Mechanistic Studies of the Fischer Indole Reaction

Article abstract of DOI:10.1021/jo00053a041

Kinetic and solvent isotope effects were measured for the Fischer indole reactions of four hydrazones.Under neat acid conditions (5percent P2O5/MeSO3H) the KIE's ranged from 3.2 to 5.8, while the solvent isotope effects (k_H/k_D) ranged from 0.4 to 0.7.Under dilute acid conditions in sulfolane solvent, both isotope effects were near unity.The large kinetic isotope effect and large inverse solvent isotope effect, along with the observation that isotopic exchange occurs in the aromatic ring of the hydrazones, suggest that a preequilibrium protonation of the aromatic ring occurs followed by the rate-determining ene-hydrazine formation under the neat acid conditions.In contrast, under the dilute acid conditions, the lack of isotope effects and the lack of ring isotope exchange indicate that no ring protonation is occurring, that ene-hydrazine formation is no longer rate-determining, and that the rate-limiting step is now most likely the <3,3> rearrangement.