Química Orgánica 2 · Enolatos: alquilación, condensaciones y adiciones conjugadas
3-(2-Oxocyclohexyl)propanenitrile by Stork enamine Michael addition
Condiciones: pyrrolidine, TsOH (cat.), −H2O; then acrylonitrile; then H3O⁺
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El mecanismo, paso a paso
Siguiente reproduce las flechas curvas de cada paso y las explica. Los pasos escritos están abajo.
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TsOH protonates the ketone
The catalytic acid protonates the carbonyl oxygen, making the carbonyl carbon a much better electrophile for the neutral amine.
Las flechas curvas
- The carbonyl oxygen lone pair takes the acid proton.
- The O–H electrons stay on the sulfonate.
Pyrrolidine adds to the carbonyl carbon
The nitrogen lone pair of the secondary amine attacks the activated carbonyl carbon; the C=O π electrons move onto oxygen, giving a neutral OH.
Las flechas curvas
- The nitrogen lone pair forms the new C–N bond.
- The C=O π electrons move onto oxygen.
The ammonium loses its proton
A second molecule of pyrrolidine (used in excess) removes the proton from the positive nitrogen, giving the neutral carbinolamine.
Las flechas curvas
- The nitrogen lone pair of a second pyrrolidine (excess amine) takes the N–H proton.
- The N–H electrons return to nitrogen.
Protonate the OH
TsOH protonates the hydroxyl so that it can leave as water.
Las flechas curvas
- The hydroxyl oxygen lone pair takes the acid proton.
- The O–H electrons stay on the sulfonate.
Water leaves, pushed by nitrogen
The nitrogen lone pair forms a C=N π bond as water departs, giving an iminium ion.
Las flechas curvas
- The nitrogen lone pair forms the C=N π bond.
- The C–O electrons leave with water.
Lose an α-proton to give the enamine
The iminium nitrogen has no N–H to lose, so another pyrrolidine molecule removes an α-hydrogen instead; the electrons form the C=C bond of the enamine and nitrogen becomes neutral.
Las flechas curvas
- A pyrrolidine nitrogen takes an α-proton.
- The C–H electrons form the C=C π bond.
- The C=N π electrons move onto nitrogen.
Why an enamine?
The enamine is a neutral, enolate-like nucleophile at the α-carbon.
Michael addition to acrylonitrile
The enamine’s nucleophilic α-carbon adds to the β-carbon of acrylonitrile while the nitrogen lone pair forms the C=N+ bond; the C=C π pair moves onto the α-carbon of the nitrile, giving a stabilized carbanion.
Las flechas curvas
- The nitrogen lone pair pushes into the ring C=C, making the α-carbon nucleophilic.
- The enamine C=C π pair forms the new C–C bond to the β-carbon of acrylonitrile.
- The acrylonitrile C=C π pair moves onto the carbon next to the nitrile.
Pyrrolidinium protonates the carbanion
The nitrile-stabilized carbanion takes a proton from a pyrrolidinium ion (the acid formed earlier), giving the neutral nitrile chain and leaving the iminium ion ready for hydrolysis.
Las flechas curvas
- The carbanion lone pair takes the N–H proton.
- The N–H pair stays on nitrogen, giving pyrrolidine.
Water adds to the iminium ion
In the aqueous acid workup, water attacks the iminium carbon and the C=N π electrons move onto nitrogen.
Las flechas curvas
- A water lone pair forms the new C–O bond.
- The C=N π electrons move onto nitrogen.
Water removes a proton from the oxonium
The added oxygen carries a positive charge; a water molecule removes one of its protons.
Las flechas curvas
- A water lone pair takes the O–H proton.
- The O–H electrons stay on oxygen.
Protonate the nitrogen
Hydronium protonates the nitrogen so that pyrrolidine can leave as a neutral amine.
Las flechas curvas
- The nitrogen lone pair takes the proton from hydronium.
- The O–H electrons stay on water.
Oxygen pushes out pyrrolidine
The OH lone pair forms a C=O π bond and expels the neutral amine, giving the protonated ketone.
Las flechas curvas
- An oxygen lone pair forms the C=O π bond.
- The C–N electrons leave with the amine nitrogen.
Deprotonate the ketone oxygen
Water removes the proton from the protonated carbonyl, releasing 3-(2-oxocyclohexyl)propanenitrile and regenerating hydronium.
Las flechas curvas
- A water lone pair takes the proton.
- The O–H electrons stay on the carbonyl oxygen.
3-(2-Oxocyclohexyl)propanenitrile
One 2-cyanoethyl group has been added at the α-carbon; the new stereocentre is racemic. Pyrrolidine is released (as its ammonium salt in the acidic workup) and the ketone oxygen now comes from the workup water.
Qué vas a practicar
Draw pyrrolidine enamine formation from cyclohexanone, conjugate addition of the enamine to acrylonitrile, protonation of the nitrile-stabilized carbanion, and hydrolysis of the iminium ion.
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