The role of the interfacial forces was emphasized in interactive processes, involving membrane surface and penetrating molecules. The surface character controlling the dissolution process of some species (CO2, H2O, C3H6O2, C4H8O2, C5H10O2) was evaluated in relation to the supra-molecular chemistry of membranes based on 80PTMO/PA12. Infrared analyses combined with the estimation of the hydrophilic and hydrophobic domains of the membrane surface yielded useful information about the distribution, availability and accessibility of the polar moieties responsible for the penetrant sorption. At the interface, attractive Lewis acid/base interactions such as H-bonding directed the sorption of vapor species into the membranes, whereas quadrupolar CO2 participated in specific Lifshitz-van der Waals interactions with the modified polymers. In both the cases, the presence of additional polar moieties such as carbonyl, sulfonamide, and hydroxyl groups enhanced the affinity of the Pebax-based membranes for the penetrating species considered in this work. As a result, the quantification of the reactivity of a membrane surface for specific molecules may allow predictive models to be constructed and selective membranes to be designed.