DFT‐HSAB Prediction of Regioselectivity in 1,3‐Dipolar Cycloadditions: Behavior of (4‐Substituted)benzonitrile Oxides towards Methyl Propiolate

Abstract

The regioselectivity of 1,3-dipolar cycloadditions between (4-substituted)benzonitrile oxides and methyl propiolate cannot be rationalized on the basis of the electron demand of the reactants or frontier molecular-orbital theory. To this problem, we have applied a quantitative formulation of the hard-soft acid-base principle developed within the density functional theory. Global and local reactivity indices were computed at B3LYP/6-311+G(d,p) level. The details of charge transfer upon the reactive encounter have been elucidated, and the computed regioselectivity has been shown to be in good agreement with experimental data.

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

“…This was in agreement with the high electrophilic character of the NBO 14, ω = 1.94 eV, and the high nucleophilic character of the 3-methylenephthalimine (15), N = 3.05 eV. Scheme 4. Recently, Ponti and Molteni [12] studied the regioselectivity of the cycloaddition reactions of 4-substituted benzonitrile oxides and methyl propiolate based on the Pearson's hard-soft acid-base (HSAB) principle. [13] The charge transfer (CT) between the two reagents in these 13DC reactions was analyzed in terms of the electronic chemical potentials, µ, of the two fragments as a first step.…”

Site- and Regioselectivity of Nitrile Oxide–Allene Cycloadditions: DFT-Based Semiquantitative Predictions

“…14 We were thus prompted to computationally investigate these cycloadditions A widespread approach is based on the analysis of density functional theory (DFT) reactivity indices, 21 which was successfully applied to the cycloaddition of nitrile oxides. 22,23 However, this method only takes purely electronic factors into account but neglects thermal and steric factors that can be important in medium-sized, crowded TSs. Therefore, in the present paper the cycloaddition between nitrile oxides 1 and To support the reliability of the present computational approach, we also investigated the four TSs of the 1b + 3 cycloaddition: in this case, the O α C β TS is the most stable one by 5-6 kcal mol -1 for both ΔE and ΔG.…”

The Nitrilimine–Alkene Cycloaddition Regioselectivity Rationalized by Density Functional Theory Reactivity Indices

“…We carried out this classification by considering the electron chemical potential of the reactant molecules since we are interested in the direction of the electron transfer at the very beginning of the 1,3-DC, before that electron reshuffling becomes important [ 25 ]. This initial step has been shown to determine the regioselectivity in 1,3-DCs [ 14 , 15 , 16 , 17 ]. Of course, we are aware that other global DFT indices have been successfully proposed to describe the molecular ability to donate or accept electrons, such as Parr’s electrophilicity index ω [ 26 ], the electroaccepting ω + and electrodonating ω − powers [ 27 ], and the nucleophilicity index N [ 28 ].…”

“…A general criterion to point out the preferred regioisomer resulting from an addition reaction has been derived by minimizing the grand potential Ω [ 13 ]. This approach, which is based on the energy and electron density of the reactants only and does not require the calculation of the TSs, was applied to the quantitative study of the regioselectivity of the 1,3-DCs of azides [ 14 ] and nitrile oxides [ 15 ]. This theoretical framework allowed us to rationalize the regioselectivity in the nitrilimine–alkyne [ 16 ] and the nitrilimine–allene cycloadditions, too [ 17 ].…”