Hydrofluoric Acid1

FH

[7664-39-3]  · FH  · Hydrofluoric Acid  · (MW 20.01)

(strong acid;1b fluorinating agent;1b forms complexes with organic bases as fluorination agents;1a deprotecting reagent2)

Physical Data: mp -83.5 °C; bp 19.5 °C; d 3.0 (air = 1) at 25 °C.

Solubility: 100 wt % in water.

Form Supplied in: gas, colorless mobile liquid, or aq. solution; HF-pyridine, HF-triethylamine and HF-pyridine polymer bound are also available.

Handling, Storage, and Precautions: HF and its containing complexes are severely human tissue corrosive, causing extremely painful and slow-healing burns and ulcers. No glassware should be used for any reaction involving hydrofluoric acid. Wash thoroughly after handling. Since hydrogen fluoride burns may not be noticed for several hours, should you have any suspicion of skin contact, flush skin with water immediately for 5 min and apply calcium gluconate gel (2.5%) on the burned area. The container should be kept in a cool and dark place which should be well ventilated. Avoid storage in glass and some metals since it corrodes most substances except lead, wax polyethylene, and platinum. Use in a fume hood.

Hydrofluorination.

Anhydrous Hydrogen Fluoride and its base solutions are useful for the fluorination of various compounds and can add to alkenes, alkynes, and some other unsaturated systems (eq 1).3 Due to the difficulties of handling anhydrous hydrogen fluoride, HF-organic base (amines,1a ketones,4 or ethers5) solutions are often used. One of the important reagents is HF in pyridine solution, which contains 9 equiv of HF and 1 equiv of pyridine (Olah's reagent).6,7 These HF-organic base solutions are very hygroscopic, and the absorption of water has a profound effect on the fluorination activity. HF-melamine (86/14, wt/wt %) complex has been reported to be superior to other HF-amine solutions (eq 2).8 Aqueous HF solution has been rarely used for this addition because of the competitive incorporation of water.9 Hydrogen fluoride adds to hydrocarbon alkenes to form the monofluoride, obeying Markovnikov's rule with the complicating effect of polymerization. By using excess HF, polymerization can be reduced. Activated charcoal10 and Boron Trifluoride11,12 have been used for catalyzing this reaction. Addition of hydrogen fluoride to halogenated alkenes has less tendency for polymerization, but the ease of this reaction decreases with the increasing number of halogen atoms (eq 3).12 Chlorine atoms can be exchanged by fluorine under some conditions (eq 4).5 Lead(IV) Oxide13 or Lead(IV) Acetate14 and anhydrous hydrogen fluoride can generate fluorine in situ to add across the double bond.

The addition of hydrogen fluoride across a triple bond can be effected by various reagents (eq 5).4,9 It is difficult to stop the addition of HF at the intermediate fluoroalkene stage, indicating that the intermediate alkene is more reactive than the parent alkyne. Hydrofluorination of alkynes with solid poly(hydrogen fluoride) is found to be efficient and convenient.9 HF is also a catalyst for addition of fluorine to alkynes by Xenon(II) Fluoride to form vicinal tetrafluorides (eq 6).15 Anhydrous HF has been used in cyclization of 1-bromoalkynes with an N-acyliminium ion to form bromofluoro derivatives (eq 7).16 The electrophilic anti addition of the elements of benzeneselenenyl fluoride to an alkyne has been achieved by using N-phenylselenophthalimide and Et3N-3HF (eq 8).17

Hydrogen fluoride can also add directly to other unsaturated compounds. Phenylcarbamoyl fluoride has been prepared by addition of HF to phenyl isocyanate in a quantitative yield (eq 9).18,19 Hydrogen fluoride can also add across the C=N double bond in moderate to good yields (eq 10).20

Hydrogen fluoride and other fluoride sources in combination with electrophilic halogens (such as NCS, NBS, or NIS) can generate halofluorides (ClF, BrF, or IF) in situ, which then add across the alkene to give the halofluorination products.21 N-Bromoacetamide or N-Bromosuccinimide with HF or its base solutions are convenient reagents for bromofluorination (eq 11).22-25 The addition follows the Markovnikov-type regioselectivity. Bromofluorination of allylic alcohols gives the vicinal fluorobromohydrins, which can form a-fluoro epoxides and/or monofluoro oxetanes (eq 12).26 Iodofluorinations are often very stereo- and regioselective (eq 13).27-29 A carbonyl group has been transformed into a CF2 moiety via its hydrazone by an in situ generated bromine monofluoride (BrF) method.30

Friedel-Crafts Reaction and Cyclodehydration.

Liquid anhydrous hydrogen fluoride is an effective dehydrating and condensing agent, comparable to strong acids such as conc. Sulfuric Acid.31 It catalyzes Friedel-Crafts acylation and alkylation to form a variety of products. Most of the reactions proceed at rt within a very short period of time. Methylcyclopropane reacts with benzene in the presence of HF to give s-butylbenzene as the only product (eq 14).32 SbF5 and BF3 have been used as catalysts in some cases (eq 15).33-35 HF has been used as a catalyst for intramolecular Friedel-Crafts acylation and is sometimes superior to Polyphosphoric Acid (eq 16).36 Ring closure of tertiary alcohols and alkenes to an aromatic ring can be achieved by treating substrates with neat HF (eq 17).37-39 Hydrogen fluoride can also effectively catalyze the Fries rearrangement.40

Hydrogen fluoride cyclodehydration provides a wide range of polycyclic aromatic compounds (eq 18).41 This is also a very useful method to prepare some heterocyclic compounds (eq 19).42,43 Trienes can undergo an intramolecular Diels-Alder reaction with good stereoselectivity, when it is catalyzed by aqueous HF (eq 20).44

Fluorodehydroxylation and Fluorodeamination.

Secondary and tertiary alcohols and their derivatives, such as acetates and mesylates, are readily fluorinated by HF-amine solutions. Olah's reagent and HF-melamine convert free secondary and tertiary alcohols into the corresponding fluoride in moderate to good yield.6,45 1-Adamantanol has been converted to 1-fluoroadamantane by HF-pyridine at rt (eq 21).46 The mesylates and tosylates of primary alcohols can be converted to the corresponding fluorinated compounds by tetrabutylammonium difluoride; however, secondary mesylates give lower yields due to the formation of alkenes as byproducts (eq 22).47 Glycosyl fluorides can be made from protected sugars and b-isomers are the major product in most of the cases (eq 23).48-50

Aromatic amines can be transformed into their corresponding fluorinated compounds by a one-pot diazotization and fluorodediazonization in good yields (eq 24).51-53 If sodium halide (chloride, bromide or iodide) is added, haloarene isomeric mixtures are formed in good yield with small amounts of fluoroarenes. a-Fluorocarboxylic acids and ketones have been prepared from amino compounds via diazotization in 70% poly(hydrogen fluoride)-pyridine, with some exceptions (eq 25).54

Halogen-Exchange Fluorination.

For most primary and secondary aliphatic halides, halogen-exchange fluorination can be carried out by using Potassium Fluoride or other inorganic fluorides. HF reagents are suitable for unreactive cyclic and tertiary alkyl halides where KF or Cesium Fluoride often fail to give good results. Copper(I) Oxide and Mercury(II) Oxide are effective catalysts for this halogen exchange reaction due to the formation of metal fluorides (eq 26).55,56 The combination of Nitronium Tetrafluoroborate and HF-pyridine exchanges bridgehead adamantyl halides with fluoride in good yield.57 Acyl fluorides can be readily made by treating acyl chlorides or anhydrides with hydrogen fluoride (eq 27).57-59

Trifluoromethylation of phenols can be achieved with carbon tetrachloride and hydrogen fluoride (eq 28).60 Chlorines on other heteroatoms, such as boron,61 silicon,62 phosphorus,63 and iodine, can be exchanged with fluoride by hydrogen fluoride.

Ring-Opening Fluorinating Reagent.

Three-membered rings, such as cyclopropanes, epoxides, aziridines, and azirines, can be opened upon treatment with HF reagents. Opening cyclopropanes with HF-pyridine gives fluoropropanes.29 Treating substituted cyclopropylmethanols with HF-pyridine, in diisopropylamine and chlorobenzene in the presence of KHF2, affords homoallylic fluorides in good yields (eq 29).64 Epoxides are much more reactive than cyclopropanes and can be readily opened by a variety of HF reagents.65-67 These reactions are often regioselective (eq 30).68 Addition takes place to give the trans products when epoxyindane (eq 31), 1,2-epoxytetralin (eq 32), and 2,3-epoxytetralin (eq 33) are treated with HF-diisopropylamine.69

Addition of HF to aziridines gives b-fluoro amines (eq 34).70 N-Alkylated aziridines are less reactive and often require higher reaction temperatures. On the other hand, N-activated aziridines give better regioselectivity but the reactions are often accompanied by the formation of oxazolines (eq 35).71 Treatment of 1,2-epoxypyrrolidines with HF-pyridine can form different ring-opening products, depending on the stereochemistry of substrates (eqs 36 and 37).72,73

In the addition of Olah's reagent to azirines, the products are very dependent on the substitution pattern of the azirines. Ethers and larger-ring heterocycles are usually stable to HF, with some exceptions.

Miscellaneous.

Deprotection of peptides with strong acid often causes serious side reactions. By using anhydrous HF in dimethyl sulfide, most peptide-protecting groups and polymeric support can be cleanly removed.2,74,75 Other silyl-protecting groups have been removed by aqueous hydrofluoric acid in excellent yields, although this reagent has not been widely used because there are better reagents available.76 When HF is used with PbO2, PbF4, anodic oxidation,77,78 or other oxidants, it can fluorinate a variety of compounds, and several perfluoroheterocyclic compounds have been made in good yields.79-82

Proton Sponge (1,8-Bis(dimethylamino)naphthalene)83 hydrofluoride can be a useful fluoride donor. Adding an anhydrous HF ether solution to the base to form the hydrofluoride salt has been used for fluorination reactions (eq 38).84

Related Reagents.

N-Bromosuccinimide-Hydrogen Fluoride; Hydrogen Fluoride; Hydrogen Fluoride-Antimony(V) Fluoride; Pyridinium Poly(hydrogen fluoride).


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Hui-Yin Li

The Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA



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