Liquid crystals (LCs) are widely used as promising stimuli-responsive materials due to their unique combination of liquid and crystalline properties, providing the capability to sense even molecular-scale events and amplify them into macroscopic optical outputs. However, encoding a high level of selectivity to a specific intermolecular event remains a key challenge, leading to prior studies regarding chemically functionalized LC interfaces. Herein, we propose an integrative strategy to significantly advance the design of chemo-responsive LCs through a deep fundamental understanding on the orientational coupling of LCs with new functional molecules, organic ionic plastic crystals (OIs), presented at LC interfaces. In combination with computational simulations and experimental validations, we reveal the correlative interplay between LCs and each functional group in OI (di-cationic headgroup, aliphatic tails, and counter anions) to offer an excellent degree of freedom in tailoring the chemo-responsive features in LCs. Especially, we find the crystalline nature of OIs to provide new insights into the effects of counter anions, generating distinct quadrupolar interactions with adjacent molecules. Overall, our results provide generalizable design principles for the chemo-responsive materials that can explicitly distinguish the specific intermolecular event such as molecular bindings of OIs with acetic acid from those with propionic acid (one carbon difference).