Catalyst-free Ligation Using Metal-free, Light-induced Click Reaction

Application(Product)Methodsand compositions to promote difficult chemical reactions, especially involvingliving organisms ProblemsAddressed    (benefits/advantages)Connection(or ligation) of two fragments to make a larger molecule or structure is oftenachieved with the help of the so-called "click chemistry". This termis used to describe a set of bimolecular reactions that meet the followingcriteria: reactions should be wide in scope but selective; produce high yieldof the product, proceed with reasonable rate under mild conditions; andtolerate broad range of solvents. Among known click reactions is the reactionof azides with acetylenes. The formation of 1,2,3-triazoles in 1,3-dipolarcycloaddition of azides to triple bond is known, but 'because the activationenergy of acetylene-azide cycloaddition is relatively high (ΔG‡ ~26 kcal/mol),the reaction is very slow under ambient conditions. The utility of the reactionof azides with alkynes was expanded by the discovery of Cu (I) ca-talysis.1,3-cycloaddition of azides to terminal acetylenes in the presence of catalyticamounts of cuprous salts is facile at room temperature in organic or aqueoussolutions. The copper-catalyzed version of the acetylene- azide cycloaddition(a.k.a. azide click reaction) found a broad range of applications from microelectronicsto virus labeling, to drug development. However, the use of cytotoxic Cu (I)catalyst has largely precluded application of this click reaction in livingsystems.  Catalyst-free 1,3-dipolarcycloaddition of azides to cyclooctynes has made possible a bio-compatible versionof the azide click reaction. The triple bond incorporated in an eight-memberedring is apparently already bent into the transition state-resembling geometry,thus reducing the activation barrier. New methods for ligating fragments tomake a larger molecule or structure and allow the use of these structures for invivo studies are needed.

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