‘Fluorine, it’s a magical element,’ says Rob Young, a drug discovery consultant and former GSK chemist. ‘[Adding fluorine is] the simplest change you can make to the architecture of a drug compound, but can have a very profound effect.’ About 40% of new pharmaceuticals contain fluorine and 25% of all those on the market, including commonly prescribed drugs like atorvastatin (Lipitor) and fluoxetine (Prozac). The drawback is the chemistry involved – creating fluorine-carbon bonds often requires harsh, toxic reagents or expensive catalysts. These reactions can also create fluorinated waste that by some definitions will be classed as polyfluoroalkyl substances (PFAS), the harmful ‘forever chemicals’ that accumulate in the environment and are currently under regulatory scrutiny. 

Of course, chemists have been looking for alternative methods that will ease the production of fluorinated drug molecules and agrochemicals. They are also looking to overcome some of the current limitations. ‘The form that fluorine takes in these molecules is inherently limited by the synthetic techniques [available],’ says chemist Julian West from Rice University in Texas, US. 

The power of fluorine stems from its small size – not much bigger than hydrogen – and strong electron-withdrawing properties. A fluorine can favourably shift the pKa and lipophilicity of a molecule. ‘Even if you just put it into a phenyl ring … it can have quite a profound effect on potency,’ says Young. The presence of a carbon–fluorine bond is also able to block metabolic ‘soft spots’ in drug molecules, sites where the drugs would otherwise be broken down inside the body. ‘When you have a drug molecule with the fluorine in, you shut down that metabolic pathway and the lifetime of that drug in the body is just longer,’ explains chemist Tim Noël from the University of Amsterdam in the Netherlands, who has designed new fluorination methods. 

The electron-withdrawing properties that allow fluorine to improve drug performance also make it difficult to introduce it into drug molecules and difficult to get exactly where you want it within a molecule. There are some highly oxidative commercial reagents to do this. One of the first was Selectfluor – a derivative of the bicyclic tertiary amine base 1,4-diazabicyclo[2.2.2]octane which provides an electrophilic source of fluorine.  

‘When you have a drug molecule with the fluorine in, you shut down that metabolic pathway and the lifetime of that drug in the body is just longer’

Tim Noël, University of Amsterdam

Going with the flow 

West has developed a method to hydrofluorinate alkenes in milder redox-neutral conditions than was previously possible, starting with fluoroalkyl carboxylic acids. The reaction uses only a cheap iron salt such as iron (iii) diacetate as the photocatalyst and an organic thiol hydrogen donor.  

The reaction is attractive because it can be carried out at a late stage in the synthesis of a bioactive molecule if an alkene group is present (which it commonly is in drug molecule intermediates), which means less fluorine waste created in previous stages of any multi-stage synthesis. The one drawback is the fluoride always adds to the less substituted carbon, due to the stability of the free-radical produced in the alkene addition.  

Another method is being developed by Noël and collaborators, including chemists at AstraZeneca. He has found that in flow reactors he can add trifluoromethyl groups attached to a sulfur, nitrogen or oxygen atom using only a caesium fluoride salt as the source of fluorine. The trifluoromethyl–heteroatom motif is commonly used in drug molecules. 

The reaction only takes 10 minutes. ‘Because we are working in a packed bed reactor where there is a rich source of fluoride, it immediately pushes the equilibrium towards the anion so the risks that are associated with handling [toxic] intermediates are also immediately tackled,’ says Noel. The advantage over existing methods is the ‘on-demand’ fluorination which cuts out the need for perfluoroalkyl precursor reagents. ‘We really have only the CF₃ group in the latest stage that is possible,’ he adds, which limits further generation of fluorinated waste. 

Back to the source 

Perhaps the biggest breakthrough in fluorination came in 2023, with a method that goes back to the source of all fluorine-containing reagents – the mineral fluorspar, calcium fluoride. At the University of Oxford in the UK, Véronique Gouverneur decided to find a way to make it more reactive. It’s insoluble in water and organic solvents and therefore needs to be treated with concentrated sulfuric acid at high temperature to produce toxic hydrogen fluoride. All fluorochemicals, including pharmaceuticals and agrochemicals, start from this dangerous reaction. 

‘The task ahead of us to make this industry “easier and more sustainable” is substantial’

Véronique Gouverneur, University of Oxford

Gouverneur’s method, developed with colleagues at University College London and Colorado State University in the UK and US, takes its inspiration from the biomineralisation that occurs in forming teeth and bone. She combined fluorspar with powdered potassium hydrogen phosphate (K2HPO4) in a ball mill and a mechanochemical process produced two new crystalline phases, K₃(HPO₄)F and K_2−xCa_y(PO₃F)_a(PO₄)_b. The powdered mixture, which Gouverneur calls Fluoromix, can create bonds between fluorine and either carbon or sulfur. Gouverneur’s group has used it to make 50 different fluorochemicals by directly substituting other halogenated bonds. They found the method does have some limitations, and wouldn’t work for fluoroarenes, which commonly feature in drug molecules. 

In her latest work Gouverneur ‘demonstrated that novel and many commonly used nucleophilic fluorinating reagents can be prepared directly from CaF₂’. The new chemical method treats fluorspar with electron-accepting boric acid (B(OH)₃) in the presence of oxalic acid which is capable of sequestering the Ca²⁺ ion.  

Fluoromix is now being commercialised by Oxford spin-out company  FluoRok and could lead to a huge paradigm shift in how all fluorochemicals are manufactured. If you can go to the source material, that’s a huge benefit, says Noel. ‘The fewer intermediates you have, the fewer problems you will have generating wastes, so it’s very exciting.’ 

Gouverneur hopes this is the start of a move towards a more circular and sustainable fluorochemicals industry, where it’s not only simple to make carbon–fluorine bonds but easier to break them too. ‘The task ahead of us to make this industry “easier and more sustainable” is substantial, and an approach looking at all these processes individually is time-consuming and demanding,’ she says. Part of the solution will be to develop ways to use waste fluorochemicals as a fluorine source because, as Gouverneur warns, fluorspar deposits on earth are finite and depleting rapidly. 

Environmental impacts 

This ambition is particularly important given the environmental impact of fluorinated compounds – most notably perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), which have both been associated with toxicity in animals and humans at sufficient levels, leading to liver damage, thyroid disease, obesity, fertility issues and cancer. Another acutely toxic fluorinated molecule is trifluoroacetic acid (TFA), which is highly persistent in water courses with no degradation pathways. A recent study showed that drugs containing trifluoromethyl groups like fluoxetine (C₁₇H₁₈F₃NO) release TFA when broken down. ‘CF₃ groups are really popular [in drug molecules] because it’s like putting a bit of Teflon in your molecule,’ says Young. Even though they only have one polyfluorinated carbon, by some definitions they are PFAS – albeit the shortest possible. 

Ultimately, it will be chemists who provide less toxic routes to fluorination reactions as well as dealing with persistent fluorinated chemicals in the environment. ‘You see people now developing new methods to defluorinate molecules,’ says Noël. ‘I think that the problem will be solved in a couple of years.’ He is sure that moving away from fluorine in drugs is not the solution. The F in pharma is almost certainly here to stay. 

Rachel Brazil is a science writer based in London, UK