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    • 专利摘要:
    Functionalization of magnetic particles by nucleophilic substitution of organic halides. The present invention develops a method for the functionalization of magnetic particles (sizes between 0.001-100 μm) such as for example: magnetite particles fe3 o4, or maghemite γ -fe2 o3, by nucleophilic substitution of halogenated derivatives. These derivatives are organic compounds that contain one or more halogens in their molecule. Some examples of organic halides capable of reacting with the magnetic particles are epichlorohydrin, triazine chloride, chloride and cyanogen bromide, tosyl chloride or other organic mono/di/poly halides capable of reacting with oh groups. By applying this method the particles are modified with reactive groups, such as epoxide, cyano, chloride or tosyl groups that allow to covalently bind biological molecules such as proteins, enzymes, dna, rna and antibodies. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2540026A1
    申请号:ES201301197
    申请日:2013-12-18
    公开日:2015-07-07
    发明作者:Francisco GARCÍA CARMONA；Samanta HERNÁNDEZ GARCÍA；María Inmaculada GARCÍA GARCÍA
    申请人:Universidad de Murcia；
    IPC主号:
    专利说明:

    Functionalization of magnetic particles by nucleophilic substitution of organic halides.
    Technical sector
    The present invention is framed within the field of new materials, and in particular within particle systems with magnetic properties. Specifically, it is aimed at systems comprising magnetic particles that are functionalized for their best and highest reactivity, to increase their stability and dispersion in solvents, respecting their size and their initial magnetic properties, and to procedures for obtaining them and their applications.
    State of the art
    Magnetic particles are applied in many areas in the industry, due to their advantages over other materials. They are applied in the manufacture of structural materials, such as ceramics and composites, to improve their mechanical performance. They are also used in magnetic printing, magnetic inks, sealing in vacuum systems, damping systems, speakers, magnetic sensors, actuators, catalysis, metal recovery and water purification, inductors and antennas. The particles are presented in the form of films, powder, dispersed in fluids or forming aerosols.
    One of the first applications of magnetic particles occurred in the field of biotechnology in the 1970s, using these particles as enzyme transporters, in processes of separation, purification and analysis of proteins, in biocatalysis and bioprocesses (Magnogel, Dynabeads and Stapor). Already in the 80s they began to be used in biomedicine as contrast agents in magnetic resonance imaging (MRI). Recently, a wide variety of utilities such as targeted drug administration have been described,
    immunoassays, molecular biology, nucleic acid purification (DNA, RNA),
    cell separation, hyperthermia therapy, and others.
    The industrial applications of the magnetic particles, indicated above, are based on their high specific surface area, their ability to cross biological barriers, ion adsorption capacity and, mainly, on their exclusive magnetic, optical and electrical properties.
    Different suspensions of these magnetic particles have been developed with organic and inorganic coatings with technological and biomedical applications [Laurent, S.Chem. Rev. 2008, 108, 2064]. The first requirement in the manufacture of these suspensions is to achieve their stability. A second point is the incorporation of one or several functionalities on the surface of the particles. To achieve both, it is usual to coat the particles with an organic or inorganic material that acts as a protection for the particle, improves its stability, prevents oxidation and allows functional groups to be incorporated on the surface of the organic or inorganic coating material. There are several strategies for coating or stabilizing particles, which can be classified according to the type of compound used in the coating or according to the stabilization method:
    1) Stabilization by electrostatic interaction: It is the first strategy that was developed to stabilize the particles in solvent medium; The particles are surrounded by low molecular weight compounds with groups capable of interacting with the surface of the particle bound to residues with affinity for the particle and for the solvent, such as surfactants, organic and inorganic acids (citric, aspartic, glutamic, oleic) and other types of molecules such as dopamine. The first patents that were developed at NASA in the 60s, added oleic acid to the particles [US3215572, US2971916], to stabilize them in organic solvents: The acid molecules are placed with the carboxyl group oriented towards the surface of the particle leaving the aliphatic chain towards the organic solvent medium achieving the stabilization of the particle. In patent W003 / 016217, metal nanoparticles and in particular metal oxides are coated with phosphoric acid, phosphonic acid or phosphine derivatives. However, it is more common to use amphiphilic molecules as a coating that can be arranged in the form of single or double layers, such as [Shen et al. Langmuir, 2000, 16, 9907] although in this case the suspensions are only stable with a pH greater than 7.4. This technology respects the particle size but electrostatic interactions are weak and easily replaceable.
    2) Polymeric coatings. In this technique the coating is done well by combining the magnetic particles with polymers soluble in liquid medium, and previously synthesized, which contain functional groups capable of interacting (hydrophobic, electrostatic interactions, Van der Waals forces) with the surface of the particles. so that these are encapsulated inside the polymer, either by adsorption of monomers or polymerization initiators and subsequent polymerization in situ, usually within micellar systems. Polymers widely used in magnetic particle coating are dextran [US4452773], proteins [US2010 / 0029902], alginates and synthetic polymers such as polystyrenes, functionalized, polypyrrole, phenolic polymers, carboxylic acid polymers [W02005 / 112758], block copolymers [Sohnet to the. J. Appl. Polym Sci. 2004, 91, 3549], polyethyleneimines [W02009 / 135937] and others. One of the preferred techniques for increasing the stability of the coating consists in the crosslinking of the polymer chains [W02003 / 005029]. Methods for coating nanoparticles with an organic double layer have also been described in which the union between the two layers is carried out by means of amide bonds [US2008 / 0226895]. The functionalization can be carried out by physical absorption of a second polymer as in [US2003 / 185757], in a first polymer, carboxydextran, is used as a stabilizer and a second polymer, carboxydextranofunctionalized with enzymes, is used to add functionality. A procedure that allows biocompatible coating and nanoparticle functionalization consists in the use of barnase and barstar proteins, but its high cost may limit its application [Nikitin et al. Proc. Nat. Acad. Sci. USA 2010 (/doi/10.1073/pnas.1001142107)]. Methods of coating nanoparticles with polymers in aerosols [US2009 / 0252965] and in supercritical fluids [W02004 / 091571] have also been described. Polymeric coatings have the advantage of forming a solid or spongy shell on the surface of the magnetic particle, they are stable, functionalizable coatings, but they have the disadvantage that in most cases they magnify the particle size and due to the shell solid polymerization the magnetization decreases by shielding it.
    3) Silicon coatings. It is the most used technique, normally it is done in two different ways:
    a) Making use of organosilane precursors such as tetraethoxysilane; it consists of the adsorption of these compounds on the surface of the particle, their subsequent hydrolysis and condensation to form silicon shells, which in turn can be activated by reaction with functionalized alkoxysilane compounds [W02008 / 058678]. [US6514481, Prasad] describes silica-coated iron oxide nanoparticles to which a peptide is attached by means of a spacer and in patent application W02006 / 055447 a similar method for performing organo-silica coatings functionalized with oligonucleotides is described. . A system widely used in the coating of particles that consists in carrying out the hydrolysis of organosilane precursors within micelles [US2007 / 110816].
    b) By deposition on the surface of the silicon oxide particle and its subsequent condensation, from sodium metasilicate [US 2010/0063263], [US 8 323 899].
    Like polymeric coatings, silicon coatings have the advantage of forming a solid or spongy shell on the surface of the magnetic particle and are easily functionalizable although not as stable as polymeric ones, since they easily degrade in very acidic or very alkaline, they also have the disadvantage of size magnification and shielding of magnetization.
    4) On the other hand, mechanical methods for coating nanoparticles [W02008 / 074087] have also been described, although the control of the structure and thickness of the coating that allow these techniques is insufficient for some applications.
    The functionalization of the particles, that is, the anchoring of active agents, is performed on the surface of the stabilizing layer once the particle is coated. This strategy entails some drawbacks such as having to include purification or separation processes and limitations in the reaction conditions to avoid aggregation or deterioration of the stabilizer layer or the functionality itself to be added. Functionalization can be carried out by electrostatic adsorption [Wang et al. IEEE Trans. Nanotech 2009, 8, 142] but it is preferable to perform it by covalent bonds through a spacer that connects the surface of the particle coating with the active agent [Georgelin et al. J Nanopart Res 2010, 12, 675]. A versatile procedure is based on the specific binding between streptavidin and biotin, although its cost is high and requires the use of biotinylated active agents.
    Description of the invention Brief Description of the Invention
    The present invention relates to a system of magnetic particles that are functionalized by reacting the hydroxyl groups on the surface of the magnetite with RX organic halides having a CX bond, where X is a halogen (F, CI, Sr, 1), leaving the organic halide residue covalently bonded to the surface of the magnetic particle, as shown in the scheme depicted in Figure 1.
    In accordance with the present invention, organic residues covalently bonded to the magnetic particle protect it from environmental agents, improve its stability and dispersion in solvents, respecting its size and initial magnetic properties. In addition, the organic residue is able to continue reacting with molecules of interest.
    The procedure proposed in this invention offers several advantages over existing procedures and represents a great advance in the state of the art.
    The present invention covalently bonds the functional groups to the surface of the magnetic particle; The covalent bond ensures a virtually unbreakable stable bond, unlike existing procedures that link the functional groups through electrostatic or hydrophobic interactions that are sensitive to breaking when changing the conditions of the environment.
    Organic waste improves the stability and dispersion of organic particles in solvent medium, in addition to protecting them from external environmental agents, without implying a large change in their size or a decrease in their magnetic capacity. In existing techniques the stability and protection of the particles are achieved by coatings of silica or organic polymers. These coating techniques are the most used although they have certain disadvantages compared to that described in this invention, such as:
    • The particle size is magnified and it can go from a particle of a few nanometers to particles of more than one hundred nanometers, to micrometric particles.
    • The coating is solid and inert, which causes a decrease in magnetization by shielding it.
    • If particles of uniform size are desired the process is complicated, since it is necessary to work with emulsion systems or micelles, which makes it less scalable and more expensive.
    The particles of the invention may possess organic residues covalently bonded to the surface, containing functional groups according to the R of the organic halide used, such as epoxide, halide, tosyl, cyano, amino, carboxyl
    or carboxylate capable of continuing to react to bind molecules with physical, chemical or biological and medical interest to the magnetic particle. In the coating techniques, the functional groups are incorporated into the coating once it is formed, which adds to the process more reaction, washing and purification phases, which are avoided in the present invention.
    Therefore, the process of the invention not only guarantees a covalent bond between the functional groups and the magnetic particles, but also simplifies the existing processes of functionalization, stabilization and protection of the magnetic particles.
    Another feature of the invention is the application of covalently functionalized magnetic particles with organic halides for magnetic cooling, magnetic printing, magnetic inks, rotor lubrication, electrical transformers, low noise solenoids, switches, magnetoreological fluids, magnetically active fibers, reinforced polymer composites, sealed in vacuum systems, damping systems, loudspeakers, magnetic sensors, actuators, catalysis, metal recovery and water purification, inductors and antennas in communication technology, magnetic shields and microwave absorption, polymer curing , hardening of epoxy resins, contact-free heating, preparation of pigments, paints and dyes, cosmetic uses and biotechnological, veterinary and medical applications. Detailed description of the invention
    The present invention relates to a process for the covalent functionalization of magnetic particles by a nucleophilic substitution reaction in which the hydroxyl groups on the surface of the magnetic particle react with organic halides, the organic residue of the halide being attached
    covalently to the particle, as shown in the scheme represented in the
    Figure 1.
    The procedure is based on the surprising ability of the surface hydroxyl groups of the magnetic particles to act as an organic hydroxyl group (alcohol) and give nucleophilic substitution reactions; The reaction comprises two stages:
    a) The nucleophilic attack of the hydroxyl group on the organic halide, and the displacement of the halide.
    b) The formation of the covalent bond of the organic residue and the magnetic particle.
    In the present invention the term nucleophilic substitution encompasses the concepts nucleophilic substitution, nucleophilic attack, SN 1 substitution reaction, SN1 type reaction, SN1 reaction and nucleophilic displacement reaction.
    Organic halide is understood to mean compounds that have an organic residue and one or more halide groups capable of giving rise to the nucleophilic substitution reaction.
    Halide is understood in the present invention to the elements included in group 17 of the periodic table.
    In the invention, organic halides containing, chlorine, bromine, iodine or fluorine or combinations thereof, especially organic chlorides and bromides, are preferred.
    Organic residue, in the present invention, is understood as the organic molecule that is covalently bound to the magnetic particle by reacting one or more of its halides by nucleophilic substitution.
    The chemical bond in the present invention is referred to as the covalent bondwhich two or more atoms share one or more electrons of the last level,forming a molecular orbital, to achieve stability.The organic residues are preferably selected from epoxide, halide,tosyl, cyano, thiol, sulfonyl, hydroxyl, carboxyl or carboxylate, amino, chainssaturated or unsaturated branched or cyclic linear aliphatics, chainsaromatic and combinations of them.
    As examples of well-known organic halides used in chemistryindustrial are: tosyl chloride, fluoride and triazine chloride, chloride andcyanogen bromide, epichlorohydrin, bromopentadione, acid 2-4dichlorophenoxyacetic, 1-4 dibromobutane, 1-6 dibromohexane, chlorobenzene,Bromobenzeno, among others.
    Magnetic particles are understood in the present invention as particles ofmetal, metal oxide, mixture of metal oxides, metal alloys or mixtureof them that have magnetic properties. In the present invention,prefer iron oxide magnetic particles, especially particles ofmagnetite (Fe304) or maghemite (yFe203).
    The present invention is understood to mean particles with magnetic propertiesto particles that being or not being intrinsically magnetic are attractedtowards a magnetic field or force when exposed to it.
    Preferably the particles have magnetic properties of the typesuperparamagnetic or ferromagnetic.
    Preferably, magnetic particles of sizes are used in the inventionbetween O.001-100IJm.
    Another feature of the invention is that the process to give rise to the particleMagnetic is selected from co-precipitation, micro-emulsion, decompositionthermal, solvo-thermal route, sono-chemical route, microwave-assisted process,Laux process, iron oxide mineral treatment, laser pyrolysis,
    - ~ -
    vapor deposition, arc discharge, gas phase synthesis, phase synthesis
    solid, chemical reduction or others.
    Preferably, the process to give rise to the magnetic particle is coprecipitation.
    Another feature of the invention is that the nucleophilic substitution reaction occurs in solvent medium; The solvent is chosen from water, THF, DMSO, dichloromethane, hexane, acetone, ethanol, methanol, isopropanol, chloroform, ionic liquids, supercritical fluids or any combination thereof.
    The pH and temperature conditions of the solvent medium where the reaction occurs are suitable for the nucleophilic substitution reaction to progress.
    Another significant feature of the invention is that the organic residue covalently bonded to the magnetic particle protects it from environmental agents, improves its stability and dispersion in solvents without thereby altering its size or magnetic capacity.
    The covalently functionalized magnetic particles of the invention can be stored dispersed in a solvent or dried as a powder or composite.
    Preferably the solvents in which the covalently functionalized magnetic particle of the invention is dispersed are selected from water, THF, DMSO, dichloromethane, hexane, acetone, ethanol, methanol, isopropanol, chloroform, ionic liquids, supercritical fluids or any combination thereof.
    Another very significant feature of the invention is that the organic residue of the covalently functionalized magnetic particles is active and can continue to react.
    Preferably, the functional residue bound to the magnetic particles is reacted with organic or inorganic molecules with physical, chemical or biological and medical interest.
    Preferably the compound with physical interest is selected from coloring or fluorescent compounds, such as rhodamine, fluorescein, Cibacron Blue, among others.
    Preferably the compound with chemical interest is selected from drugs, catalysts, absorbents, polymerization precursors or any combination thereof, such as noble metals with catalytic capacity, polyamines, polyacids, among others.
    Preferably the compound with biological and medical interest is selected from proteins, chaperones, enzymes, antibodies, single chain nucleic acids
    or double, monosaccharides, polysaccharides, glycoproteins, fatty acids, terpenes, steroids, lipoproteins, hormones, vitamins, metabolites, oligonucleotides or any combination thereof.
    Another feature of the invention is the use of covalently functional magnetic particles hoisted in industrial applications belonging, for example, to the following areas: magnetic cooling, magnetic printing, magnetic inks, rotor lubrication, electrical transformers, low noise solenoids , switches, magnetoreological fluids, magnetically active fibers, reinforced polymer composites, sealing in vacuum systems, damping systems, speakers, magnetic sensors, actuators, catalysis, metal recovery and water purification, inductors and antennas in communication technology, magnetic shields and microwave absorption, polymer curing, hardening of epoxy resins, contact-free heating, preparation of pigments, paints and dyes, cosmetic uses and biotechnological, veterinary and medical applications.
    Among the industrial applications based on the magnetothermal properties of the magnetic particles, the hyperthermic use of magnetic particles in polymer curing, hardening of epoxy resins, contact-free heating and biomedical applications can be mentioned without limiting them.
    As previously mentioned, the magnetic particles of the invention can anchor biologically active molecules, which facilitates their application to the biotechnological field, in any of the specific areas, for example, agrifood, environment, chemical synthesis by enzymes, veterinary and medicine A particular embodiment of the invention is the use of the magnetic particles of the invention in the field of diagnosis and therapy of human or animal diseases.
    In this sense, the use of magnetic particles in diagnosis and clinical treatment is a very significant leap in these fields, since, for example, a small amount of magnetic particles can be resuspended in large volumes of sample to be analyzed and recovered. subsequently by applying an external magnetic field. Thus, it is possible to purify and / or pre-concentrate very minor and diluted quantities of a target biological material that specifically hybridizes with an organic biomolecule that acts immobilized on said particles, thereby greatly reducing the detection limit and exponentially improve the chances of a correct clinical diagnosis. This type of systems allows to determine the presence of specific biological material of interest in situations where an early detection of it can be critical, to avoid the damaging effects of the existence of the species or strains of organisms that have said characteristic sequences. This fact has great application in human and veterinary biomedicine, among others in the following areas: i) detection of viral, bacterial, fungal or protozoan pathogens; ii) characterization of mutations or genetic polymorphisms (SNPs) in said agents that can make them resistant to drugs or facilitate their immunity to vaccines; iii) characterization of mutations or SNPs in human or animal genes related to or prone to diseases; iv) detection of markers of human diseases as specific tumors. Likewise, this detection potential has important applications in food and environmental control, in relation to aspects such as: i) detection of specific microorganisms, pathogens or contaminants; ii) detection of the presence of genetically manipulated organisms (GMOs) or transgenics, and can be quantified if their presence is above the allowed limits.
    On the other hand, magnetic particles can also be used in human therapies where it is necessary to destroy cells in patients, for example, cancer cells, immune system cells in autoimmune processes, pathogenic microorganisms, etc. The particles can have biomolecules anchored, for example an antibody, that specifically recognizing a specific tumor marker, for example, of breast cancer, would allow the particle to be transported to these target cells, which would transfer said particle to its interior and where thanks to the Hyperthermia property could destroy the target cell.
    Other medical uses of magnetic particles are also included, such as: contrast for nuclear magnetic resonance imaging (MRI), such as drug transporter, magnetofection (insertion of nucleic acids into cells), for tissue repair, among others.
    Brief description of the content of the figures
    FIGURE 1. Schematic representation of the nucleophilic substitution reaction by which magnetic particles are functionalized with organic halides.
    Description of a preferred embodiment of the invention
    EXAMPLE 1. Preparation of magnetic particles by coprecipitation.
    For the preparation of magnetic particles the method of Kim et al (Kim et al, 2001. J. Magn. Magn. Mater. 225, 30-36) is used, with small variations,
    13.51 gr FeCI3 are dissolved in 25 ml of distilled water, 6.95 g of FeS04 are dissolved in 25 ml 0.5 M of HCI, the solutions are mixed and dripping over 150 ml 5 M of NaOH, a black precipitate is formed with magnetic properties; While the iron salts are incorporated into the NaOH solution, it is kept under constant stirring (1500-2000 rpm). After the reaction, the mixture is activated to neutral pH with 5 M HCI, once the black precipitate is neutralized, it is washed with 100 ml of water three times.
    EXAMPLE 2. Functionalization of magnetic particles with oxirane groups by reaction with epichlorohydrin.
    5 g of magnetic particles obtained according to example 1 are dissolved in 50 ml of water and sonicated for 10 minutes. After that time, 12 ml of epichlorohydrin dissolved in 8 ml of DMSO is added to the suspension, the mixture is sonicated again for another 10 minutes, the pH is adjusted to 12 with 0.1 MY NaOH and the mixture is left under moderate stirring for 12 hours at room temperature. After 12 hours, the functionalized particles are washed with acetone, ethanol and water to remove the remains of DMSO. They are obtained approximately
    2.21 mmol Epoxide / g particles.
    EXAMPLE 3. Functionalization of magnetic particles with reactive chlorides by reaction with triazine chloride.
    5 g of magnetic particles obtained according to example 1 are dissolved in 50 ml of water and sonicated for 10 minutes. After that time, 5 g of triazine chloride dissolved in 50 ml of acetone is added to the suspension of particles, the mixture is sonicated again for another 10 minutes, the pH is adjusted to 12 with 0.1 MY NaOH and the mixture is left under stirring. Moderate at 50 ° C 12 hours. The hoisted functional particles are washed with ethanol and water. Approximately 1 mmol reactive chlorines / g of particles are obtained.
    EXAMPLE 4. Covalent bonding to epoxy functionalized magnetic particles of a residue of biological interest: an enzyme.
    30 mg of the oxirane-functionalized magnetic particles of Example 2 are re-suspended in 2 ml of potassium phosphate buffer (50mM, pH 7), on the other hand 30 mg of Pseudomonas fluorence lipase are dissolved in 4 ml of potassium phosphate buffer ( 50mM, pH 7) to which 5001J1 of PEG 600 is added. The enzyme mixture is added to the particle suspension and allowed to react in a 30 ° C water bath for 6 hours. The support is washed once with ethanol and twice with potassium phosphate buffer (50mM, pH 7). The enzyme not bound to the support is quantified by the Bradford method, obtaining a loading capacity of 997 mg of enzyme per gram of support. The relative activity of the immobilized enzyme for the hydrolysis of p-nitrophenyl acetate is 73.63%.
    EXAMPLE 5. Covalent bonding to the functionalized magnetic particles with reactive chlorides of a residue with chemical interest: a diamine.
    100 mg of triazine chlorinated functional particles of Example 3 are re-suspended in 1 ml of distilled water, 1 ml of ethylenediamine is added to the particle suspension and the mixture is incubated for 12 hours with moderate stirring at 50 ° C . The particles are washed with ethanol and with water and the amino groups on the surface of the particle are titrated with the naphthoquinone method, obtaining 885 IJmol amines / g particles.
    权利要求:
    Claims (27)
    [1]
    1. Method for functionalizing magnetic particles by nucleophilic substitution reactions between the hydroxyl groups on the surface of the magnetic particle and organic halides, comprising the following steps:
    to. the reaction of at least one hydroxyl group on the surface of the magnetic particle with an organic halide molecule, the molar ratio being between the hydroxyl groups of the magnetic particles and the organic halide in the range of 1-1000, in a solvent medium Y
    b. the formation of a covalent bond between the organic halide residue and the oxygen of the surface of the magnetic particle.
    [2]
    2. Method according to claim 1 characterized in that the particle is selected from a metal, a metal oxide, a metal alloy or a combination of metal oxides.
    [3]
    3. Process according to claim 2 characterized in that the metal oxide is an iron oxide.
    [4]
    Four. Method according to claim 3 characterized in that the iron oxide is preferably magnetite (Fe304) or maghemite (y-Fe203).
    [5]
    5. Method according to claims 1-4 characterized in that the particle size is selected in a range between 0.001-100 ~ m.
    [6]
    6. Method according to claims 1-5 characterized in that the metal particle has magnetic capacity.
    [7]
    7. Method according to claims 1-6, characterized in that the type of magnetization of the magnetic particle is superparamagnetism or ferromagnetism.
    [8]
    8. Method according to claims 1-7, characterized in that the magnetic particle is obtained by co-precipitation, microemulsion, thermal decomposition, solvothermal route, sonochemical route, microwave-assisted process, Laux process, iron oxide mineral treatment, laser pyrolysis, deposition steam, arc discharge, gas phase synthesis, solid phase synthesis, chemical reduction or others.
    [9]
    9. Method according to claim 8, characterized in that the process of obtaining the magnetic particles is preferably co-precipitation.
    [10]
    10. Process according to claims 1-9, characterized in that the organic halide is a molecule that contains one or more halide groups, capable of reacting with hydroxyl groups by nucleophilic substitution, and also contains an organic residue that is covalently bound to the magnetic particle once finished. the reaction.
    [11]
    eleven. Method according to claims 1-10, characterized in that the halide is selected from chlorine, bromine, iodine, fluorine or combinations thereof, preferably chlorine or bromine.
    [12]
    12. Method according to claims 1-11, characterized in that the organic halide residue is selected with epoxy, halide, tosyl, cyano, thiol, sulfonyl, hydroxyl, carboxy or carboxylate, amino, branched or cyclic linear saturated or unsaturated aliphatic chains, chains aromatic and combinations of them.
    [13]
    13. Method according to claims 1-12 characterized in that the organic halide residue is covalently bound to the magnetic particle and functionalizes it.
    [14]
    14. Process according to claims 1-13 characterized in that the organic residue of the magnetic particle protects it from environmental agents and prevents its oxidation.
    [15]
    15.Procedure according to claims 1-14 characterized in that the
    Organic residue of the magnetic particle, improves its dispersion and stability in solvents.
    [16]
    16. Process according to claim 15 characterized in that the solvent in which the functionalized magnetic particles are dispersed is selected from water, THF, DMSO, dichloromethane, hexane, acetone, ethanol, methanol, isopropanol, chloroform, ionic liquids, supercritical fluids or any of their combinations
    [17]
    17. Method according to claims 1-14 characterized in that the covalently functional magnetic particles hoisted are dry, in the form of powder or composite.
    [18]
    18. Procedure according to claims 1-17 characterized in that the nucleophilic substitution reaction between the magnetic particles and the organic halides is carried out in solvent medium.
    [19]
    19. Method according to claim 18, characterized in that the solvent medium for the nucleophilic substitution reaction is selected from water, THF, DMSO, dichloromethane, hexane, acetone, ethanol, methanol, isopropanol, chloroform, ionic liquids, supercritical fluids or any combination thereof.
    [20]
    twenty. Method according to claim 17 characterized in that the solvent medium for the nucleophilic substitution reaction is maintained at a temperature and pH suitable for the reaction to proceed.
    [21]
    twenty-one. Method according to claim 13 characterized in that the organic residue that functionalizes the magnetic particle is active to continue reacting.
    [22]
    22 Method according to claim 21 characterized in that the organic residue that functionalizes the magnetic particle is reacted with a
    organic or inorganic compound with physical, chemical, biological and medical interest, which is attached to the magnetic particle by covalent bond.
    [23]
    2. 3. Method according to claim 22, characterized in that the compound with physical interest is selected from dye or fluorescent compounds.
    [24]
    24. Method according to claim 22, characterized in that the compound with chemical interest is selected from drugs, catalysts, absorbents, polymerization precursors or any combination thereof.
    [25]
    25. Method according to claim 22, characterized in that the compound with biological and medical interest is selected from proteins, chaperones, enzymes, antibodies, single or double chain nucleic acids, monosaccharides, polysaccharides, glycoproteins, fatty acids, terpenes, steroids, lipoproteins, hormones, vitamins, metabolites, oligonucleotides or any combination thereof.
    [26]
    26. Magnetic particles characterized in that they are covalently functionalized by reacting their surface hydroxyl groups with organic halides by the nucleophilic substitution reaction, by the method described in any of claims 1-25.
    [27]
    27. Application of the functionalized magnetic particles described according to claim 26 for magnetic cooling, magnetic printing, magnetic inks, lubrication of rotors, electrical transformers, low noise solenoids, switches, magnetoreological fluids, magnetically active fibers, reinforced polymer composites, sealed in vacuum systems, damping systems, loudspeakers, magnetic sensors, actuators, catalysis, metal recovery and water purification, inductors and antennas in communication technology, magnetic shields and microwave absorption, polymer curing, resin hardening epoxy, contact-free heating, preparation of pigments, paints and dyes, cosmetic uses and biotechnological, biological or medical applications and capture separation and purification of biological, veterinary and medical molecules.
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    公开号 | 公开日
    WO2015092106A1|2015-06-25|
    ES2540026B1|2016-04-13|
    引用文献:
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    CN106733177B|2016-12-24|2018-08-24|浙江师范大学|A kind of ore separation device based on magnetic rheology effect|
    CN106645485A|2016-12-27|2017-05-10|广州市食品检验所|Method for determining content of anionic synthetic pigment in drinks by aminized magnetic nano material|
    CN113135593B|2021-05-25|2022-01-28|西南科技大学|Method for preparing high-purity nano zirconium dioxide by hydrothermal-assisted sol-gel method|
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    PCT/ES2014/070935| WO2015092106A1|2013-12-18|2014-12-18|Functionalisation of magnetic particles by means of nucleophilic substitution of organic halides|
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