Combined Inductive and Dispersion Effects Enhance Bioorthogonal Reactivity of Tetrazines Toward Isonitriles.

ABSTRACT: Inverse-electron demand cycloaddition reactions of tetrazines are widely used in bioorthogonal chemistry, but the opposing effects of substituents on reactivity and stability make optimizing tetrazines for chemical biology applications challenging. Building on the discovery that bulky substituents can unexpectedly enhance both the stability of tetrazines and their reactivity toward isonitriles, we hypothesized that substituents that are both bulky and electron-withdrawing could yield tetrazines with desirable properties. We synthesized a series of tetrazines designed to explore these kinetic properties. A novel computational method quantifying intermolecular atomic contributions to dispersion forces supported the analysis substituent effects on tetrazine reactivity. Study results indicate

SUBMITTER: Biswas S 

PROVIDER: S-EPMC12455400 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature