Theoretical Study of Intramolecular Nucleophilic Substitution on Nitrogen to Three-Membered N-Heterocycle

Using^-CH(CHO)-CH₂-NFR(R=H, CH₃)as the computational model, two possible intramolecular reactions, nucleophilic substitution on nitrogen and elimination reaction, were investigated by adopting a popular density functional theory—M062X with the 6-31+G^** basis set. The energy barrier of nucleophilic substitution was predicted to be 49.7 kJ/mol for R=H, while it was 68.6 kJ/mol for R=CH₃, showing the steric hindrance of CH₃ significantly increases the energy barrier. For R=CH₃, the nucleophilic substitution with a three-membered N-heterocycle as product was the favorable pathway, while its elimination reaction has a higher energy barrier, 151.7 kJ/mol, with the chain compound as product. These theoretical prediction suggests the nucleophilic substitution on nitrogen for three-membered N-heterocycle can occur easily, and takes some advantage over the corresponding elimination reaction. Therefore, the nucleophilic substitution on nitrogen has certain potential for future experiment.