Ring Size and Substituent Effects in the Beckmann Rearrangement: A Systematic Experimental and DFT Study of Cyclic Oxime Reactivity
Тип публікації :
Препринт
Дата випуску :
12 березня 2026 р.
Автор(и) :
Tetiana Zubatiuk
Bohdan Yu Solod
Eugeniy N. Ostapchuk
Vitalii A. Palchykov
Ievgenii A. Iermolenko
Artem A Artemenko
M. B. Vovk
Dmytro M. Volochnyuk
Olexandr Isayev
Serhiy V Ryabukhin
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Tetiana, Z., Bohdan, Y. S., Eugeniy, N. O., Vitalii, A. P., Ievgenii, A. I., Artem, A. A., M., B. V., Dmytro, M. V., Olexandr, I., & Serhiy, V. R. (2026). Ring Size and Substituent Effects in the Beckmann Rearrangement: A Systematic Experimental and DFT Study of Cyclic Oxime Reactivity. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15000860/v1
[ДСТУ] Ring Size and Substituent Effects in the Beckmann Rearrangement: A Systematic Experimental and DFT Study of Cyclic Oxime Reactivity / Z. Tetiana та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15000860/v1 (дата звернення: 11.09.2026).
The Beckmann rearrangement remains a cornerstone transformation in organic synthesis, particularly for the preparation of cyclic amides (lactams) from ketoximes.Despite its long history and widespread application in the industrial production of important molecules such as nylon-6 and paracetamol, systematic comparative studies on the reactivity of structurally related cyclic oximes, specifically those derived from 1-indanone and 1-tetralone, are surprisingly scarce.This work presents a detailed investigation of the polyphosphoric acid (PPA)-mediated Beckmann rearrangement of diversely substituted 1-indanone and 1-tetralone oximes under optimized conditions (150 °C, 5 min).The reaction proceeds with high efficiency, affording the corresponding benzolactams in isolated yields of 92-97%.A clear dependence of regioselectivity on ring size is revealed: five-membered 1-indanone oximes predominantly undergo alkyl migration (type A product), whereas six-membered 1-tetralone oximes favor aryl migration (type B product).Substituent effects are also pronounced: electron-donating groups enhance aryl migration, electron-withdrawing groups and ortho-substitution promote alkyl migration, and the reaction tolerates a broad range of functional groups (halogens, CF₃, NO₂).The developed protocol offers a significant improvement over earlier high-temperature, lowselectivity methods and provides a practical route to medicinally relevant 2,3,4,5-tetrahydro-1H-benzo[b]azepines and related scaffolds via subsequent reduction of the lactams.In addition, we develop an orbital-resolved electronic routing framework to distinguish rearrangement from fragmentation in the Beckmann reaction manifold by quantifying hyperconjugative competition, frontier antibonding localization, and activation-dependent orbital reshuffling along the N-O coordinate.Application to a 5-membered series containing electron-donating (OMe, H, Me) and electron-withdrawing (F) substituents reveals that rearrangement requires a coordinated redistribution of virtual orbital character, enabling transfer of antibonding localization from the leaving-group channel to the migrating bond.Only the Me derivative satisfies this electronic criterion, whereas OMe, H, and F maintain fragmentation-biased frontier topology and do not undergo rearrangement.
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