Mechanistic Investigation of the Staudinger Ligation

Fiona L. Lin,† Helen M. Hoyt,† Herman van Halbeek,† Robert G. Bergman,† and Carolyn R. Bertozzi*†‡§
Contribution from the Departments of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, and Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720
J. Am. Chem. Soc., 2005, 127 (8), pp 2686–2695
DOI: 10.1021/ja044461m
Publication Date (Web): February 1, 2005
Copyright © 2005 American Chemical Society
†

 Department of Chemistry.

,
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

,
‡

 Department of Molecular and Cell Biology.

,
§

 Howard Hughes Medical Institute.

, crb@berkeley.edu

Abstract

Abstract Image

The Staudinger ligation of azides and phosphines has found widespread use in the field of chemical biology, but the mechanism of the transformation has not been characterized in detail. In this work, we undertook a mechanistic study of the Staudinger ligation with a focus on factors that affect reaction kinetics and on the identification of intermediates. The Staudinger ligation with alkyl azides was second-order overall and proceeded more rapidly in polar, protic solvents. Hammett analyses demonstrated that electron-donating substituents on the phosphine accelerate the overall reaction. The electronic and steric properties of the ester had no significant impact on the overall rate but did affect product ratios. Finally, the structure of an intermediate that accumulates under anhydrous conditions was identified. These findings establish a platform for optimizing the Staudinger ligation for expanded use in biological applications.

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History

  • Published In Issue March 02, 2005
  • Received September 13, 2004

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