In a joint experimental-theoretical effort reported in Nature Communications, highly accelerated azide-cycoalkyne have been achieved and analyzed with DFT. The ‘click’ type reaction has also been demonstrated in a one-pot three-component protein labeling reaction and shows great promise for future applications in multi-component reactions.
ADF calculations reveal that the reaction between the electron-deficient azides and strained cyclooctyne follows an asynchronous inverse-electron demand pathway (i.e. the alkyne HOMO donates first into the azide LUMO in the transition state). The predicted activation barriers decrease in the order A, D, E, F, G in agreement with the experimental reaction rates for these azides. Activation-strain analysis reveals that the favorable orbital interactions in the asynchronous transition state is counterbalanced by increased steric (Pauli) repulsion.
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J. Dommerholt, O, van Rooijen, Annika Borrmann, C. Fonseca Guerra, F. M.Bickelhaupt and F. L. van Delft, Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes, Nature Comm. 5, 5378 (2014)Key conceptsADF bonding analysis catalysis Reactivity