The mechanism of the enzyme- and antibody-catalyzed Claisen rearrangement of chorismate to prephenate was investigated experimentally on model compounds and by using quantum chemistry calculations at the Becke3LYP/6-31G* level of theory. Conformational restriction of the allyl vinyl ether fragment to the reactive chairlike conformation in 1 induces a 2 x 10(5)-fold rate acceleration (Delta Delta G(double dagger) = 7.3 kcal/mol) of the Claisen rearrangement in C6D6 relative to an unrestricted analogue 3. A direct relationship between activation barrier lowering and the distance between reactive termini has been observed in additional model systems. Compression of the reactive centers from 4.0 to 3.0 Angstrom results in a barrier lowering from 24 kcal/mol to 12 kcal/mol in one conformationally restricted model. Further compression reduces the activation barrier to a mere 4 kcal/mol. Rearrangement rate increases via conformational restriction and reactive center compression derive mainly from ground-state destabilization in which entropic factors do not contribute significantly. The chorismate mutase mechanism is rationalized as a series of three steps involving (1) capture of the unstable pseudo-diaxial conformer of chorismate in a chairlike geometry (<3 kcal/mol contribution to barrier lowering); (2) further confinement of the reacting termini with a potential for >10 kcal/mol barrier reduction; and (3) rearrangement accompanied by additional transition-state stabilization from ionic I-I-bonding at the ether oxygen. Since the total barrier lowering is greater than that required to account for the observed 3 x 10(6)-fold enzymatic catalysis, the rearrangement itself is probably not the rate-determining step. The major contribution to catalysis could, in principle, come from confining the reactive centers to contact distances, a conclusion consistent with the spatiotemporal precept.