strainpromoted

Strain-promoted, in the context of chemistry, refers to reactions whose rate is increased by the presence of ring strain in a substrate. The term is most commonly applied to strain-promoted azide-alkyne cycloaddition (SPAAC), a copper-free variant of click chemistry used to linking molecules under mild, often biological, conditions.

Mechanistically, the concept hinges on strained cyclic alkynes or related structures having higher energy and reactivity than unstrained counterparts. This elevated reactivity lowers the activation barrier for cycloaddition with azides, enabling rapid formation of 1,2,3-triazoles without the need for metal catalysts. The ability to proceed in aqueous or physiological environments makes strain-promoted reactions valuable for labeling in living systems.

Common reagents in SPAAC include cyclooctynes such as dibenzocyclooctyne (DBCO) and various BCN derivatives. These strained alkynes are typically attached to probes, drugs, or biomolecules, which then react selectively with azide-functionalized targets to yield stable conjugates.

Applications of strain-promoted chemistry are wide-ranging within bioconjugation and chemical biology. SPAAC is used for tagging proteins, glycans, nucleic acids, and other biomolecules, enabling imaging, tracking, and delivery studies in cells and whole organisms. As part of the broader bioorthogonal chemistry field, such reactions aim to minimize interference with native biological processes.

History and scope: Strain-promoted approaches gained prominence in the early 2000s through work led by Carolyn R. Bertozzi and collaborators, among others. Since then, development of new strained reagents has improved reactivity and biocompatibility, though copper-catalyzed methods can still offer faster rates in non-biological contexts. Other strain-influenced cycloadditions also exist, expanding the toolbox of strain-promoted chemistry.