**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.