An unusual parabolic dependence of rate on acidity in the fischer indole reaction

Over the H0 acidity range from + 2 to −8, four different mechanistic variations occur in the Fischer indole reaction, leading to an unusual parabolic dependence of the rate constants on the acidity of the medium. In strongly acidic media kinetic isotope effects indicate that the rate‐determining step is deprotonation to form the ene–hydrazine tautomer, whereas in weakly acidic media the tautomerization is so rapid that [3,3]‐rearrangement becomes rate limiting. At an intermediate acidity, the deprotonation is rate determining, with the rate being strongly dependent on the concentration of the anionic counter ion.