In 1894, E. Knoevenagel discovered a catalytic reaction involving the condensation of diethyl malonate with formaldehyde, producing a bis adduct. He observed similar results when other aldehydes were condensed with ethyl benzoyl acetate or acetylacetone in the presence of primary or secondary amines. This reaction was named Knoevenagel condensation.
Knoevenagel Condensation
The Knoevenagel condensation involves the nucleophilic addition of an activated methylene compound to an aldehyde or ketone, catalyzed by an amine base.
This is followed by dehydration, leading to the formation of α,β-unsaturated carbonyl compounds (enones). Similar to the Aldol reaction, the Knoevenagel reaction is used for C=C bond formation in organic chemistry.
The activated methylene compound has a structure of Z-CH2-Z, where Z is an electron-withdrawing group.
The overall reaction sums up to be:
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Reaction Steps:
The main characteristics of the Knoevenagel condensation are as follows:
1. Reactant Preferences: Aldehydes vs. Ketones
Aldehydes react more rapidly than ketones in this reaction.
2. Active Methylene Compounds: Key Players in the Reaction
Compounds with two electron-withdrawing groups, like malonic esters, acetoacetic esters, malonodinitrile, and acetylacetone, are used as active methylene compounds.
3. Catalysts
Primary, secondary, and tertiary amines, along with their ammonium salts, Lewis acids combined with tertiary amines, and certain inorganic compounds like potassium fluoride or aluminum phosphate, serve as catalysts.
4. By-Product and Equilibrium
Water is produced as a by-product, and removing it from the reaction mixture (e.g., via azeotropic distillation or molecular sieves) helps drive the equilibrium toward product formation.
5. Choice of Solvent
Dipolar aprotic solvents (e.g., DMF) are preferred, as protic solvents hinder the final elimination step.
6. Product Transformation
The dicarbonyl product can undergo hydrolysis and decarboxylation to form α, β-unsaturated carbonyl compounds.
7. Isomer Formation
When different substituents are present in specific positions, the product may exist as a mixture of geometrical isomers, influenced by steric effects.
8. Major Product
Typically, the more thermodynamically stable compound is the major product.
Reaction Mechanism
The Knoevenagel condensation, a base-catalyzed reaction resembles the aldol condensation reactions, whose mechanism is based on substrate characteristics and catalyst nature. A.C.O. Hann and A. Lapworth initially proposed the mechanism (Hann-Lapworth mechanism) in 1904. When tertiary amines act as catalysts, an anticipated β-hydroxy dicarbonyl intermediate forms and later dehydrates to yield the end product.
Conversely, secondary or primary amine catalysts trigger aldehyde-amine condensation, forming an iminium salt that interacts with the enolate. Eventually, a 1,2-elimination step generates the desired α,β-unsaturated dicarbonyl or related compounds.
The final product might undergo Michael addition with an excess of an enolate, resulting in a bis adduct.
Examples of Knoevenagel Condensation
The synthesis of cinnamic acid and coumarin involves the Knoevenagel condensation reaction.
Modifications
Doebner Modification
The Doebner variation of the Knoevenagel condensation involves the reaction of acrolein and malonic acid in the presence of pyridine. This results in the formation of trans-2,4-pentadienoic acid, accompanied by the removal of carbon dioxide.
In situations where one of the electron-withdrawing groups on the nucleophilic partner is a carboxylic acid, such as with malonic acid, the product from the condensation can subsequently experience decarboxylation.
This modified process, known as the Doebner modification, utilizes pyridine as the base. For instance, the reaction between acrolein and malonic acid in pyridine generates trans-2,4-pentadienoic acid with a single carboxylic acid group instead of two.
Synthetic Applications
1. Synthesis of Sarcodictyin
In the laboratory of K.C. Nicolaou, the total synthesis of the marine-derived diterpenoid sarcodictyin A was successfully achieved.
The central challenge involved creating the tricyclic core, featuring a 10-membered ring. The formation of this macrocycle was accomplished through an intramolecular 1,2-addition of an acetylide anion to an α,β-unsaturated aldehyde.
The introduction of this unsaturated aldehyde moiety relied on the Knoevenagel condensation, catalyzed by β-alanine. Interestingly, the resulting Knoevenagel product was exclusively the (E)-cyanoester.
2. Enantioselective Synthesis of Hirsutine
F. Tietze and colleagues utilized a domino Knoevenagel condensation/hetero-Diels-Alder reaction for the enantioselective total synthesis of hirsutine, an active anti-influenza A virus indole alkaloid, along with related compounds.
The Knoevenagel condensation took place between an enantiopure aldehyde and Meldrum’s acid, facilitated by ethylenediamine diacetate. The ensuing highly reactive 1-oxa-1,3-butadiene participated in an in situ hetero-Diels-Alder reaction with 4-methoxybenzyl butenyl ether (E/Z = 1:1). Impressively, the product exhibited a 1,3-asymmetric induction exceeding 20:1.
This synthetic approach allowed for the creation of valuable compounds with notable enantioselectivity in an efficient manner.
3. Total Synthesis of (±)-Leporin
In the total synthesis of (±)-leporin A, B.B. Snider and collaborators harnessed a tandem Knoevenagel condensation/inverse electron demand intramolecular hetero-Diels-Alder reaction.
This strategic approach was instrumental in constructing the pivotal tricyclic intermediate. The process involved the condensation of pyridone with an enantiopure acyclic aldehyde, catalyzed by triethylamine.
This initial condensation yielded an intermediate compound, which subsequently engaged in a [4+2] cycloaddition. This cycloaddition reaction led to the formation of the tricyclic core intrinsic to the desired final product.
This innovative synthetic methodology efficiently generated the complex molecular framework of (±)-leporin A, showcasing the intricate interplay of reaction sequences.
4. Stereocontrolled Total Synthesis of (±)-Gelsemine
T. Fukuyama and collaborators achieved the stereocontrolled total synthesis of (±)-gelsemine. This accomplishment involved the application of the Knoevenagel condensation to create a precursor pivotal for the significant divinyl cyclopropane-cycloheptadiene rearrangement.
By employing 4-iodooxindole as the active methylene component, they effectively produced the (Z)-alkylidene indolinone product with exclusive stereoisomeric purity.
Concepts Berg
Who is credited with the discovery of the Knoevenagel condensation?
The Knoevenagel condensation is named after the German chemist Emil Knoevenagel, who first described this reaction in the early 20th century.
What is the role of the base in the Knoevenagel condensation?
The base in the Knoevenagel condensation, such as sodium ethoxide (NaOEt) or sodium hydroxide (NaOH), deprotonates the active methylene compound, generating an enolate ion. This enolate then attacks the carbonyl group of the aldehyde or ketone, initiating the condensation reaction.
What are some common examples of active methylene compounds used in Knoevenagel condensations?
Examples of active methylene compounds include malonic esters, ethyl acetoacetate, and 1,3-dicarbonyl compounds like dimedone.
What types of products are typically formed in a Knoevenagel condensation?
The Knoevenagel condensation typically yields β-unsaturated carbonyl compounds, which have a carbon-carbon double bond adjacent to a carbonyl group.
What factors can influence the success of a Knoevenagel condensation reaction?
Factors such as the choice of base, solvent, temperature, and the nature of the starting materials can all impact the success of a Knoevenagel condensation reaction. Careful selection of these parameters is essential to achieve high yields and selectivity.
References Books
- A Textbook of Strategic Applications of Named Reactions in Organic Synthesis book by Laszlo Kurti and Barbara Czako
- A Textbook of Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications book by Jie Jack Li
References link
- An Article (organic-chemistry.org)
- An Article (chemistrylearner.com)
- An Article (name-reaction.com)
