We report binding studies of an octa‐pyridinium super aryl‐extended calix[4]pyrrole receptor with neutral difunctional aliphatic guests in water. The guests have terminal isonitrile and formamide groups, and the complexes display an inclusion binding geometry and 1:1 stoichiometry. Using 1H NMR titrations and ITC experiments, we characterized the dissimilar thermodynamic and kinetic properties of the complexes. The bis‐isonitriles possess independent reacting groups, however, in the presence of 1 equiv. of the receptor the hydrolysis reaction produces mixtures of non‐statistical composition and a significant decrease in reaction rates. The selectivity for the mono‐formamide product is specially enhanced in the case of the bis‐isonitrile having a spacer with five methylene groups. The analysis of the kinetic data suggests that the observed modifications in reaction rates and selectivity are related to the formation of highly stable inclusion complexes in which the isonitrile is hidden from bulk water molecules. The concentration of the reacting substrates in the bulk solution is substantially reduced by binding to the receptor. In turn, the hydrolysis rates of the isonitrile groups for the bound substrates are slower than in the bulk solution. The receptor acts as both a sequestering and supramolecular protecting group.