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.
| Pinacol coupling reaction | |
|---|---|
| Named after | Pinacol |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | pinacol-coupling-reaction |
Reaction mechanism
editThe 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
editThe 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
edit- ^ Fittig R (1859). "Ueber einige Producte der trockenen Destillation essigsaurer Salze" [On some products of the dry distillation of acetate salts]. Justus Liebigs Annalen der Chemie (in German). 110: 23–45. doi:10.1002/jlac.18591100103.
- ^ a b c Smith (2020), March's Organic Chemistry, rxn. 19-80.
- ^ a b c Chatterji, Anamitra; Joshi, N. N (2006). "Evolution of the stereoselective pinacol coupling reaction". Tetrahedron, vol. 62, pp. 12137-12158. Report #778. doi:10.1016/j.tet.2006.09.002
- ^ Bachmann WE (1943). "Benzopinacol". Organic Syntheses; Collected Volumes, vol. 2, p. 71.
- ^ Xu X, Hirao T (October 2005). "Vanadium-catalyzed pinacol coupling reaction in water". The Journal of Organic Chemistry. 70 (21): 8594–8596. doi:10.1021/jo051213f. PMID 16209617.
- ^ Hongjun Z, Jitai L, Yanjiang B, Tongshuang L (2003). "Pinacolization of aromatic aldehydes using Zn/montmorillonite K10-ZnCl2 in aqueous THF under ultrasound". Chemical Journal on Internet. 5 (1): 8. Archived from the original on 2002-11-21.
- ^ Kim YH, Kim SM, Youn SW (2001). "Asymmetric synthesis by stereocontrol". Pure and Applied Chemistry. 73 (2): 283–286. doi:10.1351/pac200173020283.
- ^ Calogero F, Magagnano G, Potenti S, Pasca F, Fermi A, Gualandi A, et al. (May 2022). "Diastereoselective and enantioselective photoredox pinacol coupling promoted by titanium complexes with a red-absorbing organic dye". Chemical Science. 13 (20): 5973–5981. doi:10.1039/D2SC00800A. PMC 9132033. PMID 35685797.
Further reading
edit- Adams R, Adams EW (1941). "Pinacol Hydrate". Organic Syntheses; Collected Volumes, vol. 1, p. 459.