An MEDT study of the mechanism and selectivities of the [3+2] cycloaddition reaction of tomentosin with benzonitrile oxide

Abstract

The [3+2] cycloaddition (32CA) reaction of tomentosin with benzonitrile oxide yielding a spiro-isoxazoline has been studied within the Molecular Electron Density Theory at the B3LYP/6-31(d,p) computational level. Given the multifunctionality of tomentosin, this 32CA reaction can take place along 16 competitive reaction paths. The chemo-, regio-, and stereoisomeric reaction paths involving the two C C double bonds of tomentosin have been studied. Density functional theory (DFT) calculations account for the total chemo-and regioselectivity, in complete agreement with the experimental outcomes, being suggestive of low diastereofacial selectivity. Analysis of the conceptual DFT indices accounts for the nonpolar character of this 32CA reaction. On the other hand, the topological analysis of the electron localization function of the selected points of the intrinsic reaction coordinate associated with the formation of the C C and C O single bonds emphasizes the zw-type reactivity of the phenyl nitrile oxide; the reaction taking place through a non-concerted two-stage one-step mechanism initialized with the formation of the C C single bond involving the β-conjugated carbon of tomentosin. K E Y W O R D S [3+2] cycloaddition reaction, molecular electron density theory conceptual, nitrile oxide, tomentosin

Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory

“…These findings have provided a rationalisation of experimental outcomes [17][18][19][20][21]. In 2017, Zaki and co-workers reported the synthesis of a series of enantiomerically pure isoxazolines by 32CA reactions of substituted aryl nitrile oxides 2 with tomentosin 1, a sesquiterpene lactone extracted from Dittrichia viscosa (see Scheme 4) [22].…”

Chemical reactivities and molecular docking studies of parthenolide with the main protease of HEP-G2 and SARS-CoV-2

“…The current reports have described several remarkable catalytic systems in the presence of hydrogen peroxide such as iron [15] , tungsten [16] , vanadium [ 17 , 18 ], Manganese [19] , [20] , [21] , bicarbonate [ 22 , 23 ] and dioxolane [24] .Various theories have been developed to elucidate the molecular mechanism, reactivity and selectivities (regio, chemo and stereo). The bonding evolution theory (BET) [25] , the conceptual density functional theory (CDFT) [26] , and the electron localization function (ELF) method [27] , have presented to scrutinize the reaction mechanism [28] within a current model named a molecular electron density theory (MEDT) [29] . Our theoretical studies devoted to the epoxidation of R-carvone with peracid demonstrate a high chemoselectivity involving the C=C double bond carrying the methyl group and the low diastereoselectivity [30] .…”

Mpro-SARS-CoV-2 Inhibitors and Various Chemical Reactivity of 1-Bromo- and 1-Chloro-4-vinylbenzene in [3 + 2] Cycloaddition Reactions

“…Progress in the theoretical comprehension of 32 CA reactions founded on molecular electron density theory [41] (MEDT) shows a relationship between the electronic structure of the simplest three-atom components (TAC) and their reactivity ethylene [42]. Thus, depending of the structure of the TACs, pseudodiradical, pseudoradical, carbenoid or zwitterionic, 32CA reactions have been classed as pseudodiradical type (pdr-type), pseudoradical type (pmr-type), carbenoid type (cb-type) and zwitterionic type (zw-type) [42][43][44][45], in such a manner that while zw-type 32CA reactions demand high activation energies to take place, while pdr-type 32CA reactions can be carried out without difficulty [42].…”