This paper investigates pseudo-polymorphism in 2-pyridylmethoxy derivatives of p-tert-butylcalix[4]arene (PyC4), p-tert-butyldihomooxa-calix[4]arenes (PyHOC4), and p-tert-butylhexahomotrioxacalix[3]arenes (PyHO3C3), presenting 11 crystal structures with 15 crystallographically independent molecules. The macrocycle of PyC4 is smaller and less flexible with respect to those of PyHOC4 and PyHO3C3, and in solution, the cone conformation of these three molecules exhibits different point symmetries: C4, Cs, and C3, respectively. A correlation is observed between the macrocycle’s structural rigidity and the number of pseudo-polymorphs formed. The more rigid PyC4 displays a higher number (six) of pseudo-polymorphs compared to PyHOC4 and PyHO3C3, which exhibit a smaller number of crystalline forms (three and two, respectively). The X-ray structures obtained show that the conformation of the macrorings is primarily influenced by the presence of an acetonitrile guest molecule within the cavity, with limited impact from crystal packing and intermolecular co-crystallized solvent molecules. Notably, both calix[4]arene derivatives produce a host–guest complex with acetonitrile, while the most flexible and less aromatic PyHO3C3 does not give crystals with acetonitrile as the guest. Intertwined 1D and 2D solvent channel networks were observed in the PyHOC4-hexane and in the PyHO3C3-H2O-MeOH crystal structures, respectively, while the other pseudopolymorphs of PyHOC4 and PyHO3C3 and all PyC4 crystal forms exhibit closely packed crystal structures without open channels.
