:Acyloin condensation

Image:Intramolecular acyloin condensation.png

Intramolecular acyloin condensation is a classical approach for aliphatic ring synthesis, and "one of the best ways of closing rings of 10 members or more".Smith (2020), March's Organic Chemistry, 8th ed. Rxn. 19-82. 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), 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).{{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}} For larger rings, unsaturation does not inhibit cyclization. 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.

Tropolone is prepared via an initial acyloin condensation that delivers 2-hydroxycycloheptanone:{{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}}File:2-hydroxylcycloheptanone.svg

The dimethyl ester of sebacic acid can be converted to cyclodecanediol by acyloin condensation followed by hydrogenation using a copper chromite catalyst.{{cite journal|last1=Blomquist|first1=A. T.|last2=Goldstein|first2=Albert|title=1,2-Cyclodecanediol|journal=Organic Syntheses|date=1956|volume=36|page=12|doi=10.15227/orgsyn.036.0012}}

center

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.{{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}} 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.{{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}}

The mechanism consists of four steps:

1. Oxidative ionization of two sodium atoms on the double bond of two ester molecules.
2. Wurtz-type coupling between two molecules of the homolytic ester derivative. Alkoxy-eliminations in both sides occur, producing a 1,2-diketone.
3. Oxidative ionization of two sodium atoms on both diketone double bonds. The sodium enediolate is formed.
4. Neutralization with water to form the enediol, which tautomerizes to acyloin.[https://www.organic-chemistry.org/namedreactions/acyloin-condensation.shtm Acyloin condensation]

Image:Acyloin condensation mecanism2.png

The intermediate enediolate dianion can be trapped with trimethylsilyl chloride.{{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}}

The reaction also produces stoichiometric quantities of alkoxide base, which can catalyze the competing Dieckmann condensation. {{Ill|Klaus Rühlmann|lt=Rühlmann's|de}}'s technique traps the alkoxide and the acyloin with trimethylchlorosilane for considerably improved yields.{{cite journal |author=Rühlmann K. |year=1971 |title=Die Umsetzung von Carbonsäureestern mit Natrium in Gegenwart von Trimethylchlorsilan |trans-title=Reaction of carboxylic acid esters with sodium in the presence of trimethylchlorosilane |journal=Synthesis |language=de |volume=1971 |issue=5 |pages=236–253 |doi=10.1055/s-1971-21707}} The disilyl diether can then be cloven with acidified water or methanol. Image:Ruehlmann.png

In general, highly pure sodium can result in lower yields. The reaction is proposed to be influenced by a potassium impurity, which served as a catalyst. Sodium–potassium alloy is a viable reductant.

Usually toluene, dioxane, tetrahydrofuran or acyclic dialkylethers are employed as solvents. Advantageously also N-methyl-morpholine has been used. It allowed in some cases a successful reaction, where an otherwise-insoluble product coated the sodium sand, inhibiting the reaction.

• Benzoin condensation
• Bouveault–Blanc reduction
• Claisen condensation
• Dieckmann condensation

{{Reflist}}

• [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