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Bioorthogonal Cycloadditions with Sub‐Millisecond Intermediates
Author(s) -
Qing Yujia,
Pulcu Gökçe Su,
Bell Nicholas A. W.,
Bayley Hagan
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201710262
Subject(s) - bioorthogonal chemistry , bioconjugation , chemistry , cycloaddition , tetrazine , reaction intermediate , bicyclic molecule , click chemistry , isotopic labeling , dynamic covalent chemistry , computational chemistry , molecule , combinatorial chemistry , stereochemistry , organic chemistry , catalysis , supramolecular chemistry
Tetrazine‐ and sydnone‐based click reactions have emerged as important bioconjugation strategies with fast kinetics and N 2 or CO 2 as the only byproduct. Mechanistic studies of these reactions have focused on the initial rate‐determining cycloaddition steps. The subsequent N 2 or CO 2 release from the bicyclic intermediates has been approached mainly through computational studies, which have predicted lifetimes of femtoseconds. In the present study, bioorthogonal cycloadditions involving N 2 or CO 2 extrusion have been examined experimentally at the single‐molecule level by using a protein nanoreactor. At the resolution of this approach, the reactions appeared to occur in a single step, which places an upper limit on the lifetimes of the intermediates of about 80 μs, which is consistent with the computational work.