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Fries Rearrangement: Mechanism, Applications, and Key Facts

Fries Rearrangement

The fries rearrangement is a rearrangement reaction of a phenolic ester to a hydroxyl aryl ketone by using Lewis as catalysts.

The Fries rearrangement, named for the German chemist Karl Theophil Fries, is a rearrangement reaction of a phenolic ester to a hydroxy aryl ketone by catalysis o

The reaction is a ortho and para selective and one of the two product can be favoured by changing the reaction condition, such as Temperature and solvent.

The Fries rearrangement is a classic organic reaction that converts phenyl esters into hydroxyaryl ketones using a Lewis acid catalyst (typically aluminum chloride, AlCl₃). This reaction is widely used in the synthesis of pharmaceuticals, fragrances, and UV stabilizers.

Mechanism of Fries Rearrangement

Step 1: Lewis Acid Coordination

AlCl₃ binds to the ester carbonyl oxygen, activating the carbonyl carbon.

Step 2: Acylium Ion Formation

The C-O bond cleaves, generating reactive species

Step 3: Electrophilic Aromatic Substitution

The acylium ion attacks the aromatic ring:

  • Ortho attack (favored at >100°C)
  • Para attack (favored at 25°C):

Step 4: Rearomatization

Proton loss yields the final product.

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Applications of Fries Rearrangement

1. Synthesis of Hydroxyaryl Ketones

  • Fries rearrangement is a direct route to compounds like hydroxyacetophenones, which are precursors in pharmaceuticals, perfumes, and dyes.

2. Pharmaceutical Industry

  • Used in the synthesis of non-steroidal anti-inflammatory drugs (NSAIDs) such as paracetamol analogs.
  • Helps in preparing intermediates for various antibacterial and anti-inflammatory agents.

3. Production of UV Stabilizers and Antioxidants

  • Many hydroxyaryl ketones derived from Fries rearrangement are used in manufacturing UV absorbers and antioxidants in plastics and rubbers.

4. Perfume Industry

  • Aromatic ketones like 4-hydroxyacetophenone are important fragrance ingredients or used in the synthesis of aroma compounds.

5. Synthesis of Agricultural Chemicals

  • Used to create intermediates in the manufacture of pesticides and herbicides.

6. Materials Chemistry

  • Starting materials for the synthesis of high-performance polymers, especially where aromatic ketones provide thermal and mechanical stability.

Photo-Fries rearrangement

The Photo-Fries Rearrangement is a photochemical version of the Fries rearrangement, in which aryl esters are rearranged under UV light to give hydroxyaryl ketones (ortho- and para-isomers). Unlike the classical Fries rearrangement that uses Lewis acids, the photo-Fries rearrangement proceeds through radical intermediates.

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