View source for Chemistry:Aldol condensation

{{Short description|Type of chemical reaction}}
{{Reactionbox
| Name = Aldol condensation
| Type = Condensation reaction
| Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = aldol-condensation
   | RSC_ontology_id = 0000017
 }}
|Reaction={{Reactionbox Reaction
   | Reactant1 = [[Chemistry:Ketone|Ketone]] or [[Chemistry:Aldehyde|Aldehyde]]
   | Reactant2 =  [[Chemistry:Ketone|Ketone]] or [[Chemistry:Aldehyde|Aldehyde]]
   | Reagent1= 
   | Product1 =[[Chemistry:Α,β-Unsaturated carbonyl compound|α,β-unsaturated Aldehyde]] {{br}}or{{br}} [[Chemistry:Α,β-Unsaturated carbonyl compound|α,β-unsaturated Ketone]]
   | Sideproduct1 = 
}}|Section1={{Reactionbox Conditions
   | Reference =
   | Solvent = 
   | Catalyst = {{center|<sup>−</sup>OH or H<sup>+</sup>}}
   | Temperature = {{center|+Δ, ~100°C{{Efn|Heat is usually added manually through the use of a hot plate, or is already present through the use of an exothermic catalyst reaction, such as when <sup>-</sup>OCH<sub>3</sub> is used as the base.{{br}}{{br}}This drives the second step, by removing water, it allows the reactions equilibrium to continually favor the dehydration mechanism, converting the temporary addition product present to its final condensation product. Otherwise a significant amount of unwanted aldol addition side product would be formed alongside the aldol condensation product.<ref>{{Cite book |last=Klein |first=David R. |url=https://www.worldcat.org/oclc/1201694230 |title=Organic chemistry |date=December 22, 2020 |publisher=Wiley |isbn=978-1-119-65959-4 |edition=4th |location=Hoboken, NJ |pages=1014 |oclc=1201694230}}</ref>}}}}
 }}}}

An '''aldol condensation''' is a [[Chemistry:Condensation reaction|condensation reaction]] in [[Chemistry:Organic chemistry|organic chemistry]] in which two carbonyl [[Chemistry:Moiety|moieties]] (of [[Chemistry:Aldehyde|aldehyde]]s or [[Chemistry:Ketone|ketone]]s) react to form a β-hydroxyaldehyde or β-hydroxyketone (an [[Chemistry:Aldol reaction|aldol reaction]]), and this is then followed by [[Chemistry:Dehydration reaction|dehydration]] to give a [[Chemistry:Conjugated system|conjugated]] [[Chemistry:Alpha-beta Unsaturated carbonyl compounds|enone]].

The overall reaction equation is as follows (where the Rs can be H)
[[File:Condensationaldolique.png|alt=Aldol condensation overview|588x588px]]

Aldol condensations are important in [[Chemistry:Organic synthesis|organic synthesis]] and [[Biology:Biochemistry|biochemistry]] as ways to form [[Chemistry:Carbon–carbon bond|carbon–carbon bond]]s.<ref name=March>{{cite book |author1=Smith, M. B. |author2=March, J. | title = Advanced Organic Chemistry |url=https://archive.org/details/organicchemistry00mich_115 |url-access=limited | publisher = Wiley Interscience | edition = 5th | year = 2001 | location = New York | pages = [https://archive.org/details/organicchemistry00mich_115/page/n1236 1218]–1223 | isbn = 0-471-58589-0 }}</ref><ref name="Carey and Sundberg PartB">{{cite book | author1 = Carey, Francis A. | author2 = Sundberg, Richard J. | title = Advanced Organic Chemistry Part B Reactions and Synthesis | publisher = Plenum | edition = 3rd | year = 1993 | location = New York, NY | pages = [https://archive.org/details/advancedorganicc00care/page/55 55] | isbn = 0-306-43440-7 | url = https://archive.org/details/advancedorganicc00care/page/55 }}</ref><ref name=Wade>{{cite book | author = Wade, L. G. | title = Organic Chemistry | url = https://archive.org/details/organicchemistry00wade_388 | url-access = limited | publisher = Prentice Hall | edition = 6th | year = 2005 | location = Upper Saddle River, NJ | pages = [https://archive.org/details/organicchemistry00wade_388/page/n1098 1056]–1066 | isbn = 0-13-236731-9 }}</ref><ref name=Mahrwald2004>{{cite book | author = Mahrwald, R. | title = Modern Aldol Reactions | volume = 1, 2 | publisher = Wiley-VCH | year = 2004 | location = Weinheim, Germany | pages = 1218–1223 | isbn = 3-527-30714-1 | url = https://archive.org/details/modernaldolreact00rain | url-access = limited }}</ref>

In its usual form, it involves the [[Chemistry:Nucleophile|nucleophilic]] addition of a [[Chemistry:Ketone|ketone]] [[Chemistry:Enolate|enolate]] to an [[Chemistry:Aldehyde|aldehyde]] to form a β-hydroxy ketone, or [[Chemistry:Aldol|aldol]] ('''ald'''ehyde + alcoh'''ol'''), a [[Chemistry:Chemical structure|structural]] unit found in many naturally occurring molecules and pharmaceuticals.<ref name=Heathcock1991>{{cite book |  author = Heathcock, C. H. | title = Additions to C-X π-Bonds, Part 2 | series = Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry | volume = 2 | publisher = Pergamon | year = 1991 | location = Oxford | pages = 133–179 | isbn =  0-08-040593-2 }}</ref><ref name=Mukaiyama1982>{{cite journal | title =  The Directed Aldol Reaction | author =  Mukaiyama T. | journal = Organic Reactions | year = 1982 | volume = 28 | pages = 203–331 | doi =  10.1002/0471264180.or028.03 | isbn = 0471264180 }}</ref><ref name=Paterson1988>{{cite journal | title = New Asymmetric Aldol Methodology Using Boron Enolates | author = Paterson, I. | journal = Chemistry and Industry | publisher = Paterson Group | location = London | year = 1988 | volume = 12 | pages = 390–394 }}</ref>

[[File:Simple aldol reaction.svg|center|570x570px|The Aldol reaction]]

The term ''aldol condensation'' is also commonly used, especially in [[Biology:Biochemistry|biochemistry]], to refer to just the first (addition) stage of the process—the [[Chemistry:Aldol reaction|aldol reaction]] itself—as catalyzed by aldolases. However, the first step is formally an [[Chemistry:Addition reaction|addition reaction]] rather than a condensation reaction because it does not involve the loss of a small molecule.

==Mechanism==
The first part of this reaction is an [[Chemistry:Aldol reaction|Aldol reaction]], the second part a dehydration—an [[Chemistry:Elimination reaction|elimination reaction]] (Involves removal of a [[Chemistry:Water|water]] molecule or an [[Chemistry:Alcohol|alcohol]] molecule). Dehydration may be accompanied by [[Chemistry:Decarboxylation|decarboxylation]] when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong [[Chemistry:Base|base]] like [[Chemistry:Potassium tert-butoxide|potassium ''t''-butoxide]], [[Chemistry:Potassium hydroxide|potassium hydroxide]] or [[Chemistry:Sodium hydride|sodium hydride]] deprotonates the product to an [[Chemistry:Enolate|enolate]], which eliminates via the [[Chemistry:E1cB-elimination reaction|E1cB mechanism]],<ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name="Carey and Sundberg PartA">{{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 }}</ref> Both ketones and aldehydes are suitable for aldol condensation reactions. In the examples below, aldehydes are used.

=== Base-catalyzed aldol condensation ===
:[[File:Base-catalysed aldol condensation.svg|center|600px|A mechanism for aldol condensation in basic conditions, which occurs via enolate intermediates and E1CB elimination.]]

=== Acid-catalyzed aldol condensation ===
:[[File:Acid-catalysed aldol condensation.svg|center|600px|A mechanism for aldol condensation in acidic conditions, which occurs through enol intermediates and an elimination reaction.]]
{| class="wikitable"
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| [[File:Aldol basisch startAnimGif 1.gif|Animation zum basenkat. Reaktionsmechanismus der Aldolkondensation]]
| [[File:Aldol sauer startAnimGif 1.gif|Animation zum säurekat. Reaktionsmechanismus der Aldolkondensation]]
|-
| animation, base catalyzed
| animation, acid catalyzed
|}

== Crossed aldol condensation ==
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 [[Chemistry:Inductive effect|+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 [[Chemistry:Cannizzaro reaction|Cannizzaro reaction]].<ref>{{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}}</ref>

==Examples==
The '''Aldox process''', developed by Royal Dutch Shell and Exxon, converts [[Chemistry:Propene|propene]] and [[Chemistry:Syngas|syngas]] to 2-ethylhexanol via [[Chemistry:Hydroformylation|hydroformylation]] to [[Chemistry:Butyraldehyde|butyraldehyde]], aldol condensation to 2-ethylhexenal and finally [[Chemistry:Hydrogenation|hydrogenation]].<ref>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}}</ref>
[[File:Aldox_process.svg|alt=Aldox process|center|frameless|635x635px]]
[[Chemistry:Pentaerythritol|Pentaerythritol]] is produced on a large scale beginning with crossed aldol condensation of [[Chemistry:Acetaldehyde|acetaldehyde]] and three equivalents of [[Physics:Formaldehyde|formaldehyde]] to give pentaerythrose, which is further reduced in a [[Chemistry:Cannizzaro reaction|Cannizzaro reaction]].<ref name="Schurink1941">{{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}}</ref>
[[File:Pentaerythritol Synthesis.svg|alt=Pentaerythritol Synthesis|center]]

== Scope ==
Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.<ref>{{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 = [[Chemistry:Molbank|Molbank]] | year = 2004 | volume = 2004 | issue = 1 | pages = M388 | doi = 10.3390/M388 |doi-access=free }}</ref> The synthetic procedure<ref>Ethyl 2-methylacetoacetate ('''2''') is added to a stirred solution of [[Chemistry:Sodium hydride|sodium hydride]] in dioxane. Then campholenic aldehyde ('''1''') is added and the mixture [[Reflux|reflux]]ed for 15 h. Then 2N [[Chemistry:Hydrochloric acid|hydrochloric acid]] is added and the mixture extracted with [[Chemistry:Diethyl ether|diethyl ether]]. The combined organic layers are washed with 2N [[Chemistry:Hydrochloric acid|hydrochloric acid]], saturated [[Chemistry:Sodium bicarbonate|sodium bicarbonate]] and [[Earth:Brine|brine]]. The organic phase is dried over anhydrous [[Chemistry:Sodium sulfate|sodium sulfate]] and the solvent evaporated under reduced pressure to yield a residue that is purified by [[Vacuum distillation|vacuum distillation]]  to give '''3''' (58%).</ref> is typical for this type of reaction. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in [[Chemistry:Decarboxylation|decarboxylation]].
[[File:Aldehyde aldol condensation example.png|alt=Aldol condensation of Ethyl 2-methylacetoacetate and campholenic aldehyde.|center|700x700px]]

Ethyl glyoxylate '''2''' and glutaconate (diethyl-2-methylpent-2-enedioate) '''1''' react to ''isoprenetricarboxylic acid'' '''3''' ([[Chemistry:Isoprene|isoprene]] (2-methylbuta-1,3-diene) skeleton) with [[Chemistry:Alkoxide|sodium ethoxide]]. This reaction product is very unstable with initial loss of [[Chemistry:Carbon dioxide|carbon dioxide]] and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the [[Chemistry:Carboxylic acid|carboxylic]] group in the ''cis''-dienoid structure.<ref>{{cite journal |author1=Goren, M. B. |author2=Sokoloski, E. A. |author3=Fales, H. M. | title = 2-Methyl-(1''Z'',3''E'')-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 }}</ref>

[[File:IsoprenetricarboxylicAcid2.png|center|500px|Isoprenetricarboxylic acid]]

Occasionally, an aldol condensation is buried in a multistep reaction or in [[Chemistry:Catalytic cycle|catalytic cycle]] as in the following example:<ref>{{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 = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]] | year = 2006 | volume = 128 | issue = 30 | pages = 9576–9577 | doi = 10.1021/ja0610434 | pmid = 16866480 }}</ref>

[[File:RuCatalyzedCyclizationofTerminalAlkynalstoCycloalkenes.png|center|500px|Ru Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes]]

In this reaction an ''alkynal'' '''1''' is converted into a [[Chemistry:Cycloalkene|cycloalkene]] '''7''' with a [[Chemistry:Ruthenium|ruthenium]] catalyst and the actual condensation takes place with intermediate '''3''' through '''5'''. Support for the [[Physics:Reaction mechanism|reaction mechanism]] is based on isotope labeling.{{Efn|The [[Chemistry:Ruthenium|ruthenium]] [[Chemistry:Catalyst|catalyst]], [CpRu(CH<sub>3</sub>CN)<sub>3</sub>]PF<sub>6</sub>, has a cyclopentadienyl [[Chemistry:Ligand|ligand]], three [[Chemistry:Acetonitrile|acetonitrile]] ligands and a phosphorus hexafluoride [[Chemistry:Counterion|counterion]]; the acidic proton in the solvent ([[Chemistry:Acetic acid|acetic acid]]) is replaced by [[Physics:Deuterium|deuterium]] for [[Physics:Isotopic labeling|isotopic labeling]]. Reaction conditions: 90°C, 24 hrs. 80% chemical yield. The first step is formation of the [[Chemistry:Transition metal carbene complex|Transition metal carbene complex]] '''2'''. Acetic acid adds to this intermediate in a [[Chemistry:Nucleophilic addition|nucleophilic addition]] to form enolate '''3''' followed by aldol condensation to '''5''' at which stage a molecule of [[Chemistry:Carbon monoxide|carbon monoxide]] is lost to '''6'''. The final step is [[Chemistry:Reductive elimination|reductive elimination]] to form the cycloalkene.}}

The reaction between [[Chemistry:Menthone|menthone]] ((2''S'',5''R'')-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 [[Chemistry:Potassium hydroxide|potassium hydroxide]] and a very polar solvent such as [[Chemistry:Dimethyl sulfoxide|DMSO]] in the reaction below:<ref>{{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 }}</ref>

[[File:Menthone Claisen-Schmidt.png|center|400px|A Claisen–Schmidt reaction]]
The product can epimerize by way of a common intermediate—[[Chemistry:Enolate|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.

== Other condensation reactions ==

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 [[Chemistry:Knoevenagel condensation|Knoevenagel condensation]].
* In a [[Chemistry:Perkin reaction|Perkin reaction]] the aldehyde is aromatic and the enolate generated from an anhydride.
* [[Chemistry:Claisen-Schmidt condensation|Claisen-Schmidt condensation]] between an aldehyde or ketone having an α-hydrogen with an aromatic carbonyl compound lacking an α-hydrogen.
* A [[Chemistry:Claisen condensation|Claisen condensation]] involves two [[Chemistry:Ester|ester]] compounds.
* A [[Chemistry:Dieckmann condensation|Dieckmann condensation]] involves two ester groups in the ''same molecule'' and yields a cyclic molecule
* In the [[Chemistry:Japp–Maitland condensation|Japp–Maitland condensation]] water is removed not by an elimination reaction but by a nucleophilic displacement
* A [[Chemistry:Robinson annulation|Robinson annulation]] involves an α,β-[[Chemistry:Saturated and unsaturated compounds|unsaturated]] [[Chemistry:Ketone|ketone]] and a carbonyl group, which first engage in a [[Chemistry:Michael reaction|Michael reaction]] prior to the aldol condensation.<ref name="Carey and Sundberg PartB" />
* In the [[Chemistry:Guerbet reaction|Guerbet reaction]], an aldehyde, formed ''[[Biology:In situ|in situ]]'' from an alcohol, self-condenses to the dimerized alcohol.

==See also==
* [[Chemistry:Auwers synthesis|Auwers synthesis]]
* Aldol addition

== References ==
{{Reflist}}

== Notes ==
{{Notelist}}

== External links ==
*[https://www.organic-chemistry.org/namedreactions/aldol-condensation.shtm Organic Chemistry Portal]

{{Organic reactions}}

[[Category:Condensation reactions]]
[[Category:Carbon-carbon bond forming reactions]]

{{Sourceattribution|Aldol condensation}}