Understanding of aqueous solutions is of significance to a wide range of fields. Crown macrocycles emerge as a new generation of model hosts for studying the chemistry of water and aqueous supramolecular chemistry. Herein, we present the oxacrown ether cyanobenzo-21-crown-7 ether (C7CN), and its selenium-containing counterpart selencrown ether C7SeCN possess only one chalcogen atom diverse in structure but exhibits dramatic difference in shape, solvation (e.g., hydration), and consequent thermodynamics of guest binding experimentally. The hydrogen bond strength of Se center dot center dot center dot H is similar to that of O center dot center dot center dot H, but theoretical calculations pointed out that there is a prominent electrostatic potential change for the entire molecule caused by Se substitution, which leads to the decrease of the interactions between water clusters and crown macrocycles thermodynamically and kinetically. Results established that C7CN and C7SeCN provide an easy-to-access model pair to exclusively probe water-solute interaction and host pocket wettability change caused by one atom substitution.