(19)
(11)EP 3 357 929 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.06.2020 Bulletin 2020/25

(21)Application number: 17305119.4

(22)Date of filing:  02.02.2017
(51)International Patent Classification (IPC): 
C07F 15/02(2006.01)

(54)

LOW TEMPERATURE PROCESS FOR THE SYNTHESIS OF MOF CARBOXYLATE NANOPARTICLES

NIEDERTEMPERATURVERFAHREN ZUR HERSTELLUNG VON MOF-CARBOXYLAT-NANOPARTIKELN

PROCÉDÉ DE PRÉPARATION DE MOF-CARBOXYLATE-NANOPARTICULES À BASSE TEMPÉRATURE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(43)Date of publication of application:
08.08.2018 Bulletin 2018/32

(73)Proprietors:
  • Centre National de la Recherche Scientifique
    75016 Paris (FR)
  • Université de Versailles Saint-Quentin-en-Yvelines
    78035 Versailles Cédex (FR)

(72)Inventors:
  • PANCHAL, Monik
    Ribbleton, Preston PR2 6BN (GB)
  • NOUAR, Farid
    78210 SAINT-CYR-L'ÉCOLE (FR)
  • SERRE, Christian
    78730 PLAISIR (FR)
  • BENZAQUI, Marvin
    75013 PARIS (FR)
  • SENE, Saad
    78140 VÉLIZY-VILLACOUBLAY (FR)
  • STEUNOU, Nathalie
    95830 FRÉMÉCOURT (FR)
  • GIMÉNEZ MARQUÉS, Monica
    94110 ARCUEIL (FR)

(74)Representative: Novagraaf Technologies 
Bâtiment O2 2, rue Sarah Bernhardt CS90017
92665 Asnières-sur-Seine Cedex
92665 Asnières-sur-Seine Cedex (FR)


(56)References cited: : 
  
  • FUMIN ZHANG: "Facile synthesis of MIL-100(Fe) under HF-free conditions and its application in the acetalization of aldehydes with diols", CHEMICAL ENGINEERING JOURNAL, vol. 259, 8 August 2014 (2014-08-08), pages 183-190, XP55363246,
  • JING SHI ET AL: "Synthesis of MIL-100(Fe) at Low Temperature and Atmospheric Pressure", JOURNAL OF CHEMISTRY, vol. 2013, 1 January 2013 (2013-01-01), pages 1-4, XP55363243, US ISSN: 2090-9063, DOI: 10.1155/2013/792827
  • MANUEL SÁNCHEZ-SÁNCHEZ ET AL: "Synthesis of metal-organic frameworks in water at room temperature: salts as linker sources", GREEN CHEMISTRY, vol. 17, no. 3, 1 January 2015 (2015-01-01), pages 1500-1509, XP55363386, GB ISSN: 1463-9262, DOI: 10.1039/C4GC01861C
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FIELD OF THE INVENTION



[0001] The present invention relates to low temperature process for preparing nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate materials with low polydispersity index, and uses thereof, particularly as catalyst support for carrying out heterogeneously catalyzed chemical reactions, or as gas storage/separation/purification material, or as matrix for encapsulating active principles (medicine, cosmetics).

BACKGROUND OF THE INVENTION



[0002] Metallo-organic lattices or metal-organic frameworks (MOFs) are porous coordination polymers, having an inorganic-organic hybrid framework that comprises metal ions and organic ligands coordinated to the metal ions. These materials are organized into one-, two- or three-dimensional lattices, in which the metallic species are joined together periodically by spacer ligands. The framework of these solids has both inorganic parts and organic parts, the cavities of which may be occupied by water molecules or by organic molecules that are easy to extract without deterioration of the backbone.
Another distinctive feature of certain hybrid solids is the existence of a flexibility of the lattice, greater than that encountered for purely inorganic phases. This is generally due to the use of flexible organic ligands (aliphatic chains), or to the shrinkage of the pores linked to the departure of molecules encapsulated within the pores.
These materials exhibit a crystalline structure, are usually porous and offer many potential industrial applications such as gas storage, adsorption of liquids, separation of liquids or gases, catalysis, controlled release of medicaments, etc.

[0003] However, MOF nanoparticles are difficult to synthesize, and especially nanoparticles smaller than 100 nm, given their nature to aggregate readily and given the tendency of these materials to organize in crystal lattices of large size (microns). In addition, current synthetic processes do not overcome or sufficiently address problems of non-uniformity of particle size (high polydispersity), which are unfavorable for certain applications; nor are they adapted for materials that are sensitive/fragile to the reaction conditions of the conventional processes for preparing MOF materials.
Therefore, there remains a need for the development of new synthetic processes which allow the preparation of MOF nanoparticles with low polydispersity index, in particular synthetic processes under mild conditions.

BRIEF DESCRIPTION OF THE DRAWINGS



[0004] 

Figure 1 shows powder X-ray diffraction (PXRD) patterns of samples of MIL-100(Fe) nanoparticles obtained in Example 1, taken from the reaction mixture after various reaction times (from bottom to top: 1h, 2h, 4h, 6h, 24h and 48h).

Figures 2A, 2B, 2C show scanning electron microscopy (SEM) images of MIL-100(Fe) nanoparticles obtained in Example 1.

Figure 3 shows a histogram representing the particle distribution of MIL-100(Fe) nanoparticles obtained in Example 1, using Image J software. The average particle size is 84 nm ± 13.

Figure 4 shows three Dynamic Light Scattering (DLS) measurements conducted on MIL-100(Fe) nanoparticles obtained in Example 1, with an average hydrodynamic diameter of the principal peaks of 242 nm ± 72 and a polydispersibilty index of 0.201.p

Figure 5 shows the Thermal gravimetric analysis plot of MIL-100(Fe) nanoparticles obtained in Example 1, conducted under oxygen atmosphere (heating rate of 5°C per minute).

Figure 6 shows N2 adsorption (dots) and desorption (diamonds) isotherms obtained from MIL-100(Fe) nanoparticles obtained in Example 1 (Evacuated under primary vacuum at 150 °C for 15h). The Surface area obtained is 1330 m2g-1 (evaluated using the BET model).

Figure 7 shows powder X-ray diffraction (PXRD) patterns of samples of MIL-100(Fe) nanoparticles obtained in Example 2, taken from the reaction mixture after various reaction times (1h, 2h, 4h, 6h, 24h and 48h).

Figures 8A, 8B show scanning electron microscopy (SEM) images of MIL-100(Fe) nanoparticles obtained in Example 2.

Figure 9 shows a histogram representing the particle distribution of MIL-100(Fe) nanoparticles obtained in Example 2, using Image J software. The average particle size is 92 nm ± 39.

Figure 10 shows three DLS measurements conducted on MIL-100(Fe) nanoparticles obtained in Example 2, with an average hydrodynamic diameter of the principal peaks of 162 nm ± 57 and a polydispersibilty index of 0.269.

Figure 11 shows the Thermal gravimetric analysis plot of MIL-100(Fe) nanoparticles obtained in Example 2, conducted under oxygen atmosphere (heating rate of 5°C per minute).

Figure 12 shows N2 adsorption (dots) and desorption (diamonds) isotherms obtained from MIL-100(Fe) nanoparticles obtained in Example 2 (Evacuated under primary vacuum at 150 °C for 15h). The Surface area obtained is 1220 m2g-1 (evaluated using the BET model).

Figure 13 shows powder X-ray diffraction (PXRD) patterns of samples of MIL-100(Fe) nanoparticles obtained in comparative Example 3, taken from the reaction mixture after various reaction times (1h, 2h, 4h, 6h, 24h and 48h).

Figure 14 shows a scanning electron microscopy (SEM) image of MIL-100(Fe) nanoparticles obtained in comparative Example 3.

Figure 15 shows a histogram representing the particle distribution of MIL-100(Fe) nanoparticles obtained in comparative Example 3, using Image J software. The average particle size is 66 nm ± 16.

Figure 16 shows three DLS measurements conducted on MIL-100(Fe) nanoparticles obtained in comparative Example 3, with an average hydrodynamic diameter of the principal peaks of 155 nm ± 80 (DLS results show the presence of two populations, hence hydrodynamic diameter provided is the average) and a polydispersibilty index of 0.346.

Figure 17 shows the thermal gravimetric analysis plot of MIL-100(Fe) nanoparticles obtained in comparative Example 3, conducted under oxygen atmosphere (heating rate of 5°C per minute).

Figure 18 shows N2 adsorption (dots) and desorption (diamonds) isotherms obtained from MIL-100(Fe) nanoparticles obtained in comparative Example 3 (Evacuated under primary vacuum at 150 °C for 15h). The Surface area obtained is 1314 m2g-1 (evaluated using the BET model).

Figure 19 shows a graph representing the polydispersibility index values of MIL-100(Fe) nanoparticles obtained at room temperature, 60°C, and under reflux, respectively.

Figure 20 shows powder X-ray diffraction (PXRD) patterns of γ-Fe2O3@MIL-100(Fe) prepared according to Example 4, and as a comparison, a PXRD of MIL-100(Fe) and γ-Fe2O3. PXRD were collected in a Siemens D5000 diffractometer (θ-2θ) using Cu Kα radiation (λ=1.5418 Å).

Figures 21A-D show transmission electron microscopy (TEM) images of γ-Fe2O3@MIL-100(Fe) composites prepared according to Example 4. TEM observations were performed using a Zeiss EM902 Transmission Electron Microscope.

Figure 22 shows a histogram representing the particle size distribution of γ-Fe2O3@MIL-100(Fe) NPs prepared in Example 4 analysed by DLS measurements. DLS measurements were performed with a zetasizer nano ZS using a suspension sample at 0.1 g/L with a pH 3.

Figure 23 shows an FT-IR spectrum of γ-Fe2O3@MIL-100(Fe) NPs prepared in Example 4.

Figure 24 shows the thermal gravimetric analysis plot of γ-Fe2O3@MIL-100(Fe) NPs prepared in Example 4. TGA were performed on a Perkins Elmer SDA 6000 apparatus. Solids were heated up to 600°C with a heating rate of 2°C.min-1 in an oxygen atmosphere.

Figure 25 shows N2 adsorption (dots) and desorption (diamonds) isotherms of γ-Fe2O3@MIL-100(Fe) NPs prepared in Example 4 at 77 K (P0 = 1 atm). N2 sorption isotherms were obtained at 77 K using a Belsorp Mini (Bel, Japan). Prior to the analysis, approximately 40-60 mg of activated sample was evacuated for 3 h at 120°C under primary vacuum. Brunauer-Emmett-Teller (BET) surface and pore volume were estimated at a relative pressure lower than 0.25.

Figure 26 shows a) Mass magnetization cycles of γ-Fe2O3@MIL-100Fe composite of Example 4 at T = 300 K (dotted line) and Langevin fit (solid line) of the magnetization; b) Magnetic moments of γ-Fe2O3@MIL-100Fe composite of Example 4 measured under an applied magnetic field of 200 Oe after zero field cooling then field cooling. The magnetic moment was measured by a Quantum Design vibrating sample magnetometer (VSM).

Figure 27 shows powder X-ray diffraction (PXRD) patterns of MIL-100(Fe) nanoparticles prepared according to Example 1 (top) and MIL-100(Fe/Ru) nanoparticles prepared according to Example 5 (bottom) (sample 2) obtained at room temperature and after washing with EtOH.

Figure 28 shows FTIR spectra of MIL-100(Fe) nanoparticles prepared according to Example 1 (bottom spectrum) and MIL-100(Fe/Ru) nanoparticles prepared according to Example 5 (top spectrum) (sample 2) obtained at room temperature and after washing with EtOH.

Figure 29 shows N2 adsorption (empty squarres) and desorption (black squarres) isotherms of MIL-100(Fe/Ru) nanoparticles prepared according to Example 5 (sample 2) at 77 K. Activation was performed by outgassing at 150 °C for 3 h.

Figure 30 shows a powder X-ray diffraction (PXRD) pattern of the new Fe/BTeC MOF prepared according to Example 6 performed at RT (Copper source with Kα1, Kα2 and a small fraction of Kβ as indicated).

Figure 31 show scanning electron microscopy (SEM) images of the new Fe/BTeC MOF prepared according to Example 6, showing needle-like particles with length between 100 and 250 nm and height and with around 50 nm.

Figure 32 shows N2 adsorption of the new Fe/BTeC MOF prepared according to Example 6 performed at 77K showing a type I isotherm.

Figure 33 shows the thermal gravimetric analysis plot of the new Fe/BTeC MOF prepared according to Example 6, showing water loss from 25°C to 100°C and the degradation of the MOF from 250°C.

Figure 34 shows an FT-IR spectrum of the new Fe/BTeC MOF prepared according to Example 6, showing typical bands of Fe_COO- (1550cm-1) and also the pending free -COOH (highlighted by a circle on the figure).

Figure 35 shows temperature-dependent XRD of the new Fe/BTeC MOF prepared according to Example 6 performed at ambient temperature and pressure from 25°C to 400°C. Temperatures from top to bottom: 400°C, 300°C, 250°C, 200°C, 150°C, 100°C, 50°C, 25°C.

Figure 36 shows powder X-ray diffraction (PXRD) patterns of the new Fe/BTeC MOF prepared according to Example 6 before (top) and after (bottom) the hydrothermal stability test (72h in reflux H2O).

Figure 37 shows different MOF carboxylate phases obtained in the same conditions safe temperature; from top to bottom : RT, Hydrothermal and Reflux synthesis.


DEFINITIONS



[0005] To facilitate an understanding of the present invention, a number of terms and phrases are defined below:
As used herein other than the claims, the terms "a," "an," "the," and/or "said" means one or more. As used herein in the claim(s), when used in conjunction with the words "comprise," "comprises" and/or "comprising," the words "a," "an," "the," and/or "said" may mean one or more than one. As used herein and in the claims, the terms "having," "has," "is," "have," "including," "includes," and/or "include" has the same meaning as "comprising," "comprises," and "comprise." As used herein and in the claims "another" may mean at least a second or more. As used herein and in the claims, "about" refers to any inherent measurement error or a rounding of digits for a value (e.g., a measured value, calculated value such as a ratio), and thus the term "about" may be used with any value and/or range.

[0006] The phrase "a combination thereof" "a mixture thereof" and such like following a listing, the use of "and/or" as part of a listing, a listing in a table, the use of "etc" as part of a listing, the phrase "such as," and/or a listing within brackets with "e.g.," or i.e., refers to any combination (e.g., any sub-set) of a set of listed components, and combinations and/or mixtures of related species and/or embodiments described herein though not directly placed in such a listing are also contemplated. Such related and/or like genera(s), sub-genera(s), specie(s), and/or embodiment(s) described herein are contemplated both in the form of an individual component that may be claimed, as well as a mixture and/or a combination that may be described in the claims as "at least one selected from," "a mixture thereof" and/or "a combination thereof."

[0007] In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulae of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds.

[0008] As used herein, the term "alkyl", refers to straight and branched alkyl groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms. Illustrative alkyl groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.

[0009] An analogous convention is used for unsaturated counterparts to alkyl groups. Namely, a C2-12alkenyl group as used herein refers to a hydrocarbon group formed by placing at least one carbon double bond in the middle or at the terminal of the C2-12alkyl group. Examples thereof are an ethenyl group, a propenyl group, or a butenyl group. A C2-12alkynyl group as used herein refers to a hydrocarbon group formed by placing at least one carbon triple bond in the middle or at the terminal of the C2-12alkyl group. Examples thereof are an ethynyl group, a propynyl group, or a butynyl group.

[0010] As used herein, the term "aryl" refers to an aromatic system comprising at least one ring that satisfies Hückel's aromaticity rule. Said aryl is optionally substituted and may comprise from 6 to 50 carbon atoms, for example 6 to 20 carbon atoms, for example 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl.

[0011] In general, the term "heteroaryl moiety", as used herein, refers a cyclic unsaturated radical having from about five to about ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0012] The term "heteroalkyl", as used herein, refers to alkyl moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroalkyl group refers to an alkyl chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, i.e., in place of carbon atoms, for example, at least one heteroatom to 20 heteroatoms, such as one to 15 heteroatoms, or one to 5 heteroatoms, or one, two, three or four heteroatoms. Heteroalkyl moieties may be branched or linear unbranched.

[0013] The term "Alkoxy", as used herein, refers to a moiety -O-alkyl, with exemplary embodiments including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy.

[0014] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0015] The abbreviation "acac", as used herein, refers to an acetylacetone ligand.

[0016] As used herein, the term "independently" refers to the fact that the substituents, atoms or moieties to which these terms refer, are selected from the list of variables independently from each other (i.e., they may be identical or the same).

[0017] As used herein, the term "about" can refer to a variation of ±5%, ±10%, ±20%, or ±25%, of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent. For integer ranges, the term "about" can include one or two integers greater than and/or less than a recited integer. Unless indicated otherwise herein, the term "about" is intended to include values, e.g., concentration values, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.

[0018] As used herein, the term "and/or" means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0019] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as cavity/pore size and BET specific surface area, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.

[0020] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of subranges thereof, as well as the individual values making up the range, particularly integer values. A recited range includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.

[0021] One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, as used in an explicit negative limitation.

[0022] As used herein, the expression "three-dimensional structure" is understood to mean a three-dimensional sequence or repetition of units, as is conventionally understood in the field of MOF materials, that are also characterized as "organometallic polymers".

[0023] As used herein, the term "solid" refers to any type of crystalline material. Said solid may be, for example, in the form of crystals, powder or particles of varied forms, for example of spherical, lamellar, etc. form. The particles may be in the form of nanoparticles.

[0024] As used herein, the term "nanoparticle" refers to a particle smaller than 1 µm in size. In particular, the solid Fe-, Al- or Ti-based MOF nanoparticles according to the invention may have a diameter of less than 1000 nanometers, preferably less than 500 nm, more preferably less than 250 nm, more preferably less than 100 nm, and most particularly less than 90 nm.

[0025] As used herein, the term "ligand" refers to a ligand (including, for example, neutral species and ions) coordinated to at least two Fe, Al or Ti metal centers (or two metal centers of different nature in the case of doped Fe, Al or Ti-based materials according to a variant of the invention, for example Ru-doped MOF materials), which participates in providing distance between these metals and in forming empty spaces or pores.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION



[0026] In one aspect, the present invention provides a microwave-free process for preparing nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate material with low polydispersity index, comprising steps of:
  1. A) mixing in an aqueous solvent system:
    1. (i) at least a first inorganic metallic precursor in the form of a metal M, a salt of a metal M or a coordination complex comprising the metal ion Mz+ selected from Fe2+, Fe3+, Ti3+, Ti4+ or Al3+;
    2. (ii) at least one precursor ligand L' having the structure R1-(C(=O)-R3)q wherein:

      q represents an integer from 2 to 6; preferably q represents 2, 3 or 4;

      each occurrence of R3 is independently selected from a halogen atom, - OH, -OR4, -O-C(=O)R4 or -NR4R4', wherein R4 and R4', identical or different, represent C1-12 alkyl radicals;

      R1 independently represents:

      1. (a) a C1-12alkyl, C2-12alkenyl or C2-12alkynyl radical;
      2. (b) a fused or non-fused monocyclic or polycyclic aryl radical, comprising 6 to 50 carbon atoms;
      3. (c) a fused or non-fused monocyclic or polycyclic heteroaryl, comprising 4 to 50 carbon atoms;

      R1 optionally bearing one or more substituents independently selected
      from a halogen atom, -OH, -NH2, -NO2 or C1-6alkyl; and

  2. B) allowing the mixture obtained in step A) to react at a temperature below the boiling point and reflux temperature of the aqueous solvent system; so as to obtain the said nanoparticles;
    wherein the process is carried out in the absence of additives aimed at solubilizing the ligand precursor L' in the solvent system.


[0027] Advantageously, the ligand precursor L' may be a di-, tri-, tetra- or hexadentate precurcor ligand selected from:





wherein R3 is as defined above,

s represents an integer from 1 to 4,

each occurrence of t independently represents an integer from 1 to 4,

u represents an integer from 1 to 7,

each occurrence of RL1 and RL2 independently represent H, a halogen or a C1 to C6 alkyl, and

each occurrence of RL3 independently represents H, a halogen atom, -OH, -NH2, -NO2 or C1-6alkyl;

X represents a covalent bond, C=O, CH2, N=N, NH, O, S, SO2, C=C, -O-(CH2)p-O-, -NH-(CH2)p-NH- or -S-(CH2)p-S- where p represents an integer ranging from 1 to 4; preferably C=O, CH2, N=N, NH, O, S, SO2, , -O-(CH2)p-O-, -NH-(CH2)p-NH- or -S-(CH2)p-S-; most preferably C=O, CH2, or N=N;

each occurrence of m independently represents an integer from 1 to 3; and each occurrence of R1 independently represents H, a halogen atom, OH, NH2, NO2 or a C1-6alkyl, preferably each occurrence of R1 represents H; and

each occurrence of R4 independently represents -OH, a halogen atom, or a -OR5, -O-C(=O)R5 or -NR5R5' moiety, wherein R5 and R5' independently represent C1-12alkyl; preferably each occurrence of R1 and R4 represents H; most preferably X represents CH2 and each occurrence of R1 and R4 represents H.

Among the bis-C6aryl-containing tetradentate ligand precursors having the structure (II), mention may be made of ligand precursors of formulae (IIA1) through (IIA3):

or

preferably formula (IIA1).
Among the bis-C6aryl-containing tetradentate ligand precursors having the structure (IIA), mention may be made of precursors of formula (II), (IIA1), (IIA2) or (IIA3) wherein X represents a covalent bond, C=O, CH2 or N=N; preferably precursors of formula (II) or (IIA1) wherein X represents CH2.
Advantageously, the bis-C6aryl-containing tetradentate ligand precursor may have one of the following structures:

or

preferably



[0028] The reader may find further guidance on the preparation of MOF materials from bis-C6aryl-containing tetradentate ligand precursors of formula (II), notably for the preparation of Ti-based MOF materials with high condensation degree, in European Patent Application N° 16305692.2 filed on 10 June 2016. In particular, the teachings of EP16305692.2 may be adapted by changing the temperature conditions and solvent system to match those of the present invention; i.e., solvent system as described herein, and temperature below the boiling point temperature of the solvent system.
Advantageously, the precursor ligand L' may be a di-, tri- or tetracarboxylic acid selected from: C2H2(CO2H)2 (fumaric acid), C2H4(CO2H)2 (succinic acid), C3H6(CO2H)2 (glutaric acid), C4H4(CO2H)2 (muconic acid), C4H8(CO2H)2 (adipic acid), C7H14(CO2H)2 (azelaic acid), C5H3S(CO2H)2 (2,5-thiophenedicarboxylic acid), C6H4(CO2H)2 (terephthalic acid), C6H2N2(CO2H)2 (2,5-pyrazine dicarboxylic acid), C10H6(CO2H)2 (naphthalene-2,6-dicarboxylic acid), C12H8(CO2H)2 (biphenyl-4,4'-dicarboxylic acid), C12H8N2(CO2H)2 (azobenzenedicarboxylic acid), C6H3(CO2H)3 (benzene-1,2,4-tricarboxylic acid), C6H3(CO2H)3 (benzene-1,3,5-tricarboxylate acid), C24H15(CO2H)3 (benzene-1,3,5-tribenzoic acid), C6H2(CO2H)4 (benzene-1,2,4,5-tetracarboxylic acid, C10H4(CO2H)4 (naphthalene-2,3,6,7-tetracarboxylic acid), C10H4(CO2H)4 (naphthalene-1,4,5,8-tetracarboxylic acid), C12H6(CO2H)4 (biphenyl-3,5,3',5'-tetracarboxylic acid); modified analogs selected from 2-aminoterephthalic acid, 2-nitroterephthalic acid, 2-methylterephthalic acid, 2-chloroterephthalic acid, 2-bromoterephthalic acid, 2,5-dihydroxoterephthalic acid, tetrafluoroterephthalic acid, tetramethylterephthalic acid, dimethyl-4,4'-biphenydicarboxylic acid, tetramethyl-4,4'-biphenydicarboxylic acid, dicarboxy-4,4'-biphenydicarboxylic acid, or 2,5-pyrazyne dicarboxylic acid; or ligand derivatives selected from 2,5-diperfluoroterephthalic acid, azobenzene-4,4'-dicarboxylic acid, 3,3'-dichloro-azobenzene-4,4'-dicarboxylic acid, 3,3'-dihydroxo-azobenzene-4,4'-dicarboxylic acid, 3,3'-diperfluoro-azobenzene-4,4'-dicarboxylic acid, 3,5,3',5'-azobenzene tetracarboxylic acid, 2,5-dimethylterephthalic acid, or perfluoroglutaric acid. For example, the precursor ligand L' may be benzene-1,3,5-tricarboxylic acid (trimesic acid) or benzene-1,2,4,5-tetracarboxylic acid.
The inorganic metallic precursor may be any precursor suitable for the preparation of Fe-, Al- or Ti-based MOF carboxylate material. The reader can draw from extensive MOF literature available to date to select suitable inorganic metallic precursors. For example, the suitable inorganic metallic precursor may be in the form of a metal (Fe, Al or Ti), a Fe-, Al- or Ti-based metallic salt or a coordination complex comprising the metal ion Mz+ selected from Fe2+, Fe3+, Ti3+, Ti4+ or Al3+.
For example, the inorganic metallic precursor may be a Fe2+ salt such as FeCl2 or Fe(CO2CH3)2 (iron acetate).
For example, the inorganic metallic precursor may be a Fe3+ salt such as FeCl3, Fe(NO3)3, Fe(ClO4)3 iron perchlorate or Fe2(SO4)3 iron sulfate.
For example, the inorganic metallic precursor may be a Al3+ salt such as AlCl3, Al(OH)3 Aluminum hydroxide, Al(NO3)3 Aluminum nitrate, Al2(SO4)3 Aluminum sulfate, Al(ClO4)3 Aluminum perchlorate or Al(CO2CH3)3 Aluminum acetate.
For example, the inorganic metallic precursor may be a Ti3+ salt such as TiCl3.
For example, the inorganic metallic precursor may be a Ti4+ salt such as TiCl4, TiO(acac)2, TiOSO4 (titanyl sulfate), Ti(SO4)2 or titanium alkoxides of formula (III):

        Ti(OR3)4     (III)

wherein each occurrence of R3 independently represents a linear or branched C1-6alkyl moiety.
In an exemplary variant, the inorganic metallic precursor may be a Fe3+ salt such as FeCl3, and the precursor ligand L' may be benzene-1,3,5-tricarboxylic acid.
In another exemplary variant, the inorganic metallic precursor may be Fe3+ salt such as FeCl3, and the precursor ligand L' may be benzene-1,2,4,5-tetracarboxylic acid (BTeC).
The process according to the invention may be carried out in any suitable solvent system. Preferably, the solvent system may be a polar solvent system, which may be composed of a single solvent or a mixture of two or more polar solvents. Advantageously, the solvent system may be an aqueous solvent system. The solvents that may be used may especially be chosen from H2O, ethanol, isopropanol, dimethyl carbonate, ethylene glycol, ethyl lactate, ethyl acetate, sulfolane, benzyl alcohol or a mixture of two or more thereof. Preferably, the solvent system is aqueous, and thus contains at least H2O, and optionally any one or more of the aforementioned solvents. Preferably, the solvent system is H2O, ethanol, or a mixture thereof; most preferably H2O. The above-mentioned solvents are all environmentaly friendly solvents. However other non environnmentaly friendly solvents could be used, such as dimethylformamide-based solvent systems.

[0029] The process according to the invention is advantageously carried out at a temperature below the boiling point and reflux temperature of the solvent system used to carry out the reaction. This is particularly advantageous compared to existing methods for preparing MOF materials, notably in the form of nanoparticles, which involve either high temperatures (reflux, or solvothermal methodology) or microwave. For example, mention may be made of Zhang et al., Chem. Eng. J., 259(8), 2014, pp. 183-190 which describes the synthesis of MIL-100(Fe) under reflux in water at 95°C under atmospheric pressure in the absence of HF (cf. page 184, right-hand column, "2.2. MIL-100(Fe) synthesis"). Also, the work by Jing Shi et al. (Journal of Chemistry, 2013(1), 2013, pp. 1-4 describes the synthesis of MIL-100(Fe) under reflux at 95°C in the presence of HF, HNO3 and H2O.
Advantageously, the process may be carried out in H2O as sole solvent system. As such, the process may be carried out at a temperature < 100°C. For example, the process may be carried out in H2O as sole solvent system at room temperature (20°C ± 5°C). In another example, the process may be carried out in H2O as sole solvent system at 60°C ± 5°C. As will be readily apparent, a great advantage of the process fo the invention is that is involves low temperatures, and thus is less costly and environmentally friendly than conventional methods (reflux, solvothermal, microwave methodologies). In addition, it allows the preparation of MOF-based composites in the presence of fragile species such as contrast agents (e.g., iron oxides), and/or allows the introduction of reactive species within the MOF framework (e.g., Ru sites) which prove very useful for applications in heterogenous catalysis. Additionally, the process of the invention allows access to brand new MOF phases that cannot be prepared by the conventional higher energy methods (reflux, solvothermal, microwave methodologies). Cf. Example 6 which describes the preparation of a new MOF(Fe) carboxylate phase, which has never been reported thus far.
As such, the present invention also relates to a new MOF carboxylate material obtainable as nanoparticles by the process of the invention, which MOF with formula Fe3O(H2O)2(OH)4(H2-BTeC)1.5 is composed of a three-dimensional succession of building units connected through BTeC linkers. Without wishing to be bound by any particular theory, it is believed that this new MOF phase is composed of µ3-oxo trimers. As exemplified in Example 6, this new MOF material (also referred to as "Fe/BTeC") may be prepared from FeCl3 as metallic precursor and 1,2,4,5-benzene tetracarboxilic acid as organic ligand precursor L'.

[0030] Advantageously, the process according to the invention may be carried out carried out under 1.105 Pa (ambient pressure conditions).

[0031] Advantageously, the process may be carried out under dilute conditions. In other words, the process of the invention may involve inorganic metallic precursor concentrations of less than 50 mM, preferably ≤ 40 mM, preferably ≤ 30 mM, most preferably ≤ 25 mM. For example, the inorganic metallic precursor concentration in the solvent system may be about 20 mM. The dilution level to be adopted will largely depend on the temperature used for the reaction. The lower the temperature (e.g., room temperature), the higher the dilution level will be. The dilute conditions are particularly advantageous as they allow to better control the nanoparticle size: smaller average particle size can be accessed, and with a lower polydispersity index (narrower distribution of particle size).
Under dilute conditions, the reacting species still are somewhat dissolved in the solvent system, even when water is used as sole solvent system. As the reaction progresses (as the MOF nanoparticles are formed and precipitate out of the solvent system), dissolved reactants are comsumed thereby slowly driving the equilibrium towards the dissolution of reactants into the solvent system. The dilute conditions also implies that the formation of nanoparticles is particularly slow and controlled. This in turn results in the formation of MOF nanoparticles of much better quality than what other conventional processes can yield, notably in terms of average particle size and monodispersity: the process according to the invention, when conducted under dilute conditions as described above allows the preparation of MOF nanoparticles of smaller average particle with a lower polydispersity index, which is a great advantage over other known processes.
Accordingly, advantageously the process according to the invention allows the preparation of nanoparticles, the average size of which is < 90 nm, preferably < 85 nm, preferably < 80 nm, preferably < 75 nm, most preferably < 70 nm. The nanoparticles are obtained as a very narrow distribution of particle size (low polydispersity index): particles of sizes starting from 20-30 nm can be obtained. However, the majority of the particles generally have sizes in the range of 70 nm-100 nm. The average particle size may be tuned between 100 nm down to 70 nm or below, depending of the reaction conditions (lower temperature and more dilute conditions will favor the formation of nanoparticles of smaller average particle size). Advantageously, the process according to the invention allows the preparation of nanoparticles, the process leads to nanoparticles having a polydispersity index 0.05 ≤ PDI ≤ 0.5, preferably 0.05 ≤ PDI ≤ 0.4, most preferably 0.05 ≤ PDI ≤ 0.3, as calculated under ISO standard 13321:1996 E and ISO 22412:2008.
The polydispersity index is a number calculated from a simple 2 parameter fit to the correlation data (the cumulants analysis). The Polydispersity Index is dimensionless and scaled such that values smaller than 0.05 are rarely seen other than with highly monodisperse standards. Values greater than 0.7 indicate that the sample has a very broad size distribution and is probably not suitable for the dynamic light scattering (DLS) technique. The various size distribution algorithms work with data that falls between these two extremes. The calculations for these parameters are defined in the ISO standard document 13321:1996 E and ISO 22412:2008.
The process according to the invention allows the preparation of nanoparticles that combine both a low PDI as well as small average particle size. This is particularly interesting as compared to conventional processes for the preparation of MOF particles, which do not allow to have both properties. For example, the microwave synthesis allows similar (or may be smaller) PDI but the average particles size if greater than 100 nm. Also the process of the invention is very easy to set up so it is possible to scale up at lower cost.
Accordingly, the invention also provides nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate material having a polydispersity index 0.05 ≤ PDI ≤ 0.5, preferably 0.05 ≤ PDI ≤ 0.4, most preferably 0.05 ≤ PDI ≤ 0.3, as calculated under ISO standard 13321:1996 E and ISO 22412:2008; and an average size < 90 nm, preferably < 85 nm, preferably < 80 nm, preferably < 75 nm, most preferably < 70 nm.

[0032] Advantageously, the process according to the invention prevents the use of additives meant to solubilize the reagents in the solvent system. Typically, in conventional processes (e.g., reflux, solvothermal, microwave methodologies), additives, such as organic or inorganic bases that allow deprotonation of the linkers and thus a better solubilization, are used to help dissolution of the reagents and accelerate the reaction. Such organic or inorganic base additives may be NaOH, KOH, amines for example. For example, mention may be made of the work by Sanchez-Sanchez et al. (Green Chemistry, 17(3), 2015, pp. 1500-1509) which reports the preparation of X-MIL-53-AI (X=none, NH2, NO2) in water at room temperature in the presence of a base aimed at solubilizing the ligand precursor into the corresponding carboxylate salt. The use of these additives is detrimental to homogeneity of nanoparticle size, and generally leads to higher particle average size. In addition, the additives must then be washed out to "clean" the MOF particle product. The process according to the invention obviates all these drawbacks in that additives for solubilizing reagents are not necessary.

[0033] Advantageously, the process according to the invention allows the preparation of mixed-metal MOF nanoparticles. As used herein, the term "mixed-metal" refers to MOFs that contain at least two different types of metallic centers: of different nature (different metal, e.g., Fe and Ru) or oxidation states (same metal, but different oxidation states, e.g., Fe2+ and Fe3+). As such, the process of the invention may involve the use of a second inorganic metallic precursor in the reaction mixture. Accordingly, step A) of the process fo the invention may further comprise mixing, in addition to the first inorganic metallic precursor, a second inorganic metallic precursor, in the form of a metal M1, a salt of a metal M1 of formula (I) or a hydroxide or oxide of a metal M1;

        M1Yp.nH2O     (I)

wherein M1 is a metal selected from Cu, Fe, Co, Ni, Mn, V, Cr, Ru, Sn, Mg or Nb; Y represents Cl-, NO3-, SO42-, AcO-, or

preferably the other metallic inorganic precursor is in the form of a salt of Cu2+, Fe2+, Fe3+, Co2+, Co3+, Ni2+, Mn2+, Mn3+, Mn4+, V3+, V4+, Cr3+, Ru3+, Ru4+, Sn4+, Mg2+, Nb4+ or Nb5+; most preferably the other metallic inorganic precursor is a metal salt such as RuCl3, VCl3, SnCl4, CrCl3 or FeCl3.
As such, the process fo the invention also allows the preparation of nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate material with low polydispersity index, which may be doped with one or more metals different from the principal metal present in the MOF framework (doped with Cu, Co, Ni, Mn, V, Cr, Fe, Ru, Sn, Mg or Nb), or which may be doped with the same metal but with a different oxidation state (for example, Fe3+ is the principal metal site present in the MOF, but it is doped with Fe2+ sites).

[0034] As used herein, with respect to doping with one or more metals, the term "doping" or "doped" refers to placing other metal atoms such as Cu, Co, Ni, Mn, V, Cr, Fe, Ru, Sn, Mg or Nb, in the Fe-, Al- or Ti-based MOF material lattice in place of Fe, Al or Ti atoms. The term "doping" or "doped" also refers to placing metal atoms of different oxidation state in the Fe-, Al- or Ti-based MOF material lattice in place of Fe, Al or Ti atoms (in other words introducing Fe2+ sites in a lattice of Fe3+ sites). For example a "Ru-doped material" is a Fe-, Al- or Ti-based MOF material according to the invention that has "implanted" Ru atoms replacing Fe, Al or Ti atoms, respectively, in the MOF material's lattice.
As such, metal ions such as Cu2+, Fe2+, Fe3+, Co2+, Co3+, Ni2+, Mn2+, Mn3+, Mn4+, V3+, V4+, Cr3+, Ru3+, Ru4+, Sn4+, Mg2+, Nb4+ or Nb5+, may be incorporated into the material's structure in place of Fe, Al or Ti atom metal centers. The metal doping ratio may be adjusted by using different amounts of starting metal salt to prepare the Fe-, Al- or Ti-based MOF material according to the invention (see infra). As such, the % doping is tunable and may range from 1% to 20% of the aforementioned metal centers. Generally, the doped Fe-, Al- or Ti-based MOF material may have the same crystal structure as the pure Fe-, Al- or Ti-based MOF material (no doping). However, they may be slight differences in unit cell parameters.
For the example, if Ru is selected as the doping metal, the process of the invention allows the incorporation of a metallic precursors at room temperature. This is turn allows to obtain small particle sizes and most importantly it is possible to tune the amount of Ru at low temperature. Therefore, the process fo the invention is particularly advantageous for doping MOF nanoparticules with metal sites whose chemistry in solution is not adapted to the use of high temperatrures (e.g., Ru).

[0035] In a variant, the process of the invention may be carried out in the presence of particles of a material different from a MOF. This enables the preparation of core-shell particles where the core is made of the material different from a MOF, encapsulated within a shell made of MOF. Advantageously, the particles of a material different from a MOF are nanoparticles, and the core-shell particles are core-shell nanoparticles. For example, the process may be carried in the presence of particles of a metal oxide, to produce core-shell nanoparticles where the metal oxide core is encapsulated within a MOF shell. For example, the metal oxide may be iron oxide, preferably iron III oxide. As such, the process of the invention may be used to encapsulate (nano)particles of contrast agent (e.g. iron oxide) within a MOF shell. Therefore, the process fo the invention is particularly advantageous for encapsulating materials that are sensitive/fragile to the reaction conditions of the conventional processes for preparing MOF materials (e.g., high temperatures (reflux, solvothermal), or microwave). Owing to the mild reaction conditions of the process of the invention (low temperature, absence of microwave), the process may be carried out in the presence of fragile materials, and may prove particularly useful as a method for encapsulating fragile materials, such as metal oxides.
Accordingly, there is also provided core-shell nanoparticles comprising a metal oxide core (e.g., iron oxide core) encapsulated within a MOF shell, wherein the MOF is as defined herein and above. These nanoparticles may advantageously be used as a contrast agent usable in medical imaging.

[0036] Advantageously, the process according to the invention further comprises a step of introducing at least one pharmaceutically active principle, a compound of cosmetic interest or a marker into said porous MOF material.
Thus, the invention also relates to the use of MOF nanoparticles according to the invention, said nanoparticles comprising in their pores or at their surface at least one molecule chosen from the group comprising a pharmaceutically active principle, a compound of cosmetic interest or a marker.

[0037] In particular, the invention also relates to the use of MOF nanoparticles according to the invention loaded with pharmaceutically active principle as a medicament. The pharmaceutically active principle may be contained either in the pores or at the surface of the nanoparticle according to the invention. This is what is understood in the rest of this document by the expression "nanoparticle loaded with pharmaceutically active principle".
More generally, the term "nanoparticle loaded with component X" refers to a nanoparticle according to the invention containing in its pores or at its surface the component X. The component X may be adsorbed or bound by covalent bonding, by hydrogen bonding, by Van der Waals bonding, by electrostatic interaction at the surface or in the pores of the nanoparticle. This component X may be, as indicated above, a pharmaceutically active principle. Alternatively, component X may be any molecule with biological activity, a compound of cosmetic interest or a marker.

[0038] Specifically, the MOF nanoparticles according to the invention have the advantage of having large adsorption capacities. In addition, they can efficiently adsorb pharmaceutical molecules that have particular encapsulation difficulties, for example on account of their instability, their high reactivity, their poor solubility, their strong tendency to crystallize, their hydrophilic or amphiphilic nature, etc.

[0039] For example, the nanoparticle according to the invention may be loaded with at least one pharmaceutically active principle that has one or more of the following characteristics: hydrophilic, amphiphilic, lipophilic, unstable, toxic, strong tendency to crystallize or substantially insoluble.
The term "toxic" refers to a pharmaceutically active principle that has toxic effects liable to hinder its use in medical or veterinary applications. They may be, for example, alkylating agents such as busulfan, cisplatin or nitrosoureas such as lomustine.
The term "strong tendency to crystallize" refers to a pharmaceutically active principle that has a tendency to self-associate in a crystal lattice instead of being included in other structures. Thus, such a compound tends to form crystals during the encapsulation process used, rather than being included in particles. This thus gives at the end of the process a mixture of particles that are poorly loaded with pharmaceutically active principles and crystals thereof. It may be, for example, busulfan. At high dose, it has a serious side effect, namely veno-occlusive liver disease. This probably results from the very strong tendency of this molecule to crystallize. The crystal stacking is governed by strong dipole-dipole interactions between the methylsulfonate groups of this active principle.

[0040] The term "substantially insoluble" refers to a pharmaceutically active principle whose solubility is less than 0.1 mg/ml in water. It may be, for example, busulfan.

[0041] The term "unstable" refers to a pharmaceutically active principle that can decompose, crystallize and/or react and in so doing lose its structure and its activity. A possible example of this is busulfan.

[0042] In addition, the pharmaceutically active principle may be any molecule that has biological activity, for instance a medicament, especially an anticancer agent, an antiviral agent, a modified or unmodified nucleoside analog, a nucleic acid, an antibody, a protein, a vitamin, etc.
Among the amphiphilic active principles that may be mentioned, for example, are busulfan, doxorubicin chloride and imipramine chloride.

[0043] Among the lipophilic active principles that may be mentioned, for example, are tamoxifen, docetaxel, paclitaxel, ibuprofen, lidocaine, liposoluble vitamins such as vitamins A (retinol), D (calciferol), E (tocopherol), K1 (phylloquinone) and K2 (menaquinone).

[0044] In particular, the nanoparticle according to the invention may be loaded with at least one pharmaceutically active principle chosen, for example, from the group comprising taxotere, busulfan, azidothymidine (AZT), azidothymidine phosphate (AZTP), cidofovir, gemcitabine and tamoxifen.

[0045] Advantageously, the active principle may be a fluorescent molecule. For example, it may be rhodamines, fluorescein, luciferase, pyrene and derivatives thereof, or aminopyrrolidino-7-nitrobenzofurazan.
Advantageously, the active principle may be a fluoro molecule, i.e. a molecule comprising at least one substituent F. It may be, for example, one of the fluoro molecules mentioned previously. These fluoro molecules are suitable for use in imaging, particularly fluorescence imaging such as the abovementioned PET technique.

[0046] Thus, the invention also relates to the use of MOF nanoparticles encapsulating one or more fluoro molecules according to the invention, as marker that may be used in medical imaging, such as PET imaging.
In addition, the nanoparticle according to the invention may be loaded with at least one compound of cosmetic interest.

[0047] The term "compound of cosmetic interest" refers to any active substance included in the formulation of a cosmetic preparation, i.e. a preparation intended to be placed in contact with various surface parts of the human body, especially the epidermis, the pilous and hair systems, the external organs, the teeth and mucous membranes, for the purpose, exclusively or mainly, of cleaning, protecting or fragrancing them, maintaining the human body in good condition, modifying its appearance or correcting its odor. The term "active substance" refers to a substance that ensures the efficacy of the cosmetic preparation.

[0048] The compound of cosmetic interest may be an active substance included in the preparation of any cosmetic preparation known to those skilled in the art, for example hygiene products (e.g. makeup remover, toothpaste, deodorant, shower gel, soap or shampoo), care products (e.g. anti-wrinkle cream, day cream, night cream, moisturizing cream, floral water, scrub, milk, beauty mask, lip balm or tonic), haircare products (e.g. hair conditioner, relaxer, gel, oil, lacquer, mask or dye), makeup products (e.g. concealer, self-tanning product, eyeliner, makeup powder, foundation, kohl, mascara, powder, skin bleaching product, lipstick or nail varnish), fragrances (e.g. eau de Cologne, eau de toilette or fragrance), antisun products (e.g. after-sun and antisun creams, oils and lotions), shaving products and hair-removing products (e.g. aftershave, hair-removing cream or shaving foam) or bath and shower preparations (e.g. bubble bath, bath oil or bath salts).

[0049] According to the invention, the compound of cosmetic interest may be chosen, for example, from the group comprising:
  • an antioxidant (for example citric acid, beta-carotene, vitamin E, glycolic acid, glutathione, vitamin C, polyphenols, lycopene, flavonoids, tannins, anthocyans, N-acetylcysteine (free-radical scavenger))
  • a vitamin (for example vitamin A, B3, B5, B6, B2, B1, B9, B8, B12, C, E, D, K, K1, K2)
  • a liporegulator (for example caffeine or theophylline)
  • a photoprotective agent (for example benzophenone-3 (2-hydroxy-4-methoxybenzophenone), benzophenone-4 (2-hydroxy-4-methoxybenzophenone-5-sulfonic acid), 2-phenylbenzimidazole-5-sulfonic acid)
  • a moisturizer (for example urea, hyaluronic acid or sorbitol).


[0050] For example, the nanoparticle according to the invention may be loaded with at least one compound of cosmetic interest chosen from the group comprising benzophenone, visnadine, salicylic acid, ascorbic acid, benzophenone and derivatives thereof, caffeine, urea, hyaluronic acid, etc.

[0051] Due to their structural features and high condensation degree, the Fe-, Al- or Ti-based MOF carboxylate material according to the present invention may be used as a catalyst support for carrying out heterogeneously catalyzed chemical reactions, or as a gas storage/separation/purification material, or as a matrix for encapsulating active principles (medicaments, cosmetics), or as a photochromic material for information storage, laser printing or as an oxygen indicator, or as proton conductive material (fuell cells), or a optoelectronic material (photovoltaic cells including Grätzel cells), or else as sensing material.
In general, the Fe-, Al- or Ti-based MOF carboxylate nanoparticles according to the invention may be used as catalyst support for carrying out heterogeneously catalyzed chemical reactions, or as gas storage/separation/purification material, or as matrix for encapsulating active principles (medicaments, cosmetics).
Advantageously, mixed-metal MOF nanoparticles obtainable by the process according to the invention, especially those mixed-metal MOF nanoparticles containing a catalytically active metal sur as Ru, may be used as a catalyst support for carrying out heterogeneously catalyzed chemical reactions.

[0052] The reader may refer to the indicated literature references for guidance as to how the Fe-, Al- or Ti-based MOF carboxylate materials of the invention may be used in the various applications of interest:
  • Heterogeneous catalysis, particularly photocatalysis [3]
  • Gas storage [4]
  • Separation of fluids [5]
  • Fuel-cells (proton conductive materials) [6]
  • Optoelectronics (Photovoltaics...) [7]
  • Sensing [8]
  • Biomedicine, health-care, cosmetics [9]


[0053] As nonlimiting examples, the solid material in accordance with the present invention more particularly being used:
  • for the adsorption of greenhouse gases (CO2, CH4), in the presence of various contaminants (water, N2, CO, H2S, etc.) in processes for capturing flue gases from factories (steelworks, cement works, thermal power plants, etc.), from units for producing methane or hydrogen from the combustion of biomass or the gasification of coal, The low production cost of these materials, combined with their non-toxicity and their good stability (thermal stability, moisture resistance or resistance to dihydrogen sulfide) makes them the candidates of choice for large-scale applications of this type;
  • for the separation of fluids (gases, vapors, liquids) such as the separation of aromatic compounds (isomers of xylene), of branched alkanes (octane number), of biomass derivatives (phenols...), the purification of fuels, etc.;
  • in biology/medicine/cosmetics, for the adsorption or encapsulation of active (pharmaceutical or cosmetic) principles of interest for the purpose either of releasing them in a controlled manner in order to provide doses at an effective level therapeutically for a suitable period, or of protecting them with respect to the outside environment (from moisture for example). As such, Fe, Al and Ti are metals that are not very toxic in the same way as carboxylic acids in general, which gives these solids (Fe-, Al- or Ti-based MOFs) an a priori low toxicity that is very advantageous for this type of application. Its very high chemical stability might particularly be of interest to prevent from a fast release of the cargos. The UV adsorption properties of Fe, Al and Ti may be applied to the field of UV-screening substances used in cosmetics, in particular with a suitable choice of organic spacer that itself also adsorbs in this wavelength range. The solid materials in accordance with the invention may also be used for the removal of toxins, for detoxification (for eliminating a posteriori toxins in the body), or for purifying biological fluids (urine, blood, etc.).


[0054] As a whole the Fe-, Al- or Ti-based MOF nanoparticles and process for making them, according to the present invention possess several unique chemical and structural features as summarized below:
  • Green solvent, mild reaction conditions (low temperature, no reflux, not microwave), easy to scale-up, cost effective
  • Access to nanoparticles that combine both low PDI and low average particle size
  • Possibility to work in the presence of materials that are sensitive/fragile to the reaction conditions of the conventional processes for preparing MOF materials (e.g., high temperatures (reflux, solvothermal), or microwave)
  • Particularly useful as a method for encapsulating fragile materials, such as metal oxides
  • Advantageous for doping MOF nanoparticules with metal sites whose chemistry in solution is not adapted to the use of high temperatrures (e.g., Ru)
  • Allows access to brand new MOF phases that cannot be prepared by the conventional higher energy methods (reflux, solvothermal, microwave methodologies).
  • Avoids the use of additives meant to solubilize reagents in the solvent system


[0055] Other advantages may also emerge to those skilled in the art upon reading the examples below, with reference to the attached figures, which are provided as nonlimiting illustrations.

EQUIVALENTS



[0056] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be constructed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. For example, the reader may refer to WO 2009/077670 and WO 2009/077671 for background on conventional synthetic methods for preparing MOFs, in particular POF carboxylate materials. [1, 2] These references are also useful for guidance on post-synthetic modifications of MOF materials (e.g., grafting, surface modification), which may be adapted in the context of the present invention. It should further be appreciated that the contents of those references are cited to help illustrate the state of the art.

[0057] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

EXAMPLES



[0058] The Fe-, Al- or Ti-based materials according to the present invention and their preparation can be understood further by the examples that illustrate some of the processes by which these conjugates are prepared or used. It will be appreciated, however, that these examples should not be construed to limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

Example 1 - Preparation of MIL-100(Fe) nanoparticles at room temperature



[0059] Trimesic acid (0.25 g, 1.19 mmol) was added to water (90 ml) followed by the addition of iron(III)nitrate nonahydrate (0.72 g, 1.78 mmol), producing a cloudy yellow solution which was stirred at room temperature at 300 rpm for 48h. The reaction mixture was removed after a period of 48 h, and the product was filtered under suction, and washed with water (90 ml) and with ethanol (90 ml), to yield an orange brown solid.

Example 2 - Preparation of MIL-100(Fe) nanoparticles at 60°C



[0060] Trimesic acid (0.25 g, 1.19 mmol) was added to water (90 ml) followed by the addition of iron(III)nitrate nonahydrate (0.72 g, 1.78 mmol), producing a cloudy yellow solution which was stirred at 60 °C at 300 rpm for 48h. The reaction mixture was removed after a period of 48 h, and the product was filtered under suction, and washed with water (90 ml) and with ethanol (90 ml), to yield an orange brown solid.

Comparative Example 3 - Preparation of MIL-100(Fe) nanoparticles under reflux



[0061] Trimesic acid (0.25 g, 1.19 mmol) was added to water (90 ml) followed by the addition of iron(III)nitrate nonahydrate (0.72 g, 1.78 mmol), producing a cloudy yellow solution which was stirred under reflux at 300 rpm for 48h. The reaction mixture was removed after a period of 48 h, and the product was filtered under suction, and washed with water (90 ml) and with ethanol (90 ml), to yield an orange brown solid.

[0062] As shown in Figure 19, the polydispersity index of the MIL-100(Fe) nanoparticles obtained according to the process of the invention (room temperature and 60°C) is much lower than MIL-100(Fe) nanoparticles obtained under a conventional process (reflux).

[0063] Table 1 compiles the calculated BET surface area of untreated and the KF-treated MIL-100(Fe) nanoparticles synthesised in Example 1 (room temperature) using N2 isotherms. These were compared with BET surface area results of MIL-100(Fe) found when using microwave and solvothermal routes. The results show that the low temperature process according to the invention, in addition to being a handy (easy to put to practice) and cost-effective method, leads to the preparation of MOF nanoparticles with comparable surface areas to those obtained with existing conventional methods to build MOF nanoparticles (microwave synthesis). After potassium fluoride treatment (KF), surface areas in the range of the surface areas found for MOF microparticles (mosty solvothermal methods) are obtained.

Example 4 - Preparation of MIL-100(Fe) core-shell nanoparticles encapsulating iron oxide as contrast agent



[0064] The low temperature synthesis condition which precludes the use of additive allows the easy preparation of core-shell composites such as iron oxides@MIL-100(Fe). Such composites can be used in theranostic as nanocarriers for drug delivery and contrast agents for Magnetic Resonance Imaging.

[0065] As used herein, the expression "X@MOF" refers to core-shell nanoparticles of MOF (shell) encapsulating a core made of X. As such, "iron oxides@MIL-100(Fe)" refers herein to core-shell iron oxides@MIL-100(Fe) composites.

[0066] Prior to the preparation of the core-shell iron oxides@MIL-100(Fe) composites, iron oxides nanoparticles were first synthesized by a coprecipitation method. 20 mL of sodium hydroxide (15 mol. L-1) were added under vigorous stirring to an acidic aqueous solution of FeCl3.6H2O (20 mL, 1 mol.L-1) and FeCl2.4H2O (5 mL, 2 mol.L-1 in HCl 2 mol.L-1). The black precipitate was isolated by magnetic settling and washed with 20 mL of water. After a magnetic separation, the precipitate was then stirred for 15 min in 30 mL of HNO3 (2 mol.L-1). For a complete oxidation of magnetite to maghemite nanoparticles (herein referred to as "NPs"), the precipitate obtained after a magnetic separation was then mixed with 10 mL of Fe(NO3)3.9H2O (0.35 mol.L-1) at 80 °C for 30 min. The isolated precipitate was peptised in water and a colloidal solution was obtained.

[0067] The iron oxide@MIL-100(Fe) composites were then prepared by adding under stirring the colloidal solution containing 70 mg of iron oxides to an aqueous solution Fe(NO3)3.9H2O (70 mL, 0.025 mol.L-1). 250 mg of trimesic acid were then added and the reaction was allowed to stir for 24 hours at room temperature (20 - 23 °C). The brown precipitate was isolated by magnetic settling and then centrifuged at 14500 rpm for 10 min. The solid was then washed by one centrifugation/redispersion cycle in water followed by three centrifugation/redispersion cycles in absolute ethanol. The γ-Fe2O3@MIL-100(Fe) NPs were stored in EtOH and could be redispersed in water before use.

[0068] X-ray diffraction analysis confirm the well synthesis of MIL-100(Fe) phase in presence of γ-Fe2O3. The structural integrity of γ-Fe2O3 is also preserved upon their association (Fig. 20).

[0069] Combination of MIL-100(Fe) with iron oxides is also confirmed by TEM analysis showing that γ-Fe2O3 NPs are embedded in the MIL-100(Fe) phase. No aggregates of iron oxides alone were observed using TEM analysis (Fig. 21A-D).

[0070] Nanoscale γ-Fe2O3@MIL-100(Fe) composites were also observed with sizes varying from 50 to 150 nm. This is in line with the DLS measurements with an average hydrodynamic diameter found around 150 nm with a polydispersity index at 0.2 (Fig. 22).

[0071] γ-Fe2O3@MIL-100(Fe) composites were also characterized by FT-Infrared. Different stretching vibration bands are observed. The bands at 1631 and 1384 cm-1 correspond to the stretching vibration bands of the carboxylate linked to the iron of the MOF while free ligand is observed through the C=O stretching vibration band at 1716 cm-1 (Fig. 23).

[0072] Using thermogravimetric analysis the weight content of iron oxides in γ-Fe2O3@MIL-100(Fe) composites was estimated to 20 ± 2 wt% (Fig. 24).

[0073] The γ-Fe2O3@MIL-100(Fe) composites present also a BET specific surface area of 1174 m2.g-1 obtained using N2 adsorption desorption. When normalized with the weight of MIL-100(Fe), a value of 1486 m2.g-1 is obtained, in line with the BET specific surface area of MIL-100(Fe) alone (Fig. 25).

[0074] Magnetisation measurements of γ-Fe2O3@MIL-100(Fe) were undertaken in order to determine its saturation magnetisation and to gain insight into the influence of MIL-100(Fe) on the superparamagnetic properties of γ-Fe2O3. A value of 68 A.m2/kg was obtained for saturation magnetisation of γ-Fe2O3@MIL-100(Fe) in line with the 53 A.m2/kg value obtained for pure γ-Fe2O3 NPs. Such results showed that the combination of both components does not have any impact on the magnetic properties of the γ-Fe2O3 core (Fig. 26).

Example 5 - Preparation of heterometallic MIL-100(Fe/Ru) nanoparticles (Inclusion of catalytically reactive species within metal carboxylate MOFs)



[0075] The introduction of catalytically active Ruthenium species in MOF structures is currently of foremost interest in the field of heterogeneous catalysis as reflected by the increasing number of publications devoted to this aim. Some reported examples are based on post-synthetic modification (PSM) of pre-formed MOFs to incorporate the Ru species in the framework by partial ligand exchanges with the corresponding metallo-ligand or by post-synthetic ion metathesis, giving rise to the desired Ru-doped MOF. Another existing approach for the synthesis of mixed-metal MOFs consists in the secondary building unit (SBU) approach for the preparation of the parent mixed-metal compound MIL-127(Fe2M) (M = Ni, Co, Mg).

[0076] Quite advantageously, the low temperature method according to the present invention permits not only to introduce Ruthenium species into the nanoMOF structure but also to tune the Fe/Ru ratio by simply modifying the metal content in the initial reaction mixture.
Generally speaking, an exemplary experimental procedure for the synthesis of heterometallic MIL-100(Fe/M) nanoparticles according to the invention follows the room temperature method described in Example 1 for the MIL-100(Fe) nanoparticle material. As an example, this green (environment-friendly) method consists essentially in a one-pot reaction in water and at room temperature, containing the ligand and the metal precursor in stoichiometric amounts. The choice of the metal precursor as well as the appropriate concentration in the reaction mixture are both important parameters for the successful preparation of nanostructured MIL-100(Fe). This approach has been extended to produce mixed-metal nanoMOF, in particular heterometallic MIL-100(Fe/Ru) nanoparticles.
In a round bottom flask, a mixture of 168 mg of trimesic acid (0.8 mmol) with 320 mg of Fe(NO3)3·9H2O (0.8 mmol) and 83 mg of RuCl3 (0.4 mmol) in 90 mL of distilled H2O was prepared. The solution was then stirred at 300 rpm for 48 hours at room temperature with the formation of a cloudy orange-yellow suspension. Then, the final suspension was filtrated and the obtained powder washed thoroughly with water. Different amounts of Ruthenium were introduced into the framework by modifying the Fe/Ru metal ratio content in the initial reaction mixture. The solids were then dispersed in 90 mL of EtOH and stirred for 12 hours at 60 °C to remove the excess of trimesic acid obtaining orange-brown solids.
All reactions were carried out following a high-throughput methodology where all parameters (concentration of reagents, T, stirring, reaction time...) were kept constant with the unique variable being the Fe/Ru metal ratio.

[0077] The structure of mixed-metal nanoMOFs samples 1-5 was ascertained by X-ray diffraction (XRD) and FT-IR analysis to verify the appropriate formation of the MIL-100 nanoMOF material, Figures 27 and 28, respectively.
Figure 28 displays the FTIR spectra for MIL-100(Fe) and MIL-100(Fe/Ru) nanoparticles obtained at room temperature. The characteristic bands assigned to MIL-100(Fe) structure (∪(C=O) carboxylate at 1577 and 1450 cm-1) are observed together with the band of the free trimesic acid band (∪(C=O) carboxylate at 1700 cm-1) corresponding to the excess of ligand non-coordinated, which remains after thoroughly washing with water and ethanol.

[0078] Once the structure was confirmed, an estimation of the metal content in the heterometallic nanoMOFs was carried out by means of EDX analysis and the results are depicted in Table 2. As expected, the Ru content was modified from 1 to 26 % (atomic %) from samples 1 to 5 by modifying the Fe/Ru metal ratio in the initial reaction mixture.
Additional studies to characterise more in detail the nanoparticles included dynamic light scattering (DLS), Energy-dispersive X-ray spectroscopy (EDX), N2 adsorption-desorption isotherms and thermogravimetric analyses (TGA). Analysis of the particle size by dynamic light scattering (DLS) was performed for all mixed-metal nanoparticles and calculated under ISO standard 13321:1996 E and ISO 22412:2008. Table 2 summarizes the particle average size distribution obtained in the different MIL-100(Fe/Ru) nanoparticles (samples 1-5) suspended in water affording a mean size distribution, which varies from 227 to 120 nm, depending on the metal content. All data was collected with a polydispersity index (PI) < 0.3.
Table 2. Average size distribution as obtained by DLS measurements at room temperature and metal content by EDX analysis.
SampleAvg particleat% EDX based
MIL-100(Fe/Ru)diameter (nm)% Ru% Fe
1 192 ± 23 1.1 98.9
2 227 ± 25 4.7 95.3
3 210 ± 35 7.6 92.4
4 164 ± 37 10.0 90.0
5 120 ± 20 25.6 74.6


[0079] N2 adsorption isotherm was measured for sample 2 to corroborate the preservation of the porous structure in the mixed-metal nanoMOF. MIL-100(Fe/Ru) nanoparticles (sample 2) exhibited the typical sorption/desorption profile expected for mesoporous MIL-100(Fe) nanoparticles, with a calculated BET surface area value of 1330 m2·g-1. In this line, thermo-gravimetric analysis (TGA) experiments were carried out to confirm the possible presence of excess of ligand partially occupying the pores.
Table 3: TGA of MIL-100(Fe) nanoparticles and MIL-100(Fe/Ru) nanoparticles (sample 2).
Sample MIL-100(Fe) Organic mass w/w %Inorganic mass w/w %
MIL-100(Fe) theoretical value 62.2 36.2
as-synthesized 68.7 31.3
2_ MIL-100(Fe/Ru) as-synthesized 67.5 32.5


[0080] Overall, the results confirm the formation of mesoporous MIL-100(Fe/Ru) nanoparticles in the absence of metal oxides. Importantly, the undesired formation of metal oxides, which is a characteristic limitation in the synthesis under reflux, is finally surpassed following the low temperature methodology according to the invention.

Example 6 - Room Temperature synthesis in water of new Fe/1,2,4,5-Benzene Tetracarboxylic based MOF as nanoparticles



[0081] 5 to 10 mmol of 1,2,4,5-Benzene Tetracarboxilic acid and 5 to 10 mmol of Iron(III) chloride anhydrous were introduced in a 100 mL vial (M/L ratio equals to 1). 50 mL of DI water were then added and the mixture was stirred for 16 h to 48 h using a magnetic stirrer at a temperature ranging from 4 to 30°C. The brown mixture was then centrifuged at 14500 RPM for 10 to 15 min to obtain a brown solid which was washed several times with absolute EtOH and dried at room temperature.

[0082] PXRD of the material shows very broad peaks indicating small particle which is confirmed by SEM images. Particles of Fe/BTeC have a nano needle shape with dimensions of 100-200*50*50 nm (Fig. 30).

[0083] Nitrogen adsorption performed at 77K indicates a type I isotherm, indicating a microporous material, with a specific surface area (BET) around 940m2/g with a sample activated at 110°C for 16h (Fig. 32).

[0084] Thermogravimetric analysis (performed under O2 at 2°C/min) brings out two weight losses: the first one from 25°C to 100°C corresponds to the loss of water trapped in the micropores; the second weight loss shows the degradation of the MOF starting from 250°C and complete at 350°C. From this second weight loss, we can estimate the ratio between the Fe and the BTeC ligand which we estimate close to two Fe for one ligand (Fig. 33).

[0085] FT-IR analysis shows the presence of carboxylate bonded to Fe and also the presence of -COOH groups coming from one or two uncoordinated -COOH of the BTeC ligand. This band at 1700cm-1 might also indicate the presence of free BTeC ligand in the pores but the formation of anhydride upon heating (>130°C) eliminates this hypothesis (Fig. 34).

[0086] Temperature-dependent PXRD allowed to study the flexibility of the framework. As it can be seen on Figure 35, there is no shift of the different peaks upon heating indicating a rigid framework. As shown by the TGA, degradation of the MOF appears at temperature higher than 250°C (Fig. 33).

[0087] Fe/BTeC is then thermally stable under ambient conditions but it is also the case under hydrothermal treatment. Several mg of Fe/BTeC are dispersed in H2O and heated up to reflux. After 72h, no degradation of the MOF appears as shown by the PXRD before and after the water stability treatment (Fig. 36).

Effect of temperature on synthesis



[0088] Synthesis conditions described above produce Fe/BTeC nanoparticles at temperature ranging from 4 to 40°C. When increasing the temperature, other known phases are obtained. For example, reflux synthesis in water yields pure MIL-61(Fe) which its Ga analogue has been described. Increasing the temperature even higher with hydrothermal conditions (150°C/24h), we obtain the MIL-61(Fe) but we also notice the apparition of an additional phase, corresponding to MIL-53(Fe)-BTeC. The latter belongs to the MIL-53 series with two free -COOH pending in the framework preventing the breathing effect.

[0089] Using the same reactants, in the same proportions and with the same solvent we obtain multiple phases depending on the temperature of the synthesis. The Fe/BTeC MOF has never been observed in any synthesis which temperature exceeds 40°C.

[0090] The crystal structure of this new Fe/BTeC MOF can be determined with high resolution powder X-ray diffraction data assisted by DFT calculation. As an exemplary protocol: the Fe/BTeC MOF sample is grinded into fine powder and sealed in glass capillaries with inner diameters of 0.3 mm or 0.7 mm. PXRD pattern of Fe/BTeC is collected on a Bruker D8 diffractometer at room temperature for 72 hours in a 2θ range from 5-50° (step size of 0.01).

TGA



[0091] Thermogravimetric analyses were carried out with a Mettler Toledo TGA/DSC 1, STAR System apparatus under an O2 flow of 50 mL/min, at a heating rate of 3 °C/min to 600 °C, unless otherwise indicated.

Temperature-dependent X-ray powder diffraction



[0092] X-ray temperature dependent diffraction experiment was performed on a Bruker-D8 Advance diffractometer equipped with a HTK-1200N (Anton Parr) high-temperature chamber furnace and a LYNXEYE XE detector (with Cu- radiation). PXRD patterns were collected every 25 °C from room temperature to 400 °C.

Infrared spectroscopy (IR)



[0093] IR spectra were measured with a Nicolet 6700 FTIR thermoscientific spectrometer between 400 and 4000 cm-1.

Scanning electron microscopy (SEM)



[0094] SEM images were taken with a JEOL JSM-7001F microscope using gold coated samples.

Nitrogen Porosimetry



[0095] Nitrogen adsorption measurements were performed with BEL Japan Belsorp Mini and Maxi apparatus at 77 K after the sample being fully activated (BEL Japan, BELSORP Prep). The MOF samples were directly activated thermally under vacuum before the nitrogen adsorption at 77K were carried out.

[0096] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the Ti-based MOFs and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

LIST OF REFERENCES



[0097] 
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Claims

1. A microwave-free process for preparing nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate material with low polydispersity index, comprising steps of:

A) mixing in an aqueous solvent system:

(i) at least a first inorganic metallic precursor in the form of a metal M, a salt of a metal M or a coordination complex comprising the metal ion Mz+ selected from Fe2+, Fe3+, Ti3+, Ti4+ or Al3+;

(ii) at least one precursor ligand L' having the structure R1-(C(=0)-R3)q wherein:

q represents an integer from 2 to 6; preferably q represents 2, 3 or 4;

each occurrence of R3 is independently selected from a halogen atom, - OH, -OR4, -O-C(=O)R4 or -NR4R4', wherein R4 and R4', identical or different, represent C1-12 alkyl radicals;

R1 independently represents:

(a) a C1-12alkyl, C2-12alkenyl or C2-12alkynyl radical;

(b) a fused or non-fused monocyclic or polycyclic aryl radical, comprising 6 to 50 carbon atoms;

(c) a fused or non-fused monocyclic or polycyclic heteroaryl, comprising 4 to 50 carbon atoms;

R1 optionally bearing one or more substituents independently selected
from a halogen atom, -OH, -NH2, -NO2 or C1-6alkyl; and

B) allowing the mixture obtained in step A) to react at a temperature below the boiling point and reflux temperature of the aqueous solvent system; so as to obtain the said nanoparticles;

wherein the process is carried out in the absence of additives aimed at solubilizing the ligand precursor L' in the solvent system.
 
2. The process of claim 1, wherein L' is a di-, tri-, tetra- or hexadentate precurcor ligand selected from:





wherein R3 is as defined in claim 1,

s represents an integer from 1 to 4,

each occurrence of t independently represents an integer from 1 to 4,

u represents an integer from 1 to 7,

each occurrence of RL1 and RL2 independently represent H, a halogen or a C1 to C6 alkyl, and

each occurrence of RL3 independently represents H, a halogen atom, -OH, -NH2, -NO2 or C1-6alkyl

X represents a covalent bond, C=O, CH2, N=N, NH, O, S, SO2, C=C, -O-(CH2)p-O-, -NH-(CH2)p-NH- or -S-(CH2)p-S- where p represents an integer ranging from 1 to 4; preferably C=O, CH2, N=N, NH, O, S, SO2,, -O-(CH2)p-O-, -NH-(CH2)p-NH- or -S-(CH2)p-S-; most preferably C=O, CH2, or N=N;

each occurrence of m independently represents an integer from 1 to 3; and each occurrence of R1 independently represents H, a halogen atom, OH, NH2, NO2 or a C1-6alkyl, preferably each occurrence of R1 represents H; and

each occurrence of R4 independently represents -OH, a halogen atom, or a -OR5, -O-C(=O)R5 or -NR5R5' moiety, wherein R5 and R5' independently represent C1-12alkyl; preferably each occurrence of R1 and R4 represents H; most preferably X represents CH2 and each occurrence of R1 and R4 represents H.


 
3. The process of claim 1 or 2, wherein the precursor ligand L' is a di-, tri- or tetracarboxylic acid selected from: C2H2(CO2H)2 (fumaric acid), C2H4(CO2H)2 (succinic acid), C3H6(CO2H)2 (glutaric acid), C4H4(CO2H)2 (muconic acid), C4H8(CO2H)2 (adipic acid), C7H14(CO2H)2 (azelaic acid), C5H3S(CO2H)2 (2,5-thiophenedicarboxylic acid), C6H4(CO2H)2 (terephthalic acid), C6H2N2(CO2H)2 (2,5-pyrazine dicarboxylic acid), C10H6(CO2H)2 (naphthalene-2,6-dicarboxylic acid), C12H8(CO2H)2 (biphenyl-4,4'-dicarboxylic acid), C12H8N2(CO2H)2 (azobenzenedicarboxylic acid), C6H3(CO2H)3 (benzene-1,2,4-tricarboxylic acid), C6H3(CO2H)3 (benzene-1,3,5-tricarboxylate acid), C24H15(CO2H)3 (benzene-1,3,5-tribenzoic acid), C6H2(CO2H)4 (benzene-1,2,4,5-tetracarboxylic acid, C10H4(CO2H)4 (naphthalene-2,3,6,7-tetracarboxylic acid), C10H4(CO2H)4 (naphthalene-1,4,5,8-tetracarboxylic acid), C12H6(CO2H)4 (biphenyl-3,5,3',5'-tetracarboxylic acid); modified analogs selected from 2-aminoterephthalic acid, 2-nitroterephthalic acid, 2-methylterephthalic acid, 2-chloroterephthalic acid, 2-bromoterephthalic acid, 2,5-dihydroxoterephthalic acid, tetrafluoroterephthalic acid, tetramethylterephthalic acid, dimethyl-4,4'-biphenydicarboxylic acid, tetramethyl-4,4'-biphenydicarboxylic acid, dicarboxy-4,4'-biphenydicarboxylic acid, or 2,5-pyrazyne dicarboxylic acid; or ligand derivatives selected from 2,5-diperfluoroterephthalic acid, azobenzene-4,4'-dicarboxylic acid, 3,3'-dichloro-azobenzene-4,4'-dicarboxylic acid, 3,3'-dihydroxo-azobenzene-4,4'-dicarboxylic acid, 3,3'-diperfluoro-azobenzene-4,4'-dicarboxylic acid, 3,5,3',5'-azobenzene tetracarboxylic acid, 2,5-dimethylterephthalic acid, or perfluoroglutaric acid.
 
4. The process of any one of claims 1 to 3, wherein the inorganic metallic precursor is a Fe3+ salt such as FeCl3, and the precursor ligand L' is benzene-1,3,5-tricarboxylic acid.
 
5. The process of any one of claims 1 to 3, wherein the inorganic metallic precursor is Fe3+ salt such as FeCl3, and the precursor ligand L' is benzene-1,2,4,5-tetracarboxylic acid.
 
6. The process of any one of claims 1 to 5, wherein the aqueous solvent system is H2O, ethanol, isopropanol, dimethyl carbonate, ethylene glycol, ethyl lactate, ethyl acetate, sulfolane, benzyl alcohol or a mixture of two or more thereof, preferably H2O, ethanol, or a mixture thereof, most preferably H2O.
 
7. The process of any one of claims 1 to 6, wherein the process is carried out in H2O as sole solvent system, at 60°C ± 5°C.
 
8. The process of any one of claims 1 to 7, wherein the process is carried out under 1.105 Pa (ambient pressure conditions).
 
9. The process of any one of claims 1 to 8, wherein the process is carried out under dilute conditions whereby the inorganic metallic precursor concentration is ≤50 mM, preferably ≤40 mM, preferably ≤30 mM, most preferably ≤25 mM.
 
10. The process of any one of claims 1-9, wherein, in addition to the first inorganic metallic precursor, a second inorganic metallic precursor, in the form of a metal M1, a salt of a metal M1 of formula (I) or a hydroxide or oxide of a metal M1, is added to the reaction mixture;

        M1Yp.nH2O     (I)

wherein M1 is a metal selected from Cu, Fe, Co, Ni, Mn, V, Cr, Ru, Sn or Nb; Y represents Cl-, NO3-, SO42-, AcO-, or

preferably the other metallic inorganic precursor is in the form of a salt of Cu2+, Fe2+, Fe3+, Co2+, Co3+, Ni2+, Mn2+, Mn3+, Mn4+, V3+, V4+, Cr3+, Ru3+, Ru4+, Sn4+, Mg2+, Nb4+ or Nb5+; most preferably the other metallic inorganic precursor is a metal salt such as RuCl3, VCl3, SnCl4, CrCl3 or FeCl3.
 
11. The process of any one of claims 1-10, wherein the process is carried in the presence of particles of iron oxide, to produce core-shell nanoparticles where the iron oxide core is encapsulated within a MOF shell.
 
12. The process of any one of claims 1-11, wherein the process leads to nanoparticles of average size < 90 nm, preferably < 85 nm, preferably < 80 nm, preferably < 75 nm, most preferably < 70 nm.
 
13. The process of any one of claims 1-12, wherein the process leads to nanoparticles having a polydispersity index 0.05 ≤PDI ≤0.5, preferably 0.05 ≤PDI ≤ 0.4, most preferably 0.05 ≤ PDI ≤ 0.3, as calculated under ISO standard 13321:1996 E and ISO 22412:2008.
 
14. A process according to any one of claims 1 to 13, further comprising a step of introducing at least one pharmaceutically active ingredient into said porous MOF material.
 
15. Nanoparticles of porous crystalline Fe-, Al- or Ti-based MOF carboxylate material having a polydispersity index 0.05 ≤PDI ≤0.5, preferably 0.05 ≤PDI ≤0.4, most preferably 0.05 ≤PDI ≤0.3, as calculated under ISO standard 13321:1996 E and ISO 22412:2008; and an average size < 90 nm, preferably < 85 nm, preferably < 80 nm, preferably < 75 nm, most preferably < 70 nm.
 
16. Nanoparticles according to claim 15 for use as a medicament.
 
17. Nanoparticles of porous crystalline MOF carboxylate material obtainable by a process according to any one of claims 1-14, wherein the MOF carboxylate material has the formula Fe3O(H2O)2(OH)4(H2-BTeC)1.5 and is composed of a three-dimensional succession of building units connected through benzene-1,2,4,5-tetracarboxylate linkers.
 
18. Nanoparticles obtainable by a process according to claim 11 for use as a contrast agent usable in medical imaging.
 
19. Use of nanoparticles obtainable by a process according to claim 10 as a catalyst support for carrying out heterogeneously catalyzed chemical reactions.
 
20. Use of nanoparticles obtainable by a process according to any one of claims 1-14, as catalyst support for carrying out heterogeneously catalyzed chemical reactions, or as gas storage/separation/purification material, or as matrix for encapsulating active principles (medicaments, cosmetics).
 


Ansprüche

1. Mikrowellenfreies Verfahren zur Herstellung von Nanopartikeln aus porösem kristallinem MOF-Carboxylatmaterial auf Fe-, Al- oder Ti-Basis mit einem niedrigen Polydispersitätsindex, umfassend die Schritte:

A) Mischen in einem wässrigen Lösungsmittelsystem:

(i) wenigstens einen ersten anorganischen metallhaltigen Vorläufer in der Form eines Metalls M, eines Salzes eines Metalls M oder eines Koordinationskomplexes, der das Metallion Mz+, ausgewählt aus Fe2+, Fe3+, Ti3+, Ti4+ oder Al3+, umfasst;

(ii) wenigstens einen Vorläuferliganden L' mit der Struktur R1-(C(=O)-R3)q, wobei:

q eine ganze Zahl von 2 bis 6 darstellt; vorzugsweise q 2, 3 oder 4 darstellt;

jedes Auftreten von R3 unabhängig ausgewählt ist aus einem Halogenatom, -OH, -OR4, -O-C(=O)R4 oder -NR4R4', wobei R4 und R4', gleich oder verschieden, C1-12Alkylreste darstellen;

R1 unabhängig darstellt:

(a) einen C1-12Alkyl-, C2-12Alkenyl- oder C2-12Alkinylrest;

(b) einen fusionierten oder nicht fusionierten, monocyclischen oder polycyclischen Arylrest, der 6 bis 50 Kohlenstoffatome umfasst;

(c) ein fusioniertes oder nicht fusioniertes, monocyclisches oder polycyclisches Heteroaryl, das 4 bis 50 Kohlenstoffatome umfasst;

wobei R1 gegebenenfalls einen oder mehrere Substituenten trägt, die unabhängig ausgewählt sind aus einem Halogenatom, -OH, -NH2, -NO2 und C1-6Alkyl; und

B) Erlauben, dass das bei Schritt A) erhaltene Gemisch bei einer Temperatur von unter dem Siedepunkt und der Rückflusstemperatur des wässrigen Lösungsmittelsystems reagiert; um die Nanopartikel zu erhalten;

wobei das Verfahren ohne Vorhandensein von Zusatzstoffen, die zum Solubilisieren des Ligandenvorläufers L' in dem Lösungsmittelsystem vorgesehen sind, durchgeführt wird.
 
2. Verfahren gemäß Anspruch 1, wobei L' ein di-, tri-, tetra- oder hexadentater Vorläuferligand ist, der ausgewählt ist aus:





wobei R3 wie in Anspruch 1 definiert ist,

s eine ganze Zahl von 1 bis 4 darstellt,

jedes Auftreten von t unabhängig eine ganze Zahl von 1 bis 4 darstellt,

u eine ganze Zahl von 1 bis 7 darstellt,

jedes Auftreten von RL1 und RL2 unabhängig H, ein Halogen oder ein C1- bis C6Alkyl darstellt und

jedes Auftreten von RL3 unabhängig H, ein Halogenatom, -OH, -NH2, -NO2 oder C1-6Alkyl darstellt,

X eine kovalente Bindung, C=O, CH2, N=N, NH, O, S, SO2, C=C, -O-(CH2)p-O-, -NH-(CH2)p-NH- oder -S-(CH2)p-S-darstellt, wobei p eine ganze Zahl in dem Bereich von 1 bis 4 darstellt; vorzugsweise C=O, CH2, N=N, NH, O, S, SO2, -O-(CH2)p-O-, -NH-(CH2)p-NH- oder -S-(CH2)p-S-; höchst bevorzugt C=O, CH2 oder N=N;

jedes Auftreten von m unabhängig eine ganze Zahl von 1 bis 3 darstellt;

und jedes Auftreten von R1 unabhängig H, ein Halogenatom, OH, NH2, NO2 oder C1-6Alkyl darstellt, wobei vorzugsweise jedes Auftreten von R1 H darstellt; und

jedes Auftreten von R4 unabhängig -OH, ein Halogenatom oder eine -OR5-, -O-C(=O)R5- oder -NR5R5'-Einheit darstellt, wobei R5 und R5' unabhängig C1-12Alkyl darstellen; vorzugsweise jedes Auftreten von R1 und R4 H darstellt; höchst bevorzugt X CH2 darstellt und jedes Auftreten von R1 und R4 H darstellt.


 
3. Verfahren gemäß Anspruch 1 oder 2, wobei der Vorläuferligand L' eine Di-, Tri- oder Tetracarbonsäure ist, die ausgewählt ist aus: C2H2(CO2H)2 (Fumarsäure), C2H4(CO2H)2 (Bernsteinsäure), C3H6(CO2H)2 (Glutarsäure), C4H4(CO2H)2 (Muconsäure), C4H8(CO2H)2 (Adipinsäure), C7H14(CO2H)2 (Azelainsäure), C5H3S (CO2H)2 (2,5-Thiophendicarbonsäure), C6H4(CO2H)2 (Terephthalsäure), C6H2N2(CO2H)2 (2,5-Pyrazindicarbonsäure), C10H6(CO2H)2 (Naphthalin-2,6-dicarbonsäure), C12H8(CO2H)2 (Biphenyl-4,4'-dicarbonsäure), C12H8N2(CO2H)2 (Azobenzoldicarbonsäure), C6H3(CO2H)3 (Benzol-1,2,4-tricarbonsäure), C6H3(CO2H)3 (Benzol-1,3,5-tricarboxylatsäure), C24H15(CO2H)3 (Benzol-1,3,5-tribenzoesäure), C6H2(CO2H)4 (Benzol-1,2,4,5-tetracarbonsäure, C10H4(CO2H)4 (Naphthalin-2,3,6,7-tetracarbonsäure), C10H4(CO2H)4 (Naphthalin-1,4,5,8-tetracarbonsäure), C12H6(CO2H)4 (Biphenyl-3,5,3',5'-tetracarbonsäure); modifizierten Analoga ausgewählt aus 2-Aminoterephthalsäure, 2-Nitroterephthalsäure, 2-Methylterephthalsäure, 2-Chlorterephthalsäure, 2-Bromterephthalsäure, 2,5-Dihydroxoterephthalsäure, Tetrafluorterephthalsäure, Tetramethylterephthalsäure, Dimethyl-4,4'-biphenydicarbonsäure, Tetramethyl-4,4'-biphenydicarbonsäure, Dicarboxy-4,4'-biphenydicarbonsäure und 2,5-Pyrazindicarbonsäure; oder Ligandenderivate ausgewählt aus 2,5-Diperfluorterephthalsäure, Azobenzol-4,4'-dicarbonsäure, 3,3'-Dichlorazobenzol-4,4'-dicarbonsäure, 3,3'-Dihydroxoazobenzol-4,4'-dicarbonsäure, 3,3'-Diperfluorazobenzol-4,4'-dicarbonsäure, 3,5,3',5'-Azobenzoltetracarbonsäure, 2,5-Dimethylterephthalsäure und Perfluorglutarsäure.
 
4. Verfahren gemäß einem der Ansprüche 1 bis 3, wobei der anorganische metallhaltige Vorläufer ein Fe3+-Salz ist, wie z. B. FeCl3, und der Vorläuferligand L' Benzol-1,3,5-tricarbonsäure ist.
 
5. Verfahren gemäß einem der Ansprüche 1 bis 3, wobei der anorganische metallhaltige Vorläufer ein Fe3+-Salz ist, wie z. B. FeCl3, und der Vorläuferligand L' Benzol-1,2,4,5-tetracarbonsäure ist.
 
6. Verfahren gemäß einem der Ansprüche 1 bis 5, wobei das wässrige Lösungsmittelsystem H2O, Ethanol, Isopropanol, Dimethylcarbonat, Ethylenglycol, Ethyllactat, Ethylacetat, Sulfolan, Benzylalkohol oder ein Gemisch von zwei oder mehr davon ist, vorzugsweise H2O, Ethanol oder ein Gemisch davon, höchst bevorzugt H2O.
 
7. Verfahren gemäß einem der Ansprüche 1 bis 6, wobei das Verfahren in H2O als alleinigem Lösungsmittelsystem bei 60 °C ± 5 °C durchgeführt wird.
 
8. Verfahren gemäß einem der Ansprüche 1 bis 7, wobei das Verfahren unter 1.105 Pa (Umgebungsdruckbedingungen) durchgeführt wird.
 
9. Verfahren gemäß einem der Ansprüche 1 bis 8, wobei das Verfahren unter verdünnten Bedingungen durchgeführt wird, wobei die Konzentration des anorganischen metallhaltigen Vorläufers ≤ 50 mM beträgt, vorzugsweise ≤ 40 mM, vorzugsweise ≤ 30 mM, höchst bevorzugt ≤ 25 mM.
 
10. Verfahren gemäß einem der Ansprüche 1-9, wobei zusätzlich zu dem ersten anorganischen metallhaltigen Vorläufer ein zweiter anorganischer metallhaltiger Vorläufer in der Form eines Metalls M1, eines Salzes eines Metalls M1 der Formel (I) oder eines Hydroxids oder Oxids eines Metalls M1 zu dem Reaktionsgemisch zugegeben wird;

        M1Yp.nH2O     (I)

wobei M1 ein Metall ausgewählt aus Cu, Fe, Co, Ni, Mn, V, Cr, Ru, Sn und Nb ist; Y Cl-, NO3-, SO42-, AcO oder

darstellt; vorzugsweise der andere metallhaltige anorganische Vorläufer in der Form eines Salzes von Cu2+, Fe2+, Fe3+, Co2+, Co3+, Ni2+, Mn2+, Mn3+, Mn4+, V3+, V4+, Cr3+, Ru3+, Ru4+, Sn4+, Mg2+, Nb4+ oder Nb5+ vorliegt; höchst bevorzugt der andere metallhaltige anorganische Vorläufer ein Metallsalz, wie z. B. RuCl3, VCl3, SnCl4, CrCl3 oder FeCl3, ist.
 
11. Verfahren gemäß einem der Ansprüche 1-10, wobei das Verfahren in Gegenwart von Partikeln von Eisenoxid durchgeführt wird, um Kern-Schale-Nanopartikel zu erzeugen, bei denen der Eisenoxidkern in einer MOF-Schale verkapselt ist.
 
12. Verfahren gemäß einem der Ansprüche 1-11, wobei das Verfahren Nanopartikel mit einer mittleren Größe von < 90 nm, vorzugsweise < 85 nm, vorzugsweise < 80 nm, vorzugsweise < 75 nm, höchst bevorzugt < 70 nm, ergibt.
 
13. Verfahren gemäß einem der Ansprüche 1-12, wobei das Verfahren Nanopartikel mit einem Polydispersitätsindex von 0,05 ≤ PDI ≤ 0,5, vorzugsweise 0,05 ≤ PDI ≤ 0,4, höchst bevorzugt 0,05 ≤ PDI ≤ 0,3, wie berechnet nach dem ISO-Standard 13321:1996 E und ISO 22412:2008, ergibt.
 
14. Verfahren gemäß einem der Ansprüche 1 bis 13, ferner umfassend einen Schritt des Einführens wenigstens eines pharmazeutischen Wirkstoffs in das poröse MOF-Material.
 
15. Nanopartikeln aus porösem kristallinem MOF-Carboxylatmaterial auf Fe-, Al- oder Ti-Basis mit einem Polydispersitätsindex von 0,05 ≤ PDI ≤ 0,5, vorzugsweise 0,05 ≤ PDI ≤ 0,4, höchst bevorzugt 0,05 ≤ PDI ≤ 0,3, wie berechnet nach dem ISO-Standard 13321:1996 E und ISO 22412:2008; und einer mittleren Größe von < 90 nm, vorzugsweise < 85 nm, vorzugsweise < 80 nm, vorzugsweise < 75 nm, höchst bevorzugt < 70 nm.
 
16. Nanopartikel gemäß Anspruch 15 zur Verwendung als Medikament.
 
17. Nanopartikel aus porösem kristallinem MOF-Carboxylatmaterial, erhältlich durch ein Verfahren gemäß einem der Ansprüche 1-14, wobei das MOF-Carboxylatmaterial die Formel Fe3O(H2O)2(OH)4(H2-BTeC)1,5 aufweist und aus einer dreidimensionalen Abfolge von Baueinheiten besteht, die durch Benzol-1,2,4,5-tetracarboxylat-Linker verbunden sind.
 
18. Nanopartikel, erhältlich durch ein Verfahren gemäß Anspruch 11, zur Verwendung als Kontrastmittel, das bei der medizinischen Bildgebung verwendbar ist.
 
19. Verwendung von Nanopartikeln, die durch ein Verfahren gemäß Anspruch 10 erhältlich sind, als Katalysatorträger zur Durchführung von heterogen katalysierten chemischen Reaktionen.
 
20. Verwendung von Nanopartikeln, die durch ein Verfahren gemäß einem der Ansprüche 1-14 erhältlich sind, als Katalysatorträger zur Durchführung von heterogen katalysierten chemischen Reaktionen oder als Gasspeicher/trenn/reinigungsmaterial oder als Matrix zum Verkapseln von Wirkstoffen (Medikamente, Kosmetika).
 


Revendications

1. Procédé sans micro-ondes pour la préparation de nanoparticules de MOF carboxylate cristallin poreux à base de Fe, Al- ou Ti avec un faible indice de polydispersité, comprenant les étapes suivantes:

A) mélanger dans un système de solvant aqueux :

(i) au moins un premier précurseur métallique inorganique sous la forme d'un métal M, d'un sel d'un métal M ou d'un complexe de coordination comprenant l'ion métallique Mz+ choisi parmi Fe2+, Fe3+, Ti3+, Ti4+ ou Al3+;

(ii) au moins un ligand précurseur L' ayant la structure R1 - (C (=O) -R3)q dans laquelle :

q représente un nombre entier de 2 à 6 ; de préférence q représente 2, 3 ou 4 ;

chaque occurrence de R3 est indépendamment choisie parmi un atome d'halogène, -OH, OR4, -O-C(=O)R4 ou -NR4R4', où R4 et R4', identiques ou différents, représentent des radicaux alkyle en C1-C12 ;

R1 représente indépendamment :

(a) un radical alkyle en C1-C12, alcényle en C2-C12 ou alcynyle en C2-C12 ;

(b) un radical aryle monocyclique ou polycyclique condensé ou non condensé, comprenant 6 à 50 atomes de carbone ;

(c) un radical hétéroaryle monocyclique ou polycyclique condensé ou non condensé, comprenant 4 à 50 atomes de carbone ;

R1 portant éventuellement un ou plusieurs substituants indépendamment choisis parmi un atome d'halogène, -OH, -NH2, -NO2 ou un alkyle en C1-C6 ; et

B) laisser réagir le mélange obtenu à l'étape A) à une température inférieure au point d'ébullition et à la température de reflux du système de solvant aqueux ; de manière à obtenir lesdites nanoparticules ;

le procédé étant réalisé en l'absence d'additifs visant à solubiliser le ligand précurseur L' dans le système de solvant.
 
2. Procédé selon la revendication 1, dans lequel L' est un ligand précurseur di-, tri-, tétra- ou hexadentate choisi parmi :





où R3 est tel que défini dans la revendication 1,

s représente un nombre entier de 1 à 4,

chaque occurrence de t représente indépendamment un nombre entier de 1 à 4,

u représente un nombre entier de 1 à 7,

chaque occurrence de RL1 et RL2 représente indépendamment H, un halogène ou un alkyle en C1 à C6, et

chaque occurrence de RL3 représente indépendamment H, un atome d'halogène, -OH, -NH2, -NO2 ou un alkyle en C1-C6

X représente une liaison covalente, C=O, CH2, N=N, NH, O, S, SO2, C=C, -O-(CH2)p-O-, -NH-(CH2)p-NH- ou -S-(CH2)p-S- où p représente un nombre entier allant de 1 à 4 ; de préférence C=O, CH2, N=N, NH, O, S, SO2, , -O-(CH2)p-O-, -NH-(CH2)p-NH- ou -S-(CH2)p-S-; plus préférentiellement C=O, CH2, ou N=N ;

chaque occurrence de m représente indépendamment un nombre entier de 1 à 3 ; et chaque occurrence de R1 représente indépendamment H, un atome d'halogène, OH, NH2, NO2 ou un alkyle en C1-C6, de préférence chaque occurrence de R1 représente H ; et

chaque occurrence de R4 représente indépendamment - OH, un atome d'halogène, ou un radical -OR5, -OC(=O)R5 ou -NR5R5', où R5 et R5' représentent indépendamment un alkyle en C1-C12 ; de préférence chaque occurrence de R1 et R4 représente H ; plus preférentiellement X représente CH2 et chaque occurrence de R1 et R4 représente H.


 
3. Procédé selon la revendication 1 ou 2, dans lequel le ligand précurseur L' est un acide di-, tri- ou tétracarboxylique choisi parmi : C2H2(CO2H)2 (acide fumarique), C2H4(CO2H)2 (acide succinique), C3H6(CO2H)2 (acide glutarique), C4H4(CO2H)2 (acide muconique), C4H8(CO2H)2 (acide adipique), C7H14(CO2H)2 (acide azélaïque), C5H3S(CO2H)2 (acide 2,5-thiophényl dicarboxylique), C6H4(CO2H)2 (acide téréphtalique), C6H2N2(CO2H)2 (acide 2,5-pyrazinyl dicarboxylique), C10H6(CO2H)2 (acide naphtalène-2,6-dicarboxylique), C12H8(CO2H)2 (acide biphényl-4, 4'-dicarboxylique), C12H8N2(CO2H)2 (acide azobenzènedicarboxylique), C6H3(CO2H)3 (acide benzène-1,2,4-tricarboxylique), C6H3(CO2H)3 (acide benzène-1,3,5-tricarboxylate), C24H15(CO2H)3 (acide benzène-1,3,5-tribenzoïque), C6H2(CO2H)4 (acide benzène-1,2,4,5-tétracarboxylique), C10H4(CO2H)4 (acide naphtalène-2,3,6,7-tétracarboxylique), C10H4(CO2H)4 (acide naphtalène-1,4,5,8-tétracarboxylique), C12H6(CO2H)4 (acide biphényl-3,5,3',5'-tétracarboxylique) ; des analogues modifiés choisis parmi l'acide 2-aminotéréphtalique, l'acide 2-nitrotéréphtalique, l'acide 2-méthyltéréphtalique, l'acide 2-chlorotéréphtalique, l'acide 2-bromotéréphtalique, l'acide 2,5-dihydroxotéréphtalique, l'acide tétrafluorotéréphtalique, l'acide tétraméthyltéréphtalique, l'acide diméthyl-4,4'-biphénydicarboxylique, l'acide tétraméthyl-4,4'-biphénydicarboxylique, l'acide dicarboxy-4,4'-biphénydicarboxylique ou l'acide 2,5-pyrazyne dicarboxylique ; ou des dérivés de ligands choisis parmi l'acide 2,5-diperfluorotéréphtalique, l'acide azobenzène-4,4'-dicarboxylique, l'acide 3,3'-dichloro-azobenzène-4,4'-dicarboxylique, l'acide 3,3'-dihydroxo-azobenzène-4,4'-dicarboxylique, l'acide 3,3'-diperfluoro-azobenzène-4,4'-dicarboxylique, l'acide 3,5,3',5'-azobenzène tétracarboxylique, l'acide 2,5-diméthyltéréphtalique ou l'acide perfluoroglutarique.
 
4. Procédé selon l'une quelconque des revendications 1 à 3, dans lequel le précurseur métallique inorganique est un sel de Fe3+ tel que FeCl3, et le ligand précurseur L' est l'acide benzène-1,3,5-tricarboxylique.
 
5. Procédé selon l'une quelconque des revendications 1 à 3, dans lequel le précurseur métallique inorganique est un sel de Fe3+ tel que FeCl3, et le ligand précurseur L' est l'acide benzène-1,2,4,5-tétracarboxylique.
 
6. Procédé selon l'une quelconque des revendications 1 à 5, dans lequel le système de solvant aqueux est H2O, l'éthanol, l'isopropanol, le carbonate de diméthyle, l'éthylèneglycol, le lactate d'éthyle, l'acétate d'éthyle, le sulfolane, l'alcool benzylique ou un mélange de deux ou plusieurs de ceux-ci, de préférence H2O, l'éthanol ou un mélange de ceux-ci, de préférence H2O.
 
7. Procédé selon l'une quelconque des revendications 1 à 6, dans lequel le procédé est effectué dans H2O comme seul système de solvant, à 60°C ± 5°C.
 
8. Procédé selon l'une quelconque des revendications 1 à 7, dans lequel le procédé est effectué sous 1.105 Pa (conditions de pression ambiante).
 
9. Procédé selon l'une quelconque des revendications 1 à 8, dans lequel le procédé est réalisé dans des conditions de dilution dans lesquelles la concentration du précurseur métallique inorganique est ≤ 50 mM, de préférence ≤ 40 mM, de préférence ≤ 30 mM, plus préférentiellement ≤ 25 mM.
 
10. Procédé selon l'une quelconque des revendications 1 à 9, dans lequel, en plus du premier précurseur métallique inorganique, un second précurseur métallique inorganique, sous la forme d'un métal M1, d'un sel d'un métal M1 de formule (I) ou d'un hydroxyde ou d'un oxyde d'un métal M1, est ajouté au mélange réactionnel ;

        M1Yp.nH2O     (I)

dans laquelle M1 est un métal choisi parmi Cu, Fe, Co, Ni, Mn, V, Cr, Ru, Sn ou Nb; Y représente Cl-, NO3-, SO42-, AcO-, ou

de préférence l'autre précurseur inorganique métallique est sous la forme d'un sel de Cu2+, Fe2+, Fe3+, Co2+, Co3+, Ni2+, Mn2+, Mn3+, Mn4+, V3+, V4+, Cr3+, Ru3+, Ru4+, Sn4+, Mg2+, Nb4+ ou Nb5+; plus préférentiellement, l'autre précurseur inorganique métallique est un sel métallique tel que RuCl3, VCl3, SnCl4, CrCl3 ou FeCl3.
 
11. Procédé selon l'une quelconque des revendications 1 à 10, dans lequel le procédé est mis en oeuvre en présence de particules d'oxyde de fer, pour produire des nanoparticules noyau-enveloppe dans lesquelles le noyau d'oxyde de fer est encapsulé dans une enveloppe de MOF.
 
12. Procédé selon l'une quelconque des revendications 1 à 11, dans lequel le procédé conduit à des nanoparticules de taille moyenne < 90 nm, de préférence < 85 nm, de préférence < 80 nm, de préférence < 75 nm, plus préférentiellement < 70 nm.
 
13. Procédé de l'une quelconque des revendications 1 à 12, dans lequel le procédé conduit à des nanoparticules ayant un indice de polydispersité de 0,05 ≤ PDI ≤ 0,5, de préférence 0,05 ≤ PDI ≤ 0,4, plus préférentiellement 0,05 ≤ PDI ≤ 0,3, calculé selon la norme ISO 13321:1996 E et ISO 22412:2008.
 
14. Procédé selon l'une quelconque des revendications 1 à 13, comprenant en outre une étape d'introduction d'au moins un ingrédient pharmaceutiquement actif dans ledit matériau poreux MOF.
 
15. Nanoparticules de MOF carboxylate cristallin poreux à base de Fe, Al- ou Ti ayant un indice de polydispersité de 0,05 ≤ PDI ≤ 0,5, de préférence 0,05 ≤ PDI ≤ 0,4, plus préférentiellement 0,05 ≤ PDI ≤ 0,3, calculé selon la norme ISO 13321:1996 E et ISO 22412:2008 ; et une taille moyenne < 90 nm, de préférence < 85 nm, de préférence < 80 nm, de préférence < 75 nm, plus préférentiellement < 70 nm.
 
16. Nanoparticules selon la revendication 15 pour leur utilisation comme médicament.
 
17. Nanoparticules de matériau MOF carboxylate cristallin poreux susceptible d'être obtenues par un procédé selon l'une quelconque des revendications 1 à 14, dans lesquelles le matériau MOF carboxylate répond à la formule Fe3O(H2O)2(OH)4(H2-BTeC)1.5 et est composé d'une succession tridimensionnelle de motifs unitaires reliés par des ligands benzène-1,2,4,5-tétracarboxylate.
 
18. Nanoparticules susceptibles d'être obtenues par un procédé selon la revendication 11 pour son utilisation comme agent de contraste utilisable en imagerie médicale.
 
19. Utilisation de nanoparticules susceptibles d'être obtenues par un procédé selon la revendication 10 comme support de catalyseur pour la réalisation de réactions chimiques en catalyse hétérogène.
 
20. Utilisation de nanoparticules susceptibles d'être obtenues par un procédé selon l'une quelconque des revendications 1 à 14, comme support de catalyseur pour la réalisation de réactions chimiques en catalyse hétérogène, ou comme matériau de stockage/ séparation/purification de gaz, ou comme matrice pour encapsuler des principes actifs (médicaments, cosmétiques).
 




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Cited references

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Patent documents cited in the description




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