Conformational analysis, NMR properties and nitrogen inversion of N-substituted 1,3-oxazines

The conformational preference of a set of selected N-substituted oxazines has been investigated at the MP2/6-311+G(d,p) and B3LYP/6-311+G(d, p) levels of theory. From the Delta G(0) calculated values, it can be concluded that when the substituent is methyl, ethyl and propyl the axial conformation is preferred in the gas phase. When the substituent is isopropyl or tert-butyl the equatorial conformer is the most abundant in the gas phase. This situation does not change in solution provided the solvent has very low polarity as Cl4C, in good agreement with the experimental findings. However, when the polarity of the solvent increases, the stabilization of the equatorial conformer is quite significant, due to its large dipole moment, and it becomes the dominant form in CHCl3 and CH2Cl2 solvents. Quite importantly, the percentage of axial conformer obtained from the values of the H-1 chemical shift are in good agreement with the percentage obtained from the calculated free energy. The nitrogen inversion barrier of N-substituted 1,3-oxazines decreases with the size of the substituent. The largest substituent stabilizes the nitrogen lone-pair to the greatest extent in the transition state and is the one that least interacts with the ring when it becomes planar.