The FE profiles obtained from DFTB3 WTMD simulations and at higher theory levels via MetaFEP indicate that the nucleophilic attack by the S160 hydroxyl group occurs more easily on PEF4 compared to PET4. provide an explanation to evidence from an atomistic perspective, we based on the principles of conceptual DFT. A first estimation of the overall chemical behaviors of the two substrates is given by the calculation of the global descriptors (𝜒, 𝜂, 𝜔) defined from the frontier molecular orbital energies (𝜖 1<=< , 𝜖 2>=< ) and reported in Table . This analysis predicts an electronegativity (𝜒) for PEF4 ≈ 1 eV higher than that of PET4, thereby suggesting higher attractivity towards electrons. On the other hand, a higher chemical hardness (𝜂) is found for PET4, indicative of lower polarizability and susceptibility to remodeling of its electron density. These two descriptors were used to estimate the global electrophilicity index (𝜔), which results ≈ 40% lower for PET4 (133.522 eV) compared to that found for PEF4 (217.073 eV).