16. chemistry of benzene: electrophilic aromatic...

16. Chemistry of Benzene:

Electrophilic Aromatic

Substitution (1)

Based on McMurry’s Organic Chemistry, 7th edition

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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

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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

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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

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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

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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)

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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

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Iodine must be oxidized to form a more powerful I+

species (with Cu2+ from CuCl2)

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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.

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Aromatic Nitration

The combination of nitric acid and sulfuric acid

produces NO2+ (nitronium ion)

The reaction with benzene produces nitrobenzene

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The Nitro group can be reduced to an Amino

group if needed

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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

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Sulfonamides are “sulfa drug” antibiotics

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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·

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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.