Tetrazine Assists Reduction of Water by Phosphines: Application in the Mitsunobu Reaction

Reaction of 3,6‐disubstituted‐1,2,4,5‐tetrazines with water and PEt₃ forms the corresponding 1,4‐dihydrotetrazine and OPEt₃. Thus PEt₃, as a stoichiometric reductant, reduces water, and the resulting two reducing equivalents serve to doubly hydrogenate the tetrazine. A variety of possible initial interactions between electron‐deficient tetrazine and electron‐rich PR₃, including a charge transfer complex, were evaluated by density functional calculations which revealed that the energy of all these make them spectroscopically undetectable at equilibrium, but one of these is nevertheless suggested as the intermediate in the observed redox reaction. The relationship of this to the Mitsunobu reaction, which absorbs the components of water evolved in the conversion of alcohol and carboxylic acid to ester, with desirable inversion at the alcohol carbon, is discussed. This enables a modified Mitsunobu reaction, with tetrazine replacing EtO₂CN=NCO₂Et (DEAD), which has the advantage that dihydrotetrazine can be recycled to tetrazine by oxidation with O₂, something impossible with the hydrogenated DEAD. For this tetrazine version, a betaine‐like intermediate is undetectable, but its protonated form is characterized, including by X‐ray structure and NMR spectroscopy.