Alkynes

The alkyne group is a structurally compact and metabolically versatile functional group with a well-established role across multiple therapeutic areas. Its linear geometry and minimal steric demand allow it to project functionality precisely within constrained binding sites, making it a valued pharmacophoric element in hit-to-lead and lead optimisation programmes. The sp-hybridised carbons of the triple bond confer distinct lipophilicity relative to the corresponding alkene or alkane, and the terminal alkyne in particular, with its weakly acidic proton, provides a handle for diverse further functionalisation, including Sonogashira coupling, CuAAC click chemistry, and metal-catalysed C-H functionalisation. Internal alkynes are also found in enediyne natural products, where the ene-diyne motif generates reactive diradical intermediates through Bergman cyclisation that abstract hydrogen atoms from tumour cell DNA, and this warhead has influenced the design of antitumour antibiotics including calicheamicin and neocarzinostatin. Alkynes are also exploited as bioorthogonal handles in chemical biology, participating in the strain-promoted azide-alkyne cycloaddition (SPAAC) for live-cell labelling without cytotoxic copper catalysis. The propargylamine motif, a structural subtype found in several marketed drugs, contributes to metabolic stability by acting as a mechanism-based inhibitor of monoamine oxidase enzymes.

Efavirenz (Sustiva, Bristol-Myers Squibb), approved by the FDA in 1998 for the treatment of HIV-1 infection, is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) whose cyclopropylethynyl group is essential to its mechanism. The alkyne positions the cyclopropyl ring into the hydrophobic NNRTI binding pocket of HIV-1 reverse transcriptase, and the precise linear geometry of the triple bond is critical to the shape complementarity that underpins its high-affinity allosteric binding. Terbinafine (Lamisil, Novartis), approved in 1992 as the first allylamine antifungal and the first squalene epoxidase inhibitor, contains an internal alkyne conjugated with an alkene in its side chain. This conjugated enyne contributes to the hydrophobic character essential for potent, non-competitive inhibition of the fungal squalene epoxidase, blocking ergosterol biosynthesis and resulting in the toxic intracellular accumulation of squalene.

In organic synthesis, the alkyne is central to a wide range of fundamental and modern named reactions. The Sonogashira coupling, a palladium and copper co-catalysed cross-coupling of terminal alkynes with aryl or vinyl halides, is one of the most widely used C-C bond-forming reactions in pharmaceutical synthesis, providing rapid access to internal alkynes from readily available building blocks. The Glaser-Hay coupling enables oxidative homocoupling of terminal alkynes to diynes, and the Eglinton reaction provides a copper(II)-mediated variant with complementary substrate scope. The Huisgen 1,3-dipolar cycloaddition between azides and alkynes, as the copper-catalysed CuAAC reaction, is the defining transformation of click chemistry, affording 1,2,3-triazoles with complete regioselectivity and broad compatibility with complex molecular environments. The Bergman cyclisation converts cis-enediyne systems to reactive 1,4-didehydrobenzene diradicals under thermal conditions, and the Nicholas reaction uses cobalt-complexed propargyl cations as stabilised electrophiles in C-C bond-forming reactions on alkyne-containing substrates.

Emerging synthetic techniques are making significant use of the alkyne. In photochemistry, visible-light photocatalysis has enabled alkyne-alkene [2+2] cycloadditions through triplet energy transfer, providing rapid access to cyclobutenes and 1,3-dienes under mild conditions that previously required high-energy UV irradiation. Photoredox-mediated thiol-yne additions generate vinyl sulphide products in a radical cascade, and vinyl radical intermediates generated from alkynes by HAT catalysis are increasingly applied for the synthesis of heterocyclic building blocks relevant to medicinal chemistry. Electrochemically, directed C-H alkynylation via anodic oxidation of metal-alkyne intermediates enables late-stage introduction of alkyne groups into complex scaffolds without external chemical oxidants, offering a practical and atom-economical approach to alkyne-bearing drug-like molecules. Electrooxidative Sonogashira-type carbonylation of alkynes has also been reported, providing direct access to ynone fragments from terminal alkynes under mild electrolytic conditions.