A molecular electron density theory study on the Chichibabin reaction: The origin of regioselectivity

A Molecular Electron Density Theory (MEDT) study was performed on the nucleophilic amination of pyridine and benzene to elucidate the observed regioselectivity in the Chichibabin reaction. For this purpose, three possible reaction paths were considered between NaNH₂ and the 2-, 3- and 4-positions of pyridine. The reaction of NaNH₂ and benzene was also investigated. The results indicated that in each reaction, the first step involves the nucleophilic attack of the NH₂‾ ion toward the aromatic system to produce an anionic intermediate. The second step, proceeds via hydride elimination of the anionic intermediate to produce the corresponding aromatic amine. This step is more favourable both kinetically and thermodynamically for the reaction at the 2-position of pyridine relative to the 4-position. In contrast to the Parr functions analysis which indicates that the 4-position is activated more electrophilically in pyridine, the PES analysis reveals that the 2-position attack with the NH₂‾ ion is more favourable both thermodynamically and kinetically. The results for the reaction of sodium amide and benzene indicated that this reaction is not feasible due to the high activation barriers. In consistent with the experimental results, the ELF analysis indicated that in the first step of the reaction between pyridine and sodium amide, the formation of the C2-N bond takes place via a pseudoradical coupling between the C2 carbon atom of pyridine and the N atom of NaNH₂. These variations occur in the second-half of the first step of the reaction. NCI analysis on the reaction revealed that the more attractive forces between the fragments, make the transition states for the 2-position attack more stable relative to the others. Thus, the NCI analysis can satisfactorily describe the observed regioselectivity in the Chichibabin reaction.