Rotational Barriers in N-Benzhydrylformamides: An NMR and DFT Study

N-Benzhydrylformamides are pharmacologically active compounds with anticonvulsant, enzyme-inducing, antihypoxic, and other types of biological activity. The conformational behavior of benzhydrylformamides is determined to a great extent by the presence of substituents at the nitrogen atom and in the ortho-position(s) of the diphenylmethane moiety. Particularly, the NMR spectra of these compounds often contain two sets of signals originating from different orientations of the formyl group. With the use of the dynamic NMR method and DFT calculations, we investigated the internal rotations of aromatic and formyl fragments and estimated the corresponding rotational barriers in N-benzhydrylformamide (BHFA), N-methyl-N-benzhydrylformamide (BHFA-NMe), and in a series of ortho-halogen-substituted N-benzhydrylformamides. It was found that the DFT method at M06-2X/6-311+G* level of theory satisfactorily reproduces the experimental barrier delta G(298)(+)(Formyl) of the formyl group rotation in BHFA-NMe. In BHFA, BHFA-NMe, and in the ortho-halogen derivatives, the calculated delta G(298)(+)(Formyl) values are close to each other and lie within 20-23 kcal/mol. On the other hand, the ortho-substituents significantly hinder the rotation of aryl fragment with delta G(298)(+)(Aryl) values varying from 2.5 kcal/mol in BHFA to 9.8 kcal/mol in ortho-iodo-N-benzhydrylformamide.

Automated summary

N-Benzhydrylformamides are pharmacologically active compounds with various biological activities. The conformation of these compounds is influenced by the presence of substituents, particularly at the nitrogen atom and in the ortho-positions of the diphenylmethane moiety. Through NMR and DFT calculations, the rotational barriers of the formyl and aryl fragments in N-benzhydrylformamides were investigated. The results showed that the DFT method satisfactorily reproduced the experimental rotational barrier of the formyl group, while ortho-substituents significantly hindered the rotation of the aryl fragment.