Pinacol coupling reaction

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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