Pinacol Rearrangement

The Pinacol Rearrangement

• The pinacol rearrangement is an acid-catalyzed rearrangement of 1,2-diols (vicinal diols)
• The acid serves to protonate one of the hydroxyl groups, which departs as water, giving a carbocation.
• Subsequently,  a C-O pi bond is formed as a C-C bond migrates to the adjacent carbon.
• It resembles the familiar hydride shifts and alkyl shifts in that a less stable carbocation is converted to a more stable carbocation (albeit with the twist is that this “more stable carbocation” is actually the resonance form of a protonated ketone).
• Pinacol rearrangements can result in ring expansions

Table of Contents

1. The Pinacol Rearrangement
2. Mechanism of the Pinacol Rearrangement
3. Pinacol Rearrangements With Ring Expansion
4. Summary
5. Notes
6. Quiz Yourself!
7. (Advanced) References and Further Reading

1. The Pinacol Rearrangement

Pinacol is a pleasant-smelling 1,2-diol (“vicinal” diol) with the following structure:

When pinacol is treated with strong acid such as sulfuric acid (H₂SO₄),  a new ketone is formed and a molecule of water is lost from the diol.  Upon inspection, it can be seen that the carbon skeleton has undergone rearrangement:

The most important thing to note here is that one of the highlighted CH₃ groups on C₂ has moved to C₃.

This reaction has become known as the pinacol rearrangement, and it is a fairly common rearrangement of 1,2-diols, having first been observed as far back as 1860. [See Ref 1]

It is a special case of our old friends the 1,2-hydride shift and the 1,2-alkyl shift (See article: Rearrangement Reactions – Hydride Shifts)

The reaction can be performed with a wide variety of other vicinal diols. Here is another example:

In this case, a phenyl group migrates to the adjacent carbon to give a new ketone adjacent to a quaternary carbon.

2. Mechanism Of The Pinacol Rearrangement

So how does this reaction work?

If we think back to 1,2-hydride shifts and 1,2-alkyl shifts, we’ll recall that they involve formation of a carbocation followed by migration of H(-) or R(-) to generate a new carbocation. (See article: Rearrangement Reactions With Alkyl Shifts)

So how might we generate a carbocation here from the vicinal diol and the acid?

By protonating one of the alcohols, we generate its conjugate acid R-OH₂(+)

Since H₂O is a much weaker base than HO(-), this molecule has a much better  leaving group. (See article: What Makes A Good Leaving Group?). Breakage of the C-O bond then generates a carbocation.

Now, the key rearrangement step can occur, whereby a methyl group (CH₃) can migrate from C-2 to C-3. The C₂-CH₃ bond breaks and the C₃-CH₃ bond forms, giving a new carbocation.

Recall that rearrangements are generally favored when they result in a more stable carbocation. Is this true in this case?

Actually, yes!

If you look at the new carbocation that is formed, it can have its octet filled through donation of a lone pair by the adjacent oxygen, forming a new pi-bond in the process. (Note: this is often called, “pi-donation” and it’s extremely important).

That is, this “carbocation” is actually just a resonance form of a protonated ketone!

The final step is deprotonation of the protonated ketone with a weak base to give the neutral ketone.

That’s it.

Although I’ve shown the reaction as proceeding stepwise, it’s also perfectly acceptable to show it as occurring in a concerted fashion. Note 1.

3. Pinacol Rearrangements With Ring Expansion

The pinacol rearrangement can also occur with ring expansion.

That is, pinacol rearrangements of cyclic molecules can result in the formation of larger rings.

This is fundamentally no different from the mechanism of a typical pinacol rearrangement, but students often find them trickier so they end up being common exam problems.

See if you can draw the key curved arrow to show the rearrangement in this cyclic example:

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Here’s another one. Slightly different challenge. Starting with the molecule on the left, can you predict what the product of the pinacol rearrangement product on the right will be?

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4. Summary

• The pinacol rearrangement is a special case of carbocation rearrangement where migration of a carbon is accompanied by formation of a new C-O (pi) bond. The product is a ketone.
• The pinacol rearrangement is promoted by the addition of acid which assists in loss of water as a leaving group.
• Make sure you can draw the mechanism of pinacol rearrangements that result in ring expansion!

Notes

Note 1. Here is an example of showing the key rearrangement step as a concerted reaction. For more discussion on the plausibility of concerted versus stepwise pinacol rearrangements, see Ref 9.

Note 2. Pinacol itself is often encountered in the Suzuki reaction, since boronic esters with pinacol are highly stable and can be purified by column chromatography.

For more notes on this process, see this reference from Organic Syntheses (Org. Synth. 2011, 88, 202-206  DOI: 10.15227/orgsyn.088.0202)

Quiz Yourself!

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(Advanced) References and Further Reading

1. Ueber einige Producte der trockenen Destillation essigsaurer Salze
   R. Fittig,
   Annalen, 1859, 110, 17, 23; 1860, 114, 54.
   DOI: 10.1002/jlac.18591100103
   Original reports on what would come to be called the Pinacol Rearrangement.
2. PINACOLONE
   A. Hill and E. W. Flosdorf
   Org. Synth. 1925, 5, 91
   DOI: 10.15227/orgsyn.005.0091
   Reproducible and tested experimental procedure for the pinacol-pinacolone rearrangement in Organic Syntheses.
3. The Pinacol Rearrangement
   Clair J. Collins
   Quarterly Reviews of the Chemical Society, 1960, 14, 357-377
   DOI: 10.1039/QR9601400357
   Review on the pinacol rearrangement covering the older literature.
4. Internally competitive methyl vs. methyl-d3 migration and kinetic isotope effects. Means of determining whether or not methyl migration occurs in the rate-controlling step
   W. M. Schubert and Paul H. LeFevre
   Journal of the American Chemical Society 1972 94 (5), 1639-1645
   DOI: 10.1021/ja00760a035
   The authors find a significant kinetic isotope effect for the migration of CH3 vs CD3 (1.232) in the pinacol rearrangement, indicating that alkyl migration is the rate-determining step after a (reversible) C-O bond-breaking step.
5. What Is a Discovery? Carbon Skeletal Rearrangements as Counter‐Examples to the Rule of Minimal Structural Change
   Jerome A. Berson
   Angewandte Chemie International Edition 2002 41 (24), 4655-4660
   DOI: 1002/anie.200290007
   This article provides a historical perspective on the discovery of the pinacol rearrangement, including the mistakes that were made in characterizing the products and also includes references to old papers (1850’s and earlier) on the topic.

6. Stereochemical fate of an asymmetric migrating group in the pinacol rearrangement
   J. J. Beggs and M. B. Meyers
   J. Chem. Soc. B 1970, 930-934
   DOI: 10.1039/J29700000930
   The authors study the pinacol rearrangement of a chiral diol and finds that migration of a chiral alkyl fragment does not result in the loss of optical activity, indicating that it proceeded with retention of configuration.

7. The Pinacol—Pinacolone Rearrangement. VI. The Rearrangement of Symmetrical Aromatic Pinacols
   W. E. Bachmann and James W. Ferguson
   Journal of the American Chemical Society 1934 56 (10), 2081-2084
   DOI: 10.1021/ja01325a023
   Very interesting study on a series of symmetrical aromatic pinacols R1R2C(OH)(HO)CR2R1 to investigate relative migratory aptitudes. Aromatic groups with p-alkoxy groups had the highest migratory aptitudes; o-halophenyls had the lowest.
8. Single Stereodifferentiation Associated with Carbon Atom Insertion during the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols
   Leo A. Paquette, James C. Lanter, and Jeffrey N. Johnston
   The Journal of Organic Chemistry 1997 62 (6), 1702-1712
   DOI: 10.1021/jo962019j
   Prof. Leo Paquette demonstrates that stereodifferentiation is possible in pinacol-type rearrangements.
9. Theoretical study of the reaction mechanism and migratory aptitude of the pinacol rearrangement
   Kensuke Nakamura and Yoshihiro Osamura
   Journal of the American Chemical Society 1993 115 (20), 9112-9120
   DOI: 10.1021/ja00073a029
   This theoretical study evaluates both concerted and stepwise pathways for the pinacol rearrangement proposes that the pinacol rearrangement proceeds through a concerted mechanism in non-ionizing solvents.
10. Dynamic Effects on Migratory Aptitudes in Carbocation Reactions
    Zhitao Feng and Dean J. Tantillo
    Journal of the American Chemical Society 2021 143 (2), 1088-1097
    DOI: 10.1021/jacs.0c11850
    Theoretical study on migratory aptitudes in carbocation rearrangement reactions.

Real-Life Examples:

Org. Synth. 1925, 5, 91

DOI Link: 10.15227/orgsyn.005.0091

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Org. Synth. 1934, 14, 12

DOI Link: 10.15227/orgsyn.014.0012

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