Aromatic Substitution Reactions

Substitution Reactions of Benzene and Other Aromatic Compounds

Fries rearrangement
The Fries rearrangement, named for the German chemist Karl Theophil Fries, is a
rearrangement reaction of a phenyl ester to a hydroxy aryl ketone by catalysis of lewis acids.

Mechanism

Despite many efforts a definitive reaction mechanism for the Fries rearrangement is not
available. Evidence for inter- and intramolecular mechanisms have been obtained by so-called
cross-experiments with mixed reactants. Reaction progress is not dependent on solvent or
substrate. A widely accepted mechanism involves a carbocation intermediate.
In the first reaction step a lewis acid for instance aluminium chloride AlCl3 co-ordinates to the
carbonyl oxygen atom of the acyl group. This oxygen atom is more electron rich than the
phenolic oxygen atom and is the preferred lewis base. This interaction polarizes the bond
between the acyl residue and the phenolic oxygen atom and the aluminium chloride group
rearranges to the phenolic oxygen atom. This generates a free acylium carbocation which reacts
in a classical electrophilic aromatic substitution with the aromat. The abstracted proton is
released as hydrochloric acid where the chlorine is derived from aluminium chloride. The
orientation of the substitution reaction is temperature dependent. A low reaction temperature
favors para substitution and with high temperatures the ortho product prevails.

Limits

In all instances only esters can be used with stable acyl components that can withstand the
harsh conditions of the Fries rearrangement. If the aromatic or the acyl component is heavily
substituted then the chemical yield will drop due to steric constraints. Deactivating meta-
directing groups on the benzene group will also have an adverse effect as can be expected for a
Friedel-Crafts acylation.

Pechmann condensation

The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a

carboxylic acid or ester containing a β-carbonyl group . The condensation is performed under
acidic conditions. The mechanism involves an esterification/transesterification followed by
attack of the activated carbonyl ortho to the oxygen to generate the new ring. The final step is a
dehydration, as seen following an aldol condensation. It was discovered by the German
chemist Hans von Pechmann .
With simple phenols, the conditions are harsh, although yields may still be good.

With highly activated phenols such as resorcinol, the reaction can be performed under much
milder conditions. This provides a useful route to umbelliferone derivatives:

For coumarins unsubstituted at the 4-position, the method requires the use of formylacetic acid
or ester. These are unstable and not commercially available, but the acid may be produced in
situ from malic acid and sulfuric acid above 100°C. As soon as it forms, the formylacetic acid
performs the Pechmann condensation. In the example shown, umbelliferone itself is produced,
albeit in low yield:
 MANNICH REACTION

The Mannich reaction is the aminoalkylation reaction, involving the condensation of an

enolizable carbonyl compound (α-CH acidic compound) with a nonenolizable aldehyde (like
formaldehyde) and ammonia; or a primary or a secondary amine to furnish a β-aminocarbonyl
compound, also known as Mannich base.

* Instead of formaldehyde, other aliphatic or aromatic aldehydes or ketones can be employed.

* The amine used may be ammonia or 1o or 2o aliphatic amine. Mostly dimethyl amine is used.
The aromatic amines do not undergo Mannish reaction.

The reaction is usually carried out with the hydrochloride salt of amine. This salt exists in
equilibrium with the free amine and proton. Hence the acidic conditions are maintained in
Mannich reaction.

* The α-CH acidic compounds include carbonyl compounds, nitriles, aliphatic nitro
compounds, alkynes, α-alkyl-pyridines or imines, activated phenyl groups and electron-rich
heterocycles such as furan, pyrrole, thiophene, Indole etc.

* The reactions are usually carried out in aqueous or alcoholic solutions.

* Since the β-aminocarbonyl compounds can be conveniently reduced to β-aminoalcohols,

which show considerable pharmacological activity, the Mannich reaction plays an important
role in pharmaceutical chemistry.

MECHANISM

* Initially an iminium ion is formed due to nucleophilic addition of amine to formaldehyde

and subsequent loss of water molecule.
* Since the reaction is carried out in acidic conditions, the enolizable carbonyl compound is
converted to enol form, which attacks the iminium ion at positively charged carbon adjacent to
nitrogen to give finally a β-aminocarbonyl compound.

ILLUSTRATIONS & APPLICATIONS OF MANNICH REACTION

1) 4-(dimethylamino)butan-2-one is obtained when acetone reacts with formaldehyde and

dimethylaminium chloride.

2) The Mannich reaction of acetophenone with formaldehyde and dimethylaminium chloride in

alcohol furnishes the salt of 2-(dimethylamino)-1-phenylethanone, which can be conveniently
eliminated to acrylophenone (1-phenylprop-2-en-1-one), an α,β-unsaturated compound by
converting it into a quaternery salt and subsequent heating (Hoffman elimination).
 Vilsmeier–Haack reaction

The Vilsmeier-Haack reaction (also called the Vilsmeier reaction) is the chemical reaction of
a substituted amide with phosphorus oxychloride and an electron-rich arene to produce an
aryl aldehyde or ketone . The reaction is named after Anton Vilsmeier and Albrecht Haack. The
reaction of a substituted amide with phosphorus oxychloride gives a substituted chloroiminium
ion , also called the Vilsmeier reagent. The initial product is an iminium ion , which is
hydrolyzed to the corresponding aromatic ketone or aldehyde .

Reaction mechanism

The reaction of the amide with phosphorus oxychloride produces an electrophilic iminium
cation. The subsequent electrophilic aromatic substitution produces an iminium ion
intermediate, which is hydrolyzed to give the desired aryl ketone or aryl aldehyde.
Applications

One recent application of this reaction involved a new synthetic route to tris(4-
formylphenyl)amine from triphenylamine which by known procedures only resulted in a
modest chemical yield of 16%. It was found that this low yield was caused by deactivation of
the remaining benzene ring by the imine groups on the other two phenyl groups in the third
formylation step. The procedure was modified by taking the reaction to di-imine compound
followed by hydrolysis to the di-formyl compound and then (with final position reactived) a
separate formylation to the tri substituted compound.

Von Richter reaction

The von Richter reaction is the chemical reaction of aromatic nitro

compounds with potassium cyanide giving carboxylation ortho to the position of the
former nitro group. The reaction is named after Victor von Richter.
Reaction mechanism
 Smiles rearrangement

The Smiles rearrangement is an organic reaction and a rearrangement reaction. It is

an intramolecular nucleophilic aromatic substitution of the type:

where X in the arene compound can be a sulfone, a sulfide, an ether or

any substituent capable of dislodging from the arene carrying a negative charge. The
terminal functional group in the chain end Y is able to act as a strong nucleophile for
instance an alcohol, amine or thiol.

Smiles (Samuel Smiles 1877 - 1953) rearrangement is a rearrangement happened on aromatic

ring with strong electron-withdrawing group. The result of this reaction is on hetero atom
replace another.
 Sommelet–Hauser rearrangement

The Sommelet–Hauser rearrangement (named after M. Sommelet and Charles R. Hauser) is

a rearrangement reaction of certain benzyl quaternary ammonium salts. The reagent is sodium
amide or another alkali metal amide and the reaction product a N-dialkyl benzyl amine with a
new alkyl group in the aromatic ortho position.

Mechanism

The benzylic methylene proton is acidic and deprotonation takes place to the ylide. The
second step is a 2,3-sigmatropic rearrangement.

The Stevens rearrangement is a competing reaction.