ipso-Substitution Reaction in the Convergent Stepwise Synthesis of Calix[8]arene with Regioselectively Functionalized Upper Rim

The acid-catalyzed multi-step synthesis of calix[8]arene 1, which contains a regioselectively functionalized upper rim, has been investigated through the careful separation of the resulting by-products. A total of 11 types of cyclic and acyclic by-products were isolated and identified by spectral and microanalytical data. Semiempirical molecular-orbital calculations demonstrated that the synthetic process involves two types of reaction mechanism, one of which leads to the favorably constructed framework, while the other results in undesirable fragmentation reactions via ipso-substitution. A comparison of the theoretical predictions and the observed by-products revealed that steric hindrance, as well as the regioselectivity of the reaction, is also an important factor for determining the reaction pathway. A possible rationale is presented to explain the overall formation process leading to calix[8]arene 1 along with the by-products.