US20240017996A1 - Fluorination processes - Google Patents

Fluorination processes Download PDF

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US20240017996A1
US20240017996A1 US18/201,569 US202318201569A US2024017996A1 US 20240017996 A1 US20240017996 A1 US 20240017996A1 US 202318201569 A US202318201569 A US 202318201569A US 2024017996 A1 US2024017996 A1 US 2024017996A1
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salt
reagent
hpo
activated
caf
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Veronique Gouverneur
Gabriele Pupo
Duncan Browne
Jamie Leitch
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University of Oxford
Oxford University Innovation Ltd
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Oxford University Innovation Ltd
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F11/00—Compounds of calcium, strontium, or barium
    • C01F11/18—Carbonates
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B9/00—General methods of preparing halides
    • C01B9/08—Fluorides
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F11/00—Compounds of calcium, strontium, or barium
    • C01F11/46—Sulfates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
    • C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
    • C07C17/208—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being MX
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity

Definitions

  • the present disclosure relates to fluorination processes and fluorination reagents.
  • the present application describes novel fluorination reagents, methods of preparation of fluorinating reagents from a salt comprising calcium and fluorine, as well as use of fluorinating reagents to prepare fluorochemicals. Fluorination process described herein can avoid a need to use hydrofluoric acid as an intermediate for fluorochemical production.
  • Fluorochemicals can be present in our daily life with applications in the metallurgical industry, Li-ion batteries, electrical appliances, luminescent nanoparticles and electronics, fluoropolymers (PTFE known as Teflon or ETFE), refrigerants (HFOs), air conditioning, as well as agrochemicals, anesthetics, and pharmaceuticals.
  • PTFE fluoropolymers
  • HFOs refrigerants
  • fluorine atoms incorporated in organic fluorochemicals can be derived from the naturally occurring mineral fluorspar (calcium fluoride, CaF 2 ) by applying a workflow commencing with its conversion into highly toxic hydrogen fluoride (HF) ( FIG. 1 ).
  • metallurgical grade Fluorspar Metalspar, 60-96% CaF 2 , ⁇ 40% of total fluorspar production
  • acid grade fluorspar AlF 3
  • HF hydrofluoric acid
  • AlF 3 aluminium trifluoride
  • a process for the preparation of a fluorinating reagent comprising the step of:
  • a fluorine-containing compound the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.
  • a fluorine-containing compound the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorinating reagent, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.
  • the fluorine-containing compound is suitably calcium fluoride (e.g., acid grade fluorspar).
  • a fluorinating reagent obtained, directly obtained or obtainable by a process of the first aspect.
  • a fluorinating reagent comprising a mixture of inorganic salts.
  • Calcium fluoride may be the sole fluorine source in the processes and uses of the invention.
  • activated fluorination reagents comprise a first salt comprising calcium and fluorine.
  • the activated fluorination reagent comprises a second salt comprising an anion, which has a lattice energy greater than 2450 KJ/mol when combined with Ca 2+ to form a third salt.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 21.9°, 30.3°, 31.6°, and/or 43.4°.
  • the methods comprise combining a first salt, the first salt comprising calcium and fluorine, with a second salt.
  • the second salt comprises an anion, which has a lattice energy greater than 2450 KJ/mol when combined with Ca 2+ to form a third salt.
  • the first and second salt are combined to form a salt mixture.
  • the methods comprise applying mechanical force to the salt mixture to form an activated salt-mixture.
  • the methods comprise combining the activated salt mixture with a first reactant.
  • the first reactant comprises an organic compound.
  • the methods comprise fluorinating the first reactant to yield an organo-fluorine compound.
  • the methods comprise combining an activated fluorination reagent with the organic compound and fluorinating the organic compound to produce an organo-fluorine compound.
  • the activated fluorination reagent has a powder x-ray diffraction spectrum of the activated reagent comprising characteristic 2 ⁇ reflections at about 21.9°, 30.3°, 31.6°, and/or 43.4°.
  • the methods comprise combining a first salt comprising calcium and fluorine, with a second salt to form a salt mixture.
  • the second salt comprises an anion, which has a lattice energy greater than 2450 KJ/mol when combined with Ca 2+ to form a third salt.
  • the methods comprise applying mechanical force to the salt mixture to yield the activated fluorination reagent.
  • the methods comprise combining a waste material comprising a first salt comprising calcium and fluorine, with a second salt to form a salt-waste mixture.
  • the second salt comprises an anion, which has a lattice energy greater than 2450 KJ/mol when combined with Ca 2+ to form a third salt.
  • the second salt combines with the first salt to form a salt-waste mixture that has a powder x-ray diffraction spectrum comprising characteristic 2 ⁇ reflections at about 21.9°, 30.3°, 31.6°, and/or 43.4°.
  • the methods comprise applying mechanical force to the salt-waste mixture to yield the activated fluorination reagent.
  • the first salt is CaF 2 .
  • the first salt is fluorapatite (Ca 5 (PO 4 ) 3 F).
  • the second salt is a metal hydroxide.
  • the second salt is NaOH.
  • the second salt is KOH.
  • the second salt is a metal sulphite.
  • the second salt is Na 2 SO 3 .
  • the second salt is K 2 SO 3 .
  • the second salt is a metal sulphate. In some embodiments, the second salt is KHSO 4 . In some embodiments, the second salt is an inorganic phosphate (e.g. K 2 HPO 4 , KH 2 PO 4 , K 3 PO 4 ). In some embodiments, the second salt is K 2 HPO 4 . In some embodiments, the second salt is KH 2 PO 4 . In some embodiments, the second salt is K 3 PO 4 . In some embodiments, the inorganic phosphate is a pyrophosphate (e.g. K 4 P 2 O 7 or Na 3 P 2 O 7 ).
  • a powder x-ray diffraction spectrum of the activated reagent comprising characteristic 2 ⁇ reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and/or 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises at least two characteristic 2 ⁇ reflections selected from the group of about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.40, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises at least three characteristic 2 ⁇ reflections selected from the group of about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic at least four 2 ⁇ reflections selected from the group of about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 21.90, 30.3°, 31.6°, and 43.4°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.
  • a ratio of the first salt to the second salt is about 1:0.5 to 1:100. In some embodiments, a ratio of the first salt to the second salt is about 1:1 to 1:10. In some embodiments, a ratio of the first salt to the second salt is about 1:1 to 1:5. In some embodiments, a ratio of the first salt to the second salt is about 1:1. In some embodiments, a ratio of the first salt to the second salt is about 1:2. In some embodiments, a ratio of the first salt to the second salt is about 1:3. In some embodiments, a ratio of the first salt to the second salt is about 1:5.
  • the mechanical force is applied using a ball mill, a mortar and pestle, a twin-screw extruder, using an ultrasonic bath, or a mechanical press.
  • the method does not comprise reacting a strong acid with the first salt to form hydrofluoric acid.
  • the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 10 Hz-20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 30 Hz. In some embodiments, the mechanical force is applied at a frequency of about 35 Hz. In some embodiments, the mechanical force is applied at a frequency of about 60 Hz.
  • the mechanical force is applied at a temperature of about 20-300° C. In some embodiments, the mechanical force is applied at a temperature of about 20-100° C. In some embodiments, the mechanical force is applied at a temperature of about 30° C. In some embodiments, the mechanical force is applied at a temperature of about 60° C. In some embodiments, the mechanical force is applied at a temperature of about 90° C.
  • the first and second salt are combined as solids without the addition of solvent.
  • the organic compound is aromatic or aliphatic and comprises at least one leaving group located at a site to be fluorinated.
  • the organic compound is a sulphonyl halide, an acyl halide, an aryl halide or an alkyl halide.
  • the organic compound is an aromatic sulphonyl halide (e.g. tosyl chloride), a benzoyl halide (e.g. 4-methoxybenzoyl chloride) a halobenzene (e.g. chlorobenzene) or a benzyl halide (e.g. benzyl chloride).
  • the first salt, second salt, and the organic compound are combined in the same step. In some embodiments, the first salt, second salt are combined prior to addition of the organic compound. In some embodiments, the first salt, second salt, and the organic compound is added together with one or more solvents in which the organic compound is soluble in at least one of the one or more solvents.
  • the one or more solvents comprise a solvent selected from the group consisting of acetonitrile, propionitrile, toluene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, 1,2-difluorobenzene, dichloroethane, trifluorotoluene, chloroform, tert-butanol, tert-amyl alcohol and water, wherein any one or more of the aforementioned organic solvents may be in admixture with water.
  • the one or more solvents comprise acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol and/or water. In some embodiments, the one or more solvents comprise a cryptand, a crown ether and a hydrogen-bonding phase transfer agent.
  • the fluorination reaction is performed at a temperature of about 20-300° C. In some embodiments, the fluorination reaction is performed at a temperature of about 20-100° C. In some embodiments, the fluorination reaction yield of the organofluorine compound is at least about 10% (measured based on a starting amount the organic compound). In some embodiments, the fluorination reaction yield is at least about 30% (measured based on a starting amount the organic compound). In some embodiments, the fluorination reaction yield is at least about 50% (measured based on a starting amount the organic compound). In some embodiments, the fluorination reaction yield is at least about 80% (measured based on a starting amount the organic compound).
  • the fluorination reaction is a mono-fluorination reaction. In some embodiments, the fluorination reaction is a di-fluorination reaction.
  • FIG. 1 shows possible manufacturing schemes of fluorochemicals from salts comprising fluorine.
  • FIG. 2 shows: Top: 19 F NMR in D 2 O of the fluorinating reagent derived from CaF 2 and K 2 HPO 4 under mechanochemical conditions. Bottom: 19 F NMR in D 2 O of the fluorinating reagent derived from CaF 2 and K 2 HPO 4 under mechanochemical conditions, following spiking with KF.
  • FIG. 3 shows the NMR yields (%) of TsF and TsCl when various phosphates were used as activators of Fluorspar.
  • FIG. 4 shows a PXRD diffractogram of the milling product of fluorspar and KH 2 PO 4 after 3 hours at 35 Hz.
  • FIG. 5 shows a PXRD diffractogram of the milling product of fluorspar and K 3 PO 4 after 3 hours at 35 Hz.
  • FIG. 6 shows a PXRD diffractogram of the milling product of fluorspar with Na 3 PO 4 after 3 hours at 30 Hz.
  • FIG. 7 shows a PXRD diffractogram of the milling product of fluorspar with Na 2 HPO 4 after 3 hours at 35 Hz.
  • FIG. 8 shows a PXRD diffractogram of the milling product of fluorspar with NaH 2 PO 4 after 3 hours at 35 Hz.
  • FIG. 9 shows a PXRD diffractogram of the milling product of fluorspar with KPO 3 after 3 hours at 35 Hz.
  • FIG. 10 shows a PXRD diffractogram of the milling product of fluorspar with K 4 P 2 O 7 after 3 hours at 35 Hz.
  • FIG. 11 shows a PXRD diffractogram of the milling product of fluorspar with K 5 P 3 O 10 after 3 hours at 35 Hz.
  • FIG. 12 shows a PXRD diffractogram of the milling product of fluorspar with Na 4 P 2 O 7 after 3 hours at 35 Hz.
  • FIG. 13 shows a PXRD diffractogram of the milling product of fluorspar with Na 5 P 3 O 10 after 3 hours at 35 Hz.
  • FIG. 14 shows a PXRD diffractogram of the milling product of fluorspar with Na(PO 3 ) 3 after 3 hours at 35 Hz.
  • FIG. 15 shows a PXRD diffractogram of the milling product of fluorspar with CaHPO 4 after 3 hours at 30 Hz.
  • FIG. 16 shows a PXRD diffractogram of the milling product of fluorspar with Ca 3 (PO 4 ) 2 after 3 hours at 30 Hz.
  • FIG. 17 shows stacked PXRD diffractograms of the milling products of fluorspar after subsequent addition and milling at 30 Hz for 3 hours of K 2 HPO 4 resulting in CaF 2 :K 2 HPO 4 ratios of 1:1, 1:2, 1:2.5, and 1:3.
  • FIG. 18 shows the NMR yields of TsF from TsCl using fluorspar and K 2 HPO 4 as an activator wherein the fluorspar and K 2 HPO 4 are milled at different frequencies.
  • FIG. 19 shows the NMR yields of TsF from TsCl using fluorspar and varying amounts of K 2 HPO 4 activator resulting in the use of different ratios of CaF 2 :K 2 HPO 4 .
  • A 1 equivalent of K 2 HPO 4 was added to fluorspar
  • B 2 equivalents total are added
  • C 2.5 total equivalents of K 2 HPO 4 are added.
  • FIG. 20 shows the NMR yields of TsF from TsCl using fluorspar and K 2 HPO 4 as an activator with different amounts of water added to the fluorination reaction.
  • FIG. 21 shows the NMR yields of TsF from TsCl using fluorspar and K 2 HPO 4 as an activator with different amounts of water added to the fluorination reaction and 5 hour or 18 hour reaction times.
  • FIG. 22 shows the fluorination substrate scope of R—SO 2 Cl species.
  • FIG. 23 shows the fluorination substrate scope of R—X species.
  • FIG. 24 shows 19 F NMR (24A) and 31 P NMR (24B) of the soluble product of milling of fluorspar and K 2 HPO 4 .
  • FIG. 25 shows the PXRD diffractogram of the milling product of fluorspar with K 2 HPO 4 after 9 hours at 30 Hz referenced to crystalline KF (bottom).
  • FIG. 26 shows the PXRD diffractogram of the milling product (Fluoromix) of fluorspar reacted with K 2 HPO 4 .
  • FIG. 27 shows stacked PXRD diffractograms of (from top to bottom), fluorspar milled with K 2 HPO 4 for 9 hours at 30 Hz, KF milled with K 2 HPO 4 for 3 hours at 30 Hz, KF milled with K 2 HPO 4 for 3 hours at 30 Hz followed by CaHPO 4 for 3 hours at 30 Hz, and crystalline CaF 2 .
  • FIG. 28 shows the simulated crystal structure of the product of KF milled with K 2 HPO 4 for 3 hours at 30 Hz (A) and KF milled with K 2 HPO 4 for 3 hours at 30 Hz followed by CaHPO 4 for 3 hours at 30 Hz, and crystalline CaF 2 (B).
  • FIG. 29 shows stacked PXRD diffractograms of fluorspar, K 2 HPO 4 , and fluorapatite.
  • FIG. 30 shows overlayed PXRD diffractograms of fluoromix, KF milled with K 2 HPO 4 for 3 hours at 30 Hz, KF milled with K 2 HPO 4 for 3 hours at 30 Hz followed by CaHPO 4 for 3 hours at 30 Hz, and crystalline CaF 2 , and fluorspar.
  • FIG. 31 shows the PXRD diffractogram of the water insoluble solid formed from the milling reaction of CaF 2 (fluorspar) and K 2 HPO 4 .
  • FIG. 32 shows the PXRD diffractogram of water insoluble solid formed from the milling reaction of CaF 2 (fluorspar) and K 2 HPO 4 overlayed with the PXRD diffractogram of the milling product of fluorspar and CaHPO 4 (32A) and the PXRD diffractogram of the product formed from the milling reaction of fluorspar and CaHPO 4 after 3 hours at 30 Hz (32B).
  • FIG. 33 shows the PXRD diffractogram of X (KF milled with K 2 HPO 4 for 3 hours at 35 Hz).
  • FIG. 34 shows the PXRD diffractogram of Y (KF milled with K 2 HPO 4 for 3 hours at 35 Hz followed by CaHPO 4 for 3 hours at 35 Hz).
  • FIG. 35 shows the NMR yield of TsF from TsCl upon reaction with fluoromix or X (KF milled with K 2 HPO 4 for 3 hours at 35 Hz) or Y (KF milled with K 2 HPO 4 for 3 hours at 35 Hz followed by CaHPO 4 for 3 hours at 35 Hz) independently.
  • FIG. 36 shows the PXRD diffractogram of fluorspar with NaOH.
  • FIG. 37 shows NMR yields of TsF from TsCl using fluorspar and various non-phosphate activators.
  • FIG. 38 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K 2 CO 3 for 3 hours at 35 Hz.
  • FIG. 39 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KHCO 3 for 3 hours at 35 Hz.
  • FIG. 40 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K 2 SO 4 for 3 hours at 35 Hz.
  • FIG. 41 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KHSO 4 for 3 hours at 35 Hz.
  • FIG. 42 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K 2 S 2 O 7 for 3 hours at 35 Hz.
  • FIG. 43 shows the PXRD diffractogram of the product of the fluorspar milling reaction with Na 2 SO 3 for 1.5 hours at 35 Hz.
  • FIG. 44 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KNO 3 for 3 hours 35 Hz.
  • FIG. 45 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KOH for 3 hours 35 Hz.
  • FIG. 46 shows the PXRD diffractogram of the product of the fluorspar milling reaction with NaOH for 3 hours 35 Hz.
  • FIG. 47 shows the reaction scope of R—SO 2 Cl species with fluorapatite using a phosphate activator and associated yields.
  • FIG. 48 shows stacked PXRD diffractograms of the products of the fluorapatite milling reaction upon subsequent additions of K 4 P 2 O 7 (4 separate additions of 1 equivalent).
  • FIG. 49 shows the PXRD diffractogram of pure fluorapatite after 1 hour of milling overlayed with a fluorapatite sample (1 equiv.) that was milled for 12 hours total at 35 Hz with K 4 P 2 O 7 (4 equiv.).
  • FIG. 50 shows stacked PXRD diffractograms of the reaction 1:4 equiv. milling reaction (D) between fluorapatite (Ca 5 (PO 4 ) 3 F) and K 4 P 2 O 7 , and the milling reaction between potassium fluoride (KF, 1 equiv.) and K 2 HPO 4 (2 equiv., 35 Hz, 3 hours) followed by CaHPO 4 (1 equiv., 35 Hz, 3 hours).
  • D fluorapatite
  • K 4 P 2 O 7 the milling reaction between potassium fluoride (KF, 1 equiv.) and K 2 HPO 4 (2 equiv., 35 Hz, 3 hours) followed by CaHPO 4 (1 equiv., 35 Hz, 3 hours).
  • FIG. 51 shows the PXRD diffractogram of the water insoluble product of the reaction between fluorapatite and potassium pyrophosphate overlayed with the PXRD diffractogram of fluorapatite.
  • FIG. 52 shows the PXRD diffractogram of the milling reaction of fluorapatite and 1 equivalent of K 4 P 2 O 7 for 9 hours at 30 Hz.
  • FIG. 53 shows the PXRD diffractogram of the milling reaction of 4 subsequent additions of 1 equivalent of K 4 P 2 O 7 to 1 equivalent of fluorapatite with 3 hours of milling at 35 Hz after each addition.
  • FIG. 54 shows a general scheme for which the effect of the variation of screw temperature on the generation of active fluorination material was tested.
  • FIG. 55 shows a general scheme for which the effect of the variation of screw speed on the generation of active fluorination material was tested.
  • FIG. 56 shows a general scheme for which the effect of the variation of the number of recycling times on the generation of active fluorination material was tested.
  • FIG. 57 shows a general scheme for which only CaF 2 is added into the twin-screw extruder without the K 2 HPO 4 .
  • FIG. 58 shows a general scheme for which the effect of varying screw configuration on generation of active fluorination material was tested.
  • the term “about” or “approximately” may mean within an acceptable error range for the particular value, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. Unless otherwise specified herein, “about” generally refers to a range of +/ ⁇ 10% of the stated value. In the case of X-ray diffraction reflections, however, “about” generally refers to a range of +/ ⁇ 0.1° of the stated value. Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.
  • ranges include the range endpoints. Additionally, every sub range and value within the range is present as if explicitly written out.
  • Certain inventive embodiments herein contemplate characteristic x-ray diffraction reflections.
  • the presence or absence of a characteristic x-ray diffraction reflection is determined by identification of a peak in an x-ray diffraction spectrum located at a characteristic 2 ⁇ value.
  • a peak is present when a 2 ⁇ signal has a signal to noise ratio of at least 3.
  • a peak is present when a 2 ⁇ signal has a signal to noise ratio of at least 5. In certain embodiments, a peak is present when a 2 ⁇ signal has a signal to noise ratio of at least 10.
  • a peak is present when a 2 ⁇ signal has a signal to noise ratio of at least 20.
  • peaks are identified in a raw powder x-ray diffraction spectrum. In certain embodiments, peaks are identified in a background subtracted powder x-ray diffraction spectrum. In some embodiments, peaks corresponding to a first salt are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, peaks corresponding to a second salt are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, one or more known contaminant peaks are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, peaks corresponding to one or more of: a first salt, a second salt, and/or a known contaminant are subtracted from a raw spectrum to yield a background subtracted spectrum.
  • weight percentage refers to the percentage of said component by weight relative to the total weight of the product as a whole. It will be understood by those skilled in the art that the sum of weight percentages of all components of a product will total 100 wt. %. However, where not all components are listed (e.g. where a product is said to “comprise” one or more particular components), the weight percentage balance may optionally be made up to 100 wt % by unspecified ingredients.
  • the present invention provides a process for the preparation of a fluorinating reagent, the process comprising the step of:
  • Calcium fluoride (CaF 2 , melting point, ⁇ 1420° C.) is a white solid that is poorly soluble in water (0.016 g/L at 20° C.) and is insoluble in organic solvents. Under ambient conditions, calcium fluoride crystallizes in the fluorite structure ( ⁇ , space group Fm-3m) wherein Ca 2+ ions are cubically coordinated to eight nearest-neighbor F ⁇ ions.
  • the calcium fluoride used as part of the invention may be naturally occurring (i.e. as fluorspar) or may be synthetic (e.g. industrially produced calcium fluoride having fewer impurities).
  • Fluorapatite is a crystalline solid having the formula Ca 5 (PO 4 ) 3 F.
  • the process of the invention involves reacting the fluorine-containing compound (i.e., calcium fluoride and/or fluorapatite) with particular ionic compounds in the solid state using a high-energy mixing technique, such as one that is sufficient to mechanically reduce the particle size of (e.g. crush) the reactants and bring them into contact with one another. Pulverising together the reactants according to step a) achieves this objective. It will, however, be appreciated that synonymous high-energy mixing techniques resulting in particle size reduction of the reactants and/or an increased surface area to volume ratio of the reactants, such as crushing together, grinding together, milling together, mashing together, macerating together and the like, are embraced by step a).
  • the process may be a mechanochemical process and/or step a) may be conducted under mechanochemical conditions.
  • Mechanochemistry is a developing area of chemical synthesis and is widely understood to refer to chemical transformations that are initiated by and/or sustained by the application of a mechanical stress to one or more solid reactants.
  • Step a) may be conducted in a ball mill, a pestle and mortar or a twin screw extruder (TSE).
  • TSE twin screw extruder
  • Other techniques and apparatuses suitable for carrying out step a) will be familiar to one skilled in the art, e.g. those skilled in the art of mechanochemistry, including an ultrasonic bath and/or a mechanical press.
  • step a) is conducted in a ball mill.
  • ball mills include a planetary ball mill, a vibratory ball mill, an attritor ball mill or a tumbling ball mill. Most suitably, the ball mill is a vibratory ball mill.
  • a stainless steel vessel and one or more stainless steel balls may be used.
  • a zirconia vessel and one or more zirconia balls may be used.
  • a ball, or balls, (each) weighing 2-20 g (e.g., 3 g, 4 g, 7 g or 16 g) may, for example, be used.
  • Step a) may be carried out for any suitable period of time.
  • step a) may be carried out for 0.5-12 hours (e.g., the fluorine-containing compound and ionic compound may be ball milled together for 0.5-12 hours).
  • step a) comprises ball milling the fluorine-containing compound together with the ionic compound at a frequency of 0.5-80 Hz. More suitably, step a) comprises ball milling the fluorine-containing compound together with the ionic compound at a frequency of 5-65 Hz. Even more suitably, step a) comprises ball milling the fluorine-containing compound together with the ionic compound at a frequency of 15-45 Hz. Most suitably, step a) comprises ball milling the fluorine-containing compound together with the ionic compound at a frequency of 20-40 Hz (e.g., 28-38 Hz).
  • Twin screw extrusion may be performed at various speeds (S S ), screw temperatures (S T ) and residence times (T R ), as described herein. A single pass through the extruder may be sufficient to form the fluorinating reagent.
  • step a) may comprise collecting the product emerging from the twin screw extruder and subjecting it to one or more additional passes through the twin screw extruder.
  • Step a) is conducted in the solid state.
  • step a) is conducted in the absence (or substantial absence) of any solvent.
  • solvent is known to offer advantages in some solid state (e.g. mechanochemical) reactions. Examples of such techniques include solvent-assisted mechanochemistry (sometimes termed liquid-assisted mechanochemistry, e.g. liquid-assisted grinding).
  • the amount and type of solvent used (if any) is such that >50 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a).
  • step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).
  • step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound and the ionic compound in a twin screw extruder.
  • step a) the fluorine-containing compound is reacted with an ionic compound, the anion of which is combinable with Ca 2+ to form a calcium salt having a lattice energy that is greater than 2400 KJ mol ⁇ 1 .
  • lattice energy denoting the amount of energy required to dissociate one mole of an ionic compound into its constituent ions in the gaseous state.
  • Calcium fluoride and fluorapatite being only slightly soluble in certain acids, are chemically inert to nearly all organic chemicals.
  • the stability of calcium fluoride and fluorapatite is attributed in a large part to their high lattice energy (2630 KJ mol ⁇ 1 for calcium fluoride).
  • the inventors have, however, determined that this stability can be overcome by pulverising together (e.g. ball milling) calcium fluoride and/or fluorapatite with certain ionic compounds according to step a).
  • the inventors believe that the energetic bar to reactivity of calcium fluoride or fluorapatite can be overcome by the use of high-energy reaction conditions, combined with the use of a thermodynamic sink for Ca 2+ .
  • the use of ionic compounds, the anions of which e.g.
  • the fluorine-containing compound is typically calcium fluoride or fluorapatite.
  • the fluorine-containing compound is calcium fluoride.
  • a quantity of fluorapatite may form (e.g., transiently) during the course of step a).
  • the calcium fluoride is acid grade fluorspar.
  • the fluorine-containing compound used in the first aspect may be calcium fluoride, fluorapatite and/or any other salt comprising calcium and fluorine.
  • Such other salts may be described elsewhere herein as a first salt comprising calcium and fluorine.
  • the anion of the ionic compound is combinable with Ca 2+ to form a calcium salt having a lattice energy that is greater than the lattice energy of calcium fluoride (i.e. greater than 2630 KJ mol ⁇ 1 ).
  • the ionic compound is suitably inorganic.
  • the ionic compound may be a salt.
  • the ionic compound is a salt of an oxoacid.
  • the ionic compound may be a phosphate, carbonate, sulphate, sulphite or nitrate salt.
  • the ionic compound may be a phosphate, carbonate or sulphate salt.
  • phosphate, carbonate, sulphate, sulphite or nitrate salts described herein are salts that contains at least one of these anions, meaning that salts such as hydrogen phosphate salts, dihydrogen phosphate salts, hydrogen sulphate salts and bicarbonate salts are also encompassed.
  • phosphate salts encompass metaphosphate salts
  • phosphate salts and sulphate salts encompass pyrophosphate salts and pyrosulfate salts respectively.
  • the ionic compound may be a hydroxide salt or a citrate salt.
  • the ionic compound may be an alkali metal salt or an alkaline earth metal salt, for example a potassium salt, a sodium salt or a magnesium salt.
  • the ionic compound is a phosphate salt.
  • the ionic compound may be a phosphate salt of potassium, sodium or calcium, a sulphate salt of potassium, sodium or caesium, a carbonate salt of potassium or sodium, a sulphite salt of potassium or sodium, a nitrate salt of potassium or sodium, a hydroxide salt of potassium or sodium, or a citrate salt of potassium or sodium.
  • the ionic compound may be selected from the group consisting of K 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 , Na 3 PO 4 , Na 2 HPO 4 , KPO 3 , K 4 P 2 O 7 , K 5 P 3 O 10 , Na 4 P 2 O 7 , Na 5 P 3 O 10 , (NaPO 3 ) 3 , CaHPO 4 , K 2 CO 3 , KHCO 3 , K 2 SO 4 , KHSO 4 , Cs 2 SO 4 , MgSO 4 , Ag 2 SO 4 , K 2 S 2 O 7 , Na 2 SO 3 , Na 2 SO 4 , Na 2 CO 3 , KNO 3 , Na 3 C 6 H 5 O 7 , NaOH and KOH.
  • the ionic compound include phosphate salts of potassium and sodium, sulphate salts of potassium and sodium, and carbonate salts of potassium and sodium.
  • the ionic compound is a phosphate salt of potassium or sodium. More suitably, the ionic compound is a phosphate salt of potassium.
  • the ionic compound is K 3 PO 4 or K 2 HPO 4 , of which K 2 HPO 4 is most preferred.
  • the ionic compound may be selected from the group consisting of K 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 , KPO 3 , Na 3 PO 4 , Na 2 HPO 4 , Cs 2 SO 4 , Na 2 SO 3 , K 4 P 2 O 7 , K 5 P 3 O 10 , Na 4 P 2 O 7 , Na 5 P 3 O 10 , Na 3 C 6 H 5 O 7 , K 2 SO 4 , Na 2 SO 4 , MgSO 4 , Na 2 CO 3 , K 2 CO 3 , KHCO 3 , NaOH and KOH.
  • the ionic compound is selected from the group consisting of K 3 PO 4 , K 2 HPO 4 , KPO 3 , Na 3 PO 4 , Na 2 HPO 4 , K 4 P 2 O 7 , K 5 P 3 O 10 , Na 4 P 2 O 7 , Na 5 P 3 O 10 , K 2 CO 3 , KHCO 3 , NaOH and KOH. More suitably, the ionic compound is selected from the group consisting of K 2 HPO 4 , KPO 3 , Na 2 HPO 4 , K 4 P 2 O 7 , K 5 P 3 O 10 and Na 4 P 2 O 7 .
  • the ionic compound used in the first aspect may be described elsewhere herein as a second salt.
  • the ionic compound is K 2 HPO 4 , KPO 3 , Na 2 HPO 4 , K 4 P 2 O 7 , K 5 P 3 O 10 or Na 4 P 2 O 7 and step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).
  • the ionic compound is a phosphate, sulphate or carbonate salt of potassium or sodium (e.g. K 3 PO 4 or K 2 HPO 4 ) and step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).
  • the molar ratio of the fluorine-containing compound to the ionic compound in step a) may be (0.1-7):1 (e.g., (0.3-6):1).
  • the molar ratio of the fluorine-containing compound to the ionic compound in step a) may be (0.5-5):1. More suitably, the molar ratio of the fluorine-containing compound to the ionic compound in step a) is (1-2):1.
  • the ionic compound is pulverized together with the fluorine-containing compound in portions.
  • step a) may comprise: (a-i) pulverising together the fluorine-containing compound and a first portion of the ionic compound, and (a-ii) pulverising together the product of step (a-i) and a second portion of the ionic compound.
  • step a) further comprises a step (a-iii) of pulverising together the product of step (a-ii) and a third portion of the ionic compound.
  • step a) further comprises a step (a-iv) of pulverising together the product of step (a-iii) and a fourth portion of the ionic compound.
  • the portions of the ionic compound may be the same or different.
  • solid CO 2 i.e., dry ice
  • fluorine-containing compound i.e., dry ice
  • ionic compound between 5 and 15 equivalents of solid CO 2 (relative to 1 equivalent of fluorine-containing compound) may be used in step a).
  • the product resulting from step a) may be heat-treated.
  • the product resulting from step a) may be heated to a temperature of 300-700° C. (e.g., 500-600° C.).
  • essentially no HF is produced at any point during step a).
  • ⁇ 1 ppm e.g., ⁇ 1 ppb
  • HF may be produced at any point during step a).
  • the fluorinating reagent afforded by step a) can be used to prepare a fluorochemical (e.g. an organic fluorochemical).
  • a fluorochemical e.g. an organic fluorochemical.
  • the organic substrate to be fluorinated may take a variety of forms.
  • the organic substrate is an electrophile.
  • the organic substrate may be aliphatic (e.g. an alkyl halide) or aromatic (e.g. an aryl halide or a heteroaryl halide) in nature.
  • the organic substrate suitably has at least one leaving group located at the site to be fluorinated. Leaving groups will be known to those of skill in the art of organic chemistry. Particular, non-limiting examples of suitable leaving groups include halide (particularly chloro or bromo), tosylate, triflate, mesylate, phosphate, nitro, ammonium and iodonium groups. Most suitably, the leaving group is halide.
  • the organic substrate may be any one of those organic substrates employed in the Examples outlined herein.
  • the exemplified leaving group(s) may, where chemically feasible, be replaced with any one of the other aforementioned leaving groups.
  • the organic substrate is a sulphonyl halide, an acyl halide, an aryl halide or an alkyl halide (including alkylaryl halides, such as benzyl halides).
  • halide is suitably chloride.
  • Sulphonyl, acyl, aryl and benzylic fluorides are among the most common fluorinated motifs in organic synthesis with broad applicability as either reagents, synthetic intermediates or biological probes. More suitably, the organic substrate is a sulphonyl halide, an acyl halide, an aryl halide or a heteroaryl halide.
  • aromatic sulphonyl halide e.g. tosyl chloride
  • benzoyl halides e.g. 4-methoxybenzoyl chloride
  • halobenzenes e.g. chlorobenzene
  • benzyl halides e.g. benzyl chloride
  • the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an ⁇ -halo carbonyl or an alkyl halide.
  • the organic substrate is ArOCHX 2 , wherein Ar is an aromatic group (e.g., biphenyl) and X is halide (e.g., chloro).
  • Ar is an aromatic group (e.g., biphenyl) and X is halide (e.g., chloro).
  • the leaving groups may be attached to the same carbon atom (e.g., 2 geminal halide leaving groups).
  • the organic substrate has a molecular weight of ⁇ 500 g mol ⁇ 1 .
  • the organic substrate has a molecular weight of ⁇ 300 g mol ⁇ 1 .
  • the organic substrate is a sulfonyl halide, an acyl halide, an aryl halide or an alkyl halide (e.g. where halide is bromide) and the ionic compound used in step a) is a phosphate, sulphate or carbonate salt of potassium or sodium (e.g. K 3 PO 4 or K 2 HPO 4 ).
  • step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound).
  • the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an ⁇ -halo carbonyl or an alkyl halide and the ionic compound used in step a) is a phosphate, carbonate, sulphate, sulphite, nitrate, hydroxide or citrate salt (e.g.
  • step a) is conducted in the absence (or substantial absence) of any solvent.
  • step a) involves pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound) or a twin screw extruder.
  • Step b) may be conducted simultaneously with step a), such that the organic substrate is available for reaction with the fluorinating reagent as soon as the latter forms during step a).
  • step b) may comprise contacting the organic substrate with the fluorinating reagent under identical conditions to those used to form the fluorinating reagent.
  • steps a) and b) may collectively define a single step in which the fluorine-containing compound, the ionic compound and the organic substrate are pulverised together in the solid state (e.g. by ball milling).
  • step b) may be conducted after step a), such that a quantity of fluorinating reagent is allowed to form before being reacted with the organic substrate.
  • step b) may be conducted in the solid state.
  • step b) may comprise pulverising together the organic substrate and the fluorinating reagent formed from step a) in the solid state.
  • step b) is conducted in a ball mill. More suitably, step b) is conducted in the absence (or substantial absence) of a solvent.
  • steps a) and b) are both conducted in a ball mill (e.g. the same ball mill), suitably in the absence (or substantial absence) of a solvent.
  • step b) may be conducted in solution.
  • step b) may comprise mixing together the organic substrate and the fluorinating reagent in a solvent in which the organic substrate is soluble. Any suitable solvent or combinations of solvents may be used depending on the nature of the organic substrate, including, for example, those solvents employed in the Examples outlined herein (e.g., those listed in Table 3.5).
  • the solvent may, for example, be selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, propionitrile, tert-butyl isocyanide, tert-butanol, tert-amyl alcohol, toluene, m-xylene, hexane, trifluorotoluene, 1,2-difluorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, fluorobenzene and chlorobenzene.
  • step b) is conducted in a solvent selected from the group consisting of acetonitrile, toluene, chlorobenzene, 1,2-difluorobenzene, dichloroethane, trifluorotoluene, chloroform, tert-butanol and tert-amyl alcohol. More suitably, step b) is conducted in acetonitrile, chlorobenzene, tert-butanol or tert-amyl alcohol. Most suitably, step b) is conducted in acetonitrile.
  • any one or more of the aforementioned organic solvents may be in admixture with water.
  • the organic solvent may be in admixture with water at a concentration of 0.01-5M.
  • the organic solvent may be in admixture with water at a concentration of 0.01-1M (e.g., 0.05-0.5M).
  • step b) is conducted after step a), and step b) is conducted a solvent selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, propionitrile, tert-butyl isocyanide, tert-butanol, tert-amyl alcohol, toluene, m-xylene, hexane, trifluorotoluene, 1,2-difluorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, fluorobenzene and chlorobenzene, any one of which may be in admixture with water.
  • a solvent selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, pro
  • the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an ⁇ -halo carbonyl or an alkyl halide and the ionic compound used in step a) is a phosphate, carbonate, sulphate, sulphite, nitrate, hydroxide or citrate salt (e.g.
  • Step a) may involve pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound) or a twin screw extruder.
  • the fluorine-containing compound e.g., calcium fluoride
  • the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound) or a twin screw extruder.
  • step b) When step b) is conducted after step a), the fluorinating reagent formed in step a) may be isolated or purified prior to reacting it with the organic substrate.
  • step b) when step b) is conducted in solution after step a), step b) may be performed at a temperature of 15-180° C. Suitably, step b) is performed at a temperature of 15-150° C.
  • Step b) may be conducted in the presence of at least one of a cryptand, a crown ether and a hydrogen-bonding phase transfer catalysts.
  • step b) is conducted after step a), and is performed in solution.
  • Suitable cryptands include Kryptofix 221® and Kryptofix 222®.
  • Suitable crown ethers include 18-crown-6, dibenzo-18-crown-6, dibenzo-30-crown-10 and dicyclohexano-18-crown-6.
  • Suitable hydrogen-bonding phase transfer catalysts include Schreiner's urea. Amongst the aforementioned cryptands, crown ethers and hydrogen-bonding phase transfer catalysts, 18-crown-6 and dibenzo-18-crown-6 are particularly suitable.
  • the process may further comprise one or more additional steps in which the fluorochemical formed in step b) is isolated and/or purified.
  • the fluorochemical may be otherwise described herein as a fluorinated compound or an organo-fluorine compound.
  • the present invention provides a process for the preparation of a fluorochemical, the process comprising the steps of:
  • the inventors have surprisingly determined that the formation of HF can be bypassed and calcium fluoride or fluorapatite can be directly converted into value-added fluorochemicals using a process that is similar to the process to the first aspect, albeit without the need for the fluorine-containing compound to be pulverised together with an ionic compound as defined herein.
  • steps a) and b) of the third aspect may have any of those definitions recited hereinbefore in relation to corresponding steps a) and b) of the first and second aspect.
  • step b) is conducted in solution, in the presence of an ionic compound as defined herein (e.g. K 2 HPO 4 ).
  • an ionic compound as defined herein e.g. K 2 HPO 4
  • the present invention provides a use of a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.
  • the present invention provides a use of a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorinating reagent, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.
  • a fluorinating reagent obtained, directly obtained or obtainable by a process of the first aspect.
  • a fluorinating reagent comprising a mixture of inorganic salts.
  • the fluorinating reagent may be provided as a mixture of inorganic salts.
  • the fluorinating reagent suitably comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur, nitrogen and carbon. More suitably, the fluorinating reagent comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur and carbon. Most suitably, the fluorinating reagent comprises calcium, fluorine, oxygen, potassium and phosphorus.
  • the fluorinating reagent may additionally comprise hydrogen.
  • the mixture of inorganic salts suitably comprises a first inorganic salt and a second inorganic salt, wherein: (i) the first inorganic salt comprises Ca 2+ and at least one anion selected from phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide, and (ii) the second inorganic salt comprises fluoride and at least one cation selected from K + and Na 2+ .
  • the first inorganic salt comprises Ca 2+ and at least one anion selected from phosphate, sulfate, carbonate and hydroxide (e.g., phosphate), and/or the second inorganic salt comprises fluoride and K + .
  • the mixture of inorganic salts may further comprise one or more additional inorganic salts (i.e., in addition to the first and second inorganic salts), each comprising a cation selected from Ca 2+ , K + and Na 2+ , and an anion selected from fluoride, phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide (e.g., fluoride, phosphate, carbonate and hydroxide).
  • additional inorganic salts i.e., in addition to the first and second inorganic salts
  • each comprising a cation selected from Ca 2+ , K + and Na 2+
  • an anion selected from fluoride, phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide e.g., fluoride, phosphate, carbonate and hydroxide.
  • the fluorinating reagent may comprise calcium fluoride and/or fluorapatite.
  • Trace quantities i.e., those detectable by XRPD
  • Fluorapatite may be present in the fluorinating reagent even when it is not used as the fluorine-containing compound in the process of the first aspect.
  • the fluorinating reagent may be provided as a powder.
  • the powder may have an average particle size, as determined by SEM or TEM analysis, of ⁇ 500 ⁇ m.
  • the powder has an average particle size of ⁇ 100 ⁇ m. More suitably, the powder has an average particle size of ⁇ 50 ⁇ m.
  • the fluorinating reagent may have an XRPD pattern comprising peaks corresponding ⁇ 0.2° 2 ⁇ to at least 10%, at least 30%, at least 50%, at least 70%, at least 90%, or 100% of the 2-theta values reported in any one of Tables 5.7.1-5.7.13, 5.12.1, and 6.3.1-6.3.9, outlined herein.
  • the fluorinating reagent may have an XRPD pattern comprising peaks corresponding ⁇ 0.2° 2 ⁇ to at least 30% of the 25 2-theta values reported in Table 5.12.1 outlined herein, meaning that the fluorinating reagent may have an XRPD pattern comprising peaks corresponding to at least 8 of those 2-theta values reported in Table 5.12.1 (e.g., those not attributed to CaF 2 ), recognising that each 2-theta value reported in Table 5.12.1 can be modified ⁇ 0.2° 2 ⁇ .
  • the fluorinating reagent may have an XRPD pattern comprising peaks corresponding ⁇ 0.2° 2 ⁇ to at least 50% of the 33 2-theta values reported in Table 6.3.3 outlined herein, meaning that the fluorinating reagent may have an XRPD pattern comprising peaks corresponding to at least 17 of those 2-theta values reported in Table 6.3.3, recognising that each 2-theta value reported in Table 5.12.1 can be modified ⁇ 0.2° 2 ⁇ .
  • the fluorinating reagent has an XRPD pattern comprising peaks corresponding ⁇ 0.2° 2 ⁇ to at least 10%, at least 30%, at least 50%, at least 70%, at least 90%, or 100% of the 2-theta values reported in any one of Tables 5.7.2-5.7.11 and 5.12.1 outlined herein. More suitably, the fluorinating reagent has an XRPD pattern comprising peaks corresponding ⁇ 0.2° 2 ⁇ to at least 10%, at least 30%, at least 50%, at least 70%, at least 90%, or 100% of the 2-theta values reported in any one of Tables 5.7.7, 5.7.8 and 5.12.1 outlined herein.
  • the fluorinating reagent may have an XRPD pattern comprising peaks at 2-theta values of 21.9 ⁇ 0.2° 2 ⁇ , 30.3 ⁇ 0.2° 2 ⁇ , 31.6 ⁇ 0.2° 2 ⁇ and 43.4 ⁇ 0.2° 2 ⁇ .
  • the XRPD pattern may comprise one or more additional peaks at 2-theta values of 18.0 ⁇ 0.2° 2 ⁇ , 18.7 ⁇ 0.2° 2 ⁇ , 22.6 ⁇ 0.2° 2 ⁇ , 24.5 ⁇ 0.2° 2 ⁇ , 25.4 ⁇ 0.2° 2 ⁇ , 26.5 ⁇ 0.2° 2 ⁇ , 27.0 ⁇ 0.2° 2 ⁇ , 28.0 ⁇ 0.2° 2 ⁇ , 29.2 ⁇ 0.2° 2 ⁇ , 33.0 ⁇ 0.2° 2 ⁇ , 34.8 ⁇ 0.2° 2 ⁇ , 36.4 ⁇ 0.2° 2 ⁇ , 37.7 ⁇ 0.2° 2 ⁇ , 39.5 ⁇ 0.2° 2 ⁇ , 40.4 ⁇ 0.2° 2 ⁇ , 41.7 ⁇ 0.2° 2 ⁇ , 42.4 ⁇ 0.2° 2 ⁇ , 46.1 ⁇ 0.2° 2 ⁇ , 48.4 ⁇ 0.2° 2 ⁇ , 49.4 ⁇ 0.2° 2 ⁇ , 52.8 ⁇ 0.2° 2 ⁇
  • the XRPD pattern may comprise peaks at at least five, at least ten, at least fifteen or at least twenty of the aforementioned 2-theta values.
  • the fluorinating reagent may have an XRPD pattern substantially the same as that shown in FIG. 10 .
  • the fluorinating reagent comprises calcium, fluorine, oxygen, potassium and phosphorus, and/or (ii) comprises a first inorganic salt and a second inorganic salt, wherein the first inorganic salt comprises Ca 2+ and phosphate, and the second inorganic salt comprises fluoride and K + .
  • the fluorinating reagent may have an XRPD pattern comprising one or more peaks at 2-theta values of 17.5 ⁇ 0.2° 2 ⁇ , 21.2 ⁇ 0.2° 2 ⁇ , 23.5 ⁇ 0.2° 2 ⁇ , 24.8 ⁇ 0.2° 2 ⁇ , 29.4 ⁇ 0.2° 2 ⁇ , 29.6 ⁇ 0.2° 2 ⁇ , 30.5 ⁇ 0.2° 2 ⁇ , 31.5 ⁇ 0.2° 2 ⁇ , 35.4 ⁇ 0.2° 2 ⁇ , 36.7 ⁇ 0.2° 2 ⁇ , 37.4 ⁇ 0.2° 2 ⁇ , 39.8 ⁇ 0.2° 2 ⁇ , 42.9 ⁇ 0.2° 2 ⁇ , 47.1 ⁇ 0.2° 2 ⁇ , 48.1 ⁇ 0.2° 2 ⁇ , 51.4 ⁇ 0.2° 2 ⁇ , 53.2 ⁇ 0.2° 2 ⁇ , 54.2 ⁇ 0.2° 2 ⁇ , 58.2 ⁇ 0.2° 2 ⁇ , 60.9 ⁇ 0.2° 2 ⁇ and 63.4 ⁇ 0.2° 2 ⁇ .
  • the XRPD pattern may at least two, at least three, at least four, at least five, at least ten, at least fifteen or at least twenty of the aforementioned 2-theta values.
  • the fluorinating reagent may have an XRPD pattern substantially the same as that shown in FIG. 26 .
  • the fluorinating reagent comprises calcium, fluorine, oxygen, potassium and phosphorus, and/or (ii) comprises a first inorganic salt and a second inorganic salt, wherein the first inorganic salt comprises Ca 2+ and phosphate, and the second inorganic salt comprises fluoride and K + .
  • the fluorinating reagent may comprise K 3 (HPO 4 )F.
  • the fluorinating reagent may comprise K 3 (HPO 4 )F and has an XRPD pattern comprising one or more peaks at 2-theta values of 21.1 ⁇ 0.2° 2 ⁇ , 29.6 ⁇ 0.2° 2 ⁇ , 30.5 ⁇ 0.2° 2 ⁇ , 37.4 ⁇ 0.2° 2 ⁇ , 42.9 ⁇ 0.2° 2 ⁇ , 54.2 ⁇ 0.2° 2 ⁇ , 58.2 ⁇ 0.2° 2 ⁇ and 60.9 ⁇ 0.2° 2 ⁇ .
  • the fluorinating reagent comprises at least two, at least three, at least four, at least five, at least six, at least seven, or eight peaks at the aforementioned 2-theta values. More suitably, the fluorinating reagent comprises peaks at all eight of the aforementioned 2-theta values.
  • the fluorinating reagent may further comprise calcium fluoride and/or fluorapatite (e.g., trace quantities of calcium fluoride and/or fluorapatite).
  • the fluorinating reagent may have an XRPD pattern substantially as shown in any one of FIGS. 4 - 16 . 26 . 38 - 46 and 52 - 53 .
  • the fluorinating reagent has an XRPD pattern substantially as shown in any one of FIGS. 10 , 11 and 26 .
  • a fluorinating reagent is a reagent which, under those conditions described herein, is able to fluorinate an organic substrate described herein.
  • the fluorinating reagent of the sixth or seventh aspect may be used in the process of the second aspect.
  • step a) of the second aspect may comprise providing a fluorinating reagent of the sixth or seventh aspect.
  • an activated fluorinated reagent comprising a first salt, the first salt comprising calcium and fluorine, and a second salt.
  • the second salt comprises an anion. The first salt and second salt are described elsewhere herein.
  • provided herein is a method of synthesizing a fluoro compound. In some embodiments, provided herein is a method of synthesizing an organo-fluorine compound. In some embodiments, the method comprises combining a first salt, the first salt comprising calcium and fluorine, with a second salt to form a salt mixture.
  • compositions and methods that use a first salt.
  • any suitable first salt is used.
  • the first salt comprises calcium and fluorine.
  • the first salt comprises fluorine.
  • the first salt comprises calcium.
  • the first salt is CaF 2 .
  • the first salt is fluorspar.
  • the first salt is fluorapatite (Ca 5 (PO 4 ) 3 F).
  • waste material comprises the first salt.
  • the first salt is added in an amount necessary to provide an activated fluorination reagent.
  • the methods and compositions described herein do not comprise reacting a strong acid with the first salt to form hydrofluoric acid. In some embodiments, essentially no HF is produced during the reaction. In some embodiments, ⁇ 1 ppm of HF is observable in a mixture at any point during the reaction. In some embodiments, ⁇ 1 ppb of HF is observable in a mixture at any point during the reaction.
  • compositions and methods that use a second salt.
  • any suitable second salt is used in any composition or method provided herein.
  • the second salt comprises an anion.
  • the second salt comprises an anion, which has a lattice energy greater than 2450 kJ/mol when combined with Ca 2+ to form a third salt.
  • the second salt comprises a cation and anion.
  • any composition or method herein comprises a second salt, the second salt comprising an anion, which has a lattice energy greater than 2450 kJ/mol when combined with Ca 2+ to form a third salt.
  • the anion and Ca 2+ can form a third salt which has a lattice energy greater than 2450 kJ/mol when combined.
  • the fluorinating reagent comprises a salt which has a lattice energy greater than 2450 kJ/mol.
  • the second salt is a metal hydroxide. In some embodiments, the second salt is NaOH and/or KOH. In some embodiments, the second salt is NaOH. In some embodiments the second salt is KOH. In some embodiments, the second salt is a metal sulphite. In some embodiments, the second salt comprises Na 2 SO 3 and/or K 2 SO 3 . In some embodiments, the second salt is Na 2 SO 3 . In some embodiments, the second salt is K 2 SO 3 . In some embodiments, the second salt is a metal sulphate. In some embodiments, the second salt comprises KHSO 4 . In some embodiments, the second salt is an inorganic phosphate.
  • the second salt comprises K 2 HPO 4 , KH 2 PO 4 , and/or K 3 PO 4 . In some embodiments, the second salt is K 2 HPO 4 . In some embodiments, the second salt is KH 2 PO 4 . In some embodiments, the second salt is K 3 PO 4 . In some embodiments, the inorganic phosphate is a pyrophosphate. In some embodiments, the inorganic phosphate comprises K 4 P 2 O 7 and/or Na 3 P 2 O 7 .
  • an inorganic phosphate is K 4 P 2 O 7 . In some embodiments, an inorganic phosphate is Na 3 P 2 O 7 .
  • the second salt is Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , K 2 SO 4 , Na 2 SO 4 , MgSO 4 , Ag 2 SO 4 , Na 2 CO 3 , and/or KHCO 3 . In some embodiments, the second salt comprises Na 3 PO 4 . In some embodiments, the second salt comprises Na 2 HPO 4 . In some embodiments, the second salt comprises NaH 2 PO 4 .
  • the second salt comprises K 2 SO 4 . In some embodiments, the second salt comprises Na 2 SO 4 . In some embodiments, the second salt comprises MgSO 4 . In some embodiments, the second salt comprises Ag 2 SO 4 . In some embodiments, the second salt comprises Na 2 CO 3 . In some embodiments, the second salt comprises KHCO 3 .
  • any suitable ratio of first salt to second is used in any composition or method provided herein. In some embodiments, any suitable ratio of first salt to second is used in any composition or method provided herein. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:150 or any range therein. In some embodiments, the ratio of first salt to second salt is about 2:1 to 150:1 or any range therein. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:100. In some embodiments, the ratio of the first salt to the second salt is about 1:1 to 1:10. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:2. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:4.
  • the ratio of first salt to second salt is about 1:0.5 to 1:8. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:10. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:20. In some embodiments, the ratio of the first salt to the second salt is about 1:1 to 1:5. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100.
  • the range of first salt to second salt is about 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1.
  • the ratio of the first salt to the second salt is about 1:1. In some embodiments, the ratio of the first salt to the second salt is about 1:2. In some embodiments, the ratio of the first salt to the second salt is about 1:3. In some embodiments, the ratio of the first salt to the second salt is about 1:5. In some embodiments, the range of first salt to second salt is 1:8. In some embodiments, the ratio of first salt to second salt is 2:1.
  • the method comprises applying mechanical force to the salt mixture to form an activated salt-mixture.
  • the activated salt mixture is the fluorinating reagent.
  • the activated salt mixture is the activated fluorinated reagent.
  • mechanical force is applied to the salt mixtures provided in any of the compositions or methods herein. In some embodiments, mechanical force is applied to the salt-waste mixtures provided herein. In some embodiments, mechanical force is applied to the salt mixtures provided herein to yield activated fluorinated reagents.
  • mechanical force is applied to the salt-waste mixtures provided herein to yield activated fluorinated reagents.
  • the mechanical force is applied using a ball mill, a mortar and pestle, a twin-screw extruder, using an ultrasonic bath, or a mechanical press.
  • the mechanical force is applied using a ball mill. In some embodiments, the mechanical force is applied using a mortar and pestle. In some embodiments, the mechanical force is applied using a twin-screw extruder. In some embodiments, the mechanical force is applied using an ultrasonic bath. In some embodiments, the mechanical force is applied using a mechanical press.
  • mechanical frequency is applied at any suitable frequency in any composition or method provided herein.
  • the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz or any range therein.
  • the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz.
  • the mechanical force is applied at a frequency of about 0.5 Hz-10 Hz.
  • the mechanical force is applied at a frequency of about 0.5 Hz-100 Hz.
  • the mechanical force is applied at a frequency of about 0.5-1 kHz.
  • the mechanical force is applied at a frequency of about 0.5-10 kHz.
  • the mechanical force is applied at a frequency of about 0.5-20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-30 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-50 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 10 Hz-20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz, 1 Hz, 5 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz, 55 Hz, or 60 Hz.
  • the mechanical force is applied at a frequency of about 1 kHz, 5 kHz, 10 kHz, 15 kHz, 20 kHz, 25 kHz, 30 kHz, 35 kHz, 40 kHz, 45 kHz, 50 kHz, 55 kHz, or 60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 30 Hz. In some embodiments, the mechanical force is applied at a frequency of about 35 Hz. In some embodiments, the mechanical force is applied at a frequency of about 60 Hz.
  • the mechanical frequency is applied at any suitable temperature in any composition or method provided herein.
  • the mechanical force is applied at a temperature of about 20° C. to about 300° C. In some embodiments, the mechanical force is applied at a temperature of about 20° C. to about 30° C., about 20° C. to about 40° C., about 20° C. to about 60° C., about 20° C. to about 90° C., about 20° C. to about 100° C., about 20° C. to about 130° C., about 20° C. to about 150° C., about 20° C. to about 200° C., about 20° C. to about 250° C., about 20° C. to about 280° C., about 20° C.
  • the mechanical force is applied at a temperature of about 20° C., about 30° C., about 40° C., about 60° C., about 90° C., about 100° C., about 130° C., about 150° C., about 200° C., about 250° C., about 280° C., or about 300° C. In some embodiments, the mechanical force is applied at a temperature of at least about 20° C., about 30° C., about 40° C., about 60° C., about 90° C., about 100° C., about 130° C., about 150° C., about 200° C., about 250° C., or about 280° C.
  • the mechanical force is applied at a temperature of at most about 30° C., about 40° C., about 60° C., about 90° C., about 100° C., about 130° C., about 150° C., about 200° C., about 250° C., about 280° C., or about 300° C. In some embodiments, the mechanical force is applied at a temperature of about 30° C. In some embodiments, the mechanical force is applied at a temperature of about 60° C. In some embodiments, the mechanical force is applied at a temperature of about 90° C.
  • the mechanical force may be applied to the first and second salt together. In any of the compositions or methods provided herein, the mechanical force may be applied to the first salt alone. In some embodiments, the mechanical force may be applied for any suitable time period.
  • the mechanical force may be applied for about 0.5 hours to about 12 hours. In some embodiments, the mechanical force may be applied for 0.5-1 hour. In some embodiments, the mechanical force may be applied for 0.5-4 hours. In some embodiments, the mechanical force may be applied for 0.5-8 hours. In some embodiments, the mechanical force may be applied for 4-8 hours. In some embodiments, the mechanical force may be applied for 4-12 hours. In some embodiments, the mechanical force may be applied for about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In some embodiments, the mechanical force is applied for about 1 hour. In some embodiments, the mechanical force is applied for about 2 hours. In some embodiments, the mechanical force is applied for about 3 hours.
  • the mechanical force is applied for about 4 hours. In some embodiments, the mechanical force is applied for about 6 hours. In some embodiments, the mechanical force is applied for about 9 hours. In some embodiments, longer mechanical force times may be associated with higher yields of fluorinated product.
  • salt mixtures produced by ball milling in any composition or method provided herein are salt mixtures produced by ball milling in any composition or method provided herein.
  • ball milling is completed by combining said salts into jars and adding balls.
  • the jars and balls comprise stainless steel.
  • the jar has a volume of 15 mL. In some embodiments, the jar has a volume of 30 mL. In some embodiments, multiple balls are used. In some embodiments, 2-20 balls are used. In some embodiments, 1 ball is used. In some embodiments, the ball weight is 1-20 g or any range therein. In some embodiments, the ball weight is 1-2 g. In some embodiments, the ball weight is 1-3 g. In some embodiments, the ball weight is 1-5 g. In some embodiments, the ball weight is 1-10 g. In some embodiments, the ball weight is 1-13 g. In some embodiments, the ball weight is 1-18 g. In some embodiments, the ball weight is 1-3 g.
  • the ball weight is 3-5 g. In some embodiments, the ball weight is 3-10 g. In some embodiments, the ball weight is 5-10 g. In some embodiments, the ball weight is 5-18 g. In some embodiments, the ball weight is 5-20 g. In some embodiments, the ball weight is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 g. In some embodiments, the ball weight is 2 g. In some embodiments, the ball weight is 3 g. In some embodiments, the ball weight is 4 g. In some embodiments, the ball weight is 7 g. In some embodiments, the ball weight is 9 g. In some embodiments, 2 balls were used and the ball weights were 3 g. In some embodiments, the ball weight is 16 g. In some instances, ball weight is used as an analog of ball size. In some embodiments, the ball size may affect the fluorination reaction yield.
  • FIG. 54 shows a schematic of a twin-screw extruder (TSE) wherein the first and second salts may be added into the TSE at a rate of F R , followed by extruding of the salts at varying screw speeds (S S ), screw temperatures (S T ), and residence times (T R ), providing the fluorinating reagent (e.g., fluoromix).
  • TSE twin-screw extruder
  • the screw configuration may be modified wherein C indicates conveying, K indicates kneading, and R indicates reverse elements.
  • the screw temperature (S T ) in a twin-screw extruder is applied at any suitable temperature in any composition or method provided herein.
  • the screw temperature is about 0° C. to about 300° C.
  • the screw temperature is about 0° C. to about 25° C., about 0° C. to about 50° C., about 0° C. to about 100° C., about 0° C. to about 150° C., about 0° C. to about 200° C., about 0° C. to about 250° C., about 0° C. to about 300° C., about 25° C. to about 50° C., about 25° C. to about 100° C., about 25° C.
  • the screw temperature is about 0° C., about 25° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., or about 300° C. In some embodiments, the screw temperature is 50° C. In some embodiments, the screw temperature is 100° C. In some embodiments, the screw temperature is 150° C. In some embodiments, the screw temperature is 200° C.
  • the screw speed (S S ) in a twin-screw extruder is applied at any suitable speed in any composition or method provided herein. In some embodiments, the screw speed is set at a range of about 1 rpm to about 80 rpm.
  • the screw speed is set at a range of about 1 rpm to about 5 rpm, about 1 rpm to about 10 rpm, about 1 rpm to about 15 rpm, about 1 rpm to about 25 rpm, about 1 rpm to about 40 rpm, about 1 rpm to about 50 rpm, about 1 rpm to about 60 rpm, about 1 rpm to about 70 rpm, about 1 rpm to about 75 rpm, about 1 rpm to about 80 rpm, about 5 rpm to about 10 rpm, about 5 rpm to about 15 rpm, about 5 rpm to about 25 rpm, about 5 rpm to about 40 rpm, about 5 rpm to about 50 rpm, about 5 rpm to about 60 rpm, about 5 rpm to about 70 rpm, about 5 rpm to about 75 rpm, about 5 rpm to about 80 rpm, about 10 rpm to about 15 rpm,
  • the screw speed is set at a range of about 1 rpm, about 5 rpm, about 10 rpm, about 15 rpm, about 25 rpm, about 40 rpm, about 50 rpm, about 60 rpm, about 70 rpm, about 75 rpm, or about 80 rpm. In some embodiments, the screw speed is 10 rpm. In some embodiments, the screw speed is 25 rpm. In some embodiments, the screw speed is 75 rpm.
  • the residence time (T R ) in a twin-screw extruder is set to any suitable time in any composition or method provided herein.
  • the residence time is about 1 seconds to about 420 seconds.
  • the residence time is about 1 seconds to about 20 seconds, about 1 seconds to about 40 seconds, about 1 seconds to about 60 seconds, about 1 seconds to about 80 seconds, about 1 seconds to about 120 seconds, about 1 seconds to about 140 seconds, about 1 seconds to about 165 seconds, about 1 seconds to about 220 seconds, about 1 seconds to about 300 seconds, about 1 seconds to about 420 seconds, about 20 seconds to about 40 seconds, about 20 seconds to about 60 seconds, about 20 seconds to about 80 seconds, about 20 seconds to about 120 seconds, about 20 seconds to about 140 seconds, about 20 seconds to about 165 seconds, about 20 seconds to about 220 seconds, about 20 seconds to about 300 seconds, about 20 seconds to about 420 seconds, about 40 seconds to about 60 seconds, about 40 seconds to about 80 seconds, about 40 seconds to about 120 seconds, about 20 seconds to about 140 seconds, about 20 seconds to about 165 seconds,
  • the residence time is about 1 seconds, about 20 seconds, about 40 seconds, about 60 seconds, about 80 seconds, about 120 seconds, about 140 seconds, about 165 seconds, about 220 seconds, about 300 seconds, or about 420 seconds. In some embodiments, the residence time is 80 seconds. In some embodiments, the residence time is 165 seconds. In some embodiments, the residence time is 420 seconds.
  • the fluorinated reagent is recycled through the twin-screw extruder (e.g., twin-screw extruder) any suitable number of times in any composition or method provided herein.
  • the fluorinated reagent was recycled through the extruder 1 time.
  • the fluorinated reagent was recycled through the extruder 2 times.
  • the fluorinated reagent was recycled through the extruder 3 times.
  • the activated fluorinating reagent or third salt described in any of the compositions or methods herein is characterized with Powder X-ray diffraction.
  • the powder x-ray diffraction spectrum of the activated fluorinating reagent described herein may exhibit one or more characteristic reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.40, 52.8°, and/or 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and/or 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises at least two characteristic 2 ⁇ reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.40, 52.8°, and/or 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises at least three characteristic 2 ⁇ reflections selected from the group of about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.40, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic at least four 2 ⁇ reflections selected from the group of about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 21.9°, 30.3°, 31.6°, and 43.4°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2 ⁇ reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.70, 39.50, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.
  • a powder x-ray diffraction spectrum of the activated reagent comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic 2 ⁇ reflections.
  • a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the tallest peak in a raw spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the tallest peak in a background subtracted spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 10%, at least 15%, or at least 20% relative to the tallest peak in a background subtracted spectrum.
  • a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the peak with the largest integration in a raw spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the peak with the largest integration in a background subtracted spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 10%, at least 15%, or at least 20% relative to the peak with the largest integration in a background subtracted spectrum.
  • a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.
  • a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.
  • a powder x-ray diffraction spectrum of the activated reagent comprises d-spacing values of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g.
  • a powder x-ray diffraction spectrum of the activated reagent comprises absolute peak intensities of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.
  • a powder x-ray diffraction spectrum of the activated reagent comprises a ratio of any spectral property of any characteristic reflection to the same spectral property of another characteristic reflection which is about a ratio of the spectral properties of the corresponding characteristic reflections described in any one of the Tables provided herein, e.g.
  • the spectral property can include an absolute intensity, a relative intensity, an absolute area, a relative area, an estimated d-spacing, a full-width at half max peak resolution, and/or combinations thereof.
  • the method comprises combining the activated salt mixture with a first reactant, the first reactant, and fluorinating the first reactant to yield a fluorinated compound.
  • the first reactant is an organic compound.
  • the fluorinated compound is an organo-fluorine compound.
  • the first reactant is an inorganic compound.
  • fluorinating is performed at any suitable temperature.
  • the fluorination reaction is performed at a temperature of about 0° C. to about 400° C.
  • the fluorination reaction is performed at a temperature of about 0° C. to about 20° C., about 0° C. to about 50° C., about 0° C. to about 100° C., about 0° C. to about 150° C., about 0° C. to about 200° C., about 0° C. to about 250° C., about 0° C. to about 300° C., about 0° C. to about 350° C., about 0° C.
  • about 400° C. about 20° C. to about 50° C., about 20° C. to about 100° C., about 20° C. to about 150° C., about 20° C. to about 200° C., about 20° C. to about 250° C., about 20° C. to about 300° C., about 20° C. to about 350° C., about 20° C. to about 400° C., about 50° C. to about 100° C., about 50° C. to about 150° C., about 50° C. to about 200° C., about 50° C. to about 250° C., about 50° C. to about 300° C., about 50° C. to about 350° C., about 50° C. to about 400° C., about 100° C.
  • the fluorination reaction is performed at a temperature of about 0° C., about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., about 350° C., or about 400° C.
  • the fluorination reaction is performed at a temperature of at least about 0° C., about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., or about 350° C. In some embodiments, the fluorination reaction is performed at a temperature of at most about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., about 350° C., or about 400° C. In some embodiments, the fluorination is performed at a temperature of about 100° C.
  • the fluorination reaction yield is measured.
  • the fluorination reaction yield is for example, measured by 19 F NMR using 4-fluoroanisole as an internal standard.
  • the reaction yield of the organo-fluorine compound is about 0.1% to about 95%.
  • the reaction yield of the organo-fluorine compound is about 0.1% to about 1%, about 0.1% to about 10%, about 0.1% to about 20%, about 0.1% to about 30%, about 0.1% to about 40%, about 0.1% to about 50%, about 0.1% to about 60%, about 0.1% to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 95%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 10% to about 70%, about 10% to
  • the reaction yield of the organo-fluorine compound is about 0.1%, about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%. In some embodiments the reaction yield of the organo-fluorine compound is measured based on a starting amount of the organic compound.
  • the organic compound in any of the compositions or methods provided herein comprises an aromatic or aliphatic and comprises at least one leaving group located at a site to be fluorinated.
  • the leaving group comprises a halogen.
  • the organic compound comprises an aromatic.
  • the organic compound comprises an aliphatic.
  • the organic compound comprises an aromatic and comprises at least one leaving group located at a site to be fluorinated.
  • the organic compound comprises an aliphatic and comprises at least one leaving group at a site to be fluorinated.
  • the fluorination occurs at the same site of the leaving group as described in Scheme 0.1.
  • R is an aromatic. In some embodiments, R is an aliphatic. In some embodiments, X is a leaving group. In some embodiments, X is a halogen. In some embodiments, X is a bromide. In some embodiments, X is a chloride.
  • the organic compound is a sulphonyl halide, an acyl halide, an aryl halide, and/or an alkyl halide. In some embodiments, the organic compound comprises a sulphonyl halide. In some embodiments, the organic compound comprises an acyl halide. In some embodiments, the organic compound comprises an aryl halide. In some embodiments, the organic compound comprises an alkyl halide.
  • the organic compound is an aromatic sulphonyl halide, a benzoyl halide, a halobenzene, or a benzyl halide. In some embodiments, the organic compound is an aromatic sulphonyl halide. In some embodiments, the organic compound comprises tosyl chloride. In some embodiments, the organic compound is a benzoyl halide. In some embodiments, the organic compound comprises 4-methoxybenzoyl chloride. In some embodiments, the organic compound is a halobenzene. In some embodiments, the organic compound comprises chlorobenzene. In some embodiments, the organic compound is a benzyl halide.
  • the organic compound is benzyl chloride. In some embodiments, the organic compound is an ⁇ -halo carbonyl. In some embodiments, the organic compound is a ⁇ -bromo carbonyl. In some embodiments, the organic compound is an alkyl halide. In some embodiments, the organic compound is an alkyl bromide. In some embodiments, the compound is a (hetero)aryl halide. In some embodiments, the compound is a (hetero)aryl chloride.
  • the fluorination reaction is a mono-fluorination reaction. In some embodiments, the fluorination reaction is a poly-fluorination reaction. In some embodiments, the fluorination reaction is a di-fluorination reaction. In some embodiments, the fluorinated product is stable to reaction against the second salt after formation.
  • the inorganic compound of any of the compositions or methods provided herein comprises a salt.
  • the inorganic compound comprises a cation and an anion.
  • the anion is a halogen.
  • the halogen is a chlorine.
  • the halogen is a bromine.
  • the halogen is an iodine.
  • the anion is exchangeable with fluorine, providing the fluoro compound.
  • the fluoro compound is NaF.
  • the fluoro compound is KF.
  • the first salt, second salt, and the organic compound are combined in the same step. In any of the methods or compositions provided herein, in other embodiments, the first salt and second salt are combined prior to addition of the organic compound.
  • a solvent is used in the fluorination of an organic compound in any of the compositions or methods provided herein.
  • the first and second salt are combined as solids without the addition of solvent.
  • the first salt, second salt, and the organic compound is added together with one or more solvents in which the organic compound is soluble in at least one of the one or more solvents.
  • the first salt and second salt are combined prior to addition of the organic compound.
  • a solvent is used in the fluorination of an organic compound in any of the compositions or methods provided herein.
  • the solvent is an aqueous solvent.
  • the solvent is a polar aprotic solvent.
  • the solvent is a polar aprotic solvent with a polarity index of less than 6.3. In some embodiments, the solvent is an organic solvent with a polarity index of 6.3 or less. In some instances, an organic solvent is a carbon containing solvent.
  • the first salt is soluble in the solvent. In some embodiments, the second salt is soluble in the solvent. In some embodiments, the organic compound is soluble in the solvent. In some embodiments, the first salt, second salt, and the organic compound are soluble in the solvent.
  • the one or more solvents comprise a solvent selected from the group consisting of acetonitrile, propionitrile, toluene, 1,2-dichlorobenze, chlorobenzene fluorobenzene, 1,2-difluorobenze, dichloroethane, trifluorotoluene, chloroform, tert-butanol, tert-amyl alcohol, and/or water.
  • the one or more solvents comprise acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol, and/or water.
  • the solvent may comprise acetonitrile.
  • the solvent may comprise propionitrile. In some embodiments, the solvent may comprise toluene. In some embodiments, the solvent may comprise 1,2-dichlorobenzene. In some embodiments, the solvent may comprise fluorobenzene. In some embodiments, the solvent may comprise 1,2-difluorobenze. In some embodiments, the solvent may comprise dichloroethane. In some embodiments, the solvent may comprise trifluorotoluene. In some embodiments, the solvent may comprise chloroform. In some embodiments, the solvent may comprise tert-butanol. In some embodiments, the solvent may comprise tert-amyl alcohol.
  • the solvent may comprise water.
  • the solvent may comprise tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl isocyanide, m-xylene, hexane, diglyme, and/or monoglyme.
  • the solvent may comprise tetrahydrofuran.
  • the solvent may comprise 2-methyltetrahydrofuran.
  • the solvent may comprise 1,4-dioxane.
  • the solvent may comprise tert-butyl isocyanide.
  • the solvent may comprise m-xylene.
  • the solvent may comprise hexane. In some embodiments, the solvent may comprise diglyme. In some embodiments, the solvent may comprise monoglyme. In some embodiments, any one or more of the aforementioned organic solvents may be in admixture with water.
  • the organic solvent in any composition or method herein, may be in admixture with water at a concentration of about 0.01M to about 5M or any range therein. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.01 M to about 1 M.
  • the organic solvent may be in admixture with water at a concentration of about 0.01 M to about 0.05 M, about 0.01 M to about 0.1 M, about 0.01 M to about 0.2 M, about 0.01 M to about 0.3 M, about 0.01 M to about 0.4 M, about 0.01 M to about 0.6 M, about 0.01 M to about 0.8 M, about 0.01 M to about 1 M, about 0.05 M to about 0.1 M, about 0.05 M to about 0.2 M, about 0.05 M to about 0.3 M, about 0.05 M to about 0.4 M, about 0.05 M to about 0.6 M, about 0.05 M to about 0.8 M, about 0.05 M to about 1 M, about 0.1 M to about 0.2 M, about 0.1 M to about 0.3 M, about 0.1 M to about 0.4 M, about 0.1 M to about 0.6 M, about 0.1 M to about 0.8 M, about 0.1 M to about 1 M, about 0.1 M to about 0.2 M, about 0.1 M to about 0.3 M, about 0.1 M to about 0.4 M,
  • the organic solvent may be in admixture with water at a concentration of about 0.01 M, about 0.05 M, about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.6 M, about 0.8 M, or about 1 M. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.25 M. In some instances, the inclusion of water may increase the yield of organo-fluorine product.
  • the one or more solvents may comprise an additive.
  • the one or more solvents may comprise a cryptand, a crown ether, and a hydrogen-bonding phase transfer agent.
  • the one or more solvents comprise a cryptand.
  • the one or more solvents comprise a crown ether.
  • the one or more solvents comprise a hydrogen-bonding phase transfer agent.
  • the crown ether is 18-crown-6.
  • the crown ether is 30-crown-6.
  • the crown ether is a dibenzo derivative of a crown ether.
  • the dibenzo derivative of the crown ether is dibenzo 18-crown-6 ether. In some embodiments the dibenzo derivative of the crown ether is dibenzo-30-crown-6-ether. In some embodiments, the crown ether is dicyclohexano-18-crown-6-ether. In some embodiments, the cryptand is [2.2.2]cryptand. In some embodiments, the cryptand is [2.2.1]cryptand. In some embodiments, the one or more solvents may comprise schreiner's urea.
  • the cryptand, crown ether, or hydrogen-bond phase transfer agent is added in any suitable amount to any composition or method provided herein. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent, are added in amount of about 0.01 equivalents to about 5 equivalents.
  • the cryptand, crown ether, or hydrogen-bond phase transfer agent are added in amount of about 0.01 equivalents to about 0.1 equivalents, about 0.01 equivalents to about 1 equivalents, about 0.01 equivalents to about 2 equivalents, about 0.01 equivalents to about 3 equivalents, about 0.01 equivalents to about 4 equivalents, about 0.01 equivalents to about 5 equivalents, about 0.1 equivalents to about 1 equivalents, about 0.1 equivalents to about 2 equivalents, about 0.1 equivalents to about 3 equivalents, about 0.1 equivalents to about 4 equivalents, about 0.1 equivalents to about 5 equivalents, about 1 equivalents to about 2 equivalents, about 1 equivalents to about 3 equivalents, about 1 equivalents to about 4 equivalents, about 1 equivalents to about 5 equivalents, about 2 equivalents to about 3 equivalents, about 2 equivalents to about 4 equivalents, about 2 equivalents to about 5 equivalents, about 3 equivalents to about 4 equivalents, about 3 equivalents to about 5 equivalents, or about 4 equivalents to about 5 equivalents.
  • the cryptand, crown ether, or hydrogen-bond phase transfer agent are added in amount of about 0.01 equivalents, about 0.1 equivalents, about 1 equivalent, about 2 equivalents, about 3 equivalents, about 4 equivalents, or about 5 equivalents. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent is added in amount to increase the yield of the organo-fluorine product.
  • fluorinating may take place for any suitable amount of time. In some embodiments, fluorinating may take place for about 0.5 hrs to about 24 hrs. In some embodiments, fluorinating may take place for about 0.5 hrs to about 1 hr, about 0.5 hrs to about 3 hrs, about 0.5 hrs to about 5 hrs, about 0.5 hrs to about 12 hrs, about 0.5 hrs to about 16 hrs, about 0.5 hrs to about 24 hrs, about 1 hr to about 3 hrs, about 1 hr to about 5 hrs, about 1 hr to about 12 hrs, about 1 hr to about 16 hrs, about 1 hr to about 24 hrs, about 3 hrs to about 5 hrs, about 3 hrs to about 12 hrs, about 3 hrs to about 16 hrs, about 3 hrs to about 24 hrs, about 5 hrs to about 12 hrs, about 5 hrs to about 16 hrs, about 5 hrs to about 24 hrs, about 5 hrs to about 12 hrs, about
  • fluorinating may take place for about 0.5 hrs, about 1 hr, about 3 hrs, about 5 hrs, about 12 hrs, about 16 hrs, or about 24 hrs. In some embodiments, fluorinating may take place for at least about 0.5 hrs, about 1 hr, about 3 hrs, about 5 hrs, about 12 hrs, or about 16 hrs. In some embodiments, fluorinating may take place for 3 hours. In some embodiments, fluorinating may take place for 5 hrs. In some embodiments, fluorinating may take place for 12 hrs. In some embodiments, fluorinating may take place for 16 hrs.
  • a method of fluorinating an organic compound comprises combining an activated fluorinating reagent with the organic compound, wherein the activated fluorinating reagent and the organic compound are described elsewhere herein. In some embodiments, the method comprises fluorinating the organic compound to produce an organo-fluorine compound.
  • the method comprises combining a first salt, the first salt comprising calcium and fluorine, with a second salt to form a salt mixture, wherein the first salt and second salt are described elsewhere herein.
  • the method comprises applying mechanical force to the salt mixture to form an activated salt mixture, wherein the mechanical force is described elsewhere herein.
  • the method comprises combining the activated salt mixture with a first reactant.
  • the first reactant is an organic compound, wherein the organic compound is described elsewhere herein.
  • the method comprises fluorinating the first reactant to yield an organo-fluorine compound.
  • a method of recovering fluorine from a waste material to form an activated fluorination reagent comprises combining a waste material comprising a first salt comprising calcium and fluorine with a second salt to form a salt-waste mixture, wherein the first salt and second salt are described elsewhere herein.
  • the method comprises applying mechanical force to the salt-waste mixture to yield the activated fluorination reagent, wherein the mechanical force is described elsewhere herein.
  • Reagent grade calcium fluoride (CaF 2 , ⁇ 97.0%, Alfa Aesar), potassium phosphate (K 3 PO 4 , ⁇ 98%, Sigma Aldrich, CAS 7778-53-2), dipotassium hydrogen phosphate (K 2 HPO 4 , ⁇ 98.0%, Alfa Aesar), potassium dihydrogen phosphate (KH 2 PO 4 , ⁇ 99.0%, Alfa Aesar), sodium phosphate (Na 3 PO 4 , ⁇ 96.0%, Sigma Aldrich), disodium hydrogen phosphate (Na 2 HPO 4 , ⁇ 98%, Fisher Scientific), sodium dihydrogen phosphate (NaH 2 PO 4 , 96%, Fisher Scientific), potassium tripolyphosphate (K 5 P 3 O 10 , ⁇ 94%, Strem Chemicals), sodium pyrophosphate tetrabasic decahydrate (Na 4 P 2 O 7 ⁇ 10H 2 O, ⁇ 99%, Sigma Aldrich, CAS 13472-36-1),
  • Potassium pyrophosphate K 4 P 2 O 7 , 97.0%, Sigma Aldrich
  • anhydrous potassium fluoride KF, 99%, Alfa Aesar
  • Fluorspar (acid grade) was purchased from Mistral Industrial Chemicals (UK), produced by Minersa group (Asturias region, Spain) and contains CaF 2 (>97%), total carbonates ( ⁇ 1.50%), SiO 2 ( ⁇ 1.00%), BaSO 4 ( ⁇ 0.50%), Pb ( ⁇ 0.10%), Fe 2 O 3 ( ⁇ 0.10%), S ( ⁇ 0.15%), H 2 O ( ⁇ 1.0%). Fluorspar (acid grade) was used without drying and stored under ambient conditions.
  • Powder X-ray diffraction (PXRD) data was collected using a Bruker D8 Advance X-Ray diffractometer with Bragg-Brentano geometry. Cu K ⁇ 1 and 2 were used and measurements were performed at room temperature unless otherwise stated. All PXRD data was collected at room temperature. For simulated structures a Rietveld refinement of powder diffraction data was performed using the TOPAS Academic (V6).
  • Ball milling experiments were performed using a Retsch MM 400 mixer mill. Mechanochemical reactions were performed in 15 mL, 30 mL or 50 mL stainless steel jars with either two stainless steel balls of mass 2 g, or one stainless steel ball of various mass (2 g, 3 g, 4 g, 7 g, or 9 g). No precaution was taken to exclude air and moisture.
  • the ball size used may have an effect on the resulting fluorinated product (TsF) yield.
  • Exemplary ball sizes may include 7 and 9 g based on organo-fluorine product (TsF) yield.
  • fluoride leaching from p-toluenesulfonyl fluoride was assessed through identification of fluoride anion by 19 F NMR, along with 11% loss of the fluorinated compound.
  • the jar was opened and the white solid residue was scratched out with a spatula and collected in a beaker.
  • the jar was rinsed with EtOAc (3 ⁇ 5 mL) and transferred to the beaker.
  • the resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ⁇ 20 mL EtOAc), and the solvent was removed in vacuo and the crude mixture purified by silica gel chromatography if required.
  • reagent grade CaF 2 is milled with 1 equivalent of K 2 HPO 4 for 3 hours at 30 Hz before 4 equivalents of the resulting reagent is reacted with TsCl in a solvent according to Scheme 3.5.2 to achieve the resulting TsF.
  • 1 equivalent of acid grade fluorspar is milled with 1 equivalent of K 2 HPO 4 for 3 hours at 30 Hz according to Scheme 3.5.3 and 4 equivalents of the resulting fluorination reagent is reacted in a solvent with TsCl to achieve the fluorinated TsF.
  • the resulting fluorinated TsF product yields resulting from reagent grade CaF 2 and acid grade fluorspar (81% and 82% respectively by NMR) may support the conclusion that either starting material can be used to synthesize the fluorinating reagent.
  • the increased yield with increased ratio of CaF 2 :K 2 HPO 4 indicates that the ratio of the two salts may play an a role in optimizing the resulting yield of organofluorine product and a ratio of 2:1 may provide the highest yield of organofluorine product (e.g., TsF).
  • CaF 2 (4.0 equiv.) is added to a 15 mL stainless steel jar and ball milled alone at 30 Hz for 3 hours before being added to an additive (see Table 5.6) and TsCl (1 mmol) in acetonitrile (0.25 M) and reacted for 5 hours at 100° C.
  • This method may result in lower yields of fluorinated product than when the additive is milled with the CaF 2 .
  • reagent grade CaF 2 was replaced with acid grade Fluorspar and screening of the various phosphate activators was completed as described in Scheme 5.7.
  • the various phosphate activators included K 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 , Na 3 PO 4 , Na 2 HPO 4 , KPO 3 , K 4 P 2 O 7 , K 5 P 3 O 10 , Na 4 P 2 O 7 , Na 5 P 3 O 10 , (NaPO 3 ) 3 , CaHPO 4 , and ⁇ -Ca 3 (PO 4 ) 2 .
  • the Fluorspar (1.0 equiv.) was added to the stainless steel jar and milled for 3 hours at 30 Hz with a phosphate activator (1 equiv.) (see FIG. 3 ). Subsequently, the solid product is added, containing CaF 2 (4 equiv.) and phosphate activator (4 equiv.), to t-butanol (0.25 M) with TsCl (1.00 mmol) and reacted for 5 hours at 100° C. to obtain the fluorinated product (TsF). The yields of the reaction (TsF(%), TsCl (%)) can be seen in FIG. 3 .
  • the results indicate that the selection of the activator salt (second salt) may play a significant role in the resulting fluorinating reagent's ability to fluorinate the substrate.
  • the results highlight potential exemplary additives including K 2 HPO 4 , Na 2 HPO 4 , K 4 P 2 O 7 and Na 4 P 2 O 7 .
  • FIG. 4 shows the PXRD pattern resulting from milling of Fluorspar with KH 2 PO 4 at 35 Hz for 3 hours.
  • Table 5.7.1 shows the PXRD data from the milling of Fluorspar with KH 2 PO 4 represented in FIG. 4 . Labels on the diffraction pattern indicate crystalline phase of CaF 2 and KH 2 PO 4 .
  • FIG. 5 shows the PXRD pattern resulting from milling of Fluorspar with K 3 PO 4 at 35 Hz for 3 hours.
  • Table 5.7.2 shows the PXRD data from the milling of Fluorspar with K 3 PO 4 represented in FIG. 5 .
  • Labels in FIG. 5 indicate crystalline phases of K 3 PO 4 *7H 2 O, CaF 2 , and an unidentified crystalline phase.
  • FIG. 6 shows the PXRD pattern resulting from milling of Fluorspar with Na 3 PO 4 at 30 Hz for 3 hours.
  • Table 5.7.3 shows the PXRD data from the milling of Fluorspar with Na 3 PO 4 represented in FIG. 6 .
  • Labels in FIG. 6 indicate crystalline phases of Na 7 F(PO 4 ) 2 (H 2 O) 19 and CaF 2 .
  • FIG. 7 shows the PXRD pattern resulting from milling of Fluorspar with Na 2 HPO 4 at 35 Hz for 3 hours.
  • Table 5.7.4 shows the PXRD data from the milling of Fluorspar with Na 2 HPO 4 represented in FIG. 7 .
  • Labels in FIG. 7 indicate crystalline phases of CaF 2 and an unidentified crystalline phase.
  • FIG. 8 shows the PXRD pattern resulting from milling of Fluorspar with NaH 2 PO 4 at 35 Hz for 3 hours.
  • Table 5.7.5 shows the PXRD data from the milling of Fluorspar with NaH 2 PO 4 represented in FIG. 8 .
  • Labels in FIG. 8 indicate crystalline phases of CaF 2 and NaH 2 PO 4 (H 2 O) 3 .
  • FIG. 9 shows the PXRD pattern resulting from milling of Fluorspar with KPO 3 at 35 Hz for 3 hours.
  • Table 5.7.6 shows the PXRD data from the milling of Fluorspar with KPO 3 represented in FIG. 9 .
  • Labels in FIG. 9 indicate crystalline phases of CaF 2 , KPO 3 , and an unidentified amorphous phase.
  • FIG. 10 shows the PXRD pattern resulting from milling of Fluorspar with K 4 P 2 O 7 at 35 Hz for 3 hours.
  • Table 5.7.7 shows the PXRD data from the milling of Fluorspar with K 4 P 2 O 7 represented in FIG. 10 .
  • Labels in FIG. 10 indicate crystalline phases of CaF 2 and an unidentified crystalline phase.
  • FIG. 11 shows the PXRD pattern resulting from milling of Fluorspar with K 5 P 3 O 10 at 35 Hz for 3 hours.
  • Table 5.7.8 shows the PXRD data from the milling of Fluorspar with K 5 P 3 O 10 represented in FIG. 11 .
  • Labels in FIG. 11 indicate crystalline phases of CaF 2 and K 3 H 3 (PO 4 ) 2 *2H 2 O and an unidentified crystalline phase.
  • FIG. 12 shows the PXRD pattern resulting from milling of Fluorspar with Na 4 P 2 O 7 at 35 Hz for 3 hours.
  • Table 5.7.9 shows the PXRD data from the milling of Fluorspar with Na 4 P 2 O 7 represented in FIG. 12 .
  • Labels in FIG. 12 indicates a crystalline phase of CaF 2 and an unidentified crystalline phase.
  • FIG. 13 shows the PXRD pattern resulting from milling of Fluorspar with Na 5 P 3 O 10 at 35 Hz for 3 hours.
  • Table 5.7.10 shows the PXRD data from the milling of Fluorspar with Na 5 P 3 O 10 represented in FIG. 13 .
  • Labels in FIG. 13 indicates a crystalline phase of CaF 2 and an unidentified amorphous phase.
  • FIG. 14 shows the PXRD pattern resulting from milling of Fluorspar with Na(PO 3 ) 3 at 35 Hz for 3 hours.
  • Table 5.7.11 shows the PXRD data from the milling of Fluorspar with Na(PO 3 ) 3 represented in FIG. 14 .
  • Labels in FIG. 14 indicates a crystalline phase of CaF 2 .
  • FIG. 15 shows the PXRD pattern resulting from milling of Fluorspar with CaHPO 4 at 30 Hz for 3 hours.
  • Table 5.7.12 shows the PXRD data from the milling of Fluorspar with CaHPO 4 represented in FIG. 15 .
  • Labels in FIG. 15 indicates crystalline phases of CaF 2 and Ca 5 (PO 4 ) 3 F.
  • FIG. 16 shows the PXRD pattern resulting from milling of Fluorspar with Ca 3 (PO 3 ) 2 at 35 Hz for 3 hours.
  • Table 5.7.13 shows the PXRD data from the milling of Fluorspar with Ca 3 (PO 3 ) 2 represented in FIG. 16 .
  • Labels in FIG. 16 indicates a crystalline phase of Ca 5 (PO 3 ) 3 F.
  • An increased consumption of crystalline CaF 2 may be achieved by successively spiking the milled mixtures (A to D in Scheme 5.8.1) with additional K 2 HPO 4 and milling for additional 3 hour periods until all of the crystalline CaF 2 was consumed as detailed in Scheme 5.8.1.
  • FIG. 17 shows Powder X-Ray Diffraction patterns of each of these mixtures, labelled to show the appearance of the new species.
  • the PXRD was obtained on a Bruker Eco D8 Diffractometer.
  • FIG. 18 shows the results of the experiment, when the powder reagent is reacted in solution with TsCl in tBuOH (0.25 M) at 100° C. for 5 hours, showing that higher frequency milling may result in powder reagents, that when used for fluorination, may lead to higher fluorination yields. Additionally, when higher equivalents of the fluorination reagent (A) are used, higher fluorinations yields may be exhibited.
  • Milled mixtures A to C as seen in Scheme 5.9.1 were investigated as fluorinating reagents, in turn allowing for fluorination of TsCl at high yield using fewer equivalents of CaF 2 (Fluorspar).
  • Scheme 5.9.3 shows a reaction wherein the powder reagents of Scheme 5.9.1 were reacted with TsCl (1 equiv., 0.125-0.25 mmol) in a 0.25 M solution of tBuOH at 100° C. for 5 hours with the addition of water.
  • the results show that the addition of water to the reaction may be beneficial to achieving higher yields of organofluorine product (e.g., TsF).
  • This solid reagent was reacted with the R—X substrate (1 equiv.), 18-C-6 (1 equiv.) and optionally H 2 O (0-5 equiv.) in a solution of tBuOH at 60-100° C. for 5-48 hours to achieve the desired product, the yields and specific solution conditions of which can be seen in FIG. 23 .
  • All isolated yields are not in parentheses and were conducted on a 0.5 mmol scale. All yields in parentheses are NMR yields. All reactions were completed using an INSOLIDO IST636 Ball Mill and using stainless steel jars (15 mL) with a 7 g ball (316 SS grade). The results indicate a range of different halogenated functionalities can undergo fluorination using the forementioned fluorination reagents.
  • Fluorspar (CaF 2 ) was milled with K 2 HPO 4 (2.5 equiv. total) as seen in Scheme 5.12.1 to form a “reagent”. The reagent was dissolved in D 2 O to form D 2 O soluble components for study via solution state NMR.
  • FIG. 24 A shows 19 F NMR indicating the presence of F ⁇ ion and PO 3 F 2 ⁇ ion in solution upon dissolution.
  • FIG. 24 B shows 31 P NMR indicating the presence of PO 4 3 ⁇ and PO 3 F 2 ⁇ .
  • FIG. 25 shows a powder x-ray diffraction pattern (PXRD) of the “reagent” with a reference PXRD pattern for potassium fluoride (KF).
  • PXRD powder x-ray diffraction pattern
  • KF potassium fluoride
  • FIG. 26 and Table 5.12.1 show PXRD data of the fluorinating reagent, “Fluoromix” that results from the “reagent” formation depicted in Scheme 5.12.1 when fluorspar is milled with 2.5 total equivalents of K 2 HPO 4 .
  • FIG. 1 powder x-ray diffraction pattern
  • FIG. 28 A shows the simulated structure of X which may be K 3 (HPO 4 )F, which is a related structure to K 3 (PO 3 F)F.
  • FIG. 28 B shows the simulated structure of Y which may be K 2-x Ca y (PO 3 F) a (PO 4 ) b F c , which is a related structure to K 2 PO 3 F.
  • FIG. 29 shows PXRD experiments for Fluorspar (acid grade), K 2 HPO 4 (Fisher Chemical), and Fluorapatite (Thermo Fisher).
  • Table 30 shows an overlay of PXRD diffractograms of fluoromix, fluorspar, X, and Y. Residual CaF 2 is also observed in the diffractogram of fluoromix.
  • Table 5.12.2 shows PXRD data of the crystalline components of X which has a proposed structure of K 3 (HPO 4 )F.
  • Table 5.12.3 shows PXRD data of the crystalline components of Y, which has a proposed structure of K 2-x Ca y (PO 3 F) a (PO 4 ) b F c .
  • Fluorspar (CaF 2 ) (1 equiv.) was milled with K 2 HPO 4 (2.5 equiv.) at 35 Hz for 9 hours total to form a “reagent” as seen in Scheme 5.12.3.
  • This reagent (“Fluoromix”) was washed with H 2 O resulting in a water insoluble solid (84.5 mg from 500 mg of reagent, 17% yield).
  • the resulting insoluble solid was examined via PXRD.
  • FIG. 31 shows this PXRD with peaks labelled showing formation of Ca 5 (PO 4 ) 3 F or Ca 5 (PO 4 ) 3 OH (diamonds) and CaF 2 (circles).
  • the PXRD data can also be found in Table 5.12.4.
  • Fluorspar (CaF 2 ) was milled with equimolar CaHPO 4 to produce Z as seen in Scheme 5.12.4. This milling was completed at 30 Hz for 3 hours;
  • FIG. 32 A shows PXRD of Z as well as the water insoluble solid resulting from the reaction forming Z.
  • FIG. 32 B shows the PXRD of Z with crystalline phases of Ca 5 (PO 4 ) 3 F and CaF 2 highlighted.
  • the PXRD data of Z can be found in Table 5.12.5.
  • the milling of CaF 2 with equimolar anhydrous CaHPO 4 produces Z consistent Ca 5 (PO 4 ) 3 F (or Ca 5 (PO 4 ) 30 H) and CaF 2 .
  • the substrate was reacted with 2 equiv. of ⁇ (CaF 2 )(K 2 HPO 4 ) 2.5 ⁇ which was obtained via milling at 35 Hz and 1 equivalent of 18-C-6 in 0.25 M solvent (described in Table 5.13.1) and reacted at 100° C. for 15 hours in a sealed tube.
  • the yields of fluorinated products and side products can be seen in Table 5.13.1.
  • the results indicate that difluorination may be achieved from dihalogenated starting materials using the fluorinating agents described herein, with low yields of monofluorinated product.
  • the substrate was reacted with 2 equiv. of ⁇ (CaF 2 )(K 2 HPO 4 ) 2.5 ⁇ which was obtained via milling at 35 Hz and 1 equivalent of an additive (see Table 5.13.2), HBD, and reacted in a solvent (0.25 M) at 100° C. for 15 hours in a sealed tube.
  • the yields of fluorinated product and side products as determined from NMR can be seen in Table 5.13.2.
  • the results indicate that difluorination may be achieved from dihalogenated starting materials using the fluorinating agents described herein, with low yields of monofluorinated product.
  • Fluorspar (CaF 2 ) is ball milled with anhydrous K 2 HPO 4 to afford a fluorinating reagent (Fluoromix) (Scheme 5.14.1) which is comprised of crystalline phases (X, Y) and residual crystalline CaF 2 .
  • Fluoromix Fluorinating reagent
  • Calcium hydrogen phosphate (CaHPO 4 ) and potassium fluoride (KF) may be products of the reaction between CaF 2 and K 2 HPO 4 .
  • X is the product of ball milled KF with K 2 HPO 4
  • X has the proposed structure K 3 (HPO 4 )F and is isostructural to K 3 (PO 3 F)F
  • Y has the proposed structure K 2-x Ca y (PO 3 )F a (PO 4 ) b F c and is isostructural to K 2 PO 3 F.
  • the formation of X and Y from ball milling fluorspar and K 2 HPO 4 may indirectly support the formation of KF and CaHPO 4 as intermediates in this reaction en route to X and Y.
  • a PXRD diffractogram of the water insoluble component of fluoromix was measured and contains reflections that are consistent with CaF 2 and Ca 5 (PO 4 ) 3 F (fluorapatite) as a mixture (mixture Z).
  • Z may be independently prepared by ball milling CaHPO 4 with CaF 2 .
  • Table 5.14.1 shows the PXRD data of starting material, Fluorspar (CaF 2 ).
  • Table 5.14.2 and FIG. 33 show PXRD data of X, consistent with K 3 (HPO 4 )F (related structure to K 3 (PO 3 F)F).
  • Table 5.14.3 and FIG. 34 show PXRD data of Y, consistent with K 2-x Ca y (PO 3 F) a (PO 4 ) b F c (related to K 2 PO 3 F).
  • Table 5.14.4 shows PXRD data of Z, consistent with Ca 5 (PO 4 ) 3 F and unreacted CaF 2 .
  • Each crystalline species of the Fluoromix was prepared independently and tested in the fluorination of tosyl chloride (TsCl).
  • TsCl tosyl chloride
  • X or Y can be used to convert S(VI)—Cl bonds into an S(VI)—F bond whilst CaF 2 or Z (“apatite structure” consistent with Ca 5 (PO 4 ) 3 F) do not afford any fluorinated product.
  • the fluorination using X or Y was carried out as described in Scheme 5.14.3, X or Y (1 equiv. with respect to fluoride) was reacted in a tBuOH solution with the TsCl (1 equiv.) with H 2 O at 100° C. for 5 hours to afford the fluorinated product.
  • Fluorspar (1 equiv.) was milled with KOH (2 equiv.) at 35 Hz for 3 hours as depicted in Scheme 6.2.1 to form Ca(OH) 2 , KCaF 3 , and residual CaF 2 (A).
  • This mixture was milled with dry ice (10 equiv.) at 20 Hz for 60 seconds to form (B) consisting of KHCO 3 , KCaF 3 , and CaF 3 .
  • the mixture (A) was also heated at 520° C. for 1 hour to form (C), CaO, KCaF 3 , and CaF 2 .
  • the non-phosphate activators included K 2 CO 3 , KHCO 3 , K 2 SO 4 , KHSO 4 , Cs 2 SO 4 , K 2 S 2 O 7 , Na 2 SO 3 , KNO 3 , and sodium citrate dihydrate.
  • the fluorination yields indicate that exemplary non-phosphate activators may include Na 2 SO 3 and sodium citrate dihydrate.
  • the resulting activated fluorspar reagent (A) was analyzed with PXRD.
  • FIG. 38 shows the PXRD pattern resulting from milling of Fluorspar with K 2 CO 3 at 35 Hz for 3 hours.
  • Table 6.3.1 shows the PXRD data from the milling of Fluorspar with K 2 CO 3 represented in FIG. 38 .
  • Labels in FIG. 38 indicates a crystalline phase of K 2 CO 3 and CaF 2 .
  • FIG. 39 shows the PXRD pattern resulting from milling of Fluorspar with KHCO 3 at 35 Hz for 3 hours.
  • Table 6.3.2 shows the PXRD data from the milling of Fluorspar with KHCO 3 represented in FIG. 39 .
  • Labels in FIG. 39 indicates a crystalline phase of KHCO 3 and CaF 2 .
  • FIG. 40 shows the PXRD pattern resulting from milling of Fluorspar with K 2 SO 4 at 35 Hz for 3 hours.
  • Table 6.3.3 shows the PXRD data from the milling of Fluorspar with K 2 SO 4 represented in FIG. 40 .
  • Labels in FIG. 40 indicates a crystalline phase of K 2 SO 4 and CaF 2 .
  • FIG. 41 shows the PXRD pattern resulting from milling of Fluorspar with KHSO 4 at 35 Hz for 3 hours.
  • Table 6.3.4 shows the PXRD data from the milling of Fluorspar with KHSO 4 represented in FIG. 41 .
  • Labels in FIG. 41 indicates a crystalline phase of KHSO 4 , K 2 Ca(SO 4 ) 2 H 2 O 2 (syngenite), and CaF 2 .
  • FIG. 42 shows the PXRD pattern resulting from milling of Fluorspar with K 2 S 2 O 7 at 35 Hz for 3 hours.
  • Table 6.3.5 shows the PXRD data from the milling of Fluorspar with K 2 S 2 O 7 represented in FIG. 42 .
  • Labels in FIG. 42 indicates a crystalline phase of K 2 S 2 O 7 and CaF 2 .
  • FIG. 43 shows the PXRD pattern resulting from milling of Fluorspar with Na 2 SO 3 at 35 Hz for 3 hours.
  • Table 6.3.6 shows the PXRD data from the milling of Fluorspar with Na 2 SO 3 represented in FIG. 43 .
  • Labels in FIG. 43 indicates a crystalline phase of Na 2 SO 3 , CaF 2 , and an unidentified amorphous phase.
  • FIG. 44 shows the PXRD pattern resulting from milling of Fluorspar with KNO 3 at 35 Hz for 3 hours.
  • Table 6.3.7 shows the PXRD data from the milling of Fluorspar with KNO 3 represented in FIG. 44 .
  • Labels in FIG. 44 indicates a crystalline phase of KNO 3 and CaF 2 .
  • FIG. 45 shows the PXRD pattern resulting from milling of Fluorspar with KOH at 35 Hz for 3 hours.
  • Table 6.3.8 shows the PXRD data from the milling of Fluorspar with KOH represented in FIG. 45 .
  • Labels in FIG. 45 indicates a crystalline phase of Ca(OH) 2 , KCaF 2 , and CaF 2 .
  • FIG. 46 shows the PXRD pattern resulting from milling of Fluorspar with NaOH at 35 Hz for 3 hours.
  • Table 6.3.9 shows the PXRD data from the milling of Fluorspar with NaOH represented in FIG. 46 .
  • Labels in FIG. 46 indicates a crystalline phase of Ca(OH) 2 , NaF, CaF 2 , and an unidentified amorphous material.
  • fluorapatite was used in combination with K 3 PO 4 to fluorinate TsCl in the solid state via ball milling as described in Scheme 7.1.1, the results of which can be found in Table 7.1. Briefly, fluorapatite (Ca 5 (PO 4 ) 3 F, 5 equiv.) and K 3 PO 4 in varying ratios were milled at 30 Hz for 1 hour in 15 mL stainless steel jars using a 7 g ball. TsCl was added and milled for 1 hour longer at 30 Hz to obtain a fluorinated product (see Table 7.1 for yields). The grains of fluorapatite used were approximately 0.06-0.19 inches. The solid state reactions resulted in yields of organo-fluorine product (TsF) of 5% or less.
  • TsF organo-fluorine product
  • Fluorapatite (Ca 5 (PO 4 ) 3 F) (approximately 0.06-0.19 in) was used in combination with K 2 HPO 4 as described in Scheme 7.2.1 to create a fluorination reagent via ball milling under varying conditions as seen in Table 7.2. Specifically, fluorapatite (4 equiv.) was milled with K 2 HPO 4 (20 equiv.) for 3 hours at varying frequencies, jar loading (mg/mL), and jar sizes (mL). The resulting powder reagent was reacted with p-TolSO 2 —Cl (TsCl) (1 equiv.) in a tBuOH (0.25 M) solution at 100° C.
  • TsF fluorinated product
  • the yield of the fluorinated product and starting material, TsCl can be found in Table 7.2.
  • the results also highlight that, the solution reaction of the fluorapatite-K 2 HPO 4 fluorination reagent with the TsCl can result in higher fluorinated product (TsF) yields than seen in the solid state reaction of Example 7.1.
  • fluorapatite (1 equiv.) was milled with an activator (see Table 7.3) at 30 Hz for 3 hours in a 15 mL stainless steel jar with a 7 g ball to create Fluoromix.
  • Fluoromix (0.2 mmol) was added to a PhCl solution (0.25 M) with p-TolSO 2 —Cl (1.0 equiv., 0.05 mmol) and reacted at 100° C. for 5 hours to form the fluorinated product, TsF.
  • the yields of TsF and the side product yields can be found in Table 7.3.
  • Successful fluorination may be possible with exemplary activators KCl+K 2 HPO 4 or potassium pyrophosphate, although the success of fluorinating the TsCl starting material may be dependent on the activator used.
  • the fluorapatite was milled first with the phosphate activator before being reacted in the solution phase with the TsCl (p-TolSO 2 —Cl).
  • TsCl p-TolSO 2 —Cl
  • fluorapatite (2 equiv.) was milled with 2 equiv. of the phosphate activator followed by solution phase reaction with 0.05 mmol of TsCl as described in Scheme 7.4.1
  • the TsF yield was 81%.
  • 1.2 equiv. of fluorapatite was milled with 1.2 equiv. of phosphate activator followed by solution phase reaction with TsCl (0.05 mmol)
  • the TsF yield was 78%.
  • fluorapatite was milled with a phosphate activator to form the fluorination agent and reacted in the solution phase with a range of RSO 2 —Cl substrates to form RSO 2 —F (see FIG. 47 ).
  • FIG. 47 shows the yields of the resulting reactions and fluorinated products which range from 12% to 79%.
  • the reactions were carried out as follows. Fluorapatite (1.2 equiv.) was milled with the phosphate activator (1.2 equiv) at 30 Hz for 9 hours in a 30 mL stainless steel jar with 1 16 g ball.
  • the resulting powder reagent was reacted with the RSO 2 —Cl substrate (1.0 equiv., 0.25 mmol) in the solution phase in t-AmOH (0.25 M) at 100° C. for 10 minutes with 18-crown-6 and 12 equiv. of H 2 O resulting in the fluorinated product.
  • the results show that the pyrophosphate activator in addition to 18-crown-6 may be used with fluorapatite as a fluorinating reagent to fluorinate a wide variety of substrates including aliphatic and aromatic substrates.
  • FIG. 48 shows the stacked PXRD patterns of products A, B, C, and D where circles indicate fluorapatite starting material and x indicate a new species.
  • This data shows the consumption of crystalline fluorapatite by mechanochemical reaction with potassium pyrophosphate and a new crystalline species forming over the course of the reaction.
  • Products C and D may be indicative of no fluorapatite starting material, whereas Ca 5 (PO 4 ) 3 F starting material is present in samples A and B.
  • FIG. 49 shows a PXRD pattern of pure fluorapatite after 1 hour of milling overlayed with a fluorapatite sample (1 equiv.) that was milled for 12 hours total at 35 Hz with K 4 P 2 O 7 (4 equiv.). The result indicates consumption of the fluorapatite by mechanochemical reaction with potassium pyrophosphate.
  • FIG. 50 shows a comparison of the PXRD pattern of the reaction 1:4 equiv. milling reaction (D) between fluorapatite (Ca 5 (PO 4 ) 3 F) and K 4 P 2 O 7 , and the milling reaction between potassium fluoride (KF, 1 equiv.) and K 2 HPO 4 (2 equiv., 35 Hz, 3 hours) followed by CaHPO 4 (1 equiv., 35 Hz, 3 hours) as seen in Scheme 7.6.2.
  • FIG. 51 shows the PXRD data of the water insoluble component and is compared to a crystalline reference pattern, in this case, pure milled, Ca 5 (PO 4 ) 3 F (fluorapatite).
  • the water insoluble product's PXRD pattern may be consistent with Ca 5 (PO 4 ) 3 F or Ca 5 (PO 4 ) 30 H.
  • Fluorapatite activation was tested using 1 equivalent of potassium pyrophosphate (K 4 P 2 O 7 ) and the milling reaction was monitored via PXRD.
  • the milling reaction proceeded as described in Scheme 7.7.1 wherein 1 equivalent of fluorapatite (Ca 5 (PO 4 ) 3 F was milled with 1 equivalent of K 4 P 2 O 7 at 30 Hz for 9 hours using a 16 g ball in a 30 mL stainless steel jar.
  • FIG. 52 and Table 7.7.1 show the PXRD data indicating presence of crystalline phases of Ca 5 (PO 4 ) 3 F and an unidentified amorphous phase. No crystalline potassium pyrophosphate was observed by PXRD.
  • fluorapatite (1 equiv.) was milled with 4 equivalents of potassium pyrophosphate to consume the crystalline fluorapatite as described in Scheme 7.7.2. Briefly, the fluorapatite was milled with 1 equivalent of potassium pyrophosphate for 3 hours at 35 Hz before the addition of a second equivalent and subsequent milling for 3 hours at 35 Hz, and this was repeated until 4 total equivalents of potassium pyrophosphate had been added and milled with the fluorapatite. The resulting product was analyzed by PXRD as seen in FIG. 53 and Table 7.7.2. The PXRD was consistent with an unidentified crystalline phase which is isostructural to K 2-x Ca y (PO 3 F) a (PO 4 ) b F c .
  • Thermofisher Process 11 Twin Screw Extruder was fixed with a gravimetric single screw feeder (hopper) for programmed addition of solids. The pressurized die was not fixed to the twin-screw extruder for these experiments.
  • Extrudite refers to the processed material that comes out the end of the extruder.
  • CaF 2 (97% reagent grade purchased from Alfa Aesar and used as received.
  • K 2 HPO 4 (anhydrous, 98%) purchased from Acros Organics and used as received. Screw configurations are shown in each graphics and are made up of conveying “C”, kneading “K”, and reverse “R” elements. Multiple individual elements make up a “section”.
  • kneading sections can be subdivided by rotation from previous element, these can be at 30°, 60° or 90°.
  • F R feed rate of solids into the extruder.
  • S S screw speed at which the stainless-steel screws co-rotate.
  • S T screw temperature, each of the six segments can be heated to an individual temperature and these are specified if used.
  • T R residence time which is measured by the first time solids fall into the twin-screw extruder to the first time solids are observed at the exit.
  • FIG. 54 shows a general scheme for which CaF 2 (40 mmol) and K 2 HPO 4 (40 mmol) are reacted to form the active fluorinated material.
  • the temperature, S T was varied between 25° C. and 200° C. and the screw speed was 50 rpm.
  • the residence time was 100 seconds.
  • the resulting “fluoromix” was reacted with TsCl in the solution state in tBuOH (0.25 M) at 100° C. for 5 hours to form the fluorinated product, TsF.
  • the screw temperatures, resulting fluorinated product, TsF, yields, and starting material yields, TsCl can be seen in Table 8.3. The results may indicate that lower screw temperatures may be helpful in achieving higher yields of organo-fluorine product (e.g., TsF) and lower yields of starting material (e.g., TsCl).
  • FIG. 55 shows a general scheme for which CaF 2 (40 mmol) and K 2 HPO 4 (40 mmol) are reacted to form the active fluorinated material.
  • the spin speed was varied between 10 rpm and 75 rpm and the residence time (T R ) was varied as shown in Table 8.4.
  • the screw temperature was 25° C. and feed rate was 10 g/min.
  • the resulting active fluorinated material, “Fluoromix” was reacted with TsCl in a tBuOH solution (0.25 M) at 100° C. for 5 hours to form the fluorinated product.
  • the spin speed (S S ), residence time (T R ), product yield (TsF), and starting material yield (TsCl) can be seen in Table 8.4.
  • the results may indicate that the screw speed and residence time may not significantly impact the resulting yield of organo-fluorine product (e.g., TsF).
  • FIG. 56 shows the general scheme for which CaF 2 (40 mmol) and K 2 HPO 4 (40 mmol) can be reacted to form the active fluorinated species.
  • the feed rate is variable, the screw speed is 50 rpm, the screw temperature is 25° C., and the residence time is 100 seconds, but the resulting material is recycled back into the extruder 1, 2, or 3 times the results of which can be seen in Table 8.5.
  • the resulting “Fluoromix” was reacted with 1 equiv. of TsCl in the solution state (0.25 M tBuOH) at 100° C. for 5 hours to form the fluorinated product.
  • the resulting fluorinated product yield, TsF, and starting material yield, TsCl can also be seen in Table 8.5.
  • FIG. 57 shows the general scheme for which CaF 2 (40 mmol) is added into the twin-screw extruder with variable feed rates, at a screw speed of 50 rpm, a screw temperature of 25° C., and a residence time of 100 seconds.
  • the resulting “CaF 2 ” that has been extruded was reacted with TsCl (1 equiv.) in a 0.25 M tBuOH solution with added K 2 HPO 4 (4 equiv.) and reacted at 100° C.
  • TsF fluorinated product
  • the result was a TsF yield of 6% and a TsCl yield of 58% when the CaF 2 was not extruded in the presence of K 2 HPO 4 .
  • CaF 2 may be activated to provide fluoride in the conversion of p-toluenesulfonyl chloride to p-toluenesulfonyl fluoride.
  • FIG. 58 shows a general scheme for which CaF 2 (40 mmol) and K 2 HPO 4 (40 mmol) are added to the twin-screw extruder with a feed rate of 2 g min ⁇ 1 , a screw speed of 50 rpm, a screw temperature of 25° C., and a residence time of 40 seconds.
  • An alternate configuration was also examined (screw configuration 2).
  • Screw configuration 2 was “C-(30-60-90)-C-(60)-C-(60-90)-C”, whereas screw configuration 1 was “C-90-C-60-C-90-C”.
  • the resulting “fluoromix” was reacted with TsCl (1 equiv.) in a solution of tBuOH (0.25 M) at 100° C. for 5 hours to form the resulting fluorinated product, TsF.
  • the yield of fluorinated, TsF was 20% and yield of starting material, TsCl, was 40% upon utilization of screw configuration 1.
  • the utilization of additional alternative screw configurations may be useful in increasing and/or tuning the yield of organo-fluorine products (e.g., TsF).
  • the Fritsch Pulverisette planetary mill was used. Zirconia jars (12 mL) and zirconia balls (3.4 g) were used in milling experiments. To a zirconia jar, added was charged fluorspar (312 mg, 4 mmol) and K 2 HPO 4 (697 mg, 4 mmol) and either one or two 3.4 g zirconia balls. The jars were sealed and attached to the planetary mill. The mill was set to 800 rpm, 15-minute milling session, 11 repeats (12 in total), with a 2 minute gap between each one, and reverse in direction of milling after each session. After this time the material was scraped out of the vial and added to a vial which was kept under vacuum overnight before use.
  • Scheme 8.8.1 shows a general scheme for which CaF 2 (4 equiv.) is milled via a planetary mill with 4 equiv. of K 2 HPO 4 .
  • the resulting powder was reacted with TsCl (1 equiv.) in a solution of tBuOH (0.25 M) at 100° C. for 5 hours.
  • the resulting yield when 1 ball was used in the milling was 12% TsF (72% TsCl starting material).
  • the resulting yield when 2 balls were used in the milling was 11% TsF (76% TsCl starting material).
  • planetary mills may be useful in creating fluorinating reagents comprising CaF 2 and an activator (e.g., K 2 HPO 4 )

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