Pharmaceutical Organic
Chemistry
By
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University
WELCOME
1-What is Benzene?
2-What is Electrophilic Substitution
Reactions?
3- Addition reaction
4- Types of addition reaction
5- Mechanisms of substitution and
addition reaction
Benzene : Resonance Description
Primary analysis revealed benzene had...
a
molecular mass of 78
a
molecular formula of C6H6
Kekulé suggested that benzene was. . PLANAR
and CYCLIC
Had Alternating Double And Single Bonds Thus
These Double Bonds Are Described As
Conjugated Bonds.
Benzene : Resonance Description
 However, all bond lengths in
benzene to be equal and
intermediate between single bond
and double bond lengths (1.39 Å)
and the ring is more stable than
expected.
 To explain the above, it was suggested that the structure oscillated between
the two Kekulé forms but was represented by neither of them. It was a
RESONANCE HYBRID ( average of two structures that differ only in the
placement of the valence electrons).
Benzene : Resonance Description
*  electron cloud delocalized all over the ring
* the resonance picture this helps to explain lack of reactivity of benzene
(substitution not addition )
Aromatic compounds are compounds that resemble benzene in chemical behavior
thus they tend to react by substitution rather than by addition
Electrophilic Substitution Reactions
 Electrophilic
substitution happens in many of the reactions of compounds
containing benzene rings – the arenes.
 Benzene, C6H6, is a planar molecule containing a ring of six carbon atoms
each with a hydrogen atom attached
Resonance
Energy = 36
Kcal / mole
Kekule
Structures
All bonds are equivalent (The ring is symmetric. Bond lengths are between a
single and a double bond)
Very Stable (Less reactive than other groupings of atoms)
The “Double Bonds” in a Benzene Ring Do Not React Like Others
Alkene
Benzene
R Cl
R
+ HCl
+ HCl
no
reaction
+ Cl2
no
reaction
+
no
reaction
H
R Cl
R
+
Cl2
Cl
R Br
R
+
Br2
Br2
Br
R
+ RCO3H
R
O
+ RCO3H
no
reaction
Reaction Mechanism
All of the reactions follow the same pattern of mechanism. The
Electrophilic substitution reaction takes place in this way:
(+) E
H
E
H
(+)
intermediate
restores
ring
resonance
E
:X
benzenium ion or a benzenonium ion
H
E+
H
H
H
SLOW
E
E
E
resonance stabilized cation
E
+ HB
H
re-aromatize
E
delocalized
cation
:B
"base"
The Nitration of Benzene
Benzene is treated with a mixture of concentrated nitric acid and
concentrated sulphuric acid at a temperature not exceeding 50°C. As
temperature increases there is a greater chance of getting more than one
nitro group, -NO2, substituted onto the ring. Nitrobenzene is formed.
If you are going to substitute a -NO2 group into the ring, then the
electrophile must be NO2+. This is called the "nitronium ion" or the
"nitryl cation", and is formed by reaction between the nitric acid and
sulphuric acid
The Halogenation of Benzene
Benzene reacts with chlorine or bromine in an electrophilic substitution
reaction, but only in the presence of a catalyst. The catalyst is either
aluminium or ferric chloride (or aluminium (ferric) bromide if you are
reacting benzene with bromine) or iron.
FeCl3
As a chlorine molecule
approaches the benzene ring,
the delocalised electrons in
the ring repel electrons in
the chlorine-chlorine bond
It is the slightly positive end of the chlorine molecule which acts as the
electrophile. The presence of the ferric chloride helps this polarisation.
Friedel-Crafts Acylation of Benzene
Named after Friedel and Crafts who discovered the reaction.
 Reagent : normally the acyl halide (e.g. usually RCOCl) with
aluminum trichloride, AlCl3, a Lewis acid catalyst.
 The AlCl3 enhances the electrophilicity of the acyl halide by
complexing with the halide.
Electrophilic species : the acyl cation or acylium ion (i.e. RCO+ )
formed by the "removal" of the halide by the Lewis acid catalyst,
which is stabilised by resonance as shown below.
Some Substitution Reactions of Benzene
Halogenation
Friedel-Crafts
Alkylation
+
+
AlCl3
Cl2
AlCl3
CH3Cl
+ CH3
C
AlCl3
Cl
O
Nitration
+
HO +N
O
O
Sulfonation
+
CH3
O
O
Friedel-Crafts
Acylation
Cl
O
O
H2SO4
N O
+
-
O
-
HO S OH
C CH
3
S OH
SO3
O
Addition Reaction
• An addition reaction is a reaction in which two molecules join together to make
a bigger one. Nothing is lost in the process. All the atoms in the original molecules
are found in the bigger one.
A + B
• In an addition reaction, new
groups X and Y are added to the
starting material. A  bond is
broken and two  bonds are
formed.
• Addition and elimination reactions are
exactly opposite. A  bond is formed in
elimination reactions, whereas a  bond
is broken in addition reactions.
AB
Addition Reaction
The double bond dissolves back to single bond and new bonds reach out to A and
B whose bond is also dissolving
C
C
C
C
A
B
C
C
A
B
A-B can be :H-H H-OH H-X OH-OH OH-X
Addition Reaction
Types of addition reactions
1) Electrophilic Addition (Reactions of Alkenes)
2) Nucleophilic Addition (aldehydes (RCHO) and ketones
(RCOR)
Electrophilic Addition
Electrophilic Addition
An electrophilic addition reaction is an addition reaction in which molecule
has a region of high electron density is attacked by another molecule, atom or
group carrying some degree of positive charge
Electrophilic addition happens in many of the
reactions of compounds containing carbon-carbon
double bonds (the alkenes e.g. ethene).
Electrophiles are strongly attracted to the exposed electrons in the π bond
Electrophilic Addition
Addition of Hydrogen Halides
Addition of HX (HI, HBr, HCl)
H-X is polarized; H is +, X is rates depend upon acid strength:
stronger the acid, faster the rate
HI > HBr > HCl>>>>>>>>HF
H2C
CH2
CH3CH2X
+ HX
X = Cl, Br, I
Mechanism
Step 2: Br- ion adds to carbocation
Step 1: H+ adds to C=C double bond
a.
H2C
b. H3C
CH2
CH2
slow
+
H
+
X-
X
fast
H3C
CH2
H3C
CH2X
When the reaction forms the carbocation intermediate,
the most highly substituted carbocation is favored :
tertiary > secondary > primary
+
X-
Electrophilic Addition
Addition of Hydrogen Halides
 Only one product is possible from the addition of these strong acids to
symmetrical alkenes such as ethene, 2-butene and cyclohexene.
A
A
A
+
A
A
A
A
HX
(x= Cl or Br or I)
A
H
X
Cl
+
HCl
CH3
H3C
H
+
H
HI
I
 However, if the double bond carbon atoms are not structurally equivalent, i.e.
unsymmetrical alkenes as in molecules of 1-propene, 1-butene, 2-methyl-2butene and 1-methylcyclohexene, the reagent may add in two different ways to
give two isomeric products. This is shown for 1-propene in the following equation.
Electrophilic Addition
 However when the addition reactions to such unsymmetrical alkenes are carried out,
it was found that 2-bromopropane is nearly the exclusive product. Thus it said the
reaction proceeded according to Markovnikov’s rule
Markovnikov’s rule stats that : In addition of unsymmetrical reagent to
unsymmetrical alkenes the positive ion adds to the carbon of the alkene that
bears the greater number of hydrogen atoms and the negative ion adds to the
other carbon of the alkene.
CH3
CH3
CH3
H3C
+
Cl
HCl
CH3
H3C
H Br
CH3
CH CH2
CH3 CH CH3
2º carbocation
more stable
CH3 CH2 CH2
1º carbocation
less stable
Br
Br
Br
Br
Mechanistic interpretation of Markovnikov’s rule: The reaction proceeds through
the more stable carbocation intermediate.
Electrophilic Addition
Addition of Hydrogen Halides
 Addition
of HCl to 1-Propene.
 It is a regioselective reaction, follow Markovnikov`s rule.
Regioselective: One of the possible products is formed in larger amounts than
the other one(s).
Regiospecific: Only one of the possible products is formed (100%).
Anti-Markovnikov addition
Addition of HBr to 1-Propene in presence of peroxide.
In the presence of peroxides (chemicals containing the general
structure ROOR'), HBr adds to a given alkene in an anti-Markovnikov
fashion
Electrophilic Addition
Addition of H2O: Hydration
 Only one product is possible from the addition of H2O in presence of acids as
catalysts to symmetrical alkenes such as ethene and cyclohexene.
Symmetrical akenes
A
A
A
+
A
H2 O
H
A
A
A
A
H
OH
OH
+
H2 O
H
CH3
H3C
H
 However, addition reactions to unsymmetrical alkenes will result in the
formation of Markovonikov’s product preferentially.
Unsymmetrical akenes
H
H
CH3
+
H2O
OH
CH3
ADDITION OF H2O
HBr and HCl easily add to alkenes. Since water also is a molecule of the type
HX which can donate a proton, H2O should be able to add to alkenes in the
same way as HBr, for example, resulting in the hydration of an alkene.
However, for the addition of H2O to alkenes to occur acid catalysts are
required.
Nucleophilic Addition
It is the most common reaction of aldehydes (RCHO) and ketones (RCOR)
e.g. The reaction of aldehydes and ketones with hydrogen cyanide
hydroxynitriles.
HW
Classify each of the following as either substitution, elimination or addition
reactions.
OH
a)
b)
c)
OH
Br
HW
Draw the product of each of these examples of A-B when they add to 1-propene.
H
CH3
C
H
H-H
H-OH
C
H
H-X OH-OH
OH-X
Characteristics of Aromatic Compounds
To be classified as aromatic, a compound must have
1-Cyclic structure
2-Coplanar structure.
3-Each atom of the ring must have a p
orbital to form a delocalized π system i.e. no
atoms in the ring can be sp3 hybridized
instead all atoms must be sp2 hybridized
(N.B. carbocation and carbanions are sp2
hybridized
Conjugated (C=C-C=C-C=C)
4-Fulfill Huckel rule i.e. the system must have 4n + 2 pi electrons:
thus by calculating n value it will be an integral number i.e. n=0,
1, 2, 3,
Examples
Examples of aromatic compounds
O
N
n=1
n=1
n=1
n=0
n=1
n=1
Examples of non aromatic compounds



sp C
3
n=1/2
n=1/2
3

sp C
n=1/2
Examples
10
6
33
Nomenclature of Aromatic Compounds
1. Monosubstituted Benzenes
a. IUPAC Names
They are named as derivatives of benzene. One side group is named as a prefix in
front of the word benzene.
 No number is needed for mono-substituted benzene.
C(CH3)3
tert-Butyl-benzene
CH2CH3
Ethyl-benzene
NO2
Nitro-benzene
Cl
Chloro-benzene
Nomenclature of Aromatic Compounds
 Benzene ring has priority over side chains with alkyl, alkoxy groups,
halogens, double and triple bonds
C CH
Vinyl-benzene
Allyl-benzene
Ethynyl-benzene
 In some cases the side chains on aromatic
ring contain functional groups of higher
priorities (NH2, OH, CHO,C=O, COOH,
COOR) thus in this case the aromatic ring will
be considered as a substituent and the side
chain will be used to give the root name. Two
aromatic radials are known.
OCH3
Butyl-benzene
Methoxy-benzene
CH2
Benzyl group
phenyl group
(C6H5-)
Nomenclature of Aromatic Compounds
b. Common Names of Monosubstituted Benzenes
CH3
Toluene
CH=CH2
Styrene
OH
Phenol
H
O
Benzaldehyde
HO
O
Benzoic acid
NH2
Aniline
OCH3
Anisol
Nomenclature of Aromatic Compounds
2. Nomenclature of Disubstituted and polysubstituted Benzenes
 All disubstituted benzenes (two groups are attached to benzene), can give
rise to three possible positional isomers.
X
X
X
Y
Y
Y
Common:
IUPAC:
orth1,2-
meta
1,3-
para
1,4-
 When the substituents are different, they are of equal priorities they should be listed
in alphabetical order.
C2 H 5
NO2
Cl
I
Common:
IUPAC:
o-Chloroethylbenzene
1-Chloro-2-ethylbenzene
Br
m-Bromonitrobenzene
1-Bromo-3-nitrobenzene
F
p-Fluoroiodobenzene
1-Fluoro-4-iodobenzene
Nomenclature of Aromatic Compounds
CH3
CH3
CH3
CH3
CH3
CH3
Common:
IUPAC:
o-Xylene
1,2-Dimethyl-benzene
m-Xylen
1,3-Dimethyl-benzene
p-Xylene
1,4-Dimethyl-benzene
 If one of the substituents is part of a parent compound, then the di-substituted
or poly-substituted benzene is named as a derivative of that parent compound
i.e. priorities determine the root name and substituents.
OH
COOH
NO2
Cl
CHO
CH3
OCH3
NO2
O2N
NO2
Br
CH3
Common: o- Chlorophenol
IUPAC: 2-Chlorophenol
m-Bromobenzoic acid
3-Bromobenzoic acid
p-Nitrotoluene
4-Nitrotoluene
o-Methoxybezaldehyde
2-Methoxybezaldehyde
2,4,6- Trinitrotoluene
Reactions of Aromatic
1-Electrophilic Aromatic Substitution Reactions
COR
RCOCl, AlCl3
Acylation
40
Reactions of Aromatic compounds
Alkyl groups and groups with lone pairs (electron donating groups) direct new groups to ortho-, parapositions and speed-up the reaction (i.e. o & p directors and activating groups).
 Halogens direct new groups to ortho-, para- positions but they slow down the reaction (i.e. halogens are
o & p directors and deactivating groups).
Electron withdrawing groups such as nitro, nitrile, and carbonyl direct new groups to the meta-position
and slow the reaction down (i.e. i.e. m directors and deactivating groups).
 Thus the order of reactivity of benzene and monosubstituted benzene derivatives in E.Ar.sub. is as in the
following chart.
Substituted benzene with
o,p directors > Benzene > Halobenzene derivatives > Substituted benzene with m- directors
Ortho , para directors
Meta directors
-OH, -OR
-NH2, -NHR, -NR2
-C6H5
-CH3, -R (alkyl)
-F, -Cl, -Br, -I
-NO2
-SO3H
-COOH, -COOR
-CHO, -COR
-CN
Reactions of Aromatic
2-Side-Chain Reactions of Aromatic Compounds
1)Halogenation
a) alkyl side chain(using UV)
CH3
Or
Br2
CHClCH3
CH2CH3
CH2Br
CH2CH2Cl
Cl2/ UV
HBr
UV
Minor
Major
b) Substituted benzene (with CCl4, AlCl3,FeCl3 (two products)
OH
OH
OH
Br
Br2/
CCl4
+
Br
Reactions of Aromatic
2. Nitration
OH
OH
OH
NO2
HNO3 / H2SO4
+
o-Nitrophenol
53 %
NO2
NO2
NO2
p-Nitrophenol
47 %
SO3 / H2SO4
SO3H
m-Nitrobezenesulfonic acid
Reactions of Aromatic
3.Oxidation
CH3
COOH
KMnO 4
Toluene
Benzoic acid
CH 2CH 3
COOH
KMnO 4
+
Benzoic acid
CO 2
+
H2O
Q1: What is the empirical formula of the following compound: (p-methyl-Toluene):
a) C8H10
b) C8H12
c) C8H14
d) C6H14
Q2: What is the final product of the following reaction?
a) o-chlorobenzaldehyde
b) m-chlorobenzaldehyde
c) p-chlorobenzaldehyde
Q3:Which one of the following compounds has aromatic
character?
d) a,c