Ground State and Transition State Contributions to the Rates of Intramolecular and Enzymatic Reactions

reactions, rate enhancements of 108 M have been observed (Table 1).2 Intramolecular reactions where severe ground state strain is relieved upon formation of the transition state are known to be as large as 1016 M.3 Kirby4 has compiled a compendium of intramolecular reactions and has pointed out the relationship of rate to exothermicity. The importance of ground state conformations and the lack of translational entropy in intramolecular and enzymatic reactions have drawn attention from Menger5 and ourselves, while Jencks and Page6 have offered an explanation based on entropic driving forces stemming from the freezing out of motions and the dampening of vibrational frequencies in the transition state. Houk,7 in a scholarly study, has provided a correlation between rate constants for certain lactonization reactions and transition state stabilization. We provide here an account of our recent computational results8-10 dealing with the driving forces for enzymatic and intramolecular reactions. We introduce8 the term near attack conformation (NAC) to define the required conformation for juxtaposed reactants to enter a transition state (TS). The greater the mole fraction of reactant conformations that are present as NACs, the greater the rate constant. Rate constants for bond making and breaking in enzymatic reactions depend on, (i) the fraction of E‚S present as NACs, (ii) the change in solvation of reactant species within the NAC, as compared to water, and (iii) electrostatic forces11 which can stabilize the TS. The latter may include hydrogen bonds and metal ligation. Covalency in metal ligation and hydrogen bonding (low barrier hydrogen bonding12) most probably are introduced in the ground state. These features are best appreciated when ground state conformations and TS structures can be examined separately.

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