FLUORINATION PROCESSES

Abstract

A process for preparing a fluorinating reagent from a calcium-containing compound is disclosed. The process bypasses the requirement to form hydrofluoric acid. The fluorinating reagent can be used to prepare high-value fluorochemicals.

Claims

1. A method of manufacturing an activated fluorination reagent, the method comprising: combining a first salt, the first salt comprising calcium and fluorine, with a second salt, the second salt comprising an anion, which said anion when combined with Ca.sup.2+ to form a third salt has a lattice energy greater than 2450 KJ/mol, to form a salt mixture; and applying mechanical force to the salt mixture to yield the activated fluorination reagent.

2. The method of claim 1, wherein the first salt is CaF.sub.2 or Ca.sub.5(PO.sub.4).sub.3F.

3. The method of claim 1, wherein the second salt is a metal hydroxide, a metal sulphite, a metal sulphate, a carbonate, or an inorganic phosphate.

4. The method of claim 3, wherein the inorganic phosphate is a pyrophosphate.

5. The method of claim 1, wherein a ratio of the first salt to the second salt is about 1:0.5 to 1:100.

6. The method of claim 5, wherein the mechanical force is applied using a ball mill, a mortar and pestle, a twin-screw extruder, using an ultrasonic bath, a resonant acoustic mixer, and/or a mechanical press.

7. The method of claim 6, wherein the mechanical press comprises a jaw crusher.

8. The method of claim 6, wherein the ball mill comprises a vibratory mill, a planetary mill, a drum mill, and/or an attritor mill.

9. The method of claim 6, wherein the method does not comprise reacting a strong acid with the first salt to form hydrofluoric acid.

10. The method of claim 9, wherein <1 ppm of HF is produced at any point during the reaction.

11. The method of any of claim 10, wherein the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz.

12. The method of any of claim 11, wherein the mechanical force is applied at a temperature of about −20-100° C.

13. The method of claim 1, further comprising combining the activated fluorination reagent, with a reactant; and fluorinating the reactant to produce a fluorinated compound.

14. The method of claim 13, wherein the fluorinated compound is an organo-fluorine compound.

15. The method of claim 13, wherein the activated fluorination reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and/or 43.4°.

16. The method of claim 13, wherein the reactant is an aromatic or aliphatic compound comprising at least one leaving group located at a site to be fluorinated.

17. The method of claim 16, wherein the leaving group is a halogen.

18. The method of claim 17, wherein a fluorination reaction yield of the organofluorine compound is at least about 10% measured based on a starting amount of the reactant.

19. The method of claim 18, wherein the fluorination reaction is a mono-fluorination reaction.

20. The method of claim 18, wherein the fluorination reaction is a di-fluorination reaction.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The novel features of the 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 “Figure” and “FIG.” herein), of which:

[0041] FIG. 1 shows possible manufacturing schemes of fluorochemicals from salts comprising fluorine.

[0042] FIG. 2 shows: Top: .sup.19F NMR in D20 of the fluorinating reagent derived from CaF.sub.2 and K.sub.2HPO.sub.4 under mechanochemical conditions. Bottom: .sup.19F NMR in D20 of the fluorinating reagent derived from CaF.sub.2 and K.sub.2HPO.sub.4 under mechanochemical conditions, following spiking with KF.

[0043] FIG. 3 shows the NMR yields (%) of TsF and TsCl when various phosphates were used as activators of Fluorspar.

[0044] FIG. 4 shows a PXRD diffractogram of the milling product of fluorspar and KH.sub.2PO.sub.4 after 3 hours at 35 Hz.

[0045] FIG. 5 shows a PXRD diffractogram of the milling product of fluorspar and K.sub.3PO.sub.4 after 3 hours at 35 Hz.

[0046] FIG. 6 shows a PXRD diffractogram of the milling product of fluorspar with Na.sub.3PO.sub.4 after 3 hours at 30 Hz.

[0047] FIG. 7 shows a PXRD diffractogram of the milling product of fluorspar with Na.sub.2HPO.sub.4 after 3 hours at 35 Hz.

[0048] FIG. 8 shows a PXRD diffractogram of the milling product of fluorspar with NaH.sub.2PO.sub.4 after 3 hours at 35 Hz.

[0049] FIG. 9 shows a PXRD diffractogram of the milling product of fluorspar with KPO.sub.3 after 3 hours at 35 Hz.

[0050] FIG. 10 shows a PXRD diffractogram of the milling product of fluorspar with K.sub.4P.sub.2O.sub.7 after 3 hours at 35 Hz.

[0051] FIG. 11 shows a PXRD diffractogram of the milling product of fluorspar with K.sub.5P.sub.3O.sub.10 after 3 hours at 35 Hz.

[0052] FIG. 12 shows a PXRD diffractogram of the milling product of fluorspar with Na.sub.4P.sub.2O.sub.7 after 3 hours at 35 Hz.

[0053] FIG. 13 shows a PXRD diffractogram of the milling product of fluorspar with Na.sub.5P.sub.3O.sub.10 after 3 hours at 35 Hz.

[0054] FIG. 14 shows a PXRD diffractogram of the milling product of fluorspar with Na(PO.sub.3).sub.3 after 3 hours at 35 Hz.

[0055] FIG. 15 shows a PXRD diffractogram of the milling product of fluorspar with CaHPO.sub.4 after 3 hours at 30 Hz.

[0056] FIG. 16 shows a PXRD diffractogram of the milling product of fluorspar with Ca.sub.3(PO.sub.4).sub.2 after 3 hours at 30 Hz.

[0057] FIG. 17 shows stacked PXRD diffractograms of the milling products of fluorspar after subsequent addition and milling at 30 Hz for 3 hours of K.sub.2HPO.sub.4 resulting in CaF.sub.2:K.sub.2HPO.sub.4 ratios of 1:1, 1:2, 1:2.5, and 1:3.

[0058] FIG. 18 shows the NMR yields of TsF from TsCl using fluorspar and K.sub.2HPO.sub.4 as an activator wherein the fluorspar and K.sub.2HPO.sub.4 are milled at different frequencies.

[0059] FIG. 19 shows the NMR yields of TsF from TsCl using fluorspar and varying amounts of K.sub.2HPO.sub.4 activator resulting in the use of different ratios of CaF.sub.2:K.sub.2HPO.sub.4. In A, 1 equivalent of K.sub.2HPO.sub.4 was added to fluorspar, in B, 2 equivalents total are added, and in C, 2.5 total equivalents of K.sub.2HPO.sub.4 are added.

[0060] FIG. 20 shows the NMR yields of TsF from TsCl using fluorspar and K.sub.2HPO.sub.4 as an activator with different amounts of water added to the fluorination reaction.

[0061] FIG. 21 shows the NMR yields of TsF from TsCl using fluorspar and K.sub.2HPO.sub.4 as an activator with different amounts of water added to the fluorination reaction and 5 hour or 18 hour reaction times.

[0062] FIG. 22 shows the fluorination substrate scope of R—SO.sub.2Cl species.

[0063] FIG. 23 shows the fluorination substrate scope of R—X species.

[0064] FIG. 24 shows .sup.19F NMR (24A) and .sup.31P NMR (24B) of the soluble product of milling of fluorspar and K.sub.2HPO.sub.4.

[0065] FIG. 25 shows the PXRD diffractogram of the milling product of fluorspar with K.sub.2HPO.sub.4 after 9 hours at 30 Hz referenced to crystalline KF (bottom).

[0066] FIG. 26 shows the PXRD diffractogram of the milling product (Fluoromix) of fluorspar reacted with K.sub.2HPO.sub.4.

[0067] FIG. 27 shows stacked PXRD diffractograms of (from top to bottom), fluorspar milled with K.sub.2HPO.sub.4 for 9 hours at 30 Hz, KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz, KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz followed by CaHPO.sub.4 for 3 hours at 30 Hz, and crystalline CaF.sub.2.

[0068] FIG. 28 shows the simulated crystal structure of the product of KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz (A) and KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz followed by CaHPO.sub.4 for 3 hours at 30 Hz, and crystalline CaF.sub.2 (B).

[0069] FIG. 29 shows stacked PXRD diffractograms of fluorspar, K.sub.2HPO.sub.4, and fluorapatite.

[0070] FIG. 30 shows overlayed PXRD diffractograms of fluoromix, KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz, KF milled with K.sub.2HPO.sub.4 for 3 hours at 30 Hz followed by CaHPO.sub.4 for 3 hours at 30 Hz, and crystalline CaF.sub.2, and fluorspar.

[0071] FIG. 31 shows the PXRD diffractogram of the water insoluble solid formed from the milling reaction of CaF.sub.2 (fluorspar) and K.sub.2HPO.sub.4.

[0072] FIG. 32 shows the PXRD diffractogram of water insoluble solid formed from the milling reaction of CaF.sub.2 (fluorspar) and K.sub.2HPO.sub.4 overlayed with the PXRD diffractogram of the milling product of fluorspar and CaHPO.sub.4 (32A) and the PXRD diffractogram of the product formed from the milling reaction of fluorspar and CaHPO.sub.4 after 3 hours at 30 Hz (32B).

[0073] FIG. 33 shows the PXRD diffractogram of X (KF milled with K.sub.2HPO.sub.4 for 3 hours at 35 Hz).

[0074] FIG. 34 shows the PXRD diffractogram of Y (KF milled with K.sub.2HPO.sub.4 for 3 hours at 35 Hz followed by CaHPO.sub.4 for 3 hours at 35 Hz).

[0075] FIG. 35 shows the NMR yield of TsF from TsCl upon reaction with fluoromix or X (KF milled with K.sub.2HPO.sub.4 for 3 hours at 35 Hz) or Y (KF milled with K.sub.2HPO.sub.4 for 3 hours at 35 Hz followed by CaHPO.sub.4 for 3 hours at 35 Hz) independently.

[0076] FIG. 36 shows the PXRD diffractogram of fluorspar with NaOH.

[0077] FIG. 37 shows NMR yields of TsF from TsCl using fluorspar and various non-phosphate activators.

[0078] FIG. 38 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K.sub.2CO.sub.3 for 3 hours at 35 Hz.

[0079] FIG. 39 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KHCO.sub.3 for 3 hours at 35 Hz.

[0080] FIG. 40 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K.sub.2SO.sub.4 for 3 hours at 35 Hz.

[0081] FIG. 41 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KHSO.sub.4 for 3 hours at 35 Hz.

[0082] FIG. 42 shows the PXRD diffractogram of the product of the fluorspar milling reaction with K.sub.2S.sub.2O.sub.7 for 3 hours at 35 Hz.

[0083] FIG. 43 shows the PXRD diffractogram of the product of the fluorspar milling reaction with Na.sub.2SO.sub.3 for 1.5 hours at 35 Hz.

[0084] FIG. 44 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KNOB for 3 hours 35 Hz.

[0085] FIG. 45 shows the PXRD diffractogram of the product of the fluorspar milling reaction with KOH for 3 hours 35 Hz.

[0086] FIG. 46 shows the PXRD diffractogram of the product of the fluorspar milling reaction with NaOH for 3 hours 35 Hz.

[0087] FIG. 47 shows the reaction scope of R—SO.sub.2Cl species with fluorapatite using a phosphate activator and associated yields.

[0088] FIG. 48 shows stacked PXRD diffractograms of the products of the fluorapatite milling reaction upon subsequent additions of K.sub.4P.sub.2O.sub.7 (4 separate additions of 1 equivalent).

[0089] FIG. 49 shows the PXRD diffractogram of pure fluorapatite after 1 hour of milling overlayed with a fluorapatite sample (1 equiv.) that was milled for 12 hours total at 35 Hz with K.sub.4P.sub.2O.sub.7 (4 equiv.).

[0090] FIG. 50 shows stacked PXRD diffractograms of the reaction 1:4 equiv. milling reaction (D) between fluorapatite (Ca.sub.5(PO.sub.4).sub.3F) and K.sub.4P.sub.2O.sub.7, and the milling reaction between potassium fluoride (KF, 1 equiv.) and K.sub.2HPO.sub.4 (2 equiv., 35 Hz, 3 hours) followed by CaHPO.sub.4 (1 equiv., 35 Hz, 3 hours).

[0091] FIG. 51 shows the PXRD diffractogram of the water insoluble product of the reaction between fluorapatite and potassium pyrophosphate overlayed with the PXRD diffractogram of fluorapatite.

[0092] FIG. 52 shows the PXRD diffractogram of the milling reaction of fluorapatite and 1 equivalent of K.sub.4P.sub.2O.sub.7 for 9 hours at 30 Hz.

[0093] FIG. 53 shows the PXRD diffractogram of the milling reaction of 4 subsequent additions of 1 equivalent of K.sub.4P.sub.2O.sub.7 to 1 equivalent of fluorapatite with 3 hours of milling at 35 Hz after each addition.

[0094] FIG. 54 shows a general scheme for which the effect of the variation of screw temperature on the generation of active fluorination material was tested.

[0095] FIG. 55 shows a general scheme for which the effect of the variation of screw speed on the generation of active fluorination material was tested.

[0096] FIG. 56 shows a general scheme for which the effect of the variation of the number of recycling times on the generation of active fluorination material was tested.

[0097] FIG. 57 shows a general scheme for which only CaF.sub.2 is added into the twin-screw extruder without the K.sub.2HPO.sub.4.

[0098] FIG. 58 shows a general scheme for which the effect of varying screw configuration on generation of active fluorination material was tested.

DETAILED DESCRIPTION OF THE INVENTION

[0099] Throughout the entirety of the description and claims of this specification, where subject matter is described herein using the term “comprise” (or “comprises” or “comprising”), the same subject matter instead described using the term “consist of” (or “consists of” or “consisting of”) or “consist essentially of” (or “consists essentially of” or “consisting essentially of”) is also contemplated.

[0100] The term “about” or “approximately” may mean within an acceptable error range for the particular value, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. Unless otherwise specified herein, “about” generally refers to a range of +1-10% of the stated value. In the case of X-ray diffraction reflections, however, “about” generally refers to a range of +1-0.1° of the stated value. Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0101] Certain inventive embodiments herein contemplate numerical ranges. When ranges are present, the ranges include the range endpoints. Additionally, every sub range and value within the range is present as if explicitly written out.

[0102] Certain inventive embodiments herein contemplate characteristic x-ray diffraction reflections. In certain embodiments, the presence or absence of a characteristic x-ray diffraction reflection is determined by identification of a peak in an x-ray diffraction spectrum located at a characteristic 2θ value.

[0103] In certain embodiments, a peak is present when a 2θ signal has a signal to noise ratio of at least 3.

[0104] In certain embodiments, a peak is present when a 2θ signal has a signal to noise ratio of at least 5. In certain embodiments, a peak is present when a 2θ signal has a signal to noise ratio of at least 10.

[0105] In certain embodiments, a peak is present when a 2θ signal has a signal to noise ratio of at least 20.

[0106] In certain embodiments, peaks are identified in a raw powder x-ray diffraction spectrum. In certain embodiments, peaks are identified in a background subtracted powder x-ray diffraction spectrum. In some embodiments, peaks corresponding to a first salt are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, peaks corresponding to a second salt are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, one or more known contaminant peaks are subtracted from a raw spectrum to yield a background subtracted spectrum. In some embodiments, peaks corresponding to one or more of: a first salt, a second salt, and/or a known contaminant are subtracted from a raw spectrum to yield a background subtracted spectrum.

[0107] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0108] Features described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted 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 in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0109] Unless otherwise specified, where the quantity 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 product as a whole. It will be understood by those skilled in the art that the sum of weight percentages of all components of a product will total 100 wt. %. However, where not all components are listed (e.g. where a product is said to “comprise” one or more particular components), the weight percentage balance may optionally be made up to 100 wt % by unspecified ingredients.

[0110] As described hereinbefore, in a first aspect the present invention provides a process for the preparation of a fluorinating reagent, the process comprising the step of: [0111] a) pulverising together a fluorine-containing compound and an ionic compound in the solid state, wherein the fluorine-containing compound is at least one of calcium fluoride and fluorapatite,
wherein the anion of said ionic compound is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than 2450 KJ mol.sup.−1.

[0112] Through rigorous investigations, the inventors have arrived at a solution to the long-standing problem described hereinbefore by devising a process that allows calcium fluoride and fluorapatite to be directly converted into a fluorinating reagent without the need for converting them into HF using sulfuric acid. This is achieved by reacting calcium fluoride and/or fluorapatite with particular ionic compounds according to the conditions outlined in step a) (e.g. ball milling, or other mechanochemical technique). The process of the invention therefore allows for the preparation of value-added fluorochemicals using more environmentally-friendly and sustainable techniques.

[0113] Calcium fluoride (CaF.sub.2, melting point, ˜1420° C.) is a white solid that is poorly soluble in water (0.016 g/L at 20° C.) and is insoluble in organic solvents. Under ambient conditions, calcium fluoride crystallizes in the fluorite structure (α, space group Fm-3m) wherein Ca.sup.2+ ions are cubically coordinated to eight nearest-neighbor F.sup.− ions. The calcium fluoride used as part of the invention may be naturally occurring (i.e. as fluorspar) or may be synthetic (e.g. industrially produced calcium fluoride having fewer impurities). Fluorapatite is a crystalline solid having the formula Ca.sub.5(PO.sub.4).sub.3F.

[0114] The process of the invention involves reacting the fluorine-containing compound (i.e., calcium fluoride and/or fluorapatite) with particular ionic compounds in the solid state using a high-energy mixing technique, such as one that is sufficient to mechanically reduce the particle size of (e.g. crush) the reactants and bring them into contact with one another. Pulverising together the reactants according to step a) achieves this objective. It will, however, be appreciated that synonymous high-energy mixing techniques resulting in particle size reduction of the reactants and/or an increased surface area to volume ratio of the reactants, such as crushing together, grinding together, milling together, mashing together, macerating together and the like, are embraced by step a).

[0115] The process may be a mechanochemical process and/or step a) may be conducted under mechanochemical conditions. Mechanochemistry is a developing area of chemical synthesis and is widely understood to refer to chemical transformations that are initiated by and/or sustained by the application of a mechanical stress to one or more solid reactants.

[0116] Step a) may be conducted in a ball mill, a pestle and mortar or a twin screw extruder (TSE). Other techniques and apparatuses suitable for carrying out step a) will be familiar to one skilled in the art, e.g. those skilled in the art of mechanochemistry, including an ultrasonic bath and/or a mechanical press.

[0117] In particular embodiments, step a) is conducted in a ball mill. Exemplary ball mills include a planetary ball mill, a vibratory ball mill, an attritor ball mill or a tumbling ball mill. Most suitably, the ball mill is a vibratory ball mill.

[0118] The person skilled in the art of ball milling will be able to select appropriate conditions, including ball size and weight, and vessel size. For example, a stainless steel vessel and one or more stainless steel balls may be used. Alternatively, a zirconia vessel and one or more zirconia balls may be used. A ball, or balls, (each) weighing 2-20 g (e.g., 3 g, 4 g, 7 g or 16 g) may, for example, be used.

[0119] Step a) may be carried out for any suitable period of time. For example, step a) may be carried out for 0.5-12 hours (e.g., the fluorine-containing compound and ionic compound may be ball milled together for 0.5-12 hours).

[0120] In particular 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).

[0121] Twin screw extrusion may be performed at various speeds (S.sub.S), screw temperatures (S.sub.T) and residence times (T.sub.R), as described herein. A single pass through the extruder may be sufficient to form the fluorinating reagent. Alternatively, when step a) is conducted in a twin screw extruder, step a) may comprise collecting the product emerging from the twin screw extruder and subjecting it to one or more additional passes through the twin screw extruder.

[0122] Step a) is conducted in the solid state. In its simplest sense, step a) is conducted in the absence (or substantial absence) of any solvent. However, the use of some solvent is known to offer advantages in some solid state (e.g. mechanochemical) reactions. Examples of such techniques include solvent-assisted mechanochemistry (sometimes termed liquid-assisted mechanochemistry, e.g. liquid-assisted grinding). Suitably, the amount and type of solvent used (if any) is such that >50 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). More suitably, >70 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). Even more suitably, >90 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). Yet more suitably, >95 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a).

[0123] In particular embodiments, step a) is conducted in the absence (or substantial absence) of any solvent. Suitably, step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).

[0124] In particular embodiments, step a) is conducted in the absence (or substantial absence) of any solvent. Suitably, step a) involves pulverising together the fluorine-containing compound and the ionic compound in a twin screw extruder.

[0125] During step a), the fluorine-containing compound is reacted with an ionic compound, the anion of which is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than 2400 KJ mol.sup.−1. The person of skill in the art will be familiar with the term lattice energy as denoting the amount of energy required to dissociate one mole of an ionic compound into its constituent ions in the gaseous state. Calcium fluoride and fluorapatite, being only slightly soluble in certain acids, are chemically inert to nearly all organic chemicals. The stability of calcium fluoride and fluorapatite is attributed in a large part to their high lattice energy (2630 KJ mol.sup.−1 for calcium fluoride). The inventors have, however, determined that this stability can be overcome by pulverising together (e.g. ball milling) calcium fluoride and/or fluorapatite with certain ionic compounds according to step a). Without wishing to be bound by theory, the inventors believe that the energetic bar to reactivity of calcium fluoride or fluorapatite can be overcome by the use of high-energy reaction conditions, combined with the use of a thermodynamic sink for Ca.sup.2+. In particular, the use of ionic compounds, the anions of which (e.g. sulphate, carbonate or phosphate) are able to form calcium salts having lattice energies that are similar to, or preferably greater than, 2630 KJ mol.sup.−1 (e.g. CaSO.sub.4=2489 KJ mol.sup.−1; CaCO.sub.3=2804 KJ mol.sup.−1; Ca.sub.3(PO.sub.4).sub.2=10,602 KJ mol.sup.−1) facilitates the formation of fluorine-containing species that have improved reactivity towards organic chemicals.

[0126] The fluorine-containing compound is typically calcium fluoride or fluorapatite. Suitably, the fluorine-containing compound is calcium fluoride. Where the fluorine-containing compound is calcium fluoride, a quantity of fluorapatite may form (e.g., transiently) during the course of step a). In particular embodiments, the calcium fluoride is acid grade fluorspar.

[0127] In some instances, the fluorine-containing compound used in the first aspect may be calcium fluoride, fluorapatite and/or any other salt comprising calcium and fluorine. Such other salts may be described elsewhere herein as a first salt comprising calcium and fluorine.

[0128] Particularly suitably, the anion of the ionic compound is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than the lattice energy of calcium fluoride (i.e. greater than 2630 KJ mol.sup.−1).

[0129] The ionic compound is suitably inorganic. The ionic compound may be a salt. Suitably, the ionic compound is a salt of an oxoacid.

[0130] The ionic compound may be a phosphate, carbonate, sulphate, sulphite or nitrate salt. Alternatively, the ionic compound may be a phosphate, carbonate or sulphate salt. It will be understood that phosphate, carbonate, sulphate, sulphite or nitrate salts described herein are salts that contains at least one of these anions, meaning that salts such as hydrogen phosphate salts, dihydrogen phosphate salts, hydrogen sulphate salts and bicarbonate salts are also encompassed. It will be understand that phosphate salts encompass metaphosphate salts, and that phosphate salts and sulphate salts encompass pyrophosphate salts and pyrosulfate salts 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 a potassium salt, a sodium salt or a magnesium salt.

[0131] In particular embodiments, the ionic compound is a phosphate salt.

[0132] The ionic compound may be a phosphate salt of potassium, sodium or calcium, a sulphate salt of potassium, sodium or caesium, a carbonate salt of potassium or sodium, a sulphite salt of potassium or sodium, a nitrate salt of potassium or sodium, a hydroxide salt of potassium or sodium, or a citrate salt of potassium or sodium. For example, the ionic compound may be selected from the group consisting of K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KH.sub.2PO.sub.4, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, KPO.sub.3, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, (NaPO.sub.3).sub.3, CaHPO.sub.4, K.sub.2CO.sub.3, KHCO.sub.3, K.sub.2SO.sub.4, KHSO.sub.4, Cs.sub.2SO.sub.4, MgSO.sub.4, Ag.sub.2SO.sub.4, K.sub.2S.sub.2O.sub.7, Na.sub.2SO.sub.3, Na.sub.2SO.sub.4, Na.sub.2CO.sub.3, KNOB, Na.sub.3C.sub.6H.sub.5O.sub.7, NaOH and KOH.

[0133] Particular, non-limiting examples of the ionic compound include phosphate salts of potassium and sodium, sulphate salts of potassium and sodium, and carbonate salts of potassium and sodium. Suitably, the ionic compound is a phosphate salt of potassium or sodium. More suitably, the ionic compound is a phosphate salt of potassium. Most suitably, the ionic compound is K.sub.3PO.sub.4 or K.sub.2HPO.sub.4, of which K.sub.2HPO.sub.4 is most preferred.

[0134] Alternatively, the ionic compound may be selected from the group consisting of K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KH.sub.2PO.sub.4KPO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, Cs.sub.2SO.sub.4, Na.sub.2SO.sub.3, K.sub.4P.sub.2O, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, Na.sub.3C.sub.6H.sub.5O.sub.7, K.sub.2SO.sub.4, Na.sub.2SO.sub.4, MgSO.sub.4, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, KHCO.sub.3, NaOH and KOH. Suitably, the ionic compound is selected from the group consisting of K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, K.sub.2CO.sub.3, KHCO.sub.3, NaOH and KOH. More suitably, the ionic compound is selected from the group consisting of K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10 and Na.sub.4P.sub.2O.sub.7.

[0135] In some instances, the ionic compound used in the first aspect may be described elsewhere herein as a second salt.

[0136] In particular embodiments, the ionic compound is K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10 or Na.sub.4P.sub.2O.sub.7 and step a) is conducted in the absence (or substantial absence) of any solvent. Suitably, step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).

[0137] In particular embodiments, the ionic compound is a phosphate, sulphate or carbonate salt of potassium or sodium (e.g. K.sub.3PO.sub.4 or K.sub.2HPO.sub.4) and step a) is conducted in the absence (or substantial absence) of any solvent. Suitably, step a) involves pulverising together the fluorine-containing compound and the ionic compound in a ball mill (i.e. ball milling the fluorine-containing compound and the ionic compound).

[0138] It will be appreciated that ionic compounds having properties similar to those recited herein may also be suitable for use in step a).

[0139] 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.

[0140] In some embodiments, the ionic compound is pulverized together with the fluorine-containing compound in portions. For example, step a) may comprise: (a-i) pulverising together the fluorine-containing compound and a first portion of the ionic compound, and (a-ii) pulverising together the product of step (a-i) and a second portion of the ionic compound. Optionally, step a) further comprises a step (a-iii) of pulverising together the product of step (a-ii) and a third portion of the ionic compound. Optionally, step a) further comprises a step (a-iv) of pulverising together the product of step (a-iii) and a fourth portion of the ionic compound. The portions of the ionic compound may be the same or different.

[0141] In some embodiments, solid CO.sub.2 (i.e., dry ice) is pulverised together with the fluorine-containing compound and the ionic compound. In such embodiments, between 5 and 15 equivalents of solid CO.sub.2 (relative to 1 equivalent of fluorine-containing compound) may be used in step a).

[0142] In some embodiments, the product resulting from step a) may be heat-treated. Suitably, the product resulting from step a) may be heated to a temperature of 300-700° C. (e.g., 500-600° C.).

[0143] In embodiments, essentially no HF is produced at any point during step a). For example, <1 ppm (e.g., <1 ppb) of HF may be produced at any point during step a).

[0144] The fluorinating reagent afforded by step a) can be used to prepare a fluorochemical (e.g. an organic fluorochemical). Thus, in a second aspect, the invention provides a process for the preparation of a fluorochemical, the process comprising the steps of: [0145] a) preparing a fluorinating reagent as described herein; and [0146] b) contacting an organic substrate with the fluorinating reagent,
wherein step b) is conducted simultaneously with, or after, step a).

[0147] The organic substrate to be fluorinated may take a variety of forms. Suitably the organic substrate is an electrophile.

[0148] The organic substrate may be aliphatic (e.g. an alkyl halide) or aromatic (e.g. an aryl halide or a heteroaryl halide) in nature. The organic substrate suitably has at least one leaving group located at the site to be fluorinated. Leaving groups will be known to those of skill in the art of organic chemistry. Particular, non-limiting examples of suitable leaving groups include halide (particularly chloro or bromo), tosylate, triflate, mesylate, phosphate, nitro, ammonium and iodonium groups. Most suitably, the leaving group is halide.

[0149] The organic substrate may be any one of those organic substrates employed in the Examples outlined herein. In such Examples, the exemplified leaving group(s) may, where chemically feasible, be replaced with any one of the other aforementioned leaving groups.

[0150] In particular embodiments, the organic substrate is a sulphonyl halide, an acyl halide, an aryl halide or an alkyl halide (including alkylaryl halides, such as benzyl halides). In such embodiments, halide is suitably chloride. Sulphonyl, acyl, aryl and benzylic fluorides are among the most common fluorinated motifs in organic synthesis with broad applicability as either reagents, synthetic intermediates or biological probes. More suitably, the organic substrate is a sulphonyl halide, an acyl halide, an aryl halide or a heteroaryl halide. Particular, non-limiting examples include aromatic sulphonyl halide (e.g. tosyl chloride), benzoyl halides (e.g. 4-methoxybenzoyl chloride), halobenzenes (e.g. chlorobenzene) and benzyl halides (e.g. benzyl chloride).

[0151] In particular embodiments, the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halo carbonyl or an alkyl halide.

[0152] In particular embodiments, the organic substrate is ArOCHX.sub.2, wherein Ar is an aromatic group (e.g., biphenyl) and X is halide (e.g., chloro).

[0153] In particular embodiments, where the organic substrate has more than one leaving group (e.g., 2 leaving groups), the leaving groups may be attached to the same carbon atom (e.g., 2 geminal halide leaving groups).

[0154] In many instances, the organic substrate has a molecular weight of <500 g mol.sup.−1. Suitably, the organic substrate has a molecular weight of <300 g mol.sup.−1.

[0155] In particular embodiments, the organic substrate is a sulfonyl halide, an acyl halide, an aryl halide or an alkyl halide (e.g. where halide is bromide) and the ionic compound used in step a) is a phosphate, sulphate or carbonate salt of potassium or sodium (e.g. K.sub.3PO.sub.4 or K.sub.2HPO.sub.4). Suitably, step a) is conducted in the absence (or substantial absence) of any solvent. Alternatively/additionally, step a) involves pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound).

[0156] In particular embodiments, the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halo carbonyl or an alkyl halide and the ionic compound used in step a) is a phosphate, carbonate, sulphate, sulphite, nitrate, hydroxide or citrate salt (e.g. K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, K.sub.2CO.sub.3, KHCO.sub.3, NaOH or KOH). Suitably, step a) is conducted in the absence (or substantial absence) of any solvent. Alternatively/additionally, step a) involves pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound) or a twin screw extruder.

[0157] Step b) may be conducted simultaneously with step a), such that the organic substrate is available for reaction with the fluorinating reagent as soon as the latter forms during step a). Accordingly, step b) may comprise contacting the organic substrate with the fluorinating reagent under identical conditions to 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 pulverised together in the solid state (e.g. by ball milling).

[0158] Alternatively, step b) may be conducted after step a), such that a quantity of fluorinating reagent is allowed to form before being reacted with the organic substrate.

[0159] When step b) is conducted after step a), step b) may be conducted in the solid state. For example, step b) may comprise pulverising together the organic substrate and the fluorinating reagent formed from step a) in the solid state. Suitably, step b) is conducted in a ball mill. More suitably, step b) is conducted in the absence (or substantial absence) of a solvent. In certain embodiments, steps a) and b) are both conducted in a ball mill (e.g. the same ball mill), suitably in the absence (or substantial absence) of a solvent.

[0160] Alternatively, when step b) is conducted after step a), step b) may be conducted in solution. For example, step b) may comprise mixing together the organic substrate and the fluorinating reagent in a solvent in which the organic substrate is soluble. Any suitable solvent or combinations of solvents may be used depending on the nature of the organic substrate, including, for example, those solvents employed in the Examples outlined herein (e.g., those listed in Table 3.5). The solvent may, for example, be selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, propionitrile, tert-butyl isocyanide, tert-butanol, tert-amyl alcohol, toluene, m-xylene, hexane, trifluorotoluene, 1,2-difluorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, fluorobenzene and chlorobenzene. Particular, 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 conducted in a solvent selected from the group consisting of acetonitrile, toluene, chlorobenzene, 1,2-difluorobenzene, dichloroethane, trifluorotoluene, chloroform, tert-butanol and tert-amyl alcohol. More suitably, step b) is conducted in acetonitrile, chlorobenzene, tert-butanol or tert-amyl alcohol. Most suitably, step b) is conducted in acetonitrile.

[0161] Any one or more of the aforementioned organic solvents may be in admixture with water. For example, the organic solvent may be in admixture with water at a concentration of 0.01-5M. Suitably, the organic solvent may be in admixture with water at a concentration of 0.01-1M (e.g., 0.05-0.5M).

[0162] In particular embodiments, step b) is conducted after step a), and step b) is conducted a solvent selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, propionitrile, tert-butyl isocyanide, tert-butanol, tert-amyl alcohol, toluene, m-xylene, hexane, trifluorotoluene, 1,2-difluorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, fluorobenzene and chlorobenzene, any one of which may be in admixture with water. Suitably, the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halo carbonyl or an alkyl halide and the ionic compound used in step a) is a phosphate, carbonate, sulphate, sulphite, nitrate, hydroxide or citrate salt (e.g. K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, K.sub.2CO.sub.3, KHCO.sub.3, NaOH or KOH). Step a) may involve pulverising together the fluorine-containing compound (e.g., calcium fluoride) and the ionic compound in a ball mill (i.e. ball milling calcium fluoride and the ionic compound) or a twin screw extruder.

[0163] When step b) is conducted after step a), the fluorinating reagent formed in step a) may be isolated or purified prior to reacting it with the organic substrate.

[0164] The skilled person will be able to select appropriate reaction conditions (e.g. temperature, pressure, etc) for carrying out step b) in solution. For example, when step b) is conducted in solution after step a), step b) may be performed at a temperature of 15-180° C. Suitably, step b) is performed at a temperature of 15-150° C.

[0165] Step b) may be conducted in the presence of at least one of a cryptand, a crown ether and a hydrogen-bonding phase transfer catalysts. Suitably, step b) is conducted after step a), and is performed in solution. Suitable cryptands include Kryptofix 2210 and Kryptofix 2220. Suitable crown ethers include 18-crown-6, dibenzo-18-crown-6, dibenzo-30-crown-10 and dicyclohexano-18-crown-6. Suitable hydrogen-bonding phase transfer catalysts include Schreiner's urea. Amongst the aforementioned cryptands, crown ethers and hydrogen-bonding phase transfer catalysts, 18-crown-6 and dibenzo-18-crown-6 are particularly suitable.

[0166] The process may further comprise one or more additional steps in which the fluorochemical formed in step b) is isolated and/or purified.

[0167] The fluorochemical may be otherwise described herein as a fluorinated compound or an organo-fluorine compound.

[0168] As described hereinbefore, in a third aspect the present invention provides a process for the preparation of a fluorochemical, the process comprising the steps of: [0169] a) pulverising a fluorine-containing compound in the solid state, wherein the fluorine-containing compound is at least one of calcium fluoride and fluorapatite; and [0170] b) contacting the product of step a) with an organic substrate;
wherein step b) is conducted simultaneously with, or after, step a).

[0171] Through further investigations, the inventors have surprisingly determined that the formation of HF can be bypassed and calcium fluoride or fluorapatite can be directly converted into value-added fluorochemicals using a process that is similar to the process to the first aspect, albeit without the need for the fluorine-containing compound to be pulverised together with an ionic compound as defined herein.

[0172] Accordingly, it will be understood that steps a) and b) of the third aspect may have any of those definitions recited hereinbefore in relation to corresponding steps a) and b) of the first and second aspect.

[0173] In particular embodiments, step b) is conducted in solution, in the presence of an ionic compound as defined herein (e.g. K.sub.2HPO.sub.4).

[0174] As described hereinbefore, in a fourth aspect, the present invention provides a use of a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.

[0175] As discussed hereinbefore, in a fifth aspect, the present invention provides a use of a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorinating reagent, wherein the process does not comprise a step of reacting the fluorine-containing compound with sulfuric acid to generate hydrofluoric acid.

[0176] It will be understood that features of the fourth and fifth aspect may have any of those definitions recited hereinbefore in relation to the first, second and third aspects.

[0177] According to a sixth aspect of the invention, there is provided a fluorinating reagent obtained, directly obtained or obtainable by a process of the first aspect.

[0178] According to a seventh aspect of the invention, there is provided a fluorinating reagent comprising a mixture of inorganic salts.

[0179] The sixth and seventh aspects of the invention may be further defined as follows.

[0180] The fluorinating reagent may be provided as a mixture of inorganic salts.

[0181] The fluorinating reagent (e.g., the mixture of inorganic salts) suitably comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur, nitrogen and carbon. More suitably, the fluorinating reagent comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur and carbon. Most suitably, the fluorinating reagent comprises calcium, fluorine, oxygen, potassium and phosphorus. The fluorinating reagent may additionally comprise hydrogen.

[0182] The mixture of inorganic salts suitably comprises a first inorganic salt and a second inorganic salt, wherein: (i) the first inorganic salt comprises Ca.sup.2+ and at least one anion selected from phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide, and (ii) the second inorganic salt comprises fluoride and at least one cation selected from K.sup.+ and Na.sup.2+. Suitably, the first inorganic salt comprises Ca.sup.2+ and at least one anion selected from phosphate, sulfate, carbonate and hydroxide (e.g., phosphate), and/or the second inorganic salt comprises fluoride and K.sup.+. The mixture of inorganic salts may further comprise one or more additional inorganic salts (i.e., in addition to the first and second inorganic salts), each comprising a cation selected from Ca.sup.2+, K.sup.+ and Na.sup.2+, and an anion selected from fluoride, phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide (e.g., fluoride, phosphate, carbonate and hydroxide).

[0183] The fluorinating reagent (e.g., the mixture of inorganic salts) may comprise calcium fluoride and/or fluorapatite. Trace quantities (i.e., those detectable by XRPD) of calcium fluoride and/or fluorapatite, originating from starting materials used in the process of the first aspect, may be present in the fluorinating reagent. Fluorapatite may be present in the fluorinating reagent even when it is not used as the fluorine-containing compound in the process of the first aspect.

[0184] The fluorinating reagent may be provided as a powder. The powder may have an average particle size, as determined by SEM or TEM analysis, of <500 μm. Suitably, the powder has an average particle size of <100 μm. More suitably, the powder has an average particle size of <50 μm.

[0185] The fluorinating reagent may be characterised 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 common practice in the solid-state chemical arts because of the variation inherent in peak values.

[0186] The fluorinating reagent may have an XRPD pattern comprising peaks corresponding ±0.2° 2θ 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 fluorinating reagent may have an XRPD pattern comprising peaks corresponding ±0.2° 2θ to at least 30% of the 25 2-theta values reported in Table 5.12.1 outlined herein, meaning that the fluorinating reagent may have an XRPD pattern comprising peaks corresponding to at least 8 of those 2-theta values reported in Table 5.12.1 (e.g., those not attributed to CaF.sub.2), recognising that each 2-theta value reported in Table 5.12.1 can be modified ±0.2° 2θ. For example, the fluorinating reagent may have an XRPD pattern comprising peaks corresponding ±0.2° 2θ to at least 50% of the 33 2-theta values reported in Table 6.3.3 outlined herein, meaning that the fluorinating reagent may have an XRPD pattern comprising peaks corresponding to at least 17 of those 2-theta values reported in Table 6.3.3, recognising that each 2-theta value reported in Table 5.12.1 can be modified ±0.2° 2θ. Suitably, the fluorinating reagent has an XRPD pattern comprising peaks corresponding ±0.2° 2θ to at least 10%, at least 30%, at least 50%, at least 70%, at least 90%, or 100% of the 2-theta values reported in any one of Tables 5.7.2-5.7.11 and 5.12.1 outlined herein. More suitably, the fluorinating reagent has an XRPD pattern comprising peaks corresponding ±0.2° 2θ 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.

[0187] The fluorinating reagent may have an XRPD pattern comprising 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 comprise one or more additional 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, 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 comprise peaks at at least five, at least ten, at least fifteen or at least twenty of the aforementioned 2-theta values. The fluorinating reagent may have an XRPD pattern substantially the same as that shown in FIG. 10. Suitably, the fluorinating reagent: (i) comprises calcium, fluorine, oxygen, potassium and phosphorus, and/or (ii) comprises a first inorganic salt and a second inorganic salt, wherein the first inorganic salt comprises Ca.sup.2+ and phosphate, and the second inorganic salt comprises fluoride and K.sup.+.

[0188] The fluorinating reagent may have an XRPD pattern comprising one or more peaks at 2-theta values of 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, 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 at least two, at least three, at least four, at least five, at least ten, at least fifteen or at least twenty of the aforementioned 2-theta values. The fluorinating reagent may have an XRPD pattern substantially the same as that shown in FIG. 26. Suitably, the fluorinating reagent: (i) comprises calcium, fluorine, oxygen, potassium and phosphorus, and/or (ii) comprises a first inorganic salt and a second inorganic salt, wherein the first inorganic salt comprises Ca.sup.2+ and phosphate, and the second inorganic salt comprises fluoride and K.sup.+. The fluorinating reagent may comprise K.sub.3(HPO.sub.4)F.

[0189] The fluorinating reagent may comprise K.sub.3(HPO.sub.4)F and has an XRPD pattern 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. Suitably, the fluorinating reagent comprises at least two, at least three, at least four, at least five, at least six, at least seven, or eight peaks at the aforementioned 2-theta values. More suitably, the fluorinating reagent comprises peaks at all eight of the aforementioned 2-theta values. The fluorinating reagent may further comprise calcium fluoride and/or fluorapatite (e.g., trace quantities of calcium fluoride and/or fluorapatite).

[0190] The fluorinating reagent may have an XRPD pattern substantially as shown in any one of FIGS. 4-16. 26. 38-46 and 52-53. Suitably, the fluorinating reagent has an XRPD pattern substantially as shown in any one of FIGS. 10, 11 and 26.

[0191] It will be understood that a fluorinating reagent is a reagent which, under those conditions described herein, is able to fluorinate an organic substrate described herein.

[0192] The fluorinating reagent of the sixth or seventh aspect may be used in the process of the second aspect. Thus, instead of preparing a fluorinating reagent, step a) of the second aspect may comprise providing a fluorinating reagent of the sixth or seventh aspect.

[0193] The following numbered statements 1 to 100 describe particular aspects and embodiments of the invention: [0194] 1. A process for the preparation of a fluorinating reagent, the process comprising the step of: [0195] a) pulverising together a fluorine-containing compound and an ionic compound in the solid state, wherein the fluorine-containing compound is at least one of calcium fluoride and fluorapatite, wherein the anion of said ionic compound is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than 2450 KJ mol.sup.−1. [0196] 2. The process of statement 1, wherein the fluorine-containing compound is calcium fluoride. [0197] 3. A process for the preparation of a fluorinating reagent, the process comprising the step of: [0198] a) pulverising together calcium fluoride and an ionic compound in the solid state, wherein the anion of said ionic compound is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than 2450 KJ mol.sup.−1. [0199] 4. The process of statement 1, 2 or 3, wherein the anion of said ionic compound is combinable with Ca.sup.2+ to form a calcium salt having a lattice energy that is greater than 2630 KJ mol.sup.−1. [0200] 5. The process of any one of the preceding statements, wherein the ionic compound is a salt. [0201] 6. The process of any one of the preceding statements, wherein the ionic compound is a salt of an oxoacid. [0202] 7. The process of any one of the preceding statements, wherein the ionic compound is a phosphate, carbonate, sulphate, sulphite, nitrate, hydroxide or citrate salt. [0203] 8. The process of any one of the preceding statements, wherein the ionic compound is a phosphate, carbonate or sulphate salt. [0204] 9. The process of any one of the preceding statements, wherein the ionic compound is a phosphate salt. [0205] 10. The process of any one of the preceding statements, wherein, the ionic compound is an alkali metal salt or an alkaline earth metal salt. [0206] 11. The process of any one of the preceding statements, wherein the ionic compound is a potassium salt, a sodium salt, a calcium salt, a caesium salt or a magnesium salt. [0207] 12. The process of any one of the preceding statements, wherein the ionic compound is a potassium salt, a sodium salt or a magnesium salt. [0208] 13. The process of any one of the preceding statements, wherein the ionic compound is selected from the group consisting of a phosphate, sulphate or carbonate salt of potassium or sodium. [0209] 14. The process of any one of the preceding statements, wherein the ionic compound is a phosphate salt of potassium or sodium. [0210] 15. The process of any one of the preceding statements, wherein the ionic compound is a phosphate salt of potassium. [0211] 16. The process of statement 1, 2 or 3, wherein the ionic compound is selected from the group consisting of K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KH.sub.2PO.sub.4, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, KPO.sub.3, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, (NaPO.sub.3).sub.3, CaHPO.sub.4, K.sub.2CO.sub.3, KHCO.sub.3, K.sub.2SO.sub.4, KHSO.sub.4, Cs.sub.2SO.sub.4, MgSO.sub.4, Ag.sub.2SO.sub.4, K.sub.2S.sub.2O.sub.7, Na.sub.2SO.sub.3, Na.sub.2SO.sub.4, Na.sub.2CO.sub.3, KNOB, Na.sub.3C.sub.6H.sub.5O.sub.7, NaOH and KOH. [0212] 17. The process of statement 16, wherein the ionic compound is selected from the group consisting of K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, K.sub.2CO.sub.3, KHCO.sub.3, NaOH and KOH. [0213] 18. The process of statement 16, wherein the ionic compound is selected from the group consisting of K.sub.2HPO.sub.4, KPO.sub.3, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10 and Na.sub.4P.sub.2O.sub.7. [0214] 19. The process of statement 1, 2 or 3, wherein the ionic compound is K.sub.3PO.sub.4 or K.sub.2HPO.sub.4. [0215] 20. The process of any one of the preceding statements, wherein >50 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). [0216] 21. The process of any one of the preceding statements, wherein >70 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). [0217] 22. The process of any one of the preceding statements, wherein >90 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). [0218] 23. The process of any one of the preceding statements, wherein >95 wt % of the fluorine-containing compound, the ionic compound, and any reaction products derived therefrom, remain in the solid state throughout step a). [0219] 24. The process of any one of the preceding statements, wherein step a) is conducted in the absence of a solvent. [0220] 25. The process of any one of the preceding statements, wherein step a) is a mechanochemical process. [0221] 26. The process of any one of the preceding statements, wherein step a) is conducted in a ball mill, a pestle and mortar, a twin screw extruder, an ultrasonic bath or a mechanical press. [0222] 27. The process of any one of the preceding statements, wherein step a) is conducted in a ball mill, a pestle and mortar or a twin screw extruder. [0223] 28. The process of any one of the preceding statements, wherein step a) is conducted in a ball mill. [0224] 29. The process of statement 28, wherein the ball mill is a planetary mill, a vibratory mill, an attritor mill or a tumbling ball bill. [0225] 30. The process of statement 28, wherein the ball mill is a vibratory mill. [0226] 31. The process 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 0.5-80 Hz (e.g., 20-40 Hz). [0227] 32. The process of any one of statements 1 to 27, wherein step a) is conducted in a twin screw extruder. [0228] 33. The process of statement 32, wherein step a) comprises collecting the product emerging from the twin screw extruder and subjecting it to one or more additional passes through the twin screw extruder. [0229] 34. The process of any one of the preceding statements, wherein the molar ratio of the fluorine-containing compound to the ionic compound in step a) is (0.1-7):1 (e.g., (0.3-6):1). [0230] 35. The process of any one of the preceding statements, 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). [0231] 46. The process of any one of the preceding statements, wherein the ionic compound is pulverized together with the fluorine-containing compound in portions. [0232] 37. The process of statement 36, wherein step a) comprises: (a-i) pulverising together the fluorine-containing compound and a first portion of the ionic compound, and (a-ii) pulverising together the product of step (a-i) and a second portion of the ionic compound. [0233] 38. The process of statement 37, wherein step a) further comprises a step (a-iii) of pulverising together the product of step (a-ii) and a third portion of the ionic compound. [0234] 39. The process of statement 38, wherein step a) further comprises a step (a-iv) of pulverising together the product of step (a-iii) and a fourth portion of the ionic compound. [0235] 40. The process of any one of the preceding statements, wherein <1 ppm (e.g., <1 ppb) of HF is produced at any point during step a). [0236] 41. A process for the preparation of a fluorochemical, the process comprising the steps of: [0237] a) preparing a fluorinating reagent as described in any one of the preceding statements; and [0238] b) contacting an organic substrate with the fluorinating reagent, wherein step b) is conducted simultaneously with, or after, step a). [0239] 42. The process of statement 41, wherein the organic substrate is aromatic or aliphatic. [0240] 43. The process of statement 41 or 42, wherein the organic substrate comprises at least one leaving group located at the site to be fluorinated. [0241] 44. The process of statement 43, wherein the organic substrate has more than one leaving group (e.g., 2 leaving groups), optionally wherein the leaving groups may be attached to the same carbon atom (e.g., 2 geminal halide leaving groups). [0242] 45. The process of any one of statements 41 to 44, wherein the organic substrate has a molecular weight of <500 g mol.sup.−1. [0243] 46. The process of statement 45, wherein the organic substrate has a molecular weight of <300 g mol.sup.−1 (e.g., <200 g mol.sup.−1). [0244] 47. The process of any one of statements 41 to 46, wherein the organic substrate is a sulphonyl halide, an aryl halide, an alkylaryl halide, an acyl halide, an α-halo carbonyl or an alkyl halide. [0245] 48 The process of any one of statements 41 to 46, wherein the organic substrate is a sulphonyl halide, an acyl halide, a heteroaryl halide, an aryl halide or an alkyl halide. [0246] 49. The process of any one of statements 41 to 46, wherein the organic substrate is an aromatic sulphonyl halide (e.g. tosyl chloride), a benzoyl halide (e.g. 4-methoxybenzoyl chloride) a halobenzene (e.g. chlorobenzene) or a benzyl halide (e.g. benzyl chloride). [0247] 50. The process of any one of statements 41 to 49, wherein step b) is conducted simultaneously with step a) and step b) comprises contacting the organic substrate with the fluorinating reagent under identical conditions to those used to form the fluorinating reagent. [0248] 51. The process of any one of statements 41 to 49, wherein and step b) is conducted after step a) and step b) comprises pulverising together the organic substrate and the fluorinating reagent formed from step a) in the solid state. [0249] 52. The process of any one of statements 41 to 49, wherein step b) is conducted after step a) and step b) comprises mixing together the organic substrate and the fluorinating reagent in one or more solvents in which the organic substrate is soluble. [0250] 53. The process of statement 52, wherein step b) is conducted in one or more solvents selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, diglyme, monoglyme, acetonitrile, propionitrile, tert-butyl isocyanide, tert-butanol, tert-amyl alcohol, toluene, m-xylene, hexane, trifluorotoluene, 1,2-difluorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, fluorobenzene and chlorobenzene. [0251] 54. The process of statement 52, wherein step b) is conducted in a 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. [0252] 55. The process of statement 52, wherein step b) is conducted 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. [0253] 56. The process of statement 52, wherein step b) is conducted in acetonitrile, propionitrile, chlorobenzene, tert-butanol or tert-amyl alcohol. [0254] 57. The process of any one of statements 53 to 56, wherein any one or more of the organic solvents are in admixture with water. [0255] 58. The process of statement 57, wherein the organic solvent may be in admixture with water at a concentration of 0.01-5M (e.g., 0.01-1M, such as 0.05-0.5M). [0256] 59. The process of any one of statements 41 to 58, wherein step b) is conducted in the presence of at least one of a cryptand, a crown ether and a hydrogen-bonding phase transfer catalyst. [0257] 60. The process of statement 59, wherein step b) is conducted in the presence of a crown ether. [0258] 61. The process of 60, wherein the crown ether is 18-crown-6 or dibenzo-18-crown-6. [0259] 62. The process of any one of statements 52 to 61, wherein step b) is conducted at a temperature of 15-180° C. [0260] 63. A process for the preparation of a fluorochemical, the process comprising the steps of: [0261] a) pulverising a fluorine-containing compound in the solid state, wherein the fluorine-containing compound is at least one of calcium fluoride and fluorapatite; and [0262] b) contacting the product of step a) with an organic substrate;
wherein step b) is conducted simultaneously with, or after, step a). [0263] 64. A process for the preparation of a fluorochemical, the process comprising the steps of: [0264] a) pulverising a calcium fluoride in the solid state; and [0265] b) contacting the product of step a) with an organic substrate;
wherein step b) is conducted simultaneously with, or after, step a). [0266] 65. The process of statement 63 or 64, wherein step b) is conducted in solution, in the presence of an ionic compound as described herein (e.g., K.sub.2HPO.sub.4). [0267] 66. Use of a fluorine-containing compound, the fluorine-containing compound being at least one of calcium fluoride and fluorapatite, as a fluorine source in a process for preparing a fluorochemical or a fluorinating reagent, wherein the process does not comprise a step of reacting the calcium fluoride with sulfuric acid to generate hydrofluoric acid. [0268] 67. Use of calcium fluoride as a fluorine source in a process for preparing a fluorochemical, wherein the process does not comprise a step of reacting the calcium fluoride with sulfuric acid to generate hydrofluoric acid. [0269] 68. A fluorinating reagent obtained, directly obtained or obtainable by the process of any one of statements 1 to 40. [0270] 69. A fluorinating reagent comprising a mixture of inorganic salts. [0271] 70. The fluorinating reagent of statement 68, wherein the fluorinating reagent comprises a mixture of inorganic salts. [0272] 71. The fluorinating reagent of statement 68, 69 or 70, wherein the fluorinating reagent comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur, nitrogen and carbon. [0273] 72. The fluorinating reagent of statement 68, 69 or 70, wherein the fluorinating reagent comprises calcium, fluorine and oxygen, as well as: (i) at least one of potassium and sodium, and (ii) at least one of phosphorus, sulfur and carbon. [0274] 73. The fluorinating reagent of statement 68, 69 or 70, wherein the fluorinating reagent comprises calcium, fluorine, oxygen, potassium and phosphorus. [0275] 74. The fluorinating reagent of any one of statements 68 to 73, wherein the fluorinating reagent comprises a mixture of inorganic salts, the mixture comprising a first inorganic salt and a second inorganic salt, wherein: (i) the first inorganic salt comprises Ca.sup.2+ and at least one anion selected from phosphate, sulfate, sulfite, nitrate, carbonate and hydroxide, and (ii) the second inorganic salt comprises fluoride and at least one cation selected from K.sup.+ and Na.sup.2+. [0276] 75. The fluorinating reagent of statement 74, wherein the first inorganic salt comprises Ca.sup.2+ and at least one anion selected from phosphate, sulfate, carbonate and hydroxide (e.g., phosphate), and/or the second inorganic salt comprises fluoride and K.sup.+. [0277] 76. The fluorinating reagent of any one of statements 68 to 75, wherein the fluorinating reagent is provided as a powder. [0278] 77. The fluorinating reagent of statements 76, wherein the powder has an average particle size, as determined by SEM or TEM analysis, of <500 μm (e.g., <100 μm). [0279] 78. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent has an XRPD pattern comprising peaks corresponding ±0.2° 2θ 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. [0280] 79. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent has an XRPD pattern comprising peaks corresponding ±0.2° 2θ 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. [0281] 80. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent has an XRPD pattern comprising peaks corresponding ±0.2° 2θ 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. [0282] 81. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent has an XRPD pattern comprising 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. [0283] 82. The fluorinating reagent of statement 81, wherein the XRPD pattern comprises one or more additional 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, 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. [0284] 83. The fluorinating reagent of statement 82, wherein the XRPD pattern comprises at least five of the additional peaks. [0285] 84. The fluorinating reagent of statement 82, wherein the XRPD pattern comprises at least ten of the additional peaks. [0286] 85. The fluorinating reagent of statement 82, wherein the XRPD pattern comprises at least fifteen of the additional peaks. [0287] 86. The fluorinating reagent of statement 82, wherein the XRPD pattern comprises at least twenty of the additional peaks. [0288] 87. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent may have an XRPD pattern comprising one or more peaks at 2-theta values of 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, 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. [0289] 88. The fluorinating reagent of statement 87, wherein the XRPD pattern comprises at least two or at least three of the peaks. [0290] 89. The fluorinating reagent of statement 87, wherein the XRPD pattern comprises at least four or at least five of the peaks. [0291] 90. The fluorinating reagent of statement 87, wherein the XRPD pattern comprises at least ten or at least fifteen of the peaks. [0292] 91. The fluorinating reagent of statement 87, wherein the XRPD pattern comprises at least twenty of the peaks. [0293] 92. The fluorinating reagent of any one of statements 87 to 91, wherein the fluorinating reagent comprises K.sub.3(HPO.sub.4)F. [0294] 93. The fluorinating reagent of any one of statements 68 to 77, wherein the fluorinating reagent comprises K.sub.3(HPO.sub.4)F and 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. [0295] 94. The fluorinating reagent of statement 93, wherein the fluorinating reagent has an XRPD pattern comprising at least two of the peaks. [0296] 95. The fluorinating reagent of statement 93, wherein the fluorinating reagent has an XRPD pattern comprising at least four of the peaks. [0297] 96. The fluorinating reagent of statement 93, wherein the fluorinating reagent has an XRPD pattern comprising at least six of the peaks. [0298] 97. The fluorinating reagent of statement 93, wherein the fluorinating reagent has an XRPD pattern comprising all eight of the peaks. [0299] 98. The fluorinating reagent of any one of statements 68 to 97, wherein the fluorinating reagent comprises calcium fluoride and/or fluorapatite (e.g., a trace quantity of calcium fluoride and/or fluorapatite). [0300] 99. The fluorinating reagent of any one of statements 68 to 98, wherein the fluorinating reagent has an XRPD pattern substantially as shown in any one of FIGS. 4-16. 26. 38-46 and 52-53. [0301] 100. The fluorinating reagent of any one of statements 68 to 98, wherein the fluorinating reagent has an XRPD pattern substantially as shown in any one of FIGS. 10, 11 and 26.

[0302] In some embodiments, provided herein is an activated fluorinated reagent. In some embodiments, the activated fluorinated reagent comprises a first salt, the first salt comprising calcium and fluorine, and a second salt. In some embodiments, the second salt comprises an anion. The first salt and second salt are described elsewhere herein.

[0303] In some embodiments, provided herein is a method of synthesizing a fluoro compound. In some embodiments, provided herein is a method of synthesizing an organo-fluorine compound. In some embodiments, the method comprises combining a first salt, the first salt comprising calcium and fluorine, with a second salt to form a salt mixture.

[0304] Provided herein, in some embodiments, are compositions and methods that use a first salt. In any composition or method provided herein, any suitable first salt is used. 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 CaF.sub.2. In some embodiments, the first salt is fluorspar. In some embodiments, the first salt is fluorapatite (Ca.sub.5(PO.sub.4).sub.3F). In some embodiments, waste material comprises the first salt. In some embodiments, the first salt is added in an amount necessary to provide an activated fluorination reagent.

[0305] In some embodiments, the methods and compositions described herein do not comprise reacting a strong acid with the first salt to form hydrofluoric acid. In some embodiments, essentially no HF is produced during the reaction. In some embodiments, <1 ppm of HF is observable in a mixture at any point during the reaction. In some embodiments, <1 ppb of HF is observable in a mixture at any point during the reaction.

[0306] In some embodiments, provided herein are compositions and methods that use a second salt. In some embodiments, any suitable second salt is used in any composition or method provided herein. In some embodiments, the second salt comprises an anion. In some embodiments, the second salt comprises an anion, which has a lattice energy greater than 2450 kJ/mol when combined with Ca.sup.2+ to form a third salt. In some embodiments, the second salt comprises a cation and anion.

[0307] In some embodiments, any composition or method herein comprises a second salt, the second salt comprising an anion, which has a lattice energy greater than 2450 kJ/mol when combined with Ca.sup.2+ to form a third salt. In some embodiments, the anion and Ca.sup.2+ can form a third salt which has a lattice energy greater than 2450 kJ/mol when combined. In some embodiments, the fluorinating reagent comprises a salt which has a lattice energy greater than 2450 kJ/mol.

[0308] 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 sulphite. In some embodiments, the second salt comprises Na.sub.2SO.sub.3 and/or K.sub.2SO.sub.3. In some embodiments, the second salt is Na.sub.2SO.sub.3. In some embodiments, the second salt is K.sub.2SO.sub.3. In some embodiments, the second salt is a metal sulphate. In some embodiments, the second salt comprises KHSO.sub.4. In some embodiments, the second salt is an inorganic phosphate.

[0309] In some embodiments, the second salt comprises K.sub.2HPO.sub.4, KH.sub.2PO.sub.4, and/or K.sub.3PO.sub.4. In some embodiments, the second salt is K.sub.2HPO.sub.4. In some embodiments, the second salt is KH.sub.2PO.sub.4. In some embodiments, the second salt is K.sub.3PO.sub.4. In some embodiments, the inorganic phosphate is a pyrophosphate. In some embodiments, the inorganic phosphate comprises K.sub.4P.sub.2O.sub.7 and/or Na.sub.3P.sub.2O.sub.7.

[0310] In some embodiments, an inorganic phosphate is K.sub.4P.sub.2O.sub.7. In some embodiments, an inorganic phosphate is Na.sub.3P.sub.2O.sub.7. In some embodiments, the second salt is Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, NaH.sub.2PO.sub.4, K.sub.2SO.sub.4, Na.sub.2SO.sub.4, MgSO.sub.4, Ag.sub.2SO.sub.4, Na.sub.2CO.sub.3, and/or KHCO.sub.3. In some embodiments, the second salt comprises Na.sub.3PO.sub.4. In some embodiments, the second salt comprises Na.sub.2HPO.sub.4. In some embodiments, the second salt comprises NaH.sub.2PO.sub.4.

[0311] In some embodiments, the second salt comprises K.sub.2SO.sub.4. In some embodiments, the second salt comprises Na.sub.2SO.sub.4. In some embodiments, the second salt comprises MgSO.sub.4. In some embodiments, the second salt comprises Ag.sub.2SO.sub.4. In some embodiments, the second salt comprises Na.sub.2CO.sub.3. In some embodiments, the second salt comprises KHCO.sub.3.

[0312] In some embodiments, any suitable ratio of first salt to second is used in any composition or method provided herein. In some embodiments, any suitable ratio of first salt to second is used in any composition or method provided herein. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:150 or any range therein. In some embodiments, the ratio of first salt to second salt is about 2:1 to 150:1 or any range therein. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5 to 1:100. In some embodiments, the ratio of the first salt to the second salt is about 1:1 to 1:10. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:2. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:4. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:8. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:10. In some embodiments, the ratio of first salt to second salt is about 1:0.5 to 1:20. In some embodiments, the ratio of the first salt to the second salt is about 1:1 to 1:5. In some embodiments, the ratio of the first salt to the second salt is about 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100. In some embodiments, the range of first salt to second salt is about 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1. 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 first salt to second salt is 1:8. In some embodiments, the ratio of first salt to second salt is 2:1.

[0313] In some embodiments, the method comprises applying mechanical force to the salt mixture to form an activated salt-mixture. In some embodiments, the activated salt mixture is the fluorinating reagent. In some embodiments, the activated salt mixture is the activated fluorinated reagent.

[0314] In some embodiments, mechanical force is applied to the salt mixtures provided in any of the compositions or methods herein. In some embodiments, mechanical force is applied to the salt-waste mixtures provided herein. In some embodiments, mechanical force is applied to the salt mixtures provided herein to yield activated fluorinated reagents.

[0315] In some embodiments, mechanical force is applied to the salt-waste mixtures provided herein to yield activated fluorinated reagents. In some embodiments, the mechanical force is applied using a ball mill, a mortar and pestle, a twin-screw extruder, using an ultrasonic bath, or a mechanical press.

[0316] 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.

[0317] In some embodiments, mechanical frequency is applied at any suitable frequency in any composition or method provided herein. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz or any range therein. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz-60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz-10 Hz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz-100 Hz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-1 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-10 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-30 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-50 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5-60 kHz. In some embodiments, the mechanical force is applied at a frequency of about 10 Hz-20 kHz. In some embodiments, the mechanical force is applied at a frequency of about 0.5 Hz, 1 Hz, 5 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz, 55 Hz, or 60 Hz. 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.

[0318] In some embodiments, the mechanical frequency is applied at any suitable temperature in any composition or method 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 150° 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° C. to about 200° C., about 60° C. to about 250° C., about 60° C. to about 280° C., about 60° C. to about 300° C., about 90° C. to about 100° C., about 90° C. to about 130° C., about 90° C. to about 150° C., about 90° C. to about 200° C., about 90° C. to about 250° C., about 90° C. to about 280° C., about 90° C. to about 300° C., about 100° C. to about 130° 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 280° C., about 100° C. to about 300° C., about 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 at most about 30° C., about 40° C., about 60° C., about 90° C., about 100° C., about 130° C., about 150° C., about 200° C., about 250° C., about 280° C., or about 300° C. In some embodiments, the mechanical force is applied at a temperature of about 30° C. In some embodiments, the mechanical force is applied at a temperature of about 60° C. In some embodiments, the mechanical force is applied at a temperature of about 90° C.

[0319] In any of the compositions or methods provided herein, the mechanical force may be applied to the first and second salt together. In any of the compositions or methods provided herein, the mechanical force may be applied to the first salt alone. In some embodiments, the mechanical force may be applied for any suitable time period.

[0320] In some embodiments, the mechanical force may be applied for about 0.5 hours to about 12 hours. In some embodiments, the mechanical force may be applied for 0.5-1 hour. In some embodiments, the mechanical force may be applied for 0.5-4 hours. In some embodiments, the mechanical force may be applied for 0.5-8 hours. In some embodiments, the mechanical force may be applied for 4-8 hours. In some embodiments, the mechanical force may be applied for 4-12 hours. In some embodiments, the mechanical force may be applied for about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In some embodiments, the mechanical force is applied for about 1 hour. In some embodiments, the mechanical force is applied for about 2 hours. In some embodiments, the mechanical force is applied for about 3 hours. In some embodiments, the mechanical force is applied for about 4 hours. In some embodiments, the mechanical force is applied for about 6 hours. In some embodiments, the mechanical force is applied for about 9 hours. In some embodiments, longer mechanical force times may be associated with higher yields of fluorinated product.

[0321] In some embodiments, provided herein are salt mixtures produced by ball milling in any composition or method provided herein. In some embodiments, ball milling is completed by combining said salts into jars and adding balls. In some embodiments, the jars and balls comprise stainless steel.

[0322] 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, 1 ball is used. In some embodiments, the ball weight is 1-20 g or any range therein. In some embodiments, the ball weight is 1-2 g. In some embodiments, the ball weight is 1-3 g. In some embodiments, the ball weight is 1-5 g. In some embodiments, the ball weight is 1-10 g. In some embodiments, the ball weight is 1-13 g. In some embodiments, the ball weight is 1-18 g. In some embodiments, the ball weight is 1-3 g. 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, 2 balls were used and the ball weights were 3 g. In some embodiments, the ball weight is 16 g. In some instances, ball weight is used as an analog of ball size. In some embodiments, the ball size may affect the fluorination reaction yield.

[0323] In some embodiments, mechanical force is applied in the compositions or methods herein using a twin-screw extruder. In some embodiments, a twin-screw extruder may be fixed with a gravimetric single screw feeder (e.g., hopper) for programmed addition of solids. FIG. 54 shows a schematic of a twin-screw extruder (TSE) wherein the first and second salts may be added into the TSE at a rate of F.sub.R, followed by extruding of the salts at varying screw speeds (S.sub.S), screw temperatures (S.sub.T), and residence times (T.sub.R), providing the fluorinating reagent (e.g., fluoromix). In some embodiments, the screw configuration may be modified wherein C indicates conveying, K indicates kneading, and R indicates reverse elements.

[0324] In some embodiments, the screw temperature (S.sub.T) in a twin-screw extruder 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° 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 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.

[0325] In some embodiments, the screw speed (S.sub.S) in a twin-screw extruder is applied at any suitable speed in any composition or method provided herein. In some embodiments, the screw speed is set at a range of about 1 rpm to about 80 rpm. In some embodiments, the screw speed is set at a range of about 1 rpm to about 5 rpm, about 1 rpm to about 10 rpm, about 1 rpm to about 15 rpm, about 1 rpm to about 25 rpm, about 1 rpm to about 40 rpm, about 1 rpm to about 50 rpm, about 1 rpm to about 60 rpm, about 1 rpm to about 70 rpm, about 1 rpm to about 75 rpm, about 1 rpm to about 80 rpm, about 5 rpm to about 10 rpm, about 5 rpm to about 15 rpm, about 5 rpm to about 25 rpm, about 5 rpm to about 40 rpm, about 5 rpm to about 50 rpm, about 5 rpm to about 60 rpm, about 5 rpm to about 70 rpm, about 5 rpm to about 75 rpm, about 5 rpm to about 80 rpm, about 10 rpm to about 15 rpm, about 10 rpm to about 25 rpm, 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, about 25 rpm to about 50 rpm, about 25 rpm to about 60 rpm, about 25 rpm to about 70 rpm, about 25 rpm to about 75 rpm, about 25 rpm to about 80 rpm, about 40 rpm to about 50 rpm, about 40 rpm to about 60 rpm, 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 at a range of about 1 rpm, about 5 rpm, about 10 rpm, about 15 rpm, about 25 rpm, about 40 rpm, about 50 rpm, about 60 rpm, about 70 rpm, about 75 rpm, or about 80 rpm. In some embodiments, the screw speed is 10 rpm. In some embodiments, the screw speed is 25 rpm. In some embodiments, the screw speed is 75 rpm.

[0326] In some embodiments, the residence time (T.sub.R) in a twin-screw extruder is set to any suitable time in any composition or method provided herein. In some embodiments, the residence time is about 1 seconds to about 420 seconds. In some embodiments, the residence time is about 1 seconds to about 20 seconds, about 1 seconds to about 40 seconds, about 1 seconds to about 60 seconds, about 1 seconds to about 80 seconds, about 1 seconds to about 120 seconds, about 1 seconds to about 140 seconds, about 1 seconds to about 165 seconds, about 1 seconds to about 220 seconds, about 1 seconds to about 300 seconds, about 1 seconds to about 420 seconds, about 20 seconds to about 40 seconds, about 20 seconds to about 60 seconds, about 20 seconds to about 80 seconds, about 20 seconds to about 120 seconds, about 20 seconds to about 140 seconds, about 20 seconds to about 165 seconds, about 20 seconds to about 220 seconds, about 20 seconds to about 300 seconds, about 20 seconds to about 420 seconds, about 40 seconds to about 60 seconds, about 40 seconds to about 80 seconds, about 40 seconds to about 120 seconds, about 40 seconds to about 140 seconds, about 40 seconds to about 165 seconds, about 40 seconds to about 220 seconds, about 40 seconds to about 300 seconds, about 40 seconds to about 420 seconds, about 60 seconds to about 80 seconds, about 60 seconds to about 120 seconds, about 60 seconds to about 140 seconds, about 60 seconds to about 165 seconds, about 60 seconds to about 220 seconds, about 60 seconds to about 300 seconds, about 60 seconds to about 420 seconds, about 80 seconds to about 120 seconds, about 80 seconds to about 140 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 to 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 seconds, about 20 seconds, about 40 seconds, about 60 seconds, about 80 seconds, about 120 seconds, about 140 seconds, about 165 seconds, about 220 seconds, about 300 seconds, or about 420 seconds. In some embodiments, the residence time is 80 seconds. In some embodiments, the residence time is 165 seconds. In some embodiments, the residence time is 420 seconds.

[0327] In some embodiments, the fluorinated reagent is recycled through the twin-screw extruder (e.g., twin-screw extruder) any suitable number of times in any composition or method provided herein. In some embodiments, the fluorinated reagent was recycled through the extruder 1 time. In some embodiments, the fluorinated reagent was recycled through the extruder 2 times. In some embodiments, the fluorinated reagent was recycled through the extruder 3 times.

[0328] In some embodiments, the activated fluorinating reagent or third salt described in any of the compositions or methods herein is characterized with Powder X-ray diffraction. The powder x-ray diffraction spectrum of the activated fluorinating reagent described herein may exhibit one or more characteristic reflections at about 18.0°, 18.7°, 21.9°, 22.6°, 24.5°, 25.4°, 26.5°, 27.0°, 28.0°, 29.2°, 30.3°, 31.6°, 33.0°, 34.8°, 36.4°, 37.7°, 39.5°, 40.4°, 41.7°, 42.4°, 43.4°, 46.1°, 48.4°, 49.4°, 52.8°, and/or 53.9°.

[0329] In some embodiments, a 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°.

[0330] In some embodiments, a 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°.

[0331] In some embodiments, a 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°.

[0332] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises characteristic at least four 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, a powder x-ray diffraction spectrum of the activated reagent comprises characteristic 2θ reflections at about 21.9°, 30.3°, 31.6°, and 43.4°.

[0333] In some embodiments, a 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°.

[0334] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic 2θ reflections.

[0335] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the tallest peak in a raw spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the tallest peak in a background subtracted spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are at least 10%, at least 15%, or at least 20% relative to the tallest peak in a background subtracted spectrum.

[0336] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the peak with the largest integration in a raw spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 0.1%, at least 1%, or at least 5% relative to the peak with the largest integration in a background subtracted spectrum. In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are at least 10%, at least 15%, or at least 20% relative to the peak with the largest integration in a background subtracted spectrum.

[0337] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak integrations of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.

[0338] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises relative peak intensities of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.

[0339] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises d-spacing values of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.

[0340] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises absolute peak intensities of characteristic reflections which are about one or more values independently selected from those described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2, and/or combinations thereof.

[0341] In some embodiments, a powder x-ray diffraction spectrum of the activated reagent comprises a ratio of any spectral property of any characteristic reflection to the same spectral property of another characteristic reflection which is about a ratio of the spectral properties of the corresponding characteristic reflections described in any one of the Tables provided herein, e.g. Tables 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8, 5.7.9, 5.7.10, 5.7.11, 5.7.12, 5.7.13, 5.12.1, 5.12.2, 5.12.3, 5.12.4, 5.12.5, 5.13.1, 5.13.2, 5.14.1, 5.14.2, 5.14.3, 5.14.4, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8, 6.3.9, 7.7.1, 7.7.2.

[0342] In some embodiments, the spectral property can include an absolute intensity, a relative intensity, an absolute area, a relative area, an estimated d-spacing, a full-width at half max peak resolution, and/or combinations thereof. In some embodiments, the method comprises combining the activated salt mixture with a first reactant, the first reactant, and fluorinating the first reactant to yield a fluorinated compound. In some embodiments, the first reactant is an organic compound. In some embodiments, the fluorinated compound is an organo-fluorine compound. In some embodiments, the first reactant is an inorganic compound.

[0343] In any of the compositions or methods described herein, fluorinating is performed at any suitable temperature. In some embodiments, the fluorination reaction is performed at a temperature of about 0° C. to about 400° C. In some embodiments, the fluorination reaction is performed at a temperature of about 0° C. to about 20° C., about 0° C. to about 50° C., about 0° C. to about 100° C., about 0° C. to about 150° C., about 0° C. to about 200° C., about 0° C. to about 250° C., about 0° C. to about 300° C., about 0° C. to about 350° C., about 0° C. 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 400° 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 performed at a temperature of about 0° C., about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., about 350° C., or about 400° C. In some embodiments, the fluorination reaction is performed at a temperature of at least about 0° C., about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., or about 350° C. In some embodiments, the fluorination reaction is performed at a temperature of at most about 20° C., about 50° C., about 100° C., about 150° C., about 200° C., about 250° C., about 300° C., about 350° C., or about 400° C. In some embodiments, the fluorination is performed at a temperature of about 100° C.

[0344] In some embodiments, the fluorination reaction yield is measured. The fluorination reaction yield is for example, measured by .sup.19F NMR using 4-fluoroanisole as an internal standard. In some embodiments, the reaction yield of the organo-fluorine compound is about 0.1%, to about 95%. In some embodiments, the reaction yield of the organo-fluorine compound is about 0.1%, to about 1%, about 0.1%, to about 10%, about 0.1%, to about 20%, about 0.1%, to about 30%, about 0.1%, to about 40%, about 0.1%, to about 50%, about 0.1%, to about 60%, about 0.1 to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 95%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1 to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 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 organo-fluorine compound is about 0.1%, about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%. In some embodiments the reaction yield of the organo-fluorine compound is measured based on a starting amount of the organic compound.

[0345] In some embodiments, the organic compound in any of the compositions or methods provided herein comprises an aromatic or aliphatic and comprises at least one leaving group located at a site to be fluorinated. In some embodiments, the leaving group comprises a halogen. In some embodiments, the organic compound comprises an aromatic. In some embodiments, the organic compound comprises an aliphatic. In some embodiments, the organic compound comprises an aromatic and comprises at least one leaving group located at a site to be fluorinated. In some embodiments, the organic compound comprises an aliphatic and comprises at least one leaving group at a site to be fluorinated. In some embodiments, the fluorination occurs at the same site of the leaving group as described in Scheme 0.1.

##STR00001##

[0346] In some embodiments, R is an aromatic. In some embodiments, R is an aliphatic. In some embodiments, X is a leaving group. In some embodiments, X is a halogen. In some embodiments, X is a bromide. In some embodiments, X is a chloride.

[0347] In some embodiments, the organic compound is a sulphonyl halide, an acyl halide, an aryl halide, and/or an alkyl halide. In some embodiments, the organic compound comprises a sulphonyl halide. In some embodiments, the organic compound comprises an acyl halide. In some embodiments, the organic compound comprises an aryl halide. In some embodiments, the organic compound comprises an alkyl halide.

[0348] In some embodiments, the organic compound is an aromatic sulphonyl halide, a benzoyl halide, a halobenzene, or a benzyl halide. In some embodiments, the organic compound is an aromatic sulphonyl halide. In some embodiments, the organic compound comprises tosyl chloride. In some embodiments, the organic compound is a benzoyl halide. In some embodiments, the organic compound comprises 4-methoxybenzoyl chloride. In some embodiments, the organic compound is a halobenzene. In some embodiments, the organic compound comprises chlorobenzene. In some embodiments, the organic compound is a benzyl halide. In some embodiments, the organic compound is benzyl chloride. In some embodiments, the organic compound is an α-halo carbonyl. In some embodiments, the organic compound is a α-bromo carbonyl. In some embodiments, the organic compound is an alkyl halide. In some embodiments, the organic compound is an alkyl bromide. In some embodiments, the compound is a (hetero)aryl halide. In some embodiments, the compound is a (hetero)aryl chloride.

[0349] In some embodiments, the fluorination reaction is a mono-fluorination reaction. In some embodiments, the fluorination reaction is a poly-fluorination reaction. In some embodiments, the fluorination reaction is a di-fluorination reaction. In some embodiments, the fluorinated product is stable to reaction against the second salt after formation.

[0350] In some embodiments, the inorganic compound of 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 a chlorine. In some embodiments, the halogen is a bromine. In some embodiments, the halogen is an iodine. In some embodiments, the anion is exchangeable with fluorine, providing the fluoro compound. In some embodiments, the fluoro compound is NaF. In some embodiments, the fluoro compound is KF.

[0351] In any of the methods or compositions provided herein, in some embodiments, the first salt, second salt, and the organic compound are combined in the same step. In any of the methods or compositions provided herein, in other embodiments, the first salt and second salt are combined prior to addition of the organic compound.

[0352] 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 and second salt are combined as solids without the addition of solvent. In other embodiments, the first salt, second salt, and the organic compound is added together with one or more solvents in which the organic compound is soluble in at least one of the one or more solvents. In some embodiments, the first salt and second salt are combined prior to addition of the organic compound.

[0353] 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.

[0354] 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 instances, an 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, second salt, and the organic compound are soluble in the solvent.

[0355] In some embodiments, the one or more solvents comprise a solvent selected from the group consisting of acetonitrile, propionitrile, toluene, 1,2-dichlorobenze, chlorobenzene fluorobenzene,1,2-difluorobenze, dichloroethane, trifluorotoluene, chloroform, tert-butanol, tert-amyl alcohol, and/or water. In some embodiments, the one or more solvents comprise acetonitrile, chlorobenzene, tert-butanol, tert-amyl alcohol, and/or water. In some embodiments, the solvent may comprise acetonitrile. In some embodiments, the solvent may comprise propionitrile. In some embodiments, the solvent may comprise toluene. In some embodiments, the solvent may comprise 1,2-dichlorobenzene. In some embodiments, the solvent may comprise fluorobenzene. In some embodiments, the solvent may comprise 1,2-difluorobenze. In some embodiments, the solvent may comprise dichloroethane. In some embodiments, the solvent may comprise trifluorotoluene. In some embodiments, the solvent may comprise chloroform. In some embodiments, the solvent may comprise tert-butanol. In some embodiments, the solvent may comprise tert-amyl alcohol.

[0356] In some embodiments, the solvent may comprise water. In some embodiments, the solvent may comprise tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl isocyanide, m-xylene, hexane, diglyme, and/or monoglyme. In some embodiments, the solvent may comprise tetrahydrofuran. In some embodiments, the solvent may comprise 2-methyltetrahydrofuran. In some embodiments, the solvent may comprise 1,4-dioxane. In some embodiments, the solvent may comprise tert-butyl isocyanide. In some embodiments, the solvent may comprise m-xylene. In some embodiments, the solvent may comprise hexane. In some embodiments, the solvent may comprise diglyme. In some embodiments, the solvent may comprise monoglyme. In some embodiments, any one or more of the aforementioned organic solvents may be in admixture with water.

[0357] In some embodiments, in any composition or method herein, the organic solvent may be in admixture with water at a concentration of about 0.01M to about 5M or any range therein. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.01 M to about 1 M. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.01 M to about 0.05 M, about 0.01 M to about 0.1 M, about 0.01 M to about 0.2 M, about 0.01 M to about 0.3 M, about 0.01 M to about 0.4 M, about 0.01 M to about 0.6 M, about 0.01 M to about 0.8 M, about 0.01 M to about 1 M, about 0.05 M to about 0.1 M, about 0.05 M to about 0.2 M, about 0.05 M to about 0.3 M, about 0.05 M to about 0.4 M, about 0.05 M to about 0.6 M, about 0.05 M to about 0.8 M, about 0.05 M to about 1 M, about 0.1 M to about 0.2 M, about 0.1 M to about 0.3 M, about 0.1 M to about 0.4 M, about 0.1 M to about 0.6 M, about 0.1 M to about 0.8 M, about 0.1 M to about 1 M, about 0.2 M to about 0.3 M, about 0.2 M to about 0.4 M, about 0.2 M to about 0.6 M, about 0.2 M to about 0.8 M, about 0.2 M to about 1 M, about 0.3 M to about 0.4 M, about 0.3 M to about 0.6 M, about 0.3 M to about 0.8 M, about 0.3 M to about 1 M, about 0.4 M to about 0.6 M, about 0.4 M to about 0.8 M, about 0.4 M to about 1 M, about 0.6 M to about 0.8 M, about 0.6 M to about 1 M, or about 0.8 M to about 1 M. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.01 M, about 0.05 M, about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.6 M, about 0.8 M, or about 1 M. In some embodiments, the organic solvent may be in admixture with water at a concentration of about 0.25 M. In some instances, the inclusion of water may increase the yield of organo-fluorine product.

[0358] In other embodiments, in any composition or method herein, the one or more solvents may comprise an additive. In some embodiments, in any composition or method herein, the one or more solvents may comprise a cryptand, a crown ether, and a hydrogen-bonding phase transfer agent. In some embodiments, the one or more solvents comprise a cryptand. In some embodiments, the one or more solvents comprise a crown ether. In some embodiments, the one or more solvents comprise 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 the crown ether is dibenzo 18-crown-6 ether. In some embodiments the dibenzo derivative of the crown ether is dibenzo-30-crown-6-ether. In some embodiments, the crown ether is dicyclohexano-18-crown-6-ether. In some embodiments, the cryptand is [2.2.2]cryptand. In some embodiments, the cryptand is [2.2.1]cryptand. In some embodiments, the one or more solvents may comprise schreiner's urea.

[0359] In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent is added in any suitable amount to any composition or method provided herein. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent, are added in amount of about 0.01 equivalents to about 5 equivalents. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent, are added in amount of about 0.01 equivalents to about 0.1 equivalents, about 0.01 equivalents to about 1 equivalents, about 0.01 equivalents to about 2 equivalents, about 0.01 equivalents to about 3 equivalents, about 0.01 equivalents to about 4 equivalents, about 0.01 equivalents to about 5 equivalents, about 0.1 equivalents to about 1 equivalents, about 0.1 equivalents to about 2 equivalents, about 0.1 equivalents to about 3 equivalents, about 0.1 equivalents to about 4 equivalents, about 0.1 equivalents to about 5 equivalents, about 1 equivalents to about 2 equivalents, about 1 equivalents to about 3 equivalents, about 1 equivalents to about 4 equivalents, about 1 equivalents to about 5 equivalents, about 2 equivalents to about 3 equivalents, about 2 equivalents to about 4 equivalents, about 2 equivalents to about 5 equivalents, about 3 equivalents to about 4 equivalents, about 3 equivalents to about 5 equivalents, or about 4 equivalents to about 5 equivalents. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent, are added in amount of about 0.01 equivalents, about 0.1 equivalents, about 1 equivalent, about 2 equivalents, about 3 equivalents, about 4 equivalents, or about 5 equivalents. In some embodiments, the cryptand, crown ether, or hydrogen-bond phase transfer agent is added in amount to increase the yield of the organo-fluorine product.

[0360] In any composition or method herein, in some embodiments, fluorinating may take place for any suitable amount of time. In some embodiments, fluorinating may take place for about 0.5 hrs to about 24 hrs. In some embodiments, fluorinating may take place for about 0.5 hrs to about 1 hr, about 0.5 hrs to about 3 hrs, about 0.5 hrs to about 5 hrs, about 0.5 hrs to about 12 hrs, about 0.5 hrs to about 16 hrs, about 0.5 hrs to about 24 hrs, about 1 hr to about 3 hrs, about 1 hr to about 5 hrs, about 1 hr to about 12 hrs, about 1 hr to about 16 hrs, about 1 hr to about 24 hrs, about 3 hrs to about 5 hrs, about 3 hrs to about 12 hrs, about 3 hrs to about 16 hrs, about 3 hrs to about 24 hrs, about 5 hrs to about 12 hrs, about 5 hrs to about 16 hrs, about 5 hrs to about 24 hrs, about 12 hrs to about 16 hrs, about 12 hrs to about 24 hrs, or about 16 hrs to about 24 hrs. In some embodiments, fluorinating may take place for about 0.5 hrs, about 1 hr, about 3 hrs, about 5 hrs, about 12 hrs, about 16 hrs, or about 24 hrs. In some embodiments, fluorinating may take place for at least about 0.5 hrs, about 1 hr, about 3 hrs, about 5 hrs, about 12 hrs, or about 16 hrs. In some embodiments, fluorinating may take place for 3 hours. In some embodiments, fluorinating may take place for 5 hrs. In some embodiments, fluorinating may take place for 12 hrs. In some embodiments, fluorinating may take place for 16 hrs.

[0361] In further embodiments, provided herein is a method of fluorinating an organic compound. In some embodiments, the method comprises combining an activated fluorinating reagent with the organic compound, wherein the activated fluorinating reagent and the organic compound are described elsewhere herein. In some embodiments, the method comprises fluorinating the organic compound to produce an organo-fluorine compound.

[0362] In some embodiments, provided herein is a method of manufacturing an activated fluorination reagent. In some embodiments, the method comprises combining a first salt, the first salt comprising calcium and fluorine, with a second salt to form a salt mixture, wherein the first salt and second salt are described elsewhere herein. In some embodiments, the method comprises applying mechanical force to the salt mixture to form an activated salt mixture, wherein the mechanical force is described elsewhere herein. In some embodiments, the method comprises combining the activated salt mixture with a first reactant. In some embodiments, the first reactant is an organic compound, wherein the organic compound is described elsewhere herein. In some embodiments, the method comprises fluorinating the first reactant to yield an organo-fluorine compound.

[0363] In other embodiments, provided herein is a method of recovering fluorine from a wate material to form an activated fluorination reagent. In some embodiments, the method comprises combining a waste material comprising a first salt comprising calcium and fluorine with a second salt to form a salt-waste mixture, wherein the first salt and second salt are described elsewhere herein. In some embodiments, the method comprises applying mechanical force to the salt-waste mixture to yield the activated fluorination reagent, wherein the mechanical force is described elsewhere herein.

Examples

Materials and Methods

[0364] 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. Dry solvents were purchased from commercial suppliers or dried on a column of alumina. Reagent grade calcium fluoride (CaF.sub.2, 97.0%, Alfa Aesar), potassium phosphate (K.sub.3PO.sub.4, ≥98%, Sigma Aldrich, CAS 7778-53-2), dipotassium hydrogen phosphate (K.sub.2HPO.sub.4, ≥98.0%, Alfa Aesar), potassium dihydrogen phosphate (KH.sub.2PO.sub.4, ≥99.0%, Alfa Aesar), sodium phosphate (Na.sub.3PO.sub.4, ≥96.0%, Sigma Aldrich), disodium hydrogen phosphate (Na.sub.2HPO.sub.4, ≥98%, Fisher Scientific), sodium dihydrogen phosphate (NaH.sub.2PO.sub.4, 96%, Fisher Scientific), potassium tripolyphosphate (K.sub.5P.sub.3O.sub.10, >94%, Strem Chemicals), sodium pyrophosphate tetrabasic decahydrate (Na.sub.4P.sub.2O.sub.7.Math.10H.sub.2O, ≥99%, Sigma Aldrich, CAS 13472-36-1), sodium tripolyphosphate (Na.sub.5P.sub.3O10, Alfa Aesar), sodium trimetaphosphate (Na.sub.3P.sub.3O.sub.9, Alfa Aesar), sodium hexametaphosphate (Graham's salt, 65-70% P.sub.2O.sub.5 basis, Sigma Aldrich), potassium metaphosphate (KPO.sub.3, 98%, Strem Chemicals), anhydrous calcium hydrogen phosphate (CaHPO.sub.4, 98.0-105.0%, Sigma Aldrich) were used without drying and stored under ambient conditions.

[0365] Potassium pyrophosphate (K.sub.4P.sub.2O.sub.7, 97.0%, Sigma Aldrich), anhydrous potassium fluoride (KF, 99%, Alfa Aesar), were used without drying and stored in a dessicator.

[0366] Fluorspar (acid grade) was purchased from Mistral Industrial Chemicals (UK), produced by Minersa group (Asturias region, Spain) and contains CaF.sub.2 (>97%), total carbonates (<1.50%), SiO.sub.2 (<1.00%), BaSO.sub.4 (<0.50%), Pb (<0.10%), Fe.sub.2O.sub.3 (<0.10%), S (<0.15%), H.sub.2O (<1.0%). Fluorspar (acid grade) was used without drying and stored under ambient conditions.

[0367] Unless otherwise stated, all reagents were purchased from commercial suppliers (Sigma-Aldrich, Alfa Aesar, Fluorochem, Minersa Group (Fluorspar), Apollo Scientific and Fisher Chemicals) and used without further purification. Unless otherwise specified, CaF.sub.2 used was purchased from Alfa Aesar (>97%, reagent grade), and K.sub.2HPO.sub.4 was acquired from Fisher Chemical (anhydrous, crystalline powder). Dry solvents were purchased from commercial suppliers or dried on a column of alumina. Column chromatography was performed on Merck silica gel (60, particle size 0.040-0.063 mm).

[0368] NMR experiments were recorded on Bruker AVIIIHD 400, AVIIIHD 500, AVII 500, or AV NEO 600 NMR Spectrometers. .sup.1H and .sup.13C 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 reported using the internal standard residual CDCl.sub.3 (δ=7.26 ppm for 1H NMR spectra and δ=77.16 ppm for .sup.13C NMR spectra). .sup.19F NMR spectra are referenced relative to CFCl.sub.3. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, pent=pentet, sept=septet, br=broad, m=multiplet), coupling constants (Hz) and integration. NMR spectra were processed with MestReNova 14.2.1 or Topspin 3.5 or 4.0. 19F 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 CDCl.sub.3, and an aliquot was taken to be analyzed by .sup.19F NMR.

[0369] Powder X-ray diffraction (PXRD) data was collected using a Bruker D8 Advance X-Ray diffractometer with Bragg-Brentano geometry. Cu K al and 2 were used and measurements were performed at room temperature unless otherwise stated. All PXRD data was collected at room temperature. For simulated structures a Rietveld refinement of powder diffraction data was performed using the TOPAS Academic (V6).

[0370] Ball milling experiments were performed using a Retsch MM 400 mixer mill. Mechanochemical reactions were performed in 15 mL, 30 mL or 50 mL stainless steel jars with either two stainless steel balls of mass 2 g, or one stainless steel ball of various mass (2 g, 3 g, 4 g, 7 g, or 9 g). No precaution was taken to exclude air and moisture.

1. One-Pot Solid State Reactions

[0371] General Procedure 1 (GP1): To a 15 mL (or 50 mL) stainless steel milling jar was added a 4 g stainless-steel ball (or 2×2 g), CaF.sub.2 (5.0 mmol), K.sub.2HPO.sub.4 (2.0 mmol) and the corresponding sulfonyl chloride (1.0 equiv). The jar was then closed and securely fitted to the mill which was set for 60 minutes at the frequency of 30 Hz. After that time, the jar was opened and the solid residue was scratched out with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3×5 mL) and transferred to the beaker. The resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc); the solvent was removed in vacuo and the crude mixture purified by silica gel chromatography if required.

1.1. Varying Salt

[0372] Following GP1 outlined above, and having regard to Scheme 1.1 below, the effect of varying the nature of the salt was investigated. The results are outlined in Table 1.1.

##STR00002##

TABLE-US-00001 TABLE 1.1 Effect of varying the salt on product yield Entry Salt TsF TsCl pTSA MB 1 K.sub.3PO.sub.4 7% 18% 0% 25% 2 K.sub.2HPO.sub.4 17%  62% 0% 79% 3 KH.sub.2PO.sub.4 <1%  97% 0% 80% 4 Na.sub.3PO.sub.4 6% 74% 0% 80% 5 Na.sub.2HPO.sub.4 2% 97% 0% 99% 6 NaH.sub.2PO.sub.4 <1%  >99%  0% >99%  7 K.sub.2SO.sub.4 1% 92% 0% 95% 8 Na.sub.2SO.sub.4 3% 92% 0% 95% 9 MgSO.sub.4 1% 97% 0% 98% 10 Ag.sub.2SO.sub.4 <1%   4% 25%  30% 11 Na.sub.2CO.sub.3 3% 93% 0% 93% 12 KHCO.sub.3 5% 80% 0% 85% with TsF = pTolSO.sub.2F; TsCl = pTolSO.sub.2Cl; MB = Mass Balance

1.2. Varying Ball Size

[0373] Following GP1 outlined above, and having regard to Scheme 1.2. below, the effect of varying the 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 7 and 9 g based on organo-fluorine product (TsF) yield.

##STR00003##

TABLE-US-00002 TABLE 1.2 Effect of varying ball size on product yield Entry Ball size (g) TsF TsCl pTSA MB 1 2 18% 45% 0% 63% 2 3 23% 55% 0% 78% 3 4 25% 40% 0% 65% 4 7 30%  9% 2% 41% 5 9 31%  6% 4% 41% 6 2 × 3 19% 46% 0% 65%

1.3. Varying Ratio of CaF.SUB.2 .to K.SUB.2.HPO.SUB.4

[0374] Following GP1 outlined above, and having regard to Scheme 1.3 below, the effect of varying the relative amounts of CaF.sub.2 and K.sub.2HPO.sub.4 was investigated. The results are outlined in Table 1.3. The data may support that higher ratios of CaF.sub.2 to K.sub.2HPO.sub.4 may be beneficial for product yield.

##STR00004##

TABLE-US-00003 TABLE 1.3 Effect of varying ratio of CaF.sub.2 to K.sub.2HPO.sub.4 on product yield Entry CaF.sub.2 (equiv) TsF TsCl pTSA MB 1 6 23% 51% 1% 75% 2 5 25% 40% 0% 65% 3 4 30% 35% 2% 67% 4 3 17% 56% 1% 74% 5 2 12% 67% 1% 80% 6 1 13% 37% 0% 50% 7  1* 13% 51% 0% 64% *using 0.5 equiv of K.sub.2HPO.sub.4

1.4. Assessing the Stability of p-Toluenesulphonyl Chloride and p-Toluenesulphonyl Fluoride Under Mechanical Forces

[0375] To investigate the stability of p-toluenesulphonyl chloride and p-toluenesulphonyl fluoride under solid state, ball milling conditions, the reactions depicted in Scheme 1.4 were performed.

[0376] In the first reaction, a 50 mL stainless steel milling jar was charged with stainless-steel balls (2×2 g), p-toluenesulfonyl chloride (1.0 equiv) and K.sub.2HPO.sub.4 (2.0 mmol). The jar was then closed and securely fitted to the mill which was set for 60 minutes at the frequency of 30 Hz. The jar was then opened and the solid residue was scratched out with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3×5 mL) and transferred in a beaker. The resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc), and the solvent was removed in vacuo. NMR yield was determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue, which dissolved in CDCl.sub.3 by swirling, and analysed by 1H NMR.

[0377] In the second reaction, a 50 mL stainless steel milling jar was charged with stainless-steel balls (2×2 g), p-toluenesulfonyl fluoride (1.0 equiv), CaF.sub.2 (5.0 equiv) and K.sub.2HPO.sub.4 (2.0 mmol). The jar was then closed and securely fitted to the mill which was set for 60 minutes at the frequency of 30 Hz. The jar was then opened and the solid residue was scratched out with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3×5 mL) and transferred in a beaker. The resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc), and the solvent was removed in vacuo. NMR yield was determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue, which was dissolved in CDCl.sub.3 by swirling, and analysed by .sup.19F NMR.

##STR00005##

[0378] Under mechanical forces, the instability of both p-toluenesulphonyl chloride and p-toluenesulphonyl fluoride was assessed with 22% and 19% loss of material, respectively.

1.5. Assessing Fluoride Leaching from p-Toluenesulphonyl Fluoride

[0379] To investigate the leaching of any fluoride from p-toluenesulphonyl fluoride under solid state, ball milling conditions, the reaction depicted in Scheme 1.5 was performed.

[0380] To a 50 mL stainless steel milling jar was added stainless-steel balls (2×2 g), p-toluenesulfonyl fluoride (1.0 equiv) and K.sub.2HPO.sub.4 (2.0 mmol). The jar was then closed and securely fitted to the mill which was set for 60 minutes at the frequency of 30 Hz. The jar was then opened and the solid residue was scratched out with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3×5 mL) and transferred in a beaker. The resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc), and the solvent was removed in vacuo. NMR yield was determined using 4-fluoroanisole as an internal standard. The standard was added to the crude residue, dissolved in CDCl.sub.3 by swirling, and analysed by .sup.19F NMR.

##STR00006##

[0381] Under mechanical forces and in presence of K.sub.2HPO.sub.4, fluoride leaching from p-toluenesulfonyl fluoride was assessed through identification of fluoride anion by .sup.19F NMR, along with 11% loss of the fluorinated compound.

2. Two-Stage Reactions—Solid State/Solid State

[0382] General Procedure 2 (GP2): To a 15 mL stainless steel milling jar was added a stainless-steel ball (3 g), CaF.sub.2 (4.0 mmol) and K.sub.2HPO.sub.4 (2.0 mmol). The jar was then closed and securely fitted to the mill which was set for 2×90 minutes at the frequency of 30 Hz (termed “pre-milling” 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 fitted to the mill which was set for another 2×90 minutes at the frequency of 30 Hz (termed “fluorination” step). Once the reaction was complete, the jar was opened and the white solid residue was scratched out with a spatula and collected in a beaker. The jar was rinsed with EtOAc (3×5 mL) and transferred to the beaker. The resulting suspension was stirred at room temperature for 5 minutes, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc), and the solvent was removed in vacuo and the crude mixture purified by silica gel chromatography if required.

2.1. Varying Pre-Milling and Fluorination Duration

[0383] Following GP2 outlined above, and having regard to 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 lead to higher yields of organofluorine products (e.g., TsF). Longer fluorination times may also lead to higher yields of organofluorine products.

##STR00007##

TABLE-US-00004 TABLE 2.1 Effect of varying the duration of pre- milling and fluorination on product yield Pre-milling Fluorination Entry (h) (h) TsF TsCl pTSA MB 1 0 3 31%  4% 0% 35% 2 1 1 29% 47% 0% 76% 3 2 1 41% 22% 0% 63% 4 3 3 66%  0% 0% 66%

2.2. Assessing the Stability of p-Toluenesulphonyl Fluoride Under Mechanical Forces

[0384] Following GP2 outlined above, and having regard to Scheme 2.2 below, the stability of p-toluenesulphonyl fluoride under two-stage, solid state, ball milling conditions was investigated by replacing p-toluenesulphonyl chloride with p-toluenesulphonyl fluoride.

##STR00008##

[0385] The partial instability of p-toluenesulfonyl fluoride under ball milling conditions was assessed. A stability experiment of p-toluenesulfonyl fluoride under mechanical forces and after pre-milling of CaF.sub.2 and K.sub.2HPO.sub.4 showed that 31% of the fluorinated product is lost.

2.3. Varying Organic Substrate

[0386] Following GP2 outlined above, and having regard to Scheme 2.3 below, the effect of varying the organic substrate was investigated. Scheme 2.4 outlines the product yield obtained for each substrate.

##STR00009##

##STR00010##

2.4. Varying Organic Substrate

[0387] Following GP2 outlined above, and having regard to Scheme 2.5 the effect of replacing the p-toluenesulphonyl chloride substrate with 4-methylbenzoyl chloride was investigated. The results are outlined in Table 2.2.

##STR00011##

TABLE-US-00005 TABLE 2.2 Effect of varying organic substrate on product yield Entry Fluorination ArC(O)F ArC(O)Cl ArCO.sub.2H (ArCO).sub.2O 1 1  5% 63% 23%  0% 2 0.25 20% 34%  0% 19%

3. Two-Stage Reactions—Solid State/Solution Phase

[0388] General Procedure 3 (GP3): To a 15 mL stainless steel milling jar was added a stainless-steel ball (7 g), CaF.sub.2 (4.0 mmol) and K.sub.2HPO.sub.4 (2.0 mmol). The jar was then closed and securely fitted to the mill which was set for 2×90 minutes at the frequency of 30 Hz (termed “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 to 16 hours (termed “fluorination” step), the resulting suspension was cooled to rt, filtered over a short plug of silica gel (washed with ˜20 mL EtOAc), and the solvent was removed in vacuo and the crude mixture purified by silica gel chromatography if required.

3.1. Inclusion of Additives

[0389] Following GP3 outlined above, and having regard to 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 may increase the yield of organofluorine product.

##STR00012##

TABLE-US-00006 TABLE 3.1 Effect of including various additives on product yield Entry Pre-milling (h) Additives (equiv) TsF TsCl pTSA 1 1 — 62% 15%   0% 2 1 18-crown-6 (1) 70% 0%  0% 3 3 Kryptofix [2.2.2] (1) 59% 0% ≈50% 4 3 Kryptofix [2.2.1] (1) 52% 0% ≈50% 5 3 Schreiner's Urea (0.1) 64% 8%  0% 6 3 Schreiner's Urea (0.1) + 79% 0% ≈20% 18-crown-6 (1)

3.2. Varying Pre-Milling Duration

[0390] Following GP3 outlined above, and having regard to 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 product (e.g., TsF) and decrease resulting yields of the starting material (e.g., TsCl).

##STR00013##

TABLE-US-00007 TABLE 3.2 Effect of varying pre-milling duration on product yield Entry Pre-milling (h) TsF TsCl pTSA 1 1 62% 15%   0% 2 3 79% 0% ≈20%  3 6 69% 0% 23%

3.3. Varying Pre-Milling Duration and Inclusion of Additives

[0391] Following GP3 outlined above, and having regard to Scheme 3.3, the effect of varying 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 may increase the yield of organofluorine product (e.g., TsF).

##STR00014##

TABLE-US-00008 TABLE 3.3 Effect of varying pre-milling duration and the inclusion of various additives on product yield Entry Pre-milling (h) Additive TsF TsCl pTSA 1 1 — 62% 15%   0% 2 1 18-crown-6 70% 0%  0% 3 3 Kryptofix [2.2.2] 59% 0% ≈50% 4 3 Kryptofix [2.2.1] 52% 0% ≈50% 5 3 Schreiner's Urea 64% 8%  0% 6 3 Urea + 18-crown-6 79% 0% ≈20%

3.4. Varying Ratio of CaF.SUB.2 .to K.SUB.2.HPO.SUB.4

[0392] Following GP3 outlined above, and having regard to Scheme 3.4, the effect of varying the amount of CaF.sub.2 and K.sub.2HPO.sub.4 introduced during pre-milling and then added in the fluorination step was investigated. The results are outlined in Table 3.4.

##STR00015##

TABLE-US-00009 TABLE 3.4 Effect of varying the amount of CaF.sub.2 and K.sub.2HPO.sub.4 on product yield K.sub.2HPO.sub.4 Additive Entry CaF.sub.2:K.sub.2HPO.sub.4 CaF.sub.2 (equiv) (equiv) TsF TsCl 1 1:0 4 0 —  7% 70%  2 2:1 4 2 — 62% 15%  3 2:1 4 2 18-crown- 70% 0% 6(1) 4 1:1 4 4 — 76% 0% 5 1:8 2 16 — 30% 8%

[0393] From the results outlined in Table 3.4, the use of a 2:1 ratio of ball milled CaF.sub.2 and K.sub.2HPO.sub.4 (4 and 2 equivalents, respectively) in the fluorination reaction in the presence of 18-crown-6 ether may give similar yield as a 1:1 ratio of ball milled CaF.sub.2 and K.sub.2HPO.sub.4 (4 equivalents each) without additive. The results also indicate that addition of 1 equivalent of 18-crown-6 ether may result in higher yields of organofluorine product and lower yields of organochlorine starting material. The results also indicate that addition of the second salt, K.sub.2HPO.sub.4 in any amount may increase the yield of organofluorine product in comparison to reactions where no K.sub.2HPO.sub.4 is added.

3.5. Varying Solvent

[0394] Following GP3 outlined above, and having regard to 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 some the use of some solvents may lead to higher yields of organofluorine product. Solvents such as DMF, DMA, and DMSO may not be effective as they yields of TsF are in trace amounts, where as other solvents such as 1,2-dichlorobenzene, chlorobenzene, t-amylOH, and t-buOH may be more effective solvents with organofluorine product (e.g., TsF) yields of over 70%. Solvents which have a polar aprotic polarity index of 6.4 or greater may be particularly suitable for use in fluorination of organic compounds using fluorination reagents (e.g. as shown Scheme 3.5.1).

##STR00016##

TABLE-US-00010 TABLE 3.5 Effect of varying solvent on product yield Entry Solvent TsF TsCl 1 DMF trace 8% 2 DMA trace 43%  3 DMSO trace 0% 4 THF 27% 64%  5 2-MeTHF 65% 0% 6 1,4-dioxane 56% 16%  7 MeCN 76% 0% 8 EtCN 80% 4% 9 tBuCN 57% 31%  10 toluene 50% 50%  11 1,2-difluorobenzene 34% 62%  12 1,2-dichlorobenzene 84% 2% 13 trifluorotoluene 69% 17%  14 fluorobenzene 33% 55%  15 chlorobenzene 92% 0% 16 m-xylene 68% 31%  17 hexane 28% 62%  18 tBuOH 82% 0% 19 t-amylOH 73% 0% 20 H.sub.2O 32% 4% 21 Diglyme 46% 0% 22 Monoglyme 37% 0%

[0395] In some instances, reagent grade CaF.sub.2 is milled with 1 equivalent of K.sub.2HPO.sub.4 for 3 hours at 30 Hz before 4 equivalents of the resulting reagent is reacted with TsCl in a solvent according to Scheme 3.5.2 to achieve the resulting TsF. In some instances, 1 equivalent of acid grade fluorspar is milled with 1 equivalent of K.sub.2HPO.sub.4 for 3 hours at 30 Hz according to Scheme 3.5.3 and 4 equivalents of the resulting fluorination reagent is reacted in a solvent with TsCl to achieve the fluorinated TsF. The resulting fluorinated TsF product yields resulting from reagent grade CaF.sub.2 and acid grade fluorspar (81% and 82% respectively by NMR) may support the conclusion that either starting material can be used to synthesize the fluorinating reagent.

##STR00017##

##STR00018##

3.6. Varying Organic Substrate

[0396] Following GP3 outlined above, and having regard to Schemes 3.6a, 3.6b, 3.6c and 3.6d the effect of replacing the p-toluenesulphonyl 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 may support that the fluorination reagent can sufficiently fluorinate various chlorinated aromatic compounds. The fluorination of toluene (40% yield), may indicate that the fluorination reagent can fluorinate non-halogenated compounds.

##STR00019##

TABLE-US-00011 TABLE 3.6a Effect of varying the organic substrate on product yield Entry Solvent ArC(O)F Arc(O)Cl ArCO.sub.2H 1 EtCN 46% 65%  0% 2 PhCl 44% 45% 10%

##STR00020##

TABLE-US-00012 TABLE 3.6b Effect of varying the organic substrate on product yield Entry Solvent ArF ArCl 1 Toluene 40%  0% 2 1,2-dichlorobenzene 60% 23% 3 Chlorobenzene 49% 44% 4 1,2-difluorobenzene 49% 26%

##STR00021##

TABLE-US-00013 TABLE 3.6c Effect of varying the organic substrate on product yield Entry Solvent CaF.sub.2 (equiv) K.sub.2HPO.sub.4 (equiv) ArF ArCl 1 MeCN 4 2 18% 41% 2 MeCN 6 4 20% 16% 3 Toluene 4 2 14% 63%

##STR00022##

3.7. Removal of Salt

[0397] To investigate the effect of removing the salt on the ability of CaF.sub.2 to fluorinate p-toluenesulphonyl chloride, the reaction depicted in Scheme 3.7 was performed according to a similar procedure to GP3, in which the salt was removed from the pre-milling step. The results are outlined in Table 3.7. These results highlight the importance that the pre-milling of additive with CaF.sub.2 has on the yield of the organofluorine product (e.g., TsF), wherein yields without the addition of the additive in the pre-milling step were less than 8%.

##STR00023##

TABLE-US-00014 TABLE 3.7 Effect of removing the salt on product yield Additive (equiv) TsF TsCl pTSA — 7% 70% trace K.sub.2HPO.sub.4 (2) <2%  91% 0% 18-crown-6 (1) 4% 49% 0% Krypt [2.2.2] (1) 4%  1% trace Krypt [2.2.1] (1) 2%  0% trace Dibenzo-18-crown-6 (1) 4% 96% 0% Dibenzo-30-crown-10 (1) 5% 91% 0% Dicyclohexano-18-crown-6 (1) 4% 84% 0% 18-crown-6 (1) + Schreiner's Urea (0.1) 4% 63% 0%

3.8. Varying Salt

[0398] Following GP3 outlined above, and having regard to Scheme 3.8 below, the effect of varying the nature of the salt was investigated. The results are outlined in Scheme 3.8. The variation of the salt from K.sub.2SO.sub.4 to K.sub.2HPO.sub.4 led to yields of 10% and 71% respectively in otherwise similar conditions. These results highlight the role the second salt may play in the formation of the fluorinating agent, and the resulting fluorinating agents ability to fluorinate the organic substrate. Specifically, the results highlight K.sub.2HPO.sub.4 as an exemplary salt additive.

##STR00024##

4. Nucleophilic Fluorination with CaF.SUB.2

[0399] To investigate the efficacy of nucleophilic fluorination with CaF.sub.2 in solution, several reactions detailed in Table 4.1 were attempted according to reaction scheme 4.1.

##STR00025##

[0400] Briefly, a crown ether or cryptand (1 equiv.) described in Table 4.1 was dissolved with Schreiner's thio(urea) (20 mol %) with CaF.sub.2 (5 equiv.). In some instances, an additive selected from K.sub.3PO or Schreiner's urea was added to the reaction. In all cases, the yield of the fluorinated product was 0% or found in trace amounts as determined by 19F-NMR using 4-fluoroanisole as an internal standard. In all instances, solvents used were anhydrous. In some cases, the side product formed was 1-(2,4-dinitrophenoxy)-4-nitro-2-nitrosobenzene and urea degradation occurred. In other cases, no reaction occurred. The low to zero NMR yields of fluorinated product associated with these reactions may highlight the role of the pre-milling (mechanical force) step discussed herein between CaF.sub.2 (first salt) and the second salt to form the fluorinating reagent.

TABLE-US-00015 TABLE 4.1 Crown ether or Entry Solvent Cryptand Additive NMR Yield 1 Kryptofix 221 — 0% 2 Kryptofix 222 — 0% 3 DMF 18-crown-6 — 0% 4 (Dibenzo)18- — 0% crown-6 (or dicyclo) 5 18-crown-6 K.sub.3PO.sub.4 Traces 6 Kryptofix 221 — 0% 7 Kryptofix 222 — 0% 8 Toluene (Dibenzo)18- — 0% crown-6 (or dicyclo) 9 Kryptofix 221 Schreiner's urea 0% 10 Kryptofix 221 — 0% 11 Kryptofix 222 — 0% 12 1,2-DCE 18-crown-6 — 0% 13 Kryptofix 221 Schreiner's urea 0% 14 18-crown-6 K.sub.3PO.sub.4 traces

5. Fluorination of 4-Toluenesulfonyl Chloride with CaF.SUB.2 .Using Ball Milling

5.1. Use of Phosphate Additives

[0401] The effect of phosphate additives on the reaction of CaF.sub.2 and TsCl as seen in Scheme 5.1.

##STR00026##

[0402] CaF.sub.2 (1.00 mmol, 5 equiv.), the phosphate additive (2 equiv., see Table 5.1), and TsCl (1 equiv.) were added to a 30 mL stainless steel jar with 2×2 g balls (316 SS grade) to undergo ball milling 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 side product (TsOH %), as seen in Table 5.1 The yields were determined by 1H and 19F-NMR with 4-fluoroanisole as an internal standard. In some instances, the phosphate additive was a carbonate additive or a sulfate additive. The experimental results indicate that the K.sub.2HPO.sub.4 and K.sub.2CO.sub.3 additives may be exemplary additives, increasing yields of organofluorine product (e.g., TsF).

TABLE-US-00016 TABLE 5.1. Phosphate Entry Additive TsCl (%) TsF (%) TsOH (%) Mass Balance (%) 1 K.sub.3PO.sub.4 12 7 0 25 2 K.sub.2HPO.sub.4 62 17 0 79  3* K.sub.2HPO.sub.4 40 25 0 65 4 KH.sub.2PO.sub.4 97 1 0 97 5 Na.sub.3PO.sub.4 74 6 0 80 6 Li.sub.3PO.sub.4 100 0 0 100 7 Na.sub.2HPO.sub.4 97 2 0 99 8 NaH.sub.2PO.sub.4 99 1 0 100 9 K.sub.2SO.sub.4 92 1 0 93 10  Na.sub.2SO.sub.4 92 3 0 95 11  MgSO.sub.4 97 1 0 98 12  Ag.sub.2SO.sub.4 4 <1 25 30 13  Na.sub.2CO.sub.3 93 3 0 93 14  KHCO.sub.3 80 5 0 85 15* K.sub.2CO.sub.3 10 24 0 34 *Using 1 × 4 g ball, 15 mL jar

5.2. CaF.SUB.2 .to K.SUB.2.HPO.SUB.4 .Ratio

[0403] Given the benefit that K.sub.2HPO.sub.4 may have as an additive in the reaction of CaF.sub.2 and TsCl ball milling fluorination experiments, the ratio of CaF.sub.2 and the K.sub.2HPO.sub.4 ratio was probed via Scheme 5.2.

##STR00027##

[0404] Briefly, CaF.sub.2 (varying equiv.) was added to a stainless steel jar with a 4 g ball (316 SS grade) along with K.sub.2HPO.sub.4 (2 equiv) and TsCl (1 equiv). The ball milling was completed with a Retsch MM400 Ball Mill at 30 Hz for 1 hour. The TsCl yield (%), TsF yield (%), and TsOH side product yield (%), were determined by 1H and 19F-NMR with 4-fluoroanisole as an internal standard. The results can be seen in Table 5.2. The increased yield with increased ratio of CaF.sub.2:K.sub.2HPO.sub.4 indicates that the ratio of the two salts may play an a role in optimizing the resulting yield of organofluorine product and a ratio of 2:1 may provide the highest yield of organofluorine product (e.g., TsF).

TABLE-US-00017 TABLE 5.2. Equivalents TsCl TsF TsOH Mass balance Entry of CaF.sub.2 (%) (%) (%) (%) 1 6 51 23 1 75 2 5 40 25 0 65 3 4 35 30 2 67 4 3 56 17 1 74 5 2 67 12 1 80 6 1 37 13 0 50

5.3. Product and Starting Material Stability

[0405] The stability of the product (TsF) and starting material (TsCl) were probed in the presence of CaF.sub.2 and K.sub.2HPO.sub.4 for TsF and in the presence of K.sub.2HPO.sub.4 for TsCl as in Scheme 5.3.

##STR00028##

[0406] In the case of the product (TsF), upon ball milling in stainless steel jars with a Retsch MM400 ball mill at 30 Hz for 1 hour in the presence of CaF.sub.2 (5.0 equiv.) and K.sub.2HPO.sub.4 (5.0 equiv), 81% of the product (TsF) was recovered. Some aqueous fluoride ion was observed in D20 by NMR. The 81% recovery of the starting material, TsF, highlight the stability of the fluorinated material in the presence of the fluorinating reagent under milling conditions.

[0407] In the case of the starting material (TsCl), upon ball milling under similar conditions in the presence of K.sub.2HPO.sub.4 (1.0 equiv), 78% of the TsCl was recovered.

5.4. Step-Wise Addition in the Solid State

[0408] The effect on product yield when step-wise addition of starting materials was examined as seen in Scheme 5.4.

##STR00029##

[0409] Ball milling was completed using a Retsch MM400 Ball Mill using 15 mL stainless steel jars and 3 g balls. Briefly, CaF.sub.2 (4.0 equiv.) was added to the stainless steel jar with K.sub.2HPO.sub.4 (2.0 equiv.) and ball milling took place at 30 Hz (varying 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 took place at 30 Hz (varying times seen in Table 5.4. Yields of TsCl and TsF (%) were determined by 1H and 19F-NMR with 4-fluoroanisole as an internal standard. The results show that the combination of pre-milling of the CaF.sub.2 and K.sub.2HPO.sub.4 followed by longer fluorination times may lead to higher yields of organofluorine product (e.g., 66% yield of TsF with 3 hrs of pre-milling followed by 3 hours of fluorination).

TABLE-US-00018 TABLE 5.4. Pre-milling Fluorination TsCl TsF Mass Entry (x h) (y h) (%) (%) balance 1 0 3 4 31 35 2 1 1 47 29 76 3 2 1 22 41 63 4 3 3 0 66 66

5.5. Step-Wise Addition in the Solid State to Solution State

[0410] The effect on product yield was examined when K.sub.2HPO.sub.4 (2.0 equiv.) was first milled with CaF.sub.2 (4.0 equiv.) at 30 Hz for 3 hours followed by a second step, solution state reaction with TsCl in acetonitrile (0.25 M) for 5 hours at 100° C. as seen in Scheme 5.5.

##STR00030##

[0411] When adding CaF.sub.2 (4 equiv.) and K.sub.2HPO.sub.4 (2.0 equiv.) to a stainless steel jar for ball milling at 30 Hz for 3 hours as seen in Scheme 5.5, followed by adding TsCl in the solution state (1.00 mmol, 0.25 M) and reacting the solution at 100° C. for 5 hours in acetonitrile, the yield of TsF was determined to be 62% with 15% of the TsCl recovered. The 62% yield of TsF may highlight the importance of pre-milling CaF.sub.2 with the phosphate activator, K.sub.2HPO.sub.4 before the solution fluorination reaction with TsCl.

5.6. Step-Wise Addition in the Solid State to Solution State

[0412] Several control experiments were completed using ball milled CaF.sub.2, as seen in Scheme 5.6, where the CaF.sub.2 is not ball milled with the additive before addition of the TsCl.

##STR00031##

[0413] In summary, CaF.sub.2 (4.0 equiv.) is added to a 15 mL stainless steel jar and ball milled alone at 30 Hz for 3 hours before being added to an additive (see Table 5.6) and TsCl (1 mmol) in acetonitrile (0.25 M) and reacted for 5 hours at 100° C. This method may result in lower yields of fluorinated product than when the additive is milled with the CaF.sub.2.

TABLE-US-00019 TABLE 5.6 Mass Additive TsCl TsF TsOH Balance Entry Additive Equiv (%) (%) (%) (%) 1 — — 70 7 <1 77 2 K.sub.2HPO.sub.4 2 91 2 0 93 3 18-crown-6 1 49 4 0 53 4 Krypt [2.2.2] 1 1 4 <1 5 5 Krypt [2.2.1] 1 0 2 <1 3 6 Dibenzo-18- 1 96 4 0 100 crown-6 7 Dibenzo-30- 1 91 5 0 96 crown-6 8 Dicyclohexano- 1 84 4 0 88 18-crown-6 9 18-crown-6 + 1 + 0.1 63 4 0 67 Schreiner's Urea

5.7. Replacement of Reagent Grade CaF.SUB.2 .with Acid Grade Fluorspar

[0414] In some instances, reagent grade CaF.sub.2 was replaced with acid grade Fluorspar and screening of the various phosphate activators was completed as described in Scheme 5.7. The various phosphate activators included K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KH.sub.2PO.sub.4, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, KPO.sub.3, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, (NaPO.sub.3).sub.3, CaHPO.sub.4, and α-Ca.sub.3(PO.sub.4).sub.2.

##STR00032##

[0415] The Fluorspar (1.0 equiv.) was added to the stainless steel jar and milled for 3 hours at 30 Hz with a phosphate activator (1 equiv.) (see FIG. 3). Subsequently, the solid product is added, containing CaF.sub.2 (4 equiv.) and phosphate activator (4 equiv.), to t-butanol (0.25 M) with TsCl (1.00 mmol) and reacted for 5 hours at 100° C. to obtain the fluorinated product (TsF). The yields of the reaction (TsF(%), TsCl (%)) can be seen in FIG. 3. Corresponding sulfonyl bromide and tosylate as substrates afforded the sulfonyl fluoride in 71%, and 26% respectively (using K.sub.2HPO.sub.4 as the additive, compared with 82% using the sulfonyl chloride). Using K.sub.4P.sub.2O.sub.7 resulted in yields of 54% TsF. In some instances, the phosphate activators (e.g., CaHPO.sub.4, (NaPO.sub.3).sub.3, α-Ca.sub.3(PO.sub.4).sub.2) led to trace amounts or 0% of TsF product yield. In brief, the results indicate that the selection of the activator salt (second salt) may play a significant role in the resulting fluorinating reagent's ability to fluorinate the substrate. The results highlight potential exemplary additives including K.sub.2HPO.sub.4, Na.sub.2HPO.sub.4, K.sub.4P.sub.2O.sub.7 and Na.sub.4P.sub.2O.sub.7.

[0416] PXRD data was obtained for each of the solid products obtained from Fluorspar activation by various phosphate activators included K.sub.3PO.sub.4, K.sub.2HPO.sub.4, KH.sub.2PO.sub.4, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, KPO.sub.3, K.sub.4P.sub.2O.sub.7, K.sub.5P.sub.3O.sub.10, Na.sub.4P.sub.2O.sub.7, Na.sub.5P.sub.3O.sub.10, (NaPO.sub.3).sub.3, CaHPO.sub.4, and α-Ca.sub.3(PO.sub.4).sub.2. FIG. 4 shows the PXRD pattern resulting from milling of Fluorspar with KH.sub.2PO.sub.4 at 35 Hz for 3 hours. Table 5.7.1 shows the PXRD data from the milling of Fluorspar with KH.sub.2PO.sub.4 represented in FIG. 4. Labels on the diffraction pattern indicate crystalline phase of CaF.sub.2 and KH.sub.2PO.sub.4.

TABLE-US-00020 TABLE 5.7.1. Pos. Height FWHM d-spacing Rel. [°2Th.] [cts] [°2Th.] [Å] Int. [%] 17.4503 686.27 0.0528 5.07796 16.95 17.5072 731.34 0.0541 5.06577 18.06 23.9279 4049.59 0.1299 3.71901 100.00 28.0696 487.06 0.0433 3.17898 12.03 28.3647 574.15 0.1515 3.14657 14.18 29.8125 339.33 0.0866 2.99698 8.38 30.7783 2994.59 0.1407 2.90510 73.95 34.0483 591.48 0.0649 2.63321 14.61 35.2759 216.71 0.1732 2.54434 5.35 38.5033 368.10 0.0758 2.33817 9.09 40.6969 138.12 0.1299 2.21706 3.41 45.8277 299.07 0.1082 1.98008 7.39 46.5419 1217.04 0.0974 1.95135 30.05 47.1639 370.38 0.1515 1.92705 9.15 47.7466 132.31 0.1732 1.90488 3.27 48.9681 32.23 0.2598 1.86019 0.80 52.3336 26.58 0.3464 1.74821 0.66 54.0701 27.15 0.2598 1.69610 0.67 55.1283 170.76 0.0866 1.66602 4.22 55.7911 105.97 0.3031 1.64779 2.62 58.4622 159.43 0.1082 1.57871 3.94 58.8671 151.82 0.1082 1.56882 3.75 59.8709 40.85 0.2598 1.54489 1.01 64.0433 146.25 0.0866 1.45394 3.61 69.7452 120.73 0.1320 1.34726 2.98

[0417] FIG. 5 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.3PO.sub.4 at 35 Hz for 3 hours. Table 5.7.2 shows the PXRD data from the milling of Fluorspar with K.sub.3PO.sub.4 represented in FIG. 5. Labels in FIG. 5 indicate crystalline phases of K.sub.3PO.sub.4*7H.sub.2O, CaF.sub.2, and an unidentified crystalline phase.

TABLE-US-00021 TABLE 5.7.2. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 5.1808 76.50 0.5196 17.05776 13.83 K.sub.3PO.sub.4 16.3622 31.25 0.2598 5.41759 5.65 K.sub.3PO.sub.4 24.4974 60.81 0.1732 3.63384 11.00 K.sub.3PO.sub.4 26.1679 28.97 0.2598 3.40552 5.24 CaF.sub.2 28.4848 552.97 0.3031 3.13357 100.00 K.sub.3PO.sub.4 29.5428 228.67 0.2598 3.02372 41.35 new phase 31.5443 118.01 0.8659 2.83628 21.34 K.sub.3PO.sub.4 32.7690 166.89 0.2165 2.73303 30.18 K.sub.3PO.sub.4 35.1033 117.05 0.1732 2.55645 21.17 new phase 36.7972 77.63 0.2165 2.44256 14.04 K.sub.3PO.sub.4 37.7484 99.72 0.2165 2.38318 18.03 K.sub.3PO.sub.4 40.5069 24.30 0.3464 2.22702 4.39 K.sub.3PO.sub.4 42.3931 25.64 0.2165 2.13220 4.64 CaF.sub.2 47.1921 403.01 0.2381 1.92597 72.88 K.sub.3PO.sub.4 50.2093 39.46 0.1732 1.81708 7.14 K.sub.3PO.sub.4 51.7624 19.86 0.2598 1.76615 3.59 CaF.sub.2 55.9692 111.97 0.2598 1.64297 20.25 CaF.sub.2 68.9523 30.23 0.8448 1.36080 5.47

[0418] FIG. 6 shows the PXRD pattern resulting from milling of Fluorspar with Na.sub.3PO.sub.4 at 30 Hz for 3 hours. Table 5.7.3 shows the PXRD data from the milling of Fluorspar with Na.sub.3PO.sub.4 represented in FIG. 6. Labels in FIG. 6 indicate crystalline phases of Na.sub.7F(PO.sub.4).sub.2(H.sub.2O).sub.19 and CaF.sub.2.

TABLE-US-00022 TABLE 5.7.3. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 11.0987 575.32 0.0758 7.97217 55.68 12.8527 230.21 0.1082 6.88791 22.28 18.1294 481.00 0.1299 4.89331 46.55 22.2114 429.50 0.0866 4.00239 41.57 25.7262 114.34 0.1515 3.46298 11.07 28.0698 819.87 0.0433 3.17896 79.35 CaF.sub.2 28.3394 1033.22 0.0758 3.14932 100.00 28.7953 453.13 0.1515 3.10049 43.86 29.3760 147.60 0.2165 3.04051 14.29 30.2262 90.55 0.1299 2.95690 8.76 30.7564 308.53 0.1299 2.90712 29.86 CaF.sub.2 31.6106 121.58 0.1515 2.83049 11.77 33.5540 611.75 0.0541 2.67086 59.21 37.0842 313.50 0.1082 2.42432 30.34 38.9278 168.51 0.1515 2.31365 16.31 41.1692 55.41 0.1732 2.19272 5.36 CaF.sub.2 47.0750 894.37 0.0528 1.92889 86.56 47.2052 643.97 0.0649 1.92546 62.33 49.4533 52.13 0.2598 1.84307 5.04 52.0627 30.14 0.8659 1.75667 2.92 CaF.sub.2 55.8334 157.23 0.2165 1.64664 15.22 57.5195 25.10 0.3464 1.60232 2.43 CaF.sub.2 68.8110 33.78 0.5280 1.36325 3.27

[0419] FIG. 7 shows the PXRD pattern resulting from milling of Fluorspar with Na.sub.2HPO.sub.4 at 35 Hz for 3 hours. Table 5.7.4 shows the PXRD data from the milling of Fluorspar with Na.sub.2HPO.sub.4 represented in FIG. 7. Labels in FIG. 7 indicate crystalline phases of CaF.sub.2 and an unidentified crystalline phase.

TABLE-US-00023 TABLE 5.7.4. Height FWHM d-spacing Rel. Int. Pos. [°2Th.] [cts] [°2Th.] [Å] [%] 20.1820 170.30 0.2598 4.40001 23.76 26.6900 46.47 0.2598 3.34008 6.48 CaF.sub.2 28.4541 716.88 0.2814 3.13689 100.00 33.2761 170.13 0.3031 2.69253 23.73 38.7654 18.81 0.5196 2.32296 2.62 CaF.sub.2 47.1554 663.65 0.2814 1.92738 92.57 CaF.sub.2 55.9176 188.00 0.3031 1.64436 26.22 CaF.sub.2 68.8390 51.16 0.4224 1.36276 7.14

[0420] FIG. 8 shows the PXRD pattern resulting from milling of Fluorspar with NaH.sub.2PO.sub.4 at 35 Hz for 3 hours. Table 5.7.5 shows the PXRD data from the milling of Fluorspar with NaH.sub.2PO.sub.4 represented in FIG. 8. Labels in FIG. 8 indicate crystalline phases of CaF.sub.2 and NaH.sub.2PO.sub.4(H.sub.2O).sub.3.

TABLE-US-00024 TABLE 5.7.5. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 5.1628 111.00 0.5196 17.11719 10.75 10.6534 324.58 0.1515 8.30443 31.42 16.9107 580.27 0.0758 5.24309 56.18 17.2912 68.53 0.1299 5.12858 6.63 19.2624 595.57 0.0974 4.60795 57.66 20.2745 49.87 0.1515 4.38016 4.83 22.6340 196.21 0.1082 3.92860 18.99 23.3705 59.97 0.1732 3.80644 5.81 24.4355 101.84 0.1515 3.64289 9.86 26.6815 527.64 0.1299 3.34113 51.08 27.4363 400.96 0.0866 3.25090 38.82 28.3572 1032.95 0.1732 3.14738 100.00 29.8795 149.68 0.1515 2.99041 14.49 30.6959 268.41 0.1082 2.91271 25.98 31.2197 391.71 0.1515 2.86502 37.92 32.0102 118.51 0.1299 2.79606 11.47 32.7605 292.25 0.1732 2.73371 28.29 34.6523 115.42 0.1082 2.58868 11.17 36.1761 149.25 0.1299 2.48306 14.45 36.5045 135.17 0.1515 2.46148 13.09 37.8231 25.18 0.1732 2.37864 2.44 39.0272 36.90 0.4330 2.30798 3.57 39.9166 161.17 0.1299 2.25859 15.60 40.9910 67.01 0.3464 2.20183 6.49 42.3863 15.91 0.2598 2.13253 1.54 43.5308 53.93 0.2598 2.07908 5.22 43.9368 83.86 0.1732 2.06081 8.12 45.2239 81.41 0.1299 2.00510 7.88 46.0782 112.69 0.2598 1.96990 10.91 47.1350 786.79 0.1515 1.92817 76.17 49.5339 19.28 0.3031 1.84026 1.87 50.4606 41.62 0.2165 1.80862 4.03 51.1946 26.58 0.1732 1.78440 2.57 52.5781 49.03 0.1299 1.74066 4.75 55.9901 237.76 0.3897 1.64241 23.02 57.7920 25.50 0.5196 1.59541 2.47 59.7053 9.88 0.5196 1.54878 0.96 60.9672 20.31 0.3464 1.51971 1.97 63.2931 31.33 0.3464 1.46935 3.03 65.7834 24.71 0.2598 1.41963 2.39 68.4277 51.66 1.0560 1.36995 5.00

[0421] FIG. 9 shows the PXRD pattern resulting from milling of Fluorspar with KPO.sub.3 at 35 Hz for 3 hours. Table 5.7.6 shows the PXRD data from the milling of Fluorspar with KPO.sub.3 represented in FIG. 9. Labels in FIG. 9 indicate crystalline phases of CaF.sub.2, KPO.sub.3, and an unidentified amorphous phase.

TABLE-US-00025 TABLE 5.7.6. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] KPO.sub.3 14.0459 162.80 0.2165 6.30536 9.79 KPO.sub.3 17.5192 108.65 0.2598 5.06233 6.53 KPO.sub.3 19.5372 32.72 0.3464 4.54377 1.97 KPO.sub.3 23.8310 52.28 0.3464 3.73391 3.14 KPO.sub.3 25.9074 266.00 0.3464 3.43917 15.99 KPO.sub.3 26.7862 254.20 0.3464 3.32830 15.28 CaF.sub.2 28.3520 1663.57 0.0866 3.14795 100.00 KPO.sub.3 31.7224 85.00 0.2598 2.82077 5.11 new phase 33.1713 75.46 0.4330 2.70079 4.54 CaF.sub.2 47.0642 1381.50 0.0660 1.92930 83.04 CaF.sub.2 55.8027 400.25 0.1082 1.64748 24.06 CaF.sub.2 68.7042 122.83 0.2112 1.36511 7.38

[0422] FIG. 10 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.4P.sub.2O.sub.7 at 35 Hz for 3 hours. Table 5.7.7 shows the PXRD data from the milling of Fluorspar with K.sub.4P.sub.2O.sub.7 represented in FIG. 10. Labels in FIG. 10 indicate crystalline phases of CaF.sub.2 and an unidentified crystalline phase.

TABLE-US-00026 TABLE 5.7.7. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 5.1444 130.15 0.2598 17.17830 10.54 17.9889 94.86 0.1732 4.93120 7.68 18.7323 79.36 0.1732 4.73714 6.43 21.8984 254.80 0.1732 4.05888 20.64 22.6004 826.97 0.0541 3.93436 66.98 24.4977 89.59 0.2165 3.63379 7.26 25.3643 87.27 0.2598 3.51157 7.07 26.4568 735.97 0.1948 3.36898 59.61 27.0316 509.38 0.1732 3.29864 41.26 28.0638 1053.98 0.1948 3.17962 85.37 CaF.sub.2 28.3868 1234.61 0.1732 3.14417 100.00 29.1860 173.05 0.1732 3.05987 14.02 30.3572 76.33 0.1732 2.94443 6.18 31.6322 61.17 0.2598 2.82860 4.95 33.0425 312.45 0.1082 2.71103 25.31 34.8349 30.59 0.3464 2.57553 2.48 36.3748 54.35 0.2165 2.46996 4.40 37.6922 100.83 0.3031 2.38660 8.17 39.5079 62.17 0.2598 2.28100 5.04 40.3630 108.66 0.1299 2.23463 8.80 41.6540 56.14 0.2598 2.16831 4.55 42.3742 83.32 0.2165 2.13311 6.75 43.4426 48.03 0.2598 2.08309 3.89 46.0690 102.39 0.2598 1.97027 8.29 CaF.sub.2 47.1347 647.18 0.1299 1.92818 52.42 48.3579 85.22 0.2165 1.88223 6.90 49.4397 67.00 0.3031 1.84354 5.43 52.7532 64.11 0.3464 1.73529 5.19 53.9036 38.86 0.2598 1.70094 3.15 CaF.sub.2 55.8878 248.87 0.2598 1.64517 20.16 61.3555 21.45 0.4330 1.51102 1.74 62.4719 17.97 0.2598 1.48668 1.46 CaF.sub.2 68.7998 53.55 0.4224 1.36344 4.34

[0423] FIG. 11 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.5P.sub.3O.sub.10 at 35 Hz for 3 hours. Table 5.7.8 shows the PXRD data from the milling of Fluorspar with K.sub.5P.sub.3O.sub.10 represented in FIG. 11. Labels in FIG. 11 indicate crystalline phases of CaF.sub.2 and K.sub.3H.sub.3(PO.sub.4).sub.2*2H.sub.2O and an unidentified crystalline phase.

TABLE-US-00027 TABLE 5.7.8. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 5.2732 114.29 0.5196 16.75922 27.96 17.2799 39.30 0.1732 5.13189 9.62 18.3993 55.60 0.1948 4.82211 13.60 19.5241 58.21 0.1299 4.54679 14.24 20.4719 53.71 0.1299 4.33836 13.14 20.8963 39.65 0.2165 4.25120 9.70 23.2997 88.92 0.1299 3.81784 21.76 25.3934 53.09 0.1299 3.50760 12.99 25.9552 58.44 0.3464 3.43294 14.30 26.8517 251.68 0.1299 3.32033 61.58 27.3606 340.00 0.1299 3.25972 83.19 CaF.sub.2 28.3670 375.75 0.3031 3.14632 91.94 29.0963 408.69 0.1732 3.06910 100.00 29.5586 337.62 0.1299 3.02214 82.61 30.2354 251.36 0.1515 2.95602 61.50 30.6491 301.67 0.1299 2.91705 73.81 31.7495 106.23 0.1732 2.81842 25.99 32.5474 69.78 0.1299 2.75113 17.08 33.6613 105.09 0.1299 2.66259 25.71 35.2089 141.22 0.1732 2.54903 34.56 36.5470 35.78 0.2598 2.45871 8.75 39.4710 71.52 0.2165 2.28305 17.50 40.0449 41.44 0.3464 2.25165 10.14 41.3836 75.03 0.1732 2.18185 18.36 41.8761 70.61 0.2598 2.15732 17.28 42.3942 65.61 0.1732 2.13215 16.05 42.8791 74.72 0.1299 2.10916 18.28 44.3482 31.39 0.3464 2.04264 7.68 46.6089 101.65 0.1732 1.94869 24.87 CaF.sub.2 47.1154 307.91 0.1732 1.92892 75.34 49.1345 20.31 0.3464 1.85428 4.97 50.2219 22.27 0.2598 1.81665 5.45 53.5032 26.67 0.5196 1.71272 6.53 CaF.sub.2 55.8875 78.51 0.4330 1.64518 19.21 56.9644 15.27 0.2598 1.61661 3.74 59.2874 12.50 0.5196 1.55869 3.06 61.4948 15.16 0.5196 1.50793 3.71 64.1902 14.04 0.5196 1.45097 3.43 CaF.sub.2 68.7999 38.69 0.4224 1.36344 9.47

[0424] FIG. 12 shows the PXRD pattern resulting from milling of Fluorspar with Na.sub.4P.sub.2O.sub.7 at 35 Hz for 3 hours. Table 5.7.9 shows the PXRD data from the milling of Fluorspar with Na.sub.4P.sub.2O.sub.7 represented in FIG. 12. Labels in FIG. 12 indicates a crystalline phase of CaF.sub.2 and an unidentified crystalline phase.

TABLE-US-00028 TABLE 5.7.9. Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%] 18.5302 32.30 0.4330 4.78835 8.95 CaF.sub.2 28.3978 360.72 0.0758 3.14297 100.00 30.4726 184.31 0.3464 2.93354 51.10 40.0968 13.45 0.5196 2.24885 3.73 43.2966 15.99 0.5196 2.08978 4.43 CaF.sub.2 47.1173 295.61 0.1515 1.92885 81.95 54.0107 13.24 0.6927 1.69782 3.67 CaF.sub.2 55.8334 76.55 0.2598 1.64664 21.22 CaF.sub.2 68.8257 22.49 0.5280 1.36299 6.24

[0425] FIG. 13 shows the PXRD pattern resulting from milling of Fluorspar with Na.sub.5P.sub.3O.sub.10 at 35 Hz for 3 hours. Table 5.7.10 shows the PXRD data from the milling of Fluorspar with Na.sub.5P.sub.3O.sub.10 represented in FIG. 13. Labels in FIG. 13 indicates a crystalline phase of CaF.sub.2 and an unidentified amorphous phase.

TABLE-US-00029 TABLE 5.7.10. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 28.2976 1396.75 0.1632 3.15126 100.00 47.0169 926.02 0.4896 1.93113 66.30 55.8035 259.77 0.4896 1.64609 18.60 68.6839 70.90 0.8160 1.36546 5.08

[0426] FIG. 14 shows the PXRD pattern resulting from milling of Fluorspar with Na(PO.sub.3).sub.3 at 35 Hz for 3 hours. Table 5.7.11 shows the PXRD data from the milling of Fluorspar with Na(PO.sub.3).sub.3 represented in FIG. 14. Labels in FIG. 14 indicates a crystalline phase of CaF.sub.2.

TABLE-US-00030 TABLE 5.7.11. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 28.2976 1396.75 0.1632 3.15126 100.00 47.0169 926.02 0.4896 1.93113 66.30 55.8035 259.77 0.4896 1.64609 18.60 68.6839 70.90 0.8160 1.36546 5.08

[0427] FIG. 15 shows the PXRD pattern resulting from milling of Fluorspar with CaHPO.sub.4 at 30 Hz for 3 hours. Table 5.7.12 shows the PXRD data from the milling of Fluorspar with CaHPO.sub.4 represented in FIG. 15. Labels in FIG. 15 indicates crystalline phases of CaF.sub.2 and Ca.sub.5(PO.sub.4).sub.3F

TABLE-US-00031 TABLE 5.7.12. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 10.8159 22.19 0.3464 8.18003 1.71 16.9988 27.36 0.3464 5.21612 2.11 21.9471 44.50 0.2598 4.04997 3.43 22.9223 87.66 0.3031 3.87984 6.76 25.9108 464.01 0.1515 3.43873 35.79 26.7231 164.61 0.1299 3.33602 12.70 CaF.sub.2 28.3972 1296.45 0.2165 3.14305 100.00 29.1216 365.28 0.1732 3.06649 28.18 31.9522 1014.39 0.1515 2.80100 78.24 32.3833 548.05 0.1948 2.76469 42.27 33.1624 541.34 0.0866 2.70150 41.76 34.1845 268.43 0.2598 2.62303 20.71 35.6375 53.32 0.1732 2.51934 4.11 39.3033 78.45 0.1732 2.29241 6.05 40.0474 226.94 0.1515 2.25151 17.50 42.2195 64.59 0.3031 2.14056 4.98 43.9611 61.89 0.2598 2.05972 4.77 45.4737 106.84 0.2598 1.99467 8.24 CaF.sub.2 46.9114 1075.26 0.1515 1.93683 82.94 49.6178 342.27 0.3031 1.83734 26.40 50.7543 131.19 0.2165 1.79884 10.12 51.5785 118.41 0.2598 1.77201 9.13 52.3593 105.86 0.2598 1.74741 8.17 53.2237 143.52 0.1732 1.72106 11.07 CaF.sub.2 55.7559 291.37 0.4330 1.64875 22.47 60.1404 30.48 0.3464 1.53861 2.35 61.8997 32.01 0.3897 1.49904 2.47 63.2828 70.58 0.3464 1.46957 5.44 64.2073 72.79 0.6061 1.45062 5.61 65.5460 30.47 0.5196 1.42420 2.35 CaF.sub.2 68.7224 84.83 0.6336 1.36479 6.54

[0428] FIG. 16 shows the PXRD pattern resulting from milling of Fluorspar with Ca.sub.3(PO.sub.4).sub.2 at 35 Hz for 3 hours. Table 5.7.13 shows the PXRD data from the milling of Fluorspar with Ca.sub.3(PO.sub.4).sub.2 represented in FIG. 16. Labels in FIG. 16 indicates a crystalline phase of Ca.sub.5(PO.sub.4).sub.3F.

TABLE-US-00032 TABLE 5.7.13. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 22.0434 15.65 0.5196 4.03250 3.25 26.0518 184.78 0.1948 3.42044 38.31 28.3091 213.59 0.3031 3.15262 44.28 29.2225 140.14 0.2598 3.05613 29.05 32.0450 482.35 0.2598 2.79310 100.00 33.1785 229.57 0.2598 2.70022 47.59 34.2570 111.95 0.2165 2.61764 23.21 40.1975 87.58 0.2165 2.24345 18.16 42.3548 16.81 0.5196 2.13404 3.49 43.9319 15.64 0.5196 2.06102 3.24 46.9721 173.42 0.3464 1.93447 35.95 48.4374 53.81 0.3464 1.87932 11.16 49.6795 132.95 0.2165 1.83521 27.56 50.9224 56.80 0.3464 1.79330 11.78 53.3052 60.24 0.3464 1.71862 12.49 56.2117 34.73 0.6061 1.63645 7.20 61.9102 13.34 0.5196 1.49881 2.77 64.2938 23.96 0.8448 1.44768 4.97

5.8. Milling Frequency and Consumption of Crystalline CaF.SUB.2 .in Solid State Reactions

[0429] An increased consumption of crystalline CaF.sub.2 may be achieved by successively spiking the milled mixtures (A to D in Scheme 5.8.1) with additional K.sub.2HPO.sub.4 and milling for additional 3 hour periods until all of the crystalline CaF.sub.2 was consumed as detailed in Scheme 5.8.1.

##STR00033##

[0430] In this reaction, Fluorspar (1 equiv.) was added to a stainless steel container with 1 equivalent of K.sub.2HPO.sub.4 the mixture was milled for 3 hours at 30 Hz, followed by successive additions of 1 additional equivalent of K.sub.2HPO.sub.4, 0.5 equiv. K.sub.2HPO.sub.4, and 0.5 equiv. K.sub.2HPO.sub.4 each accompanied by 3 hours of milling at 30 Hz. FIG. 17 shows Powder X-Ray Diffraction patterns of each of these mixtures, labelled to show the appearance of the new species. The PXRD was obtained on a Bruker Eco D8 Diffractometer.

[0431] The effect of milling intensity was investigated as shown in Scheme 5.8.2. Acid grade Fluorspoar (1 equiv.) was milled with K.sub.2HPO.sub.4 (1 equiv.) at 30 Hz or 35 Hz for 3 hours and the powder reagent (A) was used in the fluorination of TsCl at 0.125 mmol scale and yields were determined by 1H NMR and .sup.19F NMR with 4-fluoroaniosole as an internal standard. Milling was completed using a Retsch MM400 ball mill and stainless steel jars (15 mL) and a 7 g ball.

##STR00034##

[0432] FIG. 18 shows the results of the experiment, when the powder reagent is reacted in solution with TsCl in tBuOH (0.25 M) at 100° C. for 5 hours, showing that higher frequency milling may result in powder reagents, that when used for fluorination, may lead to higher fluorination yields. Additionally, when higher equivalents of the fluorination reagent (A) are used, higher fluorinations yields may be exhibited.

5.9. Varying Stoichiometry of CaF.SUB.2 .(Fluorpar)

[0433] Milled mixtures A to C as seen in Scheme 5.9.1 were investigated as fluorinating reagents, in turn allowing for fluorination of TsCl at high yield using fewer equivalents of CaF.sub.2 (Fluorspar).

##STR00035##

[0434] In A, 1 equivalent of Fluorspar was milled with 1 equivalent of K.sub.2HPO.sub.4 at 30 or 35 Hz for 3 hours. In B, 1 additional equivalent of K.sub.2HPO.sub.4 was added and milled for 3 hours at 30 or 35 Hz. In C, 0.5 additional equivalent of K.sub.2HPO.sub.4 was added and milled for 3 hours at 30 or 35 Hz. The powder reagents were reacted with TsCl (1 equiv., 0.125-0.25 mmol) in solution as seen in Scheme 5.9.2 in tBuOH (0.25 M) at 100° C. for 5 hours. FIG. 19 shows the experimental results which indicate that lower equivalents of CaF.sub.2 can lead to higher fluorination yields of organofluorine product (e.g., TsF).

##STR00036##

[0435] Scheme 5.9.3 shows a reaction wherein the powder reagents of Scheme 5.9.1 were reacted with TsCl (1 equiv., 0.125-0.25 mmol) in a 0.25 M solution of tBuOH at 100° C. for 5 hours with the addition of water. The results (see FIG. 20) show that the addition of water to the reaction may be beneficial to achieving higher yields of organofluorine product (e.g., TsF).

##STR00037##

[0436] Various experimental conditions were used using powder reagent C from Scheme 5.9.1 (containing 0.5 equivalents of CaF.sub.2) as seen in Scheme 5.9.4 where C (0.5 equiv.) is reacted with TsCl (1 equiv., 0.125-0.25 mmol) in a solution of tBuOH (0.25 M) at 100° C. for 5 hours with the addition of varying amounts of water. FIG. 21 shows the results of these reactions. These results may indicate that larger amounts of added water may lower yields of fluorinated product but longer reaction times may increase product yield.

5.10. S—F Bond Scope

[0437] ##STR00038##

[0438] A series of reactions were completed to assess the scope of SO.sub.2—Cl substrates that could undergo fluorination, and the associated fluorination yields. All yields were isolated unless otherwise stated and all reactions were on 0.5 mmol scale unless otherwise stated .sup.19F NMR yields were determined using 4-fluoroanisole as an internal standard. In FIG. 22, .sup.b indicates that EtCN was used instead of tBuOH (anhydrous), .sup.c indicates that the product was prepared via addition of all trans farnesyl-mercaptan to ESF, .sup.d indicates that the reaction was completed using 2.2 equivalents of “reagent’, .sup.e indicates that the reaction was completed on 0.25 mmol scale, .sup.f indicates that 1.25 mmol of “reagent” was used. In all instances, a INSOLIDO IST636 Ball Mill was used with stainless steel jars (15 mL) and ball (7 g) (316 SS grade). These reactions were carried out as detailed in Scheme 5.10.1 wherein Fluorspar (CaF.sub.2) (1 equiv., acid grade) was milled with K.sub.2HPO.sub.4 (2.5 equiv. total) at 35 Hz for 9 hours total. The “reagent” (1 equiv.) was reacted with the R—SO.sub.2Cl (1 equiv.) and H.sub.2O (0-2 equiv) in tBuOH or EtCN (0.25 M) at 40-100° C. for 2-24 hours to achieve the fluorinated product. FIG. 22 shows all of the fluorinated products and their fluorinated yields. The results indicate that a wide range of substrates may undergo fluorination using the fluorination agents described herein.

5.11. C—F Bond Scope

[0439] A series of reactions were completed to assess the scope of R—X substrates that could undergo fluorination, wherein X indicates a halogen (Br or CI) and the associated fluorination yields. Benzyl fluorides, acyl fluorides, alpha-fluoro carbonyls, alkyl fluorides, and (hetero)aryl fluorides were of those C—F bonds investigated as seen in FIG. 23. The fluorination reagent was created via ball milling as shown in Scheme 5.11.1 wherein CaF.sub.2 (FluorSpar) (1-4 equiv.) was milled with K.sub.2HPO.sub.4 (4-8 equiv.) at 35 Hz for 3-9 hours total. This solid reagent was reacted with the R—X substrate (1 equiv.), 18-C-6 (1 equiv.) and optionally H.sub.2O (0-5 equiv.) in a solution of tBuOH at 60-100° C. for 5-48 hours to achieve the desired product, the yields and specific solution conditions of which can be seen in FIG. 23. All isolated yields are not in parentheses and were conducted on a 0.5 mmol scale. All yields in parentheses are NMR yields. All reactions were completed using an INSOLIDO IST636 Ball Mill and using stainless steel jars (15 mL) with a 7 g ball (316 SS grade). The results indicate a range of different halogenated functionalities can undergo fluorination using the forementioned fluorination reagents.

##STR00039##

5.12 Solution State NMR and Powder X-Ray Diffraction

[0440] Fluorspar (CaF.sub.2) was milled with K.sub.2HPO.sub.4 (2.5 equiv. total) as seen in Scheme 5.12.1 to form a “reagent”. The reagent was dissolved in D20 to form D20 soluble components for study via solution state NMR. FIG. 24A shows .sup.19F NMR indicating the presence of F.sup.− ion and PO.sub.3F.sup.2− ion in solution upon dissolution. FIG. 24B shows 31P NMR indicating the presence of PO.sub.4.sup.3− and PO.sub.3F.sup.2−.

##STR00040##

[0441] FIG. 25 shows a powder x-ray diffraction pattern (PXRD) of the “reagent” with a reference PXRD pattern for potassium fluoride (KF). The PXRD pattern indicated no presence of KF upon completion of the ball milling reaction. FIG. 26 and Table 5.12.1 show PXRD data of the fluorinating reagent, “Fluoromix” that results from the “reagent” formation depicted in Scheme 5.12.1 when fluorspar is milled with 2.5 total equivalents of K.sub.2HPO.sub.4. FIG. 27 shows the crystalline components of “reagent” consistent with X (KF (1 equiv.) milled with K.sub.2HPO.sub.4 (1 equiv.) at 30 Hz for 3 hours), Y (KF (1 equiv.) milled with K.sub.2HPO.sub.4 (1 equiv.) at 30 Hz for 3 hours followed by the addition of CaHPO.sub.4 (1 equiv.)), and crystalline CaF.sub.2 as a reference PXRD pattern. X and Y could be synthesized independently via Scheme 5.12.2.

##STR00041##

[0442] This PXRD may indirectly support the formation and involvement of KF and CaHPO.sub.4 species in the solid state reaction. The structures of X and Y were simulated based upon their PXRD patterns. FIG. 28A shows the simulated structure of X which may be K.sub.3(HPO.sub.4)F, which is a related structure to K.sub.3(PO.sub.3F)F. FIG. 28B shows the simulated structure of Y which may be K.sub.2-xCa.sub.y(PO.sub.3F).sub.a(PO.sub.4).sub.bF.sub.c, which is a related structure to K.sub.2PO.sub.3F. FIG. 29 shows PXRD experiments for Fluorspar (acid grade), K.sub.2HPO.sub.4 (Fisher Chemical), and Fluorapatite (Thermo Fisher). FIG. 30 shows an overlay of PXRD diffractograms of fluoromix, fluorspar, X, and Y. Residual CaF.sub.2 is also observed in the diffractogram of fluoromix. Table 5.12.2 shows PXRD data of the crystalline components of X which has a proposed structure of K.sub.3(HPO.sub.4)F. Table 5.12.3 shows PXRD data of the crystalline components of Y, which has a proposed structure of K.sub.2-xCa.sub.y(PO.sub.3F).sub.a(PO.sub.4).sub.bF.sub.c.

TABLE-US-00033 TABLE 5.12.1. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] X 17.5396 65.74 0.1515 5.05648 6.01 Y 21.1279 153.67 0.3031 4.20512 14.06 X 23.5473 63.33 0.3031 3.77826 5.79 X 24.8414 38.29 0.2165 3.58428 3.50 CaF.sub.2 28.3270 387.64 0.1732 3.15067 35.46 X 29.3567 889.96 0.1515 3.04246 81.42 Y 29.6240 919.11 0.1299 3.01562 84.08 Y 30.5396 1093.11 0.1948 2.92727 100.00 X 31.5267 226.92 0.3031 2.83783 20.76 X 35.3807 392.48 0.0758 2.53704 35.91 X 36.7453 327.57 0.3897 2.44590 29.97 Y 37.3937 109.61 0.2165 2.40496 10.03 X 39.8065 109.97 0.3031 2.26458 10.06 Y 42.9495 272.27 0.4330 2.10586 24.91 X 47.1639 263.14 0.2381 1.92705 24.07 CaF.sub.2 47.8144 104.83 0.1732 1.90234 9.59 X 48.0882 90.13 0.3464 1.89215 8.24 X 51.4329 21.62 0.6927 1.77669 1.98 X 53.1839 95.20 0.2598 1.72225 8.71 Y 54.2330 105.76 0.2598 1.69139 9.68 CaF.sub.2 55.8995 80.81 0.1732 1.64485 7.39 Y 58.2038 53.48 0.2598 1.58510 4.89 Y 60.9230 31.01 0.2598 1.52071 2.84 X 63.4275 54.12 0.6061 1.46656 4.95 CaF.sub.2 68.7124 26.36 0.4224 1.36496 2.41

TABLE-US-00034 TABLE 5.12.2. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 15.5985 40.81 0.1299 5.68107 2.34 17.5367 177.21 0.1082 5.05732 10.16 23.3979 99.97 0.1082 3.80204 5.73 24.8981 123.18 0.2165 3.57625 7.06 26.5567 27.17 0.5196 3.35654 1.56 28.0843 158.50 0.0325 3.17734 9.09 28.8933 359.19 0.0974 3.09019 20.60 29.3501 1540.63 0.0660 3.04062 88.34 29.4006 1743.95 0.0433 3.03802 100.00 29.6670 626.50 0.1082 3.01134 35.92 31.3455 918.24 0.0758 2.85381 52.65 35.3783 844.95 0.0974 2.53721 48.45 36.4954 710.20 0.0866 2.46207 40.72 36.7261 985.15 0.1299 2.44713 56.49 38.4075 43.66 0.1732 2.34379 2.50 39.8011 290.42 0.1299 2.26487 16.65 42.8332 73.55 0.2598 2.11131 4.22 46.2683 122.18 0.2598 1.96224 7.01 47.7691 316.46 0.1299 1.90404 18.15 48.1576 199.11 0.1299 1.88959 11.42 48.7914 68.65 0.1299 1.86651 3.94 51.3864 36.92 0.6927 1.77819 2.12 53.1696 153.70 0.3031 1.72268 8.81 54.3855 72.83 0.4330 1.68701 4.18 54.8541 100.27 0.1299 1.67370 5.75 57.5120 39.39 0.3464 1.60251 2.26 58.1605 89.36 0.3031 1.58618 5.12 59.8088 33.81 0.3464 1.54635 1.94 60.8554 73.32 0.2165 1.52223 4.20 62.1974 28.45 0.2598 1.49258 1.63 63.7003 56.77 0.3031 1.46094 3.26 65.4523 51.25 0.3464 1.42601 2.94 66.7273 39.38 0.3464 1.40183 2.26 67.6556 48.24 0.4224 1.38369 2.77

TABLE-US-00035 TABLE 5.12.3. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 21.2490 76.30 0.2598 4.18143 12.32 29.5875 473.30 0.3464 3.01925 76.40 30.7329 619.48 0.3897 2.90929 100.00 35.9522 41.32 0.6927 2.49801 6.67 37.5864 65.52 0.3464 2.39308 10.58 43.1662 208.62 0.2598 2.09579 33.68 63.7377 27.33 0.7392 1.45896 4.41

[0443] Fluorspar (CaF.sub.2) (1 equiv.) was milled with K.sub.2HPO.sub.4 (2.5 equiv.) at 35 Hz for 9 hours total to form a “reagent” as seen in Scheme 5.12.3. This reagent (“Fluoromix”) was washed with H.sub.2O resulting in a water insoluble solid (84.5 mg from 500 mg of reagent, 17% yield). The resulting insoluble solid was examined via PXRD. FIG. 31 shows this PXRD with peaks labelled showing formation of Ca.sub.5(PO.sub.4).sub.3F or Ca.sub.5(PO.sub.4).sub.30H (diamonds) and CaF.sub.2 (circles). The PXRD data can also be found in Table 5.12.4.

##STR00042##

TABLE-US-00036 TABLE 5.12.4. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 25.9666 64.58 0.2165 3.43147 5.97 26.7534 64.57 0.1299 3.33231 5.97 CaF.sub.2 28.4315 1080.91 0.2598 3.13933 100.00 31.9708 174.80 0.1515 2.79941 16.17 32.3361 113.01 0.1299 2.76862 10.45 33.1708 97.67 0.2598 2.70084 9.04 34.1856 47.24 0.1732 2.62295 4.37 40.1111 44.33 0.2598 2.24808 4.10 42.3659 13.44 0.5196 2.13351 1.24 CaF.sub.2 47.0602 1011.70 0.1584 1.92946 93.60 47.1777 927.10 0.1515 1.92652 85.77 49.6779 42.95 0.2598 1.83526 3.97 50.8430 17.12 0.2598 1.79591 1.58 52.3671 13.80 0.2598 1.74717 1.28 53.3150 27.45 0.3464 1.71832 2.54 CaF.sub.2 55.8298 292.84 0.1948 1.64674 27.09 64.2404 13.33 0.5196 1.44996 1.23 CaF.sub.2 68.7885 84.35 0.5280 1.36364 7.80

[0444] In another instance, Fluorspar (CaF.sub.2) was milled with equimolar CaHPO.sub.4 to produce Z as seen in Scheme 5.12.4. This milling was completed at 30 Hz for 3 hours; FIG. 32A shows PXRD of Z as well as the water insoluble solid resulting from the reaction forming Z. FIG. 32B shows the PXRD of Z with crystalline phases of Ca.sub.5(PO.sub.4).sub.3F and CaF.sub.2 highlighted. The PXRD data of Z can be found in Table 5.12.5. The milling of CaF.sub.2 with equimolar anhydrous CaHPO.sub.4 produces Z consistent Ca.sub.5(PO.sub.4).sub.3F (or Ca.sub.5(PO.sub.4).sub.3OH) and CaF.sub.2.

##STR00043##

TABLE-US-00037 TABLE 5.12.5. FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 10.8159 22.19 0.3464 8.18003 1.71 16.9988 27.36 0.3464 5.21612 2.11 21.9471 44.50 0.2598 4.04997 3.43 22.9223 87.66 0.3031 3.87984 6.76 25.9108 464.01 0.1515 3.43873 35.79 26.7231 164.61 0.1299 3.33602 12.70 CaF.sub.2 28.3972 1296.45 0.2165 3.14305 100.00 29.1216 365.28 0.1732 3.06649 28.18 31.9522 1014.39 0.1515 2.80100 78.24 32.3833 548.05 0.1948 2.76469 42.27 33.1624 541.34 0.0866 2.70150 41.76 34.1845 268.43 0.2598 2.62303 20.71 35.6375 53.32 0.1732 2.51934 4.11 39.3033 78.45 0.1732 2.29241 6.05 40.0474 226.94 0.1515 2.25151 17.50 42.2195 64.59 0.3031 2.14056 4.98 43.9611 61.89 0.2598 2.05972 4.77 45.4737 106.84 0.2598 1.99467 8.24 CaF.sub.2 46.9114 1075.26 0.1515 1.93683 82.94 49.6178 342.27 0.3031 1.83734 26.40 50.7543 131.19 0.2165 1.79884 10.12 51.5785 118.41 0.2598 1.77201 9.13 52.3593 105.86 0.2598 1.74741 8.17 53.2237 143.52 0.1732 1.72106 11.07 CaF.sub.2 55.7559 291.37 0.4330 1.64875 22.47 60.1404 30.48 0.3464 1.53861 2.35 61.8997 32.01 0.3897 1.49904 2.47 63.2828 70.58 0.3464 1.46957 5.44 64.2073 72.79 0.6061 1.45062 5.61 65.5460 30.47 0.5196 1.42420 2.35 CaF.sub.2 68.7224 84.83 0.6336 1.36479 6.54

5.13. Polyfluorination Using Fluorspar Activated with K.SUB.2.HPO.SUB.4

[0445] Gem-Difluorination was tested using fluorspar and K.sub.2HPO.sub.4 as an activating agent as described in Scheme 5.13.1.

##STR00044##

[0446] Briefly, the substrate was reacted with 2 equiv. of {(CaF.sub.2)(K.sub.2HPO.sub.4).sub.2.5} which was obtained via milling at 35 Hz and 1 equivalent of 18-C-6 in 0.25 M solvent (described in Table 5.13.1) and reacted at 100° C. for 15 hours in a sealed tube. The yields of fluorinated products and side products can be seen in Table 5.13.1. The results indicate that difluorination may be achieved from dihalogenated starting materials using the fluorinating agents described herein, with low yields of monofluorinated product.

TABLE-US-00038 TABLE 5.13.1. Entry Solvent ArOCHCl.sub.2.sup.[a] ArOCHClF.sup.[b] ArOCHF.sub.2.sup.[b] ArOCHO.sup.[a] 1 AcOH n.d. 0%  0% 65% 2 DMSO n.d. 0%  0% <1% 3 tAmOH n.d. 0% 18% <1% 4 PhCl n.d. 11%  19% <1%   5.sup.[c] PhCl n.d. 9% 17% <1% 6 MeCN n.d. 4% 30%  0% .sup.[a]quantified by .sup.1H-NMR; .sup.[b]quantified by .sup.19F-NMR; .sup.[c]entry from previous screening (30 Hz ball milling); n.d. = not determined due to overlapping signal

[0447] In some instances, the gem-difluorination was tested as described in Scheme 5.13.2.

##STR00045##

[0448] Briefly, the substrate was reacted with 2 equiv. of {(CaF.sub.2)(K.sub.2HPO.sub.4).sub.2.5} which was obtained via milling at 35 Hz and 1 equivalent of an additive (see Table 5.13.2), HBD, and reacted in a solvent (0.25 M) at 100° C. for 15 hours in a sealed tube. The yields of fluorinated product and side products as determined from NMR can be seen in Table 5.13.2. Similarly to above, the results indicate that difluorination may be achieved from dihalogenated starting materials using the fluorinating agents described herein, with low yields of monofluorinated product.

TABLE-US-00039 TABLE 5.13.2 Entry Additive HBD ArOCHCl.sub.2.sup.[a] ArOCHClF.sup.[b] ArOCHF.sub.2.sup.[b] ArOCHO.sup.[a] 1 1 eq. 18-C-6 — n.d. 18%  36% 0%  2.sup.[c] 1 eq. 18-C-6 — n.d. 13%  32% 0%  3.sup.[d] 1 eq. 18-C-6 — n.d. 8% 24% 0% 4 1 eq. — n.d. 5% 21% 0% [2.2.2]Cryptand 5 1 eq. 18-C-6 1 eq. n.d. 1%  5% n.d. Schreiner's urea.sup.[e] 6 1 eq. 18-C-6 0.2 eq. n.d. 9% 34% n.d. Science cat..sup.[e]

5.14. Mechanistic Understanding of Mechanochemical Activation of Fluorpsar with K.SUB.2.HPO.SUB.4

[0449] Fluorspar (CaF.sub.2) is ball milled with anhydrous K.sub.2HPO.sub.4 to afford a fluorinating reagent (Fluoromix) (Scheme 5.14.1) which is comprised of crystalline phases (X, Y) and residual crystalline CaF.sub.2. Powder X-Ray Diffraction (PXRD) patterns of species X and Y match the reflection (peaks) positions and peak intensities observed in Fluoromix. Calcium hydrogen phosphate (CaHPO.sub.4) and potassium fluoride (KF) may be products of the reaction between CaF.sub.2 and K.sub.2HPO.sub.4. X is the product of ball milled KF with K.sub.2HPO.sub.4, and X has the proposed structure K.sub.3(HPO.sub.4)F and is isostructural to K.sub.3(PO.sub.3F)F. Y has the proposed structure K.sub.2-xCa.sub.y(PO.sub.3)F.sub.a(PO.sub.4).sub.bF.sub.c and is isostructural to K.sub.2PO.sub.3F. The formation of X and Y from ball milling fluorspar and K.sub.2HPO.sub.4 may indirectly support the formation of KF and CaHPO.sub.4 as intermediates in this reaction en route to X and Y. A PXRD diffractogram of the water insoluble component of fluoromix was measured and contains reflections that are consistent with CaF.sub.2 and Ca.sub.5(PO.sub.4).sub.3F (fluorapatite) as a mixture (mixture Z). Z may be independently prepared by ball milling CaHPO.sub.4 with CaF.sub.2.

##STR00046##

[0450] Table 5.14.1 shows the PXRD data of starting material, Fluorspar (CaF.sub.2). Table 5.14.2 and FIG. 33 show PXRD data of X, consistent with K.sub.3(HPO.sub.4)F (related structure to K.sub.3(PO.sub.3F)F). Table 5.14.3 and FIG. 34 show PXRD data of Y, consistent with K.sub.2-xCa.sub.y(PO.sub.3F).sub.a(PO.sub.4).sub.bF.sub.c (related to K.sub.2PO.sub.3F). Table 5.14.4 shows PXRD data of Z, consistent with Ca.sub.5(PO.sub.4).sub.3F and unreacted CaF.sub.2.

TABLE-US-00040 TABLE 5.14.1. Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] 28.2976 3.15126 100.00 47.0169 1.93113 66.30 55.8035 1.64609 18.60 68.6839 1.36546 5.08

TABLE-US-00041 TABLE 5.14.2. Pos. [°2Th.] Rel. Int. [%] 15.5985 2.34 17.5367 10.16 23.3979 5.73 24.8981 7.06 26.5567 1.56 28.0843 9.09 28.8933 20.60 29.3501 88.34 29.4006 100.00 29.6670 35.92 31.3455 52.65 35.3783 48.45 36.4954 40.72 36.7261 56.49 38.4075 2.50

TABLE-US-00042 TABLE 5.14.3. Pos. [°2Th.] Rel. Int. [%] 21.2490 12.32 29.5875 76.40 30.7329 100.00 35.9522 6.67 37.5864 10.58 43.1662 33.68 63.7377 4.41

TABLE-US-00043 TABLE 5.14.4. Pos. [°2Th.] Rel. Int. [%] 22.0434 3.25 26.0518 38.31 28.3091 44.28 29.2225 29.05 32.0450 100.00 33.1785 47.59 34.2570 23.21 40.1975 18.16 42.3548 3.49 43.9319 3.24 46.9721 35.95 48.4374 11.16 49.6795 27.56 50.9224 11.78 53.3052 12.49 56.2117 7.20 61.9102 2.77 64.2938 4.97

[0451] Each crystalline species of the Fluoromix (X or Y) was prepared independently and tested in the fluorination of tosyl chloride (TsCl). X or Y can be used to convert S(VI)—Cl bonds into an S(VI)—F bond whilst CaF.sub.2 or Z (“apatite structure” consistent with Ca.sub.5(PO.sub.4).sub.3F) do not afford any fluorinated product. The fluorination using X or Y was carried out as described in Scheme 5.14.3, X or Y (1 equiv. with respect to fluoride) was reacted in a tBuOH solution with the TsCl (1 equiv.) with H.sub.2O at 100° C. for 5 hours to afford the fluorinated product. The resulting yields when Fluoromix was used, or when X or Y were used independently are seen in FIG. 35 for fluorinated product yield TsF and starting material yield TsCl. Fluoromix and X (ball milled KF with K.sub.2HPO.sub.4) afford toslyl fluoride (TsF) in high yield. Fluorination yield is decreased when Y (ball milled KF, K.sub.2HPO.sub.4 and CaHPO.sub.4) is used, indicative of reduced fluorinating ability when CaHPO.sub.4 is incorporated into product X, which may be ameliorated through the addition of water (2 equiv.).

##STR00047##

6. Alternative Activators of Fluorspar (CaF.SUB.2.)

6.1. Formation of KCaF.SUB.3 .and NaF Using Hydroxide Activators

[0452] Hydroxide activators (KOH and NaOH) were probed as alternative activators as described in Schemes 6.1.1 and 6.1.2. Briefly, Fluorspar (CaF.sub.2, 1 equiv.) was added to a stainless steel jar with KOH (1 equiv.) and milled for 3 hours at 35 Hz. Based on PXRD data, this reaction resulted in the formation of KCaF.sub.3 and Ca(OH).sub.2. Alternatively, Fluorspar (CaF.sub.2, 1 equiv.) was milled with NaOH (2 equiv.) for 6 hours at 35 Hz. As determined by PXRD, this reaction led to the formation of NaF and Ca(OH).sub.2. FIG. 36 shows the PXRD of products from the reaction shown in Scheme 6.1.2 between Fluorspar and NaOH.

##STR00048##

##STR00049##

6.2. Fluorination of TsCl Using Hydroxide Activators

[0453] Fluorspar (1 equiv.) was milled with KOH (2 equiv.) at 35 Hz for 3 hours as depicted in Scheme 6.2.1 to form Ca(OH).sub.2, KCaF.sub.3, and residual CaF.sub.2 (A). This mixture was milled with dry ice (10 equiv.) at 20 Hz for 60 seconds to form (B) consisting of KHCO.sub.3, KCaF.sub.3, and CaF.sub.3. The mixture (A) was also heated at 520° C. for 1 hour to form (C), CaO, KCaF.sub.3, and CaF.sub.2. These mixtures (2 equiv.) were reacted in solution with TsCl (1 equiv., 0.125 mmol) according to scheme 6.2.1 in acetonitrile (anhydrous) at 100° C. for 3 hours to form the fluorinated product. In some case, an additive such as Schreiner's Urea or 18-crown-6 was added (see Table 6.2). Fluorination of TsCl using either the treated or untreated KCaF.sub.3/Ca(OH).sub.2 mixture was achieved. The results indicate that using hydroxide activators with Fluorspar, fluorination can occur. Exemplary conditions include the addition of additives such as crown ethers or Schreiner's urea.

TABLE-US-00044 TABLE 6.2. Mixture Entry (2 eq) Additive (1 eq) TsF (%) TsCl (%) TsOH (%) 1 A — 0 0 100 2 B — 12 37 51 3 C — 11 36 53 4 A 18-crown-6 17 0 70 5 B 18-crown-6 17 0 70 6 C 18-crown-6 36 34 30 7 A Schreiner's urea 31 52 17

##STR00050##

6.3. Fluorination of TsCl Using Alternative Non-Phosphate Activators

[0454] Alternative non-phosphate activators were investigated and fluorination of TsCl was investigated via Scheme 6.3.1. Fluorspar (CaF.sub.2, 1 equiv.) was milled with the activator (1.0 or 2.0 equiv., see FIG. 37) for 3 hours at 35 Hz to form A. A was used as the fluorinating reagent with TsCl in a tBuOH (0.25 M) solution and reacted at 100° C. for 5 hours to from a fluorinated product. The NMR yields of the reactions using various activators are shown in FIG. 37. The reaction using sodium sulfite (Na.sub.2SO.sub.3) as an activator resulted in an itractable mixture of products in the solution phase. The non-phosphate activators included K.sub.2CO.sub.3, KHCO.sub.3, K.sub.2SO.sub.4, KHSO.sub.4, Cs.sub.2SO.sub.4, K.sub.2S.sub.2O.sub.7, Na.sub.2SO.sub.3, KNO.sub.3, and sodium citrate dihydrate. The fluorination yields indicate that exemplary non-phosphate activators may include Na.sub.2SO.sub.3 and sodium citrate dihydrate. The resulting activated fluorspar reagent (A) was analyzed with PXRD.

##STR00051##

[0455] FIG. 38 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.2CO.sub.3 at 35 Hz for 3 hours. Table 6.3.1 shows the PXRD data from the milling of Fluorspar with K.sub.2CO.sub.3 represented in FIG. 38. Labels in FIG. 38 indicates a crystalline phase of K.sub.2CO.sub.3 and CaF.sub.2.

TABLE-US-00045 TABLE 6.3.1 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 12.9106 144.72 0.0866 6.85716 24.98 25.8539 101.94 0.1299 3.44616 17.59 26.6959 31.71 0.1299 3.33935 5.47 26.9959 49.07 0.1515 3.30292 8.47 28.3703 579.44 0.1515 3.14597 100.00 29.7826 196.84 0.1299 2.99991 33.97 30.8164 76.76 0.1082 2.90160 13.25 32.2202 235.71 0.0758 2.77831 40.68 32.4335 324.62 0.0758 2.76053 56.02 32.7123 347.33 0.0649 2.73764 59.94 35.2790 40.41 0.1299 2.54412 6.97 38.7430 65.59 0.2165 2.32425 11.32 39.1613 57.38 0.2165 2.30039 9.90 39.8516 57.63 0.2165 2.26212 9.95 40.5478 39.16 0.1299 2.22488 6.76 41.4026 122.91 0.0866 2.18089 21.21 47.0989 443.53 0.1082 1.92956 76.55 49.4343 20.97 0.2598 1.84373 3.62 50.9012 18.98 0.2598 1.79399 3.28 51.3471 15.41 0.6927 1.77946 2.66 53.7815 18.31 0.2598 1.70452 3.16 55.8616 121.34 0.2598 1.64588 20.94 68.7508 30.46 0.4224 1.36430 5.26

[0456] FIG. 39 shows the PXRD pattern resulting from milling of Fluorspar with KHCO.sub.3 at 35 Hz for 3 hours. Table 6.3.2 shows the PXRD data from the milling of Fluorspar with KHCO.sub.3 represented in FIG. 39. Labels in FIG. 39 indicates a crystalline phase of KHCO.sub.3 and CaF.sub.2.

TABLE-US-00046 TABLE 6.3.2 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 12.2501 123.64 0.1299 7.22535 27.19 24.4342 359.63 0.1732 3.64308 79.09 28.4554 435.01 0.2165 3.13675 95.67 28.9876 115.83 0.1299 3.08036 25.47 30.2433 454.69 0.0758 2.95526 100.00 31.4423 373.37 0.1948 2.84525 82.11 31.6259 389.58 0.1299 2.82915 85.68 31.9991 116.90 0.1299 2.79700 25.71 34.2459 130.85 0.1082 2.61846 28.78 38.0312 76.88 0.1732 2.36610 16.91 39.4041 196.56 0.1948 2.28677 43.23 40.8305 89.69 0.1732 2.21012 19.72 44.6882 80.08 0.1732 2.02789 17.61 47.1870 351.72 0.2381 1.92616 77.35 49.8903 69.65 0.2165 1.82795 15.32 50.9410 47.90 0.3464 1.79268 10.54 52.5013 55.63 0.2598 1.74302 12.23 56.0264 96.82 0.3031 1.64143 21.29 60.9589 15.94 0.6927 1.51990 3.51 65.6349 9.80 0.5196 1.42249 2.16 68.8465 32.51 0.4224 1.36263 7.15

[0457] FIG. 40 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.2SO.sub.4 at 35 Hz for 3 hours. Table 6.3.3 shows the PXRD data from the milling of Fluorspar with K.sub.2SO.sub.4 represented in FIG. 40. Labels in FIG. 40 indicates a crystalline phase of K.sub.2SO.sub.4 and CaF.sub.2.

TABLE-US-00047 TABLE 6.3.3 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 5.1556 100.92 0.5196 17.14099 11.33 17.7779 36.96 0.2598 4.98925 4.15 21.4518 292.38 0.1948 4.14236 32.83 23.8955 141.47 0.1299 3.72398 15.88 25.5175 46.92 0.1732 3.49084 5.27 26.4249 109.07 0.1299 3.37299 12.25 28.4008 706.53 0.2381 3.14265 79.33 29.2377 76.72 0.1299 3.05458 8.61 29.8670 833.06 0.0792 2.98916 93.54 29.9401 809.94 0.0528 2.98943 90.94 30.8750 890.60 0.1056 2.89383 100.00 31.1020 655.56 0.1584 2.87322 73.61 33.7120 49.11 0.1848 2.65650 5.51 34.5815 14.87 0.3168 2.59168 1.67 35.7248 83.91 0.1584 2.51131 9.42 36.0391 128.92 0.1848 2.49013 14.48 37.2299 267.29 0.1056 2.41317 30.01 37.9967 105.23 0.2112 2.36621 11.82 40.5344 186.48 0.1320 2.22374 20.94 40.9781 123.32 0.1320 2.20068 13.85 43.1380 77.39 0.1584 2.09536 8.69 43.5430 254.60 0.1584 2.07680 28.59 45.4011 59.57 0.2112 1.99603 6.69 47.0925 613.94 0.2112 1.92821 68.94 48.2283 114.70 0.1056 1.88542 12.88 48.8066 52.18 0.2112 1.86442 5.86 49.2157 47.15 0.2640 1.84988 5.29 51.6379 21.04 0.4224 1.76865 2.36 53.6603 17.56 0.3168 1.70667 1.97 54.1987 54.01 0.1584 1.69098 6.06 55.0831 70.70 0.1584 1.66590 7.94 55.7987 159.66 0.1584 1.64622 17.93 58.8748 48.50 0.3696 1.56733 5.45 62.8418 18.13 0.4224 1.47759 2.04 64.2204 50.41 0.2640 1.44916 5.66 64.6329 57.18 0.1056 1.44090 6.42 65.1681 35.16 0.3168 1.43036 3.95 68.7906 49.87 0.4224 1.36360 5.60 69.4698 51.79 0.1584 1.35192 5.82

[0458] FIG. 41 shows the PXRD pattern resulting from milling of Fluorspar with KHSO.sub.4 at 35 Hz for 3 hours. Table 6.3.4 shows the PXRD data from the milling of Fluorspar with KHSO.sub.4 represented in FIG. 41. Labels in FIG. 41 indicates a crystalline phase of KHSO.sub.4, K.sub.2Ca(SO.sub.−4).sub.2H.sub.2O.sub.2 (syngenite), and CaF.sub.2.

TABLE-US-00048 TABLE 6.3.4 FWHM Rel. Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Int. [%] 9.4797 62.07 0.1732 9.32980 10.47 Syngenite 15.6743 57.87 0.1299 5.65376 9.76 18.2434 113.03 0.1732 4.86298 19.06 18.8952 64.59 0.1732 4.69668 10.89 Syngenite 19.4234 42.96 0.1515 4.57012 7.24 19.9139 83.23 0.1515 4.45866 14.03 20.5445 43.12 0.1299 4.32320 7.27 21.6718 30.63 0.1732 4.10080 5.17 23.3210 593.11 0.0541 3.81439 100.00 25.4818 325.95 0.1948 3.49564 54.96 Syngenite 26.3384 453.30 0.1515 3.38386 76.43 26.7634 121.85 0.1299 3.33109 20.54 27.5127 464.84 0.0866 3.24204 78.37 28.4297 569.90 0.1948 3.13953 96.09 29.6910 393.27 0.1515 3.00896 66.31 Syngenite 30.6219 98.75 0.2598 2.91958 16.65 31.5012 126.68 0.1299 2.84006 21.36 31.8374 218.30 0.1948 2.81084 36.81 32.7922 180.11 0.1732 2.73115 30.37 33.6933 46.12 0.1515 2.66014 7.78 34.9230 58.91 0.1299 2.56924 9.93 35.8691 45.63 0.1299 2.50361 7.69 36.4744 33.67 0.1732 2.46344 5.68 36.8389 48.58 0.1732 2.43990 8.19 37.3834 75.15 0.1948 2.40560 12.67 38.0312 189.76 0.1082 2.36610 31.99 38.6991 85.51 0.1515 2.32679 14.42 39.8702 103.10 0.2165 2.26111 17.38 41.9603 48.09 0.1299 2.15319 8.11 42.8908 55.71 0.1299 2.10861 9.39 45.0074 102.01 0.2598 2.01424 17.20 47.2173 385.29 0.1948 1.92500 64.96 48.1065 74.23 0.2165 1.89147 12.52 49.2473 55.11 0.1732 1.85030 9.29 51.7741 33.44 0.2598 1.76578 5.64 52.9853 18.43 0.4330 1.72824 3.11 55.5297 67.74 0.3464 1.65493 11.42 56.0099 72.11 0.3464 1.64187 12.16 59.4932 19.67 0.2598 1.55379 3.32 61.0679 11.65 0.3464 1.51745 1.96 62.0966 12.94 0.2598 1.49476 2.18 64.3255 26.65 0.2598 1.44824 4.49 66.4721 11.96 0.6061 1.40659 2.02 67.5187 17.00 0.2598 1.38731 2.87 68.5917 21.96 0.7392 1.36707 3.70

[0459] FIG. 42 shows the PXRD pattern resulting from milling of Fluorspar with K.sub.2S.sub.2O.sub.7 at 35 Hz for 3 hours. Table 6.3.5 shows the PXRD data from the milling of Fluorspar with K.sub.2S.sub.2O.sub.7 represented in FIG. 42. Labels in FIG. 42 indicates a crystalline phase of K.sub.2S.sub.2O.sub.7 and CaF.sub.2.

TABLE-US-00049 TABLE 6.3.5 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 18.6759 158.99 0.1515 4.75132 19.51 24.5269 213.14 0.1515 3.62953 26.15 24.9651 223.94 0.2598 3.56681 27.48 25.8936 81.49 0.4330 3.44098 10.00 27.6051 292.05 0.2598 3.23141 35.83 28.1502 512.13 0.1299 3.17005 62.83 28.4887 815.05 0.1082 3.13315 100.00 29.6651 116.36 0.2165 3.01153 14.28 30.8497 134.66 0.2165 2.89854 16.52 34.5076 53.64 0.2165 2.59921 6.58 36.1930 16.57 0.5196 2.48194 2.03 37.8307 47.81 0.8659 2.37818 5.87 39.8507 39.48 0.6927 2.26217 4.84 41.3817 17.93 0.5196 2.18195 2.20 43.2539 26.00 0.5196 2.09174 3.19 44.9790 24.93 0.6927 2.01545 3.06 47.1481 476.17 0.1948 1.92766 58.42 55.9592 126.70 0.4330 1.64324 15.54 58.2197 8.73 0.6927 1.58471 1.07 68.7851 52.76 0.4224 1.36370 6.47

[0460] FIG. 43 shows the PXRD pattern resulting from milling of Fluorspar with Na.sub.2SO.sub.3 at 35 Hz for 3 hours. Table 6.3.6 shows the PXRD data from the milling of Fluorspar with Na.sub.2SO.sub.3 represented in FIG. 43. Labels in FIG. 43 indicates a crystalline phase of Na.sub.2SO.sub.3, CaF.sub.2, and an unidentified amorphous phase.

TABLE-US-00050 TABLE 6.3.6 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 23.8355 155.83 0.1732 3.73321 21.77 28.1608 715.75 0.0433 3.16889 100.00 28.4753 622.31 0.1948 3.13460 86.95 32.9735 156.27 0.2165 2.71654 21.83 34.8502 131.51 0.2598 2.57444 18.37 41.0281 13.76 0.8659 2.19993 1.92 47.1164 387.85 0.1082 1.92888 54.19 48.6067 69.26 0.3464 1.87317 9.68 55.9232 109.79 0.3031 1.64421 15.34 59.8245 19.50 0.6927 1.54598 2.72 68.8731 43.89 0.4224 1.36217 6.13

[0461] FIG. 44 shows the PXRD pattern resulting from milling of Fluorspar with KNO.sub.3 at 35 Hz for 3 hours. Table 6.3.7 shows the PXRD data from the milling of Fluorspar with KNO.sub.3 represented in FIG. 44. Labels in FIG. 44 indicates a crystalline phase of KNO.sub.3 and CaF.sub.2.

TABLE-US-00051 TABLE 6.3.7 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 19.0933 166.39 0.1515 4.64838 22.78 23.6201 730.32 0.0758 3.76677 100.00 23.8949 426.50 0.1515 3.72408 58.40 28.3673 462.76 0.1732 3.14629 63.36 29.5161 370.32 0.1948 3.02640 50.71 32.4746 143.69 0.1948 2.75712 19.68 33.1816 102.66 0.1299 2.69998 14.06 33.9155 403.95 0.0866 2.64321 55.31 37.4570 21.26 0.2598 2.40105 2.91 38.6730 61.71 0.1732 2.32830 8.45 41.2213 299.90 0.1082 2.19006 41.07 41.8893 124.68 0.2165 2.15667 17.07 44.1951 129.97 0.1082 2.04936 17.80 46.7107 259.71 0.2598 1.94468 35.56 47.0655 348.31 0.3897 1.93085 47.69 51.8589 16.72 0.3464 1.76309 2.29 55.8970 78.75 0.6061 1.64492 10.78 58.3619 15.97 0.2598 1.58118 2.19 61.0249 22.10 0.5196 1.51841 3.03 66.9806 17.43 0.2598 1.39714 2.39 68.9193 53.99 0.3696 1.36137 7.39

[0462] FIG. 45 shows the PXRD pattern resulting from milling of Fluorspar with KOH at 35 Hz for 3 hours. Table 6.3.8 shows the PXRD data from the milling of Fluorspar with KOH represented in FIG. 45. Labels in FIG. 45 indicates a crystalline phase of Ca(OH).sub.2, KCaF.sub.2, and CaF.sub.2.

TABLE-US-00052 TABLE 6.3.8 FWHM Rel. Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Int. [%] Ca(OH).sub.2 18.3059 55.74 0.3031 4.84651 11.78 KCaF.sub.3 20.4243 53.12 0.2165 4.34838 11.22 26.8143 11.39 0.2598 3.32487 2.41 CaF.sub.2 28.3800 144.77 0.1732 3.14491 30.58 KCaF.sub.3 28.9043 473.34 0.2165 3.08905 100.00 KCaF.sub.3 32.4309 19.70 0.3464 2.76074 4.16 Ca(OH).sub.2 34.1756 142.38 0.3897 2.62369 30.08 KCaF.sub.3 35.6082 66.30 0.3464 2.52135 14.01 KCaF.sub.3 38.5478 17.24 0.2598 2.33558 3.64 KCaF.sub.3 41.3008 308.88 0.1299 2.18604 65.26 Ca(OH).sub.2 47.2316 123.86 0.4330 1.92445 26.17 KCaF.sub.3 51.1272 175.11 0.3897 1.78659 36.99 Ca(OH).sub.2 54.5376 32.39 0.4330 1.68266 6.84 CaF.sub.2 55.7686 27.72 0.3031 1.64840 5.86 KCaF.sub.3 59.7330 68.83 0.4330 1.54813 14.54 Ca(OH).sub.2 62.8171 18.65 0.3464 1.47934 3.94 CaF.sub.2 67.6726 26.77 0.6336 1.38338 5.65

[0463] FIG. 46 shows the PXRD pattern resulting from milling of Fluorspar with NaOH at 35 Hz for 3 hours. Table 6.3.9 shows the PXRD data from the milling of Fluorspar with NaOH represented in FIG. 46. Labels in FIG. 46 indicates a crystalline phase of Ca(OH).sub.2, NaF, CaF.sub.2, and an unidentified amorphous material.

TABLE-US-00053 TABLE 6.3.9 FWHM Rel. Pos. [°2Th.] Height [cts] [°2Th.] d-spacing[Å] Int. [%] Ca(OH).sub.2 18.0813 122.86 0.6061 4.90620 13.13 Ca(OH).sub.2 28.0362 493.55 0.0325 3.18268 52.73 CaF.sub.2 28.2772 936.03 0.2165 3.15610 100.00 Ca(OH).sub.2 34.2959 199.53 0.3464 2.61477 21.32 NaF 38.4222 319.14 0.4763 2.34292 34.09 CaF.sub.2 47.0805 700.67 0.1732 1.93027 74.86 Ca(OH).sub.2 50.9401 63.28 0.3464 1.79271 6.76 NaF 55.8343 213.37 0.3031 1.64662 22.80 CaF.sub.2 68.7807 53.36 0.5280 1.36378 5.70

7. Fluorination Using Fluorapatite

7.1. S—F Bond Formation Using Fluorapatite in the Solid State

[0464] In some instances, fluorapatite was used in combination with K.sub.3PO.sub.4 to fluorinate TsCl in the solid state via ball milling as described in Scheme 7.1.1, the results of which can be found in Table 7.1. Briefly, fluorapatite (Ca.sub.5(PO.sub.4).sub.3F, 5 equiv.) and K.sub.3PO.sub.4 in varying ratios were milled at 30 Hz for 1 hour in 15 mL stainless steel jars using a 7 g ball. TsCl was added and milled for 1 hour longer at 30 Hz to obtain a fluorinated product (see Table 7.1 for yields). The grains of fluorapatite used were approximately 0.06-0.19 inches. The solid state reactions resulted in yields of organo-fluorine product (TsF) of 5% or less.

##STR00052##

TABLE-US-00054 TABLE 7.1 Ca.sub.5(PO.sub.4).sub.3F/K.sub.3PO.sub.4 Ca.sub.5(PO.sub.4).sub.3F Mass Entry ratio (equiv) TsF TsCl Balance 1 2.5:1 5  5% trace  5% 2  10:1 5 <1% 35% <36% 0.25 mmol scale; .sup.19F NMR yields (4-fluoroanisole) in CDCl.sub.3

7.2. S—F Bond Formation Using Fluorapatite in the Solid State and Solution State

[0465] Fluorapatite (Ca.sub.5(PO.sub.4).sub.3F) (approximately 0.06-0.19 in) was used in combination with K.sub.2HPO.sub.4 as described in Scheme 7.2.1 to create a fluorination reagent via ball milling under varying conditions as seen in Table 7.2. Specifically, fluorapatite (4 equiv.) was milled with K.sub.2HPO.sub.4 (20 equiv.) for 3 hours at varying frequencies, jar loading (mg/mL), and jar sizes (mL). The resulting powder reagent was reacted with p-TolSO.sub.2—Cl (TsCl) (1 equiv.) in a tBuOH (0.25 M) solution at 100° C. for 5 hours resulting in a fluorinated product, TsF. The yield of the fluorinated product and starting material, TsCl can be found in Table 7.2. The results indicate that jar loading may affect ball milling/fluorination yield and higher frequencies may be beneficial to yield. The results also highlight that, the solution reaction of the fluorapatite-K.sub.2HPO.sub.4 fluorination reagent with the TsCl can result in higher fluorinated product (TsF) yields than seen in the solid state reaction of Example 7.1.

##STR00053##

7.3. Activator Screening Using Fluorapatite

[0466] Various activators were used in combination with fluorapatite to test their efficacy in forming a fluorinating reagent. The resulting fluorinating reagents, “Fluoromix”, were probed as fluorinating reagents via reaction with p-TolSO.sub.2—Cl (TsCl) and yields of TsF were determined via .sup.19F NMR using 4-fluoroanisole as an internal standard. The reactions were carried out as described in Scheme 7.3.1.

##STR00054##

[0467] Briefly, fluorapatite (1 equiv.) was milled with an activator (see Table 7.3) at 30 Hz for 3 hours in a 15 mL stainless steel jar with a 7 g ball to create Fluoromix. Fluoromix (0.2 mmol) was added to a PhCl solution (0.25 M) with p-TolSO.sub.2—Cl (1.0 equiv., 0.05 mmol) and reacted at 100° C. for 5 hours to form the fluorinated product, TsF. The yields of TsF and the side product yields can be found in Table 7.3. Successful fluorination may be possible with exemplary activators KCl +K.sub.2HPO.sub.4 or potassium pyrophosphate, although the success of fluorinating the TsCl starting material may be dependent on the activator used.

TABLE-US-00055 TABLE 7.3 Entry Activator Total Mass PO.sub.3F.sup.2− F.sup.− TsF TsCl 1 KCl (9 equiv.) 1000 mg 0% 0% 0% 87%  2 K.sub.2CO.sub.3 (4.5 equiv.) 1000 mg 0% 0% 0% 0% 3 KCl (9 equiv.) + K.sub.2HPO.sub.4 (1 equiv.) 600 mg 0% 2% 9% 0% 4 K.sub.2CO.sub.3 (4.5 equiv.) + K.sub.2HPO.sub.4 (1 equiv.) 600 mg 0% 15%  0% 0% 5 K.sub.2CO.sub.3 (4.5 equiv.) + K.sub.2HPO.sub.4 (2 equiv.) 600 mg 0% 17%  0% 0% 6 KHCO.sub.3 (5 equiv.) 600 mg 0% 5% 0% 0% 7 KHCO.sub.3 (5 equiv.) + K.sub.2HPO.sub.4 (2 equiv.) 600 mg 0% 3% trace 0% 8 KH.sub.2PO.sub.4 (5 equiv.) 500 mg 0% 1% 0% 85%  9 K.sub.3PO.sub.4 (5 equiv.) 500 mg 0% 14%  10 Potassium pyrophosphate (2.5 equiv.) 500 mg 0% 25%  4% 26%  11 Potassium triphosphate (1.67 equiv.) 500 mg 6% 3% trace 51% 

7.4. Varying Stoichiometry of Fluorapatite Fluorination

[0468] Various conditions were probed in order to examine changes in fluorination yield using fluoroapatite. This included changing the stoichiometry between fluorapatite, the phosphate activator, the TsCl, as well as changing the reaction time, as seen in Schemes 7.4.1-7.4.3.

##STR00055##

##STR00056##

##STR00057##

[0469] In all conditions, the fluorapatite was milled first with the phosphate activator before being reacted in the solution phase with the TsCl (p-TolSO.sub.2—Cl). When fluorapatite (2 equiv.) was milled with 2 equiv. of the phosphate activator followed by solution phase reaction with 0.05 mmol of TsCl as described in Scheme 7.4.1, the TsF yield was 81%. 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 TsF yield was 78%. Finally, when fluorapatite (1.2 equiv.) was milled with 1.2 equiv. of phosphate followed by solution phase reaction for 10 minutes with 0.25 mmol of TsCl, the yield of TsF was 74%. The yields of the organo-fluorine product indicate that pyrophosphate activator along with 18-crown-6 may be an exemplary combination to achieve high organo-fluorination yields.

7.5. Reaction Scope of Fluorapatite Fluorination

[0470] As described in scheme 7.5.1, fluorapatite was milled with a phosphate activator to form the fluorination agent and reacted in the solution phase with a range of RSO.sub.2—Cl substrates to form R502-F (see FIG. 47). FIG. 47 shows the yields of the resulting reactions and fluorinated products which range from 12% to 79%. The reactions were carried out as follows. Fluorapatite (1.2 equiv.) was milled with the phosphate activator (1.2 equiv) at 30 Hz for 9 hours in a 30 mL stainless steel jar with 1 16 g ball. The resulting powder reagent was reacted with the R502-CI substrate (1.0 equiv., 0.25 mmol) in the solution phase in t-AmOH (0.25 M) at 100° C. for 10 minutes with 18-crown-6 and 12 equiv. of H.sub.2O resulting in the fluorinated product. The results show that the pyrophosphate activator in addition to 18-crown-6 may be used with fluorapatite as a fluorinating reagent to fluorinate a wide variety of substrates including aliphatic and aromatic substrates.

##STR00058##

7.6. Mechanistic Insight of Fluorapatite Mechanochemical Reaction by PXRD

[0471] The mechanism of the mechanochemical reaction between fluorapatite (Ca.sub.5(PO.sub.4).sub.3F) and K.sub.4P.sub.2O.sub.7 was investigated via subsequent additions and milling as described in Scheme 7.6.1 via the formation and analysis of products A-D.

##STR00059##

[0472] FIG. 48 shows the stacked PXRD patterns of products A, B, C, and D where circles indicate fluorapatite starting material and x indicate a new species. This data shows the consumption of crystalline fluorapatite by mechanochemical reaction with potassium pyrophosphate and a new crystalline species forming over the course of the reaction. Products C and D may be indicative of no fluorapatite starting material, whereas Ca.sub.5(PO.sub.4).sub.3F starting material is present in samples A and B.

[0473] FIG. 49 shows a PXRD pattern of pure fluorapatite after 1 hour of milling overlayed with a fluorapatite sample (1 equiv.) that was milled for 12 hours total at 35 Hz with K.sub.4P.sub.2O.sub.7 (4 equiv.). The result indicates consumption of the fluorapatite by mechanochemical reaction with potassium pyrophosphate.

[0474] FIG. 50 shows a comparison of the PXRD pattern of the reaction 1:4 equiv. milling reaction (D) between fluorapatite (Ca.sub.5(PO.sub.4).sub.3F) and K.sub.4P.sub.2O.sub.7, and the milling reaction between potassium fluoride (KF, 1 equiv.) and K.sub.2HPO.sub.4 (2 equiv., 35 Hz, 3 hours) followed by CaHPO.sub.4 (1 equiv., 35 Hz, 3 hours) as seen in Scheme 7.6.2. The resulting patterns may indicate a similar structure of D to one of the components in the Y (Y═K.sub.2-xCa.sub.y (PO.sub.3F).sub.a(PO.sub.4).sub.bF.sub.c). The peaks at higher degrees 2-theta value than those observed in the PXRD of the crystalline phase of Y are consistent with a closely related structure to Y with different ratios of Ca.sup.2+, K.sup.+, F.sup.−, or PO.sub.4.sup.3−.

##STR00060##

[0475] Product D from Scheme 7.6.1 was washed with water and separated into an H.sub.2O insoluble component and an H.sub.2O soluble component. FIG. 51 shows the PXRD data of the water insoluble component and is compared to a crystalline reference pattern, in this case, pure milled, Ca.sub.5(PO.sub.4).sub.3F (fluorapatite). The water insoluble product's PXRD pattern may be consistent with Ca.sub.5(PO.sub.4).sub.3F or Ca.sub.5(PO.sub.4).sub.3OH.

7.7. Fluorapatite Activation Using Potassium Pyrophosphate

[0476] Fluorapatite activation was tested using 1 equivalent of potassium pyrophosphate (K.sub.4P.sub.2O.sub.7) and the milling reaction was monitored via PXRD. The milling reaction proceeded as described in Scheme 7.7.1 wherein 1 equivalent of fluorapatite (Ca.sub.5(PO.sub.4).sub.3F was milled with 1 equivalent of K.sub.4P.sub.2O.sub.7 at 30 Hz for 9 hours using a 16 g ball in a 30 mL stainless steel jar. FIG. 52 and Table 7.7.1 show the PXRD data indicating presence of crystalline phases of Ca.sub.5(PO.sub.4).sub.3F and an unidentified amorphous phase. No crystalline potassium pyrophosphate was observed by PXRD.

##STR00061##

TABLE-US-00056 TABLE 7.7.1 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 25.9458 189.47 0.1732 3.43417 42.12 28.0927 147.16 0.1732 3.17642 32.71 29.0831 149.29 0.2598 3.07046 33.19 31.8944 449.86 0.1515 2.80595 100.00 33.0730 230.80 0.2165 2.70860 51.30 34.1646 94.18 0.2598 2.62451 20.94 39.9834 64.49 0.2598 2.25497 14.34 46.8705 71.79 0.2598 1.93843 15.96 48.2530 37.20 0.3464 1.88607 8.27 49.5507 96.86 0.3464 1.83967 21.53 50.7233 43.60 0.2598 1.79986 9.69 52.2369 41.11 0.2598 1.75122 9.14 53.1801 43.37 0.3464 1.72236 9.64 63.3126 19.73 0.6336 1.46773 4.39

[0477] In another instance, fluorapatite (1 equiv.) was milled with 4 equivalents of potassium pyrophosphate to consume the crystalline fluorapatite as described in Scheme 7.7.2. Briefly, the fluorapatite was milled with 1 equivalent of potassium pyrophosphate for 3 hours at 35 Hz before the addition of a second equivalent and subsequent milling for 3 hours at 35 Hz, and this was repeated until 4 total equivalents of potassium pyrophosphate had been added and milled with the fluorapatite. The resulting product was analyzed by PXRD as seen in FIG. 53 and Table 7.7.2. The PXRD was consistent with an unidentified crystalline phase which is isostructural to K.sub.2-xCa.sub.y(PO.sub.3F).sub.a(PO.sub.4).sub.bF.sub.c.

##STR00062##

TABLE-US-00057 TABLE 7.7.2 FWHM Pos. [°2Th.] Height [cts] [°2Th.] d-spacing [Å] Rel. Int. [%] 21.5831 92.10 0.3464 4.11746 13.29 24.1496 48.92 0.6061 3.68537 7.06 26.0036 45.04 0.2598 3.42666 6.50 28.0998 238.05 0.0433 3.17562 34.35 30.0617 479.63 0.3897 2.97270 69.20 31.2880 693.08 0.2381 2.85893 100.00 33.1727 63.32 0.3464 2.70068 9.14 36.4610 31.20 0.6061 2.46431 4.50 38.3505 58.81 0.6061 2.34714 8.48 43.7833 141.57 0.5196 2.06767 20.43 46.9843 14.31 0.6927 1.93400 2.06 59.1913 20.45 0.6927 1.56099 2.95 65.1133 39.12 0.8448 1.43143 5.64

7.8. Fluorapatite and Fluorspar Activation

[0478] Fluorapatite and Fluorspar activation with K.sub.4P.sub.2O.sub.7 (4 equiv.) and K.sub.2HPO.sub.4 (2.5 equiv.) respectively were compared via PXRD as seen in FIG. X. The activations reactions were completed as described in Scheme 7.8.1 and 7.8.2.

##STR00063##

##STR00064##

8. Alternative Mechanochemical Procedures: Twin-Screw Extruder & Planetary Ball Mill

8.1. Materials and Abbreviations

[0479] Thermofisher Process 11 Twin Screw Extruder was fixed with a gravimetric single screw feeder (hopper) for programmed addition of solids. The pressurized die was not fixed to the twin-screw extruder for these experiments. Extrudite refers to the processed material that comes out the end of the extruder. CaF.sub.2 (97% reagent grade purchased from Alfa Aesar and used as received. K.sub.2HPO.sub.4 (anhydrous, 98%) purchased from Acros Organics and used as received. Screw configurations are shown in each graphics and are made up of conveying “C”, kneading “K”, and reverse “R” elements. Multiple individual elements make up a “section”. Furthermore, kneading sections can be subdivided by rotation from previous element, these can be at 30°, 60° or 90°. F.sub.R=feed rate of solids into the extruder. S.sub.S=screw speed at which the stainless-steel screws co-rotate. S.sub.T=screw temperature, each of the six segments can be heated to an individual temperature and these are specified if used. T.sub.R=residence time which is measured by the first time solids fall into the twin-screw extruder to the first time solids are observed at the exit.

8.2. General Procedure for Twin-Screw Extrusion

[0480] To a 100 mL conical flask was charged CaF.sub.2 (3.12 g, 40 mmol) and K.sub.2HPO.sub.4 (6.97 g, 40 mmol). The solids were loosely mixed with a spatula and then charged into the single screw feeder. At this point the relevant feed rate (F.sub.R), screw speed (S.sub.S), and screw temperature (S.sub.T) were programmed on the twin-screw extruder. The extruder was turned on, followed swiftly by the hopper. A 50 mL collection beaker was placed at the exit of the screw. After observation of the first appearance of solids coming out the exit, the beaker was used to collect the first ˜200 mg. Following this the collection beakers were exchanged and the “fluoromix” extrudite collected. This was continued until amount collected slows down significantly. At this point the beaker is exchanged back again for the first beaker to collect any residual extrudite. The “fluoromix” is then weighed (usually about 7 grams). The material is decanted into a vial and kept under vacuum overnight.

8.3. Variation of Screw Temperature on Generation of Active Fluorination Material

[0481] Following the general procedure outlined above (Example 8.2), the effect of screw temperature (S.sub.T) was investigated. FIG. 54 shows a general scheme for which CaF.sub.2 (40 mmol) and K.sub.2HPO.sub.4 (40 mmol) are reacted to form the active fluorinated material. The temperature, S.sub.T, was varied between 25° C. and 200° C. and the screw speed was 50 rpm. The residence time was 100 seconds. The resulting “fluoromix” was reacted with TsCl in the solution state in tBuOH (0.25 M) at 100° C. for 5 hours to form the fluorinated product, TsF. The screw temperatures, resulting fluorinated product, TsF, yields, and starting material yields, TsCl can be seen in Table 8.3. The results may indicate that lower screw temperatures may be helpful in achieving higher yields of organo-fluorine product (e.g., TsF) and lower yields of starting material (e.g., TsCl).

TABLE-US-00058 TABLE 8.3 S.sub.T (° C.) TsF (%) TsCl (%) 25 7 68 50 6 77 100 6 79 150 5 78 200 3 85

8.4. Variation of Screw Speed on Generation of Active Fluorination Material

[0482] Following the general procedure outlined above (Example 8.2), the effect of screw speed (Se) on generation of active fluorination material was investigated. FIG. 55 shows a general scheme for which CaF.sub.2 (40 mmol) and K.sub.2HPO.sub.4 (40 mmol) are reacted to form the active fluorinated material. The spin speed was varied between 10 rpm and 75 rpm and the residence time (T.sub.R) was varied as shown in Table 8.4. The screw temperature was 25° C. and feed rate was 10 g/min. The resulting active fluorinated material, “Fluoromix” was reacted with TsCl in a tBuOH solution (0.25 M) at 100° C. for 5 hours to form the fluorinated product. The spin speed (S.sub.S), residence time (T.sub.R), product yield (TsF), and starting material yield (TsCl) can be seen in Table 8.4. The results may indicate that the screw speed and residence time may not significantly impact the resulting yield of organo-fluorine product (e.g., TsF).

TABLE-US-00059 TABLE 8.4 S.sub.S (rpm) T.sub.R (secs) TsF (%) TsCl (%) 10 torqued — —  10* 420 6 68 25 165 6 77 75 80 6 67 *F.sub.R = 5 g min.sup.−1

8.5. Variation of Amount of Times Recycled Through Extruder on Generation of Active Fluorination Species

[0483] Following the general procedure outlined above (Example 8.2), in this instance the solids were fed by spatula into the twin-screw extruder (without the use of a hopper), and at the end of the screwing process, the extrudite was added back into the extruder for a further number of runs (e.g., recycled). This serves to impar the same amount of mechanical force but increase the residence time. The effect of extrudite recycling was investigated via the Scheme seen in FIG. 56. FIG. 56 shows the general scheme for which CaF.sub.2 (40 mmol) and K.sub.2HPO.sub.4 (40 mmol) can be reacted to form the active fluorinated species. In this instance, the feed rate is variable, the screw speed is 50 rpm, the screw temperature is 25° C., and the residence time is 100 seconds, but the resulting material is recycled back into the extruder 1, 2, or 3 times the results of which can be seen in Table 8.5. The resulting “Fluoromix” was reacted with 1 equiv. of TsCl in the solution state (0.25 M tBuOH) at 100° C. for 5 hours to form the fluorinated product. The resulting fluorinated product yield, TsF, and starting material yield, TsCl, can also be seen in Table 8.5. These results indicate that increased recycling times may result in higher yield of organo-fluorine product (e.g., TsF) and lower yields of starting material (e.g., TsCl).

TABLE-US-00060 TABLE 8.5 Recycled TsF (%) TsCl (%) 1 7 67 2 9 58 3 9 54

8.6. Extruding CaF.SUB.2 .without the Presence of K.SUB.2.HPO.SUB.4

[0484] Following the general procedure outlined above (Example 8.2), in this instance, CaF.sub.2 fed into the twin-screw extruder without the presence of K.sub.2HPO.sub.4. FIG. 57 shows the general scheme for which CaF.sub.2 (40 mmol) is added into the twin-screw extruder with variable feed rates, at a screw speed of 50 rpm, a screw temperature of 25° C., and a residence time of 100 seconds. The resulting “CaF.sub.2” that has been extruded was reacted with TsCl (1 equiv.) in a 0.25 M tBuOH solution with added K.sub.2HPO.sub.4 (4 equiv.) and reacted at 100° C. for 5 hours to form a fluorinated product, TsF. The result was a TsF yield of 6% and a TsCl yield of 58% when the CaF.sub.2 was not extruded in the presence of K.sub.2HPO.sub.4. Under mechanical forces, and without the presence of an ionic salt in the mechanochemical process, CaF.sub.2 may be activated to provide fluoride in the conversion of p-toluenesulfonyl chloride to p-toluenesulfonyl fluoride.

8.7. Investigations into Altering the Screw Configuration

[0485] Following the general procedure outlined above (Example 8.2), in this instance, a screw configuration (configuration 1) is outlined as seen in FIG. 58. The effect of screw configuration 1 was analyzed. FIG. 58 shows a general scheme for which CaF.sub.2 (40 mmol) and K.sub.2HPO.sub.4 (40 mmol) are added to the twin-screw extruder with a feed rate of 2 g min 1, a screw speed of 50 rpm, a screw temperature of 25° C., and a residence time of 40 seconds. An alternate configuration was also examined (screw configuration 2). Screw configuration 2 was “C-(30-60-90)-C-(60)-C-(60-90)-C”, whereas screw configuration 1 was “C-90-C-60-C-90-C”. The resulting “fluoromix” was reacted with TsCl (1 equiv.) in a solution of tBuOH (0.25 M) at 100° C. for 5 hours to form the resulting fluorinated product, TsF. The yield of fluorinated, TsF was 20% and yield of starting material, TsCl, was 40% upon utilization of screw configuration 1. The utilization of additional alternative screw configurations may be useful in increasing and/or tuning the yield of organo-fluorine products (e.g., TsF).

8.8. Planetary Mills

[0486] The Fritsch Pulverisette planetary mill was used. Zirconia jars (12 mL) and zirconia balls (3.4 g) were used in milling experiments. To a zirconia jar, added was charged fluorspar (312 mg, 4 mmol) and K.sub.2HPO.sub.4 (697 mg, 4 mmol) and either one or two 3.4 g zirconia balls. The jars were sealed and attached to the planetary mill. The mill was set to 800 rpm, 15-minute milling session, 11 repeats (12 in total), with a 2 minute gap between each one, and reverse in direction of milling after each session. After this time the material was scraped out of the vial and added to a vial which was kept under vacuum overnight before use. Scheme 8.8.1 shows a general scheme for which CaF.sub.2 (4 equiv.) is milled via a planetary mill with 4 equiv. of K.sub.2HPO.sub.4. The resulting powder was reacted with TsCl (1 equiv.) in a solution of tBuOH (0.25 M) at 100° C. for 5 hours. The resulting yield when 1 ball was used in the milling was 12% TsF (72% TsCl starting material). The resulting yield when 2 balls were used in the milling was 11% TsF (76% TsCl starting material). Thus, planetary mills may be useful in creating fluorinating reagents comprising CaF.sub.2 and an activator (e.g., K.sub.2HPO.sub.4).

##STR00065##

[0487] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.

[0488] 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).