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Nat Commun. 2014 Nov 10;5:5378. doi: 10.1038/ncomms6378.

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

Author information

1
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
2
Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
3
1] Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands [2] Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

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.

PMID:
25382411
DOI:
10.1038/ncomms6378

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