DFT-based analysis on the effect of polar substituents functionalization on the aqueous solvation of calix[4]arenes

Abstract This study examines the effect of functionalizing the upper rim of calix[4]arene in cone conformation with polar substituents (–NH 2 , –SO 3 H, and –COOH) to enhance its solvation in aqueous media, using density functional theory (DFT) at the B3LYP-D3/6-311++G(d,p) level of theory. Incorporating implicit solvent effects via the Solvation Model based on Density (SMD) showed that polar functionalization improves aqueous compatibility. The sulfonated derivative (–SO 3 H) showed the most negative solvation free energy among the studied systems (Δ G ₛₒₗᵥ) of −68.67 kcal/mol and the largest dipole moment of 21.97 D, together with the largest MEP-derived polar surface (80.31%). The ammonium ion (NH 4 + ) was used as a test system to analyze the molecular recognition properties of the functionalized calixarenes. It was observed that although the –SO 3 H derivative exhibited the strongest interaction energy in the gas phase (− 63.18 kcal/mol), the –NH 2 -functionalized complex exhibited the most favorable interaction energy (− 7.32 kcal/mol). The non-covalent interaction (NCI/RDG) and Quantum Theory of Atoms in Molecules (QTAIM) analyses show that in the CX[4]-NH 2 ···NH 4 + complex, the N–H···O contact at the lower rim is accompanied by the most favorable calculated interaction energy in the continuum. In the CX[4]-SO 3 H···NH 4 + complex, three N–H···O contacts at the upper rim, with the largest local hydrogen-bond energies, are found, although dielectric screening strongly reduces the interaction energy in water. N–H···O interactions in the upper rim, with the highest interaction local energies for hydrogen bonds, increase the surface area for the host−guest molecular recognition in the CX[4]- SO 3 H−NH 4 + complex. The results provide a first electronic-structure basis for guiding the future design of water-compatible macrocycles with defined molecular recognition properties.