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Discovery
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David Clark, PhD

Making Fluorination Chemistry Safer and Easier

A synthetic catalyst inspired by Mother Nature

Earlier this year, I was privileged to attend an online lecture by Prof. Veronique Gouverneur of the University of Oxford who has devoted her research career to the study of the chemistry of fluorine, a vital constituent element of many agrochemicals, pharmaceuticals and materials (Figure 1).

Fluorine in agrochemicals and drugs

Figure 1: Some examples of agrochemicals, pharmaceuticals and materials that contain fluorine

Most fluorine is currently sourced from a mineral known as fluorspar or fluorite (CaF2) by treating it with sulphuric acid to yield hydrogen fluoride (HF), an extremely corrosive and toxic gas. This is then converted into safer fluorinating reagents that can be used in the lab. All of this requires a lot of energy and great attention to health and safety.

In medicinal chemistry, the introduction of one or more fluorine atoms into a molecule can affect its properties in many useful ways. For instance, fluorine is often used to block a site of metabolism in a compound so that a drug can exert its effect for longer in the body. In addition, an isotope of fluorine, 18F, is used in PET ( Positron Emission Tomography ) scanning, which can play a vital role in the diagnosis and treatment of diseases such as cancer.

Given the importance of fluorine in so many applications, it is vital for the future that we develop more sustainable ways of obtaining it and of introducing it into molecules such as those shown above. It is to this challenge, among others, that Prof. Gouverneur and her research colleagues have turned their attention in recent years.

A crucial realisation in their journey was that there exist a few natural fluorinase enzymes that can catalyse the formation of a carbon-fluorine bond under ambient conditions. The first of these enzymes (Figure 2) was reported in 2002.

 

X-ray crystallization of fluorine enzyme.

 

Figure 2: X-ray crystal structure of fluorinase enzyme from Streptomyces cattleya (RCSB entry: 1RQP )

This inspired the Gouverneur research group to try to design a synthetic compound that could mimic the catalysing action of the fluorinase enzyme. By means of ingenious and closely coupled computational and experimental investigations, they were able to design a class of organic compound capable of catalysing fluorination reactions using readily available metal fluorides (e.g., potassium fluoride, KF) as the fluorine source. The chemical structure of one such synthetic catalyst is shown in Figure 3 and this compound is now commercially available from Sigma-Aldrich enabling its widespread use by the organic chemistry community.

Chemical structure of synthetic fluorination catalyst

 

Figure 3: Chemical structure of a synthetic fluorination catalyst

The development of this type of catalyst enables the introduction of fluorine into organic compounds in a safer, easier, and more environmentally friendly way than was previously possible and so allows the synthesis and testing of a greater diversity of fluorine-containing molecules as potential drugs and agrochemicals.