Fischer-S; Grootenhuis-PDJ; Groenen-LC; vanHoorn-WP; vanVeggel-FCJM;
Reinhoudt-DN; Karplus-M

JOURNAL-OF-THE-AMERICAN-CHEMICAL-SOCIETY. FEB 8 1995; 117 (5) : 1611-1620, 1995.

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.