Fig. 4. Kinetic studies for the iEDDA reaction between azanorbornene 2 and tetrazines 13a–13c. Lowest-energy conformations calculated for N-Moc-protected (Moc = methyl carbamate) cyclic 2,5-dihydro-1H-pyrrole (A1c) and bicyclic azanorbornene (A1b) models and their iEDDA reactions with tetrazine 13a calculated with PCMDMF/M06-2X/6-31+G(d,p). Five-membered ring puckering is represented by the dihedral angle φ and relative reaction rate constants at 37 °C (310 K, k310rel) are calculated from activation free energies (ΔG‡). A significant distortion of the dihydropyrrole ring is required to achieve the transition state geometry in A1c, while in A1b such distortion is already developed up in the dienophile, translating into a reaction rate acceleration of several orders of magnitude.
