Year: 2026
Type: preprint
Abstract: Biaryl 1,2,4,5-tetrazines are established as a new class of bench-stable bifunctional click reagents for chemoselective double Diels-Alder reaction sequences. A unified approach to both symmetric and unsymmetric biaryl tetrazines via Pd-catalyzed coupling of bromotetrazines is described, providing derivatives amenable to further functionalization, including via mutually orthogonal Cu-catalyzed azide-alkyne Huisgen click reactions. Diels-Alder studies reveal that biaryl tetrazines undergo chemoselective mono-cycloaddition reactions with strained alkynes as dienophiles, which can be followed by a second Diels-Alder reaction with a dienophile at either the alkyne or alkene oxidation level. Computational analysis reveals that a subtle interplay between electronic interactions and substrate distortion energies governs cycloaddition chemoselectivity. Leveraging this reactivity, we demonstrate a model bioconjugative double Diels-Alder sequence that exhibits advantageous proximity-enabled fluorescence quenching properties.
Source: ChemRxiv
Institution: University of Georgia
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7140286446