Electrophilic heteroaromatic substitutions: reactions of 5-X-substituted indoles with 4,6-dinitrobenzofuroxan

Abstract

The S_EAr substitutions of a number of 5-X-substituted indoles (1a–f), 5-X-substituted 2-methylindoles (1g–j) and N-methylindole (1k) by 4,6-dinitrobenzofuroxan (DNBF) have been kinetically studied in 70–30 (v/v) H₂O–Me₂SO, 50–50 (v/v) H₂O–Me₂SO, methanol and acetonitrile. The absence of a significant dependence of the rates of reactions on the hydrogen or deuterium labelling at C-3 of the indole ring indicates that electrophilic attack (k₁^DNBF)by DNBF at this position is the rate-limiting step of the substitutions. However, the k₁^DNBF rate constants are strongly sensitive to the solvent polarity, the observed reactivity sequence being 70–30 H₂O–Me₂SO > 50–50 H₂O–Me₂SO > methanol > acetonitrile. This trend is consistent with a highly dipolar transition state where the development of negative charge in the DNBF moiety is concomitant with that of a partial positive charge on the indole nitrogen. The finding of relatively large negative ρ values (–3.85) for the Hammett plots log k₁^DNBF=f(σ^_pX)supports this idea. An interesting result is that the effect of the X substituent on the rates (k₁^DNBF) is the same in the four solvents studied and does not depend upon the substitution at C-2 of the indole ring. However, the Bronsted or Hammett lines for the 5-X-2-methylindoles are located about 1.5 log k unit below those for the 5-X-indoles in a given solvent, showing that the 2-methyl group causes significant steric hindrance to the approach of DNBF from the adjacent C-3 position. Rates of protiodetritiation of a large number of [3-³H]indoles have also been measured in aqueous solution. The data define a unique Brönsted line (β_InH= 0.65), implying that the 2-substituents do not exert any steric effect on the rates of the exchange process and suggesting that the correlation can be used to estimate unknown pK_a values of indoles with a free 3-position. Comparison of the rates of coupling of indoles with 4,6-dinitrobenzofuroxan with similar data for coupling of these heterocycles with p-nitrobenzenediazonium cation reveals that, despite its neutral character, DNBF is the most electrophilic species. DNBF also appears to be a much stronger electrophile than the proton.