Module 7: Aromatic Compounds

Pharmaceutical Organic Chemistry (Lecture)

PChem 1202 | Kristine Chesley D. Dullan | BS Pharmacy 1A | Prof. Taytayon

AROMATIC COMPOUNDS STRUCTURE OF BENZENE

Aromatic Benzene (C₆H₆)

● class of compounds that contain 6-membered benzene-like ● has 8 fewer H than alkane (C₆H₁₄)
rings w/ 3 double bonds ● clearly unsaturated
● in the early days, was used to describe such fragrant ● 6-membered ring w/ alternating double & single bond
substances such as ● all C-C-C bond angles are 120°
○ benzaldehyde (cherries, peaches, almonds) ● each C has a p orbital perpendicular to the plane
○ toluene (tolu balsam) SOME NONSYSTEMATIC NAMES ALLOWED BY IUPAC
○ benzene (coal distillate)
SOME AROMATIC CARBONS FOUND IN COAL TAR
1. Benzene
2. Toluene
3. Xylene
4. Indene
5. Naphthalene
6. Biphenyl
7. Anthracene
8. Phenathrene

NOMENCLATURE

MONOSUBSTITUTED BENZENE
Monosubstituted benzene
● named systematically in the same manner as HC
● parent name = benzene
PHARMACEUTICAL PREPARATIONS
Pharmaceutical Preparations Bromobenzene C₆H₅Br
● Steroids
○ estrone Nitrobenzene C₆H₅NO₂
● Lipitor
● Benzene Propylbenzene C₆H₅CH₂CH₂CH₃
○ causes leukopenia on prolonged exposure
○ should not be used as laboratory solvent
○ major source:
■ Coal
■ Petroleum

alkyl if alkyl substituent is smaller than the ring

substituted (6 or fewer C)

Ph or Φ

used if alkyl substituent is larger than the ring (7 or

PHYSICAL PROPERTIES phenyl
more C)
Physical Properties substituted
● generally nonpolar used for -C₆H₅ unit when benzene ring is a
● Immiscible with water substituent
● often unreactive = useful as solvents for other nonpolar
compounds benzyl used for C₆H₅CH₂ group
● due to higher ratio of C to H, characterized by a sooty
yellow flame

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 STRUCTURE & STABILITY OF BENZENE

Benzene
● less reactive than alkanes because of their resonance

Cyclohexene
● reacts rapidly with Br2
○ gives the addition product
1,2-dibromocyclohexane
DISUBSTITUTED BENZENE
● but benzene only reacts slowly with Br2
Disubstituted benzene
○ gives the substitution product C₆H₅Br
● named using prefixes
○ ortho (o)
○ meta (m)
○ para (p)

ortho 1,2

meta 1,3

para 1,4 BENZENE REPRESENTATION CAN BE:

2 benzene resonance forms
● can be represented by a single structure with a circle in the
center to indicate equivalence of C-C bonds

Alternative representations of benzene. The “circle” representation

must be used carefully since it doesn’t indicate the number of
electrons in the ring

AROMATICITY & THE HUCKEL 4n+2 RULE

Hückel 4n+2 rule

● needed to complete a description of aromaticity
● theory devised in 1931 by the German physicist Erich
3/TRI- OR MORE SUBSTITUENTS Hückel
● states that a molecule is aromatic only if
Benzene with 3 or more substituents
○ it has a planar, monocyclic system of conjugation
● Numbers with the lowest possible values are chosen
○ contains a total of 4n+2p electrons, where n is an
○ List substituents alphabetically with hyphenated
integer (n = 0, 1, 2, 3, . . .)
numbers
○ only molecules with 2, 6, 10, 14, 18,... π electrons
can be aromatic
Antiaromatic
● Planar conjugate molecule with 4n π electrones
● because delocalization of their π electrons would lead to
their destabilization

Note in the second and third examples shown that -phenol and
-toluene are used as the parent names rather than -benzene.
Any of the monosubstituted aromatic compounds shown in the table
above can serve as a parent name, with the principal substituent (-OH
in phenol or -CH3 in toluene) attached to C1 on the ring.

Has four π electrons and is antiaromatic

The p electrons are localized in two double bonds rather than
delocalized around the ring, as indicated by the electrostatic potential
map.

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 OTHER ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS
ELECTROPHILIC AROMATIC SUBSTITUTION REACTION
1. Aromatic Halogenation
Electrophilic Aromatic Substitution a. Fluorination
● most common reaction of aromatic compounds b. Chlorination
● a process in which an electrophile (E+) reacts with an c. Iodination
aromatic ring & substitutes for one of the hydrogens 2. Aromatic Nitration
3. Sulfonation

Cl, Br, I
● introduced in the aromatic ring by EAS

1. Fluorination - F is too reactive

F containing medicines
● Sitagliptin (Januvia)
● Fluoxetine (Prozac)

Halogenation 2. Chlorination
● aromatic rings react w Cl2
● FeCl₃ - catalyst
● used in synthesis of anti allergy meds
○ Loratad (Claritin)

3. Iodination
● Iodine is unreactive in aromatic ring
● H₂O₂ or CuCl₂ is added
● Biosynthesis of Thyroxine

aromatic rings are nitrated by reaction with a

Nitration
mixture of conc. nitric & sulfuric acids

aromatic rings are sulfonated by reaction with

Substituents can be substituted in the aromatic ring Sulfonation so-called fuming sulfuric acid
● Mixture of SO₃ & H₂SO₄
BROMINATION
Bromination
● reaction occurs in 2 steps
● involves a resonance-stabilized carbocation intermediate

Chlorination

Nitration

Mechanism for the Electrophilic Bromination of Benzene

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 Sulfonation

ALKYLATION & ACYLATION OF AROMATIC RINGS:

THE FRIEDEL-CRAFT

Alkylation
● introduction of an alkyl group onto the benzene ring
● called the Friedel–Crafts alkylation reaction
Friedel–Crafts alkylation reaction
● reaction is carried out by treating an aromatic compound
with an alkyl chloride, RCl, in the presence of AlCl₃ (catalyst)
● to generate a carbocation electrophile, R+
● loss of H+ = reaction complete

PRACTICE:
1. What products would you expect from bromination of
aniline (C₆H₅NH₂)

SUBSTITUENT EFFECTS IN ELECTROPHILIC DISTRIBUTION

2 effects of initial presence of substituent in the ring:

1. Substituents affect reactivity of aromatic ring
2. Substituents affect orientation of reaction
Substituent Classification 2. What products would you expect from sulfonation of
1. meta-directing deactivators a. Nitrobenzene
2. ortho- & para-directing deactivators b. Bromobenzene
3. ortho- & para-directing activators

all activating groups ortho- & para-directing

all deactivating groups halogen & meta-directing

unique in being deactivating but

halogens
ortho- & para-directing

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 ACTIVATING & DEACTIVATING EFFECTS PHARMACEUTICAL PREPARATIONS WITH AROMATIC RING

donate electrons to the ring

● making the ring more
electron-rich
Activating group
● stabilizing carbocation intermediate
● lowering activation energy for its
formation

withdraw electrons from the ring

● making the ring electron-poor
Deactivating ● destabilizing carbocation
groups intermediate
● raising activation energy for its
formation

SUMMARY OF SUBSTITUENT

Effects in Electrophilic Aromatic Substitution

Orienting Inductive
Substituent Reactivity
Effect Effect

Weak
-CH₃ Activating Ortho, Para
donating

Weak
-OH, -NH₂ Activating Ortho, Para
withdrawing

-F, -CL
Strong
Deactivating Ortho, Para
withdrawing
-Br, -I

-NO₂, -CN

Strong
-CHO, -CO₂R Deactivating Meta
withdrawing

-COR, CO₂H

OXIDATION & REDUCTION OF AROMATIC COMPOUNDS

Alkyl groups
● that are attached to aromatic rings
● readily attacked by oxidizing agents
● converted into carbonyl groups