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 investigations 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-(CO2 )2 ) and the biologically relevant substrate chorismate is investigated in gas phase, water and in chorismate mutase. Comparing the reaction in water and the protein it is found that only for chorismate the differential barrier is negative, which leads to the experimentally observed catalytic effect of the enzyme. The molecular origins of these effects are the positioning of AVE-(CO2 )2 and chorismate in the protein active site compared to AVE which occupies a different conformational space in the active site pocket. Furthermore, in going from AVE-(CO2 )2 to chorismate entropic effects due to rigidification 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.