Field of the Invention

The present invention relates in general to a method of preparing polymer particles, and in particular to a method of preparing an aqueous dispersion of polymer particles. The invention also relates to polymer particles prepared in accordance with the method, and to products comprising the particles.

Background of the Invention

Polymer particles are used extensively in a diverse array of applications. For example, they may be used in coating (eg. paint), adhesive, rheology modification, filler, primer, sealant, pharmaceutical, cosmetic, separation science (eg. chromatography) and diagnostic applications.

Numerous factors play a role in determining the properties of polymer particles, with particle morphology playing a particularly important role. Being able to control polymer particle morphology has therefore been the subject of considerable research and development.

Polymer particles are commonly prepared using aqueous dispersion polymerisation techniques such as conventional emulsion, mini-emulsion and suspension polymerisation.

One approach for controlling polymer particle morphology involves using a two stage conventional emulsion polymerisation process, whereby a monomer composition is polymerised in a first stage and a different monomer composition is polymerised in a second stage. The resulting polymer particles comprise at least two different polymeric materials and are commonly referred to as composite or heterogeneous polymer particles.

Through appropriate selection of the polymerisation conditions and/or the reagents used in the polymerisation, different particle morphologies can be formed. Such morphologies include those known as core-shell, inverted core-shell, core-shell with internal occlusions, hemispheres, sandwich- and raspberry-like structures.

However, the formation of these morphologies typically requires consideration of a complex interplay between thermodynamic and/or kinetic factors associated with the polymerisation conditions and/or the reagents used in the polymerisation. Furthermore, variation in particle morphology can generally only be achieved by repeating an entire polymerisation with different polymerisation conditions and/or reagents.

An opportunity therefore remains to address or ameliorate one or more disadvantages or short comings associated with existing techniques for preparing polymer particles or to at least provide a useful alternative technique for preparing such particles.

Summary of the Invention

The present invention therefore provides a method of preparing an aqueous dispersion of polymer particles, the method comprising:

providing a dispersion comprising a continuous aqueous phase, a dispersed organic phase comprising one or more ethylenically unsaturated monomers and a stimulus responsive polymer having a controlled radical polymerisation moiety covalently bound thereto, and a stabiliser for the organic phase; and

polymerising the one or more ethylenically unsaturated monomers under the control of the controlled radical polymerisation moiety to form the dispersion of polymer particles.

The stimulus responsive polymer used in accordance with the invention has a controlled radical polymerisation (CRP) moiety covalently bound thereto. By polymerising the one or more ethylenically unsaturated monomers under the control of the CRP moiety, a polymer chain derived from the monomers can be coupled to the stimulus responsive polymer. The resulting copolymer forms the basis of the resulting dispersed polymer particles.

The stabiliser used in accordance with the invention may be a conventional non-ionic or ionic stabiliser. In one embodiment, the stabiliser for the organic phase of the dispersion is an ionic stabiliser (i.e. a cationic or anionic stabiliser).

The polymer particles prepared in accordance with the invention comprise stimulus responsive polymer and may therefore also be described as stimulus responsive polymer particles. Stimulus responsive polymers (also referred to as "smart" polymers) are known in the art as polymers which undergo a physical change in response to stimuli such as a change in temperature, pH, ionic strength and/or wavelength of light.

The physical change exhibited by a stimulus responsive polymer in response to a given stimulus can vary depending upon the type of polymer employed. One form of physical change is where in response to a stimulus the polymer undergoes a reversible transition from being hydrophobic in character to being hydrophilic in character.

By subjecting the polymer particles formed in accordance with the invention to an appropriate stimulus, it has been found that the morphology of the particle can be readily modified. Thus, in contrast with conventional techniques for modifying polymer particle morphology that are reliant upon factors associated with the polymerisation conditions and/or the reagents used in the polymerisation, the morphology of polymer particles prepared in accordance with the invention can advantageously be modified after the particles have been formed.

In one embodiment, the stimulus responsive polymer used in accordance with the invention is of a type that in response to a stimulus undergoes a transition, preferably a reversible transition, from being hydrophobic in character to being hydrophilic in character or vice versa. - A -

In one embodiment, the stimulus responsive polymer used in accordance with the invention comprises a temperature responsive polymer that in response to a change in temperature undergoes a transition, preferably a reversible transition, from being hydrophobic in character to being hydrophilic in character or vice versa.

Those skilled in the art will appreciate that expressions such as "hydrophobic in character" and "hydrophilic in character" are generally used in the art to convey favourable or unfavourable interactions between one substance relative to another (e.g. attractive or repulsive interactions) and not to define absolute qualities of a particular substance. For example, hydrophilic materials are more likely to be wetted or dissolved by an aqueous medium (attractive interaction), whereas hydrophobic materials are less likely to be wetted or dissolved by an aqueous medium (repulsive interaction). Unless otherwise stated, in the context of the present invention these expressions are intended to be a reference to the polarity of the stimulus responsive polymer relative to the polarity of the continuous aqueous phase. Thus, by being hydrophilic in character the stimulus responsive polymer is more likely to be wetted or dissolved by the aqueous phase. By being hydrophobic in character the stimulus responsive polymer is less likely to be wetted or dissolved by the aqueous phase.

Poly(N-isopropyl acrylamide) (P(NIPAAm)) is a well known temperature responsive polymer and exhibits a lower critical solution temperature (LCST) of about 36 ⁰ C in an aqueous medium. It can reversibly assume (i) an expanded random coil structure below the LCST that is hydrophilic in character and readily wet or solvated by the aqueous medium, and (ii) a collapsed globular structure above the LCST that is hydrophobic in character and not readily wet or solvated by the aqueous medium.

Where the stimulus responsive polymer used in accordance with the invention is a temperature responsive polymer that exhibits hydrophobic character above its LCST and hydrophilic character below its LCST, the polymerisation according to the method may be conducted at a temperature so as to form the polymer particles above the LCST. Upon cooling the particles to a temperature below the LCST, they can advantageously undergo a morphogenic transformation. For example, polymer particles having a spherical or spheroidal type shape above the LCST can undergo a morphogenic transformation into rod, vesical, loop, or multi-lobed like structures upon being cooled to a temperature below the LCST.

Accordingly, in one embodiment the method of the invention further comprises subjecting the so-formed polymer particles to an appropriate stimulus that causes the stimulus responsive polymer to undergo a physical change and as a result promote a morphogenic transformation of the polymer particles.

The diverse array of polymer particle morphologies that can be formed in accordance with the invention can advantageously present unique properties. For example, an aqueous dispersion of rod shaped polymer particles formed in accordance with the invention has been found to undergo a reversible transition from being a relatively free-flowing liquid to being a substantially solid gel.

The different polymer particle morphologies that may be prepared in accordance with the invention are therefore expected to give rise to new materials applications.

Further aspects of the invention are discussed in more detail below.

Brief Description of the Drawings

Preferred embodiments of the invention will hereinafter be illustrated by way of example only with reference to the accompanying drawings in which:

Figure 1 illustrates by Transition Electron Microprosopy (TEM) morphogenic transformations of polymer particles prepared in accordance with the invention (using a dispersion with about 4 wt. % polymer particles);

Figure 2 illustrates by TEM morphogenic transformations of polymer particles prepared in accordance with the invention (using a dispersion with about 7 wt.% polymer particles);

Figure 3 illustrates by TEM morphogenic transformations of polymer particles prepared in accordance with the invention (using a dispersion with about 7 wt.% polymer particles);

Figure 4 illustrates by Cryo-TEM rod-like particles derived from the polymer particles prepared in accordance with Reaction 1 (Table S 2);

Figure 5 illustrates by TEM the effect of introducing toluene to polymer particles prepared in accordance with Reaction 2 (Table S2) and cooling to yield: with no toluene, rod-like particles (iv); from 1.5 mL of the dispersion with lOμL toluene, spherical or spheroidal particles (v); and from 1.5 mL of the dispersion with 30μL toluene, loop particles (vi);

Figure 6 illustrates by TEM the effect of introducing toluene to polymer particles prepared in accordance with Reaction 3 (Table S2) and cooling to yield: with no toluene, jelly-fish particles (vii); from 1.5 mL of the dispersion with lOμL toluene, morphology between jelly-fish and rod-like particles (viii); and from 1.5 mL of the dispersion with 30μL toluene, rod-like particles (ix);

Figure 7 illustrates by TEM the effect of introducing toluene to polymer particles prepared in accordance with Reaction 2 (Table S2) and cooling with sonication to yield: with no toluene, small rod-like particles (vii); from 1.5 mL of the dispersion with lOμL toluene, spherical or spheroidal particles (viii); and from 1.5 mL of the dispersion with 30μL toluene, vesicle particles (ix); and

Figure 8 illustrates reversible gelation properties of rod-like particles prepared in accordance with the invention.

Detailed Description on the Invention

The method in accordance with the invention can be performed using conventional dispersion polymerisation techniques (eg. conventional emulsion, mini-emulsion and suspension polymerisation) and equipment.

The method comprises providing a dispersion having a continuous aqueous phase, a dispersed organic phase comprising one or more ethylenically unsaturated monomers and a stimulus responsive polymer having a controlled radical polymerisation moiety covalently bound thereto, and a stabiliser for the organic phase.

The dispersion may therefore be simplistically described as an aqueous phase having droplets of organic phase dispersed therein. In this context, the term "phase" is used to convey that there is an interface between the aqueous and organic media formed as a result of the media being substantially immiscible.

In isolation, it will be appreciated that the aqueous and organic phases will typically be an aqueous and organic medium (eg. liquid), respectively. In other words, the term "phase" simply assists with describing these media when provided in the form of a dispersion. However, for convenience the aqueous and organic media used to prepare the dispersion may hereinafter simply be referred to as the aqueous and organic phases, respectively.

In addition to the organic phase, the continuous aqueous phase may comprise one or more other components. For example, the aqueous phase may comprise one or more solvents and/or ethylenically unsaturated monomers that are soluble therein.

In addition to the one or more ethylenically unsaturated monomers and the stimulus responsive polymer, the dispersed organic phase may comprise one or more other components. For example, the dispersed organic phase may comprise one or more organic solvents that are soluble with at least the monomers.

The dispersion will generally be prepared using some form of agitation, for example sheering means. Techniques and equipment for this are well known in the art. Suitable ethylenically unsaturated monomers for use in accordance with the invention include those which can form a dispersed phase within the continuous aqueous phase and can also be polymerised by a controlled radical polymerisation process. If desired, the monomers should also be capable of being polymerised with other monomers. The factors which determine copolymerisability of various monomers are well documented in the art. For example, see: Greenlee, R.Z., in Polymer Handbook 3 ^rd Edition (Brandup, J., and Immergut. E.H. Eds) Wiley: New York, 1989 p 11/53.

Suitable ethylenically unsaturated monomers that may be used in accordance with the invention include those of formula (I):

U

\

H V

(I) where U and W are independently selected from -CO ₂ H, -CO ₂ R ¹ , -COR ¹ , -CSR ¹ , - CSOR ¹ , -COSR ¹ , -CONH ₂ , -CONHR ¹ , -CONR^, hydrogen, halogen and optionally substituted C ₁ -C ₄ alkyl or U and W form together a lactone, anhydride or imide ring that may itself be optionally substituted, where the optional substituents are independently selected from hydroxy, -CO ₂ H, -CO ₂ R ¹ , -COR ¹ , -CSR ¹ , -CSOR ¹ , -COSR ¹ , -CN, -CONH ₂ , -CONHR ¹ , -CONR^, -OR ¹ , -SR ¹ , -O ₂ CR ¹ , -SCOR ¹ , and - OCSR ¹ ;

V is selected from hydrogen, R ¹ , -CO ₂ H, -CO ₂ R ¹ , -COR ¹ , -CSR ¹ , -CSOR ¹ , - COSR ¹ , -CONH ₂ , -CONHR ¹ , -CONR^, -OR ¹ , -SR ¹ , -O ₂ CR ¹ , -SCOR ¹ , and - OCSR ¹ ;

where the or each R ¹ is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and an optionally substituted polymer chain.

The or each R ¹ may also be independently selected from optionally substituted C ₁ -C ₂₂ alkyl, optionally substituted C ₂ -C ₂₂ alkenyl, optionally substituted C ₂ -C ₂₂ alkynyl, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₃ -C ₁₈ heteroaryl, optionally substituted C ₃ -C ₁₈ carbocyclyl, optionally substituted C ₂ -C ₁₈ heterocyclyl, optionally substituted C ₇ -C ₂₄ arylalkyl, optionally substituted C ₄ -C ₁₈ heteroarylalkyl, optionally substituted C ₇ -C ₂₄ alkylaryl, optionally substituted C ₄ -C ₁₈ alkylheteroaryl, and an optionally substituted polymer chain.

R ¹ may also be selected from optionally substituted C ₁ -C ₁₈ alkyl, optionally substituted C ₂ - C ₁₈ alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkaryl, optionally substituted alkylheteroaryl and a polymer chain.

In one embodiment, R ¹ may be independently selected from optionally substituted C ₁ -C ₆ alkyl.

Examples of optional substituents for R ¹ include those selected from alkyleneoxidyl (epoxy), hydroxy, alkoxy, acyl, acyloxy, formyl, alkylcarbonyl, carboxy, sulfonic acid, alkoxy- or aryloxy-carbonyl, isocyanato, cyano, silyl, halo, amino, including salts and derivatives thereof. Examples polymer chains include those selected from polyalkylene oxide, polyarylene ether and polyalkylene ether.

Examples of monomers of formula (I) include maleic anhydride, N-alkylmaleimide, N- arylmaleimide, dialkyl fumarate and cyclopolymerisable monomers, acrylate and methacrylate esters, acrylic and methacrylic acid, styrene, acrylamide, methacrylamide, and methacrylonitrile, mixtures of these monomers, and mixtures of these monomers with other monomers. Further examples of monomers of formula (I) include: methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2- ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, alpha-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl 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), N,N-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-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol acrylate, methacrylamide, N-methylacrylamide, N ₃ N- dimethylacrylamide, N-tert-butylmethacrylamide, N-n-butylmethacrylamide, N- methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, N-n- butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, vinyl benzoic acid (all isomers), diethylamino styrene (all isomers), alpha-methylvinyl benzoic acid (all isomers), diethylamino alpha-methylstyrene (all isomers), p-vinylbenzene sulfonic acid, p- vinylbenzene sulfonic 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, tributoxysilylpropylacrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl 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, N-vinylpyrrolidone, N-vinylcarbazole, butadiene, ethylene and chloroprene. This list is not exhaustive. As part of the dispersed organic phase, the one or more ethylenically unsaturated monomers will be hydrophobic in character relative to the continuous aqueous phase. This will typically be reflected by the monomers being substantially insoluble in the aqueous phase. Polymer derived from the monomers will also be hydrophobic in character and therefore substantially insoluble in the aqueous phase.

Having said this, the aqueous phase may also comprise one or more solvated ethylenically unsaturated monomers (i.e. monomers that are hydrophilic in character) that become copolymerised with monomers in the dispersed organic phase. Polymer derived under these circumstances will nevertheless still be overall hydrophobic in character. In other words, a degree of hydrophilic monomer may be copolymerised with monomer in the organic phase provided that the polarity of the resulting polymer is overall hydrophobic in character.

The one or more ethylenically unsaturated monomers used in preparing the dispersion will generally not be of a type that can be polymerised to form a stimulus responsive polymer. In particular, they will generally not be of a type that can be polymerised to form a stimulus responsive polymer that in response to a stimulus undergoes a transition from being hydrophobic in character to being hydrophilic in character or vice versa.

In addition to ethylenically unsaturated monomer, the dispersed organic phase comprises stimulus responsive polymer. Stimulus responsive polymers used in accordance with the invention are, as hereinbefore described, polymers that undergo a physical change in response to stimuli such as a change in temperature, pH, ion concentration and/or wavelength of light.

The physical change exhibited by a stimulus responsive polymer in response to a given stimulus can vary depending upon the type of polymer employed. In one embodiment of the invention, the stimulus responsive polymer is of a type that upon being subjected to a stimulus undergoes a transition from being hydrophobic in character to being hydrophilic in character or vice versa. The physical change exhibited by the polymer may be, and preferably is, reversible.

Representative stimulus responsive polymers include temperature responsive polymers, pH responsive polymers, light responsive polymers, and specific ion responsive polymers.

The stimulus responsive polymer may be in the form of a homopolymer or a copolymer.

The stimulus responsive polymer may be a natural polymer or a synthetic polymer.

Examples of temperature responsive polymers include homopolymer and copolymers of N-isopropyl acrylamide (NIPAAm) (i.e. P(NIPAAm) and NIPAAm copolymerised with one or more other ethylenically unsaturated monomers as hereinbefore described, respectively).

When NIPAAm is copolymerised with one or more hydrophilic comonomers such as acrylamide, the LCST of the copolymer can be raised relative to that of P(NIPAAm). The opposite may occur when it is copolymerised with one or more hydrophobic comonomers, such as N-t-butyl acrylamide. Copolymers of NIPAAm with hydrophilic monomers such as acrylamide have a higher LCST and generally a broader temperature range of precipitation (relative to P(NIPAAm)), while copolymers of NIPAAm with hydrophobic monomers such as N-t-butyl acrylamide have a lower LCST (relative to P(NIPPAAm) and are generally more likely to retain the sharp transition characteristic of P(NIPAAm).

Examples of pH responsive polymers are generally derived from pH responsive vinyl monomers such as acrylic acid, methacrylic acid, and other alkyl-substituted acrylic acids, maleic anhydride, maleic acid, 2-acryamido-2-methyl-l-propanesulfonic acid, N- vinyl formamide, N-vinyl acetamide, aminoethyl methacrylate, phosphoryl ethyl acrylate or methacrylate. pH responsive polymers may also be prepared as polypeptides from amino acids (e.g. polylysine or polyglutiamic acid) all derived from naturally occurring polymers such as proteins (e.g. lysozyme, albumin, casein), or polysaccharides (e.g. alginic acid, hyaluronic acid, carrageenan, chitosan, carboxymethyl, cellulose) or nucleic acids such as DNA. pH responsive polymers usually comprise pendant pH sensitive functional groups such as -OPO(OH) ₂ , -COOH or -NH ₂ .

By copolymerising a monomer that gives rise to a temperature responsive polymer such as NIPAAm with a small amount (less than about 10 mole %) of a comonomer that gives rise to a pH responsive polymer such as acrylic acid, the resulting copolymer can display both temperature and pH responsiveness. The LCST of such a copolymer can remain unaffected, sometimes even lowered a few degrees, at a pH where the copolymer is not ionised, but the LCST can be dramatically raised if the pH sensitive groups become ionised. When pH sensitive groups are present at a high concentration, the LCST response of the temperature responsive effect may be for all practical purposes eliminated.

Block copolymers derived from pH and temperature responsive monomers can be prepared such that they retain both pH and temperature transitions independently. For example, a block copolymer having a pH responsive block (polyacrylic acid) and a temperature responsive block (P(NIPAAm)) can retain independent pH and temperature responsiveness.

Examples of light responsive polymers include those that contain chromophoric groups pendant to or along the main chain of the polymer and, when exposed to an appropriate wavelength of light, can be isomerised from a trans to a cis form, which can be dipolar and more hydrophilic and promote reversible polymer conformational changes. Other light sensitive groups can also be converted by light stimulation from a relatively non-polar hydrophobic, non-ionised state to a hydrophilic ionic state.

In the case of pendant light-sensitive groups such as a light-sensitive dye (e.g. aromatic azo compounds or stilbene derivatives), they may be conjugated to a reactive monomer (an exception is a dye such as chlorophyllin, which already comprises a vinyl group) and then homopolymerised or copolymerised with one or more other monomers, including temperature responsive or pH responsive monomers. The light sensitive group may also be conjugated to an end of a polymer chain, including a stimulus responsive polymer chain. Techniques for conjugating such light sensitive groups to monomers or polymer chains are known.

Generally, the light responsive polymers will be prepared from vinyl monomers that contain light-sensitive pendant groups. Such monomers may be homopolymerised or copolymerised with one or more other ethylenically unsaturated monomers as hereinbefore described.

The light-sensitive groups may be dye molecules that isomerise or become ionised when they absorb certain wavelength of light, converting them from hydrophobic to hydrophilic confirmations or vice versa, or they may be dye molecules which give off heat when they absorb certain wavelength of light. In the former case, the isomerisation alone can cause chain expansion or collapse, while in the later case the polymer can precipitate if it is also temperature responsive.

Examples of chromophoric groups that may give rise to the light responsive properties include aromatic diazo dyes. When a dye of this type is exposed to 350-410nm UV light, the trans form of the dye, which is hydrophobic in character, can be isomerised to its cis form, which is dipolar and more hydrophilic in character, this in turn can cause polymer conformational changes. Exposure of the dye to visible light at about 750nm can reverse this phenomenon.

Examples of specific ion responsive polymers include polysaccharides such as carrageenan that change their confirmation, for example, from a random to an ordered confirmation, as a function of exposure to ions such as K ⁺ or Ca ²⁺ . Other examples of specific ion responsive polymers include polymers with pendant ion chelating groups such histidine or EDTA.

As indicated above, the stimulus responsive polymers may be responsive to multiple stimuli. For example, if a light responsive polymer is also temperature responsive, a UV or visible light stimulated conversion of a chromophor conjugated along the polymer backbone to a more hydrophobic or hydrophilic confirmation can also stimulate the dissolution/wetting or precipitation of the copolymer, depending upon the polymer composition and temperature. Alternatively, if the chromophor absorbs light and converts it to thermal energy rather than stimulating isomerisation, then the localised heating can also stimulate a phase change in a temperature responsive polymer such as P(NIPAAm) when the system temperature is near the phase separation temperature. The incorporation of multiple sensitivities through the copolymerisation of appropriate monomers can lend greater versatility to the stimulus responsive polymers used in accordance with the invention.

In one embodiment, the stimulus responsive polymer used in accordance with the invention comprises a temperature responsive polymer that in response to a change in temperature undergoes a transition, preferably a reversible transition, from being hydrophobic in character to being hydrophilic in character or vice versa.

There is no particular limitation regarding the number average molecular weight of the stimulus responsive polymer that may be used in accordance with the invention provided that it can form part of the dispersed organic phase. The number average molecular weight of the stimulus responsive polymer can fall within the range of about 1500 to about 40,000, for example from about 2000 to about 20,000, or form about 2,000 to about 10,000.

It will be appreciated that in order to prepare the dispersion and subsequently polymerise the monomers, the stimulus responsive polymer will at that point in the process be sufficiently hydrophobic in character so as to form part of the dispersed organic phase.

A stimulus responsive polymer used in accordance with the invention has a CRP moiety covalently bound thereto. The CRP moiety may be covalently bound directly to the stimulus responsive polymer or covalently bound indirectly to the stimulus responsive polymer through a linking group. Accordingly, the stimulus responsive polymer may comprise a moiety represented by formula (II): SRP-(L) _r -CRP (H)

where SRP is a stimulus responsive polymer, L is a linking group, CRP is a controlled radical polymerisation moiety, and r is 0 or 1.

As used herein, a "controlled radical polymerisation moiety" is intended to mean a moiety that can participate in and control or mediate the radical polymerisation of one or more ethylenically unsaturated monomers so as to form a polymer chain.

Examples of CRP include iniferter polymerisation, stable free radical mediated polymerisation (SFRP), atom transfer radical polymerisation (ATRP), and reversible addition fragmentation chain transfer (RAFT) polymerisation.

In one embodiment of the invention, the CRP moiety controls iniferter polymerisation, or in other words the CRP moiety is an iniferter moiety. Iniferter polymerisation is a well known form of CRP, and is generally understood to proceed by a mechanism illustrated below in Scheme 1.

a) AB A« + »B

b) A* + M

C) Aywwv* 4. »β A^B d) A* + AB A^B + *A e) A*** ¹ + B^^A ^ΛW B + * ^<ΛΛΛΛΛ Α

f) ^ΛΛΛΛΛΛ t + t ΛVWvΑ A ^ΛW A

Scheme 1 : General mechanism of controlled radical polymerisation with iniferters.

With reference to Scheme 1, the iniferter AB dissociates chemically, thermally or photochemically to produce a reactive radical species A and generally a relatively stable radical species B (for symmetrical iniferters the radical species B will be the same as the radical species A) (step a). The radical species A can initiate polymerisation of monomer M (in step b) and may be deactivated by coupling with radical species B (in step c). Transfer to the iniferter (in step d) and/or transfer to dormant polymer (in step e) followed by termination (in step f) characterises iniferter chemistry.

As a CRP moiety used in accordance with the invention, an iniferter moiety may therefore be represented as -AB or -BA, where AB or BA can dissociate chemically, thermally or photochemically as illustrated above in Scheme 1. In other words, the iniferter moiety - AB or -BA will be covalently bound to the stimulus responsive polymer (optionally via a linking group). Suitable moieties for conducting iniferter polymerisation are well known to those skilled in the art, and include dithiocarbonate, disulphide, and thiuram disulphide moieties. In a further embodiment of the invention, the CRP moiety controls SFRP, or in other words the CRP moiety is a SFRP moiety. As suggested by its name, this mode of radical polymerisation is believed to involve the generation of a stable radical species as illustrated below in Scheme 2.

CD . C + -D

M

Scheme 2: General mechanism of controlled radical polymerisation with stable free radical mediated polymerisation.

With reference to Scheme 2, the SFRP moiety CD dissociates to produce an active radical species C and a stable radical species D. The active radical species C reacts with monomer M, which resulting propagating chain may recombine with the stable radical species D. Unlike iniferter moieties, SFRP moieties do not provide for a transfer step.

As a CRP moiety used in accordance with the invention, a SFRP moiety may therefore be represented as -CD or -DC, where CD or DC can dissociate chemically, thermally or photochemically as illustrated above in Scheme 2. In other words, the SFRP moiety -CD or -DC will be covalently bound to the stimulus responsive (optionally via a linking group) polymer. Suitable moieties for conducting SFRP are well known to those skilled in the art, and include moieties capable of generating phenoxy and nitroxy radicals. Where the moiety generates a nitroxy radical, the polymerisation technique is more commonly known as nitroxide mediated polymerisation (NMP).

Examples of SFRP moieties capable of generating phenoxy radicals include those comprising a phenoxy group substituted in the 2 and 6 positions by bulky groups such as tert-alkyl (e.g. t-butyl), phenyl or dimethylbenzyl, and optionally substituted at the 4 position by an alkyl, alkyloxy, aryl, or aryloxy group or by a heteroatom containing group (e.g. S, N or O) such dimethylamino or diphenylamino group. Thiophenoxy analogues of such phenoxy containing moieties are also contemplated.

SFRP moieties capable of generating nitroxy radicals include those comprising the substituent R ¹ R ² N-O-, where R ¹ and R ² are tertiary alkyl groups, or where R ¹ and R ² together with the N atom form a cyclic structure, preferably having tertiary branching at the positions α to the N atom. Examples of such nitroxy substituents include 2,2,5,5- tetraalkylpyrrolidinoxyl, as well as those in which the 5-membered hetrocycle ring is fused to an alicyclic or aromatic ring, hindered aliphatic dialkylaminoxyl and iminoxyl substituents. A common nitroxy substituent employed in SFRP is 2,2,6,6-tetramethyl-l- piperidinyloxy.

In another embodiment of the invention, the CRP moiety controls ATRP, or in other words the CRP moiety is an ATRP moiety. ATRP generally employs a transition metal catalyst and is believed to reversibly deactivate a propagating radical by transfer of a transferable atom or group such as a halogen atom to the propagating polymer chain, thereby reducing the oxidation state of the metal catalyst as illustrated below in Scheme 3.

E-X + M _t ⁿ . E. + M _t ⁿ X

M

Scheme 3: General mechanism of controlled radical polymerisation with atom transfer radical polymerisation. With reference to Scheme 3, a transferable group or atom (X , e.g. halide, hydroxyl, C ₁ -C ₆ - alkoxy, cyano, cyanato, thiocyanato or azido) is transferred from the organic compound (E) (which may represent the stimulus responsive polymer or a linking group) to a transition metal catalyst (M _t , e.g. copper, iron, gold, silver, mercury, palladium, platinum, cobalt, manganese, ruthenium, molybdenum, niobium, or zinc) having oxidation number (n), upon which a radical species is formed that initiates polymerisation with monomer (M). As part of this process, the metal complex is oxidised (M _t ⁿ⁺¹ X). A similar reaction sequence is then established between the propagating polymer chain and the dormant X end-capped polymer chains.

As a CRP moiety used in accordance with the invention, an ATRP moiety may therefore be represented as -EX, where E is an organic group (e.g. the stimulus responsive polymer or a linking group such as an optionally substituted alkyl, optionally substituted aryl, or optionally substituted alkylaryl) and X is an atom or group that can participate in a redox cycle with a transition metal catalyst to reversibly generate a radical species and the oxidised metal catalyst as illustrated above in Scheme 3. In other words, the ATRP moiety -EX or simply -X will be covalently bound to the stimulus responsive polymer (optionally via a linking group).

Although ATRP requires the presence of a transition metal catalyst to proceed, it is not intended that the transition metal catalyst form part of the CRP moiety used in accordance with the invention.

In a further embodiment of the invention, the CRP moiety controls RAFT polymerisation, or in other words the CRP moiety is a RAFT moiety. RAFT polymerisation is believed to operate through a mechanism outlined below in Scheme 4. a) b)

Scheme 4: General mechanism of controlled radical polymerisation with reversible addition fragmentation chain transfer polymerisation.

With reference to Scheme 4, RAFT polymerisation is believed to proceed through initial reaction sequence (a) that involves reaction of a RAFT moiety (1) with a propagating radical. The labile intermediate radical species (2) that is formed fragments to form a temporarily deactivated dormant polymer species (3) together a radical (R-) derived from the RAFT moiety. This radical can then promote polymerisation of monomer (M), thereby reinitiating polymerisation. The propagating polymer chain can then react with the dormant polymer species (3) to promote the reaction sequence (b) that is similar to reaction sequence (a). Thus, a labile intermediate radical (4) is formed and subsequently fragments to form again a dormant polymer species together with a radical which is capable of further chain growth.

RAFT moieties suitable for use in accordance with the invention comprise a thiocarbonylthio group (which is a divalent moiety represented by: -C(S)S-). Examples of RAFT moieties are described in Moad G.; Rizzardo, E; Thang S, H. Polymer 2008, 49, 1079-1131 (the contents of which are incorporated herein by reference) and include xanthates, dithioesters, dithiocarbamates and trithiocarbonates.

A stimulus responsive polymer comprising a RAFT moiety suitable for use in accordance with the invention may be represented by formula (III) or (IV):

(HI) (IV) where SRP is a stimulus responsive polymer; SRP* is a x-valent stimulus responsive polymer; L is a linking group; Z is a group, and Z* is a y-valent group, that is independently selected to enable the RAFT moiety to control or mediate the polymerisation of ethylenically unsaturated monomers; r is 0 or 1 ; x is an integer > 1 ; and y is an integer > 2.

In formula (III), the stimulus responsive polymer -SRP* is a x-valent stimulus responsive polymer, with x being an integer > 1. Accordingly, -SRP* may be mono-valent, di-valent, tri-valent or of higher valency. For example, -SRP* may be a branched stimulus responsive polymer (eg. a star polymer) having RAFT agent moieties covalently bound to one or more of the branch limbs. Alternatively, -SRP* may be a linear stimulus responsive polymer having one or more RAFT moieties covalently bound thereto. Accordingly, x may be an integer as high as 20, 50, 100 or even 500. In some embodiments, x will be an integer ranging from 1 to about 10, for example from 1 to about 5.

Similarly, in formula (IV) Z* is a y-valent group, with y being an integer > 2. Z* may therefore be di-valent, tri-valent or of higher valency. Generally, y will be an integer ranging from 2 to about 20, for example from about 2 to about 10, or from 2 to about 5. Examples of suitable -SRP and -SRP* include those stimulus responsive polymers described herein.

The Z and Z* in RAFT moieties used in accordance with the invention represents a group that functions to convey a suitable reactivity to the C=S moiety in the RAFT moiety towards free radical addition without slowing the rate of fragmentation of the RAFT- adduct radical to the extent that polymerisation is unduly retarded.

The Z in RAFT moieties used in accordance with the invention may be selected from optionally substituted, and in the case of Z* may be selected from a y-valent form of optionally substituted: F, Cl, Br, I, alkyl, aryl, acyl, amino, carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, aryloxy, acyloxy, acylamino, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy, alkylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, arylheteroarylthio, dialkyloxy- , diheterocyclyloxy- or diaryloxy- phosphinyl, dialkyl-, diheterocyclyl- or diaryl- phosphinyl, cyano (i.e. -CN), and -S-(L) _r -SRP, where L, SRP and r are as herein defined.

The Z in RAFT moieties used in accordance with the invention may be selected from optionally substituted, and in the case of Z* may be selected from a y-valent form of optionally substituted: F, Cl, C ₁ -C ₁₈ alkyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ acyl, amino, C ₃ -C ₁₈ carbocyclyl, C ₂ -C ₁₈ heterocyclyl, C ₃ -C ₁₈ heteroaryl, C ₁ -C ₁₈ alkyloxy, C ₆ -C ₁₈ aryloxy, C ₁ - C ₁₈ acyloxy, C ₃ -C ₁₈ carbocyclyloxy, C ₂ -C ₁₈ heterocyclyloxy, C ₃ -C ₁₈ heteroaryloxy, C ₁ -C ₁₈ alkylthio, C ₆ -C ₁₈ arylthio, C ₁ -C ₁₈ acylthio, C ₃ -C ₁₈ carbocyclylthio, C ₂ -C ₁₈ heterocyclylthio, C ₃ -C ₁₈ heteroarylthio, C ₇ -C ₂₄ alkylaryl, C ₂ -C ₁₈ alkylacyl, C ₄ -C ₁₈ alkylcarbocyclyl, C ₃ -Ci ₈ alkylheterocyclyl, C ₄ -C ₁₈ alkylheteroaryl, C ₂ -Ci ₈ alkyloxyalkyl, C ₇ -C ₂₄ aryloxyalkyl, C ₂ - C ₁₈ alkylacyloxy, C ₄ -C ₁₈ alkylcarbocyclyloxy, C ₃ -C ₁₈ alkylheterocyclyloxy, C ₄ -C ₁₈ alkylheteroaryloxy, C ₂ -C ₁₈ alkylthioalkyl, C ₇ -C ₂₄ arylthioalkyl, C ₂ -C ₁₈ alkylacylthio, C ₄ - C ₁₈ alkylcarbocyclylthio, C ₃ -C ₁₈ alkylheterocyclylthio, C ₄ -C ₁₈ alkylheteroarylthio, C ₈ -C ₂₄ alkylarylalkyl, C ₃ -C ₁₈ alkylacylalkyl, C ₁₃ -C ₂₄ arylalkylaryl, Ci ₃ -C ₂₄ arylacylaryl, C ₇ -C ₁₈ arylacyl, C ₉ -C ₁₈ arylcarbocyclyl, C ₈ -C ₁₈ arylheterocyclyl, C ₉ -C ₁₈ arylheteroaryl, C ₁₂ -C ₂₄ aryloxyaryl, C ₇ -Ci ₈ arylacyloxy, C ₉ -C ₁₈ arylcarbocyclyloxy, C ₈ -C ₁₈ arylheterocyclyloxy, C ₉ -C ₁₈ arylheteroaryloxy, C ₇ -Ci ₈ alkylthioaryl, Ci ₂ -C ₂₄ arylthioaryl, C ₇ -Ci ₈ arylacylthio, C ₉ -C ₁₈ arylcarbocyclylthio, C ₈ -C ₁₈ arylheterocyclylthio, C ₉ -Ci ₈ arylheteroarylthio, dialkyloxy- , diheterocyclyloxy- or diaryloxy- phosphinyl (i.e. -P(=O)OR ^k ₂ ), dialkyl-, diheterocyclyl- or diaryl- phosphinyl (i.e. -P(=O)R ^k ₂ ), where R ^k is selected from optionally substituted C ₁ -C ₁₈ alkyl, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₂ -C ₁₈ heterocyclyl, and optionally substituted C ₇ -C ₂₄ alkylaryl, cyano (i.e. -CN), and -S-(L) ₁ - SRP, where L, SRP and r are as herein defined.

In one embodiment, the RAFT moiety used in accordance with the invention is a trithiocarbonate moiety and the Z is an optionally substituted alkylthio group.

When present, the linking group L is a multi-valent group, preferably a di-valent organic group. In some embodiments of the invention the linking group is not present (i.e. r=0) and the CRP moiety is covalently bound directly to the stimulus responsive polymer.

Suitable linking groups may be selected from a di-valent form of alkyl, alkenyl, alkynyl, aryl, acyl, carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkyloxyacylalkyl, alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl, aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, and arylheteroarylthio.

When present, the linking group may also be selected from a di-valent form of C ₁ -C ₁₈ alkyl, C ₂ -C ₁₈ alkenyl, C ₂ -C ₁₈ alkynyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ acyl, C ₃ -C ₁₈ carbocyclyl, C ₂ -C ₁₈ heterocyclyl, C ₃ -C ₁₈ heteroaryl, C ₁ -C ₁₈ alkyloxy, C ₂ -C ₁₈ alkenyloxy, C ₂ -C ₁₈ alkynyloxy, C ₆ -C ₁₈ aryloxy, C ₁ -C ₁₈ acyloxy, C ₃ -C ₁₈ carbocyclyloxy, C ₂ -C ₁₈ heterocyclyloxy, C ₃ -C ₁₈ heteroaryloxy, C ₁ -C ₁₈ alkylthio, C ₂ -C ₁₈ alkenyltliio, C ₂ -C ₁₈ alkynylthio, C ₆ -C ₁₈ arylthio, C ₁ -C ₁₈ acylthio, C ₃ -C ₁₈ carbocyclylthio, C ₂ -C ₁₈ heterocyclylthio, C ₃ -C ₁₈ heteroarylthio, C ₃ - C ₁₈ alkylalkenyl, C ₃ -C ₁₈ alkylalkynyl, C ₇ -C ₂₄ alkylaryl, C ₂ -C ₁₈ alkylacyl, C ₄ -C ₁₈ alkylcarbocyclyl, C ₃ -C ₁₈ alkylheterocyclyl, C ₄ -C ₁₈ alkylheteroaryl, C ₂ -C ₁₈ alkyloxyalkyl, C ₃ -C ₁₈ alkenyloxyalkyl, C ₃ -C ₁₈ alkynyloxyalkyl, C ₇ -C ₂₄ aryloxyalkyl, C ₂ -C ₁₈ alkylacyloxy, C ₂ - ₁₈ alkyloxyacyl C ₂ - ₁₈ alkyl, C ₄ -C ₁₈ alkylcarbocyclyloxy, C ₃ -C ₁₈ alkylheterocyclyloxy, C ₄ -C ₁₈ alkylheteroaryloxy, C ₂ -C ₁₈ alkylthioalkyl, C ₃ -C ₁₈ alkenylthioalkyl, C ₃ -C ₁₈ alkynylthioalkyl, C ₇ -C ₂₄ arylthioalkyl, C ₂ -C ₁₈ alkylacylthio, C ₄ -C ₁₈ alkylcarbocyclylthio, C ₃ -C ₁₈ alkylheterocyclylthio, C ₄ -C ₁₈ alkylheteroarylthio, C ₄ -C ₁₈ alkylalkenylalkyl, C ₄ -C ₁₈ alkylalkynylalkyl, C ₈ -C ₂₄ alkylarylalkyl, C ₃ -C ₁₈ alkylacylalkyl, C ₁₃ -C ₂₄ arylalkylaryl, C ₁₄ - C ₂₄ arylalkenylaryl, C ₁₄ -C ₂₄ arylalkynylaryl, C ₁₃ -C ₂₄ arylacylaryl, C ₇ -C ₁₈ arylacyl, Cg-C ₁₈ arylcarbocyclyl, C ₈ -C ₁₈ arylheterocyclyl, C ₉ -C ₁₈ arylheteroaryl, C ₈ -C ₁₈ alkenyloxyaryl, C ₈ - C ₁₈ alkynyloxyaryl, C ₁₂ -C ₂₄ aryloxyaryl, C ₇ -C ₁₈ arylacyloxy, C ₉ -C ₁₈ arylcarbocyclyloxy, C ₈ -C ₁₈ arylheterocyclyloxy, C ₉ -C ₁₈ arylheteroaryloxy, C ₇ -C ₁₈ alkylthioaryl, C ₈ -C ₁₈ alkenylthioaryl, C ₈ -C ₁₈ alkynylthioaryl, C ₁₂ -C ₂₄ arylthioaryl, C ₇ -C ₁₈ arylacylthio, C ₉ -C ₁₈ arylcarbocyclylthio, C ₈ -C ₁₈ arylheterocyclylthio, and C ₉ -C ₁₈ arylheteroarylthio.

When present, the linking group may also be selected from a di-valent form of alkyl (e.g. C ₁ -C ₁₈ , C ₁ -C ₆ , C ₁ -C ₅ , C ₈ -C ₁₈ , or C ₉ -C ₁₈ ), aryl (e.g. C ₆ -C ₁₈ ), heteroaryl (e.g. C ₃ -C ₁₈ ), carbocyclyl (e.g. C ₃ -C ₁₈ ), heterocyclyl (e.g. C ₂ -C ₁₈ ), alkylaryl (e.g. C ₇ -C ₂₄ ), alkylheteroaryl (e.g. C ₄ -C ₁₈ ), alkylcarbocyclyl (e.g. C ₄ -C ₁₈ ), alkyloxyacylalkyl (e.g. wherein each alkyl is C ₂ - ₁₈ ) and alkylheterocyclyl (e.g. C ₃ -C ₁₈ ).

In the lists above defining groups from which Z, Z* and the linking group L may be selected, each alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, SRP moiety may be optionally substituted. For avoidance of any doubt, where a given Z, Z*, or linking group L contains two or more of such moieties (e.g. alkylaryl), each of such moieties may be optionally substituted with one, two, three or more optional substituents as herein defined.

In the lists above defining groups from which Z, Z* and the linking group L may be selected, where a given Z, Z* or linking group L contains two or more subgroups (e.g. [group A] [group B]), the order of the subgroups is not intended to be limited to the order in which they are presented. Thus, a Z, Z* or linking group L with two subgroups defined as [group A] [group B] (e.g. alkylaryl) is intended to also be a reference to a Z, Z* or linking group L with two subgroups defined as [group B] [group A] (e.g. arylalkyl).

The Z, Z* or linking group L may be branched and/or optionally substituted. Where the Z, Z* or linking group L comprises an optionally substituted alkyl moiety, an optional substituent includes where a -CH ₂ - group in the alkyl chain is replaced by a group selected from -O-, -S-, -NR ^a -, -C(O)- (i.e. carbonyl), -C(O)O- (i.e. ester), and -C(0)NR ^a - (i.e. amide), where R ^a may be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl.

Reference herein to a x-valent, y-valent, multi-valent or di-valent "form of...." is intended to mean that the specified group is a x-valent, y-valent, multi-valent or di-valent radical, respectively. For example, where x or y is 2, the specified group is intended to be a divalent radical. In that case, a divalent alkyl group is in effect an alkylene group (e.g. - CH ₂ -). Similarly, the divalent form of the group alkylaryl may, for example, be represented by -(C ₆ H ₄ )OH ₂ -, a divalent alkylarylalkyl group may, for example, be represented by -CH ₂ -(C ₆ H ₄ )-CH ₂ -, a divalent alkyloxy group may, for example, be represented by -CH ₂ -O-, and a divalent alkyloxyalkyl group may, for example, be represented by -CH ₂ -O-CH ₂ -. Where the term "optionally substituted" is used in combination with such a x-valent, y-valent, multi-valent or di-valent groups, that group may or may not be substituted or fused as herein described. Where the x-valent, y-valent, multi-valent, di-valent groups comprise two or more subgroups, for example [group A] [group B] [group C] (e.g. alkylarylalkyl), if viable one or more of such subgroups may be optionally substituted. Those skilled in the art will appreciate how to apply this rationale in providing for higher valent forms.

The dispersion used in accordance with the invention comprises a stabiliser for the organic phase. The dispersion may be prepared using conventional stabilisers such as ionic and non-ionic surfactants. Examples of su itable non-ionic surfactants include alkylphenol ethoxylates, polyoxyethylenated alkyl alcohols, amine polyglycol condensates, modified polyethoxy adducts, long chain carboxylic acid esters, modified terminated alkylaryl ether, and alkylpolyether alcohols. Examples of suitable anionic stabilisers include dodecyl sulphates, nonyl phenol ethoxylate sulphates, alkyl ethoxylate sulphates, alkyl sulphonates, alkyl succinates, alkyl phosphates, alkyl carboxylates and other alternatives well known to those skilled in the art. Examples of suitable cationic stabilisers include dodecyltrimethylammonium bromide (DTAB), tetrabutylammonium chloride (TBAC), tetramethyl ammonium chloride, tetrabutyl ammonium bromide, and benzyltriethyl ammonium chloride.

The stabiliser will typically be used in an amount ranging from about 0.01 wt.% to about 1 wt.% relative to the mass of the dispersed organic phase.

In one embodiment, the stabiliser used is an ionic stabiliser, preferably an anionic stabiliser such as sodium dodecyl sulphate (SDS).

Having prepared the dispersion, the one or more ethylenically unsaturated monomers are polymerised under the control of the CRP moiety. By being polymerised "under the control" of the CRP moiety is meant that polymerisation of the monomers proceeds via the appropriate controlled radical polymerisation mechanism to form polymer. For example, where the CRP moiety is a RAFT moiety, the polymerisation of the monomers will proceed via a RAFT mechanism to form polymer.

The polymerisation will usually require initiation from a source of free radicals. The source of initiating radicals can be provided by any suitable method of generating free radicals, such as the thermally induced homolytic scission of suitable compound(s) (thermal initiators such as peroxides, peroxyesters, or azo compounds), the spontaneous generation from monomers (e.g. styrene), redox initiating systems, photochemical initiating systems or high energy radiation such as electron beam, X- or gamma-radiation. The initiating system is chosen such that under the reaction conditions there is no substantial adverse interaction of the initiator or the initiating radicals with the SRP under the conditions of the reaction. The initiator ideally should also have the requisite solubility in the reaction medium.

Thermal initiators are chosen to have an appropriate half life at the temperature of polymerisation. These initiators can include one or more of the following compounds:

2,2'-azobis(isobutyronitrile), 2,2'-azobis(2-cyanobutane), dimethyl 2,2'- azobis(isobutyrate), 4,4'-azobis(4-cyano valeric acid), 1,1'- azobis(cyclohexanecarbonitrile), 2-(t-butylazo)-2-cyanopropane, 2,2'-azobis{2- methyl-N-[l,l-bis(hydroxymethyl)-2-hydroxyethyl]propionamide }, 2,2'-azobis[2- methyl-N-(2-hydroxyethyl)propionamide] , 2,2'-azobis(N,N'- dimethyleneisobutyramidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 2,2'-azobis{2- methyl-N-[l , 1 -bis(hydroxymethyl)-2-hydroxyethyl]propionamide} , 2,2'-azobis {2- methyl-N-[l,l-bis(hydroxymethyl)-2-ethyl]propionamide}, 2,2'-azobis[2-methyl- N-(2-hydroxyethyl)propionamide], 2,2'-azobis(isobutyramide) dihydrate, 2,2'- azobis(2,2,4-trimethylpentane), 2,2'-azobis(2-methylpropane), t-butyl peroxyacetate, t-butyl peroxybenzoate, t-butyl peroxyneodecanoate, t-butylperoxy isobutyrate, t-amyl peroxypivalate, t-butyl peroxypivalate, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, dicumyl peroxide, dibenzoyl peroxide, dilauroyl peroxide, potassium peroxydisulfate, ammonium peroxydisulfate, di-t-butyl hyponitrite, dicumyl hyponitrite. This list is not exhaustive.

Photochemical initiator systems are chosen to have the requisite solubility in the reaction medium and have an appropriate quantum yield for radical production under the conditions of the polymerisation. Examples include benzoin derivatives, benzophenone, acyl phosphine oxides, and photo-redox systems.

Redox initiator systems are chosen to have the requisite solubility in the reaction medium and have an appropriate rate of radical production under the conditions of the polymerisation; these initiating systems can include, but are not limited to, combinations of the following oxidants and reductants:

oxidants: potassium, peroxydisulfate, hydrogen peroxide, t-butyl hydroperoxide,

reductants: iron (II), titanium (III), potassium thiosulfϊte, potassium bisulfite.

Other suitable initiating systems are described in recent texts. See, for example, Moad and Solomon "the Chemistry of Free Radical Polymerisation", Pergamon, London, 1995, pp 53-95.

Suitable water soluble initiators include, but are not limited to, 4,4-azobis(cyanovaleric acid), 2,2'-azobis {2-methyl-N- [1,1 -bis(hydroxymethyl)-2-hydroxyethyl]propionamide } , 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide], 2,2'-azobis(N,N'- dimethyleneisobutyramidine), 2,2'-azobis(N,N'-dimethyleneisobutyramidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis{2-methyl-N- [l,l-bis(hydroxymethyl)-2-ethyl]propionamide}, 2,2'-azobis[2-methyl-N-(2- hydroxyethyl)propionamide], 2,2'-azobis(isobutyramide) dihydrate, and derivatives thereof. Suitable monomer soluble initiators may vary depending on the polarity of the monomer, but typically would include oil soluble initiators such as azo compounds exemplified by the well known material 2,2'- azobisisobutyronitrile. The other class of readily available compounds are the acyl peroxide class such as acetyl and benzoyl peroxide as well as alkyl peroxides such as cumyl and t-butyl peroxides. Hydroperoxides such as t-butyl and cumyl hydroperoxides are also widely used. A convenient method of initiation applicable to suspension processes is redox initiation where radical production occurs at more moderate temperatures. This can aid in maintaining stability of the polymer particles from heat induced aggregation processes.

Polymerisation of the one or more ethylenically unsaturated monomers may be performed using conventional dispersion polymerisation techniques and equipment. The polymerisation may be performed in continuous, semi-continuous or batch modes.

In one embodiment, the dispersion used in accordance with the invention may be prepared by introducing to a reaction vessel the stimulus responsive polymer having a CRP moiety covalently bound thereto, water and a stabiliser and subjecting this composition to sheering means. A solution of a thermal initiator dissolved in one or more ethylenically unsaturated monomers may then be introduced to the reactor and the resulting composition subjected to sheering means to produce the dispersion. The composition may then be degassed by purging with an inert gas. Polymerisation of the monomers may then be initiated by increasing the temperature of the degassed composition such that thermally induced homolytic scission of the initiator occurs. The polymerisation of the monomer then proceeds under the control of the CRP moiety to provide for the aqueous dispersion of polymer particles.

The polymer particles prepared from the polymerisation in accordance with the method will generally have a spherical or spheroidal shape, and depending upon the polymerisation conditions and/or the reagents used may exhibit a morphology of a type that can be prepared using conventional techniques (eg. a core-shell structure). The size of the particles can be readily varied using techniques known in the art. Generally the largest dimension of the particles will be less than about lOOOnm, for example less than about 500nm, less than about 250nm, or less than about lOOnm.

The size of the particles referred to herein is that as determined by TEM.

However, unlike polymer particles prepared by conventional techniques, the polymer particles prepared from the polymerisation in accordance with the invention incorporate a stimulus responsive polymer that upon being subjected to an appropriate stimulus can promote a morphogenic transformation of the so formed particles. Variation in the manner in which the particles are subjected to the stimulus may further modify the form of the morphogenic transformation. The present invention therefore provides an extremely versatile means for controlling and modifying the morphology of polymer particles.

Accordingly, in one embodiment of the invention the method of the invention further comprises subjecting the so-formed polymer particles to an appropriate stimulus that causes the stimulus responsive polymer to undergo a physical change and as a result promote a morphogenic transformation of the polymer particles.

It will be appreciated that at least up to the end of the polymerisation the polymer chains that form the particles will be overall hydrophobic in character relative to the continuous aqueous phase. It has been found that a convenient way to promote the morphogenic transformation of the particles after the polymerisation is to use a stimulus responsive polymer that in response to a stimulus undergoes a transition from being hydrophobic in character to being hydrophilic in character.

Without wishing to be limited by theory, it is believed that stimulus responsive polymer within the overall hydrophobic environment of a given polymer particle will, upon becoming hydrophilic in character, attempt to reach a more thermodynamically favourable state by repositioning to be in contact with or as close as possible to the hydrophilic environment of the continuous aqueous phase. This drive to attain a more thermodynamically favourable state is in turn believed to promote a morphogenic transformation in the particles.

In other words, the polymer particles may be simplistically described as comprising intertwined di-block copolymer chains, where one block is represented by the stimulus sensitive polymer and the other block is represented by polymer that is formed through polymerisation of the monomers. At least up until the end of the polymerisation, the entire di-block copolymer will be overall hydrophobic in character relative to the continuous aqueous phase. Upon being subjected to an appropriate stimulus, the stimulus responsive block of the copolymer may undergo a transition to become hydrophilic in character to afford a di-block copolymer having a hydrophilic block and a hydrophobic block. It is believed that these chains then reorganise themselves within the particles so as attain a more thermodynamically favourable state and in doing so promote a morphogenic transformation in the particles.

Without wishing to be limited by theory, it is also believed that the ability for particles prepared in accordance with the invention to undergo morphogenic transformations may in part be due to stabiliser associating with the stimulus responsive polymer and becoming imbedded within the resulting polymer particles. For example, upon the stimulus responsive polymer undergoing a transition to become hydrophilic in character, the embedded stabiliser is believed to facilitate the particle in attaining a more thermodynamically favourable state.

Temperature responsive polymers have been found to be particularly effective at promoting morphogenic transformations in polymer particles prepared in accordance with the invention. For example, the polymer particles may be prepared such that they comprise a temperature sensitive polymer such as P(NIPAAm). The temperature responsive polymer may be selected such that above its LCST it is hydrophobic in character and below its LCST it is hydrophilic in character, and also such that its LCST falls below the temperature at which the polymer particles are prepared. In that case, the polymer particles may be prepared at a temperature above the LCST with the temperature responsive polymer presenting in its hydrophobic form. After the polymer particles have been prepared, they may be cooled to a temperature below the LCST so as to cause the polymer to transition from being hydrophobic in character to being hydrophilic in character. This transition in polarity can in turn promote a morphogenic transformation in the particles. For example, the "as formed" polymer particles having a spherical or spheroidal type shape above the LCST can undergo a morphogenic transformation into rod, vesical, loop (i.e. hulla-hoop) or multi-lobed like particles upon being cooled to a temperature below the LCST.

The nature of the morphogenic transformation may vary depending upon the conditions under which the polymer particles are subjected to an appropriate stimulus and/or the composition of the particles.

For example, Figure 1 illustrates polymer particles prepared in accordance with the invention using P(NIPAAm) as the stimulus responsive polymer, a RAFT moiety as the CPR moiety, styrene as the ethylenically unsaturated monomer and sodium dodecyl sulfate as the stabiliser. The resulting dispersion comprised approximately 4.4wt.% polymer particles. A relatively rapid cooling rate may result in the "as formed" polymer particles, which have a spherical or spheroidal type shape above the LCST, transforming into multi- lobed particles below the LCST (see Figure 1 - particles in image A being transformed into particles in image B).

Plasticisation of the same "as formed" polymer particles with a plasticiser such as an organic solvent (eg. toluene) or unreacted ethylenically unsaturated monomer, and cooling the particles to below the LCST may result in their spherical or spheroidal type shape transforming into jelly fish like particles (see Figure 1 - particles in image A being transformed into particles in image C) instead of multi-lobed particles.

Adjusting the wt.% of the same "as formed" polymer particles within the aqueous dispersion and cooling the diluted dispersion to below the LCST may result in their spherical or spheroidal type shape transforming into rod like particles (see Figure 1 - particles in image A being transformed into particles in image D) instead of multi-lobed or jelly fish like particles. In that case, the wt.% of the "as formed" polymer particles was reduced from about 4 wt% to about 0.2wt.% by the addition of hot water and the resulting dispersion cooled.

Figure 2 similarly illustrates polymer particles prepared in accordance with the invention using P(NIPAAm) as the stimulus responsive polymer, a RAFT moiety as the CPR moiety, styrene as the ethylenically unsaturated monomer and sodium dodecyl sulfate as the stabiliser. In that case, polymerisation was stopped at approximately 50% conversion thereby retaining monomer as plasticiser within the formed particles. The resulting dispersion comprised approximately 7wt.% polymer particles. Cooling of this dispersion to below the LCST gave rise to moderately entangled rod-like particles (see Figure 2 - particles in image A being transformed into particles in image B). Entanglement of the rod-like particles could be reduced by subjecting the resulting dispersion to a number of heating and cooling cycles to above and below the LCST (see Figure 2 - particles in image B being transformed into particles in image F)

Removal of unreacted styrene monomer from the "as formed" particles through evaporation and subsequently cooling the particles to below the LCST gave rise to multi- lobed particles similar to that shown in image B of Figure 1 (see Figure 2 - particles in image A being transformed into particles in image C).

Further plasticisation of the "as formed" polymer particles with toluene and subjecting the dispersion to a relatively slow cooling rate to below the LCST may result in the spherical or spheroidal polymer particles undergoing a morphogenic transformation into a loop or "hulla-hoop" like particles (see Figure 2 - particles in image A being transformed into particles in image D).

Further plasticisation of the "as formed" polymer particles with toluene and subjecting the dispersion to sonication while cooling to below the LCST may result in the spherical or spheroidal polymer particles undergoing a morphogenic transformation into vesical particles (see Figure 2 - particles in image A being transformed into particles in image E).

By modifying the conditions under which the polymer particles are subjected to an appropriate stimulus the morphology of particles prepared in accordance with the invention can therefore be varied significantly. This can be more clearly illustrated with reference to Figure 3 that shows "as formed" polymer particles of the type mentioned above in describing Figure 2 undergoing morphogenic transformation under the conditions of (a) rapid cooling to a temperature below the LCST to form rod like particles, or (b) being further plasticised with toluene and then slowly cooled to a temperature below the LCST to form loop particles.

Thus, where the stimulus responsive polymer used comprises a temperature responsive polymer, the morphology of the particles may be varied by modifying the cooling/heating rate of the dispersion and/or subjecting the polymer particles to heating/cooling cycles above and below the LCST.

The morphology of the particles may be varied by introducing a plasticiser to the polymer particles, increasing or decreasing the wt.% of polymer particles within the aqueous dispersion, and/or subjecting the polymer particles to sonication.

Those skilled in the art will appreciate that other conditions and/or reagents may be used to vary the morphology of the particles.

A combination of such conditions and/or reagents may be used to vary the morphology of the particles.

The morphology of polymer particles prepared in accordance with the invention may be assessed with analytical techniques well known to those skilled in the art. For example, the particles may be analysed using TEM.

The diverse array of polymer particle morphologies that can be formed in accordance with the invention are expected to give rise to new materials applications. For example, the polymer particles may find use in coating (eg. paint), adhesive, rheology modification, filler, primer, sealant, pharmaceutical, cosmetic, separation science (eg. chromatography), diagnostic, therapeutic , and tissue engineering applications.

Polymer particle morphologies formed in accordance with the invention may in their own right give rise to unique properties. For example, polymer particles comprising temperature responsive polymer prepared in accordance with the invention may be transformed into rod-like particles. At concentrations of at least about 5wt.% the aqueous dispersion of rod-like particles have been found to undergo a reversible temperature induced transition from being a relatively free-flowing liquid to being a substantially solid gel. In particular, below the LCST of the temperature sensitive polymer the dispersion presents as a free-flowing liquid and above the LCST of the temperature sensitive polymer the dispersion presents as a substantially solid gel. Such significant and reversible changes in the rheological properties of the dispersion are expected to be useful in a diverse range of applications such as tissue engineering to biomolecular separation.

Accordingly, the present invention also provides a coating, adhesive, rheology modification, filler, primer, sealant, pharmaceutical, cosmetic, separation science, diagnostic, therapeutic, and tissue engineering product comprising polymer particles prepared in accordance with the invention.

The present invention also provides a coating, adhesive, rheology modification, filler, primer, sealant, pharmaceutical, cosmetic, separation science, diagnostic, therapeutic, and tissue engineering product comprising an aqueous dispersion of polymer particles prepared in accordance with the invention.

The stimulus responsive polymer having a CRP moiety covalently bound thereto may be prepared by any suitable means. For example, the stimulus responsive polymer may be purchased or prepared by conventional radical polymerisation techniques and subsequently covalently coupled directly to or through a linking group using conventional functional group coupling chemistry known to those skilled in the art.

Alternatively, monomers that give rise to a stimulus responsive polymer may be polymerised with a CRP agent, with the resulting stimulus responsive polymer inherently having the CRP moiety covalent bound thereto. For example, a temperature responsive polymer such as P(NIPAAm) may be prepared by polymerising NIPAAm under the control of a RAFT agent.

Suitable RAFT agents that may be used in preparing the stimulus responsive polymer include those of formula (V) or (VI):

(V) (VI)

where Z, Z*, x and y are as herein defined; R is a group, and R* is a x-valent group, that enables the RAFT agent to control or mediate the polymerisation of ethylenically unsaturated monomers.

Reference to a "x-valent" R* group in the context of formula (V) is similar to that described herein in respect of -SRP* in formula (III).

Those skilled in the art will appreciate that R and R* represent groups that function as a free radical leaving group under the polymerisation condition employed and yet, as a free radical leaving group, retain the ability to reinitiate polymerisation.

The R* in RAFT agents of formula (V) may be selected from a x-valent form of optionally substituted, and in the case of R in RAFT agents of formula (VI) may be selected from optionally substituted: alkyl, alkenyl, alkynyl, aryl, acyl, carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyclyloxy, alkylheterocyclyloxy, alkyllieteroaryloxy, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl, aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, and arylheteroarylthio.

The R* in RAFT agents of formula (V) may also be selected from a x-valent form of optionally substituted, and in the case of R in RAFT agents of formula (VI) may also be selected from optionally substituted: C ₁ -C ₁₈ alkyl, C ₂ -C ₁₈ alkenyl, C ₂ -C ₁₈ alkynyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ acyl, C ₃ -C ₁₈ carbocyclyl, C ₂ -C ₁₈ heterocyclyl, C ₃ -C ₁₈ heteroaryl, C ₁ -C ₁₈ alkyloxy, C ₂ -C ₁₈ alkenyloxy, C ₂ -C ₁₈ alkynyloxy, C ₆ -C ₁₈ aryloxy, C ₁ -C ₁₈ acyloxy, C ₃ -C ₁₈ carbocyclyloxy, C ₂ -C ₁₈ heterocyclyloxy, C ₃ -C ₁₈ heteroaryloxy, C ₁ -C ₁₈ alkylthio, C ₂ -C ₁₈ alkenylthio, C ₂ -C ₁₈ alkynylthio, C ₆ -C ₁₈ arylthio, C ₁ -C ₁₈ acylthio, C ₃ -C ₁₈ carbocyclylthio, C ₂ -C ₁₈ heterocyclylthio, C ₃ -C ₁₈ heteroarylthio, C ₃ -C ₁₈ alkylalkenyl, C ₃ -C ₁₈ alkylalkynyl, C ₇ -C ₂₄ alkylaryl, C ₂ -C ₁₈ alkylacyl, C ₄ -C ₁₈ alkylcarbocyclyl, C ₃ -C ₁₈ alkylheterocyclyl, C ₄ - CJ ₈ alkylheteroaryl, C ₂ -Ci ₈ alkyloxyalkyl, C ₃ -C ₁₈ alkenyloxyalkyl, C ₃ -C ₁₈ alkynyloxyalkyl, C ₇ -C ₂₄ aryloxyalkyl, C ₂ -C ₁₈ alkylacyloxy, C ₄ -C ₁₈ alkylcarbocyclyloxy, C ₃ -Ci ₈ alkylheterocyclyloxy, C ₄ -Ci ₈ alkylheteroaryloxy, C ₂ -C ₁₈ alkylthioalkyl, C ₃ -Ci ₈ alkenylthioalkyl, C ₃ -Ci ₈ alkynylthioalkyl, C ₇ -C ₂₄ arylthioalkyl, C ₂ -Ci ₈ alkylacylthio, C ₄ - C ₁₈ alkylcarbocyclylthio, C ₃ -C ₁₈ alkylheterocyclylthio, C ₄ -C ₁₈ alkylheteroarylthio, C ₄ -Cj ₈ alkylalkenylalkyl, C ₄ -C ₁₈ alkylalkynylalkyl, C ₈ -C ₂₄ alkylarylalkyl, C ₃ -Ci ₈ alkylacylalkyl, Ci ₃ -C ₂₄ arylalkylaryl, C ₁₄ -C ₂₄ arylalkenylaryl, C ₁₄ -C ₂₄ arylalkynylaryl, C ₁₃ -C ₂₄ arylacylaryl, C ₇ -Ci ₈ arylacyl, C ₉ -Ci ₈ arylcarbocyclyl, C ₈ -Ci ₈ arylheterocyclyl, C ₉ -C _{J 8} arylheteroaryl, C ₈ -Ci ₈ alkenyloxyaryl, C ₈ -C ₁₈ alkynyloxyaryl, Ci ₂ -C ₂₄ aryloxyaryl, C ₇ -C ₁₈ arylacyloxy, . C ₉ -C ₁₈ arylcarbocyclyloxy, C ₈ -C ₁₈ arylheterocyclyloxy, C ₉ -C ₁₈ arylheteroaryloxy, C ₇ -C ₁₈ alkylthioaryl, C ₈ -C ₁₈ alkenylthioaryl, C ₈ -C ₁₈ alkynylthioaryl, C ₁₂ -C ₂₄ arylthioaryl, C ₇ -C ₁₈ arylacylthio, C ₉ -C ₁₈ arylcarbocyclylthio, C ₈ -C ₁₈ arylheterocyclylthio, and C ₉ -C ₁₈ arylheteroarylthio.

In one embodiment, RAFT agents of formula (VI) are used in preparing the stimulus responsive polymer and R is an optionally substituted alkylacyloxy group such as - C(CH ₃ )COOCH ₃ .

In the lists above defining the groups from which R and R* may be selected, each alkyl, aryl, carbocyclyl, heteroaryl, and heterocyclyl moiety may be optionally substituted. For avoidance of any doubt, where a given R or R* contains two or more of such moieties (eg. alkylaryl), each of such moieties may be optionally substituted with one, two, three or more optional substituents as herein defined.

In the lists above defining groups from which R or R* may be selected, where a given R or R* contains two or more subgroups (e.g. [group A] [group B]), the order of the subgroups is not intended to be limited to the order in which they are presented. Thus, a R or R* with two subgroups defined as [group A] [group B] (e.g. alkylaryl) is intended to also be a reference to a R or R* with two subgroups defined as [group B] [group A] (e.g. arylalkyl).

The R or R* may be branched and/or optionally substituted. Where the R or R* comprises an optionally substituted alkyl moiety, an optional substituent includes where a -CH ₂ - group in the alkyl chain is replaced by a group selected from -O-, -S-, -NR ^a -, -C(O)- (i.e. carbonyl), -C(O)O- (i.e. ester), and -C(0)NR ^a - (i.e. amide), where R ^a may be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl.

As used herein, the term "alkyl", used either alone or in compound words denotes straight chain, branched or cyclic alkyl, preferably C _1-20 alkyl, e.g. C _1-10 or C _1-6 Examples of straight chain and branched alkyl include methyl, ethyl, ^-propyl, isopropyl, «-butyl, sec- butyl, ^-butyl, rø-pentyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2- trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3- dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4- dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6- methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, A-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, A-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-metliylundecyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", butyl" etc, it will be understood that this can refer to any of straight, branched and cyclic isomers where appropriate. An alkyl group may be optionally substituted by one or more optional substituents as herein defined.

The term "alkenyl" as used herein denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined, preferably C _2-20 alkenyl (e.g. C _2-10 or C _2-6 ). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, 1 ,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl group may be optionally substituted by one or more optional substituents as herein defined. As used herein the term "alkynyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C _2-2 O alkynyl (e.g. C _2-10 or C _2-6 ). Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substituents as herein defined.

The term "halogen" ("halo") denotes fluorine, chlorine, bromine or iodine (fluoro, chloro, bromo or iodo).

The term "aryl" (or "carboaryl") denotes any of single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems (e.g C _6-18 aryl). Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Preferred aryl include phenyl and naphthyl. An aryl group may or may not be optionally substituted by one or more optional substituents as herein defined. The term "arylene" is intended to denote the divalent form of aryl.

The term "carbocyclyl" includes any of non-aromatic monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C _3-2O (e.g. C _3-10 or C _3-8 ). The rings may be saturated, e.g. cycloalkyl, or may possess one or more double bonds (cycloalkenyl) and/or one or more triple bonds (cycloalkynyl). Particularly preferred carbocyclyl moieties are 5- 6-membered or 9-10 membered ring systems. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctatetraenyl, indanyl, decalinyl and indenyl. A carbocyclyl group may be optionally substituted by one or more optional substituents as herein defined. The term "carbocyclylene" is intended to denote the divalent form of carbocyclyl. The term "heteroatom" or "hetero" as used herein in its broadest sense refers to any atom other than a carbon atom which may be a member of a cyclic organic group. Particular examples of heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, selenium and tellurium, more particularly nitrogen, oxygen and sulfur.

The term "heterocyclyl" when used alone or in compound words includes any of monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C _3-20 (e.g. C _3-10 or C _3-8 ) wherein one or more carbon atoms are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatoms include O, N, S, P and Se, particularly O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. The heterocyclyl group may be saturated or partially unsaturated, i.e. possess one or more double bonds. Particularly preferred heterocyclyl are 5-6 and 9-10 membered heterocyclyl. Suitable examples of heterocyclyl groups may include azridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2H-pyrrolyl, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholinyl, indolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, thiomorpholinyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, pyrazolinyl, dioxalanyl, thiazolidinyl, isoxazolidinyl, dihydropyranyl, oxazinyl, thiazinyl, thiomorpholinyl, oxathianyl, dithianyl, trioxanyl, thiadiazinyl, dithiazinyl, trithianyl, azepinyl, oxepinyl, thiepinyl, indenyl, indanyl, 3H-indolyl, isoindolinyl, 4H-quinolazinyl, chromenyl, chromanyl, isochromanyl, pyranyl and dihydropyranyl. A heterocyclyl group may be optionally substituted by one or more optional substituents as herein defined. The term "heterocyclylene" is intended to denote the divalent form of heterocyclyl.

The term "heteroaryl" includes any of monocyclic, polycyclic, fused or conjugated hydrocarbon residues, wherein one or more carbon atoms are replaced by a heteroatom so as to provide an aromatic residue. Preferred heteroaryl have 3-20 ring atoms, e.g. 3-10. Particularly preferred heteroaryl are 5-6 and 9-10 membered bicyclic ring systems. Suitable heteroatoms include, O, N, S, P and Se, particularly O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heteroaryl groups may include pyridyl, pyrrolyl, thienyl, imidazolyl, furanyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, quinolyl, isoquinolyl, phthalazinyl, 1,5-naphthyridinyl, quinozalinyl, quinazolinyl, quinolinyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadialzolyl, oxatriazolyl, triazinyl, and furazanyl. A heteroaryl group may be optionally substituted by one or more optional substituents as herein defined. The term "heteroarylene" is intended to denote the divalent form of heteroaryl.

The term "acyl" either alone or in compound words denotes a group containing the moiety C=O (and not being a carboxylic acid, ester or amide) Preferred acyl includes C(O)-R ⁶ , wherein R ^e is hydrogen or an alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl residue. Examples of acyl include formyl, straight chain or branched alkanoyl (e.g. C _1-20 ) such as acetyl, propanoyl, butanoyl, 2-methylproρanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl and thienylglyoxyloyl. The R ^e residue may be optionally substituted as described herein.

The term "sulfoxide", either alone or in a compound word, refers to a group -S(O)R ^f wherein R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, and aralkyl. Examples of preferred R ^f include C _1-20 alkyl, phenyl and benzyl.

The term "sulfonyl", either alone or in a compound word, refers to a group S(O) ₂ -R , wherein R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl and aralkyl. Examples of preferred R include C _1-2 oalkyl, phenyl and benzyl.

The term "sulfonamide", either alone or in a compound word, refers to a group S(O)NR R wherein each R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, and aralkyl. Examples of preferred R include C _{1- 2} oalkyl, phenyl and benzyl. In one embodiment at least one R is hydrogen. In another embodiment, both R are hydrogen.

The term, "amino" is used here in its broadest sense as understood in the art and includes groups of the formula NR ^a R ^b wherein R ^a and R may be any independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl. R ^a and R , together with the nitrogen to which they are attached, may also form a monocyclic, or polycyclic ring system e.g. a 3-10 membered ring, particularly, 5-6 and 9- 10 membered systems. Examples of "amino" include NH ₂ , NHalkyl (e.g. C _1-2 oalkyl), NHaryl (e.g. NHphenyl), NHaralkyl (e.g. NHbenzyl), NHacyl (e.g. NHC(O)C _1-20 alkyl, NHC(O)phenyl), Nalkylalkyl (wherein each alkyl, for example C _1-20 , may be the same or different) and 5 or 6 membered rings, optionally containing one or more same or different heteroatoms (e.g. O, N and S). The term "amido" is used here in its broadest sense as understood in the art and includes groups having the formula C(O)NR ^a R ^b , wherein R ^a and R ^b are as defined as above. Examples of amido include C(O)NH ₂ , C(O)NHalkyl (e.g. C _1-20 alkyl), C(O)NHaryl (e.g. C(O)NHphenyl), C(O)NHaralkyl (e.g. C(O)NHbenzyl), C(O)NHacyl (e.g. C(O)NHC(O)C _1-20 alkyl, C(O)NHC(O)phenyl), C(O)Nalkylalkyl (wherein each alkyl, for example C _1-20 , may be the same or different) and 5 or 6 membered rings, optionally containing one or more same or different heteroatoms (e.g. O, N and S).

The term "carboxy ester" is used here in its broadest sense as understood in the art and includes groups having the formula CO ₂ R ⁸ , wherein R ^g may be selected from groups including alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and acyl. Examples of carboxy ester include CO ₂ C _1-20 alkyl, C0 ₂ aryl (e.g.. C0 ₂ phenyl), CO ₂ aralkyl (e.g. CO ₂ benzyl).

As used herein, the term "aryloxy" refers to an "aryl" group attached through an oxygen bridge. Examples of aryloxy substituents include phenoxy, biphenyloxy, naphthyloxy and the like.

As used herein, the term "acyloxy" refers to an "acyl" group wherein the "acyl" group is in turn attached through an oxygen atom. Examples of "acyloxy" include hexylcarbonyloxy (heptanoyloxy), cyclopentylcarbonyloxy, benzoyloxy, 4-chlorobenzoyloxy, decylcarbonyloxy (undecanoyloxy), propylcarbonyloxy (butanoyloxy), octylcarbonyloxy (nonanoyloxy), biphenylcarbonyloxy (eg 4-phenylbenzoyloxy), naphthylcarbonyloxy (eg 1-naphthoyloxy) and the like.

As used herein, the term "alkyloxycarbonyl" refers to a "alkyloxy" group attached through a carbonyl group. Examples of "alkyloxycarbonyl" groups include butylformate, sec- butylformate, hexylformate, octylformate, decylformate, cyclopentylformate and the like. As used herein, the term "arylalkyl" refers to groups formed from straight or branched chain alkanes substituted with an aromatic ring. Examples of arylalkyl include phenylmethyl (benzyl), phenylethyl and phenylpropyl.

As used herein, the term "alkylaryl" refers to groups formed from aryl groups substituted with a straight chain or branched alkane. Examples of alkylaryl include methylphenyl and isopropylphenyl.

In this specification "optionally substituted" is taken to mean that a group may or may not be substituted or fused (so as to form a condensed polycyclic group) with one, two, three or more of organic and inorganic groups, including those selected from: alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, acyl, aralkyl, alkaryl, alkheterocyclyl, alkheteroaryl, alkcarbocyclyl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halocarbocyclyl, haloheterocyclyl, haloheteroaryl, haloacyl, haloaryalkyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycarbocyclyl, hydroxyaryl, hydroxyheterocyclyl, hydroxyheteroaryl, hydroxyacyl, hydroxyaralkyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbocyclyl, alkoxyaryl, alkoxyheterocyclyl, alkoxyheteroaryl, alkoxyacyl, alkoxyaralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, carbocyclyloxy, aralkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy, halocarbocyclyloxy, haloaralkyloxy, haloheteroaryloxy, haloheterocyclyloxy, haloacyloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, nitroheteroayl, nitrocarbocyclyl, nitroacyl, nitroaralkyl, amino (NH ₂ ), alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, aralkylamino, diaralkylamino, acylamino, diacylamino, heterocyclamino, heteroarylamino, carboxy, carboxyester, amido, alkylsulphonyloxy, arylsulphenyloxy, alkylsulphenyl, arylsulphenyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, aralkylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, acylthio, sulfoxide, sulfonyl, sulfonamide, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocarbocyclyl, aminoaryl, aminoheterocyclyl, aminoheteroaryl, aminoacyl, aminoaralkyl, thioalkyl, thioalkenyl, thioalkynyl, thiocarbocyclyl, thioaryl, thioheterocyclyl, thioheteroaryl, thioacyl, thioaralkyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxycarbocyclyl, carboxyaryl, carboxyheterocyclyl, carboxyheteroaryl, carboxyacyl, carboxyaralkyl, carboxyesteralkyl, carboxyesteralkenyl, carboxyesteralkynyl, carboxyestercarbocyclyl, carboxyesteraryl, carboxyesterheterocyclyl, carboxyesterheteroaryl, carboxyesteracyl, carboxyesteraralkyl, amidoalkyl, amidoalkenyl, amidoalkynyl, amidocarbocyclyl, amidoaryl, amidoheterocyclyl, amidoheteroaryl, amidoacyl, amidoaralkyl, formylalkyl, formylalkenyl, formylalkynyl, formylcarbocyclyl, formylaryl, formylheterocyclyl, formylheteroaryl, formylacyl, formylaralkyl, acylalkyl, acylalkenyl, acylalkynyl, acylcarbocyclyl, acylaryl, acylheterocyclyl, acylheteroaryl, acylacyl, acylaralkyl, sulfoxidealkyl, sulfoxidealkenyl, sulfoxidealkynyl, sulfoxidecarbocyclyl, sulfoxidearyl, sulfoxideheterocyclyl, sulfoxideheteroaryl, sulfoxideacyl, sulfoxidearalkyl, sulfonylalkyl, sulfonylalkenyl, sulfonylalkynyl, sulfonylcarbocyclyl, sulfonylaryl, sulfonylheterocyclyl, sulfonylheteroaryl, sulfonylacyl, sulfonylaralkyl, sulfonamidoalkyl, sulfonamidoalkenyl, sulfonamidoalkynyl, sulfonamidocarbocyclyl, sulfonamidoaryl, sulfonamidoheterocyclyl, sulfonamidoheteroaryl, sulfonamidoacyl, sulfonamidoaralkyl, nitroalkyl, nitroalkenyl, nitroalkynyl, nitrocarbocyclyl, nitroaryl, nitroheterocyclyl, nitroheteroaryl, nitroacyl, nitroaralkyl, cyano, sulfate, phosphate, triarylmethyl, triarylamino, oxadiazole, and carbazole groups. Optional substitution may also be taken to refer to where a -CH ₂ - group in a chain or ring is replaced by a group selected from -O-, -S-, -NR ^a -, -C(O)- (i.e. carbonyl), -C(O)O- (i.e. ester), and -C(O)NR ^a - (i.e. amide), where R ^a is as defined herein.

Preferred optional substituents include alkyl, (e.g. C _1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g. methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (e.g. C _1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl, hydroxy, phenyl (which itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), benzyl (wherein benzyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), phenoxy (wherein phenyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), benzyloxy (wherein benzyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), amino, alkylamino (e.g. Ci _-6 alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (e.g. Ci _-6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (e.g. NHC(O)CH ₃ ), phenylamino (wherein phenyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyCi _-6 alkyl, Ci _-6 alkoxy, haloC _1-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), nitro, formyl, -C(O)-alkyl (e.g. C _1-6 alkyl, such as acetyl), O-C(O)-alkyl (e.g. Ci- ₆ alkyl, such as acetyloxy), benzoyl (wherein the phenyl group itself may be further substituted e.g., by Ci- ₆ alkyl, halo, hydroxy hydroxyCi _-6 alkyl, Ci _-6 alkoxy, haloCi _-6 alkyl, cyano, nitro OC(O)C _1-6 alkyl, and amino), replacement of CH ₂ with C=O, CO ₂ H, C0 ₂ alkyl (e.g. C _1-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), C0 ₂ phenyl (wherein phenyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyl Ci _-6 alkyl, Ci _-6 alkoxy, halo Ci _-6 alkyl, cyano, nitro OC(O)Ci _-6 alkyl, and amino), CONH ₂ , CONHphenyl (wherein phenyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy, hydroxyl C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, cyano, nitro OC(O)Ci _-6 alkyl, and amino), CONHbenzyl (wherein benzyl itself may be further substituted e.g., by C _1-6 alkyl, halo, hydroxy hydroxyl C _1-6 alkyl, C _1-6 alkoxy, halo Ci _-6 alkyl, cyano, nitro OC(O)Ci _-6 alkyl, and amino), CONHalkyl (e.g. Ci _-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide) CONHdialkyl (e.g. Ci _-6 alkyl) aminoalkyl (e.g., HN C _1-6 alkyl-, C _1-6 alkylHN-C _1-6 alkyl- and (Ci _-6 alkyl) ₂ N-C _1-6 alkyl-), thioalkyl (e.g., HS C _1-6 alkyl-), carboxyalkyl (e.g., HO ₂ CC _1-6 alkyl-), carboxyesteralkyl (e.g., C _1-6 alkylO ₂ CCi _-6 alkyl-), amidoalkyl (e.g., H ₂ N(O)CC _1-6 alkyl-, H(C _1-6 alkyl)N(O) CC _1-6 alkyl-), formylalkyl (e.g., OHCC^alkyl-), acylalkyl (e.g., Ci _-6 alkyl(O)CCi _-6 alkyl-), nitroalkyl (e.g., O ₂ NCi _-6 alkyl-), sulfoxidealkyl (e.g., R(O)SC _1-6 alkyl, such as C _1-6 alkyl(O)SCi _-6 alkyl-), sulfonylalkyl (e.g., R(O) ₂ SC _1-6 alkyl- such as Ci _-6 alkyl(O) ₂ SC _1-6 alkyl-), sulfonamidoalkyl (e.g., ₂ HRN(O)SC _1-6 alkyl, H(C _1-6 alkyl)N(O)SC _1-6 alkyl-), triarylmethyl, triarylamino, oxadiazole, and carbazole.

The invention will now be described with reference to the following non-limiting examples. EXAMPLES

Materials

The following chemicals were used as received; activated basic alumina (Aldrich: Brockmann I ₅ standard grade, ~ 150 mesh, 58 A), ammonium persulfate (APS, 98.0 %, UNIVAR), anhydrous magnesium sulfate (MgSO ₄ : Scharlau, extra pure), 1-butanethiol (Aldrich, 99 %), carbon disulfide (CS ₂ : Aldrich, >99 %) dichloromethane (DCM: Labscan, AR grade), diethyl ether (Univar, AR grade), ethyl acetate (EtOAc: Labscan, AR grade), hydrochloric acid (HCl: Labscan, 37%), methanol (MeOH: Mallinckrodt, 99.9 %, HPLC grade), methyl-2-bromopropionate (MBP: Aldrich, 98%), MiIIiQ water (Biolab, 18.2 MΩm), petroleum ether (Labscan, AR grade), silica (Alltech, 40-63 micron) sodium chloride (NaCl: Univar, 99.9 %), sodium dodecyl sulphate (SDS, 99 %, Aldrich), tetrahydrofuran (THF: Labscan, HPLC grade), toluene (Labscan, AR Grade) and triethylamine (TEA: Fluka, 98 %). Styrene (STY: Aldrich, >99 %) was deinhibited before use by passing through a basic alumina column. N-isopropylacrylamide (97 %, Aldrich) was recrystallised from petroleum ether prior to use. Azobisisobutyronitrile (AIBN) was recrystallized twice from methanol prior to use.

Example 1

Part (a): Synthesis of methyl 2-(butylthiocarbonothioylthio)propanoate

MCEBTTC

To a stirred solution of 1-butanethiol (10 mL, 0.093 mol) and TEA (14.3 mL, 0.103 mol) in DCM (100 mL) under nitrogen atmosphere was added dropwise carbon disulfide (6.18 mL, 0.103 mol) in DCM (50 niL) over a period of 30 min at 0 ⁰ C. The solution gradually turned yellow during the addition. After complete addition the solution was stirred at room temperature for 1 hour. MBP (11.5 niL, 0.103 mol) in DCM (50 mL) was then added dropwise to the solution over a period of 30 min, and stirred for 2 hours. DCM was removed under nitrogen and the residue dissolved in diethylether. This solution was then washed with cold 10 % HCl solution (3 x 50 mL) and MiIIiQ water (3 x 50 mL) and then dried over anhydrous MgSO ₄ . The ether was removed under vacuum and the residual yellow oil was purified by column chromatography (9:1 petroleum ether/ethyl acetate on silica, second band).

¹ H NMR (CDCl ₃ ) δ 0.92 (tr, J= 7.5 Hz, 3H, CH ₃ ), 1.43 (mult, J= 7.5 Hz ₅ 2H, CH ₂ ), 1.62 (d, J= 7.5 Hz, 3H, CH ₃ ), 1.65 (quin, J = 7.5 Hz, 2H, CH ₂ ), 3.36 (tr, J= 7.5 Hz, 2H, CH ₂ ), 3.73 (s, 3H, CH ₃ ), 4.84 (quad, J = 7.5 Hz ₃ IH, CH); ¹³ C NMR (CDCl ₃ ) δ 13.55, 16.91, 22.02, 29.89, 36.94, 47.68, 52.82, 171.63 (CH-C(=O)-O), 221.99 (S-C(=S)-S)

Part (b): Synthesis ofpoly(N-isopropylacrylamide) (PNIPAM ₄₁ -SC(=S)SC ₄ H ₉ )

N-isopropylacrylamide (NIPAM, 5.22 g, 0.046 mol), AIBN (0.0169 g, 1.03 x 10 ^"4 mol), 1 (0.266 g, 1.06 x 10 ^"3 mol) and DMF (10.4 g) was added to a 50 mL round bottom flask equipped with a magnetic stirrer bar. The mixture was deoxygenated by purging with Argon for 20 min. The flask was then heated in an oil bath at 60 ⁰ C for 16 h. The solution was cooled, exposed to air then diluted with THF. The polymer was recovered by precipitation into hexane then dried under high vacuum for 24 h. (M _n = 4770, PDI = 1.10).

Part (c): Solution polymerization ofstyrene mediated with PNIPAM ₄ i-SC(=S)SC ₄ H$ - comparative

PNIP AM ₄₁ -SCt=S)SC ₄ H ₉ (0.450 g, 9.43 x 10 ^"5 mol) from part (b) , styrene (0.456 g, 4.40 x 10 ^"4 mol), AIBN (0.0016 g, 9.76 x 10 ^"6 mol) and DMF (1.5 g) was added to a 10 mL schlenk flask equipped with a magnetic stirrer bar. The mixture was deoxygenated by purging with Argon for 10 min and the polymerization commenced by heating the flask in an oil bath at 60 ⁰ C for 24 h. Samples were taken at regular intervals for determination of monomer conversion and molecular weight, (see Table Sl).

Table Sl: Conversion vs_ time and MWD w conversion data for the solution polymerization of PNIP AM ₄₁ -SC(^S)SC ₄ H ₉ with STY initiated with AIBN at 60 ⁰ C in DMF.

Part (d): Synthesis ofP(NIPAM ₄₁ -b-STY)-SC(=S)SC ₄ H ₉ from PNIPAM ₄₁ -SC(=S)SC ₄ H ₉

PNIPAM ₄₁ -SCeS)SC ₄ H ₉ (0.354 g, 7.42 x 10 ^"5 mol) from part (b), SDS (0.0145 g, 5.03 x 10 ^"5 mol, 0.8 x CMC) and MiIIiQ Water (6.25 g) were added to a 10 mL schlenk flask equipped with a magnetic stirrer bar. After dissolution of the a solution of AIBN (0.00120 g, 7.32 x 10 ^"6 mol) dissolved in styrene (0.350 g, 3.38 x 10 ^'3 mol) was added to the mixture. The mixture was deoxygenated by purging with Argon for 10 min then heated at 70 ⁰ C to first form the nanoreactors and commence polymerization. Samples were taken at regular intervals for determination of monomer conversion and molecular weight (see Table S2). Table S2: Conversion vs time and MWD vs _. conversion data for the polymerization of STY in PNIPAM ₄₁ -SCC=S)SC ₄ H ₉ with SDS, initiated with AIBN at 70 ⁰ C in water.

Analytical Methodologies

Size Exclusion Chromatography (SEC)

Size Exclusion Chromatography measurements were performed using a Waters Alliance 2690 Separations Module equipped with an auto-sampler, Differential Refractive Index (RI) detector and a Photo Diode Array (PDA) detector connected in series. HPLC grade tetrahydrofuran was used as eluent at flow rate 1 mL/min. The columns consisted of two 7.8 x 300 mm Waters linear Ultrastyragel SEC columns connected in series. Polystyrene standards ranging from 200K - 517 g mol ^"1 were used for calibration.

Dynamic Light Scattering (DLS)

Dynamic Light Scattering measurements were performed using a Malvern Zetasizer 3000HS. The sample refractive index (RI) was set at 1.59 for polystyrene. The dispersant viscosity and RJ were set to 0.89 and 0.89 Ns/m ² , respectively. The number-average particle diameter was measured for each sample.

Transmission Electron Microscopy (TEM)

The polymerization mixtures were characterized using a JEOL-1010 transmission electron microscope utilizing an accelerating voltage of 80 IcV with spot size 2, at ambient temperature.

(a) A typical 'room temperature' TEM grid preparation was as follows: A polymerization mixture was diluted with milliQ water to approximately 0.05 wt%. A 10 μL aliquot of the solution was then allowed to air dry onto a formvar precoated copper TEM grid.

(b) A typical 'hot' TEM grid preparation was as follows: A polymerization mixture was heated at 50 ⁰ C for 1 h. The 'hot' mixture was then diluted with 'hot' milliQ water (50 ⁰ C) to approximately 0.05 wt-%. A 10 μL aliquot of the solution was then dispensed onto a pre-heated formvar pre-coated copper TEM grid and allowed to dry in an oven at 50 ⁰ C.

Cryogenic Transmission Electron Microscopy (Cryo-TEM)

Samples for Cryo-TEM were prepared by freezing a 0.05 wt% polymer solution in liquid ethane. The samples were transferred to and analysed using a Philips Technai 120 kV electron microscope with BioTWIN lens configuration. Scanning Electron Microscopy (SEM)

A polymer film was allowed to form, by air drying the polymerization mixture, onto a formvar pre-coated copper TEM grid. The grid was platinum-coated and the film characterized using a JEOL JSM-6300F scanning electron microscope operating at 15 kV.

Atomic Force Microscopy (AFM)

A polymerization mixture was diluted with milliQ water to approximately 0.01 wt%. A 100 μL aliquot of the diluted mixture was then allowed to air dry onto a glass slide. The sample was then characterized using a VEECO Multi-mode atomic force microscope operating in tapping mode.

Morphology and nanostructure of P(NIP AM ₄₁ -b-STY)-SC(=S)SC ₄ H ₉ in water

Experiments were conducted on the final mixtures (see Table S2) generated from a 2.5 wt %, 5 wt% and 10 wt% PNIP AM ₄ i-SC(=S)SC ₄ H ₉ polymerization with STY.

(1) Cryo-TEM of polymerization mixtures after rapid cooling below the LCST

(i) Using the product of Reaction 1 : After polymerization the mixture was cooled to room temperature by immersing in a water bath at 23 ⁰ C. The Cryo-TEMs showed hemisphere particles.

(ii) Using the product of Reaction 2: After polymerization was stopped, toluene (50 μL) was added to a 2 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was cooled to room temperature by immersing in a water bath at 23 ⁰ C and the Cryo-TEMs showed rod-like particles (see Figure 4). (2) TEM of polymerization mixtures after slow cooling below the LCST

(i) Using the product of Reaction 1 : After polymerization was stopped, the mixture was cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 ⁰ C over a period of 2 h. The TEM showed multi-lobed spherical or spheroidal particles.

(ii) Using the product of Reaction 1 : After polymerization was stopped, toluene (10 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed spherical or spheroidal particles.

(iii) Using the product of Reaction 1: After polymerization was stopped, toluene (30 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed a network-type morphology.

(iv) Using the product of Reaction 2: After polymerization was stopped, the mixture was cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 ⁰ C over a period of 2 h. The TEM showed jelly-fish like particles (see Figure 5(iv)).

(v) Using the product of Reaction 2: After polymerization was stopped, toluene (10 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed spherical or spheroidal particles (see Figure 5(v)).

(vi) Using the product of Reaction 2: After polymerization was stopped, toluene (30 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed loop-type particles (see Figures 5(vi)). (vii) Using the product of Reaction 3 : After polymerization was stopped, the mixture was cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 ⁰ C over a period of 2 h. The TEM showed jelly-fish type particles (see Figures 6(vii)).

(viii) Using the product of Reaction 3: After polymerization was stopped, toluene (10 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed a transition between jelly -fish and rod- like particles (see Figures 6(viii)).

(ix) Using the product of Reaction 3: After polymerization was stopped, toluene (30 μL) was added to a 1.5 mL aliquot of the reaction mixture at 70 ⁰ C and stirred for 1 h. The mixture was then cooled to 40 ⁰ C over a period of 2 h, and further cooled to 25 0C over a period of 2 h. The TEM showed rod-like particles (see Figures 6(ix)).

(3) TEM of polymerization mixtures subjected to sonication

(i) Using the product of Reaction 1 : After polymerization was stopped, a 1.5 mL aliquot of the reaction mixture was added to a screw-capped vial and placed in a sonication bath at 40 ⁰ C. The mixture was sonicated for a period of 10 min during which time the temperature of the bath was reduced to room temperature with the addition of small amounts of ice. The mixture was sonicated for 5 more min. The TEM showed multi-lobed spherical or spheroidal particles

(ii) Using the product of Reaction 1 : The above procedure 3(i) was repeated but with the addition of toluene (10 μL) to the 1.5 mL reaction aliquot. The TEM showed rod-like particles.

(iii) Using the product of Reaction 1 : The above procedure 3(i) was repeated but with the addition of toluene (30 μL) to the 1.5 mL reaction aliquot. The TEM showed rod like particles. (iv) Using the product of Reaction 2: After polymerization was stopped, a 1.5 rnL aliquot of the reaction mixture was added to a screw-capped vial and placed in a sonication bath at 40 ⁰ C. The mixture was sonicated for a period of 10 min during which time the temperature of the bath was reduced to room temperature with the addition of small amounts of ice. The mixture was sonicated for 5 more min. The TEM showed rod-like particles (see Figure 7(iv)).

(v) Using the product of Reaction 2: The above procedure 3(iv) was repeated but with the addition of toluene (10 μL) to the 1.5 mL reaction aliquot. The TEM showed spherical or spheroidal particles (see Figure 7(v)).

(vi) Using the product of Reaction 2: The above procedure 3(iv) was repeated but with the addition of toluene (30 μL) to the 1.5 mL reaction aliquot. The TEM showed vesicle particles (see Figure 7(vi)).

(vii) Using the product of Reaction 3 : After polymerization was stopped, a 1.5 mL aliquot of the reaction mixture was added to a screw-capped vial and placed in a sonication bath at 40 ⁰ C. The mixture was sonicated for a period of 10 min during which time the temperature of the bath was reduced to room temperature with the addition of small amounts of ice. The mixture was sonicated for 5 more min. The TEM showed rod-like particles. The rod-like particles were found to undergo reversible gelation upon being heated and cooled to above and below, respectively, the LCST, with gel formation occurring above the LCST (see Figure 8).

(viii) Using the product of Reaction 3: The above procedure 3 (vii) was repeated but with the addition of toluene (10 μL) to the 1.5 mL reaction aliquot. The TEM showed rod-like particles. (ix) Using the product of Reaction 3: The above procedure 3(vii) was repeated but with the addition of toluene (30 μL) to the 1.5 rnL reaction aliquot. The TEM showed a network structure.

(4) TEM of polymerization mixtures diluted prior to cooling

(i) Using the product of Reaction 1 : After polymerization was stopped, a 400 μL aliquot of the mixture was added to 9.6 mL of milliQ water at 70 ⁰ C. The mixture was stirred and heated at 70 ⁰ C for 5 min then cooled to room temperature by immersing in a water bath at 23 ⁰ C. The TEM showed rod-like particles.

(ii) Using the product of Reaction 1 : The above procedure 4(i) was repeated but with the addition of toluene (10 μL) to the hot diluted mixture. The TEM showed jelly-fish like particles.

(iii) Using the product of Reaction 2: After polymerization was stopped, a 100 μL aliquot of the mixture was added to 4.9 mL of milliQ water at 70 ⁰ C. The mixture was stirred and heated at 70 ⁰ C for 5 min then cooled to room temperature by immersing in a water bath at 23 ⁰ C. The TEM showed spherical or spheroidal particles.

(iv) Using the product of Reaction 2: The above procedure 4(iii) was repeated but with the addition of toluene (10 μL) to the hot diluted mixture. The TEM showed unimolecular particles.

(v) Using the product of Reaction 3: After polymerization was stopped, a 100 μL aliquot of the mixture was added to 9.9 mL of milliQ water at 70 ⁰ C. The mixture was stirred and heated at 70 ⁰ C for 5 min then cooled to room temperature by immersing in a water bath at 23 ⁰ C. The TEM showed rod-like particles. (vi) Using the product of Reaction 3 : The above procedure 4(v) was repeated but with the addition of toluene (10 μL) to the hot diluted mixture. The TEM showed core- shell sperical particles.

(5) TEM of polymerization mixtures with added sodium dodecyl sulphate (SDS)

(i) Using the product of Reaction 1 : After polymerization was stopped, SDS was added to the mixture at 70 ⁰ C to obtain a concentration at 1.6 times the critical micelle concentration. The mixture was stirred and heated at 70 ⁰ C for 1 h then cooled to room temperature by immersing in a water bath at 23 ⁰ C. The TEM showed spherical or spheroidal particles.

(ii) Using the product of Reaction 2: The procedure for 5(i) was repeated. The TEM showed short rod-like and spherical or spheroidal particles.

(iii) Using the product of Reaction 3: The procedure for 5(i) was repeated. The TEM showed long rod-like and vesicle particles.

Polymer film generated from the product of Reaction 2

Using the product of Reaction 2: After polymerization, the mixture was cooled to room temperature by immersing in a water bath at 23 ⁰ C. The resulting dispersion was left to air dry which resulted in the formation of a polymer film.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Many modifications will be apparent to those skilled in the art without departing from the scope of the present invention.