Synthesis of Macrocyclic Structures by Intramolecular Photoclick Reaction.

The photo-SPAAC reaction allows for the efficient preparation of medium- to large-sized macrocycles. Photo-SPAAC cyclization of bifunctional linear molecules, which carry a cyclopropenone-caged dibenzocyclooctyne moiety at one terminus and an azide group at the other, leads to the formation of macrocycles in high to quantitative yields. Macrocycles with 18- to 51-membered ring sizes were prepared both in solution and in the neat state, indicating an unusually high effective molarity of bifunctional cyclooctyne-azide linear molecules. No dimers or higher oligomers were observed in the reaction mixtures. SPAAC cyclization pathways were analyzed at the DFT level of theory. Macrocycles with 17- to 34-membered ring sizes were also successfully prepared by the SPAAC-photo-SPAAC reaction sequence, where monobifunctional dibenzocyclooctadiyne or bis-dibenzocyclooctynes react with bis-azides. This method also produces macrocycles in high yield, albeit small amounts of dimeric cyclic byproducts were detected in some cases.