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Definitions

• This invention relates to the field of chromatographic sample separation that includes liquid chromatography and solid phase extraction and, in particular, it relates to material and the synthesis of material for use as a stationary phase in chromatographic sample separation.
• LC Liquid chromatography
• SPE solid phase extraction
• separation of a sample comprising a mixture of components is achieved by conveying the sample in a liquid mobile phase through a stationary phase in a column, thereby causing the sample to separate into its components due to different partitioning between the mobile and stationary phases of each of the components (i.e. the components have different partition coefficients).
• the stationary phase is typically in the form of a bed of particles packed within the column, or in the form of a monolithic material held in the column.
• porous particles are commonly used which contain a network of pores to increase the surface area of the stationary phase and thus improve the capacity of the separation.
• the porous particles may be fully porous, wherein the pores extend throughout the bulk of the particles.
• fused core particles which are also termed superficially porous particles. These are particles that have a non-porous core (also termed a fused or solid core) and are porous only in an outer layer or region that surrounds the non-porous core.
• Silica particles are commonly used as the stationary phase, either as non- porous, fully porous or superficially porous particles.
• silica spheres by hydrolyzing alkylsilicates such as tetraethylorthosilicate, also termed tetraethoxysilane (TEOS), in mixed solutions of ammonia, alcohol and water in 1968, the sol-gel based wet-chemistry route to prepare silica spheres has widely been used. About 30 years later, Unger's group (Grun, M.; Lauer, I.; Unger, K.K.; Adv. Mater. 1997,9 , 254) successfully prepared ordered mesoporous silica spheres in the same system by introducing alkylammonium halide surfactants (e.g.
• Hybrid silica material wherein an organic functionality, for example alkyl, is incorporated in both the bulk and the surface of the silica, is also known as described in US 4,017,528 and US 6,686,035.
• Such approach comprises a polycondensation of a mixture of tetraethoxysilane (TEOS) and an organotriethoxysilane such as alkyltriethoxysilane.
• TEOS tetraethoxysilane
• organotriethoxysilane such as alkyltriethoxysilane.
• Surface modification of silica particles is also well established for producing apolar stationary phases. This comprises reacting the hydroxylated surface of the silica with a surface modifier such as a mono-, bi-, or tri- functional organochlorosilane for example.
• a surface modifier such as a mono-, bi-, or tri- functional organochlorosilane for example.
• a particulate material comprising particles having a skeleton structure containing silsesquioxane moieties.
• the particles are preferably silica particles having a skeleton structure containing silsesquioxane moieties.
• the silsesquioxane moieties have a cage structure.
• a method of preparing a particulate material comprising condensing at least a silsesquioxane to produce particles.
• the method comprises hydrolysing a silsesquioxane in a condensation reaction to produce silica particles having a skeleton structure containing silsesquioxane moieties having a cage structure.
• the invention in such aspect resides in the use of a silsesquioxane as a co-component of a hydrolysis mixture to produce particles.
• the particles are preferably silica particles.
• the method of preparing a particulate material comprises co-condensing a silsesquioxane and a silane to produce the particles.
• a chromatography column packed with the particulate material, for example for use in liquid chromatography or solid phase extraction.
• the present invention thus relates to the use of nanometer sized moieties (silsesquioxanes, also termed polyhedral oligomeric silsesquioxanes, commercially available under the trademark POSS) to make porous or non-porous particulate materials for chromatographic applications, e.g. as a stationary phase.
• the materials formed exhibit excellent pH resistance, high mechanical robustness, and greatly improved thermal stability compared to known chromatographic materials.
• the materials comprise silica or hybrid organo silica particles.
• the enhanced thermal, mechanical and pH stabilities e.g. across a pH 1 - 1 1 ), may be attributed to the incorporation of rigid nano-sized silsesquioxane cages or cores in the silica.
• the basic structure of the silsesquioxanes used in the present invention can be viewed as a cage-like structure of molecular silica comprising a number of silicon atoms linked together with oxygen atoms in an orderly manner.
• the preferred "cage" silsesquioxanes of the present invention are thus compounds having a cage-like structure, generally a cubic cage structure.
• the silicon atoms are positioned at the corners of the cage.
• the cage typically comprises eight silicon atoms positioned at the corners of the cage linked together with oxygen atoms. In some embodiments, less or more than eight silicon atoms may be present in the cage, e.g.
• cages may be referred to as an 8-silicon cage, 7-silicon cage, 6-silicon cage etc.
• one or more silicon atoms positioned at the corners of the cage carry a substituent selected from: hydroxyl, hydrogen and an organic group (especially a hydrocarbon, e.g. an alkyl or aryl). More preferably at each of the silicon corners of the cage is preferably a substituent, which can be hydroxyl, hydrogen, or an organic group (especially a hydrocarbon, e.g. an alkyl).
• one or more silicon atoms, especially a plurality of silicon atoms, positioned at the corners carry a hydroxyl (silanol) group. In such embodiments, preferably the remainder of the silicon atoms at the corners carry an organic group.
• the organic substituents at the silicon corners of the cage may be selected from a hydrocarbon group (e.g. alkyl, aryl, which herein includes alkene, alkyne etc.).
• the organic substituents may contain S, OH, halide, amide, sulphonamide, ester, carboxylate, or sulfonate groups etc. Such organic substituents are defined in more detail below.
• Cage silsesquioxanes wherein the corner silicon atoms carry only hydroxyl substituents, i.e. silanol groups, are useful for producing inorganic ("pure" or "non- hybrid") silica.
• the 8-silicon cage silsesquioxane with silanol groups at each corner is useful for making cage-consisting silica material that is non-hybrid (i.e. does not contain organic groups).
• the hydroxyl (silanol) groups are required for the condensation (polycondensation) reaction.
• Non-porous, non-hybrid particles can also be made by calcination and/or sintering of hybrid organo-silica particles.
• hybrid organo-silica materials in this invention are made from cage silsesquioxanes having at least one corner silicon atom carrying an organic substituent as well as at least one silicon atom carrying a hydroxyl group. More preferably, one or more silicon atoms, especially a plurality of silicon atoms, positioned at the corners carry a hydroxyl group with at least the remainder of the silicon atoms at the corners carrying an organic group.
• the cage structure preferably comprises seven or six corner silicon atoms and each corner silicon atom carries an organic group.
• all of the silicon atoms at the corners carry an organic group and one or more of the corner silicon atoms, especially a plurality of corner silicon atoms, also carry a hydroxyl group.
• cages with organic groups at the corners typically also have one or more corners missing (i.e. 7-silicon or 6-silicon cages) to provide the silanol groups necessary for the condensation reaction.
• the silsesquioxanes comprise cages wherein each corner silicon atom carries an organic group and a plurality of the silicon corner atoms also carry a hydroxyl group.
• Such silsesquioxanes are preferably 7-silicon or 6-silicon cages (most preferably 7-silicon cages).
• the nanometer sized molecules i.e. the polyhedral oligomeric silsesquioxanes
• the present invention employs the nanometer sized silsesquioxane molecules in the particle-making process so that silsesquioxane moieties are contained in the skeleton or internal structure of the silica, as well as on the surface.
• the skeletal units of the particle preferably contain Si-silsesquioxane-Si linkages.
• silsesquioxanes have been used previously in the synthesis of chromatographic material but not in the manner of the present invention.
• silsesquioxanes have been used as a stationary phase surface modifier as described in US 2012/0205315 A1 .
• silsesquioxanes could be used to form the silica particles themselves.
• the silsesquioxane moieties are contained in the skeleton or internal structure of the silica, not merely on the surface.
• Silsesquioxanes have also been used as a cross-linker for preparation of an inorganic-organic hybrid monolithic material as described in Wu, et ai, Polyhedral Oligomeric Silsesquioxane as a Cross-linker for Preparation of Inorganic-Organic Hybrid Monolithic Columns,. Analytical Chemistry (2010), 82(13), 5447-5454).
• the silsesquioxane was co-polymerized with an organic monomer to form a polymer-like monolithic material.
• the present invention synthesizes nonporous or porous, pure silica or hybrid silica particles.
• the synthesis of monoliths and particles is very different and techniques for making one usually cannot be transferred to making the other.
• the method described in Wu, et al was designed to produce material for narrow capillary columns and such systems generally cannot be scaled up, for example due to the problem of wall attachment.
• the present invention is not limited to capillary columns.
• the material according to the present invention may be used in HPLC applications where the column diameter is 1 mm or higher, e.g. in the range 1 to 10 mm, more particularly 2 to 5 mm, such as conventional HPLC diameter columns of 2.1 mm to 4.6 mm, or SPE applications where the column diameter is for example up to 10 mm.
• there are no particular limits of column dimension for the application of the present invention which may be used from nano-scale to preparative-scale.
• the chromatography properties of the materials in the present invention differ from and are better controlled compared to the prior art monoliths.
• Silsesquisiloxanes are synthesised by polymerising organotrialcoxysilane.
• the polymerisation occurs through the hydrolysis and condensation of the organotrialcoxysilane.
• Polymerisation leads to the formation of many siloxane rings with eight membered rings being the most stable. Further polymerisation produces polyhedral oligomeric structures.
• Today, silsesquisiloxanes are available as commercial starting materials.
• the basic silsesquisiloxane structure can be viewed as a cage of molecular silica comprised of defined number of silicon atoms linked together with oxygen atoms in an orderly manner. At each corner is a substituent which can be a hydroxyl or just about any chemical group known in organic chemistry. Their three dimensionality, high symmetry, and size has been found to makes silsesquioxanes useful building blocks in the formation of silica particles according to the present invention. The diversity of possible functional groups along with their controlled orientation in three dimensional space allows for highly tailored nanometer-by- nanometer construction in all three dimensions.
• the silsesquioxane cage desirably confers rigidity and thermal stability that provides mechanical and thermal properties surpassing typical organic-silica hybrid materials.
• the hybrid organo silica particles according to the present invention thus comprise organic groups or moieties linked to silicon atoms of the silsesquioxane moiety.
• the organic moieties are preferably hydrocarbon moieties and especially alkyl or aryl moieties, as hereinafter described. As described below, such hydrocarbon moieties may be substituted hydrocarbon moieties.
• the present invention in preferred embodiments comprises the incorporation of silsesquioxane molecules into a Stober or modified Stober process, i.e. via a co- condensation approach with a silane such as a tetraalkoxysilane (e.g. TEOS), to produce a variety of silica or hybrid silica particles, porous or non-porous, possessing the attractive physical properties described herein.
• a silane such as a tetraalkoxysilane (e.g. TEOS)
• TEOS tetraalkoxysilane
• An example of another method includes the incorporation of silsesquisiloxane moieties into a polyethoxysilane (PEOS) of known molecular weight, e.g. by co-condensation of the same.
• PEOS polyethoxysilane
• hybrid polyethoxysilane hybrid silsesquisiloxane- polyethoxysilane
• a further example involves functionalisation of a silica sol with silsesquisiloxane moieties to form a hybrid sol, followed by emulsification of the hybrid sol in a non polar organic solvent with a surfactant to form emulsified beads.
• the emulsified beads can then be gelled using an acidic catalyst to form particles.
• the silane used in co-condensing a silsesquioxane and a silane is preferably a tetraalkoxysilane, more preferably tetraethoxysilane (TEOS).
• TEOS tetraethoxysilane
• the condensing of the silsesquioxane and silane takes place preferably in a hydrolysis solution and more preferably in a basic medium.
• the hydrolysis solution preferably thus contains a base (which term also includes a mixture of bases) and more preferably ammonium hydroxide or an alkali metal hydroxide (e.g. sodium or potassium hydroxide), most preferably ammonium hydroxide.
• a base which term also includes a mixture of bases
• ammonium hydroxide or an alkali metal hydroxide e.g. sodium or potassium hydroxide
• silica can also be formed under acidic conditions as known in the art.
• the hydrolysis solution preferably comprises water and an organic solvent.
• the organic solvent preferably comprises an alcohol and more preferably comprises ethanol. A hydrolysis solution of water and ethanol is thus preferred.
• the hydrolysis solution preferably contains a template for providing a porous structure.
• the hydrolysis solution preferably contains a surfactant template (which term also includes a mixture of surfactant templates).
• the surfactant serves as a porogen template, which once removed (e.g. burnt out) provides the porous structure.
• the surfactant is preferably water-soluble.
• the surfactant preferably forms micelles under the hydrolysis and condensation conditions of the process.
• the surfactant may be ionic or non-ionic, but preferably is ionic and more preferably cationic.
• Preferred surfactants are cationic, quaternary ammonium surfactants, more preferably with either bromide or chloride counter-ions, with more preferred examples being of a formula: (R 4 )(R 5 )(R6)(R 7 )(N) + X " , where each of R 4 , R 5 , R6, R 7 is independently selected from H, alkyl, alkenyl, alkynyl, benzyl and aryl (especially alkyl), each of which may be unsubstituted or substituted (preferably each R , R 5 , R6, is independently an alkyl group and R 7 is an alkyl or benzyl group (especially an alkyl group)) and X is Br or CI.
• R 4 , R 5 , R6, R7 is a Cs-2o alkyl group (unsubstituted or substituted). More especially, each R 4 , R 5 , R6, is independently a Ci-2 alkyl group (especially methyl) and R 7 is a Cs-2o alkyl group.
• alkyltrimethylammonium bromide or chloride more especially (Cs ⁇ oalkyljtrimethylammonium bromide or chloride, with lauryl (C12), myristyl (CM), and cetyl (hexadecyl) (C16) and stearyl (Cis) and didecyl (C20) analogues most preferred, with cetyltrimethylammonium bromide (CTAB) and/or cetyltrimethylammonium chloride (CTAC) being especially good examples.
• Cs ⁇ oalkyljtrimethylammonium bromide or chloride with lauryl (C12), myristyl (CM), and cetyl (hexadecyl) (C16) and stearyl (Cis) and didecyl (C20) analogues most preferred, with cetyltrimethylammonium bromide (CTAB) and/or cetyltrimethylammonium chloride (CTAC) being especially good examples.
• the co-condensation of silsesquioxane and silane typically initially results in the formation of a sol.
• the sol can then be gelled, e.g. by agitation, to form a precipitate of silica particles which can be separated from the solution.
• the formation of the sol and the gelation to form particles may be performed in a single pot, i.e. as a one-pot process.
• the separated silica precipitate can be optionally washed and dried.
• the surfactant can be removed from the silica particles, e.g. by acid extraction and/or burnt out by heat.
• the silica particles may be calcined prior to chromatographic use.
• the order of addition and/or mixing of reagents is not especially limited.
• the surfactant is dissolved in the solution comprising water and an organic solvent, optionally along with the base, or the base is added to the solution after the surfactant, and then a mixture of the silsesquioxane and the silane is added to the solution to form a sol.
• the mixture is typically stirred, for example from 2 to 48 hrs, or from 10 to 30 hrs, or about 24 hrs.
• the silsesquioxane/silane mixture may be dissolved in an organic solvent, such as ethanol, prior to addition to the hydrolysis solution.
• the method includes (i) preparing a surfactant-containing hydrolysis solution of water, organic solvent (e.g. ethanol) and surfactant (e.g. hexadecyltrimethylammonium bromide), (ii) providing a base (e.g. ammonium hydroxide) in said surfactant solution, (iii) preparing a precursor solution of a mixture of tetraalkoxysilane (e.g. TEOS) and silsesquioxane, and (iv) adding the precursor solution to the hydrolysis solution thereby co-condensing the tetraalkoxysilane and silsesquioxane and forming particles.
• organic solvent e.g. ethanol
• surfactant e.g. hexadecyltrimethylammonium bromide
• a base e.g. ammonium hydroxide
• the particles can be washed and dried and the surfactant can be removed from the silica particles to leave a porous structure in the particles.
• the silsesquioxane carries an organic substituent
• hybrid organo silica particles are formed.
• silsesquioxane does not carry an organic substituent
• pure inorganic silica particles are formed.
• Adjustment of the ratio of TEOS to silsesquioxane, wherein the silsesquioxane carries an organic substituent can give a range of %carbon (%C) in the formed particles.
• silsesquioxane is a disilanol alkyl silsesquioxane or trisilanol alkyl silsesquioxane, e.g. trisilanol isooctyl silsesquioxane.
• the silanol groups on the molecule render the moiety available for co-condensation in the reaction. Adjustment of the hydrolysis solution concentrations and the condensation reaction temperature can provide a range of particle sizes.
• the invention preferably utilises a Stober approach for making the (non-porous) particles and preferably a modified Stober approach that facilitates the production of porous particles.
• Stober approach for making the (non-porous) particles
• modified Stober approach that facilitates the production of porous particles.
• Such approach may be performed as a one-pot process.
• the formed silica particles may be subjected to one or more further treatments, e.g. pore expansion, calcination, and/or sintering.
• a pore expansion step e.g. on non-calcined particles
• the pore-expanded particles may be subsequently calcined and/or sintered.
• the silsesquioxane used in the present invention is not especially limited. Different silsesquioxanes may be selected to impart different properties to the silica particles. One species of silsesquioxane molecule may be used in the present invention to form the particles, or two or more different species of silsesquioxane molecule may be used.
• any silsesquioxane may be used, which is capable of reacting with the co-component of the hydrolysis mixture, e.g. the alkoxysilane.
• Porous and non-porous silica particles may be formed using silsesquioxane- silanol molecules as a co-component in the process.
• silsesquioxane-silanol molecules one or more of the silicon atoms (preferably two or more, or three or more of the silicon atoms) carries a hydroxyl substituent. In this way the silsesquioxane can take part in the co-condensation reaction to form the sol.
• one or more of the silicon corner atoms is missing from the silsesquioxane cubic cage structure, i.e. the cage comprises seven silicon atoms or fewer.
• silsesquioxanes with a missing silicon corner and having seven silicon atoms suitably have silanol substituents on the silicon atoms that would otherwise be attached to the silicon atom of the missing corner.
• the other silicon atoms may have a hydroxyl substituent or, where is it desired to form hybrid silica, an organic substituent. It will be appreciated that the silsesquioxane-silanols may be used as a salt form thereof.
• Porous and non-porous pure (i.e. inorganic) silica particles may be formed using silsesquioxane-silanol molecules that do not carry an organic substituent on the silicon atoms.
• Porous and non-porous hybrid silica/organo particles may be formed using nano-sized silsesquioxane-silanol molecules that have an organic substituent on one or more of the silicon atoms of the silsesquioxane.
• the invention provides a method of introduction of different chemical moieties into the skeleton or substructure of the silica particle that modify its chemical, thermal and pH stability.
• silsesquioxane-silanols are preferred starting materials as moieties to be incorporated into the silica particles by co-condensation with alkoxysilanes.
• the silsesquioxane-silanols having no organic substituent may be used ("inorganic silsesquioxane-silanols").
• the structure of an exemplary inorganic silsesquioxane-silanol for forming inorganic silica particles is shown in Figure 1 .
• the molecule shown has eight silicon atoms in the cage structure each silicon carrying a hydroxyl group.
• silsesquioxane-silanols may have seven silicon atoms, or fewer.
• the silsesquioxane-silanol may be provided or used in a salt form thereof, e.g. as an ammonium salt or other salt thereof, such as the tetramethyl ammonium (TMA) salt of the octa-silanol silsesquioxane shown in Figure 1 .
• TMA tetramethyl ammonium
• silsesquioxane-silanols having an organic substituent may be used.
• organic silsesquioxane-silanols examples of suitable organic silsesquioxane-silanols:
• the present invention may employ one silsesquioxane species or a mixture of two or more silsesquioxane species, i.e. the particles may comprise in their skeleton structure two or more different silsesquioxane moieties.
• the molar ratio of alkoxysilane to silsesquioxane in the starting materials and/or final particles may be in the range 1 :x, that is 1 mole of alkoxysilane to x mole of silsesquioxane, where x is from 0.01 to 3, preferably from 0.02 to 2, more preferably from 0.1 to 1 .5, especially 0.1 to 1 , or 0.3 to 1 .
• the organic group or substituent on the silsesquioxane or silsesquioxane- silanol is preferably a hydrocarbon and more preferably is selected from the following group: alkyl and aryl.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons).
• saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl (e.g., -CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -CH 2 -), isopropyl, n-butyl, tbutyl, isobutyl, sec- butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
• groups such as methyl, ethyl, n- propyl (e.g., -CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -CH 2 -), isopropyl, n-butyl, tbutyl, isobutyl, sec-
• An unsaturated alkyl group is one having one or more double bonds or triple bonds.
• unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(1 ,4-pentadienyl), ethynyl, 1 - and 3- propynyl, 3-butynyl, and the higher homologs and isomers.
• alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as "heteroalkyl”. Alkyl groups that are limited to hydrocarbon groups are termed "homoalkyl".
• alkyl can also mean "alkylene" or
• alkyldiyl as well as alkylidene in those cases where the alkyl group is a divalent radical.
• alkylene or "alkyldiyl” by itself or as part of another substituent means a divalent radical derived from an alkyl group, as exemplified, but not limited, by -CH 2 CH 2 CH 2 - (propylene or propane-1 ,3-diyl), and further includes those groups described below as “heteroalkylene”.
• an alkyl (or alkylene) group will have from 1 to about 30 carbon atoms, preferably from 1 to about 25 carbon atoms, more preferably from 1 to about 20 carbon atoms, even more preferably from 1 to about 15 carbon atoms and most preferably from 1 to about 10 carbon atoms.
• a “lower alkyl”, “lower alkylene” or “lower alkyldiyl” is a shorter chain alkyl, alkylene or alkyldiyl group, generally having about 10 or fewer carbon atoms, about 8 or fewer carbon atoms, about 6 or fewer carbon atoms or about 4 or fewer carbon atoms.
• an alkylidene group will have from 1 to about 30 carbon atoms, preferably from 1 to about 25 carbon atoms, more preferably from 1 to about 20 carbon atoms, even more preferably from 1 to about 15 carbon atoms and most preferably from 1 to about 10 carbon atoms.
• a “lower alkyl” or “lower alkylidene” is a shorter chain alkyl or alkylidene group, generally having about 10 or fewer carbon atoms, about 8 or fewer carbon atoms, about 6 or fewer carbon atoms or about 4 or fewer carbon atoms.
• alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
• heteroalkyi by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si, S and B, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N, B, S and Si may be placed at any interior position of the heteroalkyi group or at the position at which the alkyl group is attached to the remainder of the molecule.
• heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyi, as exemplified, but not limited by, -CH 2 - CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroalkylene groups heteroatoms can also occupy either or both of the chain termini ⁇ e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
• alkylene and heteroalkylene linking groups no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
• the formula -CO 2 R'- optionally represents both -C(O)OR' and -OC(O)R'.
• cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
• heterocycloalkyl examples include, but are not limited to, 1 -(1 ,2,5,6-tetrahydropyridyl), 1 - piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran- 2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2- piperazinyl, and the like.
• halo or halogen
• haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
• halo(Ci-C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, S, Si and B, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indo
• aryl when used in combination with other terms ⁇ e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group ⁇ e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom ⁇ e.g., a methylene group) has been replaced by, for example, an oxygen atom ⁇ e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(1 -naphthyloxy)propyl, and the like).
• R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyi, substituted or unsubstituted aryl, e.g., aryl substituted with 1 -3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
• each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
• R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7- membered ring.
• -NR'R is meant to include, but not be limited to, 1 - pyrrolidinyl and 4-morpholinyl.
• alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl ⁇ e.g., - CF 3 and -CH 2 CF 3 ) and acyl ⁇ e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
• substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.
• the silsesquioxane moieties are contained in the skeleton structure of the silica, not merely on the surface of the silica, although silsesquioxane moieties may be present at the surface as well.
• the inorganic (pure) silica particles according to the invention preferably have a formula:
• the hybrid organo silica particles according to the invention preferably have a formula selected from the group consisting of:
• R is the organic (preferably hydrocarbon) moiety on the (corner(s) of the) silsesquioxane moiety.
• Preferred silsesquioxane moieties have a missing corner or missing edge.
• Approach 1 using cage silsesquioxanes having only silanol groups at the corners and not organic groups, e.g. octa-silsesquioxanes (eight silanol groups at the corners) as an additive or co- component in making porous silica particles, preferably using TEOS as a co- component.
• Approach 2 using cage silsesquioxanes having only silanol groups at the corners and not organic groups, e.g.
• octa-silsesquioxanes (eight silanols) as an additive or co-component in making non-porous silica particles, preferably using TEOS as a co-component.
• the resulting materials from approaches 1 and 2 will be "pure", i.e. inorganic, silica with enhanced mechanical, thermal, and chemical stability.
• Approach 3 using di-, tri, and/or tetra silanol hydrocarbon silsesquioxanes as additives or co-component in making porous silica particles, preferably using TEOS as a co-component.
• Approach 4 using di, tri-, and/or tetra silanol hydrocarbon silsesquioxanes as additives or co-component in making non-porous organo silica particles, preferably using TEOS as a co-component.
• the resulting materials from approaches 3 and 4 will be organo-silica hybrid material with enhanced mechanical, thermal, and chemical stability.
• Hybrid silica particles have desirable properties for many applications, i.e. hybrid silica wherein an organic, especially alkyl, functionality is incorporated into the skeleton structure, optionally and the surface of the silica.
• the particulate material of the present invention is desirably chromatographic material for use, e.g., in LC or SPE applications.
• the material may be used in nano- LC, analytical-LC, or preparative scale LC.
• multiple particles are disposed in a packed bed.
• a plastic or metal column is packed with the particles.
• the silica or hybrid silica particles are typically and preferably substantially spherical but may be irregular in shape in some embodiments.
• the silica or hybrid silica particles preferably have a narrow size distribution.
• the silica particles are essentially "monodisperse” or essentially “homodisperse", which indicates that the particle size of the majority of the particles (e.g., 80, 90 or 95% of the particles) does not vary substantially (e.g., not more than 10%) below or above the median particle size (D 50 ).
• 90% of the particles have an average particle size of between about 0.9 x D 50 and about 1 .1 x D 50 . This is advantageous for chromatographic applications. Whilst monodispersed particles are preferred, particles with a broader particle size distribution may be useful in many applications.
• the silica particles are typically microparticles, preferably 0.1 m or larger in diameter, preferably up to 1000 ⁇ in median particle diameter. More preferably the particles are from 1 to 1000 ⁇ , or 0.1 to 500 ⁇ or 1 to 500 ⁇ in diameter, or still more preferably 0.1 to 100 ⁇ or 1 to 100 ⁇ in diameter, or even more preferably 0.2 to 50 ⁇ in diameter, especially 0.1 to 10 ⁇ or 1 to 10 ⁇ and most preferably 1 .5 to 5 ⁇ in diameter.
• the particles may be porous (including partially porous, totally porous or superficially porous) or non-porous particles.
• the particles may be useful for preparing solid core chromatographic materials.
• the pores of the particles can be of any size.
• the nominal pore size is typically measured in angstroms (10 "1 ° m, A).
• a pore size distribution (PSD) is calculated from adsorption data using the BJH (Barrett Joyner-Halenda) method and the average pore size (W B JH) is defined as the maximum of the PSD.
• W B JH average pore size
• the average size or diameter of the pores is between about 1 and about 5000 A.
• the volume average diameter of the pores is between about 10 and about 5000 A, between about 10 and about 4000 A, between about 10 and about 3000 A, between about 10 and about 2000 A, between about 10 and about 1000 A, between about 10 and about 800 A, between about 10 and about 600 A, between about 10 and about 500 A, between about 10 and about 400 A, between about 10 and about 300 A, between about 10 and about 200 A, between about 10 and about 100 A, between about 20 and about 2000 A, between about 20 and about 1000 A, between about 20 and about 500 A, between about 20 and about 300 A, between about 20 and about 200 A, between about 20 and about 100 A, between about 30 and about 2000 A, between about 30 and about 1000 A, between about 30 and about 500 A, between about 30 and about 300 A, between about 30 and about 200 A, between about 30 and about 100 A, between about 40 and about 2000 A, between about 40 and about 1000 A, between about 40 and about 500 A, between about 40 and about 300 A, between about 40 and about 200 A, between about 40 and about 100 A, between about 40
• the (BET) specific surface area of the particulate material is typically between about 0.1 and about 2,000 m 2 /g.
• the specific surface area of the particulate material is between about 1 and about 1 ,000 m 2 /g, between about 1 and about 800 m 2 /g, between about 1 and about 600 m 2 /g, between about 1 and about 500 m 2 /g, between about 1 and about 400 m 2 /g, between about 1 and about 200 m 2 /g or between about 1 and about 100 m 2 /g.
• the specific surface area of the material is between about 10 and about 1 ,000 m 2 /g, between about 10 and about 800 m 2 /g, between about 10 and about 600 m 2 /g, between about 10 and about 500 m 2 /g, between about 10 and about 400 m 2 /g, between about 10 and about 200 m 2 /g or between about 10 and about 100 m 2 /g.
• the specific surface area of the material is between about 50 and about 1 ,000 m 2 /g, between about 50 and about 800 m 2 /g, between about 50 and about 600 m 2 /g, between about 50 and about 500 m 2 /g, between about 50 and about 400 m 2 /g, between about 50 and about 200 m 2 /g or between about 50 and about 100 m 2 /g.
• the specific surface area of the particulate material is between about 1 and about 500 m 2 /g, or between about 10 and about 500 m 2 /g (especially between about 50 and about 500 m 2 /g).
• the specific surface area more preferably is between about 10 and about 100 m 2 /g.
• the specific surface area preferably is between about 0.5 - 10 m 2 /g.
• the median particle diameter is preferably from 0.1 to 5 ⁇ .
• silica or hybrid silica particles may be C18 surface modified.
• the silica or hybrid silica particles in certain embodiments may even be surface modified using silsesquioxane moieties as described in US 2012/0205315 A1 .
• the same or different silsesquioxane could used as a surface modifier as used to form the skeleton of the silica particles.
• these molecules can be used to introduce new features into both the bulk and surface of particles for chromatography applications, in order to deliver higher thermal stability, higher pH stability, improved mechanical stability and chemical robustness.
• the advantages of the materials in accordance with the present invention may include: rugged chemical stability, improved temperature stability, high physical strength, high pH stability, and a greener synthetic process (e.g. using less of volatile and toxic silane reagents).
• the materials provide a platform for a variety of high- performance separation media. Description of the drawings
• Figure 1 shows schematically the structure of an exemplary inorganic silsesquioxane-silanol for forming inorganic silica particles in accordance with the present invention.
• Figure 2 shows schematically examples 1 -6 of suitable organic silsesquioxane-silanols for the production of hybrid organic silica particles (R is an organic substituent).
• Figures 3A and 3B show SEM images (x7k and x10k respectively) of particles obtained in Example 1 below.
• Figures 4A and 4B show SEM images (x4k and x10k respectively) of particles obtained in Example 4 below.
• Figures 5A and 5B show SEM images (x4k and x9k respectively) of particles obtained in Example 7 below.
• Figures 6A and 6B show SEM images (x5k and x10k respectively) of particles obtained in Example 9a below.
• Figures 7A and 7B show SEM images (x5k and x10k respectively) of particles obtained in Example 12.5 below.
• Figure 8 shows the Log Differential Intrusion vs. Pore Size Diameter isotherm obtained from Mercury Intrusion porosimetry for the particles of increased pore diameter obtained in Example 13 below using 5% trisilanol iso octyl POSS.
• Figure 9 shows the BJH desorption isotherm for the particles of increased pore diameter obtained in Example 13 below using 5% trisilanol phenyl POSS.
• Figures 10A and 10B show SEM images (x5k and x10k respectively) of particles obtained in Example 28a below.
• Figures 11A and 11 B show SEM images (x2.5k and x10k respectively) of particles obtained in Example 29a below. Description of Examples
• tetraethylorthosilicate also known as tetraethoxysilane (TEOS), ethanol (absolute preservative free), acetic anhydride (reagent grade) and hexadecyltrimethylammonium bromide (CTAB, 98%) were all purchased from Sigma Aldrich (UK).
• Ammonium hydroxide solution (35% wt NH 3 ) and toluene (reagent grade) were purchased from Fisher (Loughborough, UK).
• Isooctyl trisilanol silsesquioxane, iso-butyl trisilanol silsesquioxane, phenyl disilanol silsesquioxane, phenyl trisilanol silsesquioxane and octa TMA silsesquioxane (trade name POSS) were all purchased from Hybrid Plastics (Hattlesburg, US). All chemicals, solvents and reagents were used as received without further purification. De-ionised (Dl) water was provided in house.
• Nitrogen sorption measurements were performed on a Micromeritics ASAP 2020 volumetric analyzer. Prior to measurement, samples were degassed at 200 °C for 12 h. The specific surface area was calculated using the BET (Brunauer Emmett- Teller) method. The pore size distribution was calculated from adsorption data using the BJH (Barrett Joyner-Halenda) method. The average pore size (W B JH) is defined as the maximum of the PSD. Scanning electron microscopy (Hitachi TM-100) was used to obtain images of the silica microspheres.
• Particle size distributions were measured using the electrical sensing zone (ESZ) technique on a Beckmann Multisizer 3 Coulter Counter as well as analysis via Centrifugal Particle Size (CPS) technique.
• D10 is defined as the particle diameter at 10% of the cumulative particle size distribution
• D90 is defined as the particle diameter at 90% of the cumulative particle size distribution
• D90/10 is defined as the ratio of the D90 value to the D10 value.
• %C composition was determined by Microanalysis using a LECO CS230 Carbon/Sulphur analyser. Synthesis of porous silica particles
• the molar ratio of alkoxysilane to silsesquioxane (POSS) in the starting material and/or particle may be in the range 1 :x, where x is from 0.01 to 3, preferably from 0.02 to 2, more preferably from 0.1 to 1 .5, especially 0.1 to 1 , or 0.3 to 1 .
• the sol was allowed to stir for 24 h at 300 rpm.
• the silica precipitate was separated by centrifugation (3700 rpm - 5 minutes), washed with methanol (5 times) and dried at 80°C (heating rate 0.2 °C/min) for 16 hours.
• the surfactant was removed by acid extraction involving 1 g of the silica spheres added to a solution of 150 mL absolute ethanol and 1 .7 mL Concentrated HCI. The acid solution was heated to 60 °C and allowed to react for 24 hours. This procedure was repeated twice further.
• POSS molecules were used in different examples, e.g. trisilanol iso-octyl POSS, or trisilanol phenyl POSS, or trisilanol ethyl POSS, or trisilanol butyl POSS etc.
• the reaction followed the general procedure described above but with a slight variation.
• the TEOS and trisilanol iso-octyl POSS were dissolved in ethanol prior to addition to the hydrolysis solution.
• a volume of ethanol equal to four times the volume of the combined precursors was used (i.e. 3.56 mL TEOS and 0.44 mL POSS (4 mL total) were dissolved in 16 mL of ethanol), which was taken from the total ethanol content (i.e. 384 mL instead of 400 mL of ethanol was mixed with 250 mL Dl H 2 O to constitute the hydrolysis solution).
• Example 2 In Example 2, the procedure of Example 1 was followed but the amounts of precursors were changed so that a 1 :1 mixture was achieved. Therefore, Example 2's composition was 2 mL TEOS and 2 mL POSS. Both Examples 1 and 2 produced spherical particles with a wider particle size distribution normally associated with silica particles obtained under modified Stober conditions. Both Examples 1 and 2 produced silica with high %C composition after synthesis (see results below).
• Examples 3 - 6 were focused on improving the resultant particle size distribution.
• the experimental protocol reverted back to the general procedure first described above, i.e. in these cases no pre-dilution of the precursors was performed.
• the TEOS and POSS reagents were mixed together in a glass vial and subjected to ultrasonic mixing for 2 minutes. After which the mixed precursors solution was added to the reaction flask.
• These Examples produced particles with a very narrow particle size distribution and mean particle diameter of ⁇ 1 .5 ⁇ .
• a 1 g portion of the recovered material from Example 6 was placed in a furnace and heated to 560 °C (rate 1 K/min) for 24 hours (calcined). This step was performed because particle size measurement by Coulter technique has practical limitations.
• the particles recovered from Examples 1 -6 had mean diameters of -1 .4 - 1 .5 ⁇ when viewed under SEM and this size is at the lower limits of detection for the Coulter instruments.
• the reported D90/10 ratios for these samples also looked greater than what was observed under SEM.
• the CPS technique has a considerably broader detection range and in this instance offers more accurate results.
• the technique uses an aqueous sucrose solution to provide a suspension gradient for analysis.
• the silica particles in the hybrid organo silica form have too much hydrophobicity associated because of the co-condensed POSS inclusion that the recovered particles could not be analysed without removal of the organic functional groups.
• the calcination facilitated this and also indicated that non porous particles could be produced if the heating temperature was increased to sintering temperatures (>800 °C).
• Particles made via this method should posses Si-(SiO1 .5)- Si linkages as opposed to the normal siloxane (Si-O-Si) linkages.
• Example 7 was used to investigate increasing the recovered mean particle diameter whilst maintaining the narrow particle size distribution. This investigation used the known parameters of the traditional Stober reaction to try and achieve this. Parameters such as lower reaction temperatures and reactant concentration changes can alter the final particle size. This experiment involved reducing the concentration of NH 3 catalyst into the system by 50%. The result from this experiment increased the final particle size from 1 .4 ⁇ to 1 .8 ⁇ whilst maintaining the final particle size distribution.
• SEM images of particles obtained in Example 1 are shown in Figure 3A (x7k) and Figure 3B (x10k).
• a 10 ⁇ scale is shown to indicate particle size and the particles are clearly spherical in shape.
• SEM images of particles obtained in Example 4 are shown in Figure 4A (x4k) and Figure 4B (x10k).
• a 20 ⁇ or 10 ⁇ scale is shown to indicate particle size and the particles are again clearly spherical in shape.
• SEM images of spherical particles obtained in Example 7 (reduced NH 3 catalyst) are shown in Figure 5A (x4k) and Figure 5B (x9k). The narrow particle size distributions are clearly evident from the SEM images.
• the particles may be subject to further treatments. Numerous protocols are now described.
• Non calcined particles are added to pre-prepared water: Dimethyldodecylamine (DMDA 3.3% v) emulsion system. After mixing for 1 hour the contents are transferred to an autoclave and hydrothernnally heated to 130°C for 3 days. The pore expanded particles are allowed to cool to room temperature and washed repeatedly with methanol, methanol: water (50%), methanol and Acetone, followed by drying overnight at 80°C.
• DMDA 3.3% v Dimethyldodecylamine
• the surfactant template is removed by repeated extraction using acidic ethanol solutions. 2g of pore expanded silsesquioxane hybrid silica particles are suspended in absolute ethanol (150 mL) after which concentrated hydrochloric acid (1 .7 mL) is added. The suspension is refluxed overnight. The particles are collected by centrifugation and repeatedly washed with ethanol. The extraction process is repeated 3 times followed by drying in oven at 80°C.
• a second pore expansion procedure may be performed by adding the particles to a mixture of Dl water and tris(hydroxymethyl)aminomethane (TRIS).
• TRIS tris(hydroxymethyl)aminomethane
• a typical example is as follows: 1 .5g of surfactant template extracted particles are dissolved in a solution of TRIS (0.4g) and Dl water (10 mL) and then hydrothernnally treated at 135°C for 24 hours followed by washing in Dl water, methanol and acetone. The particles are dried at 80°C overnight
• hybrid totally porous particles are also included within the scope of the invention. Such methods may require classification to produce narrow particle size distributions.
• CTAB 3.2g CTAB was first dissolved in a mixture consisting of 1000 mL of water and 1600 mL of absolute ethanol. 15 mL of ammonium hydroxide solution (25% wt NH 3 ) was added to the mixture and stirred for 15 minutes before the single step addition of 16 mL TEOS. The suspension was allowed to stir for 24 hours at 250 rpm. The silica particles were separated by centrifugation and washed repeatedly with methanol, water and acetone before drying overnight at 60°C and then calcined at 560°C for 24 hours to remove the template.
• CTAB 3.2g (3.3mmol) CTAB was first dissolved in a mixture consisting of 1000 ml_ of water and 1600 ml_ of absolute ethanol. 15 mL of ammonium hydroxide solution (25% wt NH 3 ) was added to the mixture and stirred for 15 minutes before the single step addition of a pre-mixed solution of 15.84 mL TEOS and 0.149g of Trisilanol Iso Octyl POSS (Example 8a). The suspension was allowed to stir for 24 hours at 250 rpm. The silica particles were separated by centrifugation and washed repeatedly with methanol, water and acetone before drying overnight at 60°C.
• the template was removed via repeated extraction with an acidic ethanol solution under reflux.
• the particles recovered from the pore swelling procedure were suspended in ethanol (1 .5% wt) after which concentrated hydrochloric acid was added (2.5 wt %).
• the suspension was refluxed for 24 hours and the particles recovered by centrifugation followed by washing with ethanol until a neutral pH was achieved. The process was repeated three times.
• Example MPD A D 5 o Mm D90/D10 %C m 2 /g cm 3 /g
• CTAB 4.4g (4.6mmol) CTAB was first dissolved in a mixture consisting of 1000 ml_ of water and 1600 ml_ of absolute ethanol. 15 ml_ of ammonium hydroxide solution (25% wt NH 3 ) was added to the mixture and stirred for 15 minutes before the single step addition of 16 mL of TEOS. The suspension was allowed to stir for 24 hours at 250 rpm. The silica particles were separated by centrifugation and washed repeatedly with methanol, water and acetone before drying overnight at 60°C. Results are shown in Table 6.
• Example 1 Increased surfactant concentration to facilitate the production of hybrid particles with increased pore volume using POSS (e.g. trisilanol iso-octyl POSS or trisilanol phenyl POSS)
• POSS e.g. trisilanol iso-octyl POSS or trisilanol phenyl POSS
• the final particle diameter can be controlled in the reaction by adjustment of the ammonium hydroxide volume. Reaction conditions and the final particle diameter obtained are shown in Table 9. An example of SEM images of particles produced from the inclusion of 5% wt trisilanol iso-octyl POSS and reduced NH OH volume (example 12.5) are shown in Figure 7A (x5k) and Figure 7B (x10k). Table 9
• pore diameter of the particles it is desirable to increase the pore diameter of the particles for use in chromatographic separations.
• Various methods are available to increase the pore width.
• a typical approach involves a template swelling method immediately after the synthesis has taken place. Removal of the template is then required via calcination for non hybrid materials or solvent extraction. Once this has taken place an etching procedure can further widen the pore diameter into the domains typically required for chromatographic separations, i.e. >50A.
• Example 13 is based around the work of Sayari et al, and the method is given below.
• silica powder (2.5% w/w) was added to the emulsion and stirred for a further hour at a reduced speed of 300rpm, then treated statically under autogeneous pressure in an autoclave at 1 10°C for 48 hours. The silica was recovered by centrifugation, dried at 65°C for 16 hours and then calcined at 560°C for 24 hours to remove the template.
• hybrid silica particles can be produced via the emulsification of a hybrid polyethoxysilane.
• a hybrid polyethoxysilane (PES) is produced initially from the co-condensation of TEOS with POSS.
• the hybrid PES is then emulsified to produce spherical beads. Control of surface area, pore volume and pore diameter can be controlled from the preparation of the hybrid PES or by additives introduced in to the emulsification.
• a mixture of 900 mL Dl Water and 300 mL ethanol were mixed in a beaker using a Silverson LSM Homogeniser (8000 rpm, 15 mins). Separately a suspension of 330 mL mL of hybrid PES, 20 mL mL of toluene and 30 mL of DMF was prepared. After 15 minutes of stirring the PES/toluene/DMF mixture was added in to the water/ethanol dispersion. The mixture was allowed to react for 20 minutes. 40 mL of ammonium hydroxide solution, (25% wt) was added to the emulsion to gel the spherical beads with stirring for a further 3 minutes after which stirring was stopped.
• the particle suspension was then heated at 50°C for 16 hours and the particles collected by filtration and washed repeatedly with methanol, methanol: water (60:40 v: v), methanol and acetone. The particles were then dried in a vacuum oven at 80°C for 24 hours. The results are given in table 1 1 .
• Absolute, preservative free, 200 proof ethanol (445 mL) and tetraethoxysilane (233 mL) are mixed in a flask. 0.01 M HCI solution is slowly added to the mixture which is then refluxed for 16 hours under a nitrogen atmosphere. The mixture is distilled under vacuum to remove any excess ethanol followed by further heating under nitrogen at an elevated temperature of 125°C for 2 hours. A colourless viscous liquid of polyethoxysilane results with a molecular weight of approximately 800.
• a mixture of Dl Water (480 mL) and iso-propanol IPA (160 mL) are mixed in a beaker using a Silverson LSM Homogeniser (4700 rpm).
• trisilanol alkyl POSS (1 18.4g) is added to polyethoxysilane (120 mL) and dimethylformamide (40 mL). The mixture is allowed to react for 20 minutes after which it is added to the stirred water/IPA solution and allowed to mix for 5 minutes.
• Ammonium hydroxide solution, 25% (50 mL) is added to the emulsion to gel the spherical beads with stirring for a further 3 minutes after which stirring is stopped.
• an aqueous silica sol consisting of 27% weight S1O2 OctaTMA POSS (8g) is added and allowed to mix for 30 minutes.
• An oil phase is prepared by dissolving 1 .08g of surfactant Span 80 and 1 .08g of stearic acid in toluene (250 mL).
• a Silverson LM homogeniser is used to make an emulsion. The stirrer is allowed to rotate at 6000rpm and the silica/POSS sol is added to the oil phase and stirred for 15 minutes.
• the silica sol turns to spherical droplets of 1 to 30 ⁇ in diameter.
• Acetic acid anhydride (10 mL) is added into the emulsion over 30 seconds and the particles are allowed to stand overnight.
• silica gel slurry prepared this way is dispersed in methanol and again allowed to settle overnight. Toluene and emulsifier previously added are removed by repeatedly decanting the supernatant methanol solution.
• Totally porous pure silica particles containing silsesquioxane cages within the framework without any organic functionality can be obtained by the following process.
• the non calcined particles were then added to pre-prepared water:dimethyldodecylamine (DMDA 3.3% v) emulsion system. After mixing for 1 hour the contents were transferred to an autoclave and hydrothernnally heated to 130°C for 3 days. The pore expanded particles were allowed to cool to room temperature and washed repeatedly with methanol, methanol: water (50%), methanol and acetone, followed by drying overnight at 80°C.
• DMDA 3.3% v dimethyldodecylamine
• the particles After drying the particles can be subjected to calcination to remove the surfactant template and the organic functionality of the POSS compound used. Calcination can be performed by heating the material in a suitable oven at 560°C (heating rate 1 °C/min) for 24 hours.
• a second pore expansion procedure is performed by adding the particles to a mixture of Dl water and tris(hydroxymethyl)aminomethane (TRIS).
• TRIS tris(hydroxymethyl)aminomethane
• a typical example is as follows: 1 .5g of surfactant template extracted particles are dissolved in a solution of TRIS (0.4g) and Dl water (10 mL) and then hydrothernnally treated at 135°C for 24 hours followed by washing in Dl water, methanol and acetone. The particles are dried at 80°C overnight.
• TRIS tris(hydroxymethyl)aminomethane
• Absolute, preservative free, 200 proof ethanol (445 mL) and tetraethoxysilane (233 mL) are mixed in a flask. 0.01 M HCI solution is slowly added to the mixture which is then refluxed for 16 hours under a nitrogen atmosphere. The mixture is distilled under vacuum to remove any excess ethanol followed by further heating under nitrogen at an elevated temperature of 125°C for 2 hours. A colourless viscous liquid of polyethoxysilane results with a molecular weight of approximately 800.
• a mixture of Dl water (480 mL) and iso-propanol IPA (160 mL) are mixed in a beaker using a Silverson LSM Homogeniser (4700 rpm).
• trisilanol POSS (1 18.4g) is added to polyethoxysilane (120 mL) and dimethylformamide (40 mL). The mixture is allowed to react for 20 minutes after which it is added to the stirred water/IPA solution and allowed to mix for 5 minutes.
• Ammonium hydroxide solution, 25% (50 mL) is added to the emulsion to gel the spherical beads with stirring for a further 3 minutes after which stirring is stopped.
• the particle suspension was then heated at 50°C for 16 hours and the particles the collected by filtration and washed repeatedly with methanol, methanol: water (60:40 v: v), methanol and acetone. The particles were then dried in a vacuum oven at 80°C for 24 hours.
• OCTMA POSS 8g
• An oil phase is prepared by dissolving 1 .08g of surfactant Span 80 and 1 .08g of stearic acid in toluene (250 ml_).
• a Silverson LM homogeniser is used to make an emulsion. The stirrer is allowed to rotate at 6000rpm and the silica/POSS sol is added to the oil phase and stirred for 15 minutes.
• the silica sol turns to spherical droplets of 1 to 30 ⁇ in diameter.
• Acetic acid anhydride (10 ml_) is added into the emulsion over 30 seconds and the particles are allowed to stand overnight.
• silica gel slurry prepared this way is dispersed in methanol and again allowed to settle overnight. Toluene and emulsifier previously added are removed by repeatedly decanting the supernatant methanol solution.
• Example 20 Stober process incorporating trisilanol POSS (any type) without sintering
• Non porous silica particles retaining organo functionality of incorporated POSS can be obtained by the following process. Absolute, preservative free, 200 proof ethanol (23 ml_) and ammonium hydroxide solutions (25%, 5 ml_) are mixed in a round bottom flask. In a separate vial, TEOS (0.49 ml_) and the trisilanol POSS (0.1 ml_) are mixed (sonication, 2 minutes) after which 2 ml_ of ethanol is added and the solution sonicated again. The TEOS/POSS/ethanol mixture is added to the ethanol/ammonium hydroxide solution with rapid stirring. The reaction is allowed to proceed for 16 hours. The particles are collected by centrifugation (3700 rpm, 5 minutes) and washed repeatedly with methanol and acetone followed by drying at 80°C overnight.
• a typical example of this process is as follows. Absolute, preservative free, 200 proof ethanol (750 mL) and ammonium hydroxide solution (25%, 200 mL) are mixed in a 2 litre round bottom flask under rapid stirring for 15 minutes at room temperature. Tetraethylorthosilicate (TEOS) (57 mL) is added to ethanol (228 mL) and thoroughly mixed. The TEOS: ethanol solution is then added to the Ethanol/ammonium hydroxide solution and the mixture allowed to react for 16 hours. The freshly formed Stober particles (600nm) are transferred to a 3 litre 3 neck round bottom flask and heated to 40°C.
• TEOS Tetraethylorthosilicate
• a hydrolysis solution consisting of Deionised (Dl) water (360 mL), ethanol (400 mL) and ammonium hydroxide solution (25%, 240 mL) is made in a 1 L borosilicate HPLC bottle and sealed.
• TEOS 140 mL
• trisilanol POSS 60 mL are mixed via sonication and added to 800 mL of ethanol in a second borosilicate bottle.
• the separately prepared hydrolysis and TEOS/POSS solutions are attached to a continuous flow syringe pump (Atlas syringe pump, Syrris) and fed into the previously prepared Stober silica particle suspension at flow rates of 5 mL/min each.
• the final particle size can be achieved after allowing the addition of the growth reagents over periods of time. For example, continuous addition for 3 hours facilitates the production of 1 ⁇ POSS hybrid spheres with a D 90 /Dio ratio of 1 .1 1 .
• the particles are allowed to stir overnight, collected by centrifugation and suspended in water/methanol solution 50%v for 2 days, after which the particles are collected and washed repeatedly with methanol and acetone. The particles are then dried overnight at 80°C Example 22 - Pure silica non porous particles which posses POSS cage in the framework but no organic functionality
• Non porous particles can be made via the incorporation of POSS compounds into the Stober reaction.
• a typical example, which in no way limits the present invention, is as follows.
• Absolute, preservative free, 200 proof ethanol (23 mL) and ammonium hydroxide solutions (25%, 5 mL) are mixed in a round bottom flask.
• TEOS 0.49 mL
• trisilanol POSS 0.1 mL
• the TEOS/POSS/ethanol mixture is added to the ethanol/ammonium hydroxide solution with rapid stirring.
• the reaction is allowed to proceed for 16 hours.
• the particles are collected by centrifugation (3700 rpm, 5 minutes) and washed repeatedly with methanol and acetone followed by drying at 80°C overnight.
• the particles can be used as recovered or subject to sintering at elevated temperatures. Sintering will remove any of the organic functional groups associated to the POSS compound but the cage structure of the compound will remain within the silica framework.
• a portion of the 'as produced' POSS Stober particles are placed into a furnace (Carbolite 1 100°C Rapid heating box furnace) and heated to 1000°C at a heating rate of 1 °C/min. The particles are held at this temperature for 2 hours then allowed to cool to room temperature. This facilitates the formation of a particle diameter determined by centrifugal particle sizing of 400nm with a D 90 /Dio ratio of 1 .10 with a Specific Surface area (BET) of 4m 2 /g.
• BET Specific Surface area
• Non porous particles greater of mean particle diameter of 800 nm or greater can be produced via a seeded growth method.
• a seed solution of Stober silica particles are firstly prepared and then grown to the desired final particle size via a continuous controlled seed growth procedure in which up to 30% of the precursor volume is replaced with appropriate POSS molecule, which in this example is Trisilanol Iso-Octyl POSS or Trisilanol Phenyl POSS.
• a typical example is as follows. Absolute, preservative free, 200 proof ethanol (750 ml_) and ammonium hydroxide solution (25%, 200 ml_) are mixed in a 2 litre round bottom flask under rapid stirring for 15 minutes at room temperature. Tetraethylorthosilicate (TEOS) (57 ml_) is added to ethanol (228 ml_) and thoroughly mixed. The TEOS: ethanol solution is then added to the ethanol/ammonium hydroxide solution and the mixture allowed to react for 16 hours. The freshly formed Stober particles (600nm) are transferred to a 3 litre 3 neck round bottom flask and heated to 40°C.
• TEOS Tetraethylorthosilicate
• a hydrolysis solution consisting of Deionised (Dl) water (360 ml_), ethanol (400 ml_) and ammonium hydroxide solution (25%, 240 ml_) is made in a 1 L borosilicate HPLC bottle and sealed.
• TEOS 140 ml_
• Trisilanol POSS 60 ml_
• the separately prepared hydrolysis and TEOS/POSS solutions are attached to a continuous flow syringe pump (Atlas syringe pump, Syrris) and fed into the previously prepared Stober silica particle suspension at flow rates of 5 mL/min each.
• the final particle size can be achieved after allowing the addition of the growth reagents over periods of time. For example, continuous addition for 3 hours facilitates the production of 1 ⁇ POSS hybrid spheres with a D 90 /Dio ratio of 1 .1 1 .
• the particles are allowed to stir overnight, collected by centrifugation and suspended in water/methanol solution 50% v for 2 days, after which the particles are collected and washed repeatedly with methanol and acetone.
• Example 24 Modified Stober process with trisilanol alkyl -POSS (iso-butyl or iso-C8 version) followed by sintering
• mesoporous silica microspheres were synthesized in a simple batch process at room temperature.
• 0.785 g surfactant (CTAB) was dissolved in a solution containing 250 mL of Dl water and 400 mL Abs ethanol in a 2L round bottomed flask at room temperature (22 °C). The suspension was allowed to mix by slow magnetic stirring (200rpm) for 1 hour.
• Particles obtained will typically have a mean particle diameter of 1 .2 ⁇ with a D90/D10 of 1 .16 and a Specific Surface Area of 4m 2 /g
• Example 25 Addition of POSS (any type) to the PEOS process to make mesoporous particles followed by sintering
• Absolute, preservative free, 200 proof ethanol (445 mL) and tetraethoxysilane (233 mL) are mixed in a flask. 0.01 M HCI solution is slowly added to the mixture which is then refluxed for 16 hours under a nitrogen atmosphere. The mixture is distilled under vacuum to remove any excess ethanol followed by further heating under nitrogen at an elevated temperature of 125°C for 2 hours. A colourless viscous liquid of polyethoxysilane results with a molecular weight of approximately 800.
• a mixture of Dl Water (480 mL) and Iso-Propanol (IPA) (160 mL) are mixed in a beaker using a Silverson LSM Homogeniser (4700 rpm).
• trisilanol iso octyl POSS (1 18.4g) is added to polyethoxysilane (120 mL) and dimethylformamide (40 mL).
• the mixture is allowed to react for 20 minutes after which it is added to the stirred water/IPA solution and allowed to mix for 5 minutes.
• Ammonium hydroxide solution, 25% (50 mL) is added to the emulsion to gel the spherical beads with stirring for a further 3 minutes after which stirring is stopped.
• the particle suspension was then heated at 50°C for 16 hours and the particles the collected by filtration and washed repeatedly with methanol, methanol: water (60:40 v: v), methanol and acetone.
• Particles obtained typically have a mean particle diameter of 1 .2 ⁇ with a D90/D10 of 1 .16 and a Specific Surface Area of 4m 2 /g
• aqueous silica sol consisting of 27% weight S1O2 particles S1O2 particles OCTMA POSS (8g) was added and allowed to mix for 30 minutes.
• An oil phase was prepared by dissolving 1 .08g of surfactant Span 80 and 1 .08g of stearic acid in toluene (250 mL).
• a Silverson LM homogeniser was used to make an emulsion.
• the stirrer was allowed to rotate at 6000rpm and the silica/POSS sol was added to the oil phase and stirred for 15 minutes.
• the silica sol turned to spherical droplets of 1 to 30 ⁇ in diameter.
• Acetic acid anhydride (10 mL) was added into the emulsion over 30 seconds and the particles were allowed to stand overnight.
• silica gel slurry prepared this way is dispersed in methanol and again allowed to settle overnight. Toluene and emulsifier previously added are removed by repeatedly decanting the supernatant methanol solution.
• the recovered particles are then placed into a furnace (Carbolite high temperature box furnace) and heated to 1000°C at a heating rate of 1 °C/min.
• a furnace Carbolite high temperature box furnace
• Example 27 Production of non porous hybrid silica nanoparticles.
• Non porous hybrid silica spheres were formed following a modification of the known Stober reaction.
• Example 28 Non porous hybrid silica spheres.
• the method described in the example 27 general procedure was modified to incorporate various forms of POSS.
• the experimental protocol used to include the POSS chemicals was based on the substitution of various % weight of the total TEOS weight in the general procedure.
• Table 12 shows the amounts of reagents used in this example.
• the particles produced via this method have enhanced physical properties when compared to the particles produced in the general procedure, by possessing significant amounts of carbon functionality. These materials can be used as made or further grown to facilitate the production of larger microspheres with even greater amounts of organic functionality.
• the hybrid seed particles were then grown to larger particle diameters by the continuous feed of silica precursor and hydrolysis solution.
• the silica precursor used for the growth step consisted of TEOS mixed with various amounts of POSS and fed into the seed solution via a pump.
• the mechanism for particle growth differed greatly to the method of growth of the seeds; therefore, larger quantities of POSS could be mixed with the precursor during this step.
• the hydrolysis solution consisted of a mixture of ethanol, water and ammonia at known concentrations. The concentrations were determined to minimise particle aggregation as the growth step proceeds.
• the final particle diameter was a function of the reaction time.
• Example 29a production of non porous hybrid silica particles containing a core with 1 % POSS by weight with growth and subsequent increase in final functionality concentration
• the hybrid seeds were then transferred into a 5L round bottomed flask located in a 5L ceramic hotplate with magnetic stirrer (300rpm). The temperature of the hotplate was increased to 55°C and the hybrid seed suspension was allowed to equilibrate for a period of one hour.
• a solution of TEOS containing 1 % wt trisilanol iso octyl POSS was prepared.
• hydrolysis solution consisting of water, ethanol and ammonia was prepared at a volume ratio of 14/80/7.
• These materials can be used as made within a chromatographic device for use in separations involving functionalized non porous silica particles. It is possible that these materials also can be used as the starting core particles with enhanced properties in the production of core shell particles made from layer by layer deposition. A further use for these materials is as starting seeds to produce totally porous silica particles via a post synthesis pseudomorphic transformation process.
• Example 30 method to produce non porous silica particles from hybrid mesoporous silica particles made with POSS
• hybrid mesoporous silica particles containing POSS produce materials with excellent particle size distribution. These materials can also provide a convenient method to produce non porous silica particles without the associated organic functionality.
• the method involves the standard production of hybrid POSS mesoporous silica particles and subjecting the materials to high sintering temperature over an extended period of time.
• the high sintering temperature applied immediately after synthesis will eliminate the surfactant template and close up any of the resultant pore network.
• the initial particle size distribution will be maintained.
• Particles produced from this method typically had the physical properties shownin Table 15.
• Example 31 Non porous silica particles produced from particles made from hybrid PES emulsification.
• Non porous particles can be prepared by thermal treatment of hybrid porous silica prepared from hybrid PES emulsification in an air muffled furnace at 1000/1 100°C for 24 hours.
• a mixture of 900 ml_ Dl water and 300 ml_ ethanol are mixed in a beaker using a Silverson LSM Homogeniser (8000 rpm, 15 mins). Separately a suspension of 330 ml_ of hybrid PES, 20 ml_ of toluene and 30 ml_ of DMF is prepared. After 15 minutes of stirring the PES/Toluene/DMF mixture is added in to the water/ethanol dispersion. The mixture is allowed to react for 20 minutes. 40 ml_ of ammonium hydroxide solution, (25% wt) is added to the emulsion to gel the spherical beads with stirring for a further 3 minutes after which stirring is stopped.
• the particle suspension is then heated at 50°C for 16 hours and the particles the collected by filtration and washed repeatedly with methanol, methanol: water (60:40 v: v), methanol and acetone.
• the particles are then dried in a vacuum oven at 80°C for 24 hours.
• a portion of the produced POSS containing Stober particles are placed into a furnace (Carbolite 1 100°C Rapid heating box furnace) and heated to 1000°C at a heating rate of 1 °C/min. The particles are held at this temperature for 18 hours then allowed to cool to room temperature.
• a furnace Carbolite 1 100°C Rapid heating box furnace
• hybrid silica particles have been formed having very narrow particle size distributions. Consequently, this method can drastically reduce the overall synthesis time as very little or no classification of the particles is necessary.
• the measured surface areas of the silica particles are very high and the pore volume can be controlled by the concentration of the surfactant template in the reaction medium. Particle size may be adjusted by changing the volume of the base (e.g. NH OH) in the reaction medium.
• known pore expansion methods may be employed with the particulate materials, for example post-synthesis hydrothermal treatments and/or the inclusion of pore swelling agents in the reaction medium to increase pore size. All N 2 isotherms displayed the typical Type 1 isotherm with H4 hysteresis typical to those obtained from MCM-41 type materials.

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