An Analysis of the Regioselectivity of 1,3‐Dipolar Cycloaddition Reactions of Benzonitrile N‐Oxides Based on Global and Local Electrophilicity and Nucleophilicity Indices

Abstract

The regioselectivity of the 1,3‐dipolar cycloaddition (13DC) reactions of benzonitrile N‐oxides (BNOs) with electrophilic and nucleophilic alkenes has been analyzed by using global and local nucleophilicity and electrophilicity reactivity indices defined within the conceptual DFT. The BNOs react with electron‐deficient and electron‐rich ethylenes, but the regioselectivities of these polar reactions are different. Whereas the reactions with electron‐rich ethylenes are completely regioselective, yielding 5‐isoxazolines, a change in the regioselectivity is observed in the reactions with electron‐deficient ethylenes, which yield a mixture of 4‐ and 5‐isoxazolines. Analysis of the energies, geometries, and electronic structures of the transition‐state structures involved in the 13DC reactions between the BNOs and two electronically activated ethylenes are in complete agreement with the analysis of the global and local electrophilicity and nucleophilicity reactivity indices.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Understanding the reactivity and regioselectivity of [3 + 2] cycloaddition reactions between substituted nitrile oxides and methyl acrylate. A molecular electron density theory study

“…In 2009, Domingo et al studied the regioselectivity of 32CA reactions of substituted benzonitrile oxides 11 based on the analysis of the conceptual DFT (CDFT) reactivity indices . Thus, benzonitrile oxide 6a reacts with electron‐deficient (ED) ethylenes, such as dicyanoethylene 12 , and electron‐rich (ER) ethylenes, such as 2‐methylene‐1,3‐dioxolane 13 , but the regioselectivities of these polar reactions are quite different (see Scheme ).…”

The 1,3-Dipolar Cycloaddition of Nitrile Oxide to Vinylacetic Acid: Computational Study of Transition States Selectivity, Solvent Effects, and Bicyclo Formation

“…According to the FMO 13 theory, the 3,5-isoxazoline product would be favored if the dipolarophile is ER, while a mix of the 3,4-and 3,5-regioisomers would be expected when ED alkenes are used because of changes in the energy levels of the FMO. 34,35 As the formation of 3,4-isoxazoline is energetically disfavored in the first cycloaddition, in the second reaction only transition structures involving the 3,5-substituted products are taken into account.…”

“…However, if the alkene has electron-withdrawing groups attached, it usually yields a mixture of 4-and 5-regioisomers. [33][34][35] Density functional theory (DFT) methods are most frequently employed for quantum mechanical calculations of 13DC because of the balance between accuracy and efficiency. A large number of studies involving the theoretical study of 13DC reactions have been published recently, and DFT has emerged as the theoretical choice in many cases.…”

“…[38][39][40] In general, B3LYP describes 13DC reaction mechanisms in a satisfactory way, compared to more high-level calculations. 34,35 In previous theoretical reports, Ess and Houk 37 systematically investigated the reactivity of diazonium, nitrilium, and azomethine betaine classes of 1,3-dipoles Vol. 27, No.…”

“…These values are in the same order of magnitude obtained in the literature for similar reactions. 24,34,35,37,69 In fact, cycloadditions involving benzonitrile oxide proceed smoothly even with completely unactivated dipolarophiles, such as ethene, under ordinary laboratory conditions. 70 Considering the three functionals, the lowest activation free energies (26.2 -28.7 kcal mol -1 ) were obtained using PBE1PBE, while CAM-B3LYP and B3LYP produced very similar barriers (29.5 -32.2 kcal mol -1 ).…”