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
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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
Ethyl 2-methylacetoacetate (2) (727 mg, 4.53 mmol) was added to a stirred solution of NaH (184 mg, 4.60 mmol) in dioxane (25 mL). Then campholenic aldehyde (1) (707 mg, 3.72 mmol) was added and the mixture refluxed for 15 h. Then 2N HCL (15 mL) was added and the mixture extracted with Et2O (3×15 mL). The combined organic layers were washed with 2N HCl (2×15 mL), saturated Na2CO3 (2×15 mL) and brine (3×15 mL). The organic phase was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure to yield a residue (900 mg) which was purified by distillation under reduced pressure to give the title compound 3 (505 mg, 2.63 mmol, 58%).
· 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
The route features a three-step process to access the pyranoquinoline butenolide rings via a Suzuki cross coupling of a 5-bromo-4-methoxycarbonylmethoxyquinoline with a vinyl boronate, followed by an α-ketohydroxylation and double cyclization by intramolecular aldol condensation and lactonization. Subsequent manipulation of the side chain to introduce the guanidine fragment completed the synthesis of distomadine B, whereas the distomadine A congener resulted from decarboxylation of a late-stage intermediate.
· 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
The catalyst showed high catalytic activity in the condensation reaction. XRD characterization indicated that the cesium nitrate below 5 wt% loading was highly dispersed on the SBA-15 support. FT-IR and XPS results confirmed that a Si-O-Cs species was formed on the surface of the catalyst. Pyridine-IR verified that an L-acid site existed on the surface. The NH3-TPD and CO2-TPD results indicated that weak Lewis acid–base pairs were loaded on the surface, and these weak acid–base active sites might favor the aldol condensation reaction. The 5Cs/SBA-15 catalyst demonstrated the highest (48.4%) conversion of methyl acetate reported and 95.0% selectivity for methyl acrylate. The deactivated catalyst was completely regenerated by calcination. The catalyst was regenerated nine times with a total operation time of more than 60 h, and the initial conversion of methyl acetate and the selectivity for methyl acrylate did not change. The high catalytic activity was mainly due to the suitable strength of weak acid–base properties, which were rooted in the Si-O-Cs species on the surface of the support.
· 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 The aldol condensations are usually performed using acidic or basic catalysts and due to this fact, the modification of MCM-41 was realized using post-grafting method by two acid groups (3-propylsulfoxy, 3-propylcarboxy) and one basic (the 3-(1,2-diethylamino)propyl) group. MCM-41 treated by sulfuric and nitric acid was also used. The prepared functionalized materials were characterized by BET, elemental analysis and UV–Vis spectroscopy. The optimal reaction conditions were found: the temperature of reaction mixture 100 °C, the molar ratio of reactants 4 isopropylbenzaldehyde:propanal = 1:2, the amount and the type of the catalyst: 50 wt% of MCM SO3H (compared to the amount of 4-isopropylbenzadehyde), the addition time of propanal 90 min and suitable solvent for the reaction was toluene. Using the optimal reaction conditions the yield of forcyclamenaldehyde was 45 %. The obtained results were compared to homogeneous catalysis with H2SO4 where the yield was 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