Theoretical Elucidation of the Origins of Substituent and Strain Effects on the Rates of Diels–Alder Reactions of 1,2,4,5-Tetrazines

Abstract

The Diels–Alder reactions of seven 1,2,4,5-tetrazines with unstrained and strained alkenes and alkynes were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The higher reactivities of alkenes compared to alkynes in the Diels–Alder reactions with tetrazines arise from the differences in both interaction and distortion energies. Alkenes have HOMO energies higher than those of alkynes and therefore stronger interaction energies in inverse-electron-demand Diels–Alder reactions with tetrazines. We have also found that the energies to distort alkenes into the Diels–Alder transition-state geometries are smaller than for alkynes in these reactions. The strained dienophiles, <i>trans</i>-cyclooctene and cyclooctyne, are much more reactive than unstrained <i>trans</i>-2-butene and 2-butyne, because they are predistorted toward the Diels–Alder transition structures. The reactivities of substituted tetrazines correlate with the electron-withdrawing abilities of the substituents. Electron-withdrawing groups lower the LUMO+1 of tetrazines, resulting in stronger interactions with the HOMO of dienophiles. Moreover, electron-withdrawing substituents destabilize the tetrazines, and this leads to smaller distortion energies in the Diels–Alder transition states