The Fries rearrangement is named after its discoverer, German chemist Karl Fries,
who first reported this reaction in 1908. It involves the rearrangement of some aryl
esters to form both ortho and para products, as is shown here. This reaction is promoted by
stoichiometric amounts of a Lewis acid like AlCl3 or BCl3, or a strong Brønsted-Lowry
acid like triflic acid can also be used. It has been shown that the reaction is in
some cases reversible, meaning that not only can the products rearrange to give the starting ester,
but the two products can undergo isomerization. In general, the para product is favored kinetically,
meaning under milder conditions when the reverse reaction is slow. At higher temperatures,
it is usually the ortho product that is favored, probably because the primary product,
before hydrolysis, is an aluminum complex where the aluminum chelates the two oxygen atoms.
This explains why the reaction is not catalytic, as the Lewis acid binds the product more tightly
than it does the starting material, and also why the ortho product is the thermodynamic one.
The mechanism itself is thought to proceed as follows. The primary site of complexation for
the acid must be the carbonyl oxygen, because it is the more electron-rich and therefore
basic one. The alternative complex where the acid binds the phenol oxygen is very unlikely.
This interaction polarizes this bond, allowing for rearrangement to occur,
with the phenol oxygen attacking aluminum, which kicks off this acylium carbocation.
The acylium ion then undergoes a reaction similar to Friedel-Crafts acylation,
which we discussed earlier in the series. As we have noted previously, the reaction
usually affords ortho and para structures due to the directing effect of the phenoxide group.
This then leads to the product, or rather an adduct of product and Lewis acid.
The one equivalent of acid comes into play here, protonating this oxygen and releasing aluminum
trichloride, and we are left with this product. Reaction of the acylium ion at the ortho position
would have afforded the other product. It has been postulated for a long time
that the reaction may be partially intramolecular and partially intermolecular. This hypothesis can
be settled by the so-called crossover studies. We can take two substrates
labeled at two different sites of the molecule, such as two different esters with R1 and R2,
as well as two different aryl groups, trying not to change the electronics of the system too much.
In most cases where such studies have been carried out, the starting material is para substituted, so
as to make the reaction products less complex, as this only allows formation of the ortho product.
In the case shown here, in addition to the expected products, the crossover products are
usually also formed in various amounts, showing that the reaction can also be intermolecular,
with the acylium ion from one substrate ending up on the other molecule.
The Fries rearrangement remains of historical importance, and it is also used in industry for
some very simple processes. Its harsh conditions and lack of complete selectivity have limited its
application to more advanced targets, such as natural products or structurally complex drugs.
Chemists have been intrigued by the challenge of obtaining 100%
ortho-selectivity, and this has been realized with a variant of the Fries rearrangement,
called the anionic Fries rearrangement. This protocol is based on the observation
that very strong bases, like alkyllithium bases in ether solvents,
will metalate phenol esters at the ortho position. This is due to the initial coordination of the Li
atom with the ester oxygen, which delivers the lithium atom selectively to the ortho position
due to proximity. This is a general process called “ortho-directed metalation” of aromatics.
This is an equilibrium but it is quantitative, lying heavily to the right since alkyllithiums
are much more basic than the aryllithium produced. If this metalation is done at low temperature,
usually -78oC, the ortho-lithiated product is formed as shown. Upon warming, usually to 0oC,
the acyl group is transferred to the ortho position in a reaction we can conceptualize
as an intramolecular attack of an anion onto the carboxyl moiety, with formation of
a less basic phenoxide. This thermodynamic favorability is what drives the reaction.
In practice, strong bases like butyllithium tend to attack the carboxyl group in
competition with the desired ortho-lithiation, and yields are rarely good with phenol esters.
It has been much more productive to use carbamates, which are less reactive
with nucleophilic bases, and which upon anionic Fries reaction yield ortho-hydroxy carboxamides.
This concept of ortho transfer has been extended to many groups other than carbonyls,
and transfer of other heteroatoms has been shown to occur smoothly. It also works on aniline
systems. Indeed, there are extensive reviews in the recent literature describing all the
wonderful substrates one can apply this reaction to, though we will stop here for the time being.
Thus, the basic framework of the Fries rearrangement is still providing new impulses to
contemporary organic synthesis. It is important to be familiar with this reaction in order to
understand the current literature, and perhaps even to pass your next organic chemistry exam!