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Wednesday 03rd September 2014 00:39
 
  The Knoevenagel Condensation

The reaction of active methylene compounds with ketones or aldehydes in the presence of a weak base to afford α,-unsaturated dicarbonyl or related compounds is known as the Knovenagel condensation . The reaction is named after Emil Knoevenagel who first reported this reaction in 1894.

The reaction is a base-catalysed aldol condensation; be sure to read the aldol reaction page for information pertaining to control and isomeric considerations.

The Knoevenagel condensation employs a weak amine base. The use of a tertiary amine follows a slightly different reaction pathway than that of a primary or secondary amine. Both mechanisms are shown below.

1. General Scheme  

Scheme K1: The Knoevenagel condensation


 
2. Mechanism (tertiary amine)

The first step of the mechanism is the formation of the enolate by removal of an acid hydrogen by base.
 



Scheme K2: Formation of the enolate


 
The carbanion attacks the slightly positive carbon on the ketone or aldehyde, and the carbonyl oxygen recaptures the original proton which was extracted in the formation of the enolate. The lone pair on the new hydroxyl group removes the hydrogen on the α-carbon. The α-carbon then donates its lone pair to form a double bond, and water is eliminated. This is exactly the same as the standard base catalysed aldol condensation.
 

Scheme K3: Knoevenagel reaction to afford a α,-unsaturated dicarbonyl compound


 
3. Mechanism (primary or secondary amine)

In this mechanism the base reacts with both reagents to form an enolate of the dicarbonyl reagent and an immine salt of the ketone or aldehyde. Let us start with the familiar formation of the enolate

 

Scheme K4: Enolate formation using a secondary amine


 
The formation of the iminium salt of the ketone or aldehyde is a simple condensation reaction whereby the C=O bond is replaced by a C=N to a quaternary nitrogen. This bond is weak and this iminium salt is readily reacted with the enolate.
 


Scheme K5: Iminium salt formation of the ketone of aldehyde


 
The formation of the iminium salt of the aldehyde or ketone happens simultaneously to the enolate formation, if the reaction is performed one-pot. As the base is regenerated in this reaction, there is no need to use two equivalents of base.

The final phase of this reaction is the same as the final step using the tertiary amine, except the amine base is the leaving group instead of water.

 

Scheme K6: Condensation of the preformed iminium salt and enolate


 
This reaction results in N-R2 and H2N+R2. The hydrogen deficient base will abstract a hydrogen from the base with the surplus hydrogen, to regenerate two molecules of the starting base.


 
4. Reaction Notes

 
  • Aldehydes react much faster than ketones.
  • The choice of solvent is critical; using polar aprotic solvents is advantageous (e.g. DMF, MeCN).
  • As with other condensation reactions, removal of the eliminated water in situ (e.g. using molecular sieves) will drive the equilibrium towards the product.
  • Mixed geometric isomers are resultant if R1, R2, R3, and R4 are different.
  • Usually the thermodynamically stable product is dominant.

 

 
5. Further Reading

 
Clayden, Greeves, Warren and Wothers; Organic Chemistry, 1st edn., 702-703.
(Oxford University Press, 1991)


Sykes; A Guidebook to Mechanisms in Organic Chemistry, 6th edn., 228-228.
(Longman Scientific & Technical, 1986)

 
Krti and Czak; Strategic Applications of Named Reactions in Organic Synthesis. 1st edn., 242-243.
(Elsevier Academic Press, 2005)
 

March and Smith; March's Advanced Organic Chemistry, Reactions, Mechanisms and Structure. 5th edn., 1225-1228.
(John Wiley & Sons, 2001)

 
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