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Selectivity in the Addition of Electron Deficient Radicals to the C2 Position of Indoles.

ABSTRACT: The addition of electron deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for reaction at C2 and a lower energy radical intermediate that benefits from benzylic radical stabilization. Trifluoromethyl radical addition has a lower energy barrier than acetonitrile radical, and the C3 addition transition state is just 0.8 kcal/mol higher than C2. This is supported by experimental observations.

SUBMITTER: Li Y

PROVIDER: S-EPMC7939109 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Selectivity in the Addition of Electron Deficient Radicals to the C2 Position of Indoles.

Li Yi Y Vaz Roy J RJ Olson Steven H SH Munson Mark M Paras Nick A NA Conrad Jay J

European journal of organic chemistry 20200818 36

The addition of electron deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for reaction at C2 and a lower energy radical intermediate that benefits from benzylic radical stab ...[more]

PMID: 33692651

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Project description:Vitamin C (ascorbate; Asc) is a biologically important antioxidant that scavenges reactive oxygen species such as deleterious alkylperoxyl radicals (ROO•), which are generated by radical-mediated oxidation of biomolecules in the presence of oxygen. The radical trapping proprieties of Asc are conventionally attributed to its ability to undergo single-electron transfers with reactive species. According to this mechanism, the reaction between Asc and ROO• results in the formation of dehydroascorbate (DHA) and the corresponding hydroperoxides (ROOH). When studying the reactivity of DNA 5-(2'-deoxyuridinyl)methylperoxyl radicals, we discovered a novel pathway of ROO• scavenging by Asc. The purpose of this study is to elucidate the underlying mechanism of this reaction with emphasis on the characterization of intermediate and final decomposition products. We show that the trapping of ROO• by Asc leads to the formation of an alcohol (ROH) together with an unstable cyclic oxalyl-l-threonate intermediate (cOxa-Thr), which readily undergoes hydrolysis into a series of open-chain oxalyl-l-threonic acid regioisomers. The structure of products was determined by detailed MS and NMR analyses. The above transformation can be explained by initial peroxyl radical addition (PRA) onto the C2=C3 enediol portion of Asc. Following oxidation of the resulting adduct radical, the product subsequently undergoes Baeyer-Villiger rearrangement, which releases ROH and generates the ring expansion product cOxa-Thr. The present investigation provides robust clarifications of the peroxide-mediated oxidation chemistry of Asc and DHA that has largely been obscured in the past by interference with autooxidation reactions and difficulties in analyzing and characterizing oxidation products. Scavenging of ROO• by PRA onto Asc may have beneficial consequences since it directly converts ROO• into ROH, which prevents the formation of potentially deleterious ROOH, although it induces the breakdown of Asc into fragments of oxalyl-l-threonic acid.

Project description:The azide radical (N3●) is one of the most important one-electron oxidants used extensively in radiation chemistry studies involving molecules of biological significance. Generally, it was assumed that N3● reacts in aqueous solutions only by electron transfer. However, there were several reports indicating the possibility of N3● addition in aqueous solutions to organic compounds containing double bonds. The main purpose of this study was to find an experimental approach that allows a clear assignment of the nature of obtained products either to its one-electron oxidation or its addition products. Radiolysis of water provides a convenient source of one-electron oxidizing radicals characterized by a very broad range of reduction potentials. Two inorganic radicals (SO4●-, CO3●-) and Tl2+ ions with the reduction potentials higher, and one radical (SCN)2●- with the reduction potential slightly lower than the reduction potential of N3● were selected as dominant electron-acceptors. Transient absorption spectra formed in their reactions with a series of quinoxalin-2-one derivatives were confronted with absorption spectra formed from reactions of N3● with the same series of compounds. Cases, in which the absorption spectra formed in reactions involving N3● differ from the absorption spectra formed in the reactions involving other one-electron oxidants, strongly indicate that N3● is involved in the other reaction channel such as addition to double bonds. Moreover, it was shown that high-rate constants of reactions of N3● with quinoxalin-2-ones do not ultimately prove that they are electron transfer reactions. The optimized structures of the radical cations (7-R-3-MeQ)●+, radicals (7-R-3-MeQ)● and N3● adducts at the C2 carbon atom in pyrazine moiety and their absorption spectra are reasonably well reproduced by density functional theory quantum mechanics calculations employing the ωB97XD functional combined with the Dunning's aug-cc-pVTZ correlation-consistent polarized basis sets augmented with diffuse functions.

Dataset Information

Selectivity in the Addition of Electron Deficient Radicals to the C2 Position of Indoles.

Publications

Selectivity in the Addition of Electron Deficient Radicals to the <i>C</i>2 Position of Indoles.

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