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Issue 11, 1975
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The mechanism of diazo-coupling to indoles and the effect of steric hindrance on the rate-limiting step


The first syntheses of 4-methyl-2-t-butyl- and 2 methyl-4,6-di-t-butyl-indole are described. Rates of diazo-coupling at the 3-position of both these compounds together with those for 2-methyl- and 2-t-butyl-indole are reported for various para-substituted arenediazonium ions in mixed aqueous and some aprotic solvents at 25°. The kinetic behaviour of 2-methylindole is examined in detail and it is shown that 3-coupling may proceed through either the neutral compound or the 2-methylindolyl anion depending on the pH, with the anion being ca. 108-fold more reactive. For neutral 2-methylindole coupling, rates increase with increasing reactivity of the diazonium ion giving p 3.3 for the Hammett (ρσ+) plot, and for coupling with p-toluenediazonium ion ΔH= 38 kJ mol–1 and ΔS= 138 J K–1 mol–1. Kinetic isotope effects for coupling to [3-2H1]- and [3-3H1]-2-methylindole and 3-deuteriated 2-t-butyl-and 4-methyl-2-t-butyl-indole are not apparent in aqueous dioxan. Coupling to 2-methyl-4,6-di-t-butylindole is also shown to proceed via both the neutral substrate and its conjugate base, but these reactions show significant primary hydrogne isotope effects (KH/KDca. 7). The results are interpreted in terms of a classical ASE2 mechanism for both neutral indoles and indolyl anions in which direct electrophilic attack by the arene diazonium ion at the 3-position is normally rate limiting. The change in the rate limiting step observed for the ASE2 mechanism with 2-methyl-4,6-di-t-butylindole is attributed to steric hindrance acting only on proton explusion in a very reactant-like transition state and not on attack of the electrophilic diazonium ion. There is no evidence for coupling to indole nitrogen and triazene intermediates are therefore not significant in any of these reactions.

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Article type: Paper
DOI: 10.1039/P29750001209
Citation: J. Chem. Soc., Perkin Trans. 2, 1975,0, 1209-1217

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    The mechanism of diazo-coupling to indoles and the effect of steric hindrance on the rate-limiting step

    B. C. Challis and H. S. Rzepa, J. Chem. Soc., Perkin Trans. 2, 1975, 0, 1209
    DOI: 10.1039/P29750001209

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