Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry
Open Access
- 24 May 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 134 (22), 9199-9208
- https://doi.org/10.1021/ja3000936
Abstract
The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called “copper-free click chemistry”, is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC’s aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC’s aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC’s central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.Keywords
Funding Information
- American Chemical Society
- National Institutes of Health
- National Science Foundation
- American Cancer Society
This publication has 40 references indexed in Scilit:
- From Mechanism to Mouse: A Tale of Two Bioorthogonal ReactionsAccounts of Chemical Research, 2011
- Increasing the Efficacy of Bioorthogonal Click Reactions for Bioconjugation: A Comparative StudyAngewandte Chemie-International Edition, 2011
- Strain‐Promoted Alkyne–Azide Cycloadditions (SPAAC) Reveal New Features of Glycoconjugate BiosynthesisChemBioChem, 2011
- Metabolic Labeling of Fucosylated Glycans in Developing ZebrafishACS Chemical Biology, 2011
- Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic AdditionsJournal of the American Chemical Society, 2010
- Biocompatible Copper(I) Catalysts for in Vivo Imaging of GlycansJournal of the American Chemical Society, 2010
- Labeling Live Cells by Copper-Catalyzed Alkyne−Azide Click ChemistryBioconjugate Chemistry, 2010
- Rapid Cu-Free Click Chemistry with Readily Synthesized BiarylazacyclooctynonesJournal of the American Chemical Society, 2010
- Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of FunctionalityAngewandte Chemie-International Edition, 2009
- Visualizing Metabolically Labeled Glycoconjugates of Living Cells by Copper‐Free and Fast Huisgen CycloadditionsAngewandte Chemie-International Edition, 2008