For 2,4,6-trisubstituted 1,3,5-trimethoxycalixarenes 1, two competing interconversion pathways have been postulated in the literature for the Cone/1,2,3Alternate exchange, viz the “tert-butyl through the annulus” and “lower rim through the annulus” pathways. Both pathways were compared with molecular modeling with the conjugate peak refinement method. One variable-size atom (Sx) was introduced to represent the lower-rim substituents R, abstracting the “O−CH2−rigid group” motifs to one “O−CH2−Sx” group. Both the postulated mechanisms of Cone → 1,2,3Alternate isomerization are plausible. For large lower-rim substituents (Sx ≥ ≈6 Å), the “tert-butyl through the annulus” mechanism is preferred over the “Sx through the annulus” mechanism. The calculated upper free energy barrier for the isomerization process is 17.5 kcal mol-1, reasonably close to the experimental value of approximately 21 kcal mol-1 (van Duynhoven et al. J. Am. Chem. Soc.1994, 116, 5814).
van Hoorn, W. P., van Veggel, F. C. J. M., & Reinhoudt, D. N. (1998). Conformational isomerism of 2,4,6-substituted 1,3,5-trimethoxycalixarenes. Journal of physical chemistry A, 102(33), 6676-6681. https://doi.org/10.1021/jp981201g