Aldol condensation

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Aldol condensation
Reaction type Coupling reaction
Identifiers
Organic Chemistry Portal aldol-condensation
RSC ontology ID RXNO:0000017

An aldol condensation is a condensation reaction in organic chemistry in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), followed by dehydration to give a conjugated enone.

Aldol condensation overview

Aldol condensations are important in organic synthesis, because they provide a good way to form carbon–carbon bonds.[1] For example, the Robinson annulation reaction sequence features an aldol condensation;[1] the Wieland–Miescher ketone product is an important starting material for many organic syntheses.[2] Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.[3][4][5] In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.[6][7][8]

The Aldol reaction

The name aldol condensation is also commonly used, especially in biochemistry, to refer to just the first (addition) stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule.

The reaction between an aldehyde or ketone having an α-hydrogen with an aromatic carbonyl compound lacking an α-hydrogen is called the Claisen–Schmidt condensation. This reaction is named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881.[9][10][11][page needed] An example is the synthesis of dibenzylideneacetone ((1E, 4E)-1,5-diphenylpenta-1,4-dien-3-one). Quantitative yields in Claisen–Schmidt reactions have been reported in the absence of solvent using sodium hydroxide as the base and plus benzaldehydes.[12] Because the enolizeable nucleophilic carbonyl compound and the electrophilic carbonyl compound are two different chemicals, the Claisen–Schmidt reaction is an example of a crossed aldol process.

Mechanism[edit]

The first part of this reaction is an aldol reaction, the second part a dehydration—an elimination reaction (Involves removal of a water molecule or an alcohol molecule). Dehydration may be accompanied by decarboxylation when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism,[13][14] or in an acid-catalyzed enol mechanism. Depending on the nature of the desired product, the aldol condensation may be carried out under two broad types of conditions: kinetic control or thermodynamic control.[15]

Enolate mechanism :Enol Mechanism
Animation zum basenkat. Reaktionsmechanismus der Aldolkondensation Animation zum säurekat. Reaktionsmechanismus der Aldolkondensation
animation, base catalyzed animation, acid catalyzed

Crossed aldol condensation is a result of dissimilar carbonyl compounds containing α-hydrogen(s) undergoing aldol condensation. When 2 dissimilar carbonyl compounds react with each other, there are 4 possible products, they being due to: (a) Carbonyl compound 1 self condensation, or, (b) carbonyl compound 2 self condensation, or, (c) carbonyl compound 1 forming enolate ion and attacking the electrophilic centre of the other carbonyl compound, or, (d) vice-versa. If formation of a β-hydroxy carbonyl compound (aldol) having carbonyl compound 1 contribute as the electrophile in the mechanism is desired, then, it being provided that the said compound does not have an α-hydrogen, the said compound is mixed with a suitable base and another carbonyl compound is slowly added to the said mixture. It must be noted that the concentration of the base must not be to high, nor should the base be too strong, as, if the carbonyl compound 1 is an aldehyde, Cannizaro reaction may result. Crossed aldol condensation between 2 dissimilar aldehydes containing α-hydrogens is rarely attempted as a synthetically useless mixture is formed, comprising 4 aldol products. The above-mentioned case may be referred to when it comes to significant crossed aldol product between two aldehydes, with one not possessing any α-hydrogens. Any crossed aldol condensation between 2 ketones is useless, as the it is useful somuch as it can cause problems for reproductive system so be careful while using equilibrium lies far to the left. In the aldol condensation between an aldehyde and a ketone, the ketone acts as the nucleophile, as its carbonyl carbon, due to +I effect and steric hindrance, does not possess high electrophilic character. Usually, the crossed product is the major one. Any traces of the self-aldol product (that between 2 molecules of the aldehyde itself) may be disallowed to form by first preparing a mixture of a suitable base and the ketone and then adding the aldehyde slowly to the said reaction mixture.[16]

Condensation types[edit]

It is important to distinguish the aldol condensation from other addition reactions of carbonyl compounds.

Aldox process[edit]

In industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propene and syngas directly to 2-ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and finally hydrogenation.[17]

Aldox process

In one study crotonaldehyde ((2E)-but-2-enal) is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system:[18]

Crotonaldehyde Aldol process

Scope[edit]

Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[19] The synthetic procedure[20] is typical for this type of reaction. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation.

Aldol condensation of Ethyl 2-methylacetoacetate and campholenic aldehyde

Ethyl glyoxylate 2 and glutaconate (diethyl-2-methylpent-2-enedioate) 1 react to isoprenetricarboxylic acid 3 (isoprene (2-methylbuta-1,3-diene) skeleton) with sodium ethoxide. This reaction product is very unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic group in the cis-dienoid structure.[21]

Isoprenetricarboxylic acid

Occasionally, an aldol condensation is buried in a multistep reaction or in catalytic cycle as in the following example:[22]

Ru Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes

In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5. Support for the reaction mechanism is based on isotope labeling.[23]

The reaction between menthone ((2S,5R)-2-isopropyl-5-methylcyclohexanone) and anisaldehyde (4-methoxybenzaldehyde) is complicated due to steric shielding of the ketone group. This obstacle is overcome by using a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below:[24]

A Claisen–Schmidt reaction

The product can epimerize by way of a common intermediate—enolate A—to convert between the original (S,R) and the (R,R) epimers. The (R,R) product is insoluble in the reaction solvent whereas the (S,R) is soluble. The precipitation of the (R,R) product drives the epimerization equilibrium reaction to form this as the major product.

See also[edit]

References[edit]

  1. ^ a b Carey, Francis A.; Sundberg, Richard J. (1993). Advanced Organic Chemistry Part B Reactions and Synthesis (3rd ed.). 233 Spring Street, NY: Plenum. p. 55. ISBN 0-306-43440-7.
  2. ^ Dzierba, C. D.; Zandi, K. S.; Moellers, T.; Shea, K. J. An Ascending Synthesis of Adrenalcorticosteroids. The Total Synthesis of (+)-Adrenosterone. J. Am. Chem. Soc. 1996, 118, 4711–4712.
  3. ^ Wade, L. G. (2005). Organic Chemistry (6th ed.). Upper Saddle River, NJ: Prentice Hall. pp. 1056–1066. ISBN 0-13-236731-9.
  4. ^ Smith, M. B.; March, J. (2001). Advanced Organic Chemistry (5th ed.). New York: Wiley Interscience. pp. 1218–1223. ISBN 0-471-58589-0.
  5. ^ Mahrwald, R. (2004). Modern Aldol Reactions. 1, 2. Weinheim, Germany: Wiley-VCH. pp. 1218–1223. ISBN 3-527-30714-1.
  6. ^ Heathcock, C. H. (1991). Additions to C-X π-Bonds, Part 2. Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. 2. Oxford: Pergamon. pp. 133–179. ISBN 0-08-040593-2.
  7. ^ Mukaiyama T. (1982). "The Directed Aldol Reaction". Organic Reactions. 28: 203–331. doi:10.1002/0471264180.or028.03. ISBN 0471264180.
  8. ^ Paterson, I. (1988). "New Asymmetric Aldol Methodology Using Boron Enolates". Chemistry and Industry. London: Paterson Group. 12: 390–394.
  9. ^ Claisen, L.; Claparède, A. (1881). "Condensationen von Ketonen mit Aldehyden" [Condensations of ketones with aldehydes]. Berichte der Deutschen Chemischen Gesellschaft. 14 (1): 2460–2468. doi:10.1002/cber.188101402192.
  10. ^ Schmidt, J. G. (1881). "Ueber die Einwirkung von Aceton auf Furfurol und auf Bittermandelöl in Gegenwart von Alkalilauge" [On the effect of acetone on furfural and on bitter almond oil (benzaldehyde) in the presence of alkali hydroxides]. Berichte der Deutschen Chemischen Gesellschaft. 14 (1): 1459–1461. doi:10.1002/cber.188101401306.
  11. ^ March, J. (1985). Advanced Organic Chemistry: Reactions, Mechanisms and Structure (3rd ed.). Wiley Interscience. ISBN 0-471-85472-7.
  12. ^ Molecules 2012, 17, 571–583; doi:10.3390/molecules17010571
  13. ^ Nielsen, A. T.; Houlihan., W. J. (1968). "The Aldol Condensation". Organic Reactions. 16: 1–438. doi:10.1002/0471264180.or016.01. ISBN 0471264180.
  14. ^ Perrin, C. L.; Chang, K. L. (2016). "The Complete Mechanism of an Aldol Condensation". J. Org. Chem. 81 (13): 5631–5. doi:10.1021/acs.joc.6b00959. PMID 27281298.
  15. ^ Carey, Francis A.; Sundberg, Richard J. (1993). Advanced Organic Chemistry Part A: Structure and Mechanisms (3rd ed.). 233 Spring Street, New York, N.Y.: Plenum. p. 458. ISBN 0-306-43440-7.
  16. ^ Sanyal, S.N. (2003). Reactions, Rearrangements and Reagents (4th ed.). 4271/3 Ansari road, Daryagunj, New Delhi 110002: Bharati Bhavan Publishers (P&D). p. 80. ISBN 978-81-7709-605-7.
  17. ^ For example, BG 881979 
  18. ^ Seki, T.; Grunwaldt, J.-D.; Baiker, A. (2007). "Continuous catalytic "one-pot" multi-step synthesis of 2-ethylhexanal from crotonaldehyde". Chemical Communications. 2007 (34): 3562–3564. doi:10.1039/b710129e.
  19. ^ Badía, C.; Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Nogueras, M.; Sánchez, A. (2004). "(E)-6-(2,2,3-Trimethyl-cyclopent-3-enyl)-hex-4-en-3-one". Molbank. 2004 (1): M388. doi:10.3390/M388.
  20. ^ Ethyl 2-methylacetoacetate (2) is added to a stirred solution of sodium hydride in dioxane. Then campholenic aldehyde (1) is added and the mixture refluxed for 15 h. Then 2N hydrochloric acid is added and the mixture extracted with diethyl ether. The combined organic layers are washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield a residue that is purified by vacuum distillation to give 3 (58%).
  21. ^ Goren, M. B.; Sokoloski, E. A.; Fales, H. M. (2005). "2-Methyl-(1Z,3E)-butadiene-1,3,4-tricarboxylic Acid, "Isoprenetricarboxylic Acid"". Journal of Organic Chemistry. 70 (18): 7429–7431. doi:10.1021/jo0507892. PMID 16122270.
  22. ^ Varela, J. A.; Gonzalez-Rodriguez, C.; Rubin, S. G.; Castedo, L.; Saa, C. (2006). "Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes". Journal of the American Chemical Society. 128 (30): 9576–9577. doi:10.1021/ja0610434. PMID 16866480.
  23. ^ The ruthenium catalyst, [CpRu(CH3CN)3]PF6, has a cyclopentadienyl ligand, three acetonitrile ligands and a phosphorus hexafluoride counterion; the acidic proton in the solvent (acetic acid) is replaced by deuterium for isotopic labeling. Reaction conditions: 90°C, 24 hrs. 80% chemical yield. The first step is formation of the Transition metal carbene complex 2. Acetic acid adds to this intermediate in a nucleophilic addition to form enolate 3 followed by aldol condensation to 5 at which stage a molecule of carbon monoxide is lost to 6. The final step is reductive elimination to form the cycloalkene.
  24. ^ Vashchenko, V.; Kutulya, L.; Krivoshey, A. (2007). "Simple and Effective Protocol for Claisen–Schmidt Condensation of Hindered Cyclic Ketones with Aromatic Aldehydes". Synthesis. 2007 (14): 2125–2134. doi:10.1055/s-2007-983746.