The pinacol-pinacolone rearrangement is a chemical reaction that involves the conversion of vicinal diols (glycols) containing alkyl or aryl groups into aldehydes or ketones. This transformation occurs under acidic conditions and follows a mechanism that includes the formation of a carbocation intermediate.
Introduction
The name “pinacol-pinacolone rearrangement” is derived from the typical starting materials used in this reaction, which are pinacol (a type of vicinal diol) and pinacolone (the corresponding ketone).
The rearrangement can also involve other groups, such as alkyl, aryl, hydrogen, or ethoxycarbonyl, as migrating groups. This reaction is particularly effective when highly substituted diols are used as starting materials, where the diol has four substituents attached.
In cases where vicinal diols have different R groups, the pinacol-pinacolone rearrangement can lead to the formation of multiple products. The specific products obtained depend on the relative abilities of the different groups to migrate during the reaction. The outcome is also influenced by the reaction conditions employed.
Reaction Mechanism
1. Protonation of Hydroxyl Group
The pinacol rearrangement begins with the protonation of one of the hydroxyl groups in the vicinal diol. Protonation triggers the elimination of a water molecule, resulting in the formation of a carbocation intermediate.
2. Formation of Carbocation Intermediate
The elimination of water leads to the generation of a carbocation intermediate.
3. [1,2]-Shift
The carbocation intermediate undergoes a [1,2]-shift, facilitating the formation of a more stable carbocation.
4. Rearrangement of Carbocation
The rearranged carbocation is more stable, driving the overall process towards this more favorable state.
5. Loss of Proton
The rearranged carbocation loses a proton, ultimately yielding the final product of the pinacol rearrangement.
Note: It is important to note that the pinacol rearrangement is strictly an intramolecular process, and during the rearrangement, both inversion and retention at the migrating center have been observed.
6. Formation of Aldehydes and Ketones
In the presence of hydrogen, phenyl, and methyl groups, the pinacol-pinacolone rearrangement can yield both aldehydes and ketones as products.
7. Influence of Reaction Conditions
The outcome of the reaction is influenced by factors such as temperature and acidity. Lower temperatures and weaker acids generally favor the formation of aldehydes, while more drastic conditions may lead to ketone formation.
8. Further Conversion to Ketones
Under harsh conditions, aldehydes formed initially may undergo further conversion to ketones.
9. Stabilization of Tertiary Carbocations
Tertiary carbocations are inherently stable. This stabilization is enhanced by the presence of an oxygen atom adjacent to the carbocation center.
10. Enhanced Stability through Oxygen Lone Pairs
The lone pairs on the adjacent oxygen further stabilize the carbocation.
11. Proton Loss and Further Stabilization
Tertiary carbocations readily lose a proton, contributing to additional stabilization.
12. Propensity for Rearrangement in Tertiary Carbocations
Despite their inherent stability, the presence of an adjacent oxygen atom and the ease of proton loss contribute to the propensity for rearrangement in tertiary carbocations.
Migration Order
In the pinacol rearrangement, the migration order of alkyl groups is determined by their electron density or level of substitution. The general trend of migration preference is as follows:
Tertiary alkyl > Cyclohexyl > Secondary alkyl > Benzyl > Phenyl > Primary alkyl > Methyl >> Hydrogen
When considering substituted aryl groups, the migration order is influenced by the nature of the substituents on the aromatic ring. The preference for migration is as follows:
p-Methoxy-aryl > p-Methyl-aryl > p-Chloro-aryl > p-Bromo-aryl > p-Nitro-aryl
These migration orders indicate that more electron-rich or highly substituted groups tend to migrate preferentially during the pinacol rearrangement.
Variations
1. Semipinacol Rearrangement
Semipinacol rearrangement is a variation of the pinacol rearrangement.
The pinacol-pinacolone rearrangement is not limited to only vicinal diols. There are other compounds where a positive charge can be placed on the carbon alpha to the one bearing an OH group, leading to this rearrangement.
One such example is beta-amino alcohols, which, when treated with nitrous acid, generate a carbocation intermediate that undergoes a rearrangement process. This specific rearrangement involving beta-amino alcohols is also known as the semipinacol rearrangement.
2. Iodohydrins Undergoing Carbocation Rearrangement
When iodohydrins are subjected to reactions with mercuric oxide or silver nitrate, they also undergo a process that generates a carbocation intermediate. This carbocation then undergoes a similar rearrangement as observed in the pinacol-pinacolone rearrangement.
3. Allylic Alcohols and Carbocation Rearrangement
Allylic alcohols, when treated with strong acids that protonate the double bond, also undergo a rearrangement similar to the pinacol-pinacolone rearrangement. This reaction involves the formation of a carbocation intermediate and subsequent rearrangement to yield different carbonyl compounds.
4. Epoxide Rearrangements
Epoxides exhibit a similar rearrangement when subjected to acidic reagents like BF3 or MgBr2 in ether. Additionally, epoxides are reported to serve as intermediates in the pinacol-pinacolone rearrangement of specific glycols.
This mechanism is supported by experimental evidence, where compounds like Me2COHCOHMe2, Me2COHCNH2Me2, and Me2COHCClMe2 undergo the same reaction at different rates, producing a mixture of two products, pinacol, and pinacolone, which indicates the existence of a common intermediate.
Furthermore, epoxides can also be converted to aldehydes or ketones when treated with specific metallic catalysts.
6. Conversion of Epoxides to β-Diketones
β-diketones can be synthesized by heating epoxy ketones at 80-140°C in toluene with the presence of a small amount of (Ph3P)4Pd and bis(diphenylphosphino)ethane.
This reaction highlights the versatility of epoxides as intermediates and their utility in various transformations leading to valuable organic compounds.
7. Transformation of Silyl Ethers into β-Hydroxyl Ketones
Likewise, the silyl ethers of α,β-epoxy alcohols can be transformed into β-hydroxyl ketones through a rearrangement process facilitated by the presence of TiCl4.
Synthetic Applications
1. Total Synthesis of (±)-Furoscrobiculin B
The total synthesis of (±)-furoscrobiculin B, a lactarane sesquiterpene found in mushrooms, involved two crucial steps: a furan ring transfer reaction and a semipinacol rearrangement.
The starting substrate was a tricyclic cis-vicinal diol with a secondary hydroxyl group, which was converted to its corresponding tosylate. This tosylate then underwent a ring-expansion reaction in situ, leading to the formation of an azulenofuran compound in high yield.
These key transformations played a vital role in the successful total synthesis of (±)-furoscrobiculin B.
2. Hydroxyphenstatin Synthesis
Hydroxyphenstatin, a potent cancer cell growth inhibitor, and antimitotic agent, was efficiently synthesized by G.R. Pettit and colleagues from a highly substituted trans-stilbene derivative.
The pivotal step in the synthesis involved a BF3·OEt2-catalyzed pinacol rearrangement of an optically active vicinal diol. This rearrangement yielded a racemic substituted diphenylacetaldehyde, which served as a key intermediate for the preparation of hydroxyphenstatin and various other derivatives during the course of the synthesis.
3. Total Synthesis of (±)-Fredericamycin A
In the total synthesis of (±)-fredericamycin A, R.D. Bach and colleagues introduced the spiro 1,3-dione center using a mild mercury-mediated semipinacol rearrangement, which included a [1,2]-acyl shift.
The reaction involved the combination of the indanone dithioacetal with 1,2-bis[(trimethylsilyl)oxy]cyclobut-1-ene in the presence of mercuric trifluoroacetate.
The rearrangement occurred in situ, leading to the formation of the desired spiro 1,3-dione intermediate as a crucial step in the total synthesis of (±)-fredericamycin A.
4. Reagent-Catalyzed Pinacol Rearrangement
A trivalent organophosphorus reagent catalyzed pinacol rearrangement
5. Involving Oxonium Ion
Pinacol rearrangement that involves oxonium ion
6. Rearrangement of Hydrobenzoin Substrates
Hydrobenzoin substrates undergo a pinacol rearrangement catalyzed by electrophilic fluorine in the presence of a Lewis acid, using NFSI (N-fluorobenzenesulfonimide) as the fluorine source.
7. Catalytic Enantioselective Rearrangement
The pinacol rearrangement carried out with catalytic enantioselectivity
Pinacol rearrangement Key Features
- The pinacol rearrangement, first reported by R. Fittig in 1860, is a widely applicable reaction that involves the dehydration and rearrangement of vicinal diols (glycols) in the presence of catalytic amounts of acid. The key features of this reaction are as follows:
- Various cyclic and acyclic vicinal diols can undergo rearrangement to produce aldehydes and/or ketones, depending on the substitution pattern.
- When all four substituents on the diol are identical, a single product is obtained, but if the substituents are different, product mixtures are formed.
- The reaction proceeds via the most stable carbocation intermediate for unsymmetrical glycol substrates, and regioselectivity is influenced by the relative migratory aptitudes of the substituents.
- The substituent that can better stabilize a positive charge tends to migrate preferentially, with aryl, hydrogen, and vinyl (alkenyl) groups being the most favorable.
- Stereoselectivity can occur, especially in complex cyclic vicinal diols.
- The rearrangement can involve both ring expansion and ring contraction, with the ring size playing a significant role.
- Aqueous sulfuric acid (25% H2SO4) is commonly used, but other acids, such as perchloric acid and phosphoric acid, as well as Lewis acids, can also be employed.
- The drawbacks include difficulty in preparing complex vicinal diols, regioselectivity issues leading to product mixtures, side reactions yielding dienes and allylic alcohols, equilibration of intermediate carbocations, and complications due to conformational effects and neighboring group participation in cyclic systems.
- The semipinacol rearrangement, named by M. Tiffeneau, is a variation of the pinacol rearrangement that involves the selective generation of carbocation intermediates when one of the hydroxyl groups is converted to a good leaving group or when using 2-heterosubstituted alcohols as substrates. Due to its predictability and mild reaction conditions, semipinacol rearrangement finds extensive use in complex molecule synthesis.
Concepts Berg
Can the semi-pinacol rearrangement also lead to the formation of multiple products?
Yes, similar to the pinacol-pinacolone rearrangement, the semi-pinacol rearrangement can also yield multiple products based on the migrating aptitudes of different groups.
How does the mechanism of pinacol-pinacolone rearrangement proceed?
The reaction involves protonation of the vicinal diol, followed by hydride or alkyl migration to form a carbocation intermediate, which then leads to the formation of an aldehyde or ketone.
What is meant by “migrating aptitudes” in rearrangement reactions?
“Migrating aptitudes” refer to the relative abilities of different groups or atoms within a molecule to move or migrate during a reaction.
What factors can affect the migrating aptitudes of groups in a molecule?
Factors such as steric hindrance, electronic effects, and resonance can influence the migrating aptitudes of groups in a molecule.
What is the main driving force behind the pinacol-pinacolone rearrangement?
The formation of a more stable carbocation intermediate drives the rearrangement.
Reference Books
- A Textbook of Strategic Applications of Named Reactions in Organic Synthesis book by Laszlo Kurti and Barbara Czako
- A Textbook of Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications book by Jie Jack Li
