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- Title
Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles.
- Authors
Tu, Julian; Svatunek, Dennis; Parvez, Saba; Liu, Albert C.; Levandowski, Brian J.; Eckvahl, Hannah J.; Peterson, Randall T.; Houk, Kendall N.; Franzini, Raphael M.
- Abstract
The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Now it is shown that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure–activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 L mol−1 s−1 were accessible by combining bulky and electron‐withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles.
- Subjects
TETRAZINE; INTERMOLECULAR forces; RING formation (Chemistry); ISOCYANIDES; ALKENES
- Publication
Angewandte Chemie, 2019, Vol 131, Issue 27, p9141
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201903877