Pinacol Coupling

The Pinacol coupling reaction is a significant organic chemical process that forms a carbon-carbon bond between the carbonyl groups of aldehydes or ketones, resulting in a vicinal diol as the product. This reaction is named after its product with acetone, pinacol (2,3-dimethyl-2,3-butanediol or tetramethylethylene glycol). The reaction can occur as a homocoupling or an intramolecular cross-coupling. Discovered by Wilhelm Rudolph Fittig in 1859, the Pinacol coupling reaction has been extensively studied and is known for its versatility in tolerating various reductants, including electrochemical syntheses[1].

Reaction Mechanism

The mechanism begins with a one-electron reduction of the carbonyl group by a reducing agent, such as magnesium, to form a ketyl radical anion species. Two of these ketyl groups then undergo a coupling reaction to yield a vicinal diol with both hydroxyl groups deprotonated. The addition of water or another proton donor subsequently protonates the hydroxyl groups to give the diol product. When magnesium is used as the 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 the addition of water, resulting in the formation of magnesium hydroxide[1].

Scope and Variants

The Pinacol coupling reaction is known for its broad scope, including homo- and cross-coupling, as well as intra- and inter-molecular reactions with appropriate diastereo- or enantioselectivity. As of 2006, the enantioselective cross-coupling of aliphatic aldehydes remained a challenge. Aryl carbonyls generally yield higher than aliphatic carbonyls, and diaryls may spontaneously react with a hydride donor in the presence of light. The reaction is adaptable to modern conditions, tolerating protic substrates and solvents, and can sometimes be performed in water. While ester groups do not react, some nitriles do. The traditional reductants for the Pinacol coupling are alkali or alkaline earth metals, but these often result in low yields and selectivity. Catalytic salts of most early transition metals and a nonmetal reductant (e.g., iodides) have shown dramatically improved performance[1].

Applications

The Pinacol coupling reaction has been utilized in the synthesis of complex molecules and in total synthesis efforts, such as the Mukaiyama Taxol total synthesis and the Nicolaou Taxol total synthesis. It has also been employed in the synthesis of diethylstilbestrol using p-hydroxypropiophenone as the substrate. An unsymmetrical Pinacol coupling reaction between para-chloro-acetophenone and acetone has been used to produce phenaglycodol[1].

In summary, the Pinacol coupling reaction is a versatile and widely studied organic reaction that forms vicinal diols from carbonyl compounds. Its broad scope, tolerance of various reductants, and potential for enantioselective and diastereoselective variants make it a valuable tool in organic synthesis and chemical research[1].

Citations:

[1] https://en.wikipedia.org/wiki/Pinacol_coupling_reaction

[2] https://onlinelibrary.wiley.com/doi/pdf/10.1002/9783527613267.ch03

[3] https://quod.lib.umich.edu/cgi/p/pod/dod-idx/progress-in-the-intermolecular-pinacol-cross-coupling-.pdf?c=ark%3Bidno%3D5550190.0013.104

[4] https://www.organic-chemistry.org/namedreactions/pinacol-coupling-reaction.shtm

[5] https://byjus.com/chemistry/pinacol-pinacolone-rearrangement/

[6] https://www.walmart.com/ip/Chemical-Engineering-Methods-and-Technology-Some-Applications-of-Ultrasound-Irradiation-in-Pinacol-Coupling-of-Carbonyl-Compounds-Paperback-9781617289781/15057642

[7] https://www.sciencedirect.com/topics/chemistry/pinacol-coupling

[8] https://www.organic-chemistry.org/namedreactions/mcmurry-reaction.shtm

[9] https://pubs.acs.org/doi/10.1021/ol900619d

[10] https://www.chemeurope.com/en/encyclopedia/Pinacol_coupling_reaction.html

[11] https://www.youtube.com/watch?v=N-EclxA4nSk

[12] https://www.sciencedirect.com/topics/chemistry/pinacol

[13] https://www.sciencemadness.org/smwiki/index.php/Pinacol_coupling_reaction

[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162391/

[15] https://www.wikiwand.com/en/Pinacol_coupling_reaction