AbstractFunctionalization of the phenolic rim of p‐tert‐butylcalix[8]arene with phenanthroline to create a cavity leads to formation of two regioisomers. Substitution of positions 1 and 5 produces the known C2v‐symmetric regioisomer 1,5‐(2,9‐dimethyl‐1,10‐phenanthroyl)‐p‐tert‐butylcalix[8]arene (L1,5), while substitution of positions 1 and 4 produces the Cs‐symmetric regioisomer 1,4‐(2,9‐dimethyl‐1,10‐phenanthroyl)‐p‐tert‐butylcalix[8]arene (L1,4) described herein. [Cu(L1,4)I] was synthesized from L1,4 and CuI in good yield and characterized spectroscopically. To evaluate the effect of its cavity on catalysis, Ullmann‐type C−S coupling was chosen as proof‐of‐concept. Selected aryl halides were used, and the results compared with the previously reported Cu(I)/L1,5 system. Only highly activated aryl halides generate the C−S coupling product in moderate yields with the Cu(I)/L1,4 system. To shed light on these observations, detailed computational investigations were carried out, revealing the influence of the calix[8]arene macrocyclic morphology on the accessible conformations. The L1,4 regioisomer undergoes a deformation that does not occur with L1,5, resulting in an exposed catalytic center, presumably the cause of the low activity of the former system. The 1,4‐connectivity was confirmed in the solid‐state structure of the byproduct [Cu(L1,4−H)(CH3CN)2] that features Cu(I) coordinated inside a cleft defined by the macrocyclic framework.