PATHWAYS FOR CONFORMATIONAL INTERCONVERSION OF CALIX[4]ARENES

Conformational optimization and reaction path calculations are performed on [1(4)]metacyclophane 3a and calix[4]arenes 1a and 2b using the CHARMM force field. For each of these compounds, a comprehensive search for all stable conformers was followed by an exhaustive exploration of the several hundred possible pathways between these conformers. The method employed for finding the reaction paths, Conjugate Peak Refinement, proved to be robust and reliable, allowing the connectivity of the complex potential energy surfaces to be charted. The relative stability of the four characteristic conformers agrees with experimental NMR data, except for the Cone form of 2b. The pathways for Cone inversion in [1(4)]metacyclophane 3a show no preference for a pathway via the 1,2Alt or the 1,3Alt conformers. The conformational entropy corrected energy barriers Delta E((conf))(not subset of) are 3.1 and 3.3 kcal/mol, respectively. For 1a, a stepwise pathway via the 1,2Alt conformer is found to be preferred for the Cone --> inverted-Cone conversion. The rate-limiting step is the transition from Cone to Paco, with a barrier of activation, Delta E(conf)(not subset of) = 14.5 kcal/mol, comparable to the experimental Delta H-double dagger = 14.2 kcal/mol. Conversion from the key Paco intermediate to the other characteristic conformers was investigated in detail in 2b. The Delta E(pot)(not subset of) values for the conversion from the most stable Paco to Cone, 1,2Alt, and 1,3Alt conformers are 19.6, 20.2, and 18.2 kcal/mol respectively, in qualitative agreement with the relative rates deduced from 2D EXSY NMR. Paths for the transition from inward to outward orientation of the methoxy moieties of 2b are calculated. The corresponding activation barriers for the rotation of a methoxy group are in the 6-8 kcal/mol range, consistent with the upper bound obtained from the NMR time scale.