Conceptual DFT analysis of the regioselectivity of 1,3-dipolar cycloadditions: nitrones as a case of study

The regioselectivity of the 1,3-dipolar cycloaddition of a model nitrone with a set of dipolarophiles, presenting diverse electronic effects, is analyzed using conceptual density functional theory (DFT) methods. We deviate from standard approaches based on frontier molecular orbitals and formulations of the local hard/soft acid/base principle and use instead the dual descriptor. A detailed analysis is carried out to determine the influence of the way to calculate the dual descriptor, the computational procedure, basis set and choice of method to condensate the values of this descriptor. We show that the qualitative regioselectivity predictions depend on the choice of “computational conditions”, something that indicates the danger of using black-box computational set-ups in conceptual DFT studies.