AbstractFluorinated chalcones are organic compounds with diverse biological activities and are of interest for drug development due to their improved properties, such as lipophilicity, bioavailability, and metabolic stability. Therefore, the correlation between structure and properties is fundamental to discover the potential use on pharmaceutical and technological applications. In this sense, we synthesized and characterized a novel fluorinated chalcone (E)-1-(4-fluorophenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (FCH), and compared its supramolecular arrangement and topological analysis with a chalcone (E)-1-(4-hydroxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (HCH). The molecular electrostatic potential, QTAIM, and frontier molecular orbitals of both chalcones were investigated using the M06-2X/6-311++G(d,p) level of theory. Our findings show that the FCH exhibits a herringbone packing with intermolecular interactions of C–H⋯F and C–H⋯π, while the HCH assumes a staircase packing coordinated by O–H⋯O and π⋯π intermolecular interactions. Furthermore, the electrostatic potential analysis shows that FCH is susceptible to electrophilic attack, while HCH is susceptible to nucleophilic attack. Finally, the structural basis analysis for both chalcones indicated that FCH has a higher lipophilicity than HCH due to the stronger hydrogen bond of HCH with water.