Aldol condensation#Aldox process

{{expand section|actually discuss the dehydration mechanisms, not just present an image of them|date=June 2018}}

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 deprotonates the product to an enolate, which eliminates via the E1cB mechanism,{{cite journal |author1=Nielsen, A. T. |author2=Houlihan., W. J. | title = The Aldol Condensation | journal = Organic Reactions | year = 1968 | volume = 16 | pages = 1–438 | doi = 10.1002/0471264180.or016.01 |isbn=0471264180 }}{{cite journal |title=The Complete Mechanism of an Aldol Condensation |journal=J. Org. Chem. |volume=81 |issue=13 |pages=5631–5 |pmid=27281298|year=2016 |last1=Perrin |first1=C. L. |last2=Chang |first2=K. L. |doi=10.1021/acs.joc.6b00959 |url=https://escholarship.org/uc/item/4786g54b }} while dehydration in acid proceeds via an E1 reaction 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.{{cite book | author1 = Carey, Francis A. | author2 = Sundberg, Richard J. | title = Advanced Organic Chemistry Part A: Structure and Mechanisms | publisher = Plenum | edition = 3rd | year = 1993 | location = New York, N.Y. | pages = [https://archive.org/details/advancedorganicc00care/page/458 458] | isbn = 0-306-43440-7 | url = https://archive.org/details/advancedorganicc00care/page/458 }} Both ketones and aldehydes are suitable for aldol condensation reactions. In the examples below, aldehydes are used.

The mechanism for base-catalyzed aldol condensation can be seen in the image below. File:Base-catalysed aldol condensation.svg

The process begins when a free hydroxide (strong base) strips the highly acidic proton at the alpha carbon of the aldehyde. This deprotonation causes the electrons from the C–H bond to shift and create a new C–C pi bond. The new pi bond then acts as a nucleophile and attacks the remaining aldehyde in the solution, resulting in the formation of a new C–C bond and regeneration of the base catalyst. In the second part of the reaction, the presence of base leads to elimination of water and formation of a new C–C pi bond. The product is referred to as the aldol condensation product.

The mechanism for acid-catalyzed aldol condensation can be seen in the image below. File:Acid-catalysed aldol condensation.svg

{{See also|Aldol reaction#Crossed-aldol reactant control}}

A crossed aldol condensation is a result of two dissimilar carbonyl compounds containing α-hydrogen(s) undergoing aldol condensation. Ordinarily, this leads to four possible products as either carbonyl compound can act as the nucleophile and self-condensation is possible, which makes a synthetically useless mixture. However, this problem can be avoided if one of the compounds does not contain an α-hydrogen, rendering it non-enolizable. In an aldol condensation between an aldehyde and a ketone, the ketone acts as the nucleophile, as its carbonyl carbon does not possess high electrophilic character due to the +I effect and steric hindrance. Usually, the crossed product is the major one. Any traces of the self-aldol product from the aldehyde may be disallowed by first preparing a mixture of a suitable base and the ketone and then adding the aldehyde slowly to the said reaction mixture. Using too concentrated base could lead to a competing Cannizzaro reaction.{{cite book|author = Sanyal, S.N.|title = Reactions, Rearrangements and Reagents|publisher = Bharati Bhavan Publishers (P&D)|edition = 4th|year = 2003|location = Daryagunj, New Delhi |pages = 80|isbn = 978-81-7709-605-7}}

The Aldox process, developed by Royal Dutch Shell and Exxon, converts propene and syngas to 2-ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexanal and finally hydrogenation.Graduated hydrogenation of aldox aldehydes to alcohols {{Cite patent |country= US|number= US3118954A|url= https://patentimages.storage.googleapis.com/53/b4/a8/65b003d4b30870/US3118954.pdf}}

File:Aldox_process.svg

Pentaerythritol is produced on a large scale beginning with crossed aldol condensation of acetaldehyde and three equivalents of formaldehyde to give pentaerythrose, which is further reduced in a Cannizzaro reaction.{{OrgSynth |author=Schurink, H. B. J. |title=Pentaerythritol |collvol=1 |collvolpages=425 |year=1925 |prep=CV1P0425 |volume=4 |pages=53 |doi=10.15227/orgsyn.004.0053}}

File:Pentaerythritol Synthesis.svg

Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.{{cite journal | title = (E)-6-(2,2,3-Trimethyl-cyclopent-3-enyl)-hex-4-en-3-one |author1=Badía, C. |author2=Castro, J. M. |author3=Linares-Palomino, P. J. |author4=Salido, S. |author5=Altarejos, J. |author6=Nogueras, M. |author7=Sánchez, A. | journal = Molbank | year = 2004 | volume = 2004 | issue = 1 | pages = M388 | doi = 10.3390/M388 |doi-access=free }} The synthetic procedureEthyl 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%). 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.

File:Aldehyde aldol condensation example.png

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.{{cite journal |author1=Goren, M. B. |author2=Sokoloski, E. A. |author3=Fales, H. M. | title = 2-Methyl-(1Z,3E)-butadiene-1,3,4-tricarboxylic Acid, "Isoprenetricarboxylic Acid" | journal = Journal of Organic Chemistry | year = 2005 | volume = 70 | issue = 18 | pages = 7429–7431 | doi = 10.1021/jo0507892 | pmid = 16122270 }}

File:IsoprenetricarboxylicAcid2.png

Occasionally, an aldol condensation is buried in a multistep reaction or in catalytic cycle as in the following example:{{cite journal |author1=Varela, J. A. |author2=Gonzalez-Rodriguez, C. |author3=Rubin, S. G. |author4=Castedo, L. |author5=Saa, C. | title = Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes | journal = Journal of the American Chemical Society | year = 2006 | volume = 128 | issue = 30 | pages = 9576–9577 | doi = 10.1021/ja0610434 | pmid = 16866480 }}

File:RuCatalyzedCyclizationofTerminalAlkynalstoCycloalkenes.png

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.{{Efn|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.}}

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:{{cite journal | title = Simple and Effective Protocol for Claisen–Schmidt Condensation of Hindered Cyclic Ketones with Aromatic Aldehydes |author1=Vashchenko, V. |author2=Kutulya, L. |author3=Krivoshey, A. | journal = Synthesis | year = 2007 | volume = 2007 | issue = 14 | pages = 2125–2134 | doi = 10.1055/s-2007-983746 }}

File:Menthone Claisen-Schmidt.png

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.

There are other reactions of carbonyl compounds similar to aldol condensation:

• When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation.
• In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride.
• Claisen-Schmidt condensation between an aldehyde or ketone having an α-hydrogen with an aromatic carbonyl compound lacking an α-hydrogen.
• A Claisen condensation involves two ester compounds.
• A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule
• In the Japp–Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement
• A Robinson annulation involves an α,β-unsaturated ketone and a carbonyl group, which first engage in a Michael reaction prior to the aldol condensation.
• In the Guerbet reaction, an aldehyde, formed in situ from an alcohol, self-condenses to the dimerized alcohol.

• Auwers synthesis
• Aldol addition

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{{Notelist}}

• [https://www.organic-chemistry.org/namedreactions/aldol-condensation.shtm Organic Chemistry Portal]

{{Commons category|Aldol condensation}}

{{Organic reactions}}

Category:Condensation reactions

Category:Carbon-carbon bond forming reactions