Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes.
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.
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
Jan
J
Dommerholt
Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Olivia
O
van Rooijen
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
Annika
A
Borrmann
Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Célia Fonseca
CF
Guerra
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.
F Matthias
FM
Bickelhaupt
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
Floris L
FL
van Delft