The pinacol coupling reaction is an organic reaction that forms a carbon–carbon bond between carbonyl groups of aldehydes or ketones, resulting in a vicinal diol, typically using an electron donor in a free radical process. Discovered in 1859, it allows for various coupling reactions and has applications in total synthesis, including notable examples like the Mukaiyama and Nicolaou Taxol syntheses. The reaction mechanism involves a one-electron reduction leading to a ketyl radical anion, which couples to form the diol, with modern variants improving yields and selectivity through different reductants and conditions.
The pinacol coupling reaction is an organic reaction that forms a carbon–carbon bond between carbonyl groups of aldehydes or ketones, resulting in a vicinal diol, typically using an electron donor in a free radical process. Discovered in 1859, it allows for various coupling reactions and has applications in total synthesis, including notable examples like the Mukaiyama and Nicolaou Taxol syntheses. The reaction mechanism involves a one-electron reduction leading to a ketyl radical anion, which couples to form the diol, with modern variants improving yields and selectivity through different reductants and conditions.
The pinacol coupling reaction is an organic reaction that forms a carbon–carbon bond between carbonyl groups of aldehydes or ketones, resulting in a vicinal diol, typically using an electron donor in a free radical process. Discovered in 1859, it allows for various coupling reactions and has applications in total synthesis, including notable examples like the Mukaiyama and Nicolaou Taxol syntheses. The reaction mechanism involves a one-electron reduction leading to a ketyl radical anion, which couples to form the diol, with modern variants improving yields and selectivity through different reductants and conditions.
The pinacol coupling reaction is an organic reaction that forms a carbon–carbon bond between carbonyl groups of aldehydes or ketones, resulting in a vicinal diol, typically using an electron donor in a free radical process. Discovered in 1859, it allows for various coupling reactions and has applications in total synthesis, including notable examples like the Mukaiyama and Nicolaou Taxol syntheses. The reaction mechanism involves a one-electron reduction leading to a ketyl radical anion, which couples to form the diol, with modern variants improving yields and selectivity through different reductants and conditions.
A pinacol coupling reaction is an organic reaction in Pinacol coupling reaction
which a carbon–carbon bond is formed between the Named after Pinacol carbonyl groups of an aldehyde or a ketone in presence of an electron donor in a free radical process.[1] The Reaction type Coupling reaction
reaction product is a vicinal diol. The reaction is Identifiers
named after pinacol (also known as 2,3-dimethyl-2,3- Organic Chemistry pinacol-coupling- butanediol or tetramethylethylene glycol), which is the Portal reaction 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 The Pinacol coupling reaction
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 1. Fittig R (1859). "Ueber einige Producte der trockenen Destillation essigsaurer Salze" (http s://zenodo.org/record/1427129) [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 (https://doi.org/10.1002%2Fjlac.18591100103). 2. Smith (2020), March's Organic Chemistry, rxn. 19-80. 3. 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 (https://doi.org/10.1016%2Fj.tet.2006.09.002) 4. Bachmann WE (1943). "Benzopinacol" (http://www.orgsyn.org/demo.aspx?prep=cv2p0071). Organic Syntheses; Collected Volumes, vol. 2, p. 71. 5. 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 (https://doi.org/1 0.1021%2Fjo051213f). PMID 16209617 (https://pubmed.ncbi.nlm.nih.gov/16209617). 6. Hongjun Z, Jitai L, Yanjiang B, Tongshuang L (2003). "Pinacolization of aromatic aldehydes using Zn/montmorillonite K10-ZnCl2 in aqueous THF under ultrasound" (https://web.archive. org/web/20021121001218/http://www.chemistrymag.org/cji/2003/051008ne.htm). Chemical Journal on Internet. 5 (1): 8. Archived from the original (http://www.chemistrymag.org/cji/200 3/051008ne.htm) on 2002-11-21. 7. Kim YH, Kim SM, Youn SW (2001). "Asymmetric synthesis by stereocontrol" (https://doi.org/ 10.1351%2Fpac200173020283). Pure and Applied Chemistry. 73 (2): 283–286. doi:10.1351/pac200173020283 (https://doi.org/10.1351%2Fpac200173020283). 8. 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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PM C9132033). Chemical Science. 13 (20): 5973–5981. doi:10.1039/D2SC00800A (https://doi.o rg/10.1039%2FD2SC00800A). PMC 9132033 (https://www.ncbi.nlm.nih.gov/pmc/articles/P MC9132033). PMID 35685797 (https://pubmed.ncbi.nlm.nih.gov/35685797).
Further reading Adams R, Adams EW (1941). "Pinacol Hydrate" (http://www.orgsyn.org/demo.aspx?prep=cv 1p0459). Organic Syntheses; Collected Volumes, vol. 1, p. 459.
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