Pinacol-Pinacolone Rearrangement Reaction

 

Pinacols are ditertiary 1, 2- diols. The simplest member of the class is Me₂C(OH).C(OH)Me₂. When this treated with dilute or moderately concentrated H₂SO₄, a rearrangement reaction takes place which lead to the formation of Me₃CCOMe (pinacolone), and the rearrangement is known as the pinacol-pinacolone rearrangement.

 

Nowadays the acid-catalysed rearrangement reactions of 1, 2-diols to oxo compounds, aldehydes or ketones, are called the pinacol-pinacolone rearrangements. For example

These examples show that the migration origin and migration terminus are the two adjacent C atoms, and the migrating group may be an aryl or an alkyl group, or an H atom etc. Migration of a bond may also occur in this rearrangement whereby ring expansion and ring contraction reactions may take place.

Rearrangement reactions of 1, 2-halohydrines and 1, 2-amino-alchohols to pinacolones are analogous reactions and called the pinacolic rearrangements; these are carried out by treating the former compounds with Ag⁺ and the latter compounds with HNO₂ (NaNO₂/HCl).

Since highly branched oxo compounds are very difficult to prepare by the other reactions, this rearrangement has interesting applications in synthesis.

For example, methyl isopropyl ketone is easily prepared from 2, 3- dichloro-2-methylbutane by this rearrangement.

Spiranes and their derivatives can also be prepared by this reaction; e.g.

The diol F₃CPhC(OH)C(OH)MeCF₃ containing strong electron-withdrawing –CF₃ group does not undergo pinacol rearrangement and this is because the –CF₃ group highly disfavors the formation of a carbocation. In fact, by intensifying the positive charge, it destabilizes the carbocation and thereby increases the energy of activation of the rate-determining step.

This electron-deficient skeletal rearrangement reaction is an example of intramolecular anionotropic 1, 2- shift which involves inversion of configuration at the migration terminus but retention of configuration of the migrating group. However, this consists of four steps, two or more of which may be concerted. 

Step 1: Reversible protonation to a hydroxyl group and the elimination of water molecule; an electron-deficient carbenium ion is thus formed in this step:

Step 2: The formation of a non-classical carbenium ion, a bridged intermediate. Here it is important to note that the migrating group never detaches itself from the substrate skeleton and thus the reaction becomes an intramolecular one. When an aryl group migrates, the bridged intermediate is an aryl cation which may be an actual compound since it is reasonably stable.

Step 3: Actual migration of a group to form the classical carbenium ion; thus the migration origin becomes an electron-definition atom, a resonance stabilized carbenium ion.

The driving force for the alkyl group is that the resulting carbocation is highly resonance stabilized by thethe hydroxy oxygen atom and it is even more stable than the initially formed tertiary carbocation. Also, the new carbocation can immediately stabilize itself by losing a proton. The migrating methyl group begins to attach itself by losing a proton. The migrating group begins to attach itself to the positive carbon before separating from its original position, i.e., it never becomes detached from the substrate skeleton and therefore, the rearrangement is an intramolecular one.

Step 4: Loss of proton from the protonated pinacolone to yield pinacolone

Since the mechanism involves the migration of a group with its bonded electrons to an adjacent carbon atom, it follows the mechanism of anionotropic 1, 2-shift. It has been known from the Kinetic study that the step in which elimination of water molecule occurs from the protonated 1, 2 -diol is the slow step and hence it is the rate-determining step. The intramolecular nature of the reaction is supported by the crossover experiment in which a mixture of Ph₂COH.COHMe₂ and Ph₂COH.COHEt₂ has been treated with acid. In this reaction, only intramolecular products, i.e., Ph₂CMe.COMe and Ph₂CEt.COEt, have been obtained; Ph₂CEt.COMe and Ph₂CMeCOEt, the possible cross products, have not yet been isolated. Thus cross migration does not take place in this reaction. This shows that the reaction is essentially and intramolecular one.

The evidence for the intermediacy of carbocation in this reaction is following:

When pinacol is treated with acid in H₂¹⁸O solution, the recovered pinacol is found to contain the ¹⁸O without the structure being rearranged. This observation suggests that this rearrangement involves reversible formation of carbocation.

When pinacol rearrangement involving a hydride shift is carried out in D₂O, no deuterium is found to be incorporated in the final rearranged product. This observation also suggests that the rearrangement is strictly intramolecular.

Now the question is which -OH groups will get protonated and leave and which of the two groups will migrate from the migration origin.

Any of the two -OH groups may leave from the symmetrical pinacol RR'C(OH)C(OH)RR' since the same carbocation is formed no matter which OH leaves. However, the -OH that lives from the unsymmetrical pinacol R₂C(OH)C(OH)R'₂ is the one whose loss gives rise to the more stable carbocation. For example 1, 1 - diphenylethanediol gives diphenylacetaldehyde, not diphenylacetophenone and this is because Ph₂C⁺CH₂OH is far more stable than Ph₂C(OH)CH₂⁺.

Which of the two groups migrate preferentially from the migration origin, i.e., the relative migratory aptitude depends on the electron donating ability of the groups, since the rearrangement involves movement of the migrating group with its bonding electrons to an electron deficient centre. The migrating tendency of a group may sometimes depends on: (i) its position in the most stable conformation of the molecule and (ii) whether the group that does not migrate is better at stabilizing the positive charge develop on the migration origin. Hence, there is no clear answer in so far as migrating tendencies are concerned. In general the relative is of migration is found to be:

p-MeOC₆H₄- > p-MeC₆H₄- > C₆H₅- > p-ClC₆H₄- > o-MeO-C₆H₄- > H > R

The migratory aptitude of hydrogen is often unpredictable. In some cases migration of hydrogen is preferred to that of aryl and in other cases migration of alkyl is preferred to that of hydrogen.

Also Aryl group migrates more readily than alkyl group because the former forms more stable bridged intermediate. The migratory aptitude of an o-aryl group is less than that of m-aryl or p-aryl group because of steric hindrance.

However, there are reactions in which mere electron donating ability does not decide which one will migrate. It has been found that a group in 'anti' or 'trans' position with respect to the leaving group, H₂O, in the more stable conformation of the protonated substrate migrates preferentially.

Since migration of a group occurs to the planner carbenium ion via bridged intermediate in this rearrangement, the migrating group has no scope to undergo inversion of configuration; thus its configuration is retained. Perhaps the detachment of H₂O and migration of the group of more or less simultaneously and the inversion of configuration of the migration terminus is observed.

When optically active (S)-2-methyl-1, 2- butanediol is subjected to the pinacol rearrangement, a racemic product is obtained. This unsymmetrical diol undergoes protonation on the –OH group at C-2 rather than on the –OH group at C-1 to form the more stable carbocation EtMeCCH₂OH. The carbocation then undergoes a 1, 2-hydride shift to yield, after proton loss, 2-methylbutanal. Since the migration of the hydride ion is relatively slow, the carbocation gets enough time to rotate. As a result of this, a racemic product is obtained.

The rearrangement is stereospecific and involves migration of the group which is stereochemically anti to the departing –⁺OH₂ group: The rearrangement occurs in an anti-manner and a C—C σ-bond may also play the role of migrating group if there is no alkyl and aryl group with right geometry at the migration origin. For example, cis-1, 2-dimethylcyclohexane-1, 2-diol(I) undergoes acid-catalyzed pincol rearrangement to give, two products as follows

When the axial –OH-group leaves, the axial methyl group on the adjacent carbon migrates to give 2, 2-dimethylcyclohexanone (II). However, when the equatorial –OH leaves, bond migration occurs to yield 1-acetyl-1-methylcyclopentane (III). Because of intramolecular hydrogen bonding, the trans-isomer (IV) exists almost entirely in the form in which the two –OH groups are equatorial. So, it reacts through this conformational isomer to yield the ring-contracted product III.

The pinacol-pinacolone rearrangement is an important synthetic tool in organic chemistry, particularly for the preparation of ketones from readily available starting materials. It's also a valuable reaction for mechanistic studies due to its well-defined mechanism and intermediates.

Reference

1) Jonathan Clayden, Nick Greeves, Stuart Warren, organic chemistry book second edition.