Enamine alkylation
Stork enamine alkylation
How the Stork enamine alkylation 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: Pyrrolidine, cat. TsOH, then R–X (or Michael acceptor), then H₃O⁺. Conditions: Toluene, Dean–Stark, then CH₃CN, reflux; aqueous acid. Bonds formed: C=C (enamine); new C–C; C=O regenerated; bonds broken: C=O; then C=N⁺. Stereochemistry: Less substituted enamine favoured; monoalkylation. Rate and selectivity: Alkylation (SN2) is rate-limiting; reactive halides (allylic, benzylic, α-halo carbonyl) work best.
At a glance
Step 1: Ketone + amine → enamine
A ketone condenses with a secondary amine (pyrrolidine is common) under acid with water removal, giving an enamine. The nitrogen lone pair conjugates into the C=C, so the enamine's β-carbon is nucleophilic — a neutral enolate equivalent that needs no strong base.
Step 2: β-Carbon attacks R–X (SN2)
The enamine's β-carbon attacks an alkyl halide (SN2), a Michael acceptor, or an acyl halide, forming a new C–C bond and an iminium ion. Because the enamine is only mildly basic, it avoids the polyalkylation and self-condensation that plague simple enolates.
Step 3: Hydrolysis returns the ketone
Aqueous acid hydrolyzes the iminium ion, returning the ketone and the amine. The net result is selective α-alkylation of a ketone under mild, essentially neutral conditions.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- X
- Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
- MeCN
- Acetonitrile. Polar aprotic solvent.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- TsOH
- p-Toluenesulfonic acid. Strong organic acid catalyst, soluble in organic solvents.
- SN2
- Bimolecular nucleophilic substitution. One concerted step with backside attack and inversion; rate = k[RX][Nu].
How it compares with related reactions
| Stork enamine alkylation | Delépine reaction | Meerwein's salt alkylation | |
|---|---|---|---|
| Reagents | Pyrrolidine, cat. TsOH, then R–X (or Michael acceptor), then H₃O⁺ | Hexamethylenetetramine (HMTA), then HCl/EtOH (or H₃O⁺) | Et₃O⁺ BF₄⁻ (Meerwein salt) |
| Conditions | Toluene, Dean–Stark, then CH₃CN, reflux; aqueous acid | CHCl₃ or EtOH, reflux; then ethanolic HCl | CH₂Cl₂, 0–25 °C, anhydrous |
| Stereochemistry | Less substituted enamine favoured; monoalkylation | Inversion at a stereogenic primary/benzylic carbon (SN2) | Inversion at carbon (SN2) — invisible for ethyl |
| Rate / selectivity | Alkylation (SN2) is rate-limiting; reactive halides (allylic, benzylic, α-halo carbonyl) work best | SN2 step rate-limiting; works for benzylic, allylic, α-halo carbonyls | Very fast; excellent leaving group (neutral ether) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Stork enamine alkylation?
Pyrrolidine, cat. TsOH, then R–X (or Michael acceptor), then H₃O⁺. Conditions: Toluene, Dean–Stark, then CH₃CN, reflux; aqueous acid.
Which bonds are formed and which are broken?
Formed: C=C (enamine); new C–C; C=O regenerated. Broken: C=O; then C=N⁺.
What is the stereochemical outcome?
Less substituted enamine favoured; monoalkylation
What controls the rate or the selectivity?
Alkylation (SN2) is rate-limiting; reactive halides (allylic, benzylic, α-halo carbonyl) work best
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go