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. Author manuscript; available in PMC: 2019 Apr 26.
Published in final edited form as: Angew Chem Int Ed Engl. 2016 Dec 8;56(1):243–247. doi: 10.1002/anie.201609607

Figure 2.

Figure 2

a) Proposed mechanism based on quantum mechanics for the IEDDA cycloaddition of vinyl ether 1a and tetrazine 2a, followed by in situ alcohol release. Only the relevant activation free energies (ΔG‡) are shown. The initial cycloaddition is the rate-limiting step. After very fast nitrogen cleavage, different dihidropyridazine tautomers int2–4 equilibrate before irreversibly decaging to the experimentally obtained products (pyridazine 4a and phenol 3a). See Figure S3 for the whole calculated minimum energy pathway. b) 1H NMR release studies of 1a upon reaction with tetrazine 2a. The reaction was performed at 3 mM of 1a and 2a in 10% D2O/CD3CN. Ph, phenyl; Py, pyridine. The reaction was followed for 96 hours; while the reaction was not always complete at 96 hours, the results obtained were consistent with the mechanism supported by the theoretical calculations.