A computational model to predict the Diels-Alder reactivity of aryl/alkyl-substituted tetrazines

Monatsh Chem. 2018;149(4):833-837. doi: 10.1007/s00706-017-2110-x. Epub 2017 Nov 29.


Abstract: The tetrazine ligation is one of the fastest bioorthogonal ligations and plays a pivotal role in time-critical in vitro and in vivo applications. However, prediction of the reactivity of tetrazines in inverse electron demand Diels-Alder-initiated ligation reactions is not straight-forward. Commonly used tools such as frontier molecular orbital theory only give qualitative and often even wrong results. Applying density functional theory, we have been able to develop a simple computational method for the prediction of the reactivity of aryl/alkyl-substituted tetrazines in inverse electron demand Diels-Alder reactions.

Keywords: Bioorthogonal chemistry; Click chemistry; Computational chemistry; Cycloadditions.