Module 8: Aromatic Hydrocarbons

The main industrial source of aromatic compounds used to be coal. Among them, benzene, toluene, and the
isomeric xylenes, sometimes collectively called BTX, are important starting materials for industrial organic
chemistry.

Benzene, like alkenes, undergoes electrophilic addition, but a proton is then eliminated from the first-formed
intermediate. Consequently, aromaticity is restored and the overall reaction is substitution: electrophilic aromatic
substitution . These reactions include halogenation, nitration, sulfonation, and Friedel–Crafts alkylation and
acylation.

Mechanism of Electrophilic Substitution Reaction

Halogenation Reaction

Nitration Reaction

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Sulfonation Reaction

Friedel-Craft Alkylation Reaction

Friedel-Craft Acylation Reaction

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Reactivity of Benzene and Regioselectivity So far, we have presented electrophilic substitution reactions of only
benzene itself; in the absence of isotopic labelling, the six C–H groups of benzene are indistinguishable to an
electrophile so there is never a question of where the reaction will be—there is only one possibility. This is not the
case for a mono-substituted benzene, C 6 H 5 -Y, which has two equivalent ortho positions, two equivalent meta
positions, and one para position. Consequently, there can be three parallel independent reactions with
electrophile Z + which, in principle, give three constitutionally isomeric products, Y-C 6 H 4 -Z. In other words, there
is a question of regioselectivity (or orientation)—at which position of the mono-substituted benzene C 6 H 5 -Y
does the electrophile bond: ortho , meta , or para ? If the reactions at the different positions had identical rate
constants, we would expect the three products to be formed in the ratios ortho : meta : para = 2 : 2 : 1; if the yields
are not in these ratios, the reaction is regioselective to a greater or lesser degree. Most electrophilic aromatic
substitutions are not reversible and the products do not equilibrate. In other words, the reactions are kinetically
controlled (see Sub-section 15.8.2) and the relative yields of the isomeric products are determined by the relative
rates at which they are formed, i.e. by the rate constants of the parallel competing reactions or, equivalently, the
relative stabilities of the transition structures in the rate-determining steps of the respective routes.

Activating and Deactivating Substituents in Electrophilic Aromatic Substitution

Electron donating groups activate the ring and direct the electrophile at the ortho- and para-positions.
Electron withdrawing groups deactivate the ring and direct the electrophile at the meta position.

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Regioselectivity of Electron-Donating Groups:

Regioselectivity of Electron-Withdrawing Groups

Classification of Substituents

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Reactions of Disubstitued Benzene

The electron-donating group will control the orientation as shown below.

Note, however, that the position between the substituents meta to each other in m -cyanotoluene in is not substituted even
though it is ortho to the methyl. This is an example of steric hindrance infl uencing regioselectivity. Positions ortho to bulky
substituents are particularly unlikely to be substituted as illustrated.

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Reactivity of Phenol
Phenol is a very reactive electrophilic aromatic compound and easily brominated.

Naturally Occurring Phenols

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Reactivity of Aniline
Aniline is produced industrially on a large scale and used, for example, as a starting material in the manufacture of
polyurethanes. It is easily obtained by reduction of the readily available nitrobenzene using iron or tin in moderately
concentrated hydrochloric acid in the laboratory, or by catalytic hydrogenation on an industrial scale.

Aniline is even more reactive than phenol (see Section 16.5) due to the powerful electron- donating activating resonance effect
of the NH 2 group, so controlling the reaction to give a mono-substitution product is often diffi cult.

Furthermore, complications may occur because the NH 2 group is basic so the ortho,para -directing NH 2 is converted into the
meta -directing NH3+ group under acidic conditions. Although aniline is almost wholly protonated in strongly acidic solutions,
the rate constant for reaction of the low concentration of the free base is very much greater than that of the more abundant
protonated form. Consequently, the proportions of regioisomeric substitution products depend on the acidity of the reaction
conditions. For example, the product distribution in the nitration of aniline in aqueous HNO 3 /H 2 SO 4
mixtures depends upon the concentration of the H 2 SO 4 .

Additionally, NH 2 is easily oxidized under strongly acidic/electrophilic reaction conditions.* To avoid these problems with
aniline, the basicity and activating effect of the NH 2 are reduced by N -acetylation: NHAc is much less easily protonated than
NH 2 , only modestly electron-donating due to the electron-attracting resonance effect of the acetyl group, and not easily
oxidized. The acetyl group can be removed by hydrolysis after the electrophilic substitution, as illustrated in Scheme 16.12 for
the preparation of p -bromoaniline via p -bromoacetanilide ( p -Br-C 6 H 4 NHAc).

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Diazotization Reaction
Aniline (and other primary arylaminesare diazotized by nitrous acid just as primary alkylamines are, and secondary arylamines
(ArNHR) give N -nitrosoamines just as secondary alkylamines do. However, arenediazonium salts are relatively stable compared
with alkanediazonium salts, and can be prepared from primary arylamines in aqueous acidic sodium nitrite with cooling by ice ).
Aqueous tetrafl uoroboric acid is the preferred acid if a crystalline arenediazonium salt (ArN2 BF + 4 ) is required.

Limitation to Friedel-Craft Alkylation

Indirect Introduction of Primary Alkyl Group

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Oxidation of Alkyl Side Chain

Important Amine-Containing Compounds

Mescaline has a psychedelic effect and the peyote cactus which contains it has been used in religious ceremonies by
native Americans in Mexico since before the arrival there of Europeans. This compound contains a 2-arylethylamine
unit (highlighted in the structures below). Ephedrine, which is the active ingredient in a traditional Chinese medicine
( má huáng ) used in the treatment of asthma and bronchitis, contains the same structural feature, as do morphine and
codeine (the powerful analgesics mentioned in Panel 6.3). These compounds, along with the others shown, participate
in the response of the sympathetic nervous system and have powerful physiological and psychological effects.
Dopamine functions in the brain as a neurotransmitter; it regulates and controls movement, motivation, and cognition,
cooperating with other neurotransmitters such as acetylcholine (AcOCH 2 CH 2 N + Me 3 ). A dopamine defi ciency in the
brain is associated with degenerative disorders such as Parkinson's disease.

Physiological oxidation of dopamine leads to noradrenaline (also called norepinephrine) and subsequent methylation
gives adrenaline (epinephrine). Adrenaline and noradrenaline are hormones and neurotransmitters, and have similar
functions. Both are released when an animal is under stress: they increase blood pressure and heart rate, and dilate air
passages to prepare the animal to fi ght or fl ee.
Amphetamine and its methylated derivative, methamphetamine, are synthetic drugs which lack the hydroxy group
of ephedrine; both are strong psychostimulants. The former has been widely used as a performance-enhancer and
the latter (which has various slang names including ‘meth’) is addictive; both are illegal drugs. Salbutamol (also called
albuterol) is a short-acting β 2 agonist used for the treatment of bronchospasms caused by asthma. It is usually administered
as sulbutamol sulfate by an inhaler or nebulizer.
Serotonin (5-hydroxytryptamine) is a neurotransmitter in the central nervous system which is sometimes called a
‘happiness hormone’ but it is not a hormone. It is involved in many central and peripheral physiological functions
including contraction of smooth muscle, vasoconstriction, appetite, sleep, pain perception, and memory. Melatonin

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is a simple derivative of serotonin which is a hormone secreted by the pineal gland in the brain during the night. It is
involved in adjusting the internal body clock and controlling the day–night rhythm.

Give the reagentsy for the following Synthesis

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