Strain-Promoted Cycloadditions for Development of Copper-Free Click Reactions

Noncatalyzed cycloadditions between strained alkynes or alkenes and 1,3-dipoles or dienes (copper-free click reactions) have emerged as powerful bioorthogonal transformations. Biomolecule labeling strategies based on applications of strain-promoted cycloaddition continue to garner considerable interest, and this chemistry is poised for rapid growth in the future. Metal-free click chemistry is also ideally suited to facilitate assembly or modification of functional materials, and so its use in materials chemistry is also expected to expand. This review examines the reactivity of the most common Cu-free click reagents currently employed: cyclooctynes, E-cyclooctenes, norbornenes, and cyclopropenes. Factors important in governing the reactivity of these strained π systems and approaches toward increasing the ability of these reagents to engage in spontaneous and selective cycloadditions with complementary dipoles/dienes are discussed. Keywords: Copper-free click, azide-alkyne cycloaddition, inverse electron demand cycloaddition, strain-promoted cycloaddition, cyclooctyne, trans-cyclooctene, tetrazine, cyclopropene.