Aldol Condensation Reaction

What is Condensation Reaction?

The aldol condensation reaction is an organic reaction introduced by Charles Wurtz, who first prepared the β-hydroxy aldehyde from acetaldehdye in 1872.¹ In an aldol condensation, an enolate ion reacts with a carbonyl compound in the presence of acid/base catalyst to form a β-hydroxy aldehyde or β-hydroxy ketone, followed by dehydration to give a conjugated enone. It is a useful carbon-carbon bond-forming reaction. The fundamental steps of the aldol condensation reaction are:

1. Aldol (aldehyde + alcohol) reaction — Reaction of aldehyde (or ketone) enolate with another molecule of the aldehyde (or ketone) in the presence of NaOH or KOH to form β-hydroxy aldehyde (or ketone).

2. Dehydration/Elimination reaction — Involves removal of a water molecule from the β-hydroxy aldehyde (or ketone) to form an α,β-unsaturated aldehyde or an α,β-unsaturated ketone.

Precautions

Please consult the Safety Data Sheet for information regarding hazards and safe handling practices.

Applications

The Aldol condensation reaction can be used for the following syntheses:

• Enzymatic synthesis of fatty acids.²
• Highly concise total synthesis of epothilone B.³
• Preparation of (E)-6-(2,2,3-trimethyl-cyclopent-3-enyl)-hex-4-en-3-one.⁴
• Synthesis of high polymers of poly(glutaraldehyde).⁵
• Stereoselective synthesis of (±)-ephedrine.⁶
• Synthesis of numerous macrolide and ionophore antibiotics (natural products).⁷
• Total synthesis of distomadines A and B, two structurally unique tetracyclic quinolones.⁸

Recent Research and Trends

• Water-soluble calix[n]arenes were employed as inverse phase-transfer catalysts for aldol-type condensations and Michael addition reactions of activated methyl and methylene compounds.⁹
• A cesium ion containing catalyst, on an SBA-15 mesoporous molecular support, has been employed for the aldol condensation of methyl acetate with formaldehyde.¹⁰
• Organocatalytic asymmetric aldol reaction of cyclohexanone with p‑nitrobenzaldehyde in water has been reported.¹¹
• One-pot Cu-catalyzed etherification/aldol condensation cascade reaction is reported to yield dibenzoxepine lactams.¹²
• Synthesis of a series of diprenylated and digeranylated chalcone analogues by alkylation, regioselective iodination, aldol condensation, Suzuki coupling and [1,3]‑sigmatropic rearrangement.¹³
• A domino sequence of Michael addition and aldol condensation of acenaphthenequinone with acetophenone in the presence of KOH in methanol solvent leads to the formation of different 2:2 adducts.¹⁴
• The aldol condensation of 4-isopropylbenzaldehyde and propanal has been performed using functionalized MCM-41.¹⁵

References

1. Nielsen AT, Houlihan WJ. The Aldol Condensation.1-438. https://doi.org/10.1002/0471264180.or016.01

2. Brady RO. 1958. The Enzymatic Synthesis of Fatty Acids by Aldol Condensation. Proceedings of the National Academy of Sciences. 44(10):993-998. https://doi.org/10.1073/pnas.44.10.993

3. Balog A, Haris C, Savin K, Zhang X, Chou T, Danishefsky S. 1998. Angew. Chem. Int. Ed.. 372675.

4. Badía C, Castro J, Linares-Palomino P, Salido S, Altarejos J, Nogueras M, Sánchez A. (E)-6-(2,2,3-Trimethyl-cyclopent-3-enyl)-hex-4-en-3-one. Molbank. 2004(1):M388. https://doi.org/10.3390/m388

5. Tashima T, Imai M, Kuroda Y, Yagi S, Nakagawa T. 1991. Structure of a new oligomer of glutaraldehyde produced by aldol condensation reaction. J. Org. Chem.. 56(2):694-697. https://doi.org/10.1021/jo00002a038

6. Heathcock CH, Buse CT, Kleschick WA, Pirrung MC, Sohn JE, Lampe J. 1980. Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation. J. Org. Chem.. 45(6):1066-1081. https://doi.org/10.1021/jo01294a030

7. Masamune S, Choy W, Kerdesky Francis A. J., Imperiali B. 1981. Stereoselective aldol condensation. Use of chiral boron enolates. J. Am. Chem. Soc.. 103(6):1566-1568. https://doi.org/10.1021/ja00396a050

8. Jolibois AER, Lewis W, Moody CJ. 2014. Total Synthesis of (±)-Distomadines A and B. Org. Lett.. 16(4):1064-1067. https://doi.org/10.1021/ol403598k

9. Shimizu S, Shirakawa S, Suzuki T, Sasaki Y. 2001. Water-soluble calixarenes as new inverse phase-transfer catalysts. Their application to aldol-type condensation and Michael addition reactions in water. Tetrahedron. 57(29):6169-6173. https://doi.org/10.1016/s0040-4020(01)00572-5

10. Yan J, Zhang C, Ning C, Tang Y, Zhang Y, Chen L, Gao S, Wang Z, Zhang W. 2015. Vapor phase condensation of methyl acetate with formaldehyde to preparing methyl acrylate over cesium supported SBA-15 catalyst. Journal of Industrial and Engineering Chemistry. 25344-351. https://doi.org/10.1016/j.jiec.2014.11.014

11. Mase N, Nakai Y, Ohara N, Yoda H, Takabe K, Tanaka F, Barbas CF. 2006. Organocatalytic Direct Asymmetric Aldol Reactions in Water. J. Am. Chem. Soc.. 128(3):734-735. https://doi.org/10.1021/ja0573312

12. Lim HS, Choi YL, Heo J. 2013. Synthesis of Dibenzoxepine Lactams via a Cu-Catalyzed One-Pot Etherification/Aldol Condensation Cascade Reaction: Application toward the Total Synthesis of Aristoyagonine. Org. Lett.. 15(18):4718-4721. https://doi.org/10.1021/ol402036t

13. Wang H, Zhang L, Liu J, Yang Z, Zhao H, Yang Y, Shen D, Lu K, Fan Z, Yao Q, et al. 2015. Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs. European Journal of Medicinal Chemistry. 92439-448. https://doi.org/10.1016/j.ejmech.2015.01.007

14. Domino reaction sequences leading to the formation of 2:2 adducts between acenaphthenequinone and acetophenone. 2014(6):127. https://doi.org/10.3998/ark.5550190.p008.834

15. Vrbková E, Vyskocilová E, Cerveny L. 2015. Functionalized MCM-41 as a catalyst for the aldol condensation of 4-isopropylbenzaldehyde and propanal. Reac Kinet Mech Cat. 114(2):675-684. https://doi.org/10.1007/s11144-014-0811-2