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16. Chemistry of Benzene:
Electrophilic Aromatic
Substitution (1)
Based on McMurry’s Organic Chemistry, 7th edition
2
Substitution Reactions of
Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6
electrons
Reactions of benzene lead to the retention of the aromatic
core
3
4
Why this Chapter?
Continuation of coverage of aromatic
compounds in preceding chapter…focus shift
to understanding reactions
Examine relationship between aromatic
structure and reactivity
Relationship critical to understanding of how
biological molecules/pharmaceutical agents
are synthesized
5
16-1 Electrophilic Aromatic Bromination
Benzene’s electrons participate as a Lewis
base in reactions with Lewis acids
The product is formed by loss of a proton, which
is replaced by bromine
6
FeBr3 is added as a catalyst to polarize the bromine
reagent
In the first step the electrons act as a nucleophile toward
Br2 (in a complex with FeBr3)
This forms a cationic addition intermediate from benzene
and a bromine cation
The intermediate is not aromatic and therefore high in
energy
7
Formation of Product from Intermediate The cationic addition intermediate
transfers a proton to FeBr4- (from Br-
and FeBr3)
This restores aromaticity (in contrast
with addition in alkenes)
8
9
16-2 Other Aromatic Halogenations
Chlorine and iodine (but not fluorine, which is too reactive)
can produce aromatic substitution with the addition of
other reagents to promote the reaction
Chlorination requires FeCl3
Diazepam
10
Iodine must be oxidized to form a more powerful I+
species (with Cu2+ from CuCl2)
11
Electropbilic aromatic halogenations occur in the biosynthesis of
numerous naturally occurring molecules, particularly those produced by
marine organisms.
In humans, the best-known example occurs in the thyroid gland during
the biosynthesis of thyroxine, a thyroid hormone involved in regulating
growth and metabolism.
The amino acid tyrosine is first iodinated by thyroid peroxidase, and
two of the iodinated tyrosine molecules then couple. The electrophilic
iodinating agent is an I+ species, perhaps hypoiodous acid (HIO), that is
formed from iodide ion by oxidation with H2O2.
12
Aromatic Nitration
The combination of nitric acid and sulfuric acid
produces NO2+ (nitronium ion)
The reaction with benzene produces nitrobenzene
13
The Nitro group can be reduced to an Amino
group if needed
14
Aromatic Sulfonation
Substitution of H by SO3 (sulfonation)
Reaction with a mixture of sulfuric acid and SO3 (Fuming H2SO4)
Reactive species is sulfur trioxide or its conjugate acid
15
Sulfonamides are “sulfa drug” antibiotics
16
Aromatic Hydroxylation Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a
phenol) is difficult and rarely done in the laboratory.
but occurs much more frequently in biological pathways.
An example is the hydroxylation of p-hydroxyphenylacetate to give 3,4-
dihydroxyphenyl acetate.
The reaction is catalysed by p-hydroxyphenylacetate-3-hydroxylase and
requires molecular oxygen plus the coenzyme reduced flavin adenine
dinucleotide, abbreviated FADH2·
17
By analogy with other
electrophilic aromatic
substitutions, you might
expect that an
electrophilic oxygen
species acting as an “OH+
equivalent" is needed for
the hydroxylation reaction.
That is exactly what
happens, with the
electrophilic oxygen
arising by protonatlon of
FAD hydroperoxide,
RO-OH, that is,
RO-OH + H+ → ROH + OH+
The FAD hydroperoxide is
itself formed by reaction
of FADH2 with O2.