Министерство науки и высшего образования Российской Федерации
Российская Академия Наук

Scientists from the ZIOC proposed a "reverse" strategy for the formation of C-O bonds

10 november 2022 г.

Nucleophilic substitution at the carbon atom is a fundamental organic transformation. In its textbook version, a nucleophilic reagent replaces a carbon-bonded atom or a well-leaving group of atoms. Nucleophilic substitution at an electrophilic carbon atom with an oxygen nucleophile is the most widely used strategy for the construction C-O bonds.

In contrast, nucleophilic substitution at the oxygen atom is much less common because O-X bonds are usually unfavorably polarized and electron-rich oxygen atoms are poor targets for nucleophiles. Therefore, "reversed" approaches, when a carbon-centered nucleophile reacts with an oxygen electrophile, are relatively uncommon.

Scientists from the Laboratory for the Study of Homolytic Reactions and the Group of Theoretical Chemistry of the Zelinsky Institute together with colleagues from Florida State University proposed an unexpected alternative to conventional approaches to construction C-O bonds — the interaction of O-electrophiles, such as organic peroxides, with carbon nucleophiles. It was found that nucleophilic substitution at the oxygen atom of cyclic diacyl peroxides with an electron-saturated carbon atom of enol acetates, followed by deacylation, led to α-acyloxy ketones with an additional carboxyl group. An analysis of the process by quantum chemical methods showed that the key stage proceeded as a bimolecular nucleophilic substitution reaction (SN2) at the oxygen atom (SN2@O). The solvent used, CF3CH2OH, plays a dual role by assisting in both steps of the reaction cascade: it lowers the activation energy of SN2@O by forming a hydrogen bond with a distant carbonyl and promotes deacylation of the intermediate cationic intermediate.

The study was supported by the RSF grant 21-13-00205.


Vera A. Vil’, Evgenii S. Gorlov, Diana V. Shuingalieva, Artem Yu. Kunitsyn, Nikolai V. Krivoshchapov, Michael G. Medvedev, Igor V. Alabugin, Alexander O. Terent’ev Activation of O-Electrophiles via Structural and Solvent Effects: SN2@O Reaction of Cyclic Diacyl Peroxides with Enol Acetates // J. Org. Chem., 2022, 87, 13980–13989. DOI: 10.1021/acs.joc.2c01634.