Closer Look at Inverse Electron Demand Diels-Alder and Nucleophilic Addition Reactions on s-Tetrazines Using Enhanced Sampling Methods

Inverse electron demand [4+2] Diels-Alder (iEDDA) reactions as well as unprecedented nucleophilic (azaphilic) additions of R-substituted silyl-enol ethers (where R is Phenyl, Methyl, and Hydrogen) to 1,2,4,5-tetrazine (s-tetrazine) catalyzed by ${\text{BF}}_3$ have recently been discovered (Simon et al. in Org Lett 23(7):2426-2430, 2021), where static calculations were employed for calculation of activation energies. In order to have a more realistic dynamic description of these reactions in explicit solution at ambient conditions, in this work we use a semiempirical tight-binding method combined with enhanced sampling techniques to calculate free energy surfaces (FESs) of the iEDDA and azaphilic addition reactions. Relevant products of not only s-tetrazine but also its derivatives such as ${\text{BF}}_3$ -mediated s-tetrazine adducts are investigated. We reconstruct the FESs of the iEDDA and azaphilic addition reactions using metadynamics and blue moon ensemble, and compare the ability of different collective variables (CVs) including bond distances, Social PeRmutation INvarianT (SPRINT) coordinates, and path-CV to describe the reaction pathway. We find that when a bulky Phenyl is used as a substituent at the dienophile the azaphilic addition is preferred over the iEDDA reaction. In addition, we also investigate the effect of ${\text{BF}}_3$ in the diene and steric hindrance in the dienophile on the competition between the iEDDA and azaphilic addition reactions, providing chemical insight for reaction design.

Supplementary information: The online version contains supplementary material available at 10.1007/s11244-021-01516-y.