Q3(b). Skraup synthesis of 8-methylquinoline; Fries rearrangement

Introduction. (i) The Skraup synthesis builds the pyridine ring of quinoline onto an aniline from glycerol. (ii) The Fries rearrangement moves the acyl group of a phenyl ester to the ring (ortho and para) under a Lewis acid.

(i) Skraup synthesis of 8-methylquinoline

Heat o-toluidine with glycerol, concentrated H₂SO₄ and a mild oxidant (o-nitrotoluene, nitrobenzene or arsenic pentoxide; FeSO₄ moderates the vigorous reaction).

1. H₂SO₄ dehydrates glycerol (-2H₂O) to acrolein, CH₂=CH-CHO.
2. Conjugate (aza-Michael) addition of the NH₂ group to acrolein: 3-(2-methylanilino)propanal.
3. Acid-catalysed cyclisation: the protonated C=O attacks the ring carbon ortho to N (electrophilic substitution); only one ortho position is open, because the other carries CH₃. Loss of H₂O gives 8-methyl-1,2-dihydroquinoline.
4. Oxidation (dehydrogenation) by the nitro compound gives the aromatic 8-methylquinoline.

Scheme: Skraup synthesis (acrolein formed in situ from glycerol).

(ii) Fries rearrangement

Example: phenyl acetate with AlCl₃ gives 2-hydroxyacetophenone (favoured above about 160°C) and 4-hydroxyacetophenone (favoured at low temperature, below about 60°C).

Scheme: AlCl₃ complexes the ester oxygen; the acylium ion is released.

1. AlCl₃ coordinates the carbonyl (or phenolic) O; the O–acyl bond breaks to give an acylium ion CH₃C#O⁺ and an aluminium phenoxide.
2. The acylium ion attacks the activated ring (SEAr) at ortho or para.
3. Evidence for an intermolecular path: in crossover experiments a mixture of two different esters (e.g. phenyl benzoate and p-cresyl acetate) gives crossed products; an added reactive arene (anisole, m-cresol) is also acylated. The acyl group must therefore be loose in solution for part of the time.
4. Evidence for an intramolecular component: the proportion of crossover is often small for the ortho product, and the ortho/para ratio depends on solvent and temperature; this is explained by an ion pair (acylium and phenoxide held together) that delivers the acyl group to the nearby ortho carbon.
5. The photo-Fries reaction goes by homolysis to a radical pair inside a solvent cage and is mainly intramolecular.

Conclusion. (i) o-Toluidine + glycerol + H₂SO₄ + oxidant (Skraup): Michael addition, cyclisation, dehydration and oxidation give 8-methylquinoline. (ii) The Lewis-acid Fries rearrangement is largely intermolecular (crossover products, acylation of an added arene) through a separated acylium ion; the ortho product is formed partly intramolecularly within an ion pair.

Application. The Skraup reaction is used to make quinoline antimalarial intermediates (6-methoxy-8-nitroquinoline for primaquine); the Fries rearrangement gives hydroxyaryl ketones used for the analgesic paracetamol precursor and for UV absorbers.