View source for Chemistry:Acyloin condensation

{{Reactionbox
| Name = Acyloin condensation
| Type = Coupling reaction
| Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = acyloin-condensation
   | RSC_ontology_id = 0000085
 }}
}}
'''Acyloin condensation''' is a [[Chemistry:Redox|reductive]] coupling of two carboxylic [[Chemistry:Ester|ester]]s using metallic [[Chemistry:Sodium|sodium]] to yield an α-hydroxyketone, also known as an [[Chemistry:Acyloin|acyloin]].<ref>{{cite journal 
 | title =  Action du sodium sur les éthers des acides monobasiques à fonction simple de la série grasse | language = fr
 | trans-title = Effect of sodium on the ethers of single-function monobasic acids of the fatty series
 | journal = Compt. Rend. 
 | volume = 140 
 | pages = 1593–1595
 | year = 1905 
 | url =  http://gallica.bnf.fr/ark:/12148/bpt6k30949/f1689.table
 }}</ref><ref>{{cite journal 
 | title = The Acyloin Condensation as a Cyclization Method  
 | author =  Finley, K. T. 
 | journal =  [[Chemistry:Chem. Rev.|Chem. Rev.]]
 | volume =  64
 | issue = 5
 | pages = 573–589
 | year = 1964 
 | doi = 10.1021/cr60231a004 
}}</ref><ref>Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. [[Chemistry:Organic Reactions|''Org. React.'']] '''1976''', ''23''.</ref>

[[Image:Acyloin Condensation.png|center|350px|The acyloin condensation]]

The reaction is most successful when ''R'' is [[Chemistry:Aliphatic compound|aliphatic]] and [[Chemistry:Chemically inert|saturated.]] The reaction is performed in aprotic solvents with a high [[Physics:Boiling point|boiling point]], such as [[Chemistry:Benzene|benzene]] and [[Chemistry:Toluene|toluene]] in an oxygen free atmosphere of nitrogen (as even traces of oxygen interfere with the reaction path and reduce the yield). The use of protic solvents results in the Bouveault-Blanc reduction of the separate esters rather than condensation.  Depending on ring size and steric<!--conformational--> properties, but independent from high dilution, the acyloin condensation of diesters favours intramolecular cyclisation over intermolecular polymerisation when diesters are used (see below). To account for such cyclisation, it is suggested that the ends, where ester groups are present, are adsorbed, albeit weakly, at nearby sites on the sodium metal. Thus, the reactive ends are not available for polymerisation, thereby decreasing competition for the cyclisation process. Diesters possessing 10 or more carbons undergo cyclisation very easily.<ref>{{Cite book|last=Sanyal|first=Somorendra Nath|title=Reactions, Rearrangements, and Reagents|publisher=Bharati Bhavan Publishers|year=2013|isbn=978-81-7709-605-7|pages=77-78|language=English}}</ref>

== Acyloin cyclization of diesters ==
[[Image:Intramolecular acyloin condensation.png|center|273px|The acyloin condensation]]
The cyclization of diesters by intramolecular acyloin condensation is a classical approach for the synthesis of aliphatic ring systems.  In general, compared to other cyclization reactions that proceed under basic conditions like the Ziegler-Thorpe and Dieckmann ring formation methods, the acyloin synthesis is suitable for more ring sizes, especially when the Rühlmann method is used to trap the cyclization product as the bis(trimethylsiloxy)alkene (enediol disilyl ether).  Although 3-membered rings are not accessible through the acyloin condensation, 5- and 6-membered rings form in high yield (80 – 85% yield), 4-, 7-, 10-, and 11-membered rings form in moderate yield (50 – 60% yield),<ref>{{cite journal|doi=10.15227/orgsyn.057.0001|first1=Jordan J.|last1=Bloomfield|first2=Janice M.|last2=Nelke |title=Acyloin Condensation in Which Chlorotrimethylsilane is Used as a Trapping Agent: 1,2-Bis(Trimethylsilyloxy)Cyclobutene and 2-Hydroxycyclobutanone|journal=Organic Syntheses|volume=57|pages=1|year=1977}}</ref> 8- and 9-membered rings form in poor to modest yield (30 – 40% yield), and finally, 12-membered and higher rings form in good to excellent yields (>70% yield).  Although yields for 4-membered and medium-sized rings are poor to moderate, the acyloin condensation constitutes one of the earliest practical cyclization reactions to prepare these challenging ring sizes.  [[Chemistry:Tropolone|Tropolone]] is prepared via an initial acyloin condensation that delivers 2-hydroxycycloheptanone.<ref>{{cite journal|doi=10.1021/ja01153a025|title=Mold Metabolites. VI. The Synthesis of Tropolone|year=1951|last1=Knight|first1=Jack D.|last2=Cram|first2=Donald J.|journal=Journal of the American Chemical Society|volume=73|issue=9|pages=4136–4138}}</ref> 
:[[File:2-hydroxylcycloheptanone.svg|thumb|center|Route to 2-hydroxylcycloheptanone via acyloin condensation]]

In comparison, the Dieckmann method is practical only for 5- to 8-membered rings (with modest yields for 7- and 8-membered).  The Thorpe method is more easily modified via high dilution (e.g., 0.001 M in benzene/ether) to enable the synthesis of large rings, but 4-membered and 9- to 13-membered rings are still not accessible. Concentration is much less important a factor for obtaining high yields for the acyloin condensation, as the reaction occurs on the surface of the sodium metal.<ref>{{Cite book|title=Principles of organic synthesis.|last=Norman, R. O. C. (Richard Oswald Chandler)|date=1993|publisher=Blackie Academic & Professional|others=Coxon, J. M. (James Morriss)|isbn=0751401269|edition= 3rd.|location=London|oclc=27813843}}</ref>  Although, the need for sodium metal limits the functional group tolerance of the reaction, compared to more modern cyclization reactions (e.g. Yamaguchi esterification, ring-closing olefin metathesis), the acyloin condensation continues to be used in the synthesis of complex natural products for the preparation of challenging ring systems.<ref>{{Cite book|title=Strategic applications of named reactions in organic synthesis : background and detailed mechanisms|last=Kürti, László|date=2005|publisher=Elsevier Academic Press|others=Czakó, Barbara.|isbn=9780124297852|location=Amsterdam|oclc=60792519}}</ref>

== Mechanism==

The mechanism consists of four steps:

:'''(1)''' Oxidative [[Physics:Ionization|ionization]] of two sodium atoms on the double bond of two ester molecules.
:'''(2)''' Free radical coupling between two molecules of the homolytic ester derivative (A [[Chemistry:Wurtz reaction|Wurtz type coupling]]). Alkoxy-eliminations in both sides occur, producing a 1,2-diketone.
:'''(3)''' Oxidative [[Physics:Ionization|ionization]] of two sodium atoms on both diketone double bonds. The sodium enodiolate is formed.
:'''(4)''' [[Chemistry:Neutralization|Neutralization]] with water to form the enodiol, which tautomerizes to acyloin.<ref>[https://www.organic-chemistry.org/namedreactions/acyloin-condensation.shtm  Acyloin condensation]</ref>

:[[Image:Acyloin condensation mecanism2.png|center|550px|The acyloin condensation]]

==Variations==
===Rühlmann-method===
The method according to Rühlmann<ref>{{cite journal 
 | title = Die Umsetzung von Carbonsäureestern mit Natrium in Gegenwart von Trimethylchlorsilan | language = de
 |trans-title= Reaction of carboxylic acid esters with sodium in the presence of trimethylchlorosilane 
 | author = Rühlmann K.  
 | journal = Synthesis
 | issue = 5
 | pages = 236–253  
 | year = 1971 
 | doi =10.1055/s-1971-21707 
 | volume = 1971 
}}</ref> employs [[Chemistry:Trimethylsilyl chloride|trimethylchlorosilane]] as a trapping reagent; by this, competing reactions are efficiently subdued. Generally, yields increase considerably. The hydrolytic cleavage of the silylether gives the acyloin. To achieve a mild cleavage methanol can be used in several cases.

[[Image:Ruehlmann.png|center|600px|Rühlmann-method]]

Usually [[Chemistry:Toluene|toluene]], dioxane, [[Chemistry:Tetrahydrofuran|tetrahydrofuran]] or acyclic dialkylethers are employed as solvents. Advantageously also ''N''-methyl-[[Chemistry:Morpholine|morpholine]] has been used. It allowed in some cases a successful reaction, in which otherwise the reaction failed in less polar media. <!--with products that contained further functional groups (amines). A lack of solubility (in "normal" solvents) caused a sticky coating and thus an irreversible deactivation of the sodium sand-->

==See also==
*[[Chemistry:Benzoin condensation|Benzoin condensation]]
*[[Chemistry:Bouveault–Blanc reduction|Bouveault–Blanc reduction]]
*[[Chemistry:Claisen condensation|Claisen condensation]]
*[[Chemistry:Dieckmann condensation|Dieckmann condensation]]

==References==
{{Reflist}}

== External links ==
* [https://commons.wikimedia.org/wiki/File:A-K_startAnimGif.gif An animation of the mechanism]
{{Organic reactions}}
[[Category:Condensation reactions]]
[[Category:Organic redox reactions]]
[[Category:Carbon-carbon bond forming reactions]]

{{Sourceattribution|Acyloin condensation}}