CAF2-based fluorination reagents, methods for their preparation and use

Abstract

A method for preparing fluorinated reagents from calcium-containing compounds is disclosed. The method avoids the need to form hydrofluoric acid. The fluorinated reagents can be used to prepare high value fluorochemicals.

Description

[Technical field]

[0001] The present disclosure relates to a fluorination method and a fluorination reagent. In particular, the present application describes a novel fluorination reagent, a method for preparing the fluorination reagent from a salt containing calcium and fluorine, and the use of the fluorination reagent to prepare fluorochemicals. The fluorination method described herein can avoid the need to use hydrofluoric acid as an intermediate in the production of fluorochemicals. [Background technology]

[0002] Fluorochemicals may be present in everyday life with applications in the metallurgical industry, Li-ion batteries, electrical products, luminescent nanoparticles and electronics, fluoropolymers (PTFE, also known as Teflon or ETFE), refrigerants (HFOs), air conditioning, as well as pesticides, anesthetics, and pharmaceuticals. In general, fluorine atoms incorporated into organic fluorochemicals can be derived from the naturally occurring mineral Fluorspar (calcium fluoride, CaF2) by applying a workflow starting with its conversion into highly toxic hydrogen fluoride (HF) (Figure 1). Specifically, metallurgical grade Fluorspar (Metspar, 60-96% CaF2, about 40% of total Fluorspar production) can be used as a flux in steelmaking, and acid grade Fluorspar (Acidspar, over 97% CaF2, about 60% of total Fluorspar production) can be used to produce hydrofluoric acid (HF) and / or aluminum trifluoride (AlF3).

[0003] Industrial practices for producing organic fluorochemicals may rely on the energy-intensive treatment of acid-grade calcium fluoride acid spar with sulfuric acid at high temperatures to produce hydrogen fluoride gas that can be stored for use as a liquefied gas or diluted in water for use as an aqueous solution. The safety of HF-based processes may be a concern for both producers and users, for example, because HF is an extremely hazardous and corrosive acid that may require extreme care for safe handling.

[0004] Developing alternative routes to access value-added fluorochemicals can be extremely challenging. This is due, for example, to the high lattice energy of CaF2 (approximately 2640 kJ mol for each mole of fluoride produced). -1 , or approximately 1320 kJ mol -1 ) due to Summary of the Invention

[0005] According to a first aspect of the present invention there is provided a method for preparing a fluorination reagent comprising the steps of: a) grinding together in the solid state a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, and an ionic compound; Including, The anion of the ionic compound is Ca 2+ can combine with 2450KJ mol -1 A method is provided for forming calcium salts with higher lattice energies.

[0006] According to a second aspect of the present invention, there is provided a method for preparing a fluorochemical comprising the steps of: a) preparing a fluorination reagent as described herein; b) contacting the organic substrate with a fluorinating reagent; Including, Methods are provided, wherein step b) is performed simultaneously with or after step a).

[0007] According to a third aspect of the present invention, there is provided a method for preparing a fluorochemical comprising the steps of: a) grinding in a solid state a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite; b) contacting the product of step a) with an organic substrate; Including, Methods are provided, wherein step b) is performed simultaneously with or after step a).

[0008] According to a fourth aspect of the present invention, there is provided the use of a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical, the process not including a step of reacting the fluorine-containing compound with sulfuric acid to produce hydrofluoric acid.

[0009] According to a fifth aspect of the present invention, there is provided the use of a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, as a fluoride source in a method for preparing a fluorination reagent, the method not including a step of reacting the fluorine-containing compound with sulfuric acid to produce hydrofluoric acid.

[0010] In the above embodiment, the fluorine-containing compound is suitably calcium fluoride (eg, acid grade Fluorospar).

[0011] According to a sixth aspect of the present invention there is provided a fluorinating reagent obtained, directly obtained or obtainable by the method of the first aspect.

[0012] According to a seventh aspect of the present invention, there is provided a fluorination reagent comprising a mixture of multiple inorganic salts.

[0013] Calcium fluoride may be the only source of fluorine in the methods and uses according to the present invention.

[0014] In one aspect, the activated fluorination reagent is as described herein. In some embodiments, the activated fluorination reagent comprises a first salt comprising calcium and fluorine. In some embodiments, the activated fluorination reagent comprises a first salt comprising Ca 2+ When combined with to form a third salt, the second salt comprises an anion having a lattice energy of greater than 2450 KJ / mol. In some embodiments, the powder X-ray diffraction spectrum of the activating reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and / or 43.4°.

[0015] In another aspect, a method for synthesizing an organofluorine compound is described herein. In some embodiments, the method includes combining a first salt comprising calcium and fluorine with a second salt. In some embodiments, the second salt comprises Ca 2+ When combined with to form a third salt, it contains an anion with a lattice energy greater than 2450 KJ / mol.

[0016] In some embodiments, the first salt and the second salt are combined to form a salt mixture. In some embodiments, the method includes applying a mechanical force to the salt mixture to form an activated salt mixture. In some embodiments, the method includes combining the activated salt mixture with a first reactant. In some embodiments, the first reactant includes an organic compound. In some embodiments, the method includes fluorinating the first reactant to obtain an organic fluorine compound.

[0017] In another aspect, a method for fluorinating an organic compound is as described herein. In some embodiments, the method includes combining an activated fluorination reagent with an organic compound and fluorinating the organic compound to produce an organic fluorine compound. In some embodiments, the activated fluorination reagent has an activated reagent powder X-ray diffraction spectrum that includes characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and / or 43.4°.

[0018] In another aspect, a method for producing an activated fluorination reagent is described herein. In some embodiments, the method includes combining a first salt comprising calcium and fluorine with a second salt to form a salt mixture. In some embodiments, the second salt comprises Ca 2+ When combined with to form a third salt, the third salt comprises an anion having a lattice energy of greater than 2450 KJ / mol. In some embodiments, the method includes applying a mechanical force to the salt mixture to obtain an activated fluorination reagent.

[0019] In another aspect, a method for recovering fluorine from a waste material to form an activated fluorination reagent is described herein. Such a method can be used, for example, to recover fluorine from fluorine-depleted waste materials or to produce a fluorination reagent from a waste stream that contains fluorine, such as waste containing CaF2 or NaF. In some embodiments, the method includes combining a waste material that contains a first salt that contains calcium and fluorine with a second salt to form a salt-waste mixture. In some embodiments, the second salt is CaF2. 2+ When combined with the first salt to form a third salt, the third salt comprises an anion having a lattice energy of greater than 2450 KJ / mol. In some embodiments, the second salt combines with the first salt to form a salt-waste mixture having a powder X-ray diffraction spectrum comprising characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and / or 43.4°. In some embodiments, the method comprises applying a mechanical force to the salt-waste mixture to obtain an activated fluorination reagent.

[0020] In some embodiments of any of the fluorination reagents or methods described herein, the first salt is CaF2. In some embodiments, the first salt is fluorapatite (Ca5(PO4)3F). In some embodiments, the second salt is a metal hydroxide. 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 sulfite. In some embodiments, the second salt is Na2SO3. In some embodiments, the second salt is K2SO3.

[0021] In some embodiments, the second salt is a metal sulfate. In some embodiments, the second salt is KHSO4. In some embodiments, the second salt is an inorganic phosphate (e.g., K2HPO4, KH2PO4, K3PO4). In some embodiments, the second salt is K2HPO4. In some embodiments, the second salt is KH2PO4. In some embodiments, the second salt is K3PO4. In some embodiments, the inorganic phosphate is a pyrophosphate (e.g., K4P2O7 or Na3P2O7).

[0022] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and / or 53.9°. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least two characteristic 2θ 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°. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least three characteristic 2θ 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°. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least four characteristic 2θ 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°. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and 43.4°.

[0023] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.

[0024] 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 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 1:1. 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.

[0025] In some embodiments of any of the methods described herein, the mechanical force is applied using a ball mill, a mortar and pestle, a twin screw extruder, an ultrasonic bath, or a mechanical press.

[0026] In some embodiments, the method does not include reacting a strong acid with the first salt to form hydrofluoric acid. In some embodiments, the mechanical power is applied at a frequency of about 0.5 Hz to 60 kHz. In some embodiments, the mechanical power is applied at a frequency of about 10 Hz to 20 kHz. In some embodiments, the mechanical power is applied at a frequency of about 30 Hz. In some embodiments, the mechanical power is applied at a frequency of about 35 Hz. In some embodiments, the mechanical power is applied at a frequency of about 60 Hz.

[0027] In some embodiments, 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.

[0028] In some embodiments, the first salt and the second salt are combined as solids without the addition of a solvent.

[0029] In some embodiments, the organic compound is aromatic or aliphatic and contains at least one leaving group located at the site to be fluorinated. In some embodiments, the organic compound is a sulfonyl halide, an acyl halide, an aryl halide, or an alkyl halide. In some embodiments, the organic compound is an aromatic sulfonyl 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). In some embodiments, the first salt, the second salt, and the organic compound are combined in the same step. In some embodiments, the first salt, the second salt, and the organic compound are combined before the addition of the organic compound. In some embodiments, the first salt, the second salt, and the organic compound are added together with one or more solvents, and the organic compound is soluble in at least one of the one or more solvents.

[0030] In some embodiments, 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, any one or more of the organic solvents above may be miscible with water.

[0031] In some embodiments, the one or more solvents include acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol, and / or water. In some embodiments, the one or more solvents include cryptands, crown ethers, and hydrogen-bonding phase transfer agents.

[0032] In some embodiments, the fluorination reaction is carried out at a temperature of about 20-300° C. In some embodiments, the fluorination reaction is carried out at a temperature of about 20-100° C. In some embodiments, the fluorination reaction yield of the organic fluorine compound is at least about 10% (measured based on the starting amount of organic compound). In some embodiments, the fluorination reaction yield is at least about 30% (measured based on the starting amount of organic compound). In some embodiments, the fluorination reaction yield is at least about 50% (measured based on the starting amount of organic compound). In some embodiments, the fluorination reaction yield is at least about 80% (measured based on the starting amount of organic compound).

[0033] In some embodiments, the fluorination reaction is a monofluorination reaction. In some embodiments, the fluorination reaction is a difluorination reaction.

[0034] The novel features believed to be characteristic of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "Figure" and "Fig."). [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 shows a possible synthesis scheme for fluorochemicals from fluorine-containing salts. [Diagram 2]Top: 19F NMR in DO of a fluorinated reagent derived from CaF2 and K2HPO4 under mechanochemical conditions. Bottom: 19F NMR in DO of a fluorinated reagent derived from CaF2 and K2HPO4 under mechanochemical conditions after spiking with KF. [Diagram 3] FIG. 1 shows the NMR yields (%) of TsF and TsCl when various phosphates are used as activators for Fluorospar. [Figure 4] FIG. 13 shows the PXRD diffractograms of Fluorospar and KH2PO4 milling products after 3 hours at 35 Hz. [Diagram 5] FIG. 13 shows the PXRD diffractograms of Fluorospar and K3PO4 milling products after 3 hours at 35 Hz. [Figure 6] FIG. 13 shows the PXRD diffractogram of the milled product of Fluorospar and Na3PO4 after 3 hours at 30 Hz. [Figure 7] FIG. 13 shows the PXRD diffractograms of Fluorospar and Na2HPO4 milling products after 3 hours at 35 Hz. [Figure 8] FIG. 13 shows the PXRD diffractogram of the milled product of Fluorospar and NaH2PO4 after 3 hours at 35 Hz. [Figure 9] FIG. 13 shows the PXRD diffractograms of Fluorospar and KPO3 milled products after 3 hours at 35 Hz. [Figure 10] FIG. 13 shows the PXRD diffractograms of Fluorospar and K4P2O7 milled products after 3 hours at 35 Hz. [Figure 11] FIG. 13 shows the PXRD diffractograms of Fluorospar and K5P3O10 milled products after 3 hours at 35 Hz. [Figure 12] FIG. 13 shows the PXRD diffractograms of Fluorospar and Na4P2O7 milling products after 3 hours at 35 Hz. [Figure 13]FIG. 13 shows the PXRD diffractograms of Fluorospar and Na5P3O10 milled products after 3 hours at 35 Hz. [Figure 14] FIG. 13 shows the PXRD diffractograms of Fluorospar and Na(PO3)3 milling products after 3 hours at 35 Hz. [Figure 15] FIG. 13 shows the PXRD diffractograms of Fluorospar and CaHPO4 milling products after 3 hours at 30 Hz. [Figure 16] FIG. 13 shows the PXRD diffractogram of the milled products of Fluorospar and Ca3(PO4)2 after 3 hours at 30 Hz. [Figure 17] FIG. 13 shows stacked PXRD diffractograms of Fluorospar milled products after subsequent addition of K2HPO4 to result in CaF2:K2HPO4 ratios of 1:1, 1:2, 1:2.5, and 1:3 and milling at 30 Hz for 3 hours. [Figure 18] FIG. 13 shows NMR yields of TsF from TsCl using fluorospar and K2HPO4 as an activator, milling fluorospar and K2HPO4 at different frequencies. [Figure 19] Figure 1 shows NMR yields of TsF from TsCl using Fluorospar and various amounts of K2HPO4 activator resulting in the use of different ratios of CaF2:K2HPO4. In A, 1 equivalent of K2HPO4 is added to the Fluorospar, in B, 2 equivalents total are added, and in C, 2.5 equivalents total of K2HPO4 are added. [Figure 20] FIG. 1 shows NMR yields of TsF from TsCl using Fluorospar and K2HPO4 as activator with different amounts of water added to the fluorination reaction. [Figure 21] FIG. 1 shows the NMR yield of TsF from TsCl using Fluorospar and K2HPO4 as activator for reaction times of 5 h or 18 h with different amounts of water added to the fluorination reaction. [Figure 22] FIG. 1 shows the fluorination substrate scope of the R-SO2Cl species. [Diagram 23]FIG. 1 shows the fluorinated substrate scope of the RX species. [Figure 24] FIG. 24 shows the 19F NMR (24A) and 31P NMR (24B) of the soluble products of milling Fluorospar and K2HPO4. [Diagram 25] FIG. 13 shows the PXRD diffractograms of Fluorospar and K2HPO4 milled products after 9 hours at 30 Hz referenced to crystalline KF (bottom). [Figure 26] FIG. 1 shows the PXRD diffractogram of the milled product of Fluorospar reacted with K2HPO4 (Fluoromix). [Figure 27] FIG. 1 shows stacked PXRD diffractograms of (from top to bottom) Fluorospar milled with K2HPO4 at 30 Hz for 9 hours, KF milled with K2HPO4 at 30 Hz for 3 hours, KF milled with K2HPO4 at 30 Hz for 3 hours followed by CaHPO4 milled at 30 Hz for 3 hours, and crystalline CaF2. [Figure 28] FIG. 1 shows the products of KF milled with K2HPO4 at 30 Hz for 3 h (A) and KF milled with K2HPO4 at 30 Hz for 3 h followed by CaHPO4 at 30 Hz for 3 h, and the simulated crystal structure of crystalline CaF2 (B). [Figure 29] FIG. 1 shows stacked PXRD diffractograms of fluorospar, K2HPO4, and fluorapatite. [Diagram 30] FIG. 1 shows overlaid PXRD diffractograms of Fluoromix, KF milled with K2HPO4 at 30 Hz for 3 hr, KF milled with K2HPO4 at 30 Hz for 3 hr followed by CaHPO4 at 30 Hz for 3 hr, and crystalline CaF2, and Fluorospar. [Diagram 31] FIG. 1 shows the PXRD diffractogram of the water-insoluble solid formed from the milling reaction of CaF2 (Fluorospar) and K2HPO4. [Diagram 32]FIG. 32A shows the PXRD diffractogram of the water-insoluble solid formed from the milling reaction of CaF2 (Fluorospar) and K2HPO4 overlaid with the PXRD diffractogram of the milled product of Fluorospar and CaHPO4 (32A) and the PXRD diffractogram of the product formed from the milling reaction of Fluorospar and CaHPO4 after 3 hours at 30 Hz (32B). [Diagram 33] FIG. 1 shows the PXRD diffractogram of X (KF milled with K2HPO4 at 35 Hz for 3 hours). [Diagram 34] FIG. 13 shows the PXRD diffractogram of Y (KF milled with KHPO at 35 Hz for 3 hr followed by CaHPO at 35 Hz for 3 hr). [Diagram 35] FIG. 1 shows NMR yields of TsF from TsCl when reacted independently with Fluoromix or X (KF milled with KHPO for 3 hr at 35 Hz) or Y (KF milled with KHPO for 3 hr at 35 Hz followed by CaHPO for 3 hr at 35 Hz). [Diagram 36] FIG. 1 shows the PXRD diffractograms of Fluorospar and NaOH. [Figure 37] FIG. 1 shows NMR yields of TsF from TsCl using fluorospar and various non-phosphate activators. [Figure 38] FIG. 1 shows the PXRD diffractogram of the product of a fluorospermill milling reaction with K2CO3 at 35 Hz for 3 hours. [Figure 39] FIG. 1 shows the PXRD diffractogram of the product of the fluorosperm milling reaction with KHCO 3 at 35 Hz for 3 hours. [Diagram 40] FIG. 1 shows the PXRD diffractogram of the product of a fluorosperm milling reaction with K2SO4 at 35 Hz for 3 hours. [Diagram 41] FIG. 1 shows the PXRD diffractogram of the product of a fluorosperm milling reaction with KHSO4 at 35 Hz for 3 hours. [Diagram 42]FIG. 1 shows the PXRD diffractogram of the product of a fluorosperm milling reaction with K2S2O7 at 35 Hz for 3 hours. [Diagram 43] FIG. 1 shows the PXRD diffractogram of the product of the fluorospermill milling reaction with Na2SO3 at 35 Hz for 1.5 hours. [Diagram 44] FIG. 1 shows the PXRD diffractogram of the product of the fluorosperm milling reaction with KNO3 at 35 Hz for 3 hours. [Diagram 45] FIG. 1 shows the PXRD diffractogram of the product of a fluorosperm milling reaction with KOH at 35 Hz for 3 hours. [Figure 46] FIG. 1 shows the PXRD diffractogram of the product of a fluorosperm milling reaction with NaOH at 35 Hz for 3 hours. [Figure 47] FIG. 1 shows the extent of reaction of R-SO2Cl species with fluorapatite using phosphate activator and associated yields. [Figure 48] FIG. 1 shows stacked PXRD diffractograms of the products of the fluorapatite milling reaction upon subsequent addition of K4P2O7 (four separate additions of 1 equivalent). [Figure 49] FIG. 1 shows the PXRD diffractogram of pure fluorapatite after 1 hour of milling overlaid with K4P2O7 (4 equivalents) and a fluorapatite sample (1 equivalent) milled at 35 Hz for a total of 12 hours. [Figure 50] Figure 1 shows stacked PXRD diffractograms of the reaction between fluorapatite (Ca5(PO4)3F) and K4P2O7, a 1:4 equivalent milling reaction (D), and the milling reaction between potassium fluoride (KF, 1 equivalent) and K2HPO4 (2 equivalents, 35 Hz, 3 hr), followed by CaHPO4 (1 equivalent, 35 Hz, 3 hr). [Figure 51] FIG. 1 shows the PXRD diffractogram of the water-insoluble product of the reaction between fluorapatite and potassium pyrophosphate overlaid with the PXRD diffractogram of fluorapatite. [Figure 52]FIG. 1 shows the PXRD diffractogram of the milling reaction of fluorapatite with 1 equivalent of K4P2O7 at 30 Hz for 9 hours. [Figure 53] FIG. 13 shows the PXRD diffractogram of a milling reaction of 4 subsequent additions of 1 equivalent of K4P2O7 to 1 equivalent of fluorapatite with 3 hours of milling at 35 Hz after each addition. [Figure 54] FIG. 1 shows a general scheme for studying the effect of varying screw temperature on the production of active fluorinated materials. [Figure 55] FIG. 1 shows a general scheme for studying the effect of varying screw speed on the production of active fluorinated materials. [Figure 56] FIG. 1 shows a general scheme for studying the effect of varying the number of recycles on the generation of active fluorinated materials. [Figure 57] FIG. 1 shows a general scheme for adding only CaF2 without K2HPO4 to a twin screw extruder. [Figure 58] FIG. 1 shows a general scheme for studying the effect of varying screw configuration on the production of active fluorinated materials. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Throughout the description and claims of this specification, when subject matter is described herein using the term "comprise" (or "comprises" or "comprising"), it is also contemplated that the same subject matter is described instead using the term "consist of" (or "consists of" or "consisting of") or "consist essentially of" (or "consists essentially of" or "consisting essentially of").

[0037] The term "about" or "approximately" may mean within an acceptable error range for a particular value, which depends 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. However, in the case of X-ray diffraction reflections, "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 number of a series of two or more numbers, the term "no more than", "less than", or "less than or equal to" applies to each of the numbers in the series. For example, 3, 2, or 1 or less is equal to 3 or less, 2 or less, or 1 or less.

[0038] Certain embodiments of the invention contemplate numerical ranges herein. Where ranges are present, the ranges include the endpoints of the ranges. Moreover, all subranges and values ​​within the ranges are included as if expressly written out.

[0039] As used herein, certain embodiments of the invention contemplate characteristic X-ray diffraction reflections. In certain embodiments, the presence or absence of characteristic X-ray diffraction reflections is determined by identifying peaks in the X-ray diffraction spectrum located at characteristic 2θ values.

[0040] In certain embodiments, a peak is present when the 2θ signal has a signal to noise ratio of at least 3.

[0041] In certain embodiments, a peak is present when the 2θ signal has a signal to noise ratio of at least 5. In certain embodiments, a peak is present when the 2θ signal has a signal to noise ratio of at least 10.

[0042] In certain embodiments, a peak is present when the 2θ signal has a signal to noise ratio of at least 20.

[0043] In certain embodiments, the peaks are identified in a raw X-ray powder diffraction spectrum. In certain embodiments, the peaks are identified in a background-subtracted X-ray powder diffraction spectrum. In some embodiments, the peaks corresponding to the first salt are subtracted from the raw spectrum to obtain a background-subtracted spectrum. In some embodiments, the peaks corresponding to the second salt are subtracted from the raw spectrum to obtain a background-subtracted spectrum. In some embodiments, one or more known contaminant peaks are subtracted from the raw spectrum to obtain a background-subtracted spectrum. In some embodiments, the peaks corresponding to one or more of the first salt, the second salt, and / or the known contaminant are subtracted from the raw spectrum to obtain a background-subtracted spectrum.

[0044] Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification is to be understood as contemplating plural as well as singular, unless the context requires otherwise.

[0045] Features described in conjunction with a particular aspect, embodiment or example of the invention should be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible. All of the features disclosed herein (including any accompanying claims, abstracts, and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the specific embodiments recited herein. The invention extends to any novel one or any novel combination of the features disclosed herein (including any accompanying claims, abstracts, and drawings), or any novel one or any novel combination of the steps of any method or process so disclosed.

[0046] Unless otherwise specified, when the amount or concentration of a particular component of a given product is specified as a weight percentage (wt% or %w / w), said weight percentage refers to the percentage of said component by weight relative to the total weight of the entire product. It will be understood by those skilled in the art that the sum of the weight percentages of all components of a product totals 100% by weight. However, when not all components are listed (e.g., when a product is said to "comprise" one or more particular components), the weight percentage balance may be made up to 100% by weight by components that are not specified.

[0047] As stated above, in a first aspect, the present invention provides a method for preparing a fluorinating reagent, comprising the steps of: a) grinding together in the solid state a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, and an ionic compound; Including, The anion of the ionic compound is Ca 2+ can combine with 2450KJ mol -1 A method is provided for forming calcium salts with higher lattice energies.

[0048] Through rigorous research, the inventors have arrived at a solution to this long-standing problem by devising a method that allows calcium fluoride and fluorapatite to be directly converted into fluorinating reagents without the need for conversion to HF using sulfuric acid. This is achieved by reacting calcium fluoride and / or fluorapatite with certain ionic compounds according to the conditions outlined in step a) (e.g. ball milling, or other mechanochemical techniques). Thus, the method according to the invention allows the preparation of value-added fluorochemicals using more environmentally friendly and sustainable techniques.

[0049] Calcium fluoride (CaF2, melting point, approximately 1420 °C) is a white solid that is sparingly soluble in water (0.016 g / L at 20 °C) and insoluble in organic solvents. Under ambient conditions, calcium fluoride is Ca 2+ Ions are 8 nearest neighbors F - It crystallizes in the fluorite structure (α, space group Fm-3m) with ions cubically coordinated. The calcium fluoride used as part of the present invention may be naturally occurring (i.e., as fluorospar) or synthetic (e.g., industrially produced calcium fluoride with fewer impurities). Fluorapatite is a crystalline solid having the formula Ca5(PO4)3F.

[0050] The method of the present invention involves reacting a fluorine-containing compound (i.e., calcium fluoride and / or fluorapatite) with a specific ionic compound in the solid state using high energy mixing techniques, such as techniques sufficient to mechanically reduce the particle size of the reactants (e.g., crushing) and bring them into contact with each other. Grinding the reactants together according to step a) achieves this objective. However, it will be appreciated that synonymous high energy mixing techniques that result in a reduction in the particle size of the reactants and / or an increase in the surface area to volume ratio of the reactants, such as crushing together, grinding together, milling together, crushing together, macerating together, etc., are encompassed by step a).

[0051] The method may be a mechanochemical process and / or step a) may be carried out under mechanochemical conditions. Mechanochemistry is a developed branch of chemical synthesis and is broadly understood to refer to chemical transformations that are initiated and / or sustained by the application of mechanical stress to one or more solid reactants.

[0052] Step a) may be carried out in a ball mill, a pestle and mortar or a twin screw extruder (TSE). Other techniques and equipment suitable for carrying out step a), including ultrasonic baths and / or mechanical presses, will be familiar to those skilled in the art, e.g. those skilled in the art of mechanochemistry.

[0053] In certain embodiments, step a) is carried out in a ball mill. Exemplary ball mills include a planetary ball mill, a vibrating ball mill, an attritor ball mill, or a tumbling ball mill. Most suitably, the ball mill is a vibrating ball mill.

[0054] For ball milling, one skilled in the art would be able to select appropriate conditions, including ball size and weight, and container size. For example, a stainless steel container and one or more stainless steel balls can be used. Alternatively, a zirconia container and one or more zirconia balls can be used. For example, balls weighing (each) 2-20 g (e.g., 3 g, 4 g, 7 g, or 16 g) can be used.

[0055] Step a) can be carried out for any suitable period of time, for example, step a) can be carried out for 0.5 to 12 hours (e.g., the fluorine-containing compound and the ionic compound can be ball milled together for 0.5 to 12 hours).

[0056] In certain embodiments, 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).

[0057] Twin screw extrusion is carried out at various speeds (S S ), screw temperature (S T ) and residence time (T R ) in a twin screw extruder. A single pass through the extruder may be sufficient to form the fluorinating reagent. Alternatively, when step a) is carried out in a twin screw extruder, step a) may include collecting the product exiting the twin screw extruder and subjecting it to one or more additional passes through the twin screw extruder.

[0058] Step a) is carried out in the solid state. In its simplest sense, step a) is carried out in the absence (or substantial absence) of any solvent. However, it is known that the use of certain solvents offers advantages in some solid-state (e.g., mechanochemical) reactions. Such techniques include, for example, solvent-assisted mechanochemistry (sometimes called liquid-assisted mechanochemistry, e.g., liquid-assisted grinding). Suitably, the amount and type of solvent (if any) used is such that more than 50% by weight of the fluorine-containing compounds, ionic compounds, and any reaction products derived therefrom remain in the solid state throughout step a). More suitably, more than 70% by weight of the fluorine-containing compounds, ionic compounds, and any reaction products derived therefrom remain in the solid state throughout step a). Even more suitably, more than 90% by weight of the fluorine-containing compounds, ionic compounds, and any reaction products derived therefrom remain in the solid state throughout step a). Even more suitably, greater than 95% by weight of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in a solid state throughout step a).

[0059] In certain embodiments, step a) is carried out in the absence (or substantial absence) of any solvent.Suitably, step a) involves grinding the fluorine-containing compound and the ionic compound together in a ball mill (i.e., ball milling the fluorine-containing compound and the ionic compound).

[0060] In certain embodiments, step a) is carried out in the absence (or substantial absence) of any solvent.Suitably, step a) involves grinding together the fluorine-containing compound and the ionic compound in a twin-screw extruder.

[0061] During step a), a fluorine-containing compound, the anion of which is Ca 2+ can combine with 2400KJ mol -1The calcium fluoride reacts with ionic compounds that form calcium salts with a higher lattice energy. Those skilled in the art will be familiar with the term lattice energy, which indicates 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 are only slightly soluble in certain acids and are chemically inert to nearly all organic chemicals. The stability of calcium fluoride and fluorapatite is due in large part to their high lattice energy (2630 KJ mol for calcium fluoride). -1 However, the inventors have determined that this stability can be overcome by milling (e.g., ball milling) calcium fluoride and / or fluorapatite together with certain ionic compounds, according to step a). Without wishing to be bound by theory, the inventors believe that Ca 2+ We believe that the energy bar for the 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 of 2630 KJ mol -1 Calcium salts having a lattice energy similar to or preferably greater than that (e.g., CaSO4=2489 KJ mol -1 ;CaCO3=2804KJ mol -1 ;Ca3(PO4)2=10,602KJ mol -1 The use of ionic compounds capable of forming fluorine-containing species with improved reactivity towards organic chemicals is advantageously used to promote the formation of fluorine-containing species with improved reactivity towards organic chemicals.

[0062] The fluorine-containing compound is typically calcium fluoride or fluorapatite.Suitably, the fluorine-containing compound is calcium fluoride.When the fluorine-containing compound is calcium fluoride, a certain amount of fluorapatite may be formed (e.g., transiently) during step a).In a particular embodiment, the calcium fluoride is acid grade fluorospar.

[0063] The fluorine-containing compound used in the first embodiment may optionally be calcium fluoride, fluorapatite, and / or any other salt containing calcium and fluorine, which may be described elsewhere herein as the first salt containing calcium and fluorine.

[0064] The anion of the ionic compound is particularly suitably Ca 2+ and has a lattice energy greater than that of calcium fluoride (i.e., 2630 KJ mol -1 It forms calcium salts with lattice energies greater than 1000.

[0065] The ionic compound is suitably inorganic. The ionic compound may be a salt. Suitably the ionic compound is a salt of an oxoacid.

[0066] The ionic compound may be a phosphate, carbonate, sulfate, sulfite or nitrate. Alternatively, the ionic compound may be a phosphate, carbonate or sulfate. It is understood that the phosphate, carbonate, sulfate, sulfite or nitrate described herein are meant to be salts containing at least one of these anions, i.e., also include salts such as hydrogen phosphate, dihydrogen phosphate, hydrogen sulfate and bicarbonate. It is understood that phosphate includes metaphosphate, and phosphate and sulfate include pyrophosphate and pyrosulfate, respectively. Alternatively, the ionic compound may be a hydroxide salt or a citrate salt. Alternatively / additionally, the ionic compound may be an alkali metal salt or an alkaline earth metal salt, for example, potassium salt, sodium salt or magnesium salt.

[0067] In certain embodiments, the ionic compound is a phosphate.

[0068] The ionic compound may be a potassium, sodium or calcium phosphate, a potassium, sodium or cesium sulfate, a potassium or sodium carbonate, a potassium or sodium sulfite, a potassium or sodium nitrate, a potassium or sodium hydroxide, or a potassium or sodium citrate. For example, the ionic compound may be K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, KPO3, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10 , (NaPO3)3, CaHPO4, K2CO3, KHCO3, K2SO4, KHSO4, Cs2SO4, MgSO4, Ag2SO4, K2S2O7, Na2SO3, Na2SO4, Na2CO3, KNO3, Na3C6H5O7, NaOH and KOH.

[0069] Specific non-limiting examples of ionic compounds include potassium and sodium phosphates, potassium and sodium sulfates, and potassium and sodium carbonates.Suitably, the ionic compound is potassium or sodium phosphate.More suitably, the ionic compound is potassium phosphate.Most suitably, the ionic compound is K3PO4 or K2HPO4, of which K2HPO4 is most preferred.

[0070] Alternatively, the ionic compound is K3PO4, K2HPO4, KH2PO4, KPO3, Na3PO4, Na2HPO4, Cs2SO4, Na2SO3, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10 , Na3C6H5O7, K2SO4, Na2SO4, MgSO4, Na2CO3, K2CO3, KHCO3, NaOH and KOH. Suitably, the ionic compound may be selected from the group consisting of K3PO4, K2HPO4, KPO3, Na3PO4, Na2HPO4, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10, K2CO3, KHCO3, NaOH and KOH. More suitably, the ionic compound is selected from the group consisting of K2HPO4, KPO3, Na2HPO4, K4P2O7, K5P3O 10 and Na4P2O7.

[0071] The ionic compounds used in the first aspect may, in some cases, be described elsewhere herein as second salts.

[0072] In certain embodiments, the ionic compound is K2HPO4, KPO3, Na2HPO4, K4P2O7, K5P3O 10 or Na4P2O7, and step a) is carried out in the absence (or substantial absence) of any solvent. Suitably, step a) involves grinding the fluorine-containing compound and the ionic compound together in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).

[0073] In certain embodiments, the ionic compound is a potassium or sodium phosphate, sulfate or carbonate (e.g., K3PO4 or K2HPO4) and step a) is carried out in the absence (or substantial absence) of any solvent. Suitably, step a) involves grinding the fluorine-containing compound and the ionic compound together in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).

[0074] It will be appreciated that ionic compounds having similar properties to those enumerated herein may also be suitable for use in step a).

[0075] 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). Suitably, 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.

[0076] In some embodiments, the ionic compound is milled together with the fluorine-containing compound in portions. For example, step a) may include (ai) milling together a first portion of the fluorine-containing compound and the ionic compound, and (a-ii) milling together a second portion of the ionic compound and the product of step (ai). Optionally, step a) further includes step (a-iii) milling together a third portion of the ionic compound and the product of step (a-ii). Optionally, step a) further includes step (a-iv) milling together a fourth portion of the ionic compound and the product of step (a-iii). The portions of the ionic compound may be the same or different.

[0077] In some embodiments, solid CO2 (i.e., dry ice) is ground together with the fluorine-containing compound and the ionic compound. In such embodiments, between 5 and 15 equivalents of solid CO2 (per equivalent of fluorine-containing compound) can be used in step a).

[0078] In some embodiments, the product obtained from step a) may be heat treated. Suitably, the product obtained from step a) may be heated to a temperature of 300 to 700° C. (e.g., 500 to 600° C.).

[0079] In one embodiment, essentially no HF is produced at any time during step a), for example, less than 1 ppm (e.g., less than 1 ppb) of HF may be produced at any time during step a).

[0080] The fluorinating reagent provided by step a) can be used to prepare a fluorochemical (e.g., an organic fluorochemical). Thus, according to a second aspect, the present invention provides a method for preparing a fluorochemical, comprising the steps of: a) preparing a fluorination reagent as described herein; b) contacting the organic substrate with a fluorinating reagent; Including, Methods are provided, wherein step b) is performed simultaneously with step a) or after step a).

[0081] The organic substrate to be fluorinated may take a variety of forms. Suitably, the organic substrate is an electrophile.

[0082] The organic substrate may be aliphatic (e.g., alkyl halide) or aromatic (e.g., aryl halide or heteroaryl halide) in nature. The organic substrate has at least one leaving group suitably located at the site to be fluorinated. Leaving groups will be known to those skilled in the art of organic chemistry. Specific non-limiting examples of suitable leaving groups include halides (especially chloro or bromo), tosylate, triflate, mesylate, phosphate, nitro, ammonium and iodonium groups. Most suitably, the leaving group is a halide.

[0083] The organic substrate may be any one of the organic substrates used in the examples outlined herein, in which the illustrated leaving group may be replaced, if chemically feasible, with any one of the other leaving groups described above.

[0084] In certain embodiments, the organic substrate is a sulfonyl halide, an acyl halide, an aryl halide, or an alkyl halide (including an alkylaryl halide such as a benzyl halide). In such embodiments, the halide is suitably a chloride. Sulfonyl fluorides, acyl fluorides, aryl fluorides, and benzyl fluorides are among the most common fluorinated motifs in organic synthesis, and are widely applicable either as reagents, synthetic intermediates, or biological probes. More suitably, the organic substrate is a sulfonyl halide, an acyl halide, an aryl halide, or a heteroaryl halide. Specific non-limiting examples include aromatic sulfonyl halides (e.g., tosyl chloride), benzoyl halides (e.g., 4-methoxybenzoyl chloride), halobenzenes (e.g., chlorobenzene), and benzyl halides (e.g., benzyl chloride).

[0085] In certain embodiments, the organic substrate is a sulfonyl halide, aryl halide, alkylaryl halide, acyl halide, α-halocarbonyl or alkyl halide.

[0086] In certain embodiments, the organic substrate is ArOCHX2, where Ar is an aromatic group (eg, biphenyl) and X is a halide (eg, chloro).

[0087] In certain embodiments, when the organic substrate has more than one leaving group (eg, two leaving groups), the leaving groups may be attached to the same carbon atom (eg, two geminal halide leaving groups).

[0088] In most cases, the organic substrate is 500 g mol -1 Suitably, the organic substrate has a molecular weight of less than 300 g mol -1 has a molecular weight of less than

[0089] In certain embodiments, the organic substrate is a sulfonyl halide, acyl halide, aryl halide or alkyl halide (e.g., the halide is a bromide) and the ionic compound used in step a) is a potassium or sodium phosphate, sulfate or carbonate (e.g., K3PO4 or K2HPO4). Suitably, step a) is carried out in the absence (or substantial absence) of any solvent. Alternatively / additionally, step a) involves grinding a fluorine-containing compound (e.g., calcium fluoride) and an ionic compound together in a ball mill (i.e., ball milling calcium fluoride and an ionic compound).

[0090] In certain embodiments, the organic substrate is a sulfonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halocarbonyl or an alkyl halide, and the ionic compound used in step a) is a phosphate, a carbonate, a sulfate, a sulfite, a nitrate, a hydroxide or a citrate (e.g., K3PO4, K2HPO4, KPO3, Na3PO4, Na2HPO4, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10 , K2CO3, KHCO3, NaOH or KOH). Suitably, step a) is carried out in the absence (or substantial absence) of any solvent. Alternatively / additionally, step a) involves grinding the fluorine-containing compound (e.g. calcium fluoride) and the ionic compound together in a ball mill or twin screw extruder (i.e. ball milling calcium fluoride and the ionic compound).

[0091] Step b) may be performed simultaneously with step a), such that the organic substrate is available for reaction with the fluorinating reagent as soon as the fluorinating reagent is formed during step a). Thus, step b) may involve contacting the organic substrate with the fluorinating reagent under the same conditions as those used to form the fluorinating reagent. In this sense, steps a) and b) may collectively define a single step in which the fluorine-containing compound, the ionic compound and the organic substrate are ground together in the solid state (e.g., by ball milling).

[0092] Alternatively, step b) can be carried out after step a), such that a quantity of the fluorinating reagent is formed before reacting with the organic substrate.

[0093] When step b) is carried out after step a), step b) may be carried out in the solid state. For example, step b) may comprise grinding together the organic substrate and the fluorinating reagent formed from step a) in the solid state. Suitably, step b) is carried out in a ball mill. More suitably, step b) is carried out in the absence (or substantial absence) of a solvent. In certain embodiments, steps a) and b) are both carried out in a ball mill (e.g., the same ball mill), suitably in the absence (or substantial absence) of a solvent.

[0094] Alternatively, when step b) is performed after step a), step b) may be performed in solution. For example, step b) may include mixing the organic substrate and the fluorinating reagent together in a solvent in which the organic substrate is soluble. Any suitable solvent or combination of solvents may be used depending on the nature of the organic substrate, including, for example, the solvents used in the examples outlined herein (e.g., those listed in Table 3.5). The solvent may be selected from the group consisting of, for example, tetrahydrofuran, 2-methyltetrahydrofuran, 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. Specific non-limiting examples include acetonitrile, propionitrile, toluene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, 1,2-difluorobenzene, dichloroethane, trifluorotoluene, chloroform, tert-butanol, tert-amyl alcohol and water. Suitably, step b) is carried out 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 carried out in acetonitrile, chlorobenzene, tert-butanol or tert-amyl alcohol. Most suitably, step b) is carried out in acetonitrile.

[0095] Any one or more of the organic solvents may be miscible with water. For example, the organic solvent may be miscible with water at a concentration of 0.01 to 5 M. Suitably, the organic solvent may be miscible with water at a concentration of 0.01 to 1 M (e.g., 0.05 to 0.5 M).

[0096] In certain embodiments, step b) is performed after step a), and step b) is performed in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 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 miscible with water. Suitably, the organic substrate is a sulfonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halocarbonyl or an alkyl halide, and the ionic compound used in step a) is a phosphate, carbonate, sulfate, sulfite, nitrate, hydroxide or citrate (e.g. K3PO4, K2HPO4, KPO3, Na3PO4, Na2HPO4, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10 , K2CO3, KHCO3, NaOH or KOH). Step a) may involve grinding the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound together in a ball mill (i.e., ball milling calcium fluoride and the ionic compound) or grinding the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound together in a twin screw extruder.

[0097] When step b) is carried out after step a), the fluorinated reagent formed in step a) may be isolated or purified before reacting with the organic substrate.

[0098] A person skilled in the art will be able to select suitable reaction conditions (e.g. temperature, pressure, etc.) for carrying out step b) in solution. For example, when step b) is carried out in solution after step a), step b) may be carried out at a temperature between 15 and 180° C. Suitably, step b) is carried out at a temperature between 15 and 150° C.

[0099] Step b) may be carried out in the presence of at least one of a cryptand, a crown ether and a hydrogen-bonding phase transfer catalyst. Suitably, step b) is carried out after step a) and is carried out 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. Among the above cryptands, crown ethers and hydrogen-bonding phase transfer catalysts, 18-crown-6 and dibenzo-18-crown-6 are particularly suitable.

[0100] The method may further comprise one or more additional steps of isolating and / or purifying the fluorochemical formed in step b).

[0101] Fluorochemicals may be otherwise described herein as fluorinated compounds or organofluorine compounds.

[0102] As stated above, according to a third aspect, the present invention provides a method for preparing a fluorochemical, comprising the steps of: a) grinding in a solid state a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite; b) contacting the product of step a) with an organic substrate; Including, Methods are provided, wherein step b) is performed simultaneously with or after step a).

[0103] Through further investigation, the inventors have surprisingly concluded that although it is not necessary to grind the fluorine-containing compound with an ionic compound as defined herein, the formation of HF can be avoided and calcium fluoride or fluorapatite can be directly converted to value-added fluorochemicals using a method similar to that of the first aspect.

[0104] It will therefore be understood that steps a) and b) of the third aspect may have any of the definitions recited above in relation to the corresponding steps a) and b) of the first and second aspects.

[0105] In certain embodiments, step b) is carried out in solution in the presence of an ionic compound as defined herein (e.g., K2HPO4).

[0106] As mentioned above, according to a fourth aspect, the present invention provides the use of a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, as a fluorine source in a method for preparing a fluorochemical, the method not including a step of reacting the fluorine-containing compound with sulfuric acid to produce hydrofluoric acid.

[0107] As mentioned above, according to a fifth aspect, the present invention provides the use of a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, as a fluoride source in a method for preparing a fluorination reagent, the method not including a step of reacting the fluorine-containing compound with sulfuric acid to produce hydrofluoric acid.

[0108] It will be appreciated that the features of the fourth and fifth aspects may have any of the definitions recited above in relation to the first, second and third aspects.

[0109] According to a sixth aspect of the present invention there is provided a fluorinating reagent obtained, directly obtained or obtainable by the method of the first aspect.

[0110] According to a seventh aspect of the present invention, there is provided a fluorination reagent comprising a mixture of multiple inorganic salts.

[0111] The sixth and seventh aspects of the invention may be further defined as follows.

[0112] The fluorinating reagent may be provided as a mixture of inorganic salts.

[0113] The fluorination reagent (e.g., a mixture of inorganic salts) suitably comprises calcium, fluorine and oxygen, and at least one of (i) potassium and sodium, and (ii) phosphorus, sulfur, nitrogen and carbon. More suitably, the fluorination reagent comprises calcium, fluorine and oxygen, and at least one of (i) potassium and sodium, and (ii) phosphorus, sulfur and carbon. Most suitably, the fluorination reagent comprises calcium, fluorine, oxygen, potassium and phosphorus. The fluorination reagent may further comprise hydrogen.

[0114] The mixture of inorganic salts suitably comprises a first inorganic salt and a second inorganic salt, (i) the first inorganic salt being 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 K + and Na 2+ Suitably, the first inorganic salt comprises at least one cation selected from Ca 2+ and at least one anion selected from phosphate, sulfate, carbonate, and hydroxide (e.g., phosphoric acid), and / or the second inorganic salt is selected from fluoride and K + The mixture of multiple inorganic salts contains 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).

[0115] The fluorination reagent (e.g., a mixture of inorganic salts) may contain calcium fluoride and / or fluorapatite. Trace amounts (i.e., amounts detectable by XRPD) of calcium fluoride and / or fluorapatite from the starting materials used in the method of the first embodiment may be present in the fluorination reagent. Fluorapatite may be present in the fluorination reagent even if it is not used as a fluorine-containing compound in the method of the first embodiment.

[0116] The fluorination reagent may be provided as a powder. The powder may have an average particle size, as determined by SEM or TEM analysis, of less than 500 μm. Suitably, the powder has an average particle size of less than 100 μm. More suitably, the powder has an average particle size of less than 50 μm.

[0117] Fluorinated reagents may be characterized by X-ray powder diffraction (XRPD) using Cu Kα1 (λ=1.5406 Å) and / or Cu Kα2 (λ=1.5444 Å). Due to differences in instruments, samples and sample preparation, peak values ​​are often reported with the modifier "±0.2°2θ". This is a common practice in solid state chemistry due to the inherent variation in peak values.

[0118] The fluorinated reagent may have an XRPD pattern that includes peaks at ±0.2° 2θ corresponding 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. For example, the fluorinated reagent may have an XRPD pattern that includes peaks at ±0.2° 2θ corresponding to at least 30% of the 25 2-theta values ​​reported in Table 5.12.1 outlined herein, which may mean that the fluorinated reagent may have an XRPD pattern that includes peaks corresponding to at least 8 of the 2-theta values ​​(e.g., those not attributable to CaF2) reported in Table 5.12.1, recognizing that each 2-theta value reported in Table 5.12.1 may be corrected ±0.2° 2θ. For example, the fluorinated reagent may have an XRPD pattern including peaks at ±0.2° 2θ corresponding to at least 50% of the 33 2-theta values ​​reported in Table 6.3.3 outlined herein, which may mean that the fluorinated reagent may have an XRPD pattern including peaks corresponding to at least 17 of the 2-theta values ​​reported in Table 6.3.3, recognizing that each 2-theta value reported in Table 5.12.1 may be a corrected ±0.2° 2θ. Suitably, the fluorinated reagent has an XRPD pattern including peaks at ±0.2° 2θ corresponding 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 that includes peaks at ±0.2° 2θ corresponding 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.

[0119] The fluorination reagent may have an XRPD pattern including peaks at 2-theta values ​​of 21.9±0.2°2θ, 30.3±0.2°2θ, 31.6±0.2°2θ, and 43.4±0.2°2θ. The XRPD pattern may include peaks at 2-theta values ​​of 18.0±0.2°2θ, 18.7±0.2°2θ, 22.6±0.2°2θ, 24.5±0.2°2θ, 25.4±0.2°2θ, 26.5±0.2°2θ, 27.0±0.2°2θ, 28.0±0.2°2θ, 29.2±0.2°2θ, 33.0±0.2°2θ, 34.8±0.2°2θ, 36.4±0.2°2θ, 2θ, 37.7±0.2°2θ, 39.5±0.2°2θ, 40.4±0.2°2θ, 41.7±0.2°2θ, 42.4±0.2°2θ, 46.1±0.2°2θ, 48.4±0.2°2θ, 49.4±0.2°2θ, 52.8±0.2°2θ, and 53.9±0.2°2θ. The XRPD pattern may include peaks at at least 5, at least 10, at least 15, or at least 20 of the above 2-theta values. The fluorination reagent may have an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 10. Suitably, the fluorination reagent (i) comprises calcium, fluorine, oxygen, potassium, and phosphorus, and / or (ii) comprises a first inorganic salt and a second inorganic salt, the first inorganic salt being Ca. 2+ and phosphoric acid, and the second inorganic salt is fluoride and K + Includes.

[0120] Fluorination reagents were: 17.5±0.2°2θ, 21.2±0.2°2θ, 23.5±0.2°2θ, 24.8±0.2°2θ, 29.4±0.2°2θ, 29.6±0.2°2θ, 30.5±0.2°2θ, 31.5±0.2°2θ, 35.4±0.2°2θ, 36.7±0.2°2θ, 37.4±0.2°2θ, 39.8±0.2°2θ, 40.0±0.2°2θ, 41.0±0.2°2θ, 42.0±0.2°2θ, 43.0±0.2°2θ, 44.0±0.2°2θ, 45.0±0.2°2θ, 46.0±0.2°2θ, 47.0±0.2°2θ, 48.0±0.2°2θ, 49.0±0.2°2θ, 50.0±0.2°2θ, 51.0±0.2°2θ, 52.0±0.2°2θ, 53.0±0.2°2θ, 54.0±0.2°2θ, 55.0±0.2°2θ, 56.0±0.2°2θ, 57.0±0.2°2θ, 58.0±0.2°2θ, 59.0±0.2°2θ, 60.0±0.2°2θ, 61.0±0.2°2θ, 62.0±0.2°2θ, 63.0±0.2°2θ, 64.0±0.2°2θ, 65.0±0.2°2θ, 66.0±0.2 2θ, 42.9±0.2°2θ, 47.1±0.2°2θ, 48.1±0.2°2θ, 51.4±0.2°2θ, 53.2±0.2°2θ, 54.2±0.2°2θ, 58.2±0.2°2θ, 60.9±0.2°2θ and 63.4±0.2°2θ. The XRPD pattern may be at least 2, at least 3, at least 4, at least 5, at least 10, at least 15 or at least 20 of the above 2-theta values. The fluorination reagent may have an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 26. Suitably, the fluorination reagent (i) comprises calcium, fluorine, oxygen, potassium and phosphorus, and / or (ii) comprises a first inorganic salt and a second inorganic salt, the first inorganic salt being Ca. 2+ and phosphoric acid, and the second inorganic salt is fluoride and K + The fluorinating reagent may include K3(HPO4)F.

[0121] The fluorination reagent may include K3(HPO4)F and have an XRPD pattern including one or more peaks at 2 theta values ​​of 21.1±0.2°2θ, 29.6±0.2°2θ, 30.5±0.2°2θ, 37.4±0.2°2θ, 42.9±0.2°2θ, 54.2±0.2°2θ, 58.2±0.2°2θ, and 60.9±0.2°2θ. Suitably, the fluorination reagent includes at least two, at least three, at least four, at least five, at least six, at least seven, or eight peaks at the above 2 theta values. More suitably, the fluorination reagent includes peaks at all eight of the above 2 theta values. The fluorination reagent may further include calcium fluoride and / or fluorapatite (e.g., trace amounts of calcium fluoride and / or fluorapatite).

[0122] The fluorinating reagent may have an XRPD pattern substantially as shown in any one of Figures 4 to 16, 26, 38 to 46 and 52 to 53. Suitably, the fluorinating reagent has an XRPD pattern substantially as shown in any one of Figures 10, 11 and 26.

[0123] It will be understood that a fluorinating reagent is a reagent that is capable of fluorinating an organic substrate as described herein under the conditions as described herein.

[0124] The fluorination reagent of the sixth or seventh aspect may be used in the method of the second aspect. Thus, step a) of the second aspect may comprise providing a fluorination reagent of the sixth or seventh aspect instead of preparing a fluorination reagent.

[0125] The following numbered statements 1-100 describe certain aspects and embodiments of the present invention. 1. A method for preparing a fluorination reagent comprising the steps of: a) grinding together in the solid state a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, and an ionic compound; Including, The anion of the ionic compound is Ca 2+ can combine with 2450KJ mol -1 forming a calcium salt having a higher lattice energy. 2. The method of statement 1, wherein the fluorine-containing compound is calcium fluoride. 3. A method for preparing a fluorination reagent comprising the steps of: a) grinding calcium fluoride and an ionic compound together in the solid state Including, The anion of the ionic compound is Ca 2+ can combine with 2450KJ mol -1 forming a calcium salt having a higher lattice energy. 4. The anion of the ionic compound is Ca 2+ can combine with 2630KJ mol -14. The method of claim 1, 2 or 3, forming a calcium salt having a higher lattice energy. 5. The method of any one of statements 1 to 4, wherein the ionic compound is a salt. 6. The method according to any one of statements 1 to 5, wherein the ionic compound is a salt of an oxoacid. 7. The method of any one of statements 1 to 6, wherein the ionic compound is a phosphate, carbonate, sulfate, sulfite, nitrate, hydroxide or citrate. 8. The method of any one of statements 1 to 7, wherein the ionic compound is a phosphate, carbonate or sulfate. 9. The method of any one of statements 1 to 8, wherein the ionic compound is a phosphate. 10. The method of any one of statements 1-9, wherein the ionic compound is an alkali metal salt or an alkaline earth metal salt. 11. The method of any one of statements 1 to 10, wherein the ionic compound is a potassium salt, a sodium salt, a calcium salt, a cesium salt or a magnesium salt. 12. The method of any one of statements 1 to 11, wherein the ionic compound is a potassium salt, a sodium salt or a magnesium salt. 13. The method of any one of statements 1 to 12, wherein the ionic compound is selected from the group consisting of potassium or sodium phosphates, sulfates, or carbonates. 14. The method of any one of statements 1 to 13, wherein the ionic compound is a potassium or sodium phosphate. 15. The method of any one of statements 1 to 14, wherein the ionic compound is a potassium phosphate. 16. The ionic compounds are K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, KPO3, K4P2O7, and K5P3O 10 , Na4P2O7, Na5P3O 104. The method of claim 1, 2 or 3, wherein the anionic surfactant is selected from the group consisting of (NaPO3)3, CaHPO4, K2CO3, KHCO3, K2SO4, KHSO4, Cs2SO4, MgSO4, Ag2SO4, K2S2O7, Na2SO3, Na2SO4, Na2CO3, KNO3, Na3C6H5O7, NaOH and KOH. 17. The ionic compounds are K3PO4, K2HPO4, KPO3, Na3PO4, Na2HPO4, K4P2O7, and K5P3O 10 , Na4P2O7, Na5P3O 10 17. The method of claim 16, wherein the alkali metal phosphate ester is selected from the group consisting of K2CO3, KHCO3, NaOH and KOH. 18. The ionic compounds are K2HPO4, KPO3, Na2HPO4, K4P2O7, and K5P3O 10 and Na4P2O7. 19. The method of statements 1, 2 or 3, wherein the ionic compound is K3PO4 or K2HPO4. 20. The method of any one of statements 1-19, wherein greater than 50% by weight of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a). 21. The method of any one of statements 1 to 20, wherein greater than 70% by weight of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a). 22. The method of any one of statements 1 to 21, wherein greater than 90% by weight of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a). 23. The method of any one of statements 1 to 22, wherein greater than 95% by weight of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a). 24. The method of any one of statements 1 to 23, wherein step a) is carried out in the absence of a solvent. 25. The method of any one of statements 1 to 24, wherein step a) is a mechanochemical process. 26. The method of any one of statements 1 to 25, wherein step a) is carried out in a ball mill, a pestle and mortar, a twin-screw extruder, an ultrasonic bath or a mechanical press. 27. The method of any one of statements 1 to 26, wherein step a) is carried out in a ball mill, a pestle and mortar, or a twin-screw extruder. 28. The method of any one of statements 1 to 27, wherein step a) is carried out in a ball mill. 29. The method of statement 28, wherein the ball mill is a planetary mill, a vibratory mill, an attritor mill, or a tumbling ball mill. 30. The method of statement 28, wherein the ball mill is a vibratory mill. 31. The method of statement 28, 29 or 30, wherein step a) comprises ball milling the fluorine-containing compound together with the ionic compound at a frequency of 0.5 to 80 Hz (e.g., 20 to 40 Hz). 32. The method of any one of statements 1 to 27, wherein step a) is carried out in a twin-screw extruder. 33. The method of statement 32, wherein step a) includes collecting the product exiting the twin screw extruder and passing it through the twin screw extruder one or more additional times. 34. The method of any one of statements 1 to 33, wherein the molar ratio of the fluorine-containing compound to the ionic compound in step a) is (0.1 to 7):1 (e.g., (0.3 to 6):1). 35. The method of any one of statements 1 to 34, wherein the molar ratio of the fluorine-containing compound to the ionic compound in step a) is (0.5-5):1 (e.g., (1-2):1). 36. The method of any one of statements 1 to 35, wherein the ionic compound is milled together with the fluorine-containing compound in portions. 37. The method of statement 36, wherein step a) includes (ai) grinding together a fluorine-containing compound and a first portion of the ionic compound, and (a-ii) grinding together the product of step (ai) and a second portion of the ionic compound. 38. The method of statement 37, wherein step a) further comprises the step (a-iii) of grinding together the product of step (a-ii) and a third portion of the ionic compound. 39. The method of statement 38, wherein step a) further comprises the step (a-iv) of grinding together the product of step (a-iii) and a fourth portion of the ionic compound. 40. The method of any one of statements 1-39, wherein less than 1 ppm (e.g., less than 1 ppb) of HF is produced at any time during step a). 41. A method for preparing a fluorochemical, comprising: a) preparing a fluorination reagent according to any one of statements 1 to 40; b) contacting the organic substrate with a fluorinating reagent; Including, The method, wherein step b) is performed simultaneously with step a) or after step a). 42. The method according to statement 41, wherein the organic substrate is aromatic or aliphatic. 43. The method of statement 41 or 42, wherein the organic substrate contains at least one leaving group located at the site to be fluorinated. 44. The method of statement 43, wherein the organic substrate has two or more leaving groups (e.g., two leaving groups), optionally where the leaving groups are attached to the same carbon atom (e.g., two geminal halide leaving groups). 45. An organic substrate is 500 g mol -1 The method of any one of statements 41 to 44, wherein the molecular weight is less than 46. ​​An organic substrate is 300 g mol -1 Less than (e.g., 200 g mol -1 The method according to claim 45, wherein the polymer has a molecular weight of less than 100 nm. 47. The method of any one of statements 41 to 46, wherein the organic substrate is a sulfonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halocarbonyl or an alkyl halide. 48. The method of any one of statements 41 to 46, wherein the organic substrate is a sulfonyl halide, an acyl halide, a heteroaryl halide, an aryl halide, or an alkyl halide. 49. The method of any one of statements 41 to 46, wherein the organic substrate is an aromatic sulfonyl 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). 50. The method of any one of statements 41-49, wherein step b) is performed simultaneously with step a), and step b) comprises contacting the organic substrate with the fluorinating reagent under conditions identical to those used to form the fluorinating reagent. 51. The method of any one of statements 41 to 49, wherein step b) is performed after step a), and step b) includes grinding the organic substrate and the fluorinating reagent formed from step a) together in the solid state. 52. The method of any one of statements 41-49, wherein step b) occurs after step a), and step b) comprises mixing the organic substrate and the fluorinating reagent together in one or more solvents in which the organic substrate is soluble. 53. The method of statement 52, wherein step b) is carried out in one or more solvents selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 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. 54. The method of statement 52, wherein step b) is carried out in one or more solvents 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. 55. The method of statement 52, wherein step b) is carried out in one or more solvents selected from the group consisting of acetonitrile, propionitrile, toluene, chlorobenzene, 1,2-difluorobenzene, dichloroethane, trifluorotoluene, chloroform, tert-butanol and tert-amyl alcohol. 56. The method of statement 52, wherein step b) is carried out in acetonitrile, propionitrile, chlorobenzene, tert-butanol or tert-amyl alcohol. 57. The method of any one of statements 53 to 56, wherein one or more of the organic solvents is miscible with water. 58. The method according to statement 57, wherein the organic solvent may be miscible with water at a concentration of 0.01 to 5 M (e.g., 0.01 to 1 M, e.g., 0.05 to 0.5 M). 59. The method of any one of statements 41 to 58, wherein step b) is carried out in the presence of at least one of a cryptand, a crown ether, and a hydrogen-bonding phase transfer catalyst. 60. The method according to statement 59, wherein step b) is carried out in the presence of a crown ether. 61. The method of statement 60, wherein the crown ether is 18-crown-6 or dibenzo-18-crown-6. 62. The method of any one of statements 52-61, wherein step b) is carried out at a temperature of 15 to 180°C. 63. A method for preparing a fluorochemical, comprising: a) grinding in a solid state a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite; b) contacting the product of step a) with an organic substrate; Including, The method, wherein step b) is performed simultaneously with step a) or after step a). 64. A method for preparing a fluorochemical, comprising: a) grinding calcium fluoride in a solid state; b) contacting the product of step a) with an organic substrate; Including, The method, wherein step b) is performed simultaneously with step a) or after step a). 65. The method of statement 63 or 64, wherein step b) is carried out in solution in the presence of an ionic compound described herein (e.g., K2HPO4). 66. Use of a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, as a fluorine source in a method for preparing a fluorochemical or fluorinating reagent, the method not including a step of reacting calcium fluoride with sulfuric acid to produce hydrofluoric acid. 67. Use of calcium fluoride as a fluorine source in a process for preparing a fluorochemical, the process not including the step of reacting calcium fluoride with sulfuric acid to produce hydrofluoric acid. 68. A fluorinating reagent obtained, directly obtained or obtainable by a method according to any one of statements 1 to 40. 69. A fluorination reagent containing a mixture of multiple inorganic salts. 70. The fluorination reagent according to statement 68, comprising a mixture of multiple inorganic salts. 71. A fluorination reagent according to statement 68, 69 or 70, comprising calcium, fluorine and oxygen, and (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur, nitrogen and carbon. 72. A fluorination reagent according to statement 68, 69 or 70, comprising calcium, fluorine and oxygen, and (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur and carbon. 73. A fluorination reagent according to statement 68, 69 or 70, comprising calcium, fluorine, oxygen, potassium and phosphorus. 74. A method for the preparation of a mixture of inorganic salts, the mixture comprising a first inorganic salt and a second inorganic salt, (i) the first inorganic salt being 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 K + and Na 2+ The fluorination reagent according to any one of Statements 68 to 73, comprising at least one cation selected from: 75. The first inorganic salt is Ca 2+ and at least one anion selected from phosphate, sulfate, carbonate, and hydroxide (e.g., phosphoric acid), and / or the second inorganic salt is selected from fluoride and K + 75. The fluorination reagent of claim 74, comprising: 76. A fluorination reagent according to any one of statements 68 to 75, provided as a powder. 77. The fluorination reagent according to statement 76, wherein the powder has an average particle size, as determined by SEM or TEM analysis, of less than 500 μm (e.g., less than 100 μm). 78. A fluorination reagent described in any one of statements 68 to 77, having an XRPD pattern including peaks at ±0.2° 2θ corresponding 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 to 5.7.13, 5.12.1, and 6.3.1 to 6.3.9 outlined herein. 79. A fluorination reagent described in any one of statements 68 to 77, having an XRPD pattern including peaks at ±0.2° 2θ corresponding 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 to 5.7.11 and 5.12.1 outlined herein. 80. A fluorination reagent described in any one of Statements 68-77, having an XRPD pattern including peaks at ±0.2° 2θ corresponding 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. 81. A fluorination reagent as described in any one of Statements 68 to 77, having an XRPD pattern including peaks at 2 theta values ​​of 21.9±0.2 degrees 2θ, 30.3±0.2 degrees 2θ, 31.6±0.2 degrees 2θ, and 43.4±0.2 degrees 2θ. 82.XRPD pattern is 18.0±0.2°2θ, 18.7±0.2°2θ, 22.6±0.2°2θ, 24.5±0.2°2θ, 25.4±0.2°2θ, 26.5±0.2 °2θ, 27.0±0.2°2θ, 28.0±0.2°2θ, 29.2±0.2°2θ, 33.0±0.2°2θ, 34.8±0.2°2θ, 36.4±0.2°2θ, 37.7± 82. The fluorination reagent of claim 81, comprising one or more additional peaks at 2-theta values ​​of 0.2° 2θ, 39.5±0.2° 2θ, 40.4±0.2° 2θ, 41.7±0.2° 2θ, 42.4±0.2° 2θ, 46.1±0.2° 2θ, 48.4±0.2° 2θ, 49.4±0.2° 2θ, 52.8±0.2° 2θ, and 53.9±0.2° 2θ. 83. The fluorination reagent according to statement 82, wherein the XRPD pattern includes at least five of the additional peaks. 84. The fluorination reagent according to statement 82, wherein the XRPD pattern comprises at least 10 of the additional peaks. 85. The fluorination reagent according to statement 82, wherein the XRPD pattern includes at least 15 of the additional peaks. 86. The fluorination reagent according to statement 82, wherein the XRPD pattern comprises at least 20 of the additional peaks. 87.17.5±0.2°2θ, 21.2±0.2°2θ, 23.5±0.2°2θ, 24.8±0.2°2θ, 29.4±0.2°2θ, 29.6±0.2°2θ, 30.5± 0.2°2θ, 31.5±0.2°2θ, 35.4±0.2°2θ, 36.7±0.2°2θ, 37.4±0.2°2θ, 39.8±0.2°2θ, 42.9±0.2°2θ, 4 78. The fluorination reagent of any one of Statements 68-77, having an XRPD pattern including one or more peaks at 2-theta values ​​of 7.1±0.2°2θ, 48.1±0.2°2θ, 51.4±0.2°2θ, 53.2±0.2°2θ, 54.2±0.2°2θ, 58.2±0.2°2θ, 60.9±0.2°2θ, and 63.4±0.2°2θ. 88. The fluorination reagent according to statement 87, wherein the XRPD pattern comprises at least two or at least three of the peaks. 89. The fluorination reagent according to statement 87, wherein the XRPD pattern comprises at least four or at least five of the peaks. 90. The fluorination reagent according to statement 87, wherein the XRPD pattern comprises at least 10 or at least 15 of the peaks. 91. A fluorination reagent according to statement 87, wherein the XRPD pattern comprises at least 20 of the peaks. 92. A fluorination reagent according to any one of statements 87 to 91, comprising K3(HPO4)F. 93. A fluorination reagent according to any one of statements 68 to 77, comprising K3(HPO4)F and comprising one or more peaks at 2-theta values ​​of 21.1±0.2°2θ, 29.6±0.2°2θ, 30.5±0.2°2θ, 37.4±0.2°2θ, 42.9±0.2°2θ, 54.2±0.2°2θ, 58.2±0.2°2θ and 60.9±0.2°2θ. 94. A fluorination reagent according to statement 93, having an XRPD pattern including at least two of the peaks. 95. A fluorination reagent according to statement 93, having an XRPD pattern including at least four of the peaks. 96. A fluorination reagent according to statement 93, having an XRPD pattern including at least six of the peaks. 97. A fluorinating reagent according to statement 93 having an XRPD pattern that includes all eight of the peaks. 98. A fluorination reagent according to any one of statements 68 to 97, comprising calcium fluoride and / or fluorapatite (e.g., trace amounts of calcium fluoride and / or fluorapatite). 99. A fluorination reagent described in any one of statements 68 to 98, having an XRPD pattern substantially as shown in any one of Figures 4 to 16, 26, 38 to 46 and 52 to 53. 100. A fluorination reagent according to any one of statements 68 to 98, having an XRPD pattern substantially as shown in any one of Figures 10, 11 and 26.

[0126] In some embodiments, an activated fluorination reagent is provided herein. In some embodiments, the activated fluorination reagent comprises a first salt comprising calcium and fluorine, and a second salt. In some embodiments, the second salt comprises an anion. The first salt and the second salt are described elsewhere herein.

[0127] In some embodiments, a method for synthesizing a fluoro compound is provided herein. In some embodiments, a method for synthesizing an organofluorine compound is provided herein. In some embodiments, the method includes combining a first salt comprising calcium and fluorine with a second salt to form a salt mixture.

[0128] In some embodiments, compositions and methods are provided herein that use a first salt. Any suitable first salt is used in any composition or method provided herein. In some embodiments, the first salt comprises calcium and fluorine. In some embodiments, the first salt comprises fluorine. In some embodiments, the first salt comprises calcium. In some embodiments, the first salt is CaF2. In some embodiments, the first salt is fluorospar. In some embodiments, the first salt is fluorapatite (Ca5(PO4)3F). In some embodiments, the waste material comprises the first salt. In some embodiments, the first salt is added in an amount necessary to provide an activated fluorination reagent.

[0129] In some embodiments, the methods and compositions described herein do not include reacting a strong acid with a first salt to form hydrofluoric acid. In some embodiments, essentially no HF is produced during the reaction. In some embodiments, less than 1 ppm of HF is observable in the mixture at any time during the reaction. In some embodiments, less than 1 ppb of HF is observable in the mixture at any time during the reaction.

[0130] In some embodiments, compositions and methods using the second salt are provided herein. In some embodiments, any suitable second salt is used in any of the compositions or methods provided herein. In some embodiments, the second salt comprises an anion. In some embodiments, the second salt comprises Ca 2+ When combined with to form a third salt, the third salt comprises an anion having a lattice energy greater than 2450 kJ / mol. In some embodiments, the second salt comprises a cation and an anion.

[0131] In some embodiments, any of the compositions or methods herein comprises Ca 2+ and a second salt comprising an anion having a lattice energy greater than 2450 kJ / mol when combined with Ca to form a third salt. 2+can combine to form a third salt having a lattice energy of greater than 2450 kJ / mol. In some embodiments, the fluorinating reagent comprises a salt having a lattice energy of greater than 2450 kJ / mol.

[0132] In some embodiments, 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 sulfite. In some embodiments, the second salt includes Na2SO3 and / or K2SO3. In some embodiments, the second salt is Na2SO3. In some embodiments, the second salt is K2SO3. In some embodiments, the second salt is a metal sulfate. In some embodiments, the second salt includes KHSO4. In some embodiments, the second salt is an inorganic phosphate.

[0133] In some embodiments, the second salt comprises K2HPO4, KH2PO4, and / or K3PO4. In some embodiments, the second salt is K2HPO4. In some embodiments, the second salt is KH2PO4. In some embodiments, the second salt is K3PO4. In some embodiments, the inorganic phosphate is pyrophosphate. In some embodiments, the inorganic phosphate comprises K4P2O7 and / or Na3P2O7.

[0134] In some embodiments, the inorganic phosphate is K4P2O7. In some embodiments, the inorganic phosphate is Na3P2O7. In some embodiments, the second salt is Na3PO4, Na2HPO4, NaH2PO4, K2SO4, Na2SO4, MgSO4, Ag2SO4, Na2CO3, and / or KHCO3. In some embodiments, the second salt comprises Na3PO4. In some embodiments, the second salt comprises Na2HPO4. In some embodiments, the second salt comprises NaH2PO4.

[0135] In some embodiments, the second salt comprises K2SO4. In some embodiments, the second salt comprises Na2SO4. In some embodiments, the second salt comprises MgSO4. In some embodiments, the second salt comprises Ag2SO4. In some embodiments, the second salt comprises Na2CO3. In some embodiments, the second salt comprises KHCO3.

[0136] In some embodiments, any suitable ratio of the first salt to the second salt is used in any of the compositions or methods provided herein. In some embodiments, any suitable ratio of the first salt to the second salt is used in any of the compositions or methods 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 the first salt to the 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 the first salt to the second salt is about 1:0.5 to 1:2. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:4. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:8. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:10. In some embodiments, the ratio of the first salt to the 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. In some embodiments, the range of the first salt to the 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. In some embodiments, 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 the first salt to the second salt is 1:8.In some embodiments, the ratio of the first salt to the second salt is 2:1.

[0137] In some embodiments, the method includes applying a mechanical force to the salt mixture to form an activated salt mixture. In some embodiments, the activated salt mixture is a fluorination reagent. In some embodiments, the activated salt mixture is an activated fluorination reagent.

[0138] In some embodiments, mechanical force is applied to a salt mixture provided in any of the compositions or methods herein. In some embodiments, mechanical force is applied to a salt-waste mixture provided herein. In some embodiments, mechanical force is applied to a salt mixture provided herein to obtain an activated fluorination reagent.

[0139] In some embodiments, mechanical force is applied to the salt-waste mixture provided herein to obtain the activated fluorination reagent, hi some embodiments, mechanical force is applied using a ball mill, a mortar and pestle, a twin screw extruder, an ultrasonic bath, or a mechanical press.

[0140] In some embodiments, 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.

[0141] In some embodiments, the mechanical force is applied at any suitable frequency in any of the compositions or methods provided herein. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz to 60 kHz or any range therein. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz to 60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz to 10 Hz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz to 100 Hz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 1 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 10 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 30 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 50 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 to 60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 10 Hz to 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. In some embodiments, 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.

[0142] In some embodiments, the mechanical frequency is applied at any suitable temperature in any of the compositions or methods provided herein. In some embodiments, 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 to about 300°C, about 30°C to about 40°C, about 30°C to about 60°C, about 30°C to about 90°C, about 30°C to about 100°C, about 30°C to about 130°C, about 30°C to about 1 50°C, about 30°C to about 200°C, about 30°C to about 250°C, about 30°C to about 280°C, about 30°C to about 300°C, about 40°C to about 60°C, about 40°C to about 90°C, about 40°C to about 100°C, about 40°C to about 130°C, about 40°C to about 150°C, about 40°C to about 200°C, about 40°C to about 250°C, about 40°C to about 280°C, about 40°C to about 300°C, about 60°C to about 90°C, about 60°C to about 100°C, about 60°C to about 130°C, about 60°C to about 150°C, about 60 ℃ to about 200℃, about 60℃ to about 250℃, about 60℃ to about 280℃, about 60℃ to about 300℃, about 90℃ to about 100℃, about 90℃ to about 130℃, about 90℃ to about 150℃, about 90℃ to about 200℃, about 90℃ to about 250℃, about 90℃ to about 280℃, about 90℃ to about 300℃, about 100℃ to about 130℃, about 100℃ to about 150℃, about 100℃ to about 200℃, about 100℃ to about 250℃, about 100℃ to about 280℃, about 100℃ to about 300℃, about It is added at a temperature of 130°C to about 150°C, about 130°C to about 200°C, about 130°C to about 250°C, about 130°C to about 280°C, about 130°C to about 300°C, about 150°C to about 200°C, about 150°C to about 250°C, about 150°C to about 280°C, about 150°C to about 300°C, about 200°C to about 250°C, about 200°C to about 280°C, about 200°C to about 300°C, about 250°C to about 280°C, about 250°C to about 300°C, or about 280°C to about 300°C. In some embodiments, 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. In some embodiments, the mechanical force is applied at a temperature of up to 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.

[0143] In any of the compositions or methods provided herein, mechanical force can be applied to the first salt and the second salt together.In any of the compositions or methods provided herein, mechanical force can be applied to the first salt only.In some embodiments, mechanical force can be applied for any suitable period of time.

[0144] In some embodiments, the mechanical power may be applied for about 0.5 hours to about 12 hours. In some embodiments, the mechanical power may be applied for 0.5 to 1 hour. In some embodiments, the mechanical power may be applied for 0.5 to 4 hours. In some embodiments, the mechanical power may be applied for 0.5 to 8 hours. In some embodiments, the mechanical power may be applied for 4 to 8 hours. In some embodiments, the mechanical power may be applied for 4 to 12 hours. In some embodiments, the mechanical power 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 power is applied for about 1 hour. In some embodiments, the mechanical power is applied for about 2 hours. In some embodiments, the mechanical power is applied for about 3 hours. In some embodiments, the mechanical power is applied for about 4 hours. In some embodiments, the mechanical power is applied for about 6 hours. In some embodiments, the mechanical power is applied for about 9 hours. In some embodiments, a longer mechanical power time may be associated with a higher yield of the fluorinated product.

[0145] In some embodiments, provided herein is a salt mixture produced by ball milling in any of the compositions or methods provided herein. In some embodiments, ball milling is completed by combining the salts in a jar and adding balls. In some embodiments, the jar and balls comprise stainless steel.

[0146] In some embodiments, 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, one 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. In some embodiments, 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, two balls are used and the ball weight is 3 g. In some embodiments, the ball weight is 16 g. In some embodiments, the ball weight is used as an analog of ball size. In some embodiments, the ball size may affect the fluorination reaction yield.

[0147] In some embodiments, mechanical force is applied in the compositions or methods described herein using a twin screw extruder. In some embodiments, the twin screw extruder can be equipped with a gravimetric single screw feeder (e.g., a hopper) for programmed addition of solids. Figure 54 shows the first salt and the second salt in F R The mixture was added to a twin screw extruder (TSE) at a rate of 0.1 g / L and subsequently mixed at various screw speeds (S S ), screw temperature (S T ), and residence time (T R 3 shows a schematic diagram of a TSE in which a salt can be extruded with a screw thread (C) to provide a fluorination reagent (e.g., Fluoromix). In some embodiments, the screw configuration can be modified, where C represents a conveying element, K represents a kneading element, and R represents a reverse element.

[0148] In some embodiments, the screw temperature (S T) is applied at any suitable temperature in any composition or method provided herein. In some embodiments, the screw temperature is about 0°C to about 300°C. In some embodiments, 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 to about 150°C, about 25°C to about 200°C, about 25°C to about 250°C, about 25°C to about 300°C, about 50°C to about 100°C, about 50 ℃ 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 100 ° C to about 150 ° C, about 100 ° C to about 200 ° C, about 100 ° C to about 250 ° C, about 100 ° C to about 300 ° C, about 150 ° C to about 200 ° C, about 150 ° C to about 250 ° C, about 150 ° C to about 300 ° C, about 200 ° C to about 250 ° C, about 200 ° C to about 300 ° C, or about 250 ° C to about 300 ° C. In some embodiments, 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.

[0149] In some embodiments, the screw speed of the twin screw extruder (S S) may be applied at any suitable speed in any of the compositions or methods provided herein. In some embodiments, the screw speed is set in the range of about 1 rpm to about 80 rpm. In some embodiments, the screw speed is set in the 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 ... 0rpm, approximately 5rpm to approximately 50rpm, approximately 5rpm to approximately 60rpm, approximately 5rpm to approximately 70rpm, approximately 5rpm to approximately 75rpm, approximately 5rpm to approximately 80rpm, approximately 10rpm to approximately 15rpm, approximately 10rpm to approximately 25rpm , about 10 rpm to about 40 rpm, about 10 rpm to about 50 rpm, about 10 rpm to about 60 rpm, about 10 rpm to about 70 rpm, about 10 rpm to about 75 rpm, about 10 rpm to about 80 rpm, about 15 rpm to about 25 rpm , about 15 rpm to about 40 rpm, about 15 rpm to about 50 rpm, about 15 rpm to about 60 rpm, about 15 rpm to about 70 rpm, about 15 rpm to about 75 rpm, about 15 rpm to about 80 rpm, about 25 rpm to about 40 rpm m, approximately 25 rpm to approximately 50 rpm, approximately 25 rpm to approximately 60 rpm, approximately 25 rpm to approximately 70 rpm, approximately 25 rpm to approximately 75 rpm, approximately 25 rpm to approximately 80 rpm, approximately 40 rpm to approximately 50 rpm, approximately 40 rpm to approximately 60 rpm m, about 40 rpm to about 70 rpm, about 40 rpm to about 75 rpm, about 40 rpm to about 80 rpm, about 50 rpm to about 60 rpm, about 50 rpm to about 70 rpm, about 50 rpm to about 75 rpm, about 50 rpm to about 80 rpm, about 60 rpm to about 70 rpm, about 60 rpm to about 75 rpm, about 60 rpm to about 80 rpm, about 70 rpm to about 75 rpm, about 70 rpm to about 80 rpm, or about 75 rpm to about 80 rpm. In some embodiments, the screw speed is set in the 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.

[0150] In some embodiments, the residence time (T R ) is set to any suitable time in any of the compositions or methods provided herein. In some embodiments, the residence time is from about 1 second to about 420 seconds. In some embodiments, the residence time is from about 1 second to about 20 seconds, from about 1 second to about 40 seconds, from about 1 second to about 60 seconds, from about 1 second to about 80 seconds, from about 1 second to about 120 seconds, from about 1 second to about 140 seconds, from about 1 second to about 165 seconds, from about 1 second to about 220 seconds, from about 1 second to about 300 seconds, from about 1 second to about 420 seconds, from about 20 seconds to about 40 seconds, from about 20 seconds to about 60 seconds, from about 20 seconds to about 80 seconds, from about 20 seconds to about 120 seconds, from about 2 seconds to about ... 0 seconds to 140 seconds, 20 seconds to 165 seconds, 20 seconds to 220 seconds, 20 seconds to 300 seconds, 20 seconds to 420 seconds, 40 seconds to 60 seconds, 40 seconds to 80 seconds, 40 seconds to 80 seconds Approximately 120 seconds, approximately 40 seconds to approximately 140 seconds, approximately 40 seconds to approximately 165 seconds, approximately 40 seconds to approximately 220 seconds, approximately 40 seconds to approximately 300 seconds, approximately 40 seconds to approximately 420 seconds, approximately 60 seconds to approximately 80 seconds, approximately 60 seconds to approximately 1 20 seconds, approximately 60 seconds to approximately 140 seconds, approximately 60 seconds to approximately 165 seconds, approximately 60 seconds to approximately 220 seconds, approximately 60 seconds to approximately 300 seconds, approximately 60 seconds to approximately 420 seconds, approximately 80 seconds to approximately 120 seconds, approximately 80 seconds to approximately 1 40 seconds, about 80 seconds to about 165 seconds, about 80 seconds to about 220 seconds, about 80 seconds to about 300 seconds, about 80 seconds to about 420 seconds, about 120 seconds to about 140 seconds, about 120 seconds to about 165 seconds, about 120 seconds The residence time is about 220 seconds, about 120 seconds to about 300 seconds, about 120 seconds to about 420 seconds, about 140 seconds to about 165 seconds, about 140 seconds to about 220 seconds, about 140 seconds to about 300 seconds, about 140 seconds to about 420 seconds, about 165 seconds to about 220 seconds, about 165 seconds to about 300 seconds, about 165 seconds to about 420 seconds, about 220 seconds to about 300 seconds, about 220 seconds to about 420 seconds, or about 300 seconds to about 420 seconds. In some embodiments, the residence time is about 1 second, 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.

[0151] In some embodiments, the fluorinating reagent is recycled through the extruder (e.g., a twin screw extruder) any suitable number of times in any composition or method provided herein. In some embodiments, the fluorinating reagent is recycled through the extruder once. In some embodiments, the fluorinating reagent is recycled through the extruder two times. In some embodiments, the fluorinating reagent is recycled through the extruder three times.

[0152] In some embodiments, the activated fluorinated reagent or third salt in any of the compositions or methods described herein is characterized by powder X-ray diffraction. The powder X-ray diffraction spectrum of the activated fluorinated reagent described herein may show 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and / or 53.9°.

[0153] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and / or 53.9°.

[0154] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least two characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and / or 53.9°.

[0155] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least three characteristic 2θ 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°.

[0156] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises at least four characteristic 2θ 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°. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and 43.4°.

[0157] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.

[0158] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic 2θ reflections.

[0159] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection of a relative peak intensity that is at least 0.1%, at least 1%, or at least 5% relative to the highest peak of the raw spectrum. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection of a relative peak intensity that is at least 0.1%, at least 1%, or at least 5% relative to the highest peak of the background subtraction spectrum. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection of a relative peak intensity that is at least 10%, at least 15%, or at least 20% relative to the highest peak of the background subtraction spectrum.

[0160] In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection with a relative peak integral that is at least 0.1%, at least 1%, or at least 5% of the peak with the largest integral in the raw spectrum. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection with a relative peak integral that is at least 0.1%, at least 1%, or at least 5% of the peak with the largest integral in the background subtraction spectrum. In some embodiments, the powder X-ray diffraction spectrum of the activated reagent comprises a characteristic reflection with a relative peak integral that is at least 10%, at least 15%, or at least 20% of the peak with the largest integral in the background subtraction spectrum.

[0161] In some embodiments, the powder X-ray diffraction spectrum of the activation reagent is as described in 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, 5.13.3, 5.13.4, 5.13.5, 5.13.6, 5.13.7, 5.13.8, 5.13.9, 5.14.10, 5.14.11, 5.14.12, 5.14.13, 5.14.14, 5.14.15, 5.14.16, 5.14.17, 5.14.18, 5.14.19, 5.15.20, 5.15.21, 5.15.22, 5.15.23, 5.15.24, 5.15.25, 5.15.30, 5.15.31, 5.15.4, 5.15.5, 5.15.6, 5.15.7, 5.15.8, 5.15.9, 5.16.10, 5.16.11, 5.16.12, 5.16.13, 5.16.14, 5.16.15, 5.16.16, and / or any combination thereof.

[0162] In some embodiments, the powder X-ray diffraction spectrum of the activation reagent is as described in 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, 5.13.3, 5.13.4, 5.13.5, 5.13.6, 5.13.7, 5.13.8, 5.13.9, 5.14.10, 5.14.11, 5.14.12, 5.14.13, 5.14.14, 5.14.15, 5.14.16, 5.14.17, 5.14.18, 5.14.19, 5.15.20, 5.15.21, 5.15.22, 5.15.23, 5.15.24, 5.15.25, 5.15.30, 5.15.31, 5.15.4, 5.15.5, 5.15.6, 5.15.7, 5.15.8, 5.15.9, 5.16.10, 5.16.11, 5.16.12, 5.16.13, 5.16.14, 5.16.15, 5.16.16, .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 any combination thereof.

[0163] In some embodiments, the powder X-ray diffraction spectrum of the activation reagent is as described in 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, 5.13.3, 5.13.4, 5.13.5, 5.13.6, 5.13.7, 5.13.8, 5.13.9, 5.13.10, 5.13.11, 5.13.12, 5.13.13, 5.13.14, 5.13.15, 5.13.16, 5.13.17, 5.13.18, 5.13.19, 5.13.20, 5.13.21, 5.13.22, 5.13.23, 5.13.24, 5.13.25, 5.13.26, 5.13.27, 5.13.28, 5.13.29, 5.13.30, 5.13.31, 5.13.32, 5.13.33, 5.13.34, 5.13.35, 5.13.36, 5.13.37, 5.13.38, 5.13.39, 5. , 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.

[0164] In some embodiments, the powder X-ray diffraction spectrum of the activation reagent is as described in 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, 5.13.3, 5.13.4, 5.13.5, 5.13.6, 5.13.7, 5.13.8, 5.13.9, 5.14.10, 5.14.11, 5.14.12, 5.14.13, 5.14.14, 5.14.15, 5.14.16, 5.14.17, 5.14.18, 5.14.19, 5.15.20, 5.15.21, 5.15.22, 5.15.23, 5.15.24, 5.15.25, 5.15.30, 5.15.31, 5.15.4, 5.15.5, 5.15.6, 5.15.7, 5.15.8, 5.15.9, 5.16.10, 5.16.11, 5.16.12, 5.16.13, 5.16.14, 5.16.15, 5.16.16, .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 any combination thereof.

[0165] In some embodiments, the powder X-ray diffraction spectrum of the activation reagent is determined using the methods described in 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, 5.13.3, 5.13.4, 5.13.5, 5.13.6, 5.13.7, 5.13.8, 5.13.9, 5.14.10, 5.14.11, 5.14.12, 5.14.13, 5.14.14, 5.14.15, 5.14.16, 5.14.17, 5.14.18, 5.14.19, 5.15.20, 5.15.21, 5.15.22, 5.15.23, 5.15.24, 5.15.25, 5.15.26, 5.15.27, 5.15.28, 5.15.30, 5.15.31, 5.15.32, 5.15.4, 5.15.5, 5.15.6, 5.15.7, 5.15.8, 5.15.9, 5.16.10, 5.16.11, 5.16. This includes a ratio of any spectral characteristic of any characteristic reflectance to the same spectral characteristic of another characteristic reflectance that is about one ratio of the spectral characteristic of a corresponding characteristic reflectance set forth in any one of Clauses 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, or 7.7.2.

[0166] In some embodiments, the spectral characteristics can include absolute intensity, relative intensity, absolute area, relative area, estimated d-spacing, full width at half maximum peak resolution, and / or combinations thereof. In some embodiments, the method includes combining the activation salt mixture with a first reactant, the first reactant, and fluorinating the first reactant to obtain a fluorinated compound. In some embodiments, the first reactant is an organic compound. In some embodiments, the fluorinated compound is an organic fluorine compound. In some embodiments, the first reactant is an inorganic compound.

[0167] In any of the compositions or methods described herein, fluorination is carried out at any suitable temperature. In some embodiments, the fluorination reaction is carried out at a temperature of about 0° C. to about 400° C. In some embodiments, the fluorination reaction is carried out 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. to 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 40 0°C, about 100°C to about 150°C, about 100°C to about 200°C, about 100°C to about 250°C, about 100°C to about 300°C, about 100°C to about 350°C, about 100°C to about 400°C, about 150°C to about 200°C, about 150°C to about 250°C, about 150°C to about 300°C, about 150°C to about 350°C, about 150°C to about 400 °C, about 200°C to about 250°C, about 200°C to about 300°C, about 200°C to about 350°C, about 200°C to about 400°C, about 250°C to about 300°C, about 250°C to about 350°C, about 250°C to about 400°C, about 300°C to about 350°C, about 300°C to about 400°C, or about 350°C to about 400°C. In some embodiments, the fluorination reaction is carried out 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. In some embodiments, the fluorination reaction is carried out 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 carried out at a temperature of up to 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 carried out at a temperature of about 100° C.

[0168] In some embodiments, the fluorination reaction yield is measured. The fluorination reaction yield is measured, for example, using 4-fluoroanisole as an internal standard. 19 The reaction yield of the organic fluorine compound is measured by F NMR. In some embodiments, the reaction yield of the organic fluorine compound is about 0.1% to about 95%. In some embodiments, the reaction yield of the organic 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 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 95%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40 % to about 90%, about 40% to about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 80% to about 90%, about 80% to about 95%, or about 90% to about 95%. In some embodiments, the reaction yield of the organic 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 organofluorine compound is measured based on the starting amount of the organic compound.

[0169] In some embodiments, the organic compound in any of the compositions or methods provided herein comprises an aromatic or aliphatic compound and comprises at least one leaving group located at the site to be fluorinated. In some embodiments, the leaving group comprises a halogen. In some embodiments, the organic compound comprises an aromatic compound. In some embodiments, the organic compound comprises an aliphatic compound. In some embodiments, the organic compound comprises an aromatic compound and comprises at least one leaving group located at the site to be fluorinated. In some embodiments, the organic compound comprises an aliphatic compound and comprises at least one leaving group at the site to be fluorinated. In some embodiments, the fluorination occurs at the same site of the leaving group as shown in Scheme 0.1.

[0170] [ka]

[0171] In some embodiments, R is aromatic. In some embodiments, R is aliphatic. In some embodiments, X is a leaving group. In some embodiments, X is a halogen. In some embodiments, X is bromide. In some embodiments, X is chloride.

[0172] In some embodiments, the organic compound is a sulfonyl halide, an acyl halide, an aryl halide, and / or an alkyl halide. In some embodiments, the organic compound comprises a sulfonyl 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.

[0173] In some embodiments, the organic compound is an aromatic sulfonyl halide, a benzoyl halide, a halobenzene, or a benzyl halide. In some embodiments, the organic compound is an aromatic sulfonyl 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. In some embodiments, the organic compound is a benzyl chloride. In some embodiments, the organic compound is an α-halocarbonyl. In some embodiments, the organic compound is an α-bromocarbonyl. 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.

[0174] In some embodiments, the fluorination reaction is a monofluorination reaction. In some embodiments, the fluorination reaction is a polyfluorination reaction. In some embodiments, the fluorination reaction is a difluorination reaction. In some embodiments, the fluorination product is stable to reaction with a second salt after formation.

[0175] In some embodiments, the inorganic compound in any of the compositions or methods provided herein comprises a salt. In some embodiments, the inorganic compound comprises a cation and an anion. In some embodiments, the anion is a halogen. In some embodiments, the halogen is chlorine. In some embodiments, the halogen is bromine. In some embodiments, the halogen is iodine. In some embodiments, the anion can be exchanged with fluorine to provide a fluoro compound. In some embodiments, the fluoro compound is NaF. In some embodiments, the fluoro compound is KF.

[0176] In some embodiments, in any of the methods or compositions provided herein, the first salt, the second salt, and the organic compound are combined in the same step. In another embodiment, in any of the methods or compositions provided herein, the first salt and the second salt are combined prior to the addition of the organic compound.

[0177] In some embodiments, a solvent is used in the fluorination of an organic compound in any of the compositions or methods provided herein. In some embodiments, the first salt and the second salt are combined as solids without the addition of a solvent. In another embodiment, the first salt, the second salt, and the organic compound are added together with one or more solvents, and the organic compound is soluble in at least one of the one or more solvents. In some embodiments, the first salt and the second salt are combined before the addition of the organic compound.

[0178] In some embodiments, a solvent is used in the fluorination of an organic compound in any of the compositions or methods provided herein. In some embodiments, the solvent is an aqueous solvent. In some embodiments, the solvent is a polar aprotic solvent.

[0179] In some embodiments, 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 embodiments, the organic solvent is a carbon-containing solvent. In some embodiments, 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, the second salt, and the organic compound are soluble in the solvent.

[0180] In some embodiments, the one or more solvents include 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 / or water. In some embodiments, the one or more solvents include acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol, and / or water. In some embodiments, the solvent may include acetonitrile. In some embodiments, the solvent may include propionitrile. In some embodiments, the solvent may include toluene. In some embodiments, the solvent may include 1,2-dichlorobenzene. In some embodiments, the solvent may include fluorobenzene. In some embodiments, the solvent may include 1,2-difluorobenzene. In some embodiments, the solvent may include dichloroethane. In some embodiments, the solvent may include trifluorotoluene. In some embodiments, the solvent may include chloroform. In some embodiments, the solvent may include tert-butanol. In some embodiments, the solvent can include tert-amyl alcohol.

[0181] In some embodiments, the solvent may include water. In some embodiments, the solvent may include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl isocyanide, m-xylene, hexane, diglyme, and / or monoglyme. In some embodiments, the solvent may include tetrahydrofuran. In some embodiments, the solvent may include 2-methyltetrahydrofuran. In some embodiments, the solvent may include 1,4-dioxane. In some embodiments, the solvent may include tert-butyl isocyanide. In some embodiments, the solvent may include m-xylene. In some embodiments, the solvent may include hexane. In some embodiments, the solvent may include diglyme. In some embodiments, the solvent may include monoglyme. In some embodiments, any one or more of the organic solvents above may be miscible with water.

[0182] In some embodiments, in any composition or method herein, the organic solvent may be miscible with water at a concentration of about 0.01 M to about 5 M, or any range therein. In some embodiments, the organic solvent may be miscible with water at a concentration of about 0.01 M to about 1 M. In some embodiments, the organic solvent is from about 0.01 M to about 0.05 M, from about 0.01 M to about 0.1 M, from about 0.01 M to about 0.2 M, from about 0.01 M to about 0.3 M, from about 0.01 M to about 0.4 M, from about 0.01 M to about 0.6 M, from about 0.01 M to about 0.8 M, from about 0.01 M to about 1 M, from about 0.05 M to about 0.1 M, from about 0.05 M to about 0.2 M, from about 0.05 M to about 0.3 M, from about 0.05 M to about 0.4 M, from about 0.05 M to about 0.6 M, from about 0.05 M to about 0.8 M, from about 0.05 M to about 1 M, from about 0.1 M to about 0.2 M, from about 0.1 M to about 0.3 M, It may be miscible with water at a concentration of 0.1M to about 0.4M, about 0.1M to about 0.6M, about 0.1M to about 0.8M, about 0.1M to about 1M, about 0.2M to about 0.3M, about 0.2M to about 0.4M, about 0.2M to about 0.6M, about 0.2M to about 0.8M, about 0.2M to about 1M, about 0.3M to about 0.4M, about 0.3M to about 0.6M, about 0.3M to about 0.8M, about 0.3M to about 1M, about 0.4M to about 0.6M, about 0.4M to about 0.8M, about 0.4M to about 1M, about 0.6M to about 0.8M, about 0.6M to about 1M, or about 0.8M to about 1M. In some embodiments, the organic solvent may be miscible 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 miscible with water at a concentration of about 0.25 M. In some cases, the inclusion of water may increase the yield of the organofluorine product.

[0183] In another embodiment, in any of the compositions or methods herein, the one or more solvents may include an additive. In some embodiments, in any of the compositions or methods herein, the one or more solvents may include a cryptand, a crown ether, and a hydrogen-bonding phase transfer agent. In some embodiments, the one or more solvents include a cryptand. In some embodiments, the one or more solvents include a crown ether. In some embodiments, the one or more solvents include a hydrogen-bonding phase transfer agent. In some embodiments, the crown ether is 18-crown-6. In some embodiments, the crown ether is 30-crown-6. In some embodiments, the crown ether is a dibenzo derivative of a crown ether. In some embodiments, the dibenzo derivative of a crown ether is dibenzo 18-crown-6 ether. In some embodiments, the dibenzo derivative of a 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 a [2.2.2]cryptand. In some embodiments, the cryptand is a [2.2.1] cryptand. In some embodiments, the one or more solvents can include Schreiner's urea.

[0184] In some embodiments, the cryptand, crown ether, or hydrogen bond phase transfer agent is added in any suitable amount in any of the compositions or methods provided herein. In some embodiments, the cryptand, crown ether, or hydrogen bond phase transfer agent is added in an amount of about 0.01 equivalents to about 5 equivalents. In some embodiments, the cryptand, crown ether, or hydrogen bond phase transfer agent is added in an amount of about 0.01 equivalents to about 0.1 equivalents, about 0.01 equivalents to about 1 equivalent, 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 equivalent, about 0.1 equivalents to about 2 equivalents, about The amount of the cryptand, crown ether, or hydrogen bond phase transfer agent is added in an amount of about 0.1 equivalent to about 3 equivalents, about 0.1 equivalent to about 4 equivalents, about 0.1 equivalent to about 5 equivalents, about 1 equivalent to about 2 equivalents, about 1 equivalent to about 3 equivalents, about 1 equivalent to about 4 equivalents, about 1 equivalent 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. In some embodiments, the cryptand, crown ether, or hydrogen bond phase transfer agent is added in an amount that increases the yield of the organofluorine product.

[0185] In some embodiments, in any composition or method herein, fluorination may be carried out for any suitable amount of time, hi some embodiments, fluorination may be carried out for about 0.5 hours to about 24 hours. In some embodiments, fluorination may be carried out for about 0.5 hours to about 1 hour, about 0.5 hours to about 3 hours, about 0.5 hours to about 5 hours, about 0.5 hours to about 12 hours, about 0.5 hours to about 16 hours, about 0.5 hours to about 24 hours, about 1 hour to about 3 hours, about 1 hour to about 5 hours, about 1 hour to about 12 hours, about 1 hour to about 16 hours, about 1 hour to about 24 hours, about 3 hours to about 5 hours, about 3 hours to about 12 hours, about 3 hours to about 16 hours, about 3 hours to about 24 hours, about 5 hours to about 12 hours, about 5 hours to about 16 hours, about 5 hours to about 24 hours, about 12 hours to about 16 hours, about 12 hours to about 24 hours, or about 16 hours to about 24 hours. In some embodiments, the fluorination may be carried out for about 0.5 hours, about 1 hour, about 3 hours, about 5 hours, about 12 hours, about 16 hours, or about 24 hours. In some embodiments, the fluorination may be carried out for at least about 0.5 hours, about 1 hour, about 3 hours, about 5 hours, about 12 hours, or about 16 hours. In some embodiments, the fluorination may be carried out for 3 hours. In some embodiments, the fluorination may be carried out for 5 hours. In some embodiments, the fluorination may be carried out for 12 hours. In some embodiments, the fluorination may be carried out for 16 hours.

[0186] In a further embodiment, provided herein is a method for fluorinating an organic compound. In some embodiments, the method includes combining an activated fluorination reagent with an organic compound, where the activated fluorination reagent and the organic compound are described elsewhere herein. In some embodiments, the method includes fluorinating the organic compound to obtain an organic fluorine compound.

[0187] In some embodiments, methods of making an activated fluorination reagent are provided herein. In some embodiments, the method includes combining a first salt comprising calcium and fluorine with a second salt to form a salt mixture, the first salt and the second salt being described elsewhere herein. In some embodiments, the method includes applying a mechanical force to the salt mixture to form an activated salt mixture, the mechanical force being described elsewhere herein. In some embodiments, the method includes combining the activated salt mixture with a first reactant. In some embodiments, the first reactant is an organic compound, the organic compound being described elsewhere herein. In some embodiments, the method includes fluorinating the first reactant to obtain an organic fluorine compound.

[0188] In another embodiment, methods are provided herein for recovering fluorine from waste materials to form an activated fluorination reagent. In some embodiments, the methods include combining waste materials comprising a first salt comprising calcium and fluorine with a second salt to form a salt-waste mixture, where the first salt and the second salt are described elsewhere herein. In some embodiments, the methods include applying a mechanical force to the salt-waste mixture to obtain an activated fluorination reagent, where the mechanical force is described elsewhere herein. EXAMPLES

[0189] [material and method] Unless otherwise stated, all reagents were purchased from commercial suppliers (Sigma-Aldrich, Alfa Aesar, Fluorochem, Apollo Scientific and Fisher Chemicals) and used without further purification. Anhydrous solvents were purchased from commercial suppliers or dried over alumina columns. Reagent grade calcium fluoride (CaF2, 97.0% min., Alfa Aesar), potassium phosphate (K3PO4, 98% min., Sigma Aldrich, CAS7778-53-2), dipotassium hydrogen phosphate (K2HPO4, 98.0% min., Alfa Aesar), potassium dihydrogen phosphate (KH2PO4, 99.0% min., Alfa Aesar), sodium phosphate (Na3PO4, 96.0% min., Sigma Aldrich), disodium hydrogen phosphate (Na2HPO4, 98% min., Fisher Scientific), sodium dihydrogen phosphate (NaH2PO4, 96%, Fisher Scientific), potassium tripolyphosphate (K5P3O 10 , >94%, Strem Chemicals), tetrasodium pyrophosphate decahydrate (Na4P2O7·10H2O, >99%, Sigma Aldrich, CAS13472-36-1), sodium tripolyphosphate (Na5P3O 10 , Alfa Aesar), sodium trimetaphosphate (Na3P3O9, Alfa Aesar), sodium hexametaphosphate (Graham's salt, 65–70% P2O5 base, Sigma Aldrich), potassium metaphosphate (KPO3, 98%, Strem Chemicals), and anhydrous calcium hydrogen phosphate (CaHPO4, 98.0–105.0%, Sigma Aldrich) were used without drying and stored under ambient conditions.

[0190] Potassium pyrophosphate (K4P2O7, 97.0%, Sigma Aldrich) and anhydrous potassium fluoride (KF, 99%, Alfa Aesar) were used without drying and stored in a desiccator.

[0191] Fluorospar (acid grade) was purchased from Mistral Industrial Chemicals (UK) and produced by Minersa group (Asturias, Spain) and contains CaF2 (>97%), total carbonates (<1.50%), SiO2 (<1.00%), BaSO4 (<0.50%), Pb (<0.10%), Fe2O3 (<0.10%), S (<0.15%) and H2O (<1.0%). Fluorospar (acid grade) was used without drying and stored under ambient conditions.

[0192] Unless otherwise stated, all reagents were purchased from commercial suppliers (Sigma-Aldrich, Alfa Aesar, Fluorochem, Minersa Group (Fluorospar), Apollo Scientific and Fisher Chemicals) and used without further purification. CaF2 was purchased from Alfa Aesar (>97%, reagent grade) and K2HPO4 was obtained from Fisher Chemical (anhydrous, crystalline powder) unless otherwise stated. Dehydrated solvents were purchased from commercial suppliers or dried over alumina columns. Column chromatography was performed on Merck silica gel (60, particle size 0.040–0.063 mm).

[0193] NMR experiments were recorded on a Bruker AVIIIHD400, AVIIIHD500, AVII500, or AV NEO600 NMR spectrometer. 1 H and 13 C NMR spectral data are reported as chemical shifts (δ) in parts per million (ppm) relative to the solvent peak using the Bruker internal referencing procedure (edlock). Chemical shifts are referenced to residual CDCl3 as internal standard (δ = 7.26 ppm for 1H NMR spectra, 13 C NMR spectra are reported using δ = 77.16 ppm. 19F NMR spectra are referenced to CFCl3. Data are reported as chemical shifts, multiplicities (s=singlet, d=doublet, t=triplet, q=quartet, pent=quintet, sept=septet, br=broad, m=multiplet), coupling constants (Hz) and integrals. NMR spectra were processed with MestReNova 14.2.1 or Topspin 3.5 or 4.0. 19 F NMR yields were determined using 4-fluoroanisole (-123.7 ppm) as an internal standard. The standard was added to the crude residue after solvent evaporation, dissolved in CDCl3, and an aliquot was taken to determine the elution time. 19 The product was analyzed by F NMR.

[0194] Powder X-ray diffraction (PXRD) data were collected using a Bruker D8 Advance X-ray diffractometer with Bragg-Brentano geometry. Measurements were performed at room temperature using CuKα1 and 2 unless otherwise stated. All PXRD data were collected at room temperature. For simulated structures, Rietveld structure refinement of the powder diffraction data was performed using TOPAS Academic (V6).

[0195] Ball milling experiments were carried out using a Retsch MM400 mixer mill. Mechanochemical reactions were carried out in 15 mL, 30 mL or 50 mL stainless steel jars using either two stainless steel balls of mass 2 g or one stainless steel ball of various masses (2 g, 3 g, 4 g, 7 g or 9 g). No precautions were taken to remove air and moisture.

[0196] [1. One-pot solid-state reaction] General Procedure 1 (GP1): To a 15 mL (or 50 mL) stainless steel milling jar were added 4 g stainless steel balls (or 2 x 2 g), CaF2 (5.0 mmol), K2HPO4 (2.0 mmol) and the corresponding sulfonyl chloride (1.0 equiv). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 60 min. The jar was then opened and the solid residue was scraped off with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3 x 5 mL) and transferred to a beaker. The resulting suspension was stirred at room temperature for 5 min, filtered through a short plug of silica gel (washed with approx. 20 mL EtOAc), the solvent removed in vacuo, and the crude mixture purified by silica gel chromatography if necessary.

[0197] (1.1. Changes in salt) According to GP1 outlined above, and considering Scheme 1.1 below, the effect of varying the nature of the salt was investigated, and the results are outlined in Table 1.1.

[0198] [ka]

[0199] [Table 1]

[0200] (1.2. Changes in ball size) According to GP1 outlined above, and considering Scheme 1.2 below, the effect of varying ball size was investigated. The results are outlined in Table 1.2. The ball size used may have an effect on the resulting fluorinated product (TsF) yield. Exemplary ball sizes may include 7g and 9g based on organofluorine product (TsF) yield.

[0201] [ka]

[0202] [Table 2]

[0203] (1.3. Change in the ratio of CaF2 to K2HPO4) Following GP1 outlined above, and considering Scheme 1.3 below, the effect of varying the relative amounts of CaF2 and K2HPO4 was investigated. The results are outlined in Table 1.3. The data may support that a higher ratio of CaF2 to K2HPO4 may be beneficial to product yield.

[0204] [ka]

[0205] [Table 3]

[0206] (1.4. Evaluation of the stability of p-toluenesulfonyl chloride and p-toluenesulfonyl fluoride under mechanical forces) To investigate the stability of p-toluenesulfonyl chloride and p-toluenesulfonyl fluoride under solid-state, ball milling conditions, the reaction shown in Scheme 1.4 was carried out.

[0207] For the first reaction, a 50 mL stainless steel milling jar was charged with stainless steel balls (2 x 2 g), p-toluenesulfonyl chloride (1.0 equiv.) and K2HPO4 (2.0 mmol). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 60 min. The jar was then opened and the solid residue was scraped off with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3 x 5 mL) and transferred to a beaker. The resulting suspension was stirred at room temperature for 5 min, filtered through a short plug of silica gel (washed with approx. 20 mL of EtOAc) and the solvent was removed in vacuo. NMR yields were determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue and dissolved in CDCl3 by swirling, 1 Analyzed by 1 H NMR.

[0208] For the second reaction, a 50 mL stainless steel milling jar was charged with stainless steel balls (2 x 2 g), p-toluenesulfonyl fluoride (1.0 equiv), CaF2 (5.0 equiv), and K2HPO4 (2.0 mmol). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 60 min. The jar was then opened and the solid residue was scraped off with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3 x 5 mL) and transferred to a beaker. The resulting suspension was stirred at room temperature for 5 min, filtered through a short plug of silica gel (washed with approximately 20 mL of EtOAc), and the solvent was removed in vacuo. NMR yields were determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue and dissolved in CDCl3 by swirling, 19 The product was analyzed by F NMR.

[0209] [ka]

[0210] Under mechanical forces, the instability of both p-toluenesulfonyl chloride and p-toluenesulfonyl fluoride was assessed with material losses of 22% and 19%, respectively.

[0211] 1.5. Evaluation of Fluoride Leaching from p-Toluenesulfonyl Fluoride To investigate the leaching of any fluoride from p-toluenesulfonyl fluoride under solid-state, ball milling conditions, the reaction shown in Scheme 1.5 was carried out.

[0212] To a 50 mL stainless steel milling jar were added stainless steel balls (2 x 2 g), p-toluenesulfonyl fluoride (1.0 equiv.) and K2HPO4 (2.0 mmol). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 60 min. The jar was then opened and the solid residue was scraped off with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3 x 5 mL) and transferred to a beaker. The resulting suspension was stirred at room temperature for 5 min, filtered through a short plug of silica gel (washed with approximately 20 mL of EtOAc) and the solvent was removed in vacuo. NMR yields were determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue and dissolved in CDCl3 by swirling, 19 The product was analyzed by F NMR.

[0213] [ka]

[0214] Fluoride leaching from p-toluenesulfonyl fluoride under mechanical force and in the presence of K2HPO4 was combined with a loss of 11% of the fluorinated compound. 19 The identification of the fluoride anion was evaluated by F NMR.

[0215] [2.2-step reaction – solid state / solid state] General Procedure 2 (GP2): To a 15 mL stainless steel milling jar were added stainless steel balls (3 g), CaF2 (4.0 mmol), and K2HPO4 (2.0 mmol). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 2 x 90 min (referred to as the "premilling" step). The jar was then opened and the corresponding sulfonyl chloride (1.0 equiv.) was added to the resulting white residue. The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for an additional 2 x 90 min (referred to as the "fluorination" step). Upon completion of the reaction, the jar was opened and the white solid residue was scraped off with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3 x 5 mL) and transferred to a beaker. The resulting suspension was stirred at room temperature for 5 min, filtered through a short plug of silica gel (washed with approximately 20 mL of EtOAc), the solvent was removed in vacuo, and the crude mixture was purified by silica gel chromatography, if necessary.

[0216] 2.1. Varying the Duration of Premilling and Fluorination According to GP2 outlined above, and considering Scheme 2.1 below, the effect of varying the duration of the pre-milling and fluorination steps was investigated. The results are outlined in Table 2.1. Longer pre-milling times result in higher yields of organofluorine products (e.g., TsF). Longer fluorination times may also result in higher yields of organofluorine products.

[0217] [ka]

[0218] [Table 4]

[0219] (2.2. Evaluation of the stability of p-toluenesulfonyl fluoride under mechanical forces) Following GP2 outlined above, and considering Scheme 2.2 below, the stability of p-toluenesulfonyl fluoride under two-step, solid-state, ball milling conditions was investigated by replacing p-toluenesulfonyl chloride with p-toluenesulfonyl fluoride.

[0220] [ka]

[0221] The partial instability of p-toluenesulfonyl fluoride under ball milling conditions was evaluated. Stability experiments of p-toluenesulfonyl fluoride under mechanical forces and after premilling with CaF2 and K2HPO4 showed that 31% of the fluorinated product was lost.

[0222] (2.3. Changes in organic substrates) Following GP2 as outlined above, and considering Scheme 2.3 below, the effect of varying the organic substrate was investigated. Scheme 2.4 outlines the product yields obtained for each substrate.

[0223] [ka]

[0224] (2.4. Changes in organic substrates) Following GP2 outlined above, and taking into account Scheme 2.5, the effect of replacing the p-toluenesulfonyl chloride substrate with 4-methylbenzoyl chloride was investigated. The results are outlined in Table 2.2.

[0225] [ka]

[0226] [Table 5]

[0227] [3. Two-step reaction – solid state / solution phase] General Procedure 3 (GP3): To a 15 mL stainless steel milling jar were added stainless steel balls (7 g), CaF2 (4.0 mmol), and K2HPO4 (2.0 mmol). The jar was then closed and securely attached to a mill set at a frequency of 30 Hz for 2 × 90 min (referred to as the "pre-milling" step). Once the reaction was complete, the jar was opened and the white solid residue was collected. A 7 mL vial was charged with the milled solid residue, the corresponding electrophile (1.0 equiv.) and MeCN (0.25 M) and then closed with a screw cap. After stirring at 100 °C for 5-16 h (referred to as the "fluorination" step), the resulting suspension was cooled to rt and filtered through a short plug of silica gel (washed with approximately 20 mL of EtOAc), the solvent was removed in vacuo, and the crude mixture was purified by silica gel chromatography, if necessary.

[0228] (3.1. Inclusion of Additives) Following GP3 as outlined above, and taking into account Scheme 3.1, the effect of including one or more additives during the fluorination step was investigated. The results are outlined in Table 3.1. The addition of additives such as 18-crown-6 or Schreiner's urea can increase the yield of the organofluorine product.

[0229] [ka]

[0230] [Table 6]

[0231] (3.2. Change in pre-mill grinding duration) According to GP3 outlined above, and considering Scheme 3.2 below, the effect of varying the pre-milling duration was investigated. The results are outlined in Table 3.2. Longer pre-milling duration may increase the yield of organofluorine products (e.g., TsF) and decrease the resulting yield of starting materials (e.g., TsCl).

[0232] [ka]

[0233] [Table 7]

[0234] 3.3. Varying Premill Grinding Duration and Inclusion of Additives Following GP3 outlined above, and taking into account Scheme 3.3, the effect of varying the pre-milling duration and including one or more additives during the fluorination step was investigated. The results are outlined in Table 3.3. The addition of crown ethers and / or Schreiner's urea can increase the yield of organofluorine products (e.g., TsF).

[0235] [ka]

[0236] [Table 8]

[0237] (3.4. Change in the ratio of CaF2 to K2HPO4) In accordance with GP3 outlined above, and taking into account Scheme 3.4, the effect of varying the amount of CaF2 and K2HPO4 introduced during pre-milling and then added to the fluorination step was investigated. The results are outlined in Table 3.4.

[0238] [ka]

[0239] [Table 9]

[0240] From the results outlined in Table 3.4, the use of a 2:1 ratio of ball-milled CaF2 and K2HPO4 (4 equivalents and 2 equivalents, respectively) in a fluorination reaction in the presence of 18-crown-6 ether can result in similar yields as a 1:1 ratio of ball-milled CaF2 and K2HPO4 (4 equivalents, respectively) without any additive. The results also show that the addition of one equivalent of 18-crown-6 ether can result in a higher yield of organofluorine product and a lower yield of organochlorine starting material. The results also show that the addition of any amount of a second salt, K2HPO4, can increase the yield of organofluorine product compared to reactions without the addition of K2HPO4.

[0241] (3.5. Change of Solvent) Following GP3 as outlined above, and taking into account Scheme 3.5.1, the effect of varying the solvent used during the fluorination step was investigated. The results are outlined in Table 3.5. The results indicate that the use of some solvents may result in higher yields of organofluorine products. Solvents such as DMF, DMA, and DMSO may not be effective as the yield of TsF is only trace, while other solvents such as 1,2-dichlorobenzene, chlorobenzene, t-amylOH, and t-buOH may be more effective with greater than 70% yield of organofluorine product (e.g., TsF). Solvents with a polar aprotic polarity index of 6.4 or greater may be particularly suitable for use in the fluorination of organic compounds using fluorinating agents (e.g., as shown in Scheme 3.5.1).

[0242] [ka]

[0243] [Table 10]

[0244] In some cases, reagent grade CaF2 is milled with 1 equivalent of K2HPO4 at 30 Hz for 3 hours, and then 4 equivalents of the resulting reagent are reacted with TsCl in a solvent according to Scheme 3.5.2 to obtain TsF. In some cases, 1 equivalent of acid grade Fluorospar is milled with 1 equivalent of K2HPO4 at 30 Hz for 3 hours, and 4 equivalents of the resulting fluorinated reagent are reacted with TsCl in a solvent to obtain fluorinated TsF. The fluorinated TsF product yields obtained from reagent grade CaF2 and acid grade Fluorospar (81% and 82% by NMR, respectively) support the conclusion that either starting material can be used to synthesize the fluorinated reagent.

[0245] [ka]

[0246] (3.6. Changes in organic substrates) Following GP3 outlined above, and considering schemes 3.6a, 3.6b, 3.6c and 3.6d, the effect of replacing the p-toluenesulfonyl chloride substrate with 4-methylbenzoyl chloride, 2,4-dinitrochlorobenzene, 2-chloro-5-nitropyridine or 2-(bromomethyl)naphthalene was investigated. The results are outlined in Tables 3.6a, 3.6b, 3.6c and Scheme 3.6d. The results can support that the fluorinating reagent can satisfactorily fluorinate various chlorinated aromatic compounds. The fluorination of toluene (40% yield) can indicate that the fluorinating reagent can fluorinate non-halogenated compounds.

[0247] [ka]

[0248] [Table 11]

[0249] [ka]

[0250] [Table 12]

[0251] [ka]

[0252] [Table 13]

[0253] [ka]

[0254] (3.7. Removal of Salt) To investigate the effect of removing the salt on the ability of CaF2 to fluorinate p-toluenesulfonyl chloride, the reaction shown in Scheme 3.7 was carried out following a similar procedure as GP3 where the salt was removed from the premilling step. The results are outlined in Table 3.7. These results highlight the importance of the additive and premilling of CaF2 on the yield of the organofluorine product (e.g., TsF), which was less than 8% without the addition of the additive in the premilling step.

[0255] [ka]

[0256] [Table 14]

[0257] (3.8. Changes in Salt) Following GP3 as outlined above, and considering Scheme 3.8 below, the effect of varying the nature of the salt was investigated. The results are outlined in Scheme 3.8. Changing the salt from K2SO4 to K2HPO4 resulted in 10% and 71% yields, respectively, under otherwise similar conditions. These results highlight the role that a second salt can play in the formation of the fluorinating agent, and the ability of the resulting fluorinating agent to fluorinate organic substrates. Specifically, the results highlight K2HPO4 as an exemplary salt additive.

[0258] [ka]

[0259] [4. Nucleophilic Fluorination with CaF2] To investigate the effectiveness of nucleophilic fluorination with CaF2 in solution, several reactions detailed in Table 4.1 were attempted according to Reaction Scheme 4.1.

[0260] [ka]

[0261] Briefly, the crown ether or cryptand (1 equiv.) listed in Table 4.1 was dissolved in Schreiner's (thio)urea (20 mol%) and CaF2 (5 equiv.). In some cases, an additive selected from K3PO or Schreiner's urea was added to the reaction. In all cases, 4-fluoroanisole was used as an internal standard. 19The yield of fluorinated products was 0% or was found to be in trace amounts as determined by F-NMR. In all cases, the solvents used were anhydrous. In some cases, the by-product formed was 1-(2,4-dinitrophenoxy)-4-nitro-2-nitrosobenzene, and urea decomposition occurred. In other cases, no reaction occurred. The low to zero NMR yields of fluorinated products associated with these reactions can highlight the role of the pre-milling (mechanical force) step discussed herein between CaF2 (first salt) and second salt to form the fluorinated reagent.

[0262] [Table 15]

[0263] [5. Fluorination of 4-toluenesulfonyl chloride with CaF2 using ball milling] 5.1. Use of Phosphate Additives The effect of phosphate additives on the reaction of CaF2 with TsCl as shown in Scheme 5.1.

[0264] [ka]

[0265] CaF2 (1.00 mmol, 5 equiv.), phosphate additive (2 equiv., see Table 5.1), and TsCl (1 equiv.) were added to a 30 mL stainless steel jar along with 2 x 2 g balls (316SS grade) and ball milling was carried out using a Retsch MM400 ball mill. The ball milling conditions were 30 Hz for 1 hour. The resulting products were examined for starting material (TsCl%), product (TsF%), and by-product (TsOH%) as shown in Table 5.1. 4-Fluoroanisole was used as an internal standard. 1 H and 19The yields were determined by F-NMR. In some cases, the phosphate additive was replaced by a carbonate additive or a sulfate additive. The experimental results show that K2HPO4 and K2CO3 additives can be exemplary additives that increase the yield of organofluorine products (e.g., TsF).

[0266] [Table 16]

[0267] (5.2. Ratio of CaF2 to K2HPO4) Considering the benefit that K2HPO4 may have as an additive in the reaction of CaF2 and TsCl ball milling fluorination experiments, the ratio of CaF2 and K2HPO4 was investigated via Scheme 5.2.

[0268] [ka]

[0269] Briefly, CaF2 (variable equivalents) was added to a stainless steel jar with 4 g balls (316SS grade) along with K2HPO4 (2 equivalents) and TsCl (1 equivalent). Ball milling was completed with a Retsch MM400 ball mill at 30 Hz for 1 hour. 4-Fluoroanisole was used as the internal standard. 1 H and 19 The percent yield of TsCl, TsF, and the percent yield of the TsOH by-product were determined by F-NMR. The results are shown in Table 5.2. The increase in yield with increasing ratio of CaF2:K2HPO4 indicates that the ratio of the two salts can play a role in optimizing the resulting yield of the organofluorine product, and that a 2:1 ratio can provide the highest yield of the organofluorine product (e.g., TsF).

[0270] [Table 17]

[0271] 5.3. Stability of Products and Starting Materials The stability of the product (TsF) and starting material (TsCl) was examined in the presence of CaF2 and K2HPO4 for TsF and in the presence of K2HPO4 for TsCl, as shown in Scheme 5.3.

[0272] [ka]

[0273] In the case of the product (TsF), ball milling in a stainless steel jar in the presence of CaF2 (5.0 equiv.) and K2HPO4 (5.0 equiv.) at 30 Hz for 1 h using a Retsch MM400 ball mill resulted in 81% recovery of the product (TsF). Some aqueous fluoride ion was observed in D2O by NMR. The 81% recovery of the starting material TsF highlights the stability of the fluorinated material under milling conditions and in the presence of fluorinating agents.

[0274] In the case of the starting material (TsCl), ball milling under similar conditions in the presence of K2HPO4 (1.0 equiv.) resulted in the recovery of 78% of TsCl.

[0275] 5.4. Stepwise addition in solid state As shown in Scheme 5.4, the effect of stepwise addition of starting materials on product yield was examined.

[0276] [ka]

[0277] Ball milling was completed using a Retsch MM400 ball mill using 15 mL stainless steel jars and 3 g balls. Briefly, CaF2 (4.0 equiv.) was added to the stainless steel jar along with K2HPO4 (2.0 equiv.) and ball milling was carried out at 30 Hz (variable times seen in Table 5.4). In the second step, TsCl (1 mmol) was added to the stainless steel jar and fluorination via ball milling was carried out at 30 Hz (variable times seen in Table 5.4). 4-Fluoroanisole was used as the internal standard. 1 H and 19 The TsCl and TsF yields (%) were determined by F-NMR. The results show that the combination of pre-milling of CaF2 and K2HPO4 followed by longer fluorination time can lead to higher yields of organofluorine products (e.g., 66% TsF yield after 3 hours of pre-milling followed by 3 hours of fluorination).

[0278] [Table 18]

[0279] (5.5. Stepwise addition from solid state to solution state) As shown in Scheme 5.5, the effect on product yield of initial milling of K2HPO4 (2.0 equiv.) with CaF2 (4.0 equiv.) at 30 Hz for 3 h, followed by a second step solution-state reaction with TsCl in acetonitrile (0.25 M) at 100 °C for 5 h, was investigated.

[0280] [ka]

[0281] As shown in Scheme 5.5, by adding CaF2 (4 equiv.) and K2HPO4 (2.0 equiv.) to a stainless steel jar for ball milling at 30 Hz for 3 h, followed by the addition of TsCl (1.00 mmol, 0.25 M) in solution, and reacting the solution at 100 °C in acetonitrile for 5 h, the yield of TsF was determined to be 62%, with 15% of TsCl recovered. The 62% yield of TsF highlights the importance of pre-milling CaF2 and the phosphate activator, K2HPO4, prior to the solution fluorination reaction with TsCl.

[0282] (5.6. Stepwise addition from solid state to solution state) Without the additive and ball milling of CaF2 prior to the addition of TsCl, several control experiments were completed using ball milled CaF2, as shown in Scheme 5.6.

[0283] [ka]

[0284] Briefly, CaF2 (4.0 equiv.) is added to a 15 mL stainless steel jar and ball milled alone at 30 Hz for 3 h, then added to an additive (see Table 5.6) and TsCl (1 mmol) in acetonitrile (0.25 M) and reacted at 100 °C for 5 h. This method may result in a lower yield of fluorinated product than if the additive was milled with CaF2.

[0285] [Table 19]

[0286] (5.7. Replacement of Reagent Grade CaF2 with Acid Grade Fluorospar) In some cases, reagent grade CaF2 was replaced with acid grade Fluorospar to complete the screening of various phosphate activators, as shown in Scheme 5.7. The various phosphate activators were K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, KPO3, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O 10 , (NaPO3)3, CaHPO4, and α-Ca3(PO4)2.

[0287] [ka]

[0288] Fluorospar (1.0 equiv.) was added to a stainless steel jar and milled with phosphate activator (1 equiv.) at 30 Hz for 3 h (see Figure 3). The solid product containing CaF2 (4 equiv.) and phosphate activator (4 equiv.) was then added to t-butanol (0.25 M) along with TsCl (1.00 mmol) and reacted at 100 °C for 5 h to obtain the fluorinated product (TsF). Figure 3 shows the reaction yields (TsF (%), TsCl (%)). The corresponding sulfonyl bromides and tosylates as substrates gave 71% and 26% of sulfonyl fluorides, respectively (compared to 82% using sulfonyl chlorides, using K2HPO4 as additive). Using K4P2O7 resulted in a TsF yield of 54%. In some cases, phosphate activators (e.g., CaHPO4, (NaPO3)3, α-Ca3(PO4)2) resulted in trace or 0% TsF product yields. Overall, the results indicate that the choice of activator salt (second salt) can play a significant role in the ability of the resulting fluorination reagent to fluorinate a substrate. Results highlight potential exemplary additives including K2HPO4, Na2HPO4, K4P2O7, and Na4P2O7.

[0289] K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, KPO3, K4P2O7, K5P3O 10 , Na4P2O7, Na5P3O10 PXRD data was obtained for each of the solid products resulting from Fluorospar activation with various phosphate activators including, (NaPO3)3, CaHPO4, and α-Ca3(PO4)2. Figure 4 shows the PXRD patterns obtained from milling Fluorospar and KH2PO4 for 3 hours at 35 Hz. Table 5.7.1 shows the PXRD data from milling Fluorospar and KH2PO4 shown in Figure 4. Labels on the diffraction patterns indicate the crystalline phases of CaF2 and KH2PO4.

[0290] [Table 20]

[0291] Figure 5 shows the PXRD patterns obtained from milling Fluorospar and K3PO4 at 35 Hz for 3 hours. Table 5.7.2 shows the PXRD data from the milling of Fluorospar and K3PO4 shown in Figure 5. The labels in Figure 5 are K3PO4 * 7H2O, CaF2, and an unspecified crystalline phase are shown.

[0292] [Table 21]

[0293] Figure 6 shows the PXRD pattern obtained from milling Fluorospar and Na3PO4 at 30 Hz for 3 hours. Table 5.7.3 shows the PXRD data from milling Fluorospar and Na3PO4 shown in Figure 6. The labels in Figure 6 are Na7F(PO4)2(H2O) 19 and the crystalline phase of CaF2.

[0294] [Table 22]

[0295] Figure 7 shows the PXRD pattern obtained from milling Fluorospar and Na2HPO4 at 35 Hz for 3 hours. Table 5.7.4 shows the PXRD data from milling Fluorospar and Na2HPO4 shown in Figure 7. The labels in Figure 7 indicate the crystalline phase of CaF2 and an unidentified crystalline phase.

[0296] [Table 23]

[0297] Figure 8 shows the PXRD pattern obtained from milling Fluorospar and NaH2PO4 at 35 Hz for 3 hours. Table 5.7.5 shows the PXRD data from milling Fluorospar and NaH2PO4 shown in Figure 8. The labels in Figure 8 indicate the crystalline phases of CaF2 and NaH2PO4(H2O)3.

[0298] [Table 24]

[0299] Figure 9 shows the PXRD patterns obtained from milling Fluorospar and KPO3 at 35 Hz for 3 hours. Table 5.7.6 shows the PXRD data from milling Fluorospar and KPO3 shown in Figure 9. The labels in Figure 9 indicate the crystalline phases of CaF2, KPO3, and an unidentified amorphous phase.

[0300] [Table 25]

[0301] Figure 10 shows the PXRD patterns obtained from milling Fluorospar and K4P2O7 at 35 Hz for 3 hours. Table 5.7.7 shows the PXRD data from milling Fluorospar and K4P2O7 shown in Figure 10. The labels in Figure 10 indicate the crystalline phase of CaF2 and an unidentified crystalline phase.

[0302] [Table 26]

[0303] Figure 11 shows the results of Fluorospar and K5P3O for 3 hours at 35 Hz. 10 The PXRD patterns obtained from milling of Fluorospar and K5P3O shown in Figure 11 are shown in Table 5.7.8. 10 The PXRD data from milling of CaF2 and K3H3(PO4)2 are shown. * The crystal phase of 2H2O as well as an unspecified crystal phase are shown.

[0304] [Table 27]

[0305] Figure 12 shows the PXRD pattern obtained from milling Fluorospar and Na4P2O7 at 35 Hz for 3 hours. Table 5.7.9 shows the PXRD data from milling Fluorospar and Na4P2O7 shown in Figure 12. The labels in Figure 12 indicate the crystalline phase of CaF2 and an unidentified crystalline phase.

[0306] [Table 28]

[0307] Figure 13 shows the results of Fluorospar and Na5P3O for 3 hours at 35 Hz. 10 The PXRD patterns obtained from milling of Fluorospar and Na5P3O shown in Figure 13 are shown in Table 5.7.10. 10 PXRD data from milling of CaF2. The labels in FIG. 13 indicate crystalline phases and an unidentified amorphous phase of CaF2.

[0308] [Table 29]

[0309] Figure 14 shows the PXRD pattern obtained from milling Fluorospar and Na(PO3)3 at 35 Hz for 3 hours. Table 5.7.11 shows the PXRD data from milling Fluorospar and Na(PO3)3 shown in Figure 14. The labels in Figure 14 indicate the crystalline phase of CaF2.

[0310] [Table 30]

[0311] Figure 15 shows the PXRD patterns obtained from milling Fluorospar and CaHPO4 at 30 Hz for 3 hours. Table 5.7.12 shows the PXRD data from milling Fluorospar and CaHPO4 shown in Figure 15. The labels in Figure 15 indicate the crystalline phases of CaF2 and Ca5(PO4)3F.

[0312] [Table 31]

[0313] Figure 16 shows the PXRD pattern obtained from milling Fluorospar and Ca3(PO4)2 at 35 Hz for 3 hours. Table 5.7.13 shows the PXRD data from milling Fluorospar and Ca3(PO4)2 shown in Figure 16. The label in Figure 16 indicates the crystalline phase of Ca5(PO4)3F.

[0314] [Table 32]

[0315] 5.8. Milling frequency and consumption of crystalline CaF2 in solid-state reactions Increasing the consumption of crystalline CaF2 can be achieved by continuously spiking additional K2HPO4 into the milled mixture (A-D in Scheme 5.8.1) as detailed in Scheme 5.8.1, and milling for an additional 3 hours until all of the crystalline CaF2 is consumed.

[0316] [ka]

[0317] In this reaction, fluorospar (1 eq.) was added to a stainless steel vessel along with 1 eq. K2HPO4, the mixture was milled at 30 Hz for 3 hours, followed by successive additions of an additional 1 eq. K2HPO4, 0.5 eq. K2HPO4, and 0.5 eq. K2HPO4, each with 3 hours of milling at 30 Hz. Figure 17 shows the powder X-ray diffraction patterns for each of these mixtures, labeled to indicate the appearance of new species. PXRDs were obtained on a Bruker Eco D8 diffractometer.

[0318] As shown in Scheme 5.8.2, the effect of mill grinding intensity was investigated. Acid grade Fluorospar (1 equiv.) was milled with K2HPO4 (1 equiv.) at 30 Hz or 35 Hz for 3 h, and the powdered reagent (A) was used for the fluorination of TsCl on a 0.125 mmol scale, with 4-fluoroanisole as the internal standard. 1 H NMR and 19 Yields were determined by F NMR. Milling was completed using a Retsch MM400 ball mill and stainless steel jars (15 mL) and 7 g balls.

[0319] [ka]

[0320] 18 shows the experimental results when the powdered reagents were reacted in a solution containing TsCl in tBuOH (0.25M) at 100° C. for 5 hours, indicating that higher frequency milling can result in powdered reagents that, when used for fluorination, can result in higher fluorination yields. Furthermore, higher fluorination yields can be shown when higher equivalents of fluorination reagent (A) are used.

[0321] (5.9. Changes in stoichiometry of CaF2 (fluorospar)) As shown in Scheme 5.9.1, the milled mixtures A-C were investigated as fluorination reagents, this time allowing the fluorination of TsCl in high yields using fewer equivalents of CaF2 (Fluorospar).

[0322] [ka]

[0323] In A, 1 equivalent of fluorospar was milled with 1 equivalent of K2HPO4 at 30 or 35 Hz for 3 hours. In B, an additional 1 equivalent of K2HPO4 was added and milled at 30 or 35 Hz for 3 hours. In C, an additional 0.5 equivalent of K2HPO4 was added and milled at 30 or 35 Hz for 3 hours. The powdered reagent was reacted with TsCl (1 equivalent, 0.125-0.25 mmol) in solution in tBuOH (0.25 M) at 100 °C for 5 hours as shown in Scheme 5.9.2. Figure 19 shows experimental results indicating that a lower equivalent of CaF2 can result in higher fluorination yields of organofluorine products (e.g., TsF).

[0324] [ka]

[0325] Scheme 5.9.3 shows the reaction of the powdered reagents of Scheme 5.9.1 with TsCl (1 equiv, 0.125-0.25 mmol) in 0.25 M tBuOH solution with the addition of water at 100° C. for 5 hours. The results (see FIG. 20) show that adding water to the reaction can be beneficial in achieving higher yields of organofluorine products (e.g., TsF).

[0326] [ka]

[0327] Various experimental conditions were used using powdered reagent C (containing 0.5 equivalents of CaF2) from Scheme 5.9.1 as shown in Scheme 5.9.4, where C (0.5 equivalents) was reacted with TsCl (1 equivalent, 0.125-0.25 mmol) in tBuOH solution (0.25 M) at 100 °C for 5 h with the addition of various amounts of water. Figure 21 shows the results of these reactions. These results may indicate that a higher amount of water added may decrease the yield of the fluorinated product, but a longer reaction time may increase the product yield.

[0328] (5.10. SF Bond Range)

[0329] [ka]

[0330] A series of reactions were completed to assess the range of SO2-Cl substrates that can undergo fluorination, and the associated fluorination yields. All yields were isolated unless otherwise stated, and all reactions were at 0.5 mmol scale unless otherwise stated. 4-Fluoroanisole was used as an internal standard. 19 The F NMR yield was determined. b indicates that EtCN was used instead of tBuOH (anhydrous), c showed that the product was prepared by adding all-trans-farnesyl-mercaptan to ESF, d indicates that the reaction was completed using 2.2 equivalents of "reagent" e indicates the reaction was completed on a 0.25 mmol scale, findicates that 1.25 mmol of "reagent" was used. In all examples, an INSOLIDO IST636 ball mill was used with stainless steel jars (15 mL) and balls (7 g) (316SS grade). These reactions were carried out as detailed in Scheme 5.10.1, where Fluorospar (CaF2) (1 eq, acid grade) was milled with K2HPO4 (2.5 eq total) at 35 Hz for a total of 9 hours. The "reagent" (1 eq) was reacted with R-SO2Cl (1 eq) and H2O (0-2 eq) in tBuOH or EtCN (0.25 M) at 40-100 °C for 2-24 hours to give the fluorinated products. Figure 22 shows all of the fluorinated products and their fluorination yields. These results indicate that a wide range of substrates can undergo fluorination using the fluorinating agents described herein.

[0331] (5.11.CF Bond Range) A series of reactions were completed to evaluate the range of RX substrates that could undergo fluorination, where X denotes a halogen (Br or Cl) and the associated fluorination yields. Benzyl fluorides, acyl fluorides, alpha-fluorocarbonyl fluorides, alkyl fluorides, and (hetero)aryl fluorides were among those C-F bonds investigated, as shown in Figure 23. Fluorination reagents were made via ball milling, as shown in Scheme 5.11.1, where CaF2 (fluorospar) (1-4 equiv.) was milled with K2HPO4 (4-8 equiv.) at 35 Hz for a total of 3-9 hours. This solid reagent was reacted with RX substrate (1 equiv.), 18-C-6 (1 equiv.) and optionally H2O (0-5 equiv.) in tBuOH solution at 60-100 °C for 5-48 hours to give the desired products, whose yields and specific solution conditions are shown in Figure 23. Not all isolated yields are in parentheses and were performed on a 0.5 mmol scale. All yields in parentheses are NMR yields. All reactions were completed using an INSOLIDO IST636 ball mill using stainless steel jars (15 mL) and 7 g balls (316SS grade). The results show that a range of different halogenated functional groups are amenable to fluorination using the above fluorinating reagents.

[0332] [ka]

[0333] (5.12 Solution-State NMR and Powder X-Ray Diffraction) Fluorospar (CaF) was milled with KHPO (total 2.5 equivalents) as shown in Scheme 5.12.1 to form the "reagent". The reagent was dissolved in DO to form the DO soluble component for examination via solution-state NMR. Figure 24A shows the F in solution upon dissolution. - ions and PO3F 2- Indicates the presence of ions 19 F NMR is shown in FIG. 3- and PO3F 2- Indicates the presence of 31 P NMR is shown.

[0334] [ka]

[0335] Figure 25 shows the powder X-ray diffraction pattern (PXRD) of the "Reagent" and the reference PXRD pattern for potassium fluoride (KF). The PXRD pattern showed that no KF was present at the completion of the ball milling reaction. Figure 26 and Table 5.12.1 show the PXRD data for the "Fluoromix" resulting from the "Reagent" formation shown in Scheme 5.12.1 when the fluorination reagent, Fluorospar, is milled with a total of 2.5 equivalents of K2HPO4. Figure 27 shows the crystalline components of the "Reagent" consistent with X (KF (1 equivalent) milled with K2HPO4 (1 equivalent) at 30 Hz for 3 hours), Y (KF (1 equivalent) milled with K2HPO4 (1 equivalent) at 30 Hz for 3 hours followed by the addition of CaHPO4 (1 equivalent)), and crystalline CaF2 as the reference PXRD pattern. X and Y can be synthesized independently via Scheme 5.12.2.

[0336] [ka]

[0337] This PXRD can indirectly support the formation and participation of KF and CaHPO4 species in the solid-state reaction. The structures of X and Y were simulated based on their PXRD patterns. Figure 28A shows the simulated structure of X, which may be K3(HPO4)F, a structure related to K3(PO3F)F. Figure 28B shows the simulated structure of K2PO3F, a structure related to K3(HPO4)F. 2-x Ca y (PO3F) a (PO4) b F c Figure 29 shows the PXRD experiments for Fluorospar (acid grade), K2HPO4 (Fisher Chemical), and fluorapatite (Thermo Fisher). Figure 30 shows the overlay of the PXRD diffractograms of Fluoromix, Fluorospar, X, and Y. Residual CaF2 is also observed in the Fluoromix diffractogram. Table 5.12.2 shows the PXRD data for the crystalline component of X, which has the proposed structure of K3(HPO4)F. Table 5.12.3 shows the PXRD data for the crystalline component of K, which has the proposed structure of K3(HPO4)F. 2-x Ca y (PO3F) a (PO4) b F c PXRD data for the crystalline component of Y having the proposed structure:

[0338] [Table 33]

[0339] [Table 34]

[0340] [Table 35]

[0341] As shown in Scheme 5.12.3, Fluorospar (CaF2) (1 eq) was milled with K2HPO4 (2.5 eq) at 35 Hz for a total of 9 hours to form the "reagent". This reagent ("fluoromix") was washed with H2O to give a water insoluble solid (84.5 mg from 500 mg of reagent, 17% yield). The resulting insoluble solid was examined via PXRD. Figure 31 shows this PXRD with peaks labeled, indicating the formation of Ca5(PO4)3F or Ca5(PO4)3OH (diamonds) and CaF2 (circles). The PXRD data can also be found in Table 5.12.4.

[0342] [ka]

[0343] [Table 36]

[0344] As another example, fluorospar (CaF2) was milled with equimolar CaHPO4 to produce Z, as shown in Scheme 5.12.4. The milling was completed at 30 Hz for 3 hours. Figure 32A shows the PXRD of the water insoluble solid resulting from the reaction to form Z and Z. Figure 32B shows the PXRD of Z highlighting the crystalline phases of Ca5(PO4)3F and CaF2. The PXRD data for Z can be found in Table 5.12.5. Milling of anhydrous CaHPO4 equimolar with CaF2 produces Z consistent with Ca5(PO4)3F (or Ca5(PO4)3OH) and CaF2.

[0345] [ka]

[0346] [Table 37]

[0347] (5.13. Polyfluorination using Fluorospar activated with K2HPO4) Gem-difluorination was examined using fluorospar and K2HPO4 as the activator, as shown in Scheme 5.13.1.

[0348] [ka]

[0349] Briefly, the substrate was dissolved in 2 equivalents of {(CaF2)(K2HPO4)} obtained via milling at 35 Hz in 0.25 M solvent (listed in Table 5.13.1). 2.5} and 1 equivalent of 18-C-6 for 15 hours at 100° C. in a sealed tube. The yields of fluorinated products and by-products can be seen in Table 5.13.1. The results demonstrate that difluorination can be achieved from dihalogenated starting materials using the fluorinating agents described herein with low yields of monofluorinated products.

[0350] [Table 38]

[0351] Optionally, gem-difluorination was examined as shown in Scheme 5.13.2.

[0352] [ka]

[0353] Briefly, the substrate was mixed with 2 equivalents of {(CaF2)(K2HPO4) 2.5} and 1 equivalent of additive (see Table 5.13.2), HBD, and reacted in a sealed tube in solvent (0.25 M) at 100° C. for 15 hours. The yields of fluorinated products and by-products as determined from NMR can be seen in Table 5.13.2. As above, the results show that difluorination can be achieved from dihalogenated starting materials using the fluorinating agents described herein, with low monofluorinated product yields.

[0354] [Table 39]

[0355] 5.14. Mechanistic understanding of mechanochemical activation of Fluorospar and K2HPO4 Fluorospar (CaF2) is ball-milled with anhydrous K2HPO4 to obtain a fluorination reagent (fluoromix) composed of crystalline phases (X,Y) and residual crystalline CaF2 (Scheme 5.14.1). Powder X-ray diffraction (PXRD) patterns of species X and Y match the reflection (peak) positions and peak intensities observed in fluoromix. Calcium hydrogen phosphate (CaHPO4) and potassium fluoride (KF) may be products of the reaction between CaF2 and K2HPO4. X is the product of ball-milling KF and K2HPO4, where X has the proposed structure K3(HPO4)F and is isostructural to K3(PO3F)F. Y has the proposed structure K3(PO3F)F. 2-x Ca y (PO3)F a (PO4) b F c and is isostructural with K2PO3F. The formation of X and Y from ball milling of fluorospar and K2HPO4 may indirectly support the formation of KF and CaHPO4 as intermediates in this reaction on the way to X and Y. The PXRD diffractogram of the water-insoluble components of Fluoromix is ​​measured and contains reflections consistent with CaF2 and Ca5(PO4)3F (fluorapatite) as a mixture (mixture Z). Z can be prepared independently by ball milling CaHPO4 and CaF2.

[0356] [ka]

[0357] Table 5.14.1 shows the PXRD data for the starting material, Fluorospar (CaF2). Table 5.14.2 and Figure 33 show the PXRD data for X, which is consistent with K3(HPO4)F (a related structure to K3(PO3F)F). Table 5.14.3 and Figure 34 show the PXRD data for K3(HPO4)F (a related structure to K3(PO3F)F). 2-x Ca y (PO3F) a (PO4) b F c Table 5.14.4 shows PXRD data for Y which was consistent with Ca5(PO4)3F and unreacted CaF2. Table 5.14.4 shows PXRD data for Z which was consistent with Ca5(PO4)3F and unreacted CaF2.

[0358] [Table 40]

[0359] [Table 41]

[0360] [Table 42]

[0361] [Table 43]

[0362] Each crystalline species of Fluoromix (X or Y) was prepared independently and tested in the fluorination of tosyl chloride (TsCl). X or Y can be used to convert the S(VI)-Cl bond to an S(VI)-F bond, but neither CaF2 nor Z (an "apatite structure" consistent with Ca5(PO4)3F) give the fluorinated product. Fluorination using X or Y was carried out as shown in Scheme 5.14.3, where X or Y (1 equivalent relative to fluoride) was reacted with TsCl (1 equivalent) and H2O in tBuOH solution at 100 °C for 5 hours to give the fluorinated product. The yields obtained using Fluoromix or using X or Y independently are seen in Figure 35 for the fluorinated product yield TsF and the starting material yield TsCl. Fluoromix and X (ball-milled KF and K2HPO4) give tosyl fluoride (TsF) in high yield. When Y (ball-milled KF, KHPO and CaHPO) was used, the fluorination yield decreased, indicating a decreased fluorination capacity when CaHPO was incorporated into the product X, which could be improved through the addition of water (2 equivalents).

[0363] [ka]

[0364] [6. Alternative activator to Fluorospar (CaF2)] 6.1. Formation of KCaF3 and NaF using hydroxide activators Hydroxide activators (KOH and NaOH) were examined as alternative activators, as shown in Schemes 6.1.1 and 6.1.2. Briefly, Fluorospar (CaF2, 1 eq) was added to a stainless steel jar along with KOH (1 eq) and milled at 35 Hz for 3 hours. Based on the PXRD data, this reaction resulted in the formation of KCaF3 and Ca(OH)2. Alternatively, Fluorospar (CaF2, 1 eq) was milled with NaOH (2 eq) at 35 Hz for 6 hours. As determined by PXRD, this reaction resulted in the formation of NaF and Ca(OH)2. Figure 36 shows the PXRD of the products from the reaction shown in Scheme 6.1.2 between Fluorospar and NaOH.

[0365] [ka]

[0366] 6.2. Fluorination of TsCl using hydroxide activators As shown in Scheme 6.2.1, fluorospar (1 equiv.) was milled with KOH (2 equiv.) for 3 h at 35 Hz to form Ca(OH)2, KCaF3, and residual CaF2 (A). This mixture was milled with dry ice (10 equiv.) for 60 s at 20 Hz to form (B), consisting of KHCO3, KCaF3, and CaF3. Mixture (A) was also heated at 520 °C for 1 h to form (C), CaO, KCaF3, and CaF2. These mixtures (2 equiv.) were reacted in solution with TsCl (1 equiv., 0.125 mmol) according to Scheme 6.2.1 at 100 °C for 3 h in acetonitrile (anhydrous) to form the fluorinated products. In some cases, additives such as Schreiner's urea or 18-crown-6 were added (see Table 6.2). Fluorination of TsCl using either treated or untreated KCaF3 / Ca(OH)2 mixtures was accomplished. Results indicate that fluorination can occur using hydroxide activators with Fluorospar. Conditions include, for example, the addition of additives such as crown ethers or Schreiner's urea.

[0367] [Table 44]

[0368] [ka]

[0369] 6.3. Fluorination of TsCl using alternative non-phosphate activators Alternative non-phosphate activators were investigated to investigate the fluorination of TsCl via Scheme 6.3.1. Fluorospar (CaF2, 1 eq.) was milled with activator (1.0 or 2.0 eq., see FIG. 37) at 35 Hz for 3 hours to form A. A was used as the fluorination reagent with TsCl in tBuOH (0.25 M) solution and reacted at 100° C. for 5 hours to form the fluorinated product. NMR yields of reactions using various activators are shown in FIG. 37. Reactions using sodium sulfite (Na2SO3) as the activator resulted in an intractable mixture of products in the solution phase. Non-phosphate activators included K2CO3, KHCO3, K2SO4, KHSO4, Cs2SO4, K2S2O7, Na2SO3, KNO3, and sodium citrate dihydrate. Fluorination yields indicate that exemplary non-phosphate activators may include Na2SO3 and sodium citrate dihydrate. The resulting activated Fluorospar reagent (A) was analyzed by PXRD.

[0370] [ka]

[0371] Figure 38 shows the PXRD pattern obtained from milling Fluorospar and K2CO3 at 35 Hz for 3 hours. Table 6.3.1 shows the PXRD data from milling Fluorospar and K2CO3 shown in Figure 38. The labels in Figure 38 indicate the crystalline phases of K2CO3 and CaF2.

[0372] [Table 45]

[0373] Figure 39 shows the PXRD patterns obtained from milling Fluorospar and KHCO3 at 35 Hz for 3 hours. Table 6.3.2 shows the PXRD data from milling Fluorospar and KHCO3 shown in Figure 39. The labels in Figure 39 indicate the crystalline phases of KHCO3 and CaF2.

[0374] [Table 46]

[0375] Figure 40 shows the PXRD pattern obtained from milling Fluorospar and K2SO4 at 35 Hz for 3 hours. Table 6.3.3 shows the PXRD data from milling Fluorospar and K2SO4 shown in Figure 40. The labels in Figure 40 indicate the crystalline phases of K2SO4 and CaF2.

[0376] [Table 47]

[0377] Figure 41 shows the PXRD patterns obtained from milling Fluorospar and KHSO4 at 35 Hz for 3 hours. Table 6.3.4 shows the PXRD data from milling Fluorospar and KHSO4 shown in Figure 41. The labels in Figure 41 indicate the crystalline phases of KHSO4, K2Ca(SO4)2H2O2 (syngenite), and CaF2.

[0378] [Table 48]

[0379] Figure 42 shows the PXRD pattern obtained from milling Fluorospar and K2S2O7 at 35 Hz for 3 hours. Table 6.3.5 shows the PXRD data from milling Fluorospar and K2S2O7 shown in Figure 42. The labels in Figure 42 indicate the crystalline phases of K2S2O7 and CaF2.

[0380] [Table 49]

[0381] Figure 43 shows the PXRD pattern obtained from milling Fluorospar and Na2SO3 at 35 Hz for 3 hours. Table 6.3.6 shows the PXRD data from the milling of Fluorospar and Na2SO3 shown in Figure 43. The labels in Figure 43 indicate the crystalline phases of Na2SO3, CaF2, and an unidentified amorphous phase.

[0382] [Table 50]

[0383] Figure 44 shows the PXRD patterns obtained from milling Fluorospar and KNO3 at 35 Hz for 3 hours. Table 6.3.7 shows the PXRD data from milling Fluorospar and KNO3 shown in Figure 44. The labels in Figure 44 indicate the crystalline phases of KNO3 and CaF2.

[0384] [Table 51]

[0385] Figure 45 shows the PXRD pattern obtained from milling Fluorospar and KOH at 35 Hz for 3 hours. Table 6.3.8 shows the PXRD data from the milling of Fluorospar and KOH shown in Figure 45. The labels in Figure 45 indicate the crystalline phases of Ca(OH)2, KCaF2, and CaF2.

[0386] [Table 52]

[0387] Figure 46 shows the PXRD pattern obtained from milling Fluorospar and NaOH at 35 Hz for 3 hours. Table 6.3.9 shows the PXRD data from the milling of Fluorospar and NaOH shown in Figure 46. The labels in Figure 46 indicate the crystalline phases of Ca(OH)2, NaF, CaF2, and unidentified amorphous material.

[0388] [Table 53]

[0389] [7. Fluorination using fluorapatite] 7.1. SF Bond Formation Using Fluorapatite in the Solid State In some cases, fluorapatite was used in combination with K3PO4 to fluorinate TsCl in the solid state via ball milling as shown in Scheme 7.1.1, and the results can be found in Table 7.1. Briefly, various ratios of fluorapatite (Ca5(PO4)3F, 5 equivalents) and K3PO4 were milled for 1 hour at 30 Hz in a 15 mL stainless steel jar using 7 g balls. TsCl was added and milled for an additional hour at 30 Hz to obtain the fluorinated product (see Table 7.1 for yields). The grain size of the fluorapatite used was approximately 0.06-0.19 inches. The solid state reaction resulted in a yield of organofluorine product (TsF) of 5% or less.

[0390] [ka]

[0391] [Table 54]

[0392] 7.2. SF Bond Formation Using Fluorapatite in the Solid State and in Solution Fluorinated reagent was made using fluorapatite (Ca5(PO4)3F) (approximately 0.06-0.19 in) in combination with K2HPO4 as shown in Scheme 7.2.1 via ball milling under various conditions as shown in Table 7.2. Specifically, fluorapatite (4 equiv.) was milled with K2HPO4 (20 equiv.) for 3 h at various frequencies, jar loadings (mg / mL), and jar sizes (mL). The resulting powdered reagent was reacted with p-TolSO2-Cl (TsCl) (1 equiv.) in tBuOH (0.25 M) solution at 100 °C for 5 h to obtain the fluorinated product, TsF. The yields of the fluorinated product and starting material, TsCl, can be found in Table 7.2. The results indicate that the jar loading can affect the ball milling / fluorination yield and that a higher frequency can be beneficial to the yield. The results also highlight that the solution reaction of fluorapatite-K2HPO4 fluorination reagent with TsCl can result in higher yields of fluorinated product (TsF) than seen in the solid-state reaction of Example 7.1.

[0393] [ka]

[0394] [Table 55]

[0395] (7.3. Activator Screening Using Fluorapatite) Various activators were used in combination with fluorapatite to test their effectiveness in forming fluorinated reagents. The resulting fluorinated reagents, "Fluoromix," were examined as fluorinated reagents via reaction with p-TolSO2-Cl (TsCl) using 4-fluoroanisole as an internal standard. 19 The yield of TsF was determined via F NMR. The reaction was carried out as shown in Scheme 7.3.1.

[0396] [ka]

[0397] Briefly, fluorapatite (1 equiv.) was milled with activator (see Table 7.3) in a 15 mL stainless steel jar using a 7 g ball at 30 Hz for 3 hours to produce fluoromix. Fluoromix (0.2 mmol) was added to p-TolSO2-Cl (1.0 equiv., 0.05 mmol) and PhCl solution (0.25 M) and reacted at 100 °C for 5 hours to form the fluorinated product, TsF. The TsF yield and by-product yield can be found in Table 7.3. Successful fluorination of the TsCl starting material may depend on the activator used, although exemplary activators KCl+K2HPO4 or potassium pyrophosphate may allow for successful fluorination.

[0398] [Table 56]

[0399] 7.4. Changes in the stoichiometry of fluorinapatite fluorination To determine the change in fluorination yield using fluorapatite, various conditions were investigated, including changing the stoichiometry between fluorapatite, phosphate activator, and TsCl, as well as changing the reaction time, as shown in Schemes 7.4.1-7.4.3.

[0400] [ka]

[0401] In all conditions, fluorapatite was first milled with phosphate activator and then reacted in solution phase with TsCl (p-TolSO2-Cl). As shown in Scheme 7.4.1, when fluorapatite (2 equiv.) was milled with 2 equiv. of phosphate activator followed by solution phase reaction with 0.05 mmol. of TsCl, the yield of TsF was 81%. When 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 yield of TsF was 78%. Finally, when fluorapatite (1.2 equiv.) was milled with 1.2 equiv. of phosphate followed by solution phase reaction with 0.25 mmol. of TsCl for 10 min, the yield of TsF was 74%. The yields of organofluorine products indicate that pyrophosphate activators in conjunction with 18-crown-6 can be an exemplary combination to achieve high organofluorination yields.

[0402] 7.5. Reaction scope of fluorinapatite fluorination As shown in Scheme 7.5.1, fluorapatite was milled with phosphate activator to form the fluorinated reagent, which was then reacted in solution phase with a range of RSO2-Cl substrates to form RSO2-F (see Figure 47). Figure 47 shows the resulting reactant and fluorinated product yields ranging from 12% to 79%. The reaction was carried out as follows: fluorapatite (1.2 equiv.) was milled with phosphate activator (1.2 equiv.) in a 30 mL stainless steel jar using 1 x 16 g balls at 30 Hz for 9 hours. The resulting powdered reagent was reacted with RSO2-Cl substrate (1.0 equiv., 0.25 mmol) in solution phase in t-AmOH (0.25 M) along with 18-crown-6 and 12 equiv. of HO at 100 °C for 10 minutes to give the fluorinated product. The results show that pyrophosphate activator in addition to 18-crown-6 can be used with fluorapatite as the fluorinating agent to fluorinate a wide variety of substrates, including aliphatic and aromatic substrates.

[0403] [ka]

[0404] 7.6. Mechanistic insight into fluorapatite mechanochemical reactions by PXRD The mechanism of the mechanochemical reaction between fluorapatite (Ca5(PO4)3F) and K4P2O7 was investigated through the formation and analysis of products A-D followed by addition and mill grinding as shown in Scheme 7.6.1.

[0405] [ka]

[0406] Figure 48 shows the stacked PXRD patterns of products A, B, C, and D, where the circles represent the fluorapatite starting material and the crosses represent new species. The data show the consumption of crystalline fluorapatite and the formation of new crystalline species by mechanochemical reaction with potassium pyrophosphate over the course of the reaction. Products C and D show no fluorapatite starting material, while samples A and B have the Ca5(PO4)3F starting material present.

[0407] The PXRD pattern of pure fluorapatite after 1 hour of milling overlaid with K4P2O7 (4 equivalents) and a fluorapatite sample (1 equivalent) milled at 35 Hz for a total of 12 hours is shown in Figure 49. The results indicate consumption of fluorapatite by mechanochemical reaction with potassium pyrophosphate.

[0408] Figure 50 shows a comparison of the PXRD patterns for the reaction between fluorapatite (Ca5(PO4)3F) and K4P2O7 in a 1:4 equivalent milling reaction (D) and the milling reaction between potassium fluoride (KF, 1 equivalent) and K2HPO4 (2 equivalents, 35 Hz, 3 hours) followed by CaHPO4 (1 equivalent, 35 Hz, 3 hours) as shown in Scheme 7.6.2. The resulting patterns show that Y (Y=K 2-x Ca y (PO3F) a (PO4) b F c ) may indicate a structure of D similar to one of the components of the crystalline phase of Y. The peaks with 2-theta values ​​higher than those observed in the PXRD of the crystalline phase of Y may indicate a structure of D similar to one of the components of the crystalline phase of Y, 2+ , K+ , F - , or PO4 3- This is consistent with a structure closely related to Y having the formula:

[0409] [ka]

[0410] Product D from Scheme 7.6.1 was washed with water and separated into H2O insoluble and H2O soluble components. Figure 51 shows the PXRD data of the water insoluble component and compares it to a crystalline reference pattern, in this case pure milled Ca5(PO4)3F (fluorapatite). The PXRD pattern of the water insoluble product can be matched to either Ca5(PO4)3F or Ca5(PO4)3OH.

[0411] 7.7. Fluorapatite activation using potassium pyrophosphate Fluorapatite activation was tested using 1 equivalent of potassium pyrophosphate (K4P2O7) and the milling reaction was monitored via PXRD. The milling reaction proceeded as shown in Scheme 7.7.1, where 1 equivalent of fluorapatite (Ca5(PO4)3F) was milled with 1 equivalent of K4P2O7 and 16 g balls in a 30 mL stainless steel jar at 30 Hz for 9 hours. Figure 52 and Table 7.7.1 show the PXRD data indicating the presence of crystalline phases of Ca5(PO4)3F and an unidentified amorphous phase. No crystalline potassium pyrophosphate was observed by PXRD.

[0412] [ka]

[0413] [Table 57]

[0414] As another example, crystalline fluorapatite was milled (1 equivalent) with 4 equivalents of potassium pyrophosphate as shown in Scheme 7.7.2. Briefly, fluorapatite was milled with 1 equivalent of potassium pyrophosphate at 35 Hz for 3 hours, then a second equivalent was added, followed by milling at 35 Hz for 3 hours, and this was repeated until a total of 4 equivalents of potassium pyrophosphate had been added, followed by milling with fluorapatite. The resulting product was analyzed by PXRD as shown in Figure 53 and Table 7.7.2. The PXRD showed that K 2-x Ca y (PO3F) a (PO4) b F c This was consistent with an unidentified crystalline phase that is isostructural with .

[0415] [ka]

[0416] [Table 58]

[0417] (7.8. Fluorapatite and Fluorospar Activated) The activation of fluorapatite and fluorospar with K4P2O7 (4 equiv.) and K2HPO4 (2.5 equiv.), respectively, was compared via PXRD as shown in Figure X. The activation reactions were completed as shown in Schemes 7.8.1 and 7.8.2.

[0418] [ka]

[0419] [8. Alternative mechanochemical procedures: twin screw extruder & planetary ball mill] 8.1. Materials and Abbreviations A Thermofisher Process 11 twin screw extruder was fitted with a gravimetric single screw feeder (hopper) for programmed solids addition. No pressure die was fitted to the twin screw extruder for these experiments. Extrudite refers to the processed material exiting the end of the extruder. CaF2 (97% reagent grade) was purchased from Alfa Aesar and used as received. K2HPO4 (anhydrous, 98%) was purchased from Acros Organics and used as received. The screw configuration is shown on each graph and consists of a conveying "C" element, a kneading "K" element, and a reverse "R" element. Multiple individual elements make up a "section". Additionally, the kneading section is further divided by rotation from the previous element, which can be 30°, 60° or 90°. F R = feed rate of solids to the extruder. S S = screw speed with co-rotating stainless steel screw. S T = screw temperature, each of the six segments can be heated to individual temperatures, which are specified if used. T R = Residence time measured from the time when solids first drop into the twin screw extruder to the time when solids are first observed at the exit.

[0420] (8.2. General Procedure for Twin Screw Extrusion) A 100 mL conical flask was charged with CaF2 (3.12 g, 40 mmol) and K2HPO4 (6.97 g, 40 mmol). The solids were mixed loosely with a spatula and then charged into the single screw feeder. At this point, the associated feed rate (F R ), screw speed (S S ), and screw temperature (S T) was programmed into the twin screw extruder. The extruder was turned on, followed quickly by the hopper. A 50 mL collection beaker was placed at the exit of the screw. After observing the first appearance of solids coming out of the exit, the beaker was used to collect the first approximately 200 mg. Following this, the collection beaker was replaced and the "fluoromix" extrudate was collected. This was continued until the amount of collection slowed significantly. At this point, the beaker was replaced again to allow the first beaker to collect the remaining extrudate. The "fluoromix" was then weighed (usually about 7 grams). The material was decanted into a vial and stored under vacuum overnight.

[0421] 8.3. Varying Screw Temperature on Formation of Active Fluorinated Materials According to the general procedure outlined above (Example 8.2), the screw temperature (S T The effect of temperature, S T The temperature was varied between 25°C and 200°C, and the screw speed was 50 rpm. The residence time was 100 s. The resulting "fluoromix" was reacted with TsCl in solution in tBuOH (0.25 M) at 100°C for 5 h to form the fluorinated product, TsF. The screw temperature, the resulting fluorinated product, TsF yield, and the starting material yield, TsCl can be seen in Table 8.3. The results can show that a lower screw temperature can help achieve a higher yield of the organofluorine product (e.g., TsF) and a lower yield of the starting material (e.g., TsCl).

[0422] [Table 59]

[0423] 8.4. Varying Screw Speed ​​on Production of Active Fluorinated Materials Following the general procedure outlined above (Example 8.2), the screw speed (S SThe effect of the residence time (T) was investigated. Figure 55 shows a general scheme for reacting CaF2 (40 mmol) with K2HPO4 (40 mmol) to form an active fluorinated material. The rotation 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 the feed rate was 10 g / min. The resulting active fluorinated material, "Fluoromix", was reacted with TsCl in tBuOH solution (0.25 M) at 100°C for 5 hours to form the fluorinated product. The rotation speed (S S ), residence time (T R ), product yield (TsF), and starting material yield (TsCl) can be seen in Table 8.4. The results can show that the screw speed and residence time can not significantly affect the yield of the resulting organofluorine product (e.g., TsF).

[0424] [Table 60]

[0425] 8.5. Change in Number of Recycles Through the Extruder on Generation of Active Fluorinated Species Following the general procedure outlined above (Example 8.2), in this example the solids were fed into the twin screw extruder by spatula (without using a hopper) and at the end of the screwing process the extrudate was added (e.g. recycled) several more times to the extruder. This serves to impart the same amount of mechanical force but to increase the residence time. The effect of extrudate recycling was investigated via the scheme seen in Figure 56. Figure 56 shows a general scheme by which CaF2 (40 mmol) and K2HPO4 (40 mmol) can be reacted to form active fluorinated species. In this example, 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 was recycled into the extruder once, twice or three times, the results of which can be seen in Table 8.5. The resulting "fluoromix" was reacted in solution (0.25 M tBuOH) with 1 equivalent of TsCl at 100 °C for 5 hours to form the fluorinated product. The resulting fluorinated product yields, TsF, and starting material yields, TsCl, can also be seen in Table 8.5. These results indicate that increasing the number of recycles can result in higher yields of organofluorine products (e.g., TsF) and lower yields of starting materials (e.g., TsCl).

[0426] [Table 61]

[0427] 8.6. Extrusion of CaF2 in the Absence of K2HPO4 Following the general procedure outlined above (Example 8.2), in this example, CaF2 was fed into a twin-screw extruder in the absence of K2HPO4. Figure 57 shows a general scheme of adding CaF2 (40 mmol) to a twin-screw extruder with variable feed rate, screw speed of 50 rpm, screw temperature of 25°C, and residence time of 100 seconds. The resulting extruded "CaF2" was reacted with TsCl (1 eq.) in 0.25 M tBuOH solution with added K2HPO4 (4 eq.) and reacted at 100°C for 5 hours to form the fluorinated product, TsF. As a result, when CaF2 was not extruded in the presence of K2HPO4, the TsF yield was 6% and the TsCl yield was 58%. Under mechanical force and in the absence of ionic salts in a mechanochemical process, CaF2 can be activated to provide fluoride in the conversion of p-toluenesulfonyl chloride to p-toluenesulfonyl fluoride.

[0428] 8.7. Investigation into changes in screw configuration Following the general procedure outlined above (Example 8.2), in this example a screw configuration (Configuration 1) is outlined as shown in Figure 58. The effect of screw configuration 1 was analyzed. Figure 58 shows the effect of screw configuration 1 on the 2 g min -1 A general scheme is shown for the addition of CaF2 (40 mmol) and K2HPO4 (40 mmol) to a twin screw extruder with a feed rate of 1000 rpm, a screw speed of 50 rpm, a screw temperature of 25 °C, and a residence time of 40 seconds. An alternative configuration was also investigated (screw configuration 2). Screw configuration 2 was "C-(30-60-90)-C-(60)-C-(60-90)-C" and screw configuration 1 was "C-90-C-60-C-90-C". The resulting "fluoromix" was reacted with TsCl (1 equiv.) in tBuOH solution (0.25 M) at 100 °C for 5 h to form the resulting fluorinated product, TsF. Utilizing screw configuration 1, the yield of fluorinated product, TsF, was 20% and the yield of starting material, TsCl, was 40%. Utilizing additional alternative screw configurations can be useful to increase and / or tailor the yield of organofluorine products (e.g., TsF).

[0429] (8.8. Planetary Mill) A Fritsch Pulverisette planetary mill was used. Zirconia jars (12 mL) and zirconia balls (3.4 g) were used for the milling experiments. The zirconia jar was charged with fluorospar (312 mg, 4 mmol) and K2HPO4 (697 mg, 4 mmol) and one or two 3.4 g zirconia balls. The jar was sealed and attached to the planetary mill. The mill was set at 800 rpm, 15 min milling sessions, 11 repetitions (12 in total), with a 2 min gap between each session, and the milling direction was reversed after each session. After this, the material was scraped out of the vial and added to a vial that was stored under vacuum overnight before use. Scheme 8.8.1 shows the general scheme for milling CaF2 (4 equiv.) with 4 equiv. of K2HPO4 through a planetary mill. The resulting powder was reacted with TsCl (1 equiv.) in tBuOH solution (0.25 M) at 100° C. for 5 h. When one ball was used for milling, the yield obtained was 12% TsF (72% TsCl starting material). When two balls were used for milling, the yield obtained was 11% TsF (76% TsCl starting material). Thus, the planetary mill can be useful for the preparation of fluorination reagents containing CaF2 and activators (e.g., K2HPO4).

[0430] [ka]

[0431] Although specific embodiments of the present invention have been described herein for purposes of reference and example, various modifications will be apparent to those skilled in the art without departing from the scope of the invention, which is defined by the appended claims.

[0432] The project leading to this application has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 832994).

Claims

1. 1. A method for preparing a fluorination reagent, comprising the steps of: a) grinding together in the solid state a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite, and an ionic compound; Including, The anion of the ionic compound is Ca ２＋ It can bind to 2450 KJ mol －１ forming a calcium salt having a higher lattice energy.

2. The method of claim 1 , wherein the ionic compound is a salt.

3. 3. The method of claim 1 or 2, wherein the ionic compound is a phosphate, carbonate or sulfate.

4. 4. The method of claim 1, 2 or 3, wherein the ionic compound is an alkali metal salt or an alkaline earth metal salt.

5. The method according to any one of claims 1 to 4, wherein the ionic compound is a potassium or sodium phosphate, sulfate or carbonate.

6. The method according to any one of claims 1 to 5, wherein the ionic compound is a potassium or sodium phosphate.

7. The ionic compound is K ３ P.O. ４ , K ２ H.P.O. ４ , K.H. ２ P.O. ４ , Na ３ P.O. ４ , Na ２ H.P.O. ４ , K.P.O. 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 , K.H.S.O. 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 , K.N.O. ３ , Na ３ C ６ H ５ O ７ 2. The method of claim 1, wherein the aqueous solution is selected from the group consisting of NaOH and KOH.

8. The ionic compound is K ２ H.P.O. ４ , K.P.O. ３ , Na ２ H.P.O. ４ , K ４ P ２ O ７ , K ５ P ３ O １０ and Na ４ P ２ O ７ The method of claim 1 , wherein the compound is selected from the group consisting of:

9. The ionic compound is K ３ P.O. ４ Or K ２ H.P.O. ４ The method of claim 1, wherein

10. 10. The method of any one of claims 1 to 9, wherein greater than 50 wt.% of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a).

11. 11. The method of any one of claims 1 to 10, wherein greater than 95 wt. % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom remain in a solid state throughout step a).

12. The process according to any one of claims 1 to 11, wherein step a) is carried out in the absence of a solvent.

13. The method according to any one of claims 1 to 12, wherein step a) is a mechanochemical process.

14. The method according to any one of claims 1 to 13, wherein step a) is carried out in a ball mill, a pestle and mortar or a twin screw extruder.

15. The method according to any one of claims 1 to 14, wherein step a) is carried out in a ball mill.

16. 16. The method of any one of claims 1 to 15, wherein the ionic compound is milled together with the fluorine-containing compound in portions.

17. 17. The method of claim 16, wherein step a) comprises: (a-i) grinding together the fluorine-containing compound and a first portion of the ionic compound; and (a-ii) grinding together the product of step (a-i) and a second portion of the ionic compound.

18. 1. A method for preparing a fluorochemical, comprising the steps of: a) preparing a fluorination reagent according to any one of claims 1 to 17; b) contacting the organic substrate with said fluorinating reagent; Including, The method, wherein step b) is performed simultaneously with step a) or after step a).

19. 20. The method of claim 18, wherein the organic substrate is aromatic or aliphatic and contains at least one leaving group located at the site to be fluorinated.

20. 20. The method of claim 18 or 19, wherein the organic substrate is a sulfonyl halide, aryl halide, alkylaryl halide, acyl halide, α-halocarbonyl or alkyl halide.

21. 20. The method of claim 18 or 19, wherein the organic substrate is a sulfonyl halide, an acyl halide, an aryl halide or an alkyl halide.

22. 21. The method of claim 18, 19 or 20, wherein the organic substrate is an aromatic sulfonyl 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).

23. The organic substrate is 500 g mol －１ The method of any one of claims 18 to 22, wherein the molecular weight is less than

24. 24. The method of any one of claims 18 to 23, wherein step b) is carried out simultaneously with step a), and step b) comprises contacting said organic substrate with said fluorinating reagent under conditions identical to those used to form said fluorinating reagent.

25. 24. The method of any one of claims 18 to 23, wherein step b) is carried out after step a), and step b) comprises grinding the organic substrate and the fluorinating reagent formed from step a) together in the solid state.

26. 24. The method of any one of claims 18 to 23, wherein step b) is carried out after step a), and step b) comprises mixing said organic substrate and said fluorinating reagent together in one or more solvents in which said organic substrate is soluble.

27. 27. The method of claim 26, wherein step b) is carried out in one or more solvents selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 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.

28. 27. The method of claim 26, wherein step b) is carried out in one or more solvents 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.

29. 21. The method of claim 20, wherein step b) is carried out in acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol or water.

30. 30. The method of any one of claims 27, 28 and 29, wherein any one or more of the organic solvents is miscible with water.

31. The method of claim 30, wherein the organic solvent is optionally miscible with water at a concentration of 0.01 to 5M.

32. The method according to any one of claims 18 to 31, wherein step b) is carried out in the presence of at least one of a cryptand, a crown ether and a hydrogen bonding phase transfer catalyst.

33. 1. A method for preparing a fluorochemical, comprising the steps of: a) grinding in the solid state a fluorine-containing compound, which is at least one of calcium fluoride and fluorapatite; b) contacting the product of step a) with an organic substrate; Including, The method, wherein step b) is performed simultaneously with step a) or after step a).

34. 1. Use of a fluorine-containing compound, at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical or fluorinating reagent, said process not including a step of reacting said calcium fluoride with sulfuric acid to produce hydrofluoric acid.

35. A fluorinating reagent obtained, directly obtained or obtainable by the method according to any one of claims 1 to 17.

36. 36. The fluorination reagent of claim 35, comprising a mixture of inorganic salts.

37. 37. The fluorination reagent of claim 35 or 36, comprising calcium, fluorine and oxygen, and (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur, nitrogen and carbon.

38. The present invention relates to a mixture of inorganic salts, the mixture comprising a first inorganic salt and a second inorganic salt, (i) the first inorganic salt being 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 K. ＋ and Na ２＋ 38. The fluorinating reagent of claim 35, 36 or 37, comprising at least one cation selected from:

39. 39. A fluorination reagent according to any one of claims 35 to 38, having an XRPD pattern comprising peaks at ±0.2° 2θ corresponding 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 to 5.7.11 and 5.12.1 outlined herein.

40. 39. The fluorination reagent of any one of claims 35 to 38, having an XRPD pattern including peaks at 2theta values ​​of 21.9±0.2 degrees 2θ, 30.3±0.2 degrees 2θ, 31.6±0.2 degrees 2θ, and 43.4±0.2 degrees 2θ.

41. 17.5±0.2°2θ, 21.2±0.2°2θ, 23.5±0.2°2θ, 24.8±0.2°2θ, 29.4±0.2°2θ, 29.6±0.2°2θ, 30.5±0 .2°2θ, 31.5±0.2°2θ, 36.7±0.2°2θ, 37.4±0.2°2θ, 42.9±0.2°2θ, 4 39. The fluorination reagent of any one of claims 35-38, which can have an XRPD pattern including one or more peaks at 2-theta values ​​of 7.1±0.2 degrees 2θ, 48.1±0.2 degrees 2θ, 51.4±0.2 degrees 2θ, 53.2±0.2 degrees 2θ, 54.2±0.2 degrees 2θ, 58.2±0.2 degrees 2θ, 60.9±0.2 degrees 2θ, and 63.4±0.2 degrees 2θ.

42. K ３ (H.P.O. ４ ) F and comprising one or more peaks at 2-theta values ​​of 21.1±0.2°2θ, 29.6±0.2°2θ, 30.5±0.2°2θ, 37.4±0.2°2θ, 42.9±0.2°2θ, 54.2±0.2°2θ, 58.2±0.2°2θ, and 60.9±0.2°2θ.

43. a first salt comprising calcium and fluorine; Ca ２＋ and a second salt containing an anion having a lattice energy greater than 2450 KJ / mol when combined with the third salt. An activated fluorination reagent comprising: An activated fluorinated reagent, wherein the powder X-ray diffraction spectrum of the activated reagent contains characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and / or 43.4°.

44. 1. A method for synthesizing a fluorinated compound, comprising the steps of: The first salt containing calcium and fluorine is ２＋ with a second salt comprising an anion having a lattice energy greater than 2450 KJ / mol when combined with said anion to form a third salt to form a salt mixture; applying a mechanical force to the salt mixture to form an activated salt mixture; combining the activation salt mixture with a first reactant comprising an organic compound; fluorinating the first reactant to obtain the fluorinated compound; A method comprising:

45. 1. A method for fluorinating a reactant, comprising the steps of: combining with the reactants an activated fluorination reagent whose powder X-ray diffraction spectrum includes characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and / or 43.4°; fluorinating the reactants to form fluorinated compounds; The method includes:

46. 1. A method for producing an activated fluorination reagent, comprising the steps of: The first salt containing calcium and fluorine is ２＋ with a second salt comprising an anion having a lattice energy greater than 2450 KJ / mol when combined with said anion to form a third salt to form a salt mixture; applying a mechanical force to the salt mixture to obtain the activated fluorination reagent; A method comprising:

47. 1. A method for recovering fluorine from a waste material to form an activated fluorination reagent, comprising: The waste material containing a first salt containing calcium and fluorine is treated with Ca ２＋ with a second salt comprising an anion that has a lattice energy greater than 2450 KJ / mol when combined with said anion to form a third salt to form a salt-waste mixture; applying a mechanical force to the salt-waste mixture to obtain the activated fluorination reagent; A method comprising:

48. 45. The method of claim 43 or 44, wherein the fluorinated compound is an organofluorine compound.

49. 45. The method of claim 43 or 44, wherein the first reactant, or said reactants, are fluorine-free prior to being used in the method.

50. The first salt is CaF ２ 44. The activated fluorination reagent of claim 43, 48. The method according to any one of claims 44 to 47.

51. The first salt is fluorapatite (Ca ５ (P.O. ４ ) ３ F) an activated fluorination reagent according to claim 43; or 48. The method according to any one of claims 44 to 47.

52. 44. The activated fluorination reagent of claim 43, wherein the second salt is a metal hydroxide (e.g., NaOH or KOH).

48. The method according to any one of claims 44 to 47.

53. The second salt is a metal sulfite (e.g., Na ２ SO ３ Or K ２ SO ３ 44. The activated fluorination reagent of claim 43, 48. The method according to any one of claims 44 to 47.

54. The second salt is a metal sulfate (e.g., KHSO ４ 44. The activated fluorination reagent of claim 43, 48. The method according to any one of claims 44 to 47.

55. The second salt is an inorganic phosphate salt (e.g., K ２ H.P.O. ４ , K.H. ２ P.O. ４ , K ３ P.O. ４ 44. The activated fluorination reagent of claim 43, 48. The method according to any one of claims 44 to 47.

56. The inorganic phosphate is pyrophosphate (e.g., K ４ P ２ O ７ or Na ３ P ２ O ７ 56. The activated fluorination reagent or method of claim 55, wherein

57. The second salt is a carbonate (e.g., CaCO ３ , H ２ CO ３ , K ２ CO ３ , or Na ２ CO ３ 44. The activated fluorination reagent of claim 43, 48. The method according to any one of claims 44 to 47.

58. 44. The activated fluorinated reagent of claim 43, wherein the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and / or 53.9°.

48. The method according to any one of claims 44 to 47.

59. 2θ reflections 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 / or 53.9°.

60. 60. The activated fluorination reagent or method of any one of claims 43-59, wherein the powder X-ray diffraction spectrum of the activated reagent comprises at least three characteristic 2θ 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°.

61. 61. The activated fluorination reagent or method of any one of claims 43-60, wherein the powder X-ray diffraction spectrum of the activated reagent comprises at least four characteristic 2θ 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°.

62. 62. The activated fluorination reagent or method of any one of claims 43 to 61, wherein the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and 43.4°.

63. 63. The activated fluorination reagent or method of any one of claims 43-62, wherein the powder X-ray diffraction spectrum of the activated reagent comprises characteristic 2θ 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°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and 53.9°.

64. 64. The activated fluorination reagent or method of any one of claims 43 to 63, wherein the ratio of the first salt to the second salt is from about 1:0.5 to 1:

100.

65. 65. The activated fluorination reagent or method of any one of claims 43 to 64, wherein the ratio of the first salt to the second salt is about 1:1 to 1:

10.

66. 66. The activated fluorination reagent or method of any one of claims 43 to 65, wherein the ratio of the first salt to the second salt is about 1:1 to 1:

5.

67. 67. The activated fluorination reagent or method of any one of claims 43 to 66, wherein the ratio of the first salt to the second salt is about 1:

1.

68. 68. The activated fluorination reagent or method of any one of claims 43 to 67, wherein the ratio of the first salt to the second salt is about 1:

2.

69. 69. The activated fluorination reagent or method of any one of claims 43 to 68, wherein the ratio of the first salt to the second salt is about 1:

3.

70. 70. The activated fluorination reagent or method of any one of claims 43 to 69, wherein the ratio of the first salt to the second salt is about 1:

5.

71. 71. The activated fluorination reagent or method of any one of claims 43, 45, or 47-70, wherein each of the characteristic 2θ reflections has a relative intensity of at least 1% when normalized to the maximum peak.

72. 71. The activated fluorination reagent or method of any one of claims 43, 45, or 47-70, wherein each of the characteristic 2θ reflections has a relative intensity of at least 5% when normalized to the maximum peak in a background-subtracted X-ray powder diffraction spectrum (e.g., a spectrum from which peaks corresponding to at least the first and second salts have been subtracted).

73. 72. The method of any one of claims 44 to 71, wherein the mechanical force is applied using a ball mill, a mortar and pestle, a twin screw extruder, using an ultrasonic bath, an acoustic mixer, and / or a mechanical press.

74. 74. The method of claim 73, wherein the mechanical press comprises a jaw crusher.

75. 74. The method of claim 73, wherein the ball mill comprises a vibratory mill, a planetary mill, a drum mill, and / or an attritor mill.

76. 74. The method of any one of claims 44 to 73, which does not include the step of reacting a strong acid with the first salt to form hydrofluoric acid.

77. 77. The method of any one of claims 44 to 76, wherein essentially no HF is produced during the reaction (e.g., less than 1 ppm or less than 1 ppb of HF is observable in the mixture at any time during the reaction).

78. 78. The method of any one of claims 44 to 77, wherein the mechanical force is applied at a frequency of about 0.5 Hz to 60 kHz.

79. 79. The method of any one of claims 44 to 78, wherein the mechanical force is applied at a frequency of about 10 Hz to 20 kHz.

80. 79. The method of any one of claims 44 to 78, wherein the mechanical force is applied at a frequency of about 30 Hz.

81. 79. The method of any one of claims 44 to 78, wherein the mechanical force is applied at a frequency of about 35 Hz.

82. 79. The method of any one of claims 44 to 78, wherein the mechanical force is applied at a frequency of about 60 Hz.

83. The method of any one of claims 44 to 82, wherein the mechanical force is applied at a temperature of about -20 to 300°C.

84. 84. The method of any one of claims 44 to 83, wherein the mechanical force is applied at a temperature of about -20 to 100°C.

85. 85. The method of any one of claims 44 to 84, wherein the mechanical force is applied at a temperature of about 20 to 90°C.

86. 85. The method of any one of claims 44 to 84, wherein the mechanical force is applied at a temperature of about 30°C.

87. The method of any one of claims 44 to 84, wherein the mechanical force is applied at a temperature of about 60°C.

88. The method of any one of claims 44 to 84, wherein the mechanical force is applied at a temperature of about 90°C.

89. 89. The method of any one of claims 44 to 88, wherein the first salt and the second salt are combined as solids without the addition of a solvent.

90. 90. The method of any one of claims 44-45 or 48-89, wherein the organic compound is aromatic or aliphatic and contains at least one leaving group (e.g., halo) located at the site to be fluorinated.

91. 91. The method of any one of claims 44-45 or 48-90, wherein the organic compound is a sulfonyl halide, an acyl halide, an aryl halide or an alkyl halide.

92. 92. The method of any one of claims 44-45 or 78-91, wherein the organic compound is an aromatic sulfonyl 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).

93. 93. The method of any one of claims 44-45 or 48-92, wherein the first salt, second salt, and organic compound are combined in the same step.

94. 93. The method of any one of claims 44-45 or 48-92, wherein the first salt and the second salt are combined prior to the addition of the organic compound.

95. 95. The method of any one of claims 44-45 or 48-94, wherein the first salt, the second salt, and the organic compound are added together with one or more solvents, and the organic compound is soluble in at least one of the one or more solvents.

96. 96. The method of any one of claims 44-45 or 48-95, wherein 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 organic solvents are optionally miscible with water.

97. 97. The method of any one of claims 44-45 or 48-96, wherein the one or more solvents comprise acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol and / or water.

98. 98. The method of any one of claims 44-45 or 48-97, wherein the one or more solvents comprise a phase transfer agent (e.g., a cryptand, a crown ether and / or a hydrogen bonding phase transfer agent).

99. 99. The method of any one of claims 44-45 or 48-98, wherein the fluorination reaction is carried out at a temperature of about 20-300°C.

100. 100. The method of any one of claims 44-45 or 48-99, wherein the fluorination reaction is carried out at a temperature of about 20-100°C.

101. 101. The method of any one of claims 44-45 or 48-100, wherein the fluorination reaction yield of the organic fluorine compound is at least about 10% (measured based on the starting amount of the organic compound).

102. 102. The method of any one of claims 44-45 or 48-101, wherein the fluorination reaction yield is at least about 30% (measured based on the starting amount of the organic compound).

103. 103. The method of any one of claims 44-45 or 48-102, wherein the fluorination reaction yield is at least about 50% (measured based on the starting amount of the organic compound).

104. 104. The method of any one of claims 44-45 or 48-103, wherein the fluorination reaction yield is at least about 80% (measured based on the starting amount of the organic compound).

105. 105. The method of any one of claims 44 to 45 or 48 to 104, wherein the fluorination reaction is a monofluorination reaction.

106. The method of any one of claims 44 to 45 or 48 to 105, wherein the fluorination reaction is a difluorination reaction.

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