PHARMACEUTICAL ORGANIC CHEMISTRY PORG111

4/18/2022

Aromatic Hydrocarbons the aromatic hydrocarbon functional group.

Benzene, a flat, symmetrical molecule with a
PHARMACEUTICAL ORGANIC
molecular formula of C6H6 (Figure 13.18),
CHEMISTRY PORG111
has a structural formula that is often
formalized as that of a cyclohexatriene—in
other words, as a structural formula that
Learning Outcomes involves a six-membered carbon ring in which
At the end of discussion, student should be three double bonds are present.
able to:

 Explain the concept of aromaticity.

 Explain the physicochemical
properties of aliphatic hydrocarbons.
 Write reaction mechanisms of
Aromatic Hydrocarbons.
 Draw the products of reactions of
Aromatic Hydrocarbons. Figure 13.18 Space-filling and ball-and-stick
 Enumerate Aromatic Hydrocarbons of models for the structure of benzene.
pharmaceutical importance.
Aromatic Hydrocarbons
Aromatic hydrocarbons are the third class of
unsaturated hydrocarbons; the alkenes and
alkynes (previously considered) are the other
two classes. An aromatic hydrocarbon is an
unsaturated cyclic hydrocarbon that does not
readily undergo addition reactions. This
reaction behavior, which is very different from
that of alkenes and alkynes, explains the This structure is one of two equivalent
separate classification for aromatic structures that can be drawn for benzene that
hydrocarbons. differ only in the locations of the double bonds
(1,3,5 positions versus 2,4,6 positions):
The fact that, even though they are
unsaturated compounds, aromatic
hydrocarbons do not readily undergo addition
reactions suggests that the bonding present
in this type of compound must differ
Neither of these conventional structures,
significantly from that in alkenes and alkynes.
however, is totally correct. Experimental
Such is indeed the case.
evidence indicates that all of the carbon–
A consideration of the bonding present in carbon bonds in benzene are equivalent
benzene, the simplest aromatic hydrocarbon, is (identical), and these preceding structures
the key to understanding the “special type” of imply three bonds of one type (double bonds)
bonding that is characteristic of an aromatic and three bonds of a different type (single
hydrocarbon and to specifying the identity of bonds).
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The equivalent nature of the carbon– The structure represented by the notation
carbon bonds in benzene is addressed by
considering the correct bonding structure for
benzene to be an average of the two “triene”
structures. Related to this “average”-structure
situation is the concept that electrons
is called an aromatic ring system, and it is the
associated with the ring double bonds are not
functional group present in aromatic
held between specific carbon atoms; instead,
compounds. An aromatic ring system is a
they are free to move “around” the carbon
highly unsaturated carbon ring system in
ring. Thus the true structure for benzene, an
intermediate between that represented by the which both localized and delocalized bonds
two “triene” structures, is a situation in which
all carbon–carbon bonds are equivalent; they
are neither single nor double bonds but
something in between. Placing a double-
headed arrow between the conventional
structures that are averaged to obtain the true are present.
structure is one way to denote the average
 Benzene (C6H6), was first isolated in
1825 by English chemist Michael
Faraday from the oily residues after
heating whale oil under pressure to
structure.
produce a gas used to illuminate
An alternative notation for denoting the buildings in London.
bonding in benzene — a notation that involves  In 1834 it was prepared from benzoic
acid (C6H5CO₂H), a compound
obtained by chemical degradation of
gum benzoin, the fragrant balsam
a single structure — is exuded by a tree that grows on the
In this “circle-in-the-ring” structure for island of Java, Indonesia.
benzene, the circle denotes the electrons  Thus benzene, toluene, and related Fluorobenze

associated with the double bonds that move hydrocarbons, while not
“around” the ring. Each carbon atom in the particularly pleasant smelling
ring can be considered to participate in three themselves, were classified as
conventional (localized) bonds (two C-C aromatic because they were obtained
bonds and one C-H bond) and in one from fragrant substances.
delocalized bond (the circle) that involves all  Joseph Loschmidt, an Austrian
six carbon atoms. A delocalized bond is a chemist, recognized in 1861 that most
covalent bond in which electrons are shared aromatic substances have formulas
among more than two atoms. This delocalized that can be derived from benzene by
bond is what causes benzene and its replacing one or more hydrogens by
derivatives to be resistant to addition other atoms or groups.
reactions, a property normally associated with
Names for Aromatic Hydrocarbons
unsaturation in a molecule.
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Replacement of one or more of the hydrogen

atoms on benzene with other groups produces
benzene derivatives. Compounds with alkyl
groups or halogen atoms attached to the
benzene ring are commonly encountered. The For monosubstituted benzene rings that have a
naming of benzene derivatives with one group attached that is not easily named as a
substituent is considered first, then the naming substituent, the benzene ring is often treated as
of those with two substituents, and finally the a group attached to this substituent. In this
naming of those with three or more reversed approach, the benzene ring
substituents. attachment is called a phenyl group, and the
Benzene Derivatives with One Substituent compound is named according to the rules for
naming alkanes, alkenes, and alkynes.
The IUPAC system of naming
monosubstituted benzene derivatives uses the
name of the substituent as a prefi x to the
name benzene. Examples of this type of
nomenclature include:

3-Phenyl-1-butene

A few monosubstituted benzenes have names

wherein the substituent and the benzene ring *The word phenyl comes from “phene,” a
taken together constitute a new parent name. European term used during the 1800s for
Two important examples of such benzene. The word is pronounced fen-nil.
Isopropylbenzene Ethylbenzene
nomenclature with hydrocarbon substituents Benzene Derivatives with Two Substituents
are
When two substituents, either the same or
different, are attached to a benzene ring, three
isomeric structures are possible.

Toluene Styrene
(not methylbenzene) (not vinylbenzene)

Both of these compounds are industrially

important chemicals.
Monosubstituted benzene structures
are often drawn with the substituent at the “12 To distinguish among these three isomers, the
o’clock” position, as in the previous positions of the substituents relative to one
structures. However, because all the hydrogen another must be specified. This can be done in
atoms in benzene are equivalent, it does not either of two ways: by using numbers or by
matter at which carbon of the ring the using nonnumerical prefixes.
substituted group is located. Each of the
following formulas represents chlorobenzene. When numbers are used, the three
isomeric dichlorobenzenes have the first-listed
set of names:
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*Learn the meaning of the prefixes ortho-,

meta-, and para-. These prefixes are
extensively used in naming disubstituted
benzenes. o-Xyl
1,2-Dichlorobenzene 1,3-Dichlorobenzene 1,4-Dichlorobenzene
(ortho-dichlorobenzene) (meta-dichlorobenzene) (para-dichlorobenzene)

*Cis–trans isomerism is not possible for

disubstituted benzenes. All 12 atoms of
benzene are in the same plane—that is,
benzene is a flat molecule. When a substituent
group replaces an H atom, the atom that
bonds the group to the ring is also in the The use of ortho-, meta-, and para in place of
plane of the ring. position numbers is reserved for disubstituted
The prefix system uses the prefixes ortho-, benzenes. The system is not used with
meta-, and para- (abbreviated o-, m-, and p-). cyclohexanes or other ring systems.

Ortho- means 1,2 disubstitution; the When neither substituent group imparts a
substituents are on adjacent carbon atoms. special name, the substituents are cited in
alphabetical order before the ending -benzene.
Meta- means 1,3 disubstitution; the The carbon of the benzene ring bearing the
substituents are one carbon removed from substituent with alphabetical priority becomes
each other. carbon 1.
Para- means 1,4 disubstitution; the
substituents are two carbons removed from
each other (on opposite sides of the ring).
When prefixes are used, the three isomeric
dichlorobenzenes have the second-listed set of
names above.
When one of the two substituents in a
disubstituted benzene imparts a special name A benzene ring bearing two methyl groups is a
to the compound (as, for example, toluene), situation that generates a new special base
the compound is named as a derivative of that name. Such compounds (there are three
parent molecule. The special substituent is isomers) are not named as dimethylbenzenes
assumed to be at ring position 1. or as methyl toluenes. They are called
1-Chloro-2-ethylbenzene 1-Bromo-3-chlorobenzene

(not 2-chloro-1-ethylbenzene) (not 3-bromo-1-chlorobenzene)

.
p-Xyleneand
The xylenes are good solvents for grease
oil and are used for cleaning microscope slides
4-Bromotoluene 2-Ethyltoluene

(not 1-bromo-4-methylbenzene) (not 1-ethyl-2-methylbenzene)

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and optical lenses and for removing wax from

skis.
Benzene Derivatives
When parent names such as toluene and
xylene are used, additional substituents  Replacing one of the hydrogens with
a different functional group
1. IUPAC: Fluorobenzene - C6H5F
2. Chlorobenzene - C6H5Cl
3. Bromobenzene - C6H5B
4. Iodobenzene - C6H5I
5. Toluene – aka: methylbenzene C7H8 or
C6H5CH3
6. Cumene – isopropylbenzene C9H12 OR
C6H5CH3CHCH3
7. Ethylbenzene – C8H10 OR
C6H5CH2CH3
8. Styrene – vinylbenzene C8H8 OR
C6H5CHCH2
1. ORTHO-XYLENE – C8H10
present cannot be the same as those included
in the parent name. If such is the case, name IUPAC: 1,2-dimethylbenzene
the compound as a substituted benzene. The
2. META-XYLENE - C8H10
compound is named as a trimethylbenzene
and not as a methylxylene or a
dimethyltoluene.

IUPAC: 1,3-dimethylbenzene
3. PARA-XYLENE - C8H10
IUPAC: 1,4-dimethylbenzene
4. PHENOL – C6H5OH
IUPAC: Hydroxybenzene
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5. BENZOIC ACID – C6H5COOH  The term aromatic thus came to mean

any compound structurally derived
IUPAC: Benzenecarboxylic Acid
from benzene.
6. BENZALDEHYDE C6H5CHO  These compounds are hydrocarbons
that contain a benzene ring as a
IUPAC: Benzenecarbaldehyde
structural unit.
7. ACETOPHENONE C6H5COCH3  In addition to benzene, other examples
include toluene and naphthalene.
IUPAC: 1-phenylethanone
SOURCES: CATALYST: CALCIUM OXIDE
8. METHYL BENZOATE – C8H8O2
IUPAC: Methyl Benzoate
1. ANISOLE - C6H5OCH
IUPAC: Methoxybenzene
2. ANILINE - C6H5NH2
IUPAC: Aminobenzene
Physical Properties OF Aromatic
3. NITROBENZENE C6H5NO2 Hydrocarbons

 All arenes are either liquids or solids

at room temperature; none are gases.
IUPAC: Nitrobenzene
 Aromatic hydrocarbons are insoluble
4. BENZONITRILE - C6H5CN in water.
 Benzene was once widely used as a
IUPAC: Benzonitrile
solvent, but evidence - of its
5. BENZAMIDE - C6H5CONH2 carcinogenic properties prompted its
replacement by less hazardous
6. BENZENESULFONIC ACID - solvents.
C6H5SO3H
Reaction Mechanisms of Aromatic
IUPAC: Benzenesulfonic Acid Hydrocarbons
7. NAPHTHALENE – C10H8 1. Substitution Reaction
IUPAC: Naphthalene • The most common reactions of aromatic
8. ANTHRACENE - C14H10 compounds involve substitution of other
atoms or groups for a ring hydrogen on the
Aromatic Hydrocarbons aromatic unit, or more precisely called an
 Benzene, C6H6, is the parent electrophilic aromatic substitution reaction.
hydrocarbon of the especially stable USUALLY NAGSUSUBSTITUTE SILA
compounds known as aromatic FROM 0-50 C
compounds.
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2. Halogenation

 The bromination or chlorination of (H-OSO3H)

benzene requires a Lewis acid such as C6H5-SO3H

ferric bromide or ferric chloride. NOTE: A sulfonic acid is a strong acid

1. BROMINATION because of the three electron withdrawing
oxygen atoms and the stability of its conjugate
base.
5. Friedel-Crafts Reaction

 Two electrophilic substitution

2. CHLORINATION
reactions bear the names of chemists
Charles Friedel and James Crafts.
o Friedel-Crafts acylation places
an acyl group on a benzene
ring
 Electrophilic iodine (I+) is obtained by
o Friedel-Crafts alkylation
treating 12 with an oxidizing agent
places an alkyl group on a
such as nitric acid.
benzene ring.
3. IODINATION

• Either an acyl halide or acid anhydride can

used for Friedel-Crafts acylation.
3. Nitration

 Nitration of benzene with nitric acid

requires sulfuric acid as a catalyst.

• Either an acyl halide or acid anhydride can

used for Friedel-Crafts acylation.
WITH ACYL HALIDE
4. Sulfonation

 Fuming sulfuric acid (a solution of

SO3 in sulfuric acid) or concentrated
sulfuric acid is used to sulfonate
aromatic rings.
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• Either an acyl halide or acid anhydride can 1. Propranolol

used for Friedel-Crafts acylation. - Classification base on its
mechanism of action: beta-
WITH ACID ANHYDRIDE
blocker
- Use: anti-HTN / Anti-hypertensive
agent (pampababa ng blood
ACETIC ACID pressure)
IUPAC: ETHANOIC ACID 2. Phenobarbital
• The Friedel-Crafts alkylation reaction - Chemical classification:
substitutes an alkyl group for a hydrogen. barbiturate
- Use: Anti-convulsant (for
epilepsy, seizures)
3. Phenytoin
- Chemical classification:
NOTE: Alkyl fluorides, alkyl chlorides, alkyl hydantoins
bromides, and alkyl iodides can all be used. - Use: Anti-convulsant (for
epilepsy, seizures) for long term
• The Friedel-Crafts alkylation reaction use, avoid also for pregnant
substitutes an alkyl group for a hydrogen. women for not to avoid the
development of fetus
4. Phenylbutazone
- Chemical classification: NSAID
- Use: Anti-inflammatory agent
5. Atorvastatin
- Use: lower cholesterol level,
• The Friedel-Crafts alkylation reaction hyperlipidemia (matataas na lipid
substitutes an alkyl group for a hydrogen. levels)
- Chemical classification: HMG
+ HCl COA reductase inhibitor – an
enzyme needed to produce
cholesterol
Note: Dapat CH2 yung nakaattach sa benzene 6. 17a-Ethinylestradiol
ring kasi pag CH3 oversaturation daw and - Steroids
would break the tetravalency of the carbon - Birth control pills, source of
estrogen or estrone – female
• The Friedel-Crafts alkylation reaction
hormone (pag kasi mataas ang
substitutes an alkyl group for a hydrogen.
estrogen di ka prone to ovulation)
for pcol
7. Warfarin S (-)-Enantiomer in
Humans
- Chemical classification: coumadin
- Uses: anti-platelet or anti-
AROMATIC COMPOUNDS OF coagulant (for patients na
PHARMACEUTICAL IMPORTANCE namumuo yung dugo, nablock sa
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certain arteries na maglead sa

stroke, aneuryms)
8. Amphetamine
- No clinical use in the Philippines
(psychostimulant drug kasi sya
kaya wala dito dahil sya ay
regulated drug na may potential
drug of abuse
- In other countries, it is the tx for
ADHD and narcolepsy (bigla
biglang nakakatulog for example
may ginagwa)
- Others for label use: for obesity