Affiliation:
1. Department of Chemistry and Biomolecular Sciences University of Ottawa 150 Louis-Pasteur Ottawa Ontario K1N 6N5 Canada
2. Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan
Abstract
Abstract3‐oxidopyridinium ions are water stable and soluble heteroaromatic betaines that behave as latent dipoles and undergo a wide variety of cycloadditions. Research into the cycloaddition reactions of 3‐oxidopyridiniums was spearheaded by Alan R. Katritzky and collaborators from the early 1970s until the late 1980s, but they have yet to be used for bioorthogonal applications. Herein we report that 3‐oxidopyridiniums can readily react with 4‐dibenzocyclooctynol (DIBO), a common bioorthogonal handle, in a [3+2] cycloaddition. The mechanism was investigated by altering the electronics of the reaction by changing the substituent on the 5 position of the pyridinium. Electron‐donating 5‐substituents have been shown to significantly increase the rate of the reaction, with bimolecular rate constants ranging from 3.3×10−4 s−1 with 5‐trifluoromethyl‐N‐methyl‐3‐oxidopyridinium to 1.07 M−1 s−1 with 5‐amino‐N‐methyl‐3‐oxidopyridinium. 3‐oxidopyridiniums’ appreciable cycloaddition rates and compatibility with bioorthogonally relevant environments give them the potential to be used in a variety of bioconjugation applications.