Acyloin condensation is a reductive coupling of two carboxylic

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

s using metallic

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

to yield an α-hydroxyketone, also known as an

acyloin Acyloins or α-hydroxy ketones are a class of organic compounds which all possess a hydroxy group adjacent to a ketone group. The name acyloin is derived from the fact that they are formally derived from reductive coupling of carboxylic acyl gro ...

. The reaction is most successful when ''R'' is

aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, or ...

and saturated. The reaction is performed in aprotic solvents with a high

boiling point The boiling point of a substance is the temperature at which the vapor pressure of a liquid equals the pressure surrounding the liquid and the liquid changes into a vapor. The boiling point of a liquid varies depending upon the surrounding envir ...

, such as

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

and

toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) at ...

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 properties, but independent from high dilution, the acyloin condensation of diesters favours intramolecular cyclisation over intermolecular

polymerisation In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many for ...

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.

Acyloin cyclization of diesters

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), 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.

Tropolone Tropolone is an organic compound with the chemical formula . It is a pale yellow solid that is soluble in organic solvents. The compound has been of interest to research chemists because of its unusual electronic structure and its role as a ligan ...

is prepared via an initial acyloin condensation that delivers 2-hydroxycycloheptanone. : 2-hydroxylcycloheptanone

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. 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.

Mechanism

The mechanism consists of four steps: :(1) Oxidative

ionization Ionization, or Ionisation is the process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged atom or molecule i ...

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 Wurtz type coupling). Alkoxy-eliminations in both sides occur, producing a 1,2-diketone. :(3) Oxidative

of two sodium atoms on both diketone double bonds. The sodium enodiolate is formed. :(4) Neutralization with water to form the enodiol, which tautomerizes to acyloin. :

Variations

Rühlmann-method

The method according to Rühlmann employs trimethylchlorosilane as a

trapping reagent In chemistry, a chemical trap is a chemical compound that is used to detect unstable compounds. The method relies on efficiency of bimolecular reactions with reagents to produce a more easily characterize trapped product. In some cases, the trappin ...

; 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. Usually

dioxane 1,4-Dioxane () is a heterocyclic organic compound, classified as an ether. It is a colorless liquid with a faint sweet odor similar to that of diethyl ether. The compound is often called simply dioxane because the other dioxane isomers ( 1,2- ...

tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...

or acyclic dialkylethers are employed as solvents. Advantageously also ''N''-methyl-

morpholine Morpholine is an organic chemical compound having the chemical formula O( C H2CH2)2 NH. This heterocycle features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium. Fo ...

has been used. It allowed in some cases a successful reaction, in which otherwise the reaction failed in less polar media.

References

External links