The study aimed to verify the possible use of DFT calculation in the prediction of the orientation in electrophilic aromatic substitution. An activated ortho/para orienting substrate, and a deactivated meta orienting substrate, were used in DFT calculations using B3LYP, B3PW91, BPV86, CAM-B3LP, HCTH, HSEH1PBE, LSDA, MPW1PW91, PBEPBE, TPSSTPSS, and WB97XD functionals. The results showed that the reactivity of anisole can be adequately described considering charge control in reaction performed in hard conditions (nitration), while frontier orbital control can play a role in reactions performed in softer conditions (chlorination). Nitration of benzaldehyde can be rationalized through Hirshfeld charges analysis. Neither the frontier orbital nor Mulliken charges approach adequately account for behavior observed in chlorination of benzaldehyde. The effect of different basis sets was tested performing calculations with B3LYP functional and aug-cc-pVDZ, 6-311G+(d,p), aug-cc-pVQZ, DGTZVP, and LanL2DZ basis sets. For anisole, all basis sets provided a HOMO electron density distribution consistent with experimental reactivity; Hirshfeld charges analysis consistently reproduced the observed reactivity of anisole across all tested basis sets. All the basis sets were able to explain the observed reactivity of benzaldehyde in hard experimental condition, while they failed to give a correct description when a softer reagent was used.
Emanuele et al. (Wed,) studied this question.