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Pharmaceutical Organic
Chemistry
211 PHC –lec. 3
Dr. Ebtehal S AlAbdullah
[email protected]
LECTURE CONTENTS:

Classes and Mechanisims of
Organic Reactions
o Types of organic reaction
** Elimination
** Addition
** Rearrangement
** Free radical
Elimination reaction
 A reaction in which a molecule loses atom or group of atoms
from its structure.
 Important method for preparation of alkenes
 commonly for R-OH Dehydration (-H2O) of alcohols
and R-X Dehydrohalogenation (-HX) of alkyl halides
C C
X
Y
C C
+
X
Y
ELIMINATION
REACTION
There are three fundamental events in these
elimination reactions:
1. removal of a proton
2. formation of the C-C π bond
3. breaking of the bond to the leaving group
Elimination reactions involving R-X
2-bromopropane
2-bromopropane
KOH and NaOH as strong bases
The mechanism
ELIMINATION VS SUBSTITUTION R-X
Both reactions involve heating the R-X under reflux with KOH or NaOH
Nucleophilic substitution
The OH- present are good nucleophiles, and one possibility is a
replacement of the X by an -OH group to give an alcohol via a
nucleophilic substitution reaction.
2-bromopropane is converted into propan-2-ol.
ELIMINATION VERSUS SUBSTITUTION IN R-X
Both reactions involve heating the R-X under reflux with KOH or NaOH
Elimination
R-X also undergo elimination reactions in the presence of sodium
or potassium hydroxide.
2-bromopropane has reacted to give an alkene - propene
What decides whether you get
substitution or elimination?
The reagents you are using are the same for both substitution or
elimination - the R-X and either NaOH or KOH.
In all cases, you will get a mixture of both reactions happening - some
substitution and some elimination.
What you get most of depends on a number of factors.
1. The type of halogenoalkane This is the most important factor.
type of halogenoalkane
substitution or elimination?
primary
mainly substitution
secondary
both substitution and elimination
tertiary
mainly elimination
2. The solvent
Water encourages substitution. Ethanol encourages elimination.
3. The temperature
Higher temperatures encourage elimination.
4. Concentration of the NaOH or KOH Higher concentrations
favour elimination.
Elimination reactions involving ROH
Alcohols, like RX undergo elimination reactions to yield alkenes
because H2O is lost in the elimination, this reaction is called dehydration
H3C
H2SO4
H3C
C
OH
H3C
H3C
H3C
C
CH2
H3C
C
H
CH2
H2C
CH2
+
H2O
+
H2 O
+
H 2O
60
tertiary
H
C
H3C
H2SO4
OH
H3C
100
secandry
H3C
H2
C
H2SO4
OH
primary
60
The mechanism - a simplified version
Information Enrichment
Drug Metabolism
• Drug metabolism can occur in every tissue (e.g. gut, lung and
kidney). However, the major drug metabolizing enzymes (DMEs)
are expressed at the highest levels in the liver, which thus
serves as the major organ of metabolic clearance
• Drug metabolism serves to control the exposure of a
potentially harmful substance. Usually via oxidation of a
lipophilic xenobiotic, DMEs increase the polarity and aqueous
solubility thus facilitating its elimination from the body
Asian flush syndrome
 Alcohol flush reaction (also known as Asian flush syndrome,
Asian flush, Asian glow, among others) is a condition in which an
individual's face or body experiences flushes or blotches as a result
of an accumulation of acetaldehyde, a metabolic byproduct of the
catabolic metabolism of alcohol. It is commonly thought that the
flush reaction is caused by an inability to metabolize alcohol.
CH3CH2OH + NAD+ ---> CH3CH=O + NADH + H+
Q: Show the mechanism of this reaction?
OH
+
cyclohexanol
H2SO4
cyclohexene
Rearrangement Reactions
 In this type of reactions, some atoms/groups shift
from one position to another within the substrate
molecule itself, give a product with a new
structure.
Rearrangement reactions
 intramolecular atomic rearrangement, which involves
migration or shift of atoms
 involves a nucleophilic attack at electron deficient atoms
e.g. C, O, N
Often a substituent moves from one atom to another atom in the
same molecule. In the example below the substituent R moves from
carbon atom 1 to carbon atom 2:
Carbocation Rearrangement
1)
CH3
CH3 C
CH3
slow
CH CH3
CH3 Br
CH3 C
CH3
CH CH3
+
_
+ Br
a carbocation
2)
CH3 C
CH3
3)
CH3
CH3
CH3 C
+
CH CH3
+
CH3
CH3
CH3
CH3 C
+
CH CH3
CH CH3
CH3
+
ROH
CH3 C
CH CH3
OR CH3
+
+
H
A Closer Look...
CH3
CH3 C
CH3
CH3
CH CH3
+
CH3 C
+
CH CH3
CH3
CH3
CH3
C
+
CH CH3
CH3
transition state
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
WWU -- Chemistry
Free radical reaction
 Free radical, radical, have no charge.
 It result from homolytic cleavage.
 It is unstable, highly reactive molecule.
 Pairs of electrically neutral "free" radicals are formed
via homolytic bond breakage.
MECHANISM OF THE REACTION
 Free radical addition is an addition reaction
 The addition may occur between a radical and a nonradical, or between two radicals.
 Radical chain mechanism are:
a) Initiation by a radical initiator: A radical is created from a
non-radical precursor.
b) Chain propagation
c) Chain termination: Two radicals react with each other to create
a non-radical species
Chlorination of Methane
 CH4 + Cl2
hv
CH3Cl + CH2Cl2 + CHCl3
+ CCl4 + HCl
 It is a very complicated free radical reaction.
Linkage with the life sciences
Information Enrichment
Oxidation
 Oxidation is the beginning of the deterioration process. Think of how
a slice of apple turns brown when exposed to air. Oxidation leads to
the formation of free radicals which are unstable molecules in the
body that have one unpaired electron. They can cause oxidation and
damage to the cells. This is how some diseases start.
 Free radical damage can occur because of too much exposure to
radiation, to smoke or because our cells have become overwhelmed
by toxins in the environment. Even eating a diet high in saturated
fats, over cooked meats and processed foods over a long period of
time can cause free radical damage.
Home Work
Find 3 different disease
caused by free radical
reactions inside the body
How Do Antioxidants Work?
 Most people realize that we need antioxidants to prevent and fight
disease but the role they play in maintaining your goal weight and
even losing fat is not so widely known.
 All antioxidants neutralize free radicals by either supplying the extra
electron or breaking down them down.
 Antioxidants help us stay vital into old age, detoxify our organs and
protect our cells from free radical damage.
 They support efficient metabolism helping us to lose fat more easily
and they support healthy brain chemistry.