Halogens play an essential role in many medicines and organic chemical reactions. Hydrohalogenation (HX) is a well-known way to convert olefins into haloalkanes. However, hydrogen halogens such as HCl, HBr and HI are expensive in solution and quite toxic in gaseous form. A KU Leuven team led by Wim De Borggraeve has therefore developed a safe and clean protocol without solvents or purification steps, in which the hydrogen can also be replaced by deuterium. The latter is useful for various applications, such as in organic electronic materials, but also as an internal standard for drug discovery.

The trick is not to start with gaseous HX, but to produce it ex situ. To do this, they use a two-chamber reactor. In one chamber (ex situ) you make the HX and in the other chamber the reaction with your substrate (solid or liquid) takes place. The various hydrogen halides are quite easy to make: H₂SO₄ and NaCl for HCl, water and PBr₃ for HBr and water and PI₃ for HI. You can do the same with the deuterated reagents: D₂SO₄ and D₂O. The gaseous HX or DX molecules then enter the second chamber and react with the substrate under partial pressure at room temperature. No purification is required after the reaction.

They carried out about 50 reactions in this way, most with yields of about 95% or more, each time with very different molecules. Deuterium labelling also worked well. The team carried out most of the reactions on the 0.5 mmol scale, but to show that it could be done on a larger scale, they carried out one of the hydrogen halogenations on the 1 mmol scale, with a yield of 7.4 g (99%). According to the authors, it should be possible to go up to the kilogram scale with these methods.

Verschueren, R.H. et al. (2023) EurJOC e202300785, DOI: 10.1002/ejoc.202300785