What Is Knoevenagel Condensation?
Esters containing active methylene groups (such as malonates) react with aldehydes on heating in the presence of piperidine to form condensation products, i.e., α,β-unsaturated dicarbonyls or related compounds. The latter can be decarboxylated by ester hydrolysis to give α,β-unsaturated acids, such as cinnamic acid. These cinnamic acids are key intermediates in the synthesis of natural and therapeutic drugs, polymers, cosmetics and perfumes.
Knoevenagel condensation of o-hydroxybenzaldehyde can directly give Coumarin. Nitro compounds can also undergo Knoevenagel condensation. An important use of Knoevenagel condensation is the conjugate addition of its products. Since a method for performing Knoevenagel condensation on resins has been established, its products have application prospects in combinatorial chemistry.
Mechanism of Knoevenagel Condensation
- Deprotonation: The active methylene compound is deprotonated by a base to form a nucleophilic enolate ion.
- Nucleophilic attack: The enolate ion then attacks the carbonyl carbon of the aldehyde or ketone to form a tetrahedral intermediate.
- Dehydration: After proton transfer and removal of a water molecule, a double bond is formed between the two carbon atoms to form a β-unsaturated carbonyl compound.
Fig 1. Knoevenagel condensation reaction and its mechanism. [1]
Modification of Knoevenagel Condensation
Doebner Modification
The Knoevenagel-Doebner reaction is based on the conversion of several different aromatic aldehydes using piperidine as a reaction base. The most significant and important change in this reaction is the use of an organic diacid instead of diethyl malonate, the most commonly used diacid being malonic acid. [2]
Verley Modification
Albert Verley improved the Knoevenagel reaction of aromatic aldehydes by introducing β-alanine as a cocatalyst, thereby discontinuing the use of the catalyst piperidine in the condensation reaction. In the Doebner and Verley modifications, the use of pyridine is still necessary, which not only acts as a base in the condensation step, but also promotes the decarboxylation reaction.
Application Examples of Knoevenagel Condensation
- Example 1: Knoevenagel condensation is a key step in the total synthetic strategy for (+)-granatumine A, a limonoid alkaloid with PTP1B inhibitory activity. In detail, treatment of 8 and aldehyde 9 with ethylenediamine diacetate (EDDA) formed a putative enedione intermediate, which spontaneously underwent oxa-6π electrocyclization under thermal conditions to give 2H-pyran 7, in 47% yield of 9. The oxa-6π electrocyclization allowed regioselective C1 ketone protection in the presence of C3 ketone. [3]
- Example 2: Alberto M. Lopez et al. developed a tin-free strategy to prepare Calyciphylline A alkaloids, which successfully cyclized various internal alkyne-containing N-chloroamine precursors to ABC cores via cyclization of neutral amino radicals. The Knoevenagel condensation of the ABC core with a β-ketoester side chain successfully constructed the seven-membered D-ring Calyciphylline A alkaloid. [4]
Fig 2. Synthetic examples via Knoevenagel condensation reaction.
Related Products
| CAS No. | Structure | Product | Inquiry |
| 138555-57-4 |  | 2-ChloroCinnamaldehyde | Inquiry |
| 138555-58-5 |  | 2-BROMOCINNAMALDEHYDE | Inquiry |
| 1466-88-2 |  | 2-NITROCINNAMALDEHYDE | Inquiry |
| 149733-71-1 |  | 2-FLUOROCINNAMALDEHYDE | Inquiry |
| 1734-79-8 |  | 4-NitroCinnamaldehyde | Inquiry |
| 24680-50-0 |  | 4-Methoxycinnamaldehyde | Inquiry |
| 262268-58-6 |  | 3-(Trifluoromethyl)cinnamaldehyde | Inquiry |
| 3893-18-3 |  | 4-Bromocinnamaldehyde | Inquiry |
| 49678-02-6 |  | 4-Chlorocinnamaldehyde | Inquiry |
| 49678-04-8 |  | 4-Bromocinnamaldehyde | Inquiry |
| 49678-08-2 |  | 4-NITROCINNAMALDEHYDE | Inquiry |
| 51791-26-5 |  | trans-4-Fluorocinnamaldehyde | Inquiry |
| 56578-35-9 |  | 2-Propenal,3-(4-methylphenyl)-,(2E) | Inquiry |
| 56578-37-1 |  | 3-Chlorocinnamaldehyde | Inquiry |
| 6203-18-5 |  | 4-(Dimethylamino)cinnamaldehyde | Inquiry |
| 93614-80-3 |  | 3-Methylcinnamaldehyde | Inquiry |
| 97985-66-5 |  | 3-Bromocinnamaldehyde | Inquiry |
References
- Li, Jie Jack. Name Reactions: A Collection of Detailed Reaction Mechanisms, 2006, 294-297.
- van Beurden, K., et al. Green Chemistry Letters and Reviews, 2020, 13(4), 349-364.
- Schuppe, Alexander W., et al. Journal of the American Chemical Society, 2019, 141(23), 9191-9196.
- Lopez, Alberto M., et al. Organic letters, 2018, 20(8), 2216-2219.
