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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

Associated data

  • PubChem-Substance/221675562
  • PubChem-Substance/221675563
  • PubChem-Substance/221675564
  • PubChem-Substance/221675565
  • PubChem-Substance/221675566
  • PubChem-Substance/221675567
  • PubChem-Substance/221675568
  • PubChem-Substance/221675569
  • PubChem-Substance/221675570
  • PubChem-Substance/221675571
  • PubChem-Substance/221675572
  • PubChem-Substance/221675573
  • PubChem-Substance/221675574
  • PubChem-Substance/221675575