A computational study of the aza-Cope rearrangement leading to angularly substituted 1-azabicyclic ring systems is presented. The calculations estimate the probability of the proton transfer between reaction intermediates and protic solvents, explain the experimentally observed reaction selectivity, and suggest new potentially more efficient systems for further in vitro and in silico investigations.
12Computational DetailsThe conformational space of all molecules has been initially searched using meta-dynamics simulations based on tight-binding quantum chemical calculations as implemented in the software package conformer-rotamer ensemble sampling tool (CREST). The structures located with CREST have then been subjected to a B3LYP-D3BJ/def2-SVP geometry optimization. The nature of all stationary points (minima and transition states) was verified through the computation of harmonic vibrational frequencies. The thermal corrections to the Gibbs free energies were combined with the single point energies calculated at the B3LYP-D3BJ/def2-TZVP level of theory to yield Gibbs free energies (‘G298’) at 298.15 K. The DFT calculations have been performed with the Gaussian 16 program package. The SMD model with parameters of methanol was applied to consider implicit solvation effects in both, the geometries, and energies. All energies are reported in kcal/mol. The energy profiles were constructed using the most stable conformation (the global minimum) of each intermediate and transition state. Free energies in solution have been corrected to a reference state of 1 mol/L at 298.15 K through the addition of RTln(24.46) = +7.925 kJ/mol to the gas phase (1 atm) free energies.
