Molecular dynamics of the Diels-Alder reactions of tetrazines with alkenes and N2 extrusions from adducts.

The cycloadditions of tetrazines with cyclopropenes and other strained alkenes have become among the most valuable bioorthogonal reactions. These reactions lead to bicyclic Diels–Alder adducts that spontaneously lose N2. We report quantum mechanical (QM) and quasiclassical trajectory simulations on a number of these reactions, with special attention to stereoelectronic and dynamic effects on spontaneous N2 loss from these adducts. QM calculations show that the barrier to N2 loss is low, and molecular dynamics calculations show that the intermediate is frequently bypassed dynamically. There is a large preference for N2 loss anti to the cyclopropane moiety rather than syn from adducts formed from reactions with cyclopropenes. This is explained by the interactions of the Walsh orbitals of the cyclopropane group with the breaking C–N bonds in N2 loss. Dynamical effects opposing the QM preferences have also been discovered involving the coupling of vibrations associated with the formation of the new C–C bonds ...