Organofluorine chemistry

Fluorine is the most electronegative element (4.0 on the Pauling scale), so the C–F bond is very polar. It is also short and strong, with a bond enthalpy of around 485 kJ mol^{-1}, compared with about 340 for C–Cl and 230 for C–I.

These two facts pull in opposite directions in nucleophilic substitution. Polarity alone would make fluoroalkanes the most reactive halogenoalkanes, but experiments with aqueous silver nitrate show the reverse: iodoalkanes give a precipitate fastest and fluoroalkanes barely react. Bond enthalpy, not polarity, controls the rate.

That same inertness made chlorofluorocarbons (CFCs) ideal refrigerants and aerosol propellants. Once in the stratosphere, though, UV light breaks the weaker C–Cl bond, never C–F, and the chlorine radicals catalyse ozone breakdown:

CFCs were replaced by hydrofluorocarbons (HFCs), which contain no chlorine and leave ozone alone, but are powerful greenhouse gases now being phased down under the 2016 Kigali Amendment.

Poly(tetrafluoroethene), PTFE, is the addition polymer of CF_2=CF_2. A sheath of fluorine atoms wraps the carbon backbone, giving very weak intermolecular forces with anything else, hence its non-stick, low-friction surface and its resistance to almost every chemical.

In drugs, fluorine often replaces a hydrogen at a position the liver would otherwise oxidise, so the drug lasts longer in the body. The trifluoromethyl group, CF_3, makes molecules more lipophilic.

Properties that matter

Fluorine's van der Waals radius (1.47 Å) is close to hydrogen's (1.20 Å), so H→F swaps are sterically modest. Its lone pairs are held so tightly that organic fluorine is a poor hydrogen-bond acceptor and is hardly polarisable, which is why perfluorocarbons have low boiling points and repel both water and oils. The inductive effect is large: trifluoroacetic acid has a pK_a near 0.5 against 4.76 for ethanoic acid, and a fluorine two carbons from an amine lowers its pK_a by around two units, which can improve oral absorption. Stereoelectronics also shift: 1,2-difluoroethane prefers the gauche conformation because \sigma_{\mathrm{C-H}} \rightarrow \sigma^*_{\mathrm{C-F}} donation is maximised when C–F bonds are not anti to each other.

Making C–F bonds

Nucleophilic fluoride. Fluoride is strongly solvated in water and a poor nucleophile, so reactions use dry KF or CsF in polar aprotic solvents, or tetraalkylammonium fluorides. The Halex process swaps Cl for F on electron-poor arenes by S_\mathrm{N}Ar. The Balz–Schiemann reaction heats an aryldiazonium tetrafluoroborate to give the aryl fluoride, N_2 and BF_3.

Deoxyfluorination. DAST (Et_2NSF_3) and its safer relatives Deoxo-Fluor and PyFluor convert an alcohol into an activated sulfur ester which fluoride displaces. With a secondary alcohol, this is S_\mathrm{N}2 with inversion: (R)-octan-2-ol gives (S)-2-fluorooctane, along with some alkene from competing elimination. Aldehydes and ketones give gem-difluorides.

Electrophilic fluorination. N–F reagents such as Selectfluor and NFSI deliver 'F^+' to enolates, silyl enol ethers and electron-rich arenes, giving α-fluoro carbonyls.

Trifluoromethylation. The Ruppert–Prakash reagent, Me_3SiCF_3, releases a CF_3 anion equivalent when a catalytic fluoride activates silicon; it adds to ketones to give trifluoromethyl carbinols.

Characterisation

^{19}F is 100% abundant with spin ½, so ^{19}F NMR is fast and sensitive. Its shift range spans several hundred ppm, and H–F and C–F couplings show up in ^1H and ^{13}C spectra, splitting the carbon attached to fluorine into a doublet with ^1J_{\mathrm{CF}} around 250 Hz.

Research on organofluorine chemistry splits into making C–F bonds more selectively and dealing with the ones already in the environment.

Late-stage fluorination aims to put fluorine into complex drug candidates at the end of a synthesis. Palladium- and silver-mediated aryl fluorination, photoredox decarboxylative fluorination with Selectfluor, and directed C(sp^3)–H fluorination all give medicinal chemists fluorinated analogues without starting the route again. Nucleophilic fluorination of unactivated sites using simple fluoride salts, with hydrogen-bond donor catalysts to tame the anion, is an active area because it is cheap and works with [^{18}F]fluoride.

Radiochemistry raises the stakes. ^{18}F has a half-life of about 110 minutes, so the fluorination, purification and formulation of a PET tracer such as [^{18}F]FDG must be finished in well under an hour, often on automated modules. Copper-mediated radiofluorination of aryl boronic esters has widened the range of tracers that can be made.

PFAS are the hard problem. The OECD definition (at least one fully fluorinated CH_3 or CH_2 unit) covers thousands of substances, including some drugs and pesticides with a CF_3 group, and whether such a broad definition should drive regulation is debated. The US EPA set a 4 ng L^{-1} limit for PFOA and PFOS in drinking water in 2024, and the EU is considering a near-universal restriction. Treatment options under study include electrochemical oxidation, supercritical water oxidation, plasma and sonolysis, and mild routes such as heating perfluorocarboxylic acids with NaOH in DMSO, which strips CF_2 units after decarboxylation. Full mineralisation to fluoride without forming shorter persistent fragments, and analysis of the many PFAS that have no reference standards, remain open challenges.