Radical Substitution at Carbon in Heterocycles (a pocketful of key basic concepts)

Both electron-rich and electron-poor heterocyclic rings are susceptible to substitution of H by radicals. The electronic properties, which are a consequence of the interaction between the SOMO of the radical and either the HOMO or the LUMO of the substrate, depending on their relative energies, are key factors. In fact, the Radical Substitution at Carbon (RSC) is understood by classifying the radicals as nucleophilic or elecrophilic.

Nucleophilic radicals (e.g., ·CH2OH, ·alkyl and ·acyl) react with electron-poor heterocycles (and will not attack electron-rich systems), allowing electron density drift away from the radical to the electron-deficient heterocycle.

Electrophilic radicals (e.g., ·CF3, ·CH(CO2Et)2) would form stabilised anions on gaining an electron, therefore react readily with electron-rich systems.

Aryl radicals can show both types of reactivity at about the same rate.

The Minisci Reaction

The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing a C=N unit is a very spread synthetic tool. They react selectively at alfa and gamma to the nitrogen. Acidic conditions are essential since it enhances reactivity and also promotes regioselectivity. The Minisci methodology is particularly useful to introduce acyl groups (equivalent to the Friedel-Crafts, impossible under normal conditions for such systems).

Regarding to the Minisci reaction, it is worthy to have in mind the following tips:

1.- Tertiary radicals are more stable, and also have more nucleophilic character and then are more reactive than methyl radicals in Minisci reactions.

2.- Many times this reaction is carried out in aqueous or partially aqueous conditions.

3.- Several methods have been employed to generate the needed radical, most of them employing sulphuric acid and a peroxide or a peroxide derivative (oxidative path), or a mixture of an alkyl iodide with tris(trimethylsilyl)silane, or a carboxylic acid precursor for alkyl and acyl radicals via silver-catalysed peroxide oxidation, etc. (reductive path).

Doesn’t surprise that, when more than one reactive position is available in a heterocycle, there are regioselectivity or/and disubstitution issues to consider. Although regioselectivity is partially dependent on the nature of the attacking radical and solvent, it can be difficult to control.