Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes

Jan Dommerholt, Olivia van Rooijen, Annika Borrmann, Célia Fonseca Guerra, F. Matthias Bickelhaupt () and Floris L. van Delft ()
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Jan Dommerholt: Institute for Molecules and Materials, Radboud University Nijmegen
Olivia van Rooijen: VU University Amsterdam
Annika Borrmann: Institute for Molecules and Materials, Radboud University Nijmegen
Célia Fonseca Guerra: VU University Amsterdam
F. Matthias Bickelhaupt: Institute for Molecules and Materials, Radboud University Nijmegen
Floris L. van Delft: Institute for Molecules and Materials, Radboud University Nijmegen

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: Abstract Strain-promoted azide–alkyne cycloaddition (SPAAC) as a conjugation tool has found broad application in material sciences, chemical biology and even in vivo use. However, despite tremendous effort, SPAAC remains fairly slow (0.2–0.5 M−1 s−1) and efforts to increase reaction rates by tailoring of cyclooctyne structure have suffered from a poor trade-off between cyclooctyne reactivity and stability. We here wish to report tremendous acceleration of strain-promoted cycloaddition of an aliphatic cyclooctyne (bicyclo[6.1.0]non-4-yne, BCN) with electron-deficient aryl azides, with reaction rate constants reaching 2.0–2.9 M−1 s−1. A remarkable difference in rate constants of aliphatic cyclooctynes versus benzoannulated cyclooctynes is noted, enabling a next level of orthogonality by a judicious choice of azide–cyclooctyne combinations, which is inter alia applied in one-pot three-component protein labelling. The pivotal role of azide electronegativity is explained by density-functional theory calculations and electronic-structure analyses, which indicates an inverse electron-demand mechanism is operative with an aliphatic cyclooctyne.

Date: 2014
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DOI: 10.1038/ncomms6378

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