[7664-39-3] · FH · Hydrogen Fluoride · (MW 20.01)
(strong Brønsted-Lowry acid2 capable of fluorinating numerous organic substrates;1 cleaves silyl3 and peptide4 protecting groups; effects lignocellulose solvolysis;5 catalyzes a number of electrophilic aromatic substitution reactions6)
Alternate Name: Hydrofluoric Acid
Physical Data: mp -83.37 °C; bp 19.54 °C; d 1.015 g cm-3 (0 °C), 0.958 g cm-3 (25 °C).
Solubility: sol water (52.7 wt %, 6 theoretical plates); strong proton donor to alcohols, carboxylic acids, ethers, and ketones (unstable); insol aliphatic hydrocarbons; very slightly sol aromatic hydrocarbons.
Form Supplied in: anhydrous liquid; 48-50% aqueous solution; most common impurity is fluorosilicic acid (<100 ppm).
Purification: for virtually all synthetic purposes, anhydrous hydrogen fluoride (AHF) is supplied in sufficiently high purity from commercial sources. Ultrapure AHF can be obtained by either distillation7 of commercially available AHF or thermal decomposition8 of potassium acid fluoride.
Handling, Storage, and Precautions: HF is an extremely toxic material. HF can cause severe damage to the respiratory system and will cause severe burns to tissue, e.g. skin, fingernails, mouth, eyes, etc.; penetration through tissue into bone is possible. If contact with HF occurs, the affected area must be flushed immediately with copious amounts of water for at least 15 min. Immediate medical attention must be sought. Recommended personnel protective equipment includes the use of gloves (neoprene/nitrile/rubber composite), goggles, a face-shield, and an apron while working in a well-ventilated hood, preferably equipped with a HF monitor.
AHF is supplied either in lecture bottles or 3 lb metal cylinders; aq HF is supplied in polyethylene bottles. The use of glassware and stainless steel vessels should be avoided when handling either AHF or aq HF.9 For reactions run at ambient temperature and pressure, polyethylene vessels can be employed; copper and iron vessels are also suitable. However, the use of an autoclave constructed of high metallurgy such as Monel or nickel, employing inert atmosphere techniques, is highly recommended.
AHF is an effective reagent for the fluorination of a wide variety of organic substrates.1 However, AHF in combination with organic bases,10 for example Olah's reagent (HF-pyridine),11 and nucleophilic fluoride transfer agents12 are more frequently employed than AHF, particularly when monofluorination of an organic substrate is desired.
Addition of AHF to unsaturated hydrocarbons occurs by an electrophilic mechanism and, for alkenes, in a Markovnikov fashion. Addition of AHF to alkynes13 proceeds with poor stereochemical control to give mixtures of (E)- and (Z)-vinyl halides and is often accompanied by the formation of gem-difluoroalkanes and fluoropolymers.
AHF reacts with carboxylic acid halides,14 esters,15 and anhydrides14 to give carboxylic acid fluorides. Acetoacetyl fluoride can be prepared in near quantitative yield by adding AHF to diketene.16 At temperatures <=0 °C, AHF is known to add to isocyanates17 to yield the corresponding carbamoyl fluorides.
Epoxides and aziridines undergo ring opening in the presence of AHF. For example, stereospecific ring opening of an epoxide18 can be accomplished as a means of introducing fluorine into the B ring of a steroid (eq 1).
AHF addition to trans-2,3-diphenylaziridine19 occurs stereospecifically to afford the erythro isomer exclusively, whereas the threo isomer predominates upon treatment with Olah's reagent (eq 2).
Halofluorination of alkenes with t-Butyl Hypochlorite, N-Bromosuccinimide, and N-Iodosuccinimide in the presence of AHF20 proceeds in good yield, although superior yields again can be obtained with Olah's reagent.21 In the presence of AHF, addition of N-Bromoacetamide and N-iodosuccinimide to cyclohexene occurs with a high degree of stereoselectivity to produce trans isomers in 43% and 72% yield, respectively.22 Halofluorination occurs in a Markovnikov fashion.23 Synthesis of gem-fluorohalides can be achieved by adding AHF to vinyl halides.24
Commercially,25 the use of AHF for the synthesis of fluoroorganic compounds via either halogen exchange (HALEX) or decomposition of diazonium salts is carried out by this route for economic reasons. For synthetic purposes, inorganic fluorides,1f tetraalkylammonium fluorides,12 and HF.base complexes10 are preferred fluorinating agents. High yields of a,a,a-trifluoromethoxybenzene26 via halogen exchange and fluoropyridines via decomposition of the corresponding diazonium salt27 in the presence of AHF can be obtained.
Desilylation of silyl ethers28 and silyl enol ethers29 is most frequently accomplished using HF/MeCN.3 Compounds containing both alcoholic and phenolic t-butyldimethylsilyl ethers can be desilylated with HF/MeCN chemoselectively, leaving the silyl ether of the phenol unscathed (eq 3).30
Cleavage of silyl enol ethers result in the formation of a-alkylidene-b-lactams31 and migration of C=C bonds, leading to g-substituted cyclohexenals32 and b-substituted cyclopentenones.33
Concomitant ring formation during desilylation of t-butyldimethylsilyl ethers occurs with a high degree of stereoselectivity to give lactones,34 and is a facile route to butenolides,35 b-methylene-g-butyrolactones,36 bis-b-ketomacrolides,37 spiroacetals (eq 4),38 and dispiroacetals.39
Similar treatment of t-butyldimethylsilyl enol ethers leads to the formation of cyclopentanecarboxylic acid40 and cis/trans carbocycles.41
Desilylation of erythro-a-silyloxyalkylboranes with concomitant protiodeboronation gives alkenes (eq 5) with (E:Z) ratios as high as 95:5 in 73% isolated yield.42
Cleavage of Si-C bonds also is an entry into alkenes,43 aldehydes,44 and a,b-unsaturated aldehydes.45 Cleavage of the Si-N bond gives amines.46
Hydrogen fluoride is a versatile reagent in peptide chemistry, cleaving N-benzyloxycarbonyl, S-benzyl, and S-p-methoxybenzyl protecting groups of peptides.5 Removal of protecting groups of aspartine residues (eq 6),47 N-nitroarginine residues,48 O-dimethylphosphinyltyrosine,49 and the O-phosphate ester of tyrosine50 is accomplished in HF/anisole at 0 °C in <=1 h. However, under similar conditions, side reactions of glutamyl peptides51 lead to Friedel-Crafts acylation of anisole.
Peptide protecting groups such as phosphonamides52 and sulfonamides53 are cleaved in the presence of HF/anisole. In the case of the tripeptide Gly-Lys-Gly, the sulfonyl protecting group of the Lys residue can be chemoselectively removed in the presence of a t-Boc protecting group.54 Polysaccharide solvolysis and glycoprotein deglycosylation is efficiently performed with HF.55
In many instances, AHF offers distinct advantages over traditional Lewis acids for the catalysis of electrophilic aromatic substitution reactions. Unlike most Lewis acids, AHF acts as both catalyst and solvent,56 and can be removed by distillation.57
Alkylation of arenes with alkenes,6a,58 alkyl halides,6b,59 and methylcyclopropane60 proceeds in moderate to good yield. Alkylation of arenes with concomitant ring closure leads to cyclic61 and heterocyclic compounds.62 Alkylation of benzene with sodium nitronate in the presence of AHF gives benzaldehyde oxime in 78% yield.63
The distribution of o-, m-, and p-isomers is known to be a function of temperature. For example, alkylation of phenol with Isobutene at -40 °C gives 2-t-butylphenol exclusively, while at 0 °C, 3-t-butylphenol is obtained in 88% yield; above 30 °C, 4-t-butylphenol begins to predominate.64
AHF is an excellent catalyst for Friedel-Crafts acylation of substrates as diverse as phenols,65 thiophenes,66 and ferrocene.67 Acylation of phenols is known to proceed with a high degree of regioselectivity to yield p-isomers almost exclusively (eq 7).68
Similarly, Fries rearrangement of phenyl esters leads to formation of the p-isomer69 unless of course the para position is blocked; then ortho substitution occurs.70 Although thiophenol does not undergo acylation in the presence of AHF, thioanisole does, giving the p-isomer.71 As opposed to Lewis acids, AHF-catalyzed acylation of 2-methoxynaphthalene proceeds with high para regioselectivity to yield 6-methoxy-2-acetonaphthone.72
Intramolecular cyclizations of 3-phenylpropionic acid and 4-phenylbutanoic acid afford a-tetralone and a-hydrindone in 92% and 73% yield, respectively.73 More sophisticated polycyclic compounds, such as anthracyclinones,74 can be constructed, as can benzo[a]fluoranthene75 via reductive cyclization.
Other electrophilic aromatic substitutions do not proceed generally as well in AHF, as is the case for the sulfonation of benzene76 and rearrangement of p-cresyl benzenesulfonate77 to 2-hydroxy-4-methyl diphenyl sulfone. However, nitration,78 amidomethylation,79 and thioamidation80 of aromatic substrates can be achieved in good to excellent yield.
Kenneth G. Davenport
Hoechst Celanese Corporation, Corpus Christi, TX, USA