This month's review is by JessTheChemist, who did her PhD working with fluorine chemistry, and is now a postdoc researching chiral amines. She blogs at The Organic Solution.
Fluorine, why do I love thee so?
Although I am no longer a fluorine chemist, I thought that I would take you on a journey into what was the background of my PhD research all those years ago. Interest in this small but potent atom has boomed over the last decade. Since there is so much literature on fluorine chemistry, I am going to show you that the addition of fluorine to a molecule can have wide ranging benefits, particularly in the pharmaceutical industry.
Organo-fluorine compounds are pretty rare as natural products, although some do exist, for example, in 1943 fluoroacetate was isolated1. It may come as a bit of a shock that at least 20–25 % of pharmaceuticals contain at least one fluorine atom. These fluorine-containing drugs can be used in the treatment of cardiovascular diseases, obesity, and bacterial and fungal infections. Approximately 15 % of all drugs launched worldwide over the past 50 years are fluorinated2. One of the first successful fluorinated drugs was 5-fluorouracil which I previously wrote about in my #toxiccarnival post from 2012.
Fluorinated organic molecules are known to perform a wide range of biological functions3. Cipro (Bayer AG) is an antibacterial, which is the fifth most prescribed antibacterial in the USA. Alternatively, Lipitor (Pfizer), which is a member of the statin drug class used for lowering blood cholesterol, has been the world’s bestselling drug for nearly a decade and has made a staggering $125 billion over 14 years.
There are a variety of reasons are behind the importance of the fluorine atom in drugs. The addition of fluorine to the 4-position of an aromatic ring is thought to prevent oxidation by cytochrome P450 due to the C-F bond being so strong4. If you want to learn more about properties of the C-F bond, then read this excellent O’Hagan review5. Substitution of hydrogen by fluorine, however, can also change the conformational preferences of a small molecule because of size and stereo-electronic effects as well as the pKa and lipophilicity of the molecule. These factors are discussed in more detail below.
The introduction of fluorine in to a molecule can have a significant effect on the acidity or basicity of a molecule due to its large inductive electron-withdrawing effect (electronegativity of F is 3.98). The effect is predictable as pKa generally decreases on increasing fluorination. For example, the pKa of acetic acid is 4.76 while the pKa of trifluoroacetic acid is 0.23.
The pKa of a drug can also have an impact on its bioavailability. For example, in a series of 3-piperidinylindole antipsychotic drugs, it was found that fluorination decreased the basicity of the amine, thereby improving bioavailability6. Changes in pKa can have effects on a variety of other parameters including physio-chemical properties (solubility), binding affinities (potency and selectivity), absorption, distribution, metabolism and safety issues2.
In HIV drug therapies, combinational therapies involving Efavirenz (Bristol-Myers Squibb) have been found to be the most active against the retrovirus. Structure–activity relationship studies have shown that the presence of the trifluoromethyl group improved drug potency by lowering the pKa of the cyclic carbamate, which makes a key hydrogen bonding interaction with the protein7.
For a drug molecule to pass through a cell membrane its lipophilicity (greasiness) must be such that it can pass into the lipid core but not become trapped within it. Increased lipophilicity often leads to increase in blood-brain barrier permeability. In general, exchange of a hydrogen atom by a fluorine atom leads to a more lipophilic molecule, however although there are exceptions, especially in aliphatic chains due to the strong electron withdrawing nature of fluorine8. Aromatic fluorination increases lipophilicity due to the good overlap between the fluorine 2s or 2p orbitals with the corresponding orbitals on carbon. This makes the C–F bond non-polarisable and, therefore, contributes to increased lipophilicity of the whole molecule9.
Substitution of a hydrogen or hydroxyl group, for example, for a fluorine atom, in biologically active molecules is thought to be tolerated because the van der Waals radius of fluorine (1.47 Å) is in-between that of oxygen (1.57 Å) and hydrogen (1.20 Å). This means that fluorine substitution only changes the steric demand at receptor sites slightly. This can be seen by the use of the fluorovinyl group (C=CHF) as a replacement for the peptide amide bond10 for example in the antibacterial agent, REF883911.
Similarly, the introduction of a trifluoromethyl group (CF3) within a molecule can change the steric bulk significantly as its van der Waals volume is estimated to be similar to that of an iso-propyl group, with both groups having an effective van der Waals radius of 2.20 Å9. These steric variations combined with the high electronegativity of the fluorine atom, can lead to changes in preferred molecular conformation upon fluorine substitution which can be seen in Prozac, the famous antidepressant drug.
Prozac acts by selectively inhibiting the reuptake of serotonin, allowing the neurotransmitter to activate its specific receptor. It has been shown that the addition of a trifluoromethyl group in the 4-position of the phenolic ring increases the potency for inhibiting 5-HT uptake 6-fold, compared to the non-fluorinated equivalent. It is believed that the size of the trifluoromethyl group at this position allows the phenoxy- ring to adopt a conformation which favours binding to the serotonin transporter6.
It has been shown that the C–F bond dipole adopts a Bürgi-Dunitz* type trajectory to amide carbonyl groups on the peptide backbone. This electrostatic effect is weak relative to other protein–ligand binding interactions but the C–F bond dipole contributes to optimising how drugs orientate at the binding site of their target enzyme/protein5.
Isn’t fluorine great? As you can see, the addition of a fluorine atom can change the properties of a molecule in many different ways. I am sure there are many other properties and benefits of fluorine that scientists are yet to find. It is certainly an exciting time to be a fluorine chemist. There are some very exciting chemists working in fluorine chemistry and, as such, I very much look forward to seeing how the field improves of the next few years, particularly in relation to selective fluorination of aromatics for use in positron emission tomography (PET) imaging.
*I met Dunitz once at ETH, what a legend!