ACID-CATALYZED ISOTOPE EXCHANGE OF RING HYDROGENS IN FLUOROIMIDAZOLES

Acid-catalyzed exchange of ring protons in 1-methylimidazole is known to occur (in D20) by electrophilic attack on the imidazolium ion (E pathway). Significant reaction rates are observed only at high temperatures and in moderately strong acid media; relative reactivities at 163 °C and 1 N DC1 are H-2 (1), H-5 (30), and H-4 (50). An alternative mechanism (E'), involving electrophilic attack at C-4 or C-5 in the neutral molecule, has now been demonstrated for imidazoles which have low pK values and which have one or two substituents capable of stabilizing a carbonium ion. Exchange by the E' pathway occurs far more readily than E exchange; thus, in 0.1-3 N DC1 at 50 °C, t1/2 ≃ 9 h for 4-fluoro-2-methyl-, 12 h for 4-fluoro-l-methyl, 16 h for 2-fluoro-4-methyl-, and 54 h for 4-fluoroimidazole. Under these conditions, no exchange is observed at C-2. For exchange of H-4 in 1-methylimidazole (50 °C, 1 N DC1) the estimated t1/2 ≃ 84 years. To date, fluorine has been found the only common substituent capable of providing the necessary combination of electronegativity and resonance overlap to permit facile exchange by the E' pathway. © 1979, American Chemical Society. All rights reserved.