Heterocycle synthesis — quinoline
Skraup synthesis
How the Skraup synthesis works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Aniline, glycerol, conc. H₂SO₄, PhNO₂ (oxidant), FeSO₄ (moderator). Conditions: Neat, 140–180 °C (exothermic). Bonds formed: C–N; C–C (ring); aromatic pyridine ring; bonds broken: C–OH (glycerol); C=O; 2 C–H (oxidation). Stereochemistry: None; achiral aromatic product. Rate and selectivity: Cyclization/dehydration limits; reaction can be violent without FeSO₄.
At a glance
Step 1: Acrolein forms, aniline adds
Glycerol dehydrates under hot sulfuric acid to form acrolein in situ, which an aniline nitrogen then attacks in a Michael-type conjugate addition.
Step 2: Friedel–Crafts cyclization, dehydration
Acid-catalyzed cyclization closes the new ring by the same intramolecular Friedel-Crafts-type logic seen in the Pictet-Spengler reaction — the aromatic ring's π electrons attack an activated carbon tethered nearby.
Step 3: Oxidation aromatizes to quinoline
Oxidation (often by a mild oxidant like nitrobenzene, added deliberately to accept the hydrogens) aromatizes the new ring, giving quinoline — a classic, if harsh, route to this pharmaceutically important heterocycle.
Abbreviations and terms
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- H2SO4
- Sulfuric acid. Strong acid and dehydrating agent.
- Δ
- Heat. Reaction is run at elevated temperature.
How it compares with related reactions
| Skraup synthesis | Combes quinoline synthesis | Doebner-Miller reaction | |
|---|---|---|---|
| Reagents | Aniline, glycerol, conc. H₂SO₄, PhNO₂ (oxidant), FeSO₄ (moderator) | Aniline, 1,3-diketone (acetylacetone); then H₂SO₄ (or PPA) | Aniline, crotonaldehyde (an α,β-unsaturated aldehyde), HCl or Lewis acid, oxidant |
| Conditions | Neat, 140–180 °C (exothermic) | Condensation 25–100 °C; cyclisation in conc. acid, heat | Aqueous HCl, reflux |
| Stereochemistry | None; achiral aromatic product | None; Z-enaminone is H-bond stabilised | None; 2-methylquinoline is achiral |
| Rate / selectivity | Cyclization/dehydration limits; reaction can be violent without FeSO₄ | Ring closure onto the protonated ketone is rate-determining | Conjugate addition reversible; cyclization/dehydration rate-limiting |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Skraup synthesis?
Aniline, glycerol, conc. H₂SO₄, PhNO₂ (oxidant), FeSO₄ (moderator). Conditions: Neat, 140–180 °C (exothermic).
Which bonds are formed and which are broken?
Formed: C–N; C–C (ring); aromatic pyridine ring. Broken: C–OH (glycerol); C=O; 2 C–H (oxidation).
What is the stereochemical outcome?
None; achiral aromatic product
What controls the rate or the selectivity?
Cyclization/dehydration limits; reaction can be violent without FeSO₄
Study guides that help with this reaction
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go
- How to answer mechanism questions in an exam