Phenols - FRIES Rearrangement - Mechanism

  • The FRIES rearrangement is a reaction that involves the rearrangement of aryl esters of phenols in the presence of Lewis acids.
  • The reaction proceeds through the formation of a carbocation intermediate.
  • The rearrangement is predominantly observed in ortho and para positions of the phenolic ring.
  • The FRIES rearrangement reaction is useful in the synthesis of substituted phenols and aromatic compounds.
  • The mechanism of the FRIES rearrangement involves several steps.

Step 1: Lewis Acid Activation

  • The reaction begins with the activation of the aryl ester by a Lewis acid such as aluminum chloride (AlCl3) or iron(III) chloride (FeCl3).
  • The Lewis acid coordinates with the carbonyl oxygen of the ester, facilitating the subsequent steps of the rearrangement.

Step 2: Electrophilic Aromatic Substitution

  • The activated aryl ester undergoes electrophilic aromatic substitution (EAS).
  • The Lewis acid generates a highly electrophilic carbocation on the aromatic ring.
  • The nucleophilic attack of the phenol oxygen on the carbocation leads to the formation of a new carbon-oxygen bond.

Step 3: Rearrangement

  • The carbocation intermediate undergoes a rearrangement to yield a more stable carbocation.
  • The rearrangement occurs through the migration of an alkyl or aryl group from one carbon atom to another.
  • The migration can occur in either ortho or para positions on the phenolic ring.

Step 4: Proton Transfer

  • After the rearrangement, a proton transfer step takes place.
  • A proton is transferred from the hydroxyl group of the phenol to the oxygen atom of the ester.
  • This step regenerates the carbonyl group and completes the formation of the rearranged product.

Step 5: Rearranged Product Formation

  • The final step of the FRIES rearrangement involves the formation of the rearranged product.
  • The rearranged product is an aryl phenyl ether, where the alkyl or aryl group has migrated to a different position on the phenolic ring.
  • The Lewis acid catalyst is regenerated during this step and can participate in subsequent reactions.

Step 6: Example Reaction

  • Let’s take a look at an example reaction of FRIES rearrangement.
  • Starting with the aryl ester, o-methoxybenzoic acid methyl ester, and FeCl3 as the Lewis acid catalyst.
  • The reaction undergoes FRIES rearrangement to form the rearranged product, 2,3-dimethoxybenzoic acid methyl ester.

Step 7: Factors Affecting FRIES Rearrangement

  • The FRIES rearrangement reaction is affected by several factors.
  • The choice of Lewis acid catalyst can influence the rate and selectivity of the rearrangement.
  • Temperature also plays a role in the reaction, with higher temperatures generally leading to faster rearrangement.
  • The structure of the aryl ester and the presence of substitution on the phenolic ring can affect the reaction outcome.

Applications of FRIES Rearrangement

  • The FRIES rearrangement reaction has several applications in organic synthesis.
  • It can be used to introduce functional groups or create substituted phenols.
  • The rearranged products obtained from FRIES rearrangement can be further utilized for the synthesis of various aromatic compounds.
  • The reaction is commonly employed in the pharmaceutical industry for the synthesis of drug intermediates.

Limitations of FRIES Rearrangement

  • Although the FRIES rearrangement is a useful reaction, it does have some limitations.
  • The reaction is predominantly observed in ortho and para positions of the phenolic ring, limiting the scope of regioselectivity.
  • Some aryl esters may not undergo rearrangement under typical reaction conditions.
  • The reaction conditions may also lead to side reactions or other competing reactions.

Comparison with other Rearrangement Reactions

  • The FRIES rearrangement is similar to other rearrangement reactions such as the Beckmann rearrangement and the Hofmann rearrangement.
  • The Beckmann rearrangement involves converting an oxime to an amide by rearrangement.
  • The Hofmann rearrangement involves converting primary amides to primary amines through a rearrangement process.
  • While these reactions have different starting materials and mechanisms, they all involve the rearrangement of functional groups.

Industrial Importance of FRIES Rearrangement

  • The FRIES rearrangement reaction finds applications in the industrial synthesis of various products.
  • It is used for the synthesis of dyes, pharmaceuticals, and agricultural chemicals.
  • The reaction can also be employed in the synthesis of fragrances and flavor compounds.
  • The ability to selectively introduce functional groups in specific positions of the phenolic ring makes the FRIES rearrangement valuable in the design and synthesis of new compounds.

Summary

  • The FRIES rearrangement is a reaction that involves the rearrangement of aryl esters of phenols in the presence of Lewis acids.
  • The mechanism includes Lewis acid activation, electrophilic aromatic substitution, rearrangement of the carbocation intermediate, proton transfer, and formation of the rearranged product.
  • Factors such as choice of catalyst, temperature, and substrate structure can influence the reaction outcome.
  • The FRIES rearrangement finds applications in organic synthesis and is especially useful in the pharmaceutical industry.

Conclusion

  • The FRIES rearrangement is an important reaction in organic chemistry.
  • It allows the regioselective introduction of functional groups in phenolic compounds.
  • Understanding the mechanism and factors affecting the reaction can aid in its efficient utilization.
  • Further research and optimization of the reaction conditions can lead to improved synthetic methodologies and the synthesis of novel compounds.

References

  • Organic Chemistry, 8th Edition by Wade, L. G.
  • Advanced Organic Chemistry: Part A Structure and Mechanisms, 5th Edition by Carey, F. A. and Sundberg, R. J.
  • Organic Chemistry, 7th Edition by McMurry, J.
  • https://en.wikipedia.org/wiki/Fries_rearrangement

Questions for Review

  1. What is the FRIES rearrangement?
  1. What is the role of the Lewis acid catalyst in the FRIES rearrangement?
  1. Explain the mechanism of the FRIES rearrangement.
  1. What factors can influence the rate and selectivity of the FRIES rearrangement?
  1. Give an example reaction of FRIES rearrangement.
  1. How is the FRIES rearrangement used in the pharmaceutical industry?
  1. What are the limitations of the FRIES rearrangement?
  1. Compare the FRIES rearrangement with other rearrangement reactions.
  1. What are the industrial applications of the FRIES rearrangement?
  1. How can the FRIES rearrangement be optimized for specific synthesis applications?

Phenols - FRIES Rearrangement - Mechanism

Factors Affecting FRIES Rearrangement

  • Choice of Lewis acid catalyst
  • Temperature
  • Structure of the aryl ester
  • Presence of substitution on the phenolic ring
  • Electronic effects of substituents on the aromatic ring

Lewis Acid Catalysts Used in FRIES Rearrangement

  • Aluminum chloride (AlCl3)
  • Iron(III) chloride (FeCl3)
  • Boron trifluoride (BF3)
  • Zinc chloride (ZnCl2)
  • Titanium tetrachloride (TiCl4)

Temperature Effects on FRIES Rearrangement

  • Higher temperatures generally lead to faster rearrangement
  • Temperature can affect the rate of the rearrangement and the selectivity of the reaction
  • Optimum reaction temperature may vary depending on the specific aryl ester and Lewis acid catalyst used

Substrate Structure Effects on FRIES Rearrangement

  • The structure of the aryl ester can influence the outcome of the FRIES rearrangement
  • Generally, aryl esters with electron-donating groups undergo rearrangement more readily
  • Steric hindrance can also affect the rearrangement, as bulky groups may hinder migration of alkyl or aryl groups

Regioselectivity in FRIES Rearrangement

  • The FRIES rearrangement is predominantly observed in ortho and para positions of the phenolic ring
  • The regioselectivity of the rearrangement can be influenced by the electronic effects of substituents on the aromatic ring
  • Electron-withdrawing groups tend to favor ortho arylation, while electron-donating groups favor para arylation

Example: FRIES Rearrangement of O-Methoxybenzoic Acid Methyl Ester

  • Starting material: O-methoxybenzoic acid methyl ester
  • Lewis acid catalyst: Aluminum chloride (AlCl3)
  • Reaction conditions: Reflux in anhydrous solvent
  • Resulting product: Ortho-methoxybenzoic acid methyl ester

Example: FRIES Rearrangement of P-Nitrobenzoic Acid Ethyl Ester

  • Starting material: P-nitrobenzoic acid ethyl ester
  • Lewis acid catalyst: Iron(III) chloride (FeCl3)
  • Reaction conditions: Room temperature in anhydrous solvent
  • Resulting product: Para-nitrobenzoic acid ethyl ester

Mechanism of FRIES Rearrangement: Step 1 – Lewis Acid Activation

  • The Lewis acid (e.g., FeCl3) coordinates with the carbonyl oxygen of the aryl ester
  • This activation step facilitates subsequent reactions by generating a more electrophilic ester

Mechanism of FRIES Rearrangement: Step 2 – Electrophilic Aromatic Substitution

  • The electrophilic ester undergoes electrophilic aromatic substitution (EAS)
  • The Lewis acid generates a highly electrophilic carbocation on the aromatic ring
  • The phenol oxygen nucleophilically attacks the carbocation, forming a new carbon-oxygen bond

Mechanism of FRIES Rearrangement: Step 3 – Rearrangement

  • The carbocation intermediate undergoes a rearrangement to form a more stable carbocation
  • This rearrangement involves the migration of an alkyl or aryl group from one carbon atom to another
  • The migration can occur in ortho or para positions on the phenolic ring