Fluorides

Fluorine is one of the most useful elements to medicinal chemists. The strategic introduction of one or more fluorine atoms into a drug candidate has become a key tool in modern medicinal chemistry. Approximately 20% of FDA-approved small-molecule drugs in 2024 contained at least one fluorine atom, a figure that has risen steadily over the past decade and reflects the element's unique combination of properties that are difficult to replicate with any other substituent. The strength and short length of the C-F bond gives exceptional metabolic stability at the site of fluorination, blocking cytochrome P450-mediated oxidation at positions that would otherwise generate reactive metabolites. Fluorine's high electronegativity modulates the pKa of adjacent basic and acidic groups, tunes lipophilicity through its influence on sigma constants, and can constrain molecular conformation through electrostatic C-F dipole interactions with adjacent bonds. The monofluoro substituent is commonly used as a bioisostere for hydrogen, hydroxyl, or methyl groups, while the trifluoromethyl (CF3) and difluoromethyl (CHF2) groups serve as polar, metabolically robust surrogates for tert-butyl, methyl, and hydroxyl groups, with the CF3 group providing a combination of high lipophilicity and resistance to oxidative attack. Fluorine also participates in binding interactions with protein residues through orthogonal multipolar interactions, fluorine-mediated hydrogen bonding, and hydrophobic pocket contacts, all of which can contribute meaningfully to binding affinity and selectivity. The 18F isotope of fluorine is additionally central to positron emission tomography (PET) imaging, enabling non-invasive visualisation of drug distribution and target engagement in clinical development.

Two first-in-class FDA-approved drugs from 2023 and 2025 illustrate the pharmacological centrality of fluorine. Pirtobrutinib (Jaypirca, Loxo Oncology/Eli Lilly), the first-in-class non-covalent (reversible) Bruton's tyrosine kinase (BTK) inhibitor, was approved in January 2023 for relapsed or refractory mantle cell lymphoma. It incorporates both a CF3 group on the 1,1,1-trifluoropropan-2-yl N-substituent of its pyrazole core and a 5-fluoro substituent on the 2-methoxybenzamide ring. The trifluoromethyl group restricts the conformation of the N-alkyl chain to position the molecule precisely within the ATP binding site of BTK in a manner that is agnostic to the C481S cysteine mutation that confers resistance to all approved covalent BTK inhibitors, while the aryl fluorine tunes the electronic properties of the amide and contributes to the compound's metabolic stability and outstanding kinase selectivity. Suzetrigine (Journavx, Vertex Pharmaceuticals), the first-in-class selective NaV1.8 pain signal inhibitor approved in January 2025, the first new class of analgesic in over two decades, carries five fluorine atoms across its tetrahydrofuranyl scaffold: a 3,4-difluorophenyl group and a quaternary CF3 group at the ring oxygen-bearing carbon. The CF3 group installs a quaternary carbon that locks the ring conformation and blocks metabolic oxidation at that position, while both aryl fluorine atoms tune the electronic character of the pendant phenyl ring and contribute to the unique binding geometry within the voltage-sensing domain 2 (VSD2) of NaV1.8, the interaction that underlies the compound's selectivity over the closely related cardiac NaV1.5 channel.

In organic synthesis, fluorinated functional groups participate in a range of fundamental named reactions and serve both as leaving groups and as electronic modulators. The Balz-Schiemann reaction converts aryl diazonium tetrafluoroborate salts to aryl fluorides under thermal or photolytic decomposition, and remains one of the few classical routes for introduction of fluorine into electron-neutral arenes. The halex (halogen exchange) reaction employs nucleophilic fluoride sources such as KF or CsF to displace chloro or nitro leaving groups from electron-deficient aromatic systems at elevated temperature, and is widely used in pharmaceutical manufacturing. Nucleophilic aromatic substitution (SNAr) exploits the unique leaving-group ability of aryl fluorides, exceptional among halides in this reaction manifold because the rate-determining step is nucleophilic addition rather than halide departure, making aryl fluorides particularly reactive electrophilic partners for SNAr with amines, alcohols, thiols, and other nucleophiles to build structurally complex heteroaryl scaffolds. The Swarts reaction converts polychlorinated alkanes to polyfluorinated analogues using metal fluoride catalysts, providing access to CF3 and CHF2 building blocks.

Emerging synthetic techniques are dramatically expanding the accessibility and scope of fluorinated drug-like molecules. In photochemistry, photosensitised C(sp3)-H fluorination using reagents such as Selectfluor and N-fluorobenzenesulfonimide (NFSI) under visible-light irradiation, mediated by triplet energy transfer from organic photosensitisers including anthraquinone and xanthone, enables the site-selective, radical-mediated introduction of fluorine into unfunctionalised C-H bonds of complex drug scaffolds without prefunctionalisation or transition-metal catalysts. Photoredox-catalysed decarboxylative fluorination of aliphatic carboxylic acids using Ru(bpy)3 2+ as photocatalyst and Selectfluor as fluorine source provides a mild, visible-light-driven route to primary C(sp3)-F bonds from abundant carboxylate starting materials, applicable to amino acid and natural product derivatives. Late-stage trifluoromethylation via photoredox catalysis, exploiting thianthrenium aryl radical precursors combined with copper-mediated CF3 transfer, has delivered direct C-H trifluoromethylation of heteroarenes and complex molecules under mild conditions that are compatible with the functional group sensitivity of drug-like structures. Electrochemically, the Simons electrochemical fluorination process enables the introduction of fluorine into organic molecules via anodic oxidation in liquid hydrogen fluoride, providing access to perfluorinated building blocks at industrial scale. More recently, electrochemical C-H fluorination of drug-like substrates using Selectfluor as both oxidant and fluorine source under constant-current conditions has been demonstrated as a practical and scalable approach for the late-stage introduction of C-F bonds without the need for photocatalysts or sacrificial oxidants.

Our catalogue of fluorinated building blocks includes a broad range of aryl, heteroaryl, and alkyl fluorides, fluoroalkyl reagents, and CHF2- and CF3-substituted scaffolds.