Aldol Condensation Reaction

Reaction

The aldol condensation 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).

                 

                            Aldehyde                                 Enolate                                    β-Hydroxy aldehyde

  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. 

                            β-Hydroxy aldehyde                                                                    α,β-Unsaturated aldehyde
                                                                                                                          (Conjugated aldehyde, an enal)

Precautions

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

Materials

     

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, A. T. and Houlihan, W. J. Organic Reactions; John Wiley and Sons, 1968
  2. Brady, R. O. Proc. Natl. Acad. Sci. U. S. A. 1958, 44, 993. 
  3. Balog, A.; Haris, C.; Savin, K.; Zhang, X. G.; Chou, T. C. and Danishefsky, S. J.  Angew. Chem., Int. Ed. 1998, 37, 2675. 
  4. Concepción, B. J. M. C; Castro, J. M.;  Linares-Palomino, P. J.; Salido, S; Altarejos , J.; Nogueras, M.  Sánchez, A. Molbank 2004, M388. 
  5. Tashima, T; Imai, M.; Kuroda, M; Yagi, S; Nakagawa, T. J. Org. Chem. 1991, 56, 694. 
  6. Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C; Sohan, J.E.; Lamp, J.  J. Org. Chem. 1980, 45, 1066. 
  7. Masamune, S.; Choy, W.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566. 
  8. Jolibois, A. E. R.; Lewis, W.; Moody, C. J. Org. Lett. 2014, 16, 1064. 
  9. Shimizu, S; Shirakawa, S; Suzuki, T.; Sasaki, Y. Tetrahedron 2001, 57, 6169. 
  10. Yan, J.; Zhangb, C.; Ningb, C.; Tangb, Y.; Zhangb, Y.; Chena, L.; Gaoa, S.; Wanga, Z.; Zhang, W. J. Ind. Eng. Chem. 2014.
  11. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C.F J. Am. Chem. Soc. 2006128, 734.
  12. Lim, H. S.; Choi, Y. L.; Heo, J. N.  Org. Lett. 2013, 15, 4718. 
  13. Wang, H-W.; Zhanga, L.; Liua, J.; Yanga, Z-L.; Zhaoa, H-Y.; Yanga, Y.; Shena, D.; Lua, K.; Fanb, Z. C.; Yaod, Q-W.; Zhange, Y-M.; Tenga, Y-O.; Peng, P. Eur. J. Med. Chem. 2015, 92, 439.
  14. Jacob, J.P.; Kunjachan,C.; Sajitha, L. U.; Thumpakara, R. K.; Rakesh K.; Nidhisha,V.; Unnikrishnan, P. A.; Prathapa S. ARKIVOC 2014, 6, 127.
  15. Vrbková, E.; Vyskočilová, E.;  Červený, L. React. Kinet., Mech. Catal. 2014, 1-10.

 

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