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J Org Chem. 2018 Jan 19;83(2):604-613. doi: 10.1021/acs.joc.7b02092. Epub 2018 Jan 8.

Investigation of Strain-Promoted Azide-Alkyne Cycloadditions in Aqueous Solutions by Capillary Electrophoresis.

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Department Chemie, Ludwig-Maximilians-Universität München , Butenandtstrasse 5-13, 81377 München, Germany.
Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University , Hlavova 8, 128 40 Prague 2, Czech Republic.


The Cu-free 1,3-dipolar cycloaddition of cyclooctynes and azides is an up-and-coming method in bioorganic chemistry and other disciplines. However, broad application is still hampered by major drawbacks such as poor solubility of the reactants in aqueous media and low reaction rates. It is thus of high demand to devise a fast and user-friendly strategy for the optimization of reaction conditions and reagent design. We describe a capillary electrophoresis (CE) study of reaction kinetics in strain-promoted azide-alkyne cycloadditions (SPAAC) using substrates with acidic or basic functionalities. This study reveals that the pH value has a significant effect on reaction rates as a result of changes in the reactants' charge state via protonation or deprotonation, and the concomitant changes of electronic properties. This novel experimental setup also enables the study of even more challenging conditions such as reactions in micelles and we did indeed observe much faster SPAAC reactions in the presence of surfactants. Careful combination of the above-mentioned parameters resulted in the identification of conditions enabling remarkable rate enhancement by a factor of 80. This electrophoretic method may thus serve as a versatile, fast and reliable tool for screening purposes in all research areas applying SPAAC reactions.


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