Alkanediyl Bridged Calix[4]arenes:  Synthesis, Conformational Analysis, and Rotational Barriers

In calix[4]arenes when one methylene bridge carries an alkyl or aryl substituent, two diastereomeric cone conformations are possible in which this substituent assumes the equatorial or axial position. Two diastereomers with cis or trans arrangement of the substituents exist for the corresponding compounds with two substituted bridges, and diastereomeric cone conformations have to be considered additionally in most cases. Molecular mechanics calculations predict an energetical preference of the equatorial position of the substituents in both systems. This preference is markedly more pronounced for alkyl groups than for aryl groups. To test these predictions a series of calix[4]arenes in which one (4) or two opposite (5) methylene bridges are substituted by alkyl or aryl groups was synthesized by fragment condensation. For these calixarenes the solution conformations, the equatorial/axial conformational equilibria, and the energy barriers for the cone to cone ring inversion were determined by ¹H NMR spectroscopy. The experimental energy differences between the two cone conformations correlate well with the calculated ones. Free energies of activation ΔG^⧧ for the cone to cone ring inversion of the monoalkyl substituted compounds 4 increase in the order methyl < tert-butyl < ethyl < isopropyl. For the bisalkyl substituted compounds (5b−d) only the cis-isomer could be isolated while cis- and trans-isomers were obtained for 5a and for the bisaryl compounds 5e−g. Among the cis-isomers 5a−d exist exclusively as the equatorial conformers, while the conformational equilibrium is strongly solvent dependent for 5e−g. Single crystal X-ray structures were obtained for several calixarenes with one (4b) or two substituted bridges (5e−g). Here the substituents are found exclusively in the equatorial position, and the molecular conformation is similar to the calculated one.