Pinacol coupling reaction

A pinacol coupling reaction is an organic reaction in which a carbon–carbon bond is formed between the carbonyl groups of an aldehyde or a ketone in presence of an electron donor in a free radical process.^[1] The reaction product is a vicinal diol. The reaction is named after pinacol (also known as 2,3-dimethyl-2,3-butanediol or tetramethylethylene glycol), which is the product of this reaction when done with acetone as reagent. The reaction is usually a homocoupling but intramolecular cross-coupling reactions are also possible. Pinacol was discovered by Wilhelm Rudolph Fittig in 1859.

Reaction mechanism

The first step in the reaction mechanism is a one-electron reduction of the carbonyl group by a reducing agent —such as magnesium— to a ketyl radical anion species. Two ketyl groups react in a coupling reaction yielding a vicinal diol with both hydroxyl groups deprotonated. Addition of water or another proton donor gives the diol. With magnesium as an electron donor, the initial reaction product is a 5-membered cyclic compound with the two oxygen atoms coordinated to the oxidized Mg²⁺ ion. This complex is broken up by addition of water with formation of magnesium hydroxide. The pinacol coupling can be followed up by a pinacol rearrangement. A related reaction is the McMurry reaction, which uses titanium(III) chloride or titanium(IV) chloride in conjunction with a reducing agent for the formation of the metal-diol complex, and which takes place with an additional deoxygenation reaction step in order to provide an alkene product.

Scope

The pinacol reaction is extremely well-studied and tolerates many different reductants, including electrochemical syntheses. Variants are known for homo- and cross-coupling, intra- and inter-molecular reactions with appropriate diastereo- or enantioselectivity;^[2] as of 2006, the only unsettled frontier was enantioselective cross-coupling of aliphatic aldehydes.^[3] In general, aryl carbonyls give higher yields than aliphatic carbonyls, and diaryls may spontaneously react with a hydride donor in the presence of light.^[2]

Although an active metal reduction, modern pinacol reactions tolerate protic substrates and solvents; it is sometimes performed in water. Ester groups do not react, but some nitriles do. In general, aza variants are less well-studied, but the analogous reaction with imines yields diamines.^[2]

Traditionally, the pinacol reductant is an alkali or alkaline earth metal, but these result in low yields and selectivity. Catalytic salts of most early transition metals and a nonmetal reductant (e.g. iodides) give dramatically improved performance, but stoichiometric reductions typically deoxygenate to the alkene (the McMurry reaction).^[3]

The reaction's applications include closure of large rings. Two famous examples of pinacol coupling used in total synthesis are the Mukaiyama Taxol total synthesis and the Nicolaou Taxol total synthesis.^[3]

Benzophenone may undergo the pinacol coupling photochemically.^[4] Benzaldehyde may also be used as a substrate with the use of catalytic vanadium(III) chloride and aluminium metal as the stoichiometric reductant.^[5] This heterogeneous reaction in water at room temperature yields 72% after 3 days with 56:44 dl:meso composition.

In another system with benzaldehyde, Montmorillonite K-10]] and zinc chloride in aqueous THF under ultrasound the reaction time is reduced to 3 hours (composition 55:45).^[6] On the other hand, certain tartaric acid derivatives can be obtained with high diastereoselectivity in a system of samarium(II) iodide and HMPA.^[7]

A titanium-catalyzed photocatalytic approach was also developed: the use of catalytic titanocene dichloride in the presence of a red-absorbing organic dye as the photosensitizer, and Hantzsch ester as the terminal reducing agent, enabled the homocoupling reactions of a wide variety of aromatic aldehydes in trifluorotoluene under orange-light irradiation, with high yields and diastereoselectivities (more than 20:1 dl:meso). An enantioselective version (up to 92% e.e.), using catalytic amounts of a chiral titanium salen, was also developed.^[8]

p-Hydroxypropiophenone is used as the substrate in the synthesis of diethylstilbestrol.

An unsymmetrical pinacol coupling reaction between para-chloro-acetophenone and acetone was employed to give phenaglycodol in a 40% yield.

References

Further reading

This page was last edited on 11 March 2024, at 19:54