26&42007 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is predicated in part on the physical and/or chemical manipulation of the surface of a solid phase and more particularly the manipulation of the surface of a polymeric solid phase to render same suitable as an anchoring grafting) substrate for a monomeric unit of a potentially growing polymeric chain.

The present invention is particularly predicated in part on the physical and/or chemical manipulation of a non-functionalized polymeric surface of a solid support to thereby generate radicals which may be employed as anchoring substrates as grafting sites) for a living/controlled polymerization process in the presence of inter alia a control agent and monomeric units or their precursor forms. Alternatively, the radicals so generated may themselves be reversibly capped by a control agent resulting in a modified substrate polymer surface that may subsequently be used as a substrate for living/controlled polymerizations.

Accordingly, a method for generating a surface or sub-surface region of a polymer forming at least part of a non-functionalized solid support for use in a living/controlled polymerization process may comprise subjecting said surface and/or sub-surface region of said polymer to radical-forming means for a time and under conditions sufficient to generate radicals wherein said radicals may be capped by a control agent for subsequent use or may participate in an anchoring reaction a graft polymerization) of a monomer or its precursor.

Terms such as "solid support", "substrate polymer", "solid phase" and "solid phase support" are used interchangeably throughout the instant specification. The solid support may comprise a homopolymer or copolymer or ter-polymer or blend of polymers. The present invention encompasses, therefore, mono-layers and multi-layers including bi- and tri-layers of homopolymers, copolymers, ter-polymers and/or blends of polymers, the surface or sub-surface region of which, is employed as a substrate for a first monomer or its precursor form during a living polymerization process.

WO 02/079305 PCT/AU02/00416 -16- The term "substrate polymer" is not to impart any limitation as to the structure or chemical composition of the polymer. The term "substrate polymer" in this context includes any polymer or any point, area or other region on the surface or sub-surface, which preferably is co-continuous with the external environment, and which is capable of presenting radicals to an external moiety such as a control agent or monomeric unit or precursor form thereof.

Reference to a particular point, area or other region of a substrate polymer means that selected surface or sub-surface areas of a substrate polymer may be capable of participating in chemical reactions via generated radicals. This is useful in the generation of a surface with a plurality of different polymer attached at different regions an array).

Useful solid supports also include but are not limited to co-continuous porous and nonporous forms of polyolefins, such as polyethylene and polypropylene and their copolymers, and fluoropolymers such as teflons. Other useful polymeric solid supports useful with the present invention are those comprising polyalkenes, substituted acrylic polymers; vinyl halide polymers; polyvinylethers; polyvinylesters; silicone polymers; natural or synthetic rubber; polyurethane; polyamide; polyester; formaldehyde resin; polycarbonate; polyoxymethylene; polyether;. and epoxy resin. Specific examples of commercial substrate polymers useful with the invention include Santoprene PMA6100, and HET6100.

The term "substrate polymer" also includes an organic/polymer coating on a solid support, for example, a coating on an organic material or on a metallic, glass or other non-organic material.

In some preferred embodiments, the methods of the present invention involve the generation of radicals directly on a surface of a polymeric solid support on a nonfunctionalized support). However, the present invention also provides methods that may be carried out on solidsupports with surfaces functionalized by chemical methods well-known in the polymer art.

WO 02/079305 PCT/AU02/00416 -17- Reference herein to a "polymer" on the solid support or in the anchored, or grafted, polymeric chain or growing polymeric chain encompasses a copolymer including a terpolymer or other form of multi-polymeric material including a blend of polymers. The term "polymer" is not to be construed as excluding a copolymer or multi-polymeric material such as blends of polymers. The term "polymer" also includes natural and synthetic polymers including lipid bi-layers, dextran-derived carbohydrates, polynucleotide sequences, peptides, polypeptides and proteins. The polymer structure may be random coand ter-polymers, sequential (as in tapered or blocks) and branched systems such as combs, ladders, hyperbranched or dendritic, and multi-arm systems such as stars and microgels and the like. The term "polymer" also includes an oligomeric structure.

Reference herein to an "oligomeric polymer" includes polymers comprising greater than two monomeric units such as up to about 20,000 homo- or hetero-units.

As used herein, the term "monomer" includes a single chemical entity or a large macromonomeric structure including a macromer, an oligomer or a polymer.

Monomers include oligomers, macromers and any reactive entity which can be added to a growing polymeric chain. In this context, therefore, a "monomer" added to the solid support or to a growing chain may also be a polymeric unit. The term "monomer" is not to be construed solely as a single unit of a multiunit polymer since the monomer may itself be polymeric.

Monomers used herein include, therefore, acrylate and methacrylate esters, acrylic and methacrylic acid, styrene, acrylamide and methacrylamide as well as their N-substituted derivatives, methacrylonitrile, mixtures of these monomers, and mixtures of these monomers with other monomers. As one skilled in the art would recognize, the choice of co-monomers is determined by their steric and electronic properties and the factors that determine co-polymerizability of various monomers are well documented in the art.

WO 02/079305 WO 02/79305PCT/AU02/00416 -i1s- Monomers or co-monomers (including reactive macromers/oligomiers) contemplated by the present invention include methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethyihexyl methacrylate, ethyl-axhydiroxymethacrylate, isobromyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl mcthacrylate, tetrahydrofurfural methacrylate, methacrylonitrile, alphamethyistyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethyihexyl acrylate, isobromyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, functional methacrylates, acrylates and styrenes selected from glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), NNdimethylamnino ethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethyleneglycol methacrylate, itaconic, anhydride. itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), INNdimethylaminoethyl acrylate, NN-diethylaminoethyl acrylate, triethyleneglycol acrylate, ethacrylamide, N-methylacrylamide, N,N-dimnethylacrylamide, Ntertbutylmethacrylamnide, N-n-butylmethacrylamide, N-methylomethacrylamide, Nethylolmethacrylamide, N-tert-butylacrylamide, N-n-butylacrylamide, Nmethylolacrylamide, N-ethylolacrylamnide, vinylbenzoic acid (all isomers), diethylamninostyrene (all isomers), aipha-methylvinyl benzoic acid (all isomers), diethylamino alpha-methylstyrene (all isomers), p-vinylbenzene sulfonic acid, pvinylbenzene sulfonic and sodium salt, trimethoxysilyipropyl methacrylate, triethoxysilyipropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxynaethylsilylpropyl methacrylate, diethioxymethylsilyipropyl methacrylate, dibutoxymcthylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilyipropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, disopropoxysilylpropyl methacrylate, trimethoxysilyipropyl acrylate, triethoxysilyipropyl acrylate, tribuitoxysilyipropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilyipropyl acrylate, dibutoxymethylsilyipropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilyipropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilyipropyl acrylate, diisopropoxysilylpropyl acrylate, vinyl acetate, vinyl butyrate, vinyl benzoate, vinyl chloride, vinyl fluoride, vinyl P AOPERRdt2007\ 2120190 2pLdoc-26/O4/2007 19bromide, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, 3-isopropenyl-a,adimethylbenzyl isocyanate, N-vinylpyrrolidone, N-vinylcarbazole, butadiene, isoprene, chloroprene, ethylene and propylene.

A polymeric surface or sub-surface region on or part of a solid support for use to graft a monomeric unit or its precursor may be provided as part of the living/controlled polymerization process described herein. The polymeric surface or sub-surface region subjected to radical-forming means for a time and under conditions sufficient to generate radicals capable of being reactive with a capping agent and/or said monomeric unit or its precursor form. The surface or sub-surface region of the solid phase polymer is, therefore, manipulated by radical-forming means to generate radicals which in turn are able to participate in a chemical reaction with a capping agent to effectively quench the radical until subsequently needed or with a monomeric unit or precursor form thereof as part of a growing polymer chain.

The radicals may be formed on the surface of the polymeric substrate or in a sub-surface region. The surface and/or sub-surface regions of the substrate polymer may be functionalized prior to radical generation. Radicals may be generated directly on a nonfunctionalized substrate polymer's surface and/or sub-surface regions.

Reference to a sub-surface region includes regions co-continuous with the external environment. A polymeric region is co-continuous with the external environment when it comprises functional groups freely accessible, i.e. co-continuous, to the external environment. An "external environment" in this context includes a surrounding solvent, solution or other liquid, solid or gaseous environment comprising, for example, reactive entities relative to the functional groups or any reactive groups attached thereto. More particularly, a sub-surface region is co-continuous with the external environment when radical-forming means are capable of generating radicals in the sub-surface region and the sub-surface region is in contact with an external environment comprising a control agent and/or monomeric units or precursor forms of the monomeric units.

P\OPERlRdl22m l 21201 gO 2Up.doo26~l07 The benefit of being able to generate radicals in sub-surface regions and having those radicals co-continuous with the external environment is that it permits the use of living polymerization to manipulate or otherwise generate polymeric pores or regions having particular architectural properties. Methods of making substrate polymers with cocontinuous architectures useful with the present invention are disclosed in co-pending patent application, U.S.S.N. 10/052,907 filed January 17, 2002, and which is hereby incorporated herein by reference.

The polymeric surface or sub-surface region after being subjected to radical-forming means effectively becomes a substrate for anchoring/grafting monomeric units and/or a control agent. Methods described herein may therefore be used for generating a substrate polymer comprising surface and/or sub-surface regions useful as a solid support for living/controlled polymerizations. This method may comprise subjecting the substrate polymer to radical-forming means for a time and under conditions sufficient to generate a population of radicals on its surface or sub-surface regions. These radicals may then chemically react with a control agent, and/or a monomeric unit or precursor form of a monomer unit, to form a modified substrate polymer surface.

As used herein, the terms "radical-forming means" and "radical-forming agent" are used interchangeably to refer to any form of pressure or force achieved by applying physical stress physical stress means), or any chemical reaction induced by chemical means, capable of generating a radical. The radical-forming means radical-forming agent) may be applied to the entire polymer or to selected or random points or areas including regions thereof. The term "radical" is used herein in its ordinary sense and refers to any atom having an unpaired electron. A measure of sufficient physical stress means or chemical means is conveniently determined by its ability to generate radicals on a polymer.

Examples of physical stress means include but are not limited to physical movement such as stretching, twisting, indenting, bending, cutting or compression. Physical stress means also encompasses radiation-induced stress including particle radiation such as exposure to plasma including atomic particle, vacuum U.V. and plasma discharge irradiation, ionizing WO 02/079305 PCT/AU02/00416 -21radiation including y-irradiation and electron beam irradiation, laser, U.V. and temperature irradiation such as exposure to high or low levels of temperature. Methods of using physical stress means to enhance radical generation on solid supports are disclosed in copending PCT/AU01/01638 filed December 21, 2001, entitled "Modifying the surface of polymer substrates by graft polymerization", and which is hereby incorporated herein by reference.

Chemically-induced radical formation includes any chemical process or reaction resulting in radical formation. Examples of chemically-induced radical formation include the use of peroxy or alkoxy radicals and oxidation followed by Norrish type process.

Particularly preferred radicals are formed from atoms within functional groups or atoms in the backbone or skeleton of a polymer chain. The radicals may also be referred to as "polymeric radicals" and promote a form of "chain extension" with a monomer unit or a monomer within an oligomeric polymer chain, generally but not exclusively resulting in an anchored monomer or oligomeric polymer having a radical, which may be reversibly capped with a control agent, which can further react with a monomer or oligomeric polymer to continue chain extension.

Although any radical is contemplated by the present invention, the most preferred radical is a carbon-centered radical. The carbon-centered radical may be formed by any number of physical and/or chemical processes well known to those familiar with the art; such as radiation-induced stress including particle radiation such as exposure to plasma including atomic particle, vacuum U.V. and plasma discharge irradiation, ionizing radiation including y-irradiation and electron beam irradiation, laser, U.V. and temperature irradiation such as exposure to high or low levels of temperature, chemically-induced hydrogen abstraction and radical propagation.

Once the radical has been formed on the surface polymer and/or on a sub-surface polymer co-continuous with an external environment, or simultaneously with radical formation, the radical may be "capped" by a control agent (CA) and/or the radical surface or sub-surface WO 02/079305 PCT/AU02/00416 -22polymers may be used for the generation of polymeric or oligomeric polymer chains which are terminated by control agents, as has been described above.

Reference to a "control agent" or "capping agent" includes reference to any inorganic or organic chemical entity capable of influencing or exerting control by formation of a reversible bond to the growing polymer chain such that radical-radical termination is reduced, whilst retaining the ability to grow the polymer chains further when monomer is present. An effect of such control agent might be the generation of a low dispersity of macromolecular sizes of anchored polymer chains.

As used herein, the term "control agent" or "capping agent" also includes those compounds used in living/controlled polymerization reactions that are referred to as e.g.

"chain transfer agents" or "initiators" halogenated compounds such as CBr 4 A range of capping agents may be employed which generally, after physical or physicochemical intervention heat or irradiation), convert to a form which promotes living/controlled free radical polymerization of a monomer unit or oligomeric polymer unit.

There are a range of control agents contemplated herein which are capable of reversibly capping the initial radical formed by physical and/or chemical means, thereby inducing a living/controlled free radical polymerization process. To achieve these desired effects, the control agent is central to the required dynamic equilibrium between dormant and active chain ends. In so doing, the main chain carrier of the free radical polymerization is a carbon centered radical, the control over the reaction is exerted by a reversible capping mechanism so that there is an equilibrium between dormant and active chains. This has the effect of reducing the overall radical concentration, thereby suppressing radical-radical termination events.

Also, as used herein, the term "control agent" encompasses the use of a single control agent or different control agents used under different conditions. The present invention P OPER\RdAL207I 2120190 2spa do-26 4207 23 contemplates multiple different control agents RAFT and ATRP), on a single solid support, that react under different conditions. In a particularly preferred embodiment, the different control agents induce living/controlled polymerization under orthogonal reaction conditions conditions may be selected wherein living/controlled polymerization occurs only at the sites of one of the types of control agents at a time).

The different control agents may be attached at different regions on the surface of the substrate polymer. Different graft polymerizations may also be carried out at different regions on the surface by selecting orthogonal reaction conditions. Consequently, the substrate polymers may be provided with different graft polymers in different regions on the surface.

Once a substrate polymer is modified with a control agent, living/controlled polymerization may occur from the support under such conditions as are appropriate for the specific control agent (or agents) that are present. Such conditions, e.g. for RAFT, ATRP or nitroxide-mediated living/controlled polymerizations are well-known in the art.

Generally, the substrate polymer is contacted with a solution including a solvent, monomer and the control agent and allowed to react under selected temperature conditions for a period of time. In a preferred embodiment of the present invention, the temperature conditions are maintained below 80 0 C, more preferably under 60'C, and most preferably below 45°C throughout the course of the polymerization reaction. By maintaining these lower temperatures, grafts may be polymerized on solid supports without causing deformation of a molded substrate polymer, or other undesirable effects that occur during high reaction temperatures.

A particularly advantageous property of living/controlled polymerization is that the molecular weight of the polymer grows in a linear fashion with time/conversion. The "living" polymers are distinguished from dead polymers by being able to grow whenever additional monomer is supplied. In addition, block copolymers can be prepared by sequential monomer addition.

WO 02/079305 PCT/AU02/00416 -24- In a particularly preferred embodiment of the present invention, the in-growth of polymers generated by living/controlled polymerizations on a substrate polymer may be controlled based on the concentration of control agent present. In-growth as used herein refers to the depth of penetration of polymer chains into the bulk of the solid support. When used in solid phase synthesis, sites on polymeric solid supports with lower in-growth yield lower amounts of undesirable reaction products impurities). In preferred embodiments of the present invention, the concentration of control agent used in a living/controlled polymerization on a substrate polymer is between about 0.001 and 1 mol% of the concentration of monomer. In particularly preferred embodiments the control agent concentration is between about 0.001 and 0.3 mol%, and more preferably, 0.1 and 0.3 mol% of the monomer concentration.

The depth of penetration in-growth) of a polymer graft into a solid support may be characterized by the thickness of the boundary layer between the substrate polymer and the graft on the surface. The boundary layer between a polymer graft and the polymer of the solid support generally corresponds to the region wherein the two different polymers overlap. The thinner the region of overlap, the less in-growth has occurred during the living/controlled polymerization process that produces the graft.

Decreased boundary layer thickness due to decreased in-growth may be characterized by a number of solid-phase physical characterization techniques well-known in the art, such as Raman micro-spectroscopy and attenuated total reflectance infrared (ATR-IR) spectroscopy. For example, a series of Raman spectra may be obtained at different points on a cross-section of a polymeric solid support from its surface towards its interior. The plot of the relative intensities of signals due to the graft polymer versus the substrate polymer indicates the thickness of the boundary layer and, consequently, the degree of graft polymer in-growth during the living/controlled polymerization process.

In preferred embodiments, the present invention provides methods of making substrate polymers with graft polymers exhibiting an average depth of penetration less than about WO 02/079305 WO 02/79305PCT/AU02/00416 25 jim, more preferably less than 60 jim, and most preferably less than 40 gim into the surface of the substrate polymer.

There are a number of different control agents available that induce living/controlled polymerization reactions by different mechanisms. In reversible-addition-fragmnentation transfer (RAFT) polymerizations, the control agent is typically a dithioester or related compound. RAFT control agents useful with the present invention include, for example, 1 phenylprop-2-yl phenyldithioacetate; 1 -phenylethyl phenyldithioacetate, cumyl phenylditioacetate, 2-phenylprop-2-yl dithiobenzoate; 1 -phenylprop-2-yl pbromodithiobenzoate; 1-phenylethyl ditbiobenzoate; 2-cyanoprop-2-yl dithiobenzoate; 4cyanopentanoic acid dithiobeuzoate; I-acetoxyethyl dithiobenzoate;hexalds(thiobenzoylthiomethyl)benzene; 1 ,4-bis(thiobenzoylthiomethyl)benzene; 1,2,4,5tetrakis(thiobenzoylthiomnethyl)benzene; ethoxycarbonylmethyl dithioacetate; 2- (ethoxycarbonyl)prop-2-yl dithiobenzoate; tert-butyl dithiobenzoate; 1 ,4-bis(2thiobenzoylthioprop-2-yl)benzene; 4-cyano-4-(thiobenzoylthio)pentanoic acid; dibenzyl tritbiocarbonate; carboxymethyl dithiobenzoate; s-benzyl diethoxyphosphinyldotbioformate; 2,4,4-trimethylpent-2-yl dithiobenzoate; 2- (cthoxycarbonyl)prop-2-yl dithiobenzoate; 2-phenylprop-2-yl 1-dithionaphthalate; 2phenylprop-2-yl 4-chlorodithiobenzoate.

There is a variety of atom transfer radical polymerization (ATRP) control agents, well known in the art, that are useful with the present invention. ATRP control agents and living/controlled reaction conditions useful with the present invention are disclosed in, for example, U.S. Patent Nos. 5,789,487 and 6,310,149 Bi, both of which are incorporated herein by reference. Among the ATRP control groups described in the art are, for example, the Cu-based compounds of the general formula CuX, wherein X Br, Cl, 1, and the other Cu ligands are selected from the list comprising 4,4'-di(5-nonyl)-2,2'-bipyridine; 2,2'bipyridine, N-alkyl-2-pyridylmethanimine (N-propyl, N-pentyl, N-butyl); NNN' pentamnethyldiethylenetriamnine; NNN",N"' ,N"'-hexamethyltriethylenetetraamnine; and tris-(2-(diniethylamino)ethyl)arninie.

WO 02/079305 PCT/AU02/00416 -26- In addition, other metal-mediated ATRP control agents known in the art that are useful with the present invention include: Fe(cyclopentadienyl)(CO) 2 1; Ti(OiPr) 4 and Ru(pentamethylcyclopentadienyl)Cl(PPh 3 Ru(cyclopentadienyl)Cl(PPh3)2; Ru(indenyl)Cl(PPh 3 2 Other suitable control agents may be found by considering the number of "metal mediated" radical polymerization methods, and appropriate iniferters, initers and chain transfer agents. For example, the chain transfer agent, CBr 4 and similar halogenated "initiator" compounds as disclosed in U.S. Patent Nos. 5,789,487, 6,310,149 BI, and Canadian Patent No. 2,341,387, are considered suitable control agents for the purposes of some embodiments of the present invention. For example, the present invention provides methods for generating substrate polymers modified with CBr 4 that are useful for graft polymerization.

Besides RAFT and ATRP, nitroxide-mediated living/controlled polymerizations may be useful with the present invention. Any of several nitroxide-based control agent molecules known in the art, such as TEMPO and DTNB, may be used for such polymerizations.

It would be readily understood that both the manner and sequence in which the generated carbon-radical may be formed and capped may vary. For instance, a radical may be induced directly on, throughout or over the solid support in an inert atmosphere, where it may subsequently be capped by treatment with a control agent either in a solution or neat. In an alternative embodiment, the radical forming means (RFM) may be applied directly on, throughout or over the solid support in the presence of the control agent, either in a suitable solvent or neat. In a further alternative embodiment, the process may be effected by applying the radical forming means directly on, throughout or over the solid support in the presence of control agent, either in a suitable solvent or neat, and in the added presence of a monomer.

Such processes contemplated by the present invention as being appropriate for generating a solid support capped with a control agent may be described schematically as follows: WO 02/079305 PCT/AU02/00416 -27- Radical CA CA RFMCA Forming Monomer Means (RFI)I RFM, CA In the present specification, the substrate polymer comprising the solid support is represented by a heavy black bar.

It will be recognized by suitably skilled persons that a range of additional processes is available, any one of which may be successfully employed to afford carbon-centered radicals which may be capped by a control agent. One such additional process involves generating directly on, throughout or over the solid support a functional coating, such as a vinyl functionality, that is reactive towards radicals. Many methods are known for the generation of vinyl groups on a surface and these range from grafting reactions in the presence of a multi-functional monomer to condensation of a moiety comprising a vinyl group, such as condensation of acryloyl chloride, methacrylic anhydride or azlactone, among others. Processes that afford a solid support comprising vinyl groups may be described schematically as follows: Gamma, Solvent (ii)'L J (iii) H 2

N-NH

2 The vinyl functional substrate is capped via its inclusion in a capping formulation comprising monomer and/or control agent and an initiating source. Such formulations are WO 02/079305 PCT/AU02/00416 -28built by virtue of the controlled nature of the polymerization in solution. Hence, polymerizing through the surface-bound vinyl functionality incorporates a chain, which is terminated with a control agent onto 'and from the surface, as shown schematically in below. In another embodiment, a similar outcome may be achieved by activating a stoichiometric equivalence of peroxy-based initiator and control agent to afford an adduct of the control agent and the substrate, as shown schematically in "II" below. In yet a further embodiment, the addition of hydrogen bromide (HBr), or similar reagent across the styrene unit may lead to an ATRP-initiating fragment, as shown schematically in "III" below.

I: Control Agent

CA

Solvent, Monomer II: Control Agent Peroxide (RO-OR) CA III: HBr Yet another embodiment of the present invention contemplates the formation of a carboncentered radical from a surface-initiated polymerization, wherein the initiator is a standard free radical initiator well known in the art, such as a peroxide and diazo moiety, that has been bound or otherwise generated on a solid support. When initiated in the presence of monomer and/or control agent, the solid support is activated by the presence of a control agent. An exemplary process may be illustrated as in the following schematic: WO 02/079305 PCT/AU02/00416 -29- I: Control Agent 0 0 O

V

^CA

Monomer

OOH

In the present specification, the oscillating line represents a growing polymer chain.

The process may also be achieved by the direct chemical modification of a solid support, resulting in the synthesis of a bound initiated fragment, essential for controlled polymerization to occur. One such transformation, for a polystyrene grafted support, may be illustrated schematically as shown below:

SO

2

CI

ATRP

S, RAFT Z (Raft System) Once functionalized, polymerization is performed under the conditions required for the particular control agent. That is, once the control agent has been linked to the solid support, growth of the same or a different macromolecule may continue, under such living/controlled polymerization conditions as are appropriate for whatever control agent is present.

P %OPER\RdtgO'I 220190 2sp doc2M14f07 The present invention further contemplates the use of the surface of the solid support to grow anchored polymeric chains. The polymerization process may be applied immediately or otherwise sequentially to generating the radicals on the polymer on the solid support, or may be initiated simultaneously with the radical-forming means.

Accordingly, a process for generating a population of polymeric chains each comprising at least one monomeric unit anchored to a polymer on the surface or sub-surface of a solid support may comprise generating a surface or sub-surface region of a polymer forming at least part of said solid support for use in a polymerization process by subjecting said surface or sub-surface region of said polymer to radical-forming means for a time and under conditions sufficient to generate radicals, optionally capping said radicals by a control agent; simultaneously or sequentially contacting said surface to monomeric units or their precursors or oligomeric polymer units and subjecting same to polymerization means to permit the generation of chains of polymers anchored to said solid support.

A polymeric chain may be linear or branched and may grow from a single monomer anchored to said solid support or the polymeric chain may have multiple anchoring points on said surface or sub-surface polymer. The terms "chain formation" or "growing polymer chain" include linear (such as blocks and tapered systems) and branched chain (such as combs and hyperbranched) formation.

A "sub-surface" polymer is a polymer being co-continuous with an external environment.

Reference to an external environment includes reference to solid, liquid and gaseous phases exogenously applied to said solid support.

The present invention further contemplates sub-surface polymers in the form of pores cocontinuous with the external environment.

As stated above, the solid support may be a single polymeric layer or multiple homopolymeric or heteropolymer layers or blends of polymers. A "heteropolymer" encompasses a copolymer and/or a ter-polymer.

P \OPERIRdU7\ 12120190 2p. dc.2614/00f -31- Reference herein to "polymerization" includes any process by which monomers or oligomeric polymers are added to a terminal region of a polymer chain. The present invention contemplates living polymerization processes including free radical living polymerization, anionic polymerization and cationic polymerization.

As used herein, "polymerization" processes may involve any mechanism by which polymeric chains grow and including combinations of mechanisms, such as the alternating sequential use of different polymerization processes. For example, the present invention contemplates a combination of living/controlled polymerizations and free radical, anionic and/or cationic polymerizations on a sequential or alternating basis. Consequently, the polymerization methods of the present invention may be used to produce homopolymers, random copolymers, ter-polymers and/or block polymers.

Polymerization processes of the present invention include living/controlled polymerization in the presence of control agents. Such processes are capable of influencing or exerting control of the polymerization reaction by formation of a reversible bond to the growing polymer chain such that radical radical termination is reduced, while retaining the ability to grow the polymer chains further reinitiate polymerization) when monomer is present. The moiety influencing control can be an atom or molecule, organic or inorganic, of synthetic or natural origin.

A process for the living/controlled polymerization of a population of two or more polymeric chains grafts) on a surface or sub-surface of a solid support may therefore comprise subjecting monomeric units or their precursors or oligomeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub-surface region of said solid support via a free radical generated on said solid support by radical-forming means.

WO 02/079305 PCT/AU02/00416 -32- The general features of the living/controlled polymerization methods contemplated by the invention include: the main chain carrier is a radical such as, but not limited to, a carbon- or oxygencentered radical; the control over the reaction is exerted by a reversible capping mechanism so that there is an equilibrium between dormant and active chains; the molecular weight of the polymer grows in a linear fashion with time/conversion; and "living" polymers are distinguished from dead polymers by being able to grow whenever additional monomer is supplied.

By using this living/controlled polymerization process, polymers including homopolymers and copolymers are produced such as block, graft, tapered, cross-linked and branched polymers. Living/controlled polymerization involves the use of capping agents as indicated above.

Without wishing to limit the present invention to any one theory or mode of action, living/controlled polymerization may be achieved by trapping a carbon-centered radical generated directly or indirectly on, throughout, or over a solid support. This includes radicals generated on a non-functionalized surface of a substrate polymer. The radical may be induced by a number of processes well known to those skilled in the art, that may act directly on, throughout, or over the solid support, or in a sequential manner, such that the resultant process generates a radical. Once generated, the carbon-centered radical may then be capped by a control agent resulting in a substrate polymer with a surface modified with a control agent. These control agent modified substrate polymers may then be used as solid supports for graft polymerization by living/controlled processes.

WO 02/079305 PCT/AU02/00416 -33- Multiple capping agents may also be employed. For example, a single solid support may be modified with a mixture or separate solutions of control agents. The resulting modified surface may then be used in different living/controlled polymerization reactions for each of the different control agents. In this manner, a plurality of different grafts may be polymerized on a substrate polymer surface. In a further embodiment, different localized areas or regions on the surface of a single solid support may be modified each with a different control agent. A substrate polymer so modified with control agents may then be used to generate different graft polymers in each of the different regions via living/controlled polymerization processes. Preferably the different control agents in the different regions undergo living/controlled polymerization under orthogonal reaction conditions.

Capping may be achieved by any one of a number of different routes, depending on the control agent. For example, where the capping agent contemplated is of the alkyoxyamine type as described above, a bi-molecular radical condensation may occur between the oxygen-centered radical of the nitroxide and a carbon-centered radical. Where, instead, capping is achieved via a reversible addition fragmentation chain termination (RAFT), a carbon-centered radical may add to a RAFT agent, resulting in the covalent coupling of a fragment of a RAFT agent to a carbon-centered radical. Further contemplated is a reverse atom transfer radical polymerization (ATRP) process, which may afford a useful bound initiator system.

The RAFT and nitroxide processes may be described schematically as follows: P OPERRdt\UOO72120190 doc26/0412007 k e, \o Cc, In 34 Rada1 Forrig Mea= 0 S 0 Control Agent

(CA)

examples include

S

S-CH

2 -Ph

N-O

Control Agent

(CA)

examples include Another process described herein relates to generating a population of one or more polymers comprising the structure:

Z-Q

wherein: Z is a chemical moiety derived from a radical generated on a surface or subsurface polymer forming part of a solid support and wherein said radical is formed by subjecting said solid support to physical and/or chemically-mediated radical forming means; Q is a chemical moiety that imparts living free radical polymerization to a process and is derived from a compound capable of influencing or exerting control by formation of a reversible bond to the growing polymer chain such that radical radical termination is reduced whilst retaining the ability to grow the polymer chains further when monomer is present; and, wherein said process comprises subjecting monomeric units or their precursors or oligomeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub-surface region of said solid support via a free radical generated on said solid support by radical-forming means.

P: OPERldIMuO,7\ 2120190 2pa doc-26 M/2007 Yet another process described herein relates to generating a population of one or more chemical species comprising the structure: H2C -X- R2 n wherein: Riand R 2 may be the same or different and each is hydrogen, halogen, optionally substituted Ci-Cio alkyl, wherein the substitutions include hydroxy, alkoxy, aryloxy, carbonxy, acyloxy, aroyloxy, alkoxy-carbonyl, aryloxy-carbonyl or halogen; X is S, O, NRI or (CRIR 2 )n; P is S, O, NRIR 2

(CRIR

2

R

3 )n or [Y]mR3 wherein Y, when present, is selected from the same substitutents as for P; n is an integer which may be 0, 1 or >1; m is an integer 1 or and

R

3 is hydrogen, halogen bromine, chlorine), optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxyl-carbonyl, optionally substituted aryloxycarbonyl, carboxy, optionally substituted acyloxy, optionally substituted carbamyol, cyano, dialkyl, diarylphosphonato, heterocycle of ring size 5, 6, 7 or 8, dialkylor diaryl-phosphonato or a polymer chain; and, wherein said process comprises subjecting monomeric units or their precursors or oligomeric polymer units to polymerization conditions wherein at least one monomer on each polymer is linked to said surface or sub- P \OPER\Rdlt2007\12120190 Upl do.-26042007 -36surface region of said solid support via a free radical generated on said solid support by radical-forming means.

A free radical polymerization process with living characteristics can therefore be provided by polymerizing one or more free radically polymerizable monomers or oligomeric polymers in the presence of a source of initiating free radicals and a chain transfer agent.

The initiating radicals are on the surface or sub-surface of a polymer or polymers forming part of a solid support.

Yet another aspect of the present invention contemplates the manipulation of polymeric chains anchored to a solid support to generate particular chemistries including reactive or functional groups at a terminal portion of the polymer. In one example, a "linker" or other functional molecule is incorporated in addition to or in place of a capping agent to facilitate further polymer growth or addition or to anchor various biomolecules. In one particular example, the control agent is subsequently utilized to act as an initiation point for the assembly of or the attachment of chemical species. These chemical species include biomolecules such as proteins, DNA and their synthetic variants. These chemical species, by virtue of the underlying, layer grafted via living/controlled free radical polymerization, are presented and displayed in useful manners, and in a way which allows for the modification and cleavage of same from the grafted surface. If more than one type of linker is employed, the present invention extends to selectively cleaving and modifying the attached molecules.

Various aspects of the present invention may be conducted in an automated or semiautomated manner, generally with the assistance of well-known data processing methods.

Computer programs and other data processing methods well known in the art may be used to store information of preferred substrate polymer surface, control agent modifications of the surface and grafted polymer and co-polymer characteristics. Data processing methods well known in the art may be used to read input data covering the desired characteristics.

WO 02/079305 PCT/AU02/00416 Alternatively, or in addition, data processing methods well known in the art may be used to control the processes involved in the present invention, including e.g. the application of physical stress involved in the grafting process, and/or the living/controlled polymerization process, and/or the reactions and interactions occurring in, within or between a population or array of polymers grafted to a substrate polymer.

The present invention is further described by the following non-limiting examples.

WO 02/079305 PCT/AU02/00416 -38- EXAMPLE 1 Materials Washed and extracted plastic samples used in the examples hereunder include the following, referred to by their trade names as indicated: Thermoplastic polymers having a range of hardness from 35 "shore A" to 50 "shore D" with the ratio of EPDM rubber to polypropylene determining the hardness.

They are moldable, extrudable or thermoformed into desired shape. They show brittle point well below -60 0 C. Modulus values are 1 to 10 MPa at 25C. Tensile Strength from 2.0 to 28 Mpa at 25 0 C. The rubbery part of the polymers can be partially or completely cross-linked. An example of such substrate polymers is commercially available from Exxon under the trade name "Santoprene".

Polymers having a Hardness Shore not less than 60, preferably 60-68; Flexural Modulus values of 800-1200 MPa and Impact Strength values of 5-12 KJ/m 2 at 23 0 C. The polymers should be injection molded or extruded using set parameters suitable to generate a crystallinity level of 20-50%, as well as a Melt Flow Index not less than 1 and preferably 4-14. An example of such a polymer is commercially available from Montel under the trade name "PMA6100".

Polymers having a Hardness Shore not less than 60, preferably 60-68; Flexural Modulus values of 900-1400 MPa and Impact Strength values of 7-14 KJ/m 2 at 23°C. The polymers should be extruded using set parameters suitable to generate a crystallinity level of 20-50%, as well as a Melt Flow Index not less than 1 and preferably 1-4. An example of such a polymer is commnnercially available from Montel under the trade name "HET6100".

WO 02/079305 PCT/AU02/00416 39 EXAMPLE 2 "irradiation y-irradiation was performed by treating desired plastic samples in glass vials. The samples were purged with nitrogen via a series of evacuations and fill cycles, and sealed. The samples were then exposed to a dose of y-irradiation, from a Cobolt 60 source, such that the samples received a dose in the range 7-50 kGy. Depending on the desired outcome, treatment occurred in the absence or presence of solvent(s), monomer(s) and control agent(s).

EXAMPLE 3 Control Agents The control agents were prepared by literature techniques and include the following compounds listed in Table 1 below: Table 1 Type Structure Reference Name RAFT S TCE

S-CH

2 Ph RAFT S TCDS

S-S

RAFT S PEPDTA S CH 2

S

H

RAFT

S

S

CH3

CH

3

CDTB

WO 02/079305 PCT/AU02/00416 Type Structure Reference Name Nitroxide

TEMPO

N-O*

Nitroxide DTBN

N

0 EXAMPLE 4 Generation, Subsequent Trapping and Linear Chain Extension Various plastics, prepared as outlined in Example 1 above and listed in Table 2 below, were placed into a glass vessel and sealed with a septum. The atmosphere within the vessel was evacuated and replaced with nitrogen gas and the cycle repeated 3 times. The plastics were then exposed to a dose of yirradiation, as outlined above in Example 2. The irradiated plastics were then treated with a degassed solution of a control agent, described above in Example 3 and listed below in Table 2. The solution was introduced via syringe, and the mixture was left to stand with agitation at room temperature for 16 hours, after which it was washed extensively with dichloromethane (DCM) and then dried.

The dried plastic samples were then added to a polymerization vessel comprising monomer, and the solution sparged with nitrogen for 15 minutes. The vessel was then sealed and heated at the prescribed temperature for the specified time, as listed in Table 2 below. After polymerization had been effected, the samples were washed extensively with (DCM) and then dried.

WO 02/079305 WO 02/79305PCT/AU02/00416 -41 Table 2 Solid Control Agent Polymerization Process____ Support Type Solvent Concentration Monomer Conditions Weight PMA6100 TEMPO Dichioro- 0.05% styrene, 80'C116 hours 14 methane neat HET6100 TEMIPO Dichioro- 0.05% Styrene, 80OC116 hours 7 methane neat Santoprene TEMPO Dichloro- 0.05% Styrene, 80'C7/16 hours 26 methane neat PMIA6100 TCE Dichloro- 0.05% Styrene, 600(C/16 hoursA 12 methane neat HET6100 TCE Dichioro- 0.05% Styrene, 6OCil6 hoursA 19 methane neat Santoprene TCE Dichloro- 0.05% Styrene, 60'C/16 hoursA methane neat PMIA6100 TCDS Dichioro- 0.05% Styrene, 60'C7/16 hours A 11 methane neat HIET6100 TCDS Dichioro- 0.05% Styrene, 60 0 0116 hours A 17 methane neat Santoprene TCDS Dichioro- 0.05% Styrene, 60 0 C016 hoursA 53 methane neat A AIBN was added to the solution.

EXAMPLE Direct RAFT polymnerizations OfpolYstYrene grafts on a non-fun ctionalized polypropylene substrate polyiner using various concentrations of control agent A 20 ml screw cap vial containing polypropylene discs (3 num dianeter, surface area 0.241 cm 2 0.148 g) was charged with methanol (4.0 ml) and phenylethyl phenyldithioacetate (0.013 M in methanol, 3.0 ml, 0.040 nimol, 0.15 mol Styrene). Styrene (3.0 ml, 26.2 inunol) was then added such that the concentration in solution was 30% v/v (2.62 M).

Following this, the solution was degassed via passing nitrogen gas through for 5 min. The vial was then sealed and placed in the ~y-irradiation chamber for 400 min (dose rate 1.53 kGy/h). The temperature within the chamber did not exceed 40'C throughout the process.

Following this, the supernatant liquid was decanted and replaced with dichloromethane.

Agitation followed in order to dissolve the excess polystyrene formed. The washing WO 02/079305 PCT/AU02/00416 -42solvent was changed periodically after this and agitation continued. After washing was complete, the samples were dried under vacuum. The mass recorded for the grafted discs was 0.190 g (28.4 increase).

A series of such RAFT polymerizations were conducted as above with varied concentrations of the RAFT control agent from 0.00 to 0.15 mol Styrene. The outcomes are summarized in the bar chart shown as Figure 1. It is evident from Figure 1 that as the concentration of the RAFT control agent increased, the amount of grafted polystyrene decreased.

EXAMPLE 6 Depth ofpenetration of grafts using surface Raman micro-spectroscopy The effect of the RAFT control agent concentration, phenylethyl phenyldithioacetate, on the depth of penetration of the styrene graft into the polypropylene substrate polymer was measured using Raman micro-spectroscopy. The Raman micro-spectroscopic depth profiling was performed using Surface Enhanced mode such that the illumination/scattering area from the substrate polymer surface was in the order of 1 micron in diameter. Grafted substrate polymer samples were sectioned, and then analyzed by collecting Raman spectra at 2 micron intervals from the outer edge of the sample towards the center. The analysis was discontinued when the acquired spectrum showed Raman peaks of the substrate polymer alone. From the series of acquired spectra, the intensity of selected Raman spectral peaks identified as corresponding to the vibrational modes of the substrate polymer and the graft, respectively, were scaled against each other to afford a plot profiling the depth of penetration of the polymer graft into the bulk substrate polymer.

For example, Raman peaks at 840 cm a 1 and 618 cm were used to plot the depth of penetration the polystyrene grafts on the polypropylene substrate, respectively. Figure 2 shows two plots, one profiling penetration depth for grafts that polymerized on the substrate polymer at a control agent concentration of 0.03 and the other at a WO 02/079305 PCT/AU02/00416 -43concentration of 0.15 It is clear from the figure that the depth of penetration is substantially less less in-growth) where the higher RAFT control agent concentration was used. The depth of penetration of the polystyrene graft for the higher concentration of control agent cut off at approximately 30-40 microns, whereas the grafts formed at lower concentration of control agent penetrated in to the solid substantially beyond approximately 50 microns, and even beyond 60 microns to some extent.

EXAMPLE 7 Direct RAFTpolymerizations ofpolystyrene grafts on a non-functionalized (porous) fluorinatedpolymer substrate polymer using various concentrations of control agent and styrene monomer A 20 ml screw cap vial containing expanded (porous) fluoropolymer discs (5 mm diameter, 1.735 g) was charged with methanol (8.88 ml) and phenylethyl phenyldithioacetate (0.037 M in methanol, 0.12 ml, 0.004 mmol). Styrene (1.0 ml, 8.73 mmol) was then added such that the concentration in solution was 10 v/v (0.87 M).

Following this, the solution was degassed via passing nitrogen gas through for 5 min. The vial was then sealed and placed in the 7-irradiation chamber for 400 min (dose rate 1.53 kGy/h). The temperature within the chamber did not exceed 40 0 C throughout the process.

Following this, the supernatant liquid was decanted and replaced with dichloromethane.

Agitation followed in order to dissolve the excess polystyrene formed. The washing solvent was changed periodically after this and agitation continued. After washing was complete, the samples were dried under vacuum. The mass recorded for the grafted discs was 1.933 g (11.5 increase).

A series of such RAFT polymerizations were conducted and the outcomes in terms of grafted mass increases are summarized in the bar chart shown as Figure 3. In addition, a series of polymerizations were carried out using 7% styrene monomer concentration. As with the polyproplyene substrate polymer described in Example 5, Figure 3 indicates that as the concentration of the RAFT control agent increased, the amount of polystyrene WO 02/079305 PCT/AU02/00416 -44grafted to the fluorinated substrate polymer decreased. This trend also was observed using the lower concentration of monomer.

EXAMPLE 8 Directpolymerizations ofpolystyrene grafts on polypropylene substrate polymers using various concentrations of an ATRP control agent and styrene monomer A 20 ml screw cap vial containing molded polypropylene tubes (10 mm length, 3 mm diameter, 1.862 g) was charged with methanol (11.6 ml) and the "chain transfer" ATRP control agent, carbon tetrabromide (CBr 4 0.03 M in methanol, 0.30 ml, 0.009 mmol).

Styrene (2.1 ml, 18.3 mmol) was then added such that the concentration in solution was v/v (2.18 Following this, the solution was degassed via passing nitrogen gas through for 5 min. The vial was then sealed and placed in the 'y-irradiation chamber for 400 min (dose rate 1.53 kGy/h), after which the supernatant liquid was decanted and replaced with dichloromethane. Agitation followed in order to dissolve the excess polystyrene formed.

The solvent was changed periodically after this and agitation continued. After washing was complete, the samples were dried under vacuum. The mass recorded for the grafted tubes was 1.910 g (3.7 increase).

A series of such polymerizations were conducted and the outcomes in terms of grafted mass increase are summarized in the bar chart shown as Figure 4. It is evident from the Figure 4 charts that as concentration of the chain transfer agent (CBr 4 increased, the amount of grafted polystyrene decreased. This trend was followed at all three concentrations of styrene monomer analyzed 15, 20, and 25% monomer).

In addition, a series of such polymerizations were investigated and in-growth of the grafted polystyrene into the support material (polypropylene homopolymer) was studied by Raman micro-spectroscopy (as described in Example It was found that increasing the concentration of the chain transfer agent (CBr 4 from 0.05 mole styrene to 0.5 mole styrene led to a decrease of the in-growth depth from 38 microns to 30 microns. In general, WO 02/079305 PCT/AU02/00416 as concentration of the chain transfer agent (CBr 4 was increased, the depth of penetration into the base polyolefin decreased.

EXAMPLE 9 Polymerization ofpolystyrene-poly(methyl methacrylate) (PS/PMMA) block copolymer grafts on polypropylene substrate polymer via re-initiation ofpolystyrene grafts capped with RAFT control agent A sealed 10 ml vial containing molded polypropylene tubes grafted with polystyrene in the presence of phenylethyl phenyldithioacetate (10 mm length, 3 mm diameter, 0.271 g), prepared similarly to Example 5, was charged with methanol (4.00 ml), phenylethyl phenyldithioacetate (0.037 M in methanol, 0.36 ml, 0.013 mmol) and 2,2'-azobis(2methylpropionitrile) (AIBN, 0.06 M in methanol, 0.14 ml, 0.009 mmol). Methyl methacrylate free of inhibitor (1.5 ml, 14.0 mmol) was then added such that the concentration in solution was 25 v/v (2.34 Following this, the solution was degassed via passing nitrogen gas through for 6 min. The vial was then placed in a heating unit at 0 C with agitation for 18 hours, after which the superatant liquid was decanted and replaced with dichloromethane. Agitation followed in order to dissolve the excess poly(methyl methacrylate) formed. The washing solvent was changed periodically after this and agitation continued. After washing was complete, the samples were dried under vacuum. The mass recorded for the re-initiated tubes was 0.282 g increase).

Further, the tubes were examined for the presence of poly(methyl methacrylate) and its relative depth penetration using Raman spectroscopy. The Raman spectra are shown in Figure 5. As illustrated by the Raman spectra shown in Figure 5, the depth of penetration of the poly(methyl methacrylate) (PMMA) graft (as indicated by Raman peak at 1725 cm 1 is much less than that of the polystyrene graft from which the reaction was initiated (indicated by peaks at ~1600 Based on its low depth of penetration, it appears that the PMMA graft has been restricted to those polystyrene grafts at the surface regions of the substrate polymer.

WO 02/079305 PCT/AU02/00416 -46- EXAMPLE Polymerization ofpolystyrene-poly(methyl methacrylate) (PS/PMMA) block copolymer grafts on expanded (porous) fluoropolynter substrate via re-initiation ofpolystyrene grafts capped with RAFT control agent A sealed 10 ml vial containing expanded (porous) fluoropolymer discs (5 mm diameter, 0.220 g) grafted with polystyrene in the presence of phenylethyl phenyldithioacetate, prepared in Example 6, was charged 8 ml of a solution consisting of inhibitor free methyl methacrylate (27.0 g, 269 mmol, 4.7 M) and 2,2'-azobis(2-methylpropionitrile) (AIBN, 0.10 g, 0.608 mmol, 0.01 M) in methanol. Following this, the solution was degassed via passing nitrogen gas through for 10 min. The vial was then placed in a heating unit at with agitation for 16 hours, after which the excess poly(methyl methacrylate) formed was dissolved in dichloromethane with agitation.

The grafted substrate was then examined for the presence of poly(methyl methacrylate) on the surface using attenuated total reflectance (ATR) IR spectroscopy. The spectra (shown in Figure 6) clearly show a peak at -1725 cm- 1 indicating that a PMMA graft exists on the surface of the grafted fluoropolymer.

EXAMPLE 11 Polymerization ofpolystyrene-poly(methyl methacrylate) (PS/PMMA) block copolymer grafts on a polypropylene substrate polymer via re-initiation of polystyrene grafts capped using the ATRP method A polymerization mixture was prepared comprising of benzyl bromide (0.855 g, 5 mmol), and 1.72 g, 2-2'dipyridyl ligand (11 mmol) dissolved in 100 g of inhibitor free methyl methacrylate monomer (1 mol). Then 10 ml of the polymerization mixture was added to a polymerization vial containing a weighed sample of grafted molded polypropylene tubes, prepared above in Example 8, and 0.050 g of the catalyst, copper chloride (5 mmol).

For comparison, a reference polymerization mixture (or blank) was concurrently prepared and exposed to the same conditions. The polymerization mixture and reference sample WO 02/079305 PCT/AU02/00416 -47were degassed by nitrogen bubbling for 15 minutes. The surface ATRP initiation was carried out overnight at 90C in a temperature controlled oil bath. The grafted molded polypropylene tubes were recovered from the polymerized mixture by repeated washing with dichloromethane. The exhaustively washed samples were dried at 35 0 C under vacuum for 24 hours before weighing. The samples exhibited a mass increase.

EXAMPLE 12 Polymerization of a polyethyl-a-hydroxymethacrylate graft using a RAFT control agent on a grafted co-continuous substrate polymer Preparation of a co-continuous polymer formulation Phenyl magnesium bromide was prepared from bromobenzene (10.0 g, 63 mmol) and magnesium turnings (1.4 g, 58 mmol) in dry tetrahydrofuran (50 ml). The-solution was warmed to 40 0 C and carbon disulfide (4.5 g, 59 mmol) was added over 15 min whilst maintaining the reaction temperature of 40 0 C. To the resultant dark brown mixture was added hexakis(bromomethyl)benzene (5.0 g, 47 mmol) over 15 min. The reaction temperature was raised to 50 0 C and maintained at that temperature for further 3 h. Ice water (200 ml) was added and the organic products were extracted with chloroform. The organic phase was washed with water (150 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent, hexakis(thiobenzoyl thiomethyl)benzene was recrystallized from ethanol/chloroform. Hexakis(thiobenzoyl thiomethyl)benzene and styrene monomer were mixed together and degassed by bubbling nitrogen through the solution. The bottles were sealed and brought into an oil bath thermostated at 60 0 C, for 24 hours. The resultant star-like polymer was recovered by precipitation into methanol, to afford a white power of Mn 25662.

Grafting of the co-continuous formulation to a substrate polymer A 10 mg/ml solution of polystyrene star polymer prepared above was dissolved in carbon disulphide. This solution was cast onto the surface of a polypropylene disc (ca. 5 mm WO 02/079305 PCT/AU02/00416 -48diameter, 1 mm thick) at 20°C in a controlled humid atmosphere (relative humidity of with a moist airflow directed over the surface of the disc. Once the macroporous film formation and drying were complete (about 5 minutes), the procedure was repeated on the opposing surface of the polypropylene disc.

Re-initiation ofpolymerization to the co-continuous graft on the substrate polymer A bulk polymerization solution containing 0.018 g (0.066 mmol) of cumyl dithiobenzoate, 0.006 g (0.036 mmol) AIBN, 5 g (38.5 mmol) ethyl-a-hydroxymethacrylate and 5 g absolute ethanol was prepared in a 25 ml conical flask. Five macroporous discs prepared above were then added and, after sealing the vials with rubber septa, the solutions were degassed by bubbling with nitrogen gas for 30 minutes. The sample was heated at 60°C in a temperature-controlled oil bath for 4 days to initiate the RAFT polymerization process both in the supematant and from the accessible RAFT end groups on the macroporous surface.

After 4 days, the macroporous discs were removed from the polymerization solution and washed repeatedly over three days with absolute ethanol. The macroporous surfaces were then solubilized in deuterated chloroform and THF for NMR and GPC analysis, respectively. Both NMR and GPC revealed the presence of surface-initiated poly(ethyl-ahydroxymethacrylate).

EXAMPLE 13 Generation of a substrate polymer modified with a control agent A 30 ml screw cap vial containing polypropylene (square pieces of 0.8 nmm thickness and 1.2 cm 2 1.589 g) and fluoropolymer (discs of 0.5 cm in diameter and 1 mm in thickness) was sealed with a septum and the atmosphere removed by vacuum. The atmosphere was replaced with nitrogen and the process repeated 5 times. The sealed vial containing the polymers was then placed in the y-irradiation chamber for 400 min at a dose rate of 1.53 kGy/h, after which a de-gassed solution of the control agent, phenylethyl WO 02/079305 PCT/AU02/00416 -49phenyldithioacetate (0.003 M in isopropanol, 4.5 ml, 0.015 mmol) was added and the solution allowed to stand overnight.

EXAMPLE 14 Controlled polymerization ofpolystyrene grafts on a substrate polymer previously modified with a control agent Inhibitor free styrene (4.5 ml, 400 mmol), isopropanol (1.5 ml) and AIBN solution (0.003 M in isopropanol, 4.5 ml, 0.014 mmol) was then added to the yellow solution, and the mixture heated at 60 0 C for 16 hours. After the reaction time, the polymer supports were removed from the vessel, washed extensively with dichloromethane and dried until constant weight was exhibited. Gravimetric analysis indicated a mass increase for the polypropylene and fluoropolymer samples of 24.0 and respectively.

The class of fluorinated polymers used in this application was a TFE copolymer with a side chain consisting of PFA. The preferred level of copolymerization was 5-20% and the crystallinity of these classes of polymers was 20-45%. Fluoropolymers of the type described are commercially available under the trade names of FEP5100, PFA340, HPJ 420, THV 500, and PFA9935. In this example, FEP5100 was employed.

EXAMPLE Polymerization ofpolystyrene grafts in selected regions on a substrate polymer via enhancement of radical forming means by physical stress A stainless steel probe is used as a physical stress means to create indentations or cavities in the surface of a polypropylene 1.2 cm 2 square pieces of 0.8 mm thickness) or fluoropolymer discs of 0.5 cm in diameter and 1 mm in thickness) substrate polymer, such as those described in Example 1. The physically treated substrate polymer sample is then placed in a 30 ml screw cap vial which is then charged with 4.0 ml methanol and ml of a phenylethyl phenyldithioacetate solution (0.013 M in dichloromethane). Styrene monomer solution (3.0 ml, 26.2 mmol) is added such that the monomer concentration is WO 02/079305 PCT/AU02/00416 v/v (2.62 M) and the concentration of the control agent, phenylethyl phenyldithioacetate is 0.15 mol of the styrene monomer. This solution is degassed with nitrogen gas for 5 min, then sealed and placed in a 7- irradiation chamber for 400 min at a dose rate 1.53 kGy/h. After irradiation the supernatant liquid is decanted and replaced with dichloromethane. The solution is then agitated in order to dissolve excess soluble polystyrene, decanted again and this washing with dichloromethane is repeated several times. After washing is complete, the substrate polymer samples are removed and dried under vacuum.

The polymerization of polystyrene grafts on the substrate polymer surface may be visualized e.g. by aminomethylation of the samples followed by development with 0.1% bromophenol blue stain in THF. (Aminomethylation may be achieved by e.g. treatment with N-(hydroxymethyl)phthalimide in the presence of methanesulfonic acid in dry DCM solution containing 20% TFA). Analysis of the intensity of staining of the substrate polymer surface should indicate that the polymerization of the polystyrene grafts is enhanced in the cavity regions on the surface created by the physical stress means of the stainless steel probe.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Claims (23)

1. A method for generating a substrate polymer useful for graft polymerization comprising: providing a substrate polymer comprising a surface; subjecting the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the substrate polymer; and contacting the substrate polymer with a control agent; whereby the control agent reacts with the generated radicals, or radicals generated therefrom, to modify the surface of the substrate polymer.

2. The method of claim 1 wherein the substrate polymer is selected from polyalkenes; substituted acrylic polymers; vinyl halide polymers; polyvinylethers; polyvinylesters; silicone polymers; fluoropolymers, natural or synthetic rubber; polyurethane; polyamide; polyester; formaldehyde resin; polycarbonate; polyoxymethylene; polyether; and epoxy resin.

3. The method of claim 1 wherein the substrate polymer has physical characteristics comprising a Hardness Shore of from about 60 to about 80; a Flexural Modulus Value of from about 600 to about 2000 Mpa; an Impact Strength Value of from about 4 to about 20 kJ/m 2 at 23 0 C; a crystallinity level of from about 10 to about 70%; and a Melt Flow Index of from about 1 to about

4. The method of any one of claims 1 to 3 wherein the control agent is selected from RAFT control agents; ATRP control agents; and nitroxide control agents.

The method of claim 4 wherein the control agent is a RAFT control agent selected from 1-phenylprop-2-yl phenyldithioacetate; 1-phenylethyl phenyldithioacetate, cumyl phenyldithioacetate, 2-phenylprop-2-yl dithiobenzoate; 1-phenylprop-2-yl p- bromodithiobenzoate; 1-phenylethyl dithiobenzoate; 2-cyanoprop-2-yl dithiobenzoate; 4- cyanopentanoic acid dithiobenzoate; 1-acetoxyethyl dithiobenzoate; P oPERR12077I212I9 2sp. dm.26KW207 -52- hexakis(thiobenzoylthiomethyl)benzene; 1,4-bis(thiobenzoylthiomethyl)benzene; 1,2,4,5- tetrakis(thiobenzoylthiomethyl)benzene; ethoxycarbonylmethyl dithioacetate; 2- (ethoxycarbonyl)prop-2-yl dithiobenzoate; tert-butyl dithiobenzoate; 1,4-bis(2- thiobenzoylthioprop-2-yl)benzene; 4-cyano-4-(thiobenzoylthio)pentanoic acid; dibenzyl trithiocarbonate; carboxymethyl dithiobenzoate; s-benzyl diethoxyphosphinyldothioformate; 2,4,4-trimethylpent-2-yl dithiobenzoate; 2- (ethoxycarboxyl)prop-2-yl dithiobenzoate; 2-phenylprop-2-yl 1-dithionaphthalate; and 2- phenylprop-2-yl 4-chlorodithiobenzoate.

6. The method of claim 4 wherein the control agent is an ATRP control agent selected from: CuX wherein X Br, Cl, I, and the other Cu ligands are selected from the list comprising 4,4'-di(5-nonyl)-2,2'-bipyridine; 2,2'-bipyridine, N-alkyl-2- pyridylmethanimine (N-propyl, N-pentyl, N-butyl); pentamethyldiethylenetriamine; N,N,N",N"',N"'-hexamethyltriethylenetetraamine; and tris-(2-(dimethylamino)ethyl)amine; Fe(cyclopentadienyl)(CO) 2 Ti(OiPr) 4 Ru(pentamethylcyclopentadienyl)CI(PPh 3 2 Ru(cyclopentadienyl)Cl(PPh 3 2 Ru(indenyl)Cl(PPh 3 2 and CBr 4

7. The method of any one of claims 1 to 6 wherein the radical-forming agent is selected from exposure to particle radiation; exposure to plasma discharge radiation; exposure to ionizing radiation including y-irradiation, electron beam radiation, X-rays; exposure to electromagnetic radiation including radiation in the UV, visible, infrared and microwave spectrum; exposure to high or low levels of temperature; and exposure to chemical agents that induce hydrogen abstraction and radical propagation.

8. A method according to claim 1 for generating a substrate polymer with a plurality of surface regions useful for graft polymerization comprising: providing a substrate polymer comprising a surface; P:\OPERRdOM7\IMI2120190 2s. dm-26(4/20)7 53 subjecting a first region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the first region; contacting the substrate polymer with a first control agent; subjecting at least a second region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub- surface of the at least second region; and contacting the substrate polymer with at least a second control agent; whereby the first and at least second control agents respectively react with the generated radical, or radicals generated therefrom, on the first and the at least second regions to modify the surface of the substrate polymer.

9. A method according to claim 1 for generating a substrate polymer with a plurality of surface regions useful for graft polymerization comprising: providing a substrate polymer comprising a surface; subjecting a first region of the surface of the substrate polymer to a physical stress means; subjecting the first region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub- surface of the first region; contacting the substrate polymer with a first control agent; subjecting at least a second region of the surface of the substrate polymer to a physical stress means; subjecting the at least second region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the at least second region; and contacting the substrate polymer with at least a second control agent; whereby the first and at least second control agents respectively react with the generated radicals, or radicals generated therefrom, on the first and the at least second regions to modify the surface of the substrate polymer.

P:\OPER\RllU007\ 12120190 2pl doc-2f6U4/2()7 -54- The method of claim 8 or 9 wherein the at least two regions of the substrate polymer are modified with different control agents.

11. The method of claim 10 wherein the different control agents require different conditions in order to promote controlled polymerization.

12. The method of claim 11 wherein the different conditions for controlled polymerization are orthogonal.

13. A method of graft polymerization comprising: providing a substrate polymer comprising a surface; subjecting the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the substrate polymer; and contacting the substrate polymer with a solution comprising monomer and a control agent; whereby the control agent reacts with the generated radicals, or radicals generated therefrom, and controlled polymerization of said monomer occurs resulting in a graft polymer on the surface of the substrate polymer.

14. The method of claim 13 comprising the further step of: contacting the substrate polymer with at least a second solution comprising a second monomer and a control agent; whereby controlled polymerization of said second monomer occurs from the end of the graft polymer on the surface resulting in a copolymer graft on the substrate polymer.

The method of claim 13 or 14 wherein the concentration of control agent in the solution is between about 0.001 mol% and 1 mol% of monomer concentration.

16. The method of any one of claims 13 to 15 wherein the monomer is selected from methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, ethyl-a-hydroxymethacrylate, P \OPER\RdA20UTU 2120190 2.p. d..26AMI2007 55 isobromyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, tetrahydrofurfural methacrylate, methacrylonitrile, aipha-methyi styrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobromyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, functional methacrylates, acrylates and styrenes selected from glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), NN-dimethylaminoethyl methacrylate, N,N- diethylaminoethyl methacrylate, triethyleneglycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dim ethyl am inoethyl acrylate, N,N- diethylaminoethyl acrylate, triethyleneglycol acrylate, ethacrylam ide, N-methylacrylamide, N,N-dimethylacrylamide, N-tertbutylmethacrylamide, N-n-butylmethacrylamide, N- methylohnethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylam ide, N-n- butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), aipha-methylvinyl benzoic acid (all isomers), diethylamino alpha-methyl styrene (all isomers), p-vinylbenzene sulfonic acid, p- vinylbenzene sulfonic and sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, di butoxymnethyl silIylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, vinyl acetate, vinyl butyrate, vinyl benzoate, vinyl chloride, vinyl fluoride, vinyl bromide, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, 3-isopropenyl-a,a- dimethylbenzyl isocyanate, N-vinylpyrrolidone, N-vinylcarbazole, butadiene, isoprene, chloroprene, ethylene and propylene. P:\OPERdM2007\12120190 2p. d-26)42(X)7 56

17. The method of any one of claims 1 to 16 wherein the substrate polymer is contacted with the control agent at a temperature of less than about

18. The method of any one of claims 13 to 16 wherein the monomer is oligomeric.

19. The method of any one of claims 13 to 16 and 18 wherein the concentration of monomer in the solution is between about 5 volume% and 40 volume%. A method of claim 13 for generating polymer grafts at a plurality of regions on the surface of a substrate polymer comprising: providing a substrate polymer comprising a surface; subjecting a first region of the surface of the substrate polymer to a physical stress means; subjecting the first region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub- surface of the first region; contacting the substrate polymer with a first solution comprising a monomer and a first control agent; subjecting at least a second region of the surface of the substrate polymer to a physical stress means; subjecting the at least a second region of the surface of the substrate polymer to a radical-forming agent to generate radicals on the surface or a sub-surface of the at least second region; and contacting the substrate polymer with at least a second solution comprising a second monomer and a second control agent; whereby the first and the at least second control agents respectively react with the generated radicals, or radicals generated therefrom, on the first and the at least second regions, and controlled polymerization of the monomers occurs resulting in a graft polymer on the first and the at least second regions of the surface of the substrate polymer.

P OPERRdt2007I 2120190 2sp doc-26A4/2007 -57-

21. The method of any one of claims 1 to 20 wherein the surface of the substrate polymer is non-functionalized.

22. A method for generating a substrate polymer according to any one of claims 1, 8, and 9 substantially as hereinbefore described.

23. A method of graft polymerisation according to claim 13 or 20 substantially as hereinbefore described.