Molecular Determinants for the Rate Acceleration in the Claisen Rearrangement Reaction

The Claisen rearrangement is a carbon-carbon bond-forming, pericyclic reaction
of fundamental importance due to its relevance in synthetic and mechanistic investi-
gations of organic and biological chemistry. Despite continued efforts, the molecular
origins of the rate acceleration in going from the aqueous phase into the protein is
still incompletely understood. In the present work the rearrangement reaction for
allyl-vinyl-ether (AVE), its dicarboxylated variant (AVE-(CO 2 ) 2 ) and the biologically
relevant substrate chorismate is investigated in gas phase, water and in chorismate
mutase. Only the rearrangement of chorismate in the enzyme shows a negative differ-
ential barrier when compared to the reaction in water, which leads to the experimen-
tally observed catalytic effect for the enzyme. The molecular origin of this effect is
the positioning of AVE-(CO 2 ) 2 and chorismate in the protein active site compared to
AVE. Furthermore, in going from AVE-(CO 2 ) 2 to chorismate entropic effects due to
1rigidification and ring formation are operative which lead to changes in the rate. Based
on ”More O’Ferrall-Jencks” diagrams it is confirmed that C-O bond breaking precedes
C-C bond formation in all cases. This effect becomes more pronounced in going from
the gas phase to the protein.