Hydrogen Fluoride and Amine Complexes (HF-NR3)

Mechanism + Description

HF complexes work essentially as HF would – protonation of the substrate followed by nucleophilic addition of fluoride ion. Depending on the substrate, they may go formally via the carbocation.

General comments

Anhydrous HF is very volatile (b.p. 20°C), highly toxic, and extremely corrosive to all organs. It is used in bulk and as a fluorine source in electrochemical fluorination, but requires specialized plant and handling techniques. More commonly used are HF-amine complexes, which consist of an amine salt with additional HF. These tend to be liquids at ambient temperature and are much easier to handle. A number of these reagents have been used and some are commercially available. The most common is Olah's salt Pyridine-HF(x) (PPHF) - Pyridinium Poly(hydrogen fluoride) (Pyridine ~30%, hydrogen fluoride ~70%). PPHF reacts with secondary and tertiary alcohols, alkenes, alkynes, epoxides, dithiolanes and chlorides. Substitution of F for NH2 is achieved by an in situ diazotization–fluorination sequence. Mixtures of Et3N and HF are often used as substitutes for Olah's reagent and are available commercially.

Key references

Bergstrom, C. G.; Nicholson, R. T.; Dodson, R. M. 9α-Fluoro-11-deoxy Steroids. J. Org. Chem. 1963, 28, 2633–2640.

Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. Synthetic methods and reactions. 63. Pyridinium poly(hydrogen fluoride) (30% pyridine-70% hydrogen fluoride): a convenient reagent for organic fluorination reactions. J. Org. Chem. 1979, 44,  3872–3881.

Olah, G. A.; Shih, J. G.; Prakash, G. K. S. Fluorine-Containing Reagents in Organic Synthesis. J. Fluorine Chem. 1986, 33 (1-4), 377–396.

Yoneda, N. The Combination of Hydrogen Fluoride with Organic Bases as Fluorination Agents. Tetrahedron, 1991, 47, 5329–5365.

Saint-Jalmes, L. Selective Aliphatic Fluorination by Halogen Exchange in Mild Conditions. J. Fluorine Chem. 2006, 127 (1), 85-90.

Relevant scale up example

Haufe, G.; Alvernhe, G.; Laurent, A.; Ernet, T.; Goj. O.; Kröger, S.; Sattler, A. Org. Synth. 1999, 76, 159.
7g scale


Kumar, A.; Pal, A. K.; Anand, R. D.; Singh, T. V.; Venugopalan, P. Tetrahedron 2011, 67, 8308-8313.
<2g scale

Green Review

  1. Atom efficiency (by-products Mwt)
    A reasonable atom economy reagent – the addition of HF to double bonds, if 100% efficient, in the fluorination of alcohols, generates H2O (18) as a by-product. HF reagents are often used in large excess compared to the stoichiometric HF usage, so the use of any excess reagent should be minimized.
  2. Safety Concerns
    HF and related complexes can cause severe burns and corrode glass vessels/equipment.
    Toxic Substances Portal - Hydrogen Fluoride (HF). Agency for Toxic Substances & Disease Registry.
  3. Toxicity and environmental/aquatic impact
    High concentrations of HF are extremely toxic to all life forms. Lower concentrations of fluoride can be harmful to aquatic life. Organofluorine compounds, especially polyfluorinated, can be persistent and bioaccumulate.
    Camargo, J. A. Fluoride Toxicity to Aquatic Organisms: A Review. Chemosphere 2003, 50, 251-264.
  4. Cost, availability & sustainable feedstocks
    HF and HF-amine complexes are available in bulk
  5. Sustainable implications
    Fluoride sources are at medium risk of depletion and all fluorine is used in a dispersive manner. The high energy needed to produce F2 would make this a high LCI impact material.
© 2015 Green Chemistry Institute Pharmaceutical Roundtable. All rights reserved.