We have reported that increasing the dihedral angle of bicyclic molecules by ortho-substitution leads to increased aqueous solubility, which is extremely important for drug candidates. Here, we investigated in detail the improvement of aqueous solubility of β-naphthoflavone analogs by means of this approach as candidate aryl hydrocarbon receptor (AhR) agonists. To confirm the contribution of molecular planarity disruption to the increased solubility, we compared the effect of ortho-substitution with that of meta-or para-substitution with the same substituent. We also compared the wavelengths of maximum UV absorption to evaluate molecular planarity in solution, and determined the X-ray crystal structures to assess molecular planarity and crystal packing. The results support the idea that disruption of molecular planarity by substituent-induced increase of the dihedral angle results in a decrease of the crystal packing energy and a lower melting point, with a consequent increase of solubility.