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

Madina Zh Sadvakassova; Andrei I Khlebnikov; Abdigali A Bakibaev; Oleg A Kotelnikov; Rakhmetulla Sh Erkassov; Madeniyet A Yelubay; Manar A Issabayeva

doi:10.3390/molecules28020535

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

Molecules. 2023 Jan 5;28(2):535. doi: 10.3390/molecules28020535.

Authors

Madina Zh Sadvakassova¹, Andrei I Khlebnikov², Abdigali A Bakibaev³, Oleg A Kotelnikov³, Rakhmetulla Sh Erkassov¹, Madeniyet A Yelubay⁴, Manar A Issabayeva⁴

Affiliations

¹ Department of Chemistry, L.N. Gumilyov Eurasian National University, 010008 Astana, Kazakhstan.
² Kizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, Russia.
³ Faculty of Chemistry, National Research Tomsk State University, 634050 Tomsk, Russia.
⁴ Department of Chemistry and Chemical Technology, Toraighyrov University, 140008 Pavlodar, Kazakhstan.

Abstract

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 ΔG298≠(Formyl) of the formyl group rotation in BHFA-NMe. In BHFA, BHFA-NMe, and in the ortho-halogen derivatives, the calculated ΔG298≠(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 ΔG298≠(Aryl) values varying from 2.5 kcal/mol in BHFA to 9.8 kcal/mol in ortho-iodo-N-benzhydrylformamide.

Keywords: DFT calculations; N-benzhydrylformamide derivatives; dynamic NMR; rotational barriers.

Grants and funding

This research was funded by the Ministry of Science and Higher Education of the Russian Federation (project no. Nauka FSWW-2020-0011); the Tomsk Polytechnic University development program; and by the Tomsk State University Development Program (Priority2030).