Acyloin Condensation

Acyloin Condensation is a coupling reaction in which two carboxylic acid esters couple in the presence of metallic sodium under inert atmosphere to yield an α-hydroxyketone (also known as acyloin).

This reaction is favoured when R is an long chain alkyl group and also when high boiling solvents are used. Intramolecular condensation also takes place leading to closed rings of different sizes (like paracyclophanes or catenanes). But again this all depends on ring size and steric properties, but independent from high dilution. Intramolecular cyclisation over intermolecular polymerisation in diesters.

If the condensation is carried out in the presence of proton donor like alcohol then reduction of ester to alcohol takes place. This reaction is also called as Bouveault-Blanc Reduction.

Mechanism of Acyloin Condensation

Above mechanism involves

(1) Oxidative 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 Würtz type coupling). 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 enodiolate is formed.

(4) Neutralization with water to form the enodiol, which tautomerizes to acyloin.

The enediolate intermediate is trapped as the bis-silyl derivative by the use of trapping agent chlorotrimethylsilane. This intermediate can be isolated and subsequently hydrolysed under acidic condition to the acyloin, which gives a better overall yield. Toluene, dioxane, THF or dialkylethers may be used and in some cases NMP (I am not sure of this) may also be used.

Literature references:

(1) Acyloin condensation in which chlorotrimethylsilane is used as a trapping agent
     Organic Syntheses, Coll. Vol. 6, p.167 (1988); Vol. 57, p.1 (1977).

(2) The Acyloin Condensation of Aralkyl Esters
      J. Am. Chem. Soc., 1952, 74 (19), pp 4861–4864

(3) The Formation of Five- and Six-membered Rings by the Acyloin Condensation.
      J. Am. Chem. Soc., 1957, 79 (22), pp 6050–6055

(4) Mechanism of the acyloin condensation
     J. Org. Chem., 1975, 40 (4), pp 393–402

Predicting Proton Chemical Shift Values

Many at times we have found it tough to predict the right chemical shift for a proton. Especially if you have just come out of college and started your research.  But I am sure with some practice and skill you will master this..:)

Below I have put a proton shift values table so that you can easily predict which proton comes at what chemical shift. Remember you cannot exactly predict the shift value but come you predict the narrow range the proton falls in.

Please note that all these values have been taken in deuterated chloroform.

If you need some practice on this you may visit the following link on the chemistry department's page of University of Wisconsin. click here.

Or you can also view the below lecture by sarutahiko on youtube to get more understanding on this topic.

Claisen Condensation

The Claisen condensation (different from  Claisen rearrangement) is a C-C bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base (like sodium ethoxide), resulting in a β-keto ester or a β-diketone.  It is named after Rainer Ludwig Claisen (German Chemist), who first published his work on the reaction in 1881.

The base used must not interfere with the reaction by undergoing nucleophilic substitution or addition with a carbonyl carbon. For this reason, the conjugate sodium alkoxide base of the alcohol formed (like sodium ethoxide if ethanol is formed) is often used, since the alkoxide is regenerated. In some cases LDA (lithium diisopropylamide) a non nucleophilic base is used (e.g. mixed claisen condensation)

The alkoxy portion of the ester must be a relatively good leaving group. Methyl and ethyl esters, which yields methoxide and ethoxide, respectively, are commonly used.

The driving force is the formation of the stabilized anion of the β-keto ester. If two different esters are used, an essentially statistical mixture of all four products is generally obtained, and the preparation does not have high synthetic utility.

However, if one of the ester partners has enolizable α-hydrogens and the other does not (e.g., aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful. If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone or a β-ketonitrile is obtained, respectively.

The use of stronger bases (like sodium amide or sodium hydride) instead of sodium ethoxide, often increases the yield.

Mixed Claisen Condensation (Reaction between enolizable ester or ketone and a nonenolizable ester)

Intramolecular Claisen Condensation (Reaction where a molecule with two ester groups reacts intramolecularly, forming a cyclic β-keto ester.  This is also called as Dieckmann Condensation)