Chem231 Study Notes on McMurry

Chapter 16: Benzene

Electrophilic Aromatic Substitution

Learning Objective & Key Concepts

1. Electrophilic aromatic substitution: mechanism, substituent effects.

2. Examples of electrophilic aromatic substitution: bromination,
alkylation, acylation, nitration.
3. Regioselectivity in electrophilic aromatic substitution reactions.
4. Nucleophilic aromatic substitutions: mechanism and examples.
5. Reactions of halobenzenes via benzyne
6. Oxidation, and bromination of aromatic alkylbenzenes.
7. Reduction of Aryl alkyl ketones.

Keywords: Acyl group, acylation, benzyne, electrophilic aromatic substitution, Friedel-Craft

reaction, inductive effect, nucleophilic aromatic substitution, resonance effect.

Tutorial Questions
These are a subset of EOC questions, hand these in for extra credit, but I strongly advise you
to complete the full set of EOC questions as well as in-text questions too.

16.30 16.32 16.33 16.36 16.46

End-of-Chapter Problems
(you must also complete all in-text questions)

16.30 16.32 16.33 16.36

16.40 16.44 16.46 16.46
16.51 16.54

Suggested Hours-by-Arrangement Activities:

(1hr) Research history of benzene discovery, chemistry, history, major industrial usage etc.
Write a one page summary of your findings. You may turn this in for 2pts extra credit

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In chapter 15, the concept of aromaticity was introduced and explained as cyclic
conjugate systems with 4n+2 -electrons. In this chapter, we expand the idea of
aromaticity: their characteristic reaction being electrophilic aromatic substitution. We
examine a large numbers of examples including halogenation, alkylation, acylation,
hydroxylation, nitration and sulfonation. We will also look at a number of biological and
pharmaceutical examples and applications of aromatic chemistry.

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16.1 Electrophilic Aromatic Substitution: Bromination

Due to its greater stability,
benzene rings are less reactive
towards electrophiles than
alkenes. Therefore, where an
alkene is readily brominated
using either HBr or Br2 in
CH2Cl2 solution, benzene
requires a catalyst (iron bromide,
FeBr3) in order to react with Br2.
The stability of the ring is so
significant that an aromatic ring
will reform from the
intermediate. The result is
electrophilic aromatic
substitution in aromatic
compounds (one of the ring
hydrogens is replaced by
electrophile) in contrast to
electrophilic addition in alkenes.

In this reaction, FeBr3 acts a catalyst by complexing with Br2 to give a bromine cation.
Br+ is much more electrophilic than Br2, and therefore reaction have lower activation
energy (faster reaction rate).

Try problem 16.1

(Hint: look at starting compound and decide which aromatic hydrogen atoms are
equivalent).

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16.2 Other Aromatic Substitution

The same general mechanism in section 16.1 is seen in several other substation reactions:

Aromatic Chlorination And Iodination

Halogens are weakly electrophilic and so their introduction into a benzene ring requires
catalysts to increase their reactivity as electrophiles. In the case of bromine, this is done
by the addition of FeBr3 (generating the much stronger electrophile Br+).

Fluorine (F2) is too unreactive in electrophilic aromatic substitution even in the presence
of a catalyst and so direct fluorination tends to give poor yields.

Chlorination occurs readily with Chlorine (Cl2) with FeCl3 catalyst in much the same
way as Br2 by FeBr3. This reaction is widely used in pharmaceutical synthesis.
One example is diazepam (Valium).

Iodine (I2) is unreactive in itself towards aromatic rings, but in the presence of CuCl2 or
hydrogen peroxide, H2O2 (both are oxidizing agents), iodine can be oxidized to generate
a much more electrophilic I+ species.

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This reaction mimics a

naturally occurring
process: biosynthesis of
a thyroid hormone:
thyroxine.

Aromatic Nitration

The electrophile is nitronium cation, NO2+. This highly reactive electrophile is formed
in situ from a mixture of conc. Nitric and conc. Sulfuric acid.

Nitration of benzene ring is an important synthetic reaction (so far there are no known
naturally occurring examples) because nitrobenzene is readily reduced to arylamines
(aromatic amines) such as aniline which are key precursors in a wide range of industrial
synthesis including dyes and pharmaceutical reagents.

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AROMATIC SULFONATION

Sulfonation of benzene ring uses fuming sulfuric acid (conc. H2SO4 with sulfur trioxide,
SO3). The electrophile may be hydrosulfonium cation, HSO3+ or SO3. This reaction is
again widely used in pharmaceutical synthesis such as that for sulfanilamide which has
antibiotic properties.

Aromatic Hydroxylation

On hydroxylation, a benzene ring is converted to a phenol (hydroxybenzene). This

reaction is very common in biological pathways (see example on page 554 in text) but
not usually done in the laboratory. We will not study details of this reaction.

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16.3 Alkylation & Acylation of Aromatic Rings Friedel-Craft Reaction

Substitution of alkyl into a
benzene ring is done using
alkyl halides in the presence
of aluminum chloride (AlCl3)
as catalyst. These Friedel-
Craft reactions are among
the most useful aromatic
substitution reactions. The
catalytic mechanism is
similar to that in bromination;
alkyl halides (RCl) dissociate
in the presence of AlCl3 to
generate the much more
electrophilic carbocation
(R+).

Friedel-Craft Alkylation is a useful reaction but it has limitations:

1) The substituent group must be alkyl (cannot be aryl or vinyl)

2) A deactivated aromatic compound is unlikely to undergo alkylation (see section

16.4).

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3) For activated aromatic compounds, polyalkylation is likely: after the first alkyl
group, second and even third alkyl group may also be substituted into the ring.
This is because an alkyl group in the benzene ring increases the rings reactivity
towards further electrophilic attack.

4) Rearrangement occurs when a carbocation is formed; especially when a primary

alkyl halide is used.

Another Friedel-Craft reaction is acylation of aromatic rings, this reaction is also

catalyzed by aluminum chloride. Instead of alkyl halide, a carboxylic acid chloride is
used instead to introduce an acyl group.

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Although this reaction shares some of the same limitation as the alkylation reaction
(benzene must NOT be deactivated) it does have one very useful advantage: the acyl
cation is resonance-stabilized and therefore does not undergo rearrangement nor is
polyacylation likely because the acyl group, once introduced into the ring, is a
deactivating group.

As well see in section 16.10, an acyl group is readily reduced to give an alkyl group.
Friedel-Craft acylation followed by reduction therefore offers an alternative route to
alkylation of benzene.

Go through worked example 16.1

Try problem 16.4

Try problem 16.6

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16.4 Substituent Effects in Substituted Aromatic Rings

A substituent already on the benzene ring affects both the rate and the orientation of the
incoming electrophile. In terms of rate, an already-present substituent may be activating
(increases rate and activity) or deactivating (decreases rate and activity). For orientation,
the incoming electrophile may be directed to the ortho-, meta- or para- position relative to
the first substituent.

There are three broad classes as summarized in table 16.1. Generally, deactivating groups
are meta-directing, and deactivating groups are ortho- and para- directing. However,
halides (and halogenated methyl groups) are deactivating but ortho- and para-directing.

How substituents affect rate and orientation depends on a combination of inductive

effect and resonance effect.

An inductive effect may donate or withdraw electron density through -bonds.

Groups that donate electron density by inductive effect into an aromatic ring will
therefore increase its attraction and reactivity towards electrophiles; conversely, groups
that withdraw electron density from an aromatic ring will decrease its reactivity towards
electrophiles.

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A resonance effect also donates or withdraws electron density, but do so via -bonds.
Look back at diagram in section 16.4: the carbonyl, cyano, and nitro groups are electron-
withdrawing . Halogens, hydroxyl and alkoxyl groups are electron-donating.

Problem (or confusion) arises because where a substituent can interact with aromatic ring
by both inductive and resonance effects, the two effects may be contradictory in terms of
activating/deactivation. For example: a hydroxyl group (and also a halogen) is
inductively electron-withdrawing, but electron-donating by resonance! In such cases, the
stronger effect wins. (Better to learn to recognize the common activating and
deactivating groups, with the generalization that activating groups are ortho- and para-
directors, and deactivating groups are meta-directions. The exceptions are the halogens
which are deactivating, but ortho- and para-directing).

Try problem 16.7

Try problem 16.8

Try problem 16.9

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16.5 An Explanation of Substituent Effects

In summary, a group that donates electron density (by inductive and/or resonance effect)
stabilizes intermediate carbocation so therefore increases reactivity of aromatic ring
towards electrophile. Conversely, a group that withdraws electron density decreases
reactivity.

Alkyl groups are ortho- and para- directing activators: alkyl groups have a positive
inductive effect (donates electron density via -bonds to stabilize cationic sites). Note
how in the ortho- and para- intermediate cations, the positive charge partially end up on
the ring carbon with alkyl group attached.

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Hydroxy and amine groups are also ortho- and para- directing activators, but do so
by positive inductive effect (donates electron density via -bonds). Again, note
intermediate cations for ortho- and para- positions have positive charge on the ring
carbon with OH or NH2 group attached.

Halogens are ortho- and para- directing deactivators. They deactivate due to a
strongly negative inductive effect (withdraw electron-density), but their resonance effect,
which affects the carbocation intermediate more than the starting aromatic compound, is
enough to favor ortho- and para- positions for the incoming electrophile.

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Nitro groups, aldehydes and ketones are meta-directing deactivators. They are
electron withdrawing groups and the meta- carbocation intermediate is more stable than
the ortho- and para- intermediates.

Try problem 16.4

(Must try, these resonance structures are challenging to draw but practice would make them easier to
understand and therefore learn)

16.6 Trisubstituted Benzenes: Additivity of Effects

This refers to adding a third substituent to a di-substituted aromatic ring. The two
already-present groups will either reinforce or oppose each others effects.

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In this example, note hydroxyl group is a stronger director activator than methyl group.

Another point to consider is steric hindrance: some meta-disubstituted aromatic rings

rarely undergo electrophilic aromatic substitution in the position between the two
already-present groups.

Work through worked example 16.3

Try problem 16.15

16.7 Nucleophilic Aromatic Substitution

Consider the following reaction: a benzene ring with sufficient electron-withdrawing
group on it undergoes NUCLEOPHILIC aromatic substitution the nucleophile is
hydroxyl (OH-) which substitutes for a chloride from the aromatic ring.

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A biochemical application of this nucleophilic aromatic substitution is seen in the use of

2,4-dinitrofluorobenzene (Sangers reagent): in the following reaction, Sangers reagent
is added to act as a label to one end of a protein molecule:

Nucleophilic aromatic substitution

mechanism is very different from
SN1 or SN2. The nucleophile
attaches to the electron-deficient aryl
halide to form a resonance-stabilized
anionic intermediate called a
Meisenheimer complex. Elimination
of halide ion in the second step
completes the reaction.

Nucleophilic aromatic substitution requires a highly electron-deficient benzene ring in

ortho- and para-positions to the halide to be substituted.

Try problem 16.17

16.8 Benzyne
In the absence of electron-withdrawing
groups, an aryl halide may still undergo
nucleophilic reactions. In a reaction
developed by Dow Chemical Company in the
early 20th century, phenol can be synthesized
from chlorobenzene. This reaction requires
high temperature and high pressure.

In a similar reaction, bromobenzene also

undergoes nucleophilic substitution with
amide nucleophiles.

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Both reactions are believed to occur via a highly reactive intermediate benzyne - cylic
dienyne.

Try problem 16.18

16.9 Oxidation of Aromatic Compounds

Oxidation of Alkylbenzene Sidechains

While the benzene ring itself is inert to oxidizing agents, it does promote oxidation in its
alkyl side-chain as long as there are benzylic hydrogens present. Therefore, in the
examples given, butylbenzene, p-xylene both undergo oxidation, but tert-butylbenzene
does not. Note a benzenecarboxylic acid is produced regardless of chain length.

Benzoic acid has many industrial uses such

as in food preservatives.

Terephthalic acid is an important

intermediate in the production of polyester
fibers.

Try problem 16.19

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Bromination of Alkylbenzene Side Chains

Alkylbenzenes with benzylic hydrogens may also be brominated. The reagent of choice is
N-bromosuccinimide (NBS). A radical initiator such as benzoyl peroxide (PhCO2)2) or
UV light is required.

Reaction mechanism is via free radicals and bromination at the benzylic position is
favored exclusively because of resonance-stabilization.

See how radical is stabilized by delocalization throughout aromatic ring:

Try problem 16.21

Challenging but very good practice in multistep synthesis.

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16.10 Reduction of Aromatic Compounds

Catalytic Hydrogenation of Aromatic Rings

Because of stability of the benzene

ring, aromatic compounds do not
readily undergo catalytic
hydrogenation under mild
conditions. Instead, its possible to
reduce C=C double bonds in the
presence of a benzene ring: (note
ketone is also unaffected under these
reaction conditions).

Reaction conditions have been developed to hydrogenate aromatic rings but these usually
require high pressure or more effect catalysts such as rhodium on carbon.

Reduction of Aryl Alkyl Ketones

Carbonyl groups directly attached to benzene rings are also susceptible to reduction. (Do
not confuses with the ketone (4-phenyl-3-buten-2-one) shown earlier which survived catalytic
hydrogenation because it was not directly attached to a benzene ring).

Aryl alkyl ketones are often synthesis by the Friedel-Craft acylation reaction, when
followed by catalytic hydrogenation, it offers an alternative to Friedel-Craft alkylation.
Often better yields are given because it avoids rearrangement via carbocations.

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Try problem 16.22

16.11 Synthesis of Trisubstituted Benzenes

Very important practice in synthesis problems

Go through worked example 16.4

Go through worked example 16.5

Try problem 16.23

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