Bottlenecks in the prediction of regioselectivity of [4 + 2] cycloaddition reactions: An assessment of reactivity descriptors

Abstract

B3LYP/6-31G(d) calculations were performed to obtain all the transition states and products for the 128 distinct reaction channels of Diels-Alder reactions by taking all possible combinations from a series of dienes (1N-a, 1N-b, 2N, 1P-a, 1P-b, 2P, 1O, 1S) and dienophiles (NE, PE, OE, SE, AE, OHE, MeE, CNE). The predictive ability of the values to gauge the regioselectivity of the putative [4 + 2] cycloaddition reactions is analysed. No correlation is obtained between the reaction energies and activation energies. The extent of asynchronicity is measured based on the bond order analysis. DFT-based descriptors such as the local softness (s + k and s k-), Fukui function indices (f + k and f k-), global electrophilicity index (ω) and local electrophilicity index (ω k) were found to be better than the conventional FMO predictions.

Conceptual, Qualitative, and Quantitative Theories of 1,3‐Dipolar and Diels–Alder Cycloadditions Used in Synthesis

“…[55] In conclusion of this section, we note that Gayatri and Sastry have assessed the performance of DFT descriptors for 64 Diels-Alder reactions shown in Scheme 9 for predicting regioselectivity. [56] Using Fukui function matching from B3LYP calculations, 53 of 64 reactions could be rationalized by this approach. This highlights the potential broad applicability of DFT descriptors to predict reactivity and selectivity, but also the approximate nature of these descriptors.…”

Hetero‐Diels–Alder (HDA) Strategy for the Preparation of 6‐Aryl‐ and Heteroaryl‐Substituted Piperidin‐2‐one Scaffolds: Experimental and Theoretical Studies

“…To support this choice and before studying the mechanism from a theoretical point of view, we analyzed the global electrophilic indices of 1f, 2a and 2b through conceptual DFT descriptors. [37,39,40] The results of this theoretical investigation have been reported in Table 3. Table 3.…”

“…0.048) due to a destabilizing entropy effect. [37] Taking advantage of the results reported by De Lucchi and Pasquato [38] on the reactivity of sulfones in the DielsAlder reaction, the next step in our studies was to consider a new reaction pathway in which the electron-demanding nature of the dienophile was increased by adding an extra sulfone group to the scaffold. To support this choice and before studying the mechanism from a theoretical point of view, we analyzed the global electrophilic indices of 1f, 2a and 2b through conceptual DFT descriptors.…”

“…The electrophilicity indices were calculated at the B3LYP/6-31g* computational level to compare the values with the reported classification of electrophilicity. [37,39,40] The global index, ω, is given by the expression ω = μ 2 /2η in terms of the electronic chemical potential, μ, and the chemical hardness, η. The absolute electronegativity, χ, is the negative of the chemical potential, μ; the softness, S, is the inverse of the hardness and the ΔN max , Ϫμ/η, is the maximum amount of electronic charge that the electrophile system may accept.…”

Comprehensive DFT Study on Site‐, Regio‐, and Stereoselectivity of Diels–Alder Reactions Leading to 5‐Hydroxybenzofurans

“…[3,4] These conceptual DFT-based descriptors have been successfully applied to interpret reactivity or site-selectivity in different cycloaddition reactions. [5] For the reactions shown in Scheme 1, for instance, we demonstrated that the local electrophilicity (ω k ) and nucleophilicity (N k ) can be used to explain the observed regioselectivity.…”