Skraup quinoline synthesis template

Hot sulfuric acid dehydrates glycerol to acrolein. Aniline adds conjugately to protonated acrolein; the aldehyde is protonated and attacked by the ortho carbon of the ring (an intramolecular electrophilic substitution). Rearomatisation and loss of water give 1,2-dihydroquinoline, which nitrobenzene oxidises to quinoline.

Mechanism step by step

Aniline, glycerol, H₂SO₄ and an oxidant give quinoline

1. Acrolein – Hot H₂SO₄ removes two waters from glycerol
2. Conjugate addition – Aniline N adds to the β-carbon of protonated acrolein
3. Tautomerisation – Enol → aldehyde; the C=O is protonated
4. Ring closure – The ortho carbon attacks C=OH⁺ (SEAr), helped by the N lone pair
5. Rearomatisation, dehydration – Loss of H⁺ and H₂O gives 1,2-dihydroquinoline
6. Oxidation – Nitrobenzene removes two H (and is reduced, finally to aniline)

Key points

• Glycerol is the source of C-2, C-3 and C-4 (as acrolein made in the flask).
• Very exothermic and can run away: FeSO₄ moderates it; arsenic acid is an alternative oxidant.
• Doebner–Miller variant: an α,β-unsaturated aldehyde or ketone replaces glycerol to give substituted quinolines.
• meta-Substituted anilines give mixtures of 5- and 7-substituted quinolines.

Drawn with 161 atoms, 13 arrows, 8 shapes – every one editable in MolDraw.

Sources

• Kürti & Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier 2005, Skraup and Doebner–Miller quinoline synthesis Textbook
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012, ch. 30 Textbook