Mechanistic Imperatives for the Reaction Catalyzed by Isopentenyl Pyrophosphate Isomerase: Free Energy Profile for Stepwise Isomerization in Water through a Tertiary Carbocation Intermediate

Rate and equilibrium constants are reported for the stepwise allylic 1,3-isomerization of 4-(4-methoxyphenyl)-2-methyl-1-butene (2) to give 4-(4-methoxyphenyl)-2-methyl-2-butene (3) in water through a simple tertiary carbocation intermediate1+, and the data are used to construct a free energy profile for the reaction. This profile shows that isopentenyl pyrophosphate isomerase stabilizes the carbocation-like transition state for the stepwise isomerization of simple alkenes by ca. 16 kcal/mol. The barriers for the deprotonation of the tertiary carbocation1+by solvent water are significantly smaller than those for the protonation of simple enolates by this solvent. This difference favors a concerted mechanism for the enzyme-catalyzed 1,3-isomerization of alkenes, which avoids the formation of a tertiary carbocation intermediate.