However, this strategy is not adapted to symmetrical substrates bearing identical remote groups as the transformation of one group has little or no influence on the reactivity of the others. With such substrates, the control of the iteroselectivity, which is the selectivity that governs the number of repeating chemical transformations on a substrate bearing multiple identical reactive functions, remains a challenge. For example, attempts to monofunctionalize (with one equiv. of a reagent) symmetrical substrates displaying two identical and independent reactive groups classically lead to a statistical mixture of three products (iteromers) and isolating the desired monofunctionalized product can furthermore be complicated (Figure ). To overcome this problem, a classical trick consists in employing a large excess of the difunctional starting material to limit the formation of the difunctionalized product. This method can however only be applied to cheap difunctional substrates that can be easily separated from the monofunctionalized product. Recently, miscellaneous strategies based on supramolecular approaches have been reported for the iteroselective functionalization of polyfunctional substrates. For example, metal oxide particles, shadow masks and coordination chemistry 8 have been used to protect one or more functional groups of polyfunctional substrates. In this context, the use of macrocyclic molecular containers as supramolecular protecting units emerges as a promising strategy. The general concept relies on the protection of a functional group of a polyfunctional substrate through its binding in the cavity of a molecular receptor and the subsequent selective transformation of an accessible functional group (Figure ). To the best of our knowledge, the first example of such a host-mediated site-selective reaction was reported by the group of Reinaud in 2009. In this seminal work, a calix [6]arene-based zinc complex was used for the regio-and iteroselective mono-carbamoylation of N-(2-aminoethyl)-1,3-propanediamine with a 63% yield. More recently, the group of Rebek exploited the binding properties of resorcin [4]arene-based cavitands in water for the monofunctionalization of various symmetrical difunctional molecules. In all cases, the supramolecular protection ensured by the resorcinarene-based cavitands was driven by the hydrophobic effect. These systems were notably applied to the iteroselective radical reduction of alkyl dihalides (>95% yield), monohydrolysis of alkyl dibromides (up to 93% yield), monoepoxidation of dienes (up to 84% yield), selective reduction of diazides (>95% yield), and monohydrolysis of diesters (>90% yield). In 2021, Ballester and coworkers showed that super aryl-extended calix [4]pyrroles could be used as supramolecular protecting molecular containers for the selective monohydrolysis of bisisonitriles in water. Very recently, we described the unique binding properties of a hexahomotrioxacalix [3]arene based molecular container (Ox3). We showed that this host is able to accommodate primary ammonium ions (RNH3 + ) in its polyaromatic cavity with high binding constants (log Ka > 4 even in a protic environment) (Figure ). Secondary, tertiary and quaternary ammoniums are not recognized and the selective recognition process for primary ammoniums relies on a threepoint H-bonding complementarity between the ethereal macrocycle of Ox3 and the ammonium head of the guest. The free amine form (RNH2) is furthermore not recognized, enabling a control of the reversibility of the host-guest process through the addition of acids and bases. This molecular container, which can reversibly bind primary ammonium ions with high affinity and selectivity, offers a wonderful playground to explore new directions for the supramolecular protection strategy and widen its synthetic applications.