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.
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