Fries Rearrangement

Mechanism

The Lewis acid, usually AlCl₃ in stoichiometric amount or more, coordinates to the carbonyl oxygen of the ester, which is the most basic one. The bond between the phenolic oxygen and the acyl group is weakened and an acylium ion, R–C≡O⁺, is released; it attacks the ring as in a Friedel-Crafts acylation (SEAr). The phenolic oxygen remains bonded to aluminum, and the final hydrolysis releases the OH group.

Crossover experiments, with two different esters in the same mixture, show that the acyl group can move to the ring of the same molecule (intramolecular process) or to that of another one (intermolecular), depending on the substrate and the conditions. That is why the detailed mechanism is still debated.

Ortho or para?

A mixture of the ortho and para hydroxyaryl ketones is obtained. At low temperature the para product, which forms faster, predominates (kinetic control). At high temperature the ortho product predominates: it forms a six-membered chelate with aluminum through the phenolic O and the C=O and is the more stable one (thermodynamic control). Nonpolar solvents also favor the ortho product.

With phenyl acetate, low temperatures give mainly the 4-hydroxyacetophenone shown in the figure, and high temperatures give 2-hydroxyacetophenone.

Scope and limitations

It is one of the best methods for preparing hydroxyaryl ketones, common intermediates in the synthesis of drugs. But the acyl group must withstand fairly harsh conditions, and bulky substituents on the ring or on the acyl group and deactivating groups (the same ones that prevent Friedel-Crafts acylation) greatly reduce the yield. Besides AlCl₃, BF₃, TiCl₄, HF or strong acids such as methanesulfonic acid are used.

There is also a photo-Fries rearrangement, induced by ultraviolet light, which proceeds through radicals and needs no catalyst. Its yields are low, but it partly explains the yellowing of some plastics, such as polycarbonate, in sunlight.

The reaction is named after Karl Theophil Fries.