This study provides strong evidence that lone pair interactions dominate over aromaticity in binding to
metal oxide surfaces, in sharp contrast to their behaviour on pure metal surfaces. Our earlier work
showed that lone pairs and aromatic groups act synergistically in organic molecules interacting with metal
surfaces. Here, we demonstrate that on metal oxides, the situation is reversed: lone pair interactions are
significantly stronger than those of aromatic bonds, and when both are present, aromatic groups actually
reduce the overall interaction strength. This finding highlights a fundamental shift in binding mechanisms
when moving from metals to metal oxides. Fluorescence spectroscopy and dynamic light scattering (DLS)
consistently confirm this trend, also revealing a rare correlation between the two techniques. To probe
these effects, we studied four isoxazole derivatives containing lone pair and aromatic functionalities on
zinc oxide nanoparticles as a representative metal oxide surface. The results show that variations in functional
groups do not significantly alter binding as long as lone pairs are present, indicating that the lone
pair itself, rather than the attached group, is the key determinant of interaction. This challenges the conventional
strategy of optimizing functional groups for surface binding and instead emphasizes the primary
role of electronic properties. Such insights open new opportunities for the rational design of molecules
that can interact more effectively with metal oxides, with implications for catalysis, sensors, corrosion resistance,
and environmental applications. The novelty of this work also lies in combining experimental and
computational approaches. Binding of isoxazoles with ZnO nanoparticles was also validated through
density functional theory (DFT) calculations, including frontier molecular orbital (FMO), non-covalent
interaction (NCI), and density of states (DOS) analyses. These computational results confirmed the dominant
role of lone pairs and supported the experimental findings. Overall, this study advances the fundamental
understanding of molecular adsorption on metal oxide surfaces. By revealing that lone pair–Zn2+
interactions outweigh π-conjugated systems and that aromatic groups may even hinder binding, it provides
crucial guidance for tailoring surface-active molecules. This dual experimental–computational
approach establishes a framework for designing next-generation functional materials.