Requirements for Terpene Cyclizations inside the Supramolecular Resorcinarene Capsule: Bound Water and Its Protonation Determine the Catalytic Activity

The elucidation of the requirements
for efficient catalysis within
supramolecular host systems is an important prerequisite for developing
novel supramolecular catalysts. The resorcinarene hexamer has recently
been shown to be the first supramolecular catalyst to promote the
tail-to-head terpene cyclization in a biomimetic fashion. We herein
present the synthesis of a number of resorcinarene-based macrocycles
composed of different ratios of resorcinol and pyrogallol units capable
of self-assembly and compare the corresponding assemblies regarding
their catalytic activity in the cyclization of monoterpenes. The assemblies
were investigated in detail with respect to a number of properties
including the encapsulation of substrate and ion pairs, the structural
incorporation of water, and the response to externally added acid
(HCl). The results obtained strongly indicate that water incorporated
into the hydrogen-bond network of the self-assembled structure plays
an integral role for catalysis, effectively acting as a proton
shuttle to activate the encapsulated substrate. These findings
are also supported by molecular dynamics simulations, providing further
insight into the protonation pathway and the relative energies of
the intermediates involved.