Pharmaceutical Organic
Chemistry
By
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University
WELCOME
1-To know classes and mechanisms of organic
reactions
2- To know elimination reaction
3- To be differentiate between elimination &
substitution
4-To understand rearrangement reaction
5- To understand free radical reaction
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
There are three fundamental events in these
elimination reactions:
1. removal of a proton
2. formation of the CC bond
3. breaking of the bond to the leaving group
C C
C C
X Y
An elimination reaction is one where starting material loses
the elements of a small molecule such as HCl or H2O or Cl2
during the course of the reaction to form the product.
+
X Y
Elimination reaction
An elimination reaction is a type of organic reaction in which
two substituents are removed from a molecule in either a one
or two-step mechanism. and the two-step mechanism is
known as the E1 reaction and The one-step mechanism is
known as the E2 reaction.
The numbers do not have to do with the number of steps in the
mechanism, but rather the kinetics of the reaction, bimolecular
and unimolecular respectively
Types of Elimination reactions
• Elimination, Unimolecular - E1
• Elimination, Bimolecular - E2
Elimination reaction
Elimination, Unimolecular - E1
Elimination reaction
Elimination, Unimolecular - E1
I) Dehydrohalogenation (-HX) of alkyl halides
 The
mechanism is similar to the SN1 reaction except the second step
involves a proton abstraction and π bond formation instead of a substitution.
 This mechanism is a two step process with the rate
determining step being an ionization of the halide to
produce a carbocation .The carbocation will then react with
a base that can pull a β hydrogen off to produce the most
stable alkene according to the Zeitsev Rule.
Elimination reaction
Elimination, Unimolecular - E1
I) Dehydrohalogenation (-HX) of alkyl halides
Alkyl Halides + Dil. Base or Conc. Acid + low heat
The removal of a β -hydrogen becomes difficult without a strong base and a
different mechanism (ionization) begins to take place
The E1 Elimination Reaction (two steps)
H
C
β
a
C
X
B:
Weak base
slow
step one
H
C
C
+
carbocation
step
two
+
:X
3o > 2 o > 1o
fast
C
C
Works best in a
polar solvent.
Elimination reaction
Elimination, Unimolecular - E1
Zaitsev’s Rule
I) Dehydrohalogenation (-HX) of alkyl halides
Elimination reactions generally give the more
highly substituted alkene.
Br
CH3CH2CHCH3
H
Dil.
base
H H
CH3CH2C CH2 + CH3C CCH3
1-butene
19%
minor
product
2-butene
81%
major
product
Elimination almost always gives a mixture of products.
Elimination reaction
Elimination, Unimolecular - E1
I) Dehydrohalogenation (-HX) of alkyl halides
Elimination reaction
Elimination, Unimolecular - E1
II) Dehydration of alcohols
Elimination of H2O from an alcohol using acid .
H2SO4 or
H3PO4
R-OH
alcohol
∆
R-R
alkene
+
H2O
acid
catalyst
The dehydration reaction is acid-catalyzed.
Elimination reaction
Elimination, Unimolecular - E1
Mechanism of
Dehydration
H
H
H C C O H
H C C O
H O
H
H
alcohol
acid
catalyst
protonated
alcohol
H
O
H
acid
catalyst
H
alkene
O
H C C
H
carbocation
Elimination reaction
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
+
H2O
60
tertiary
H
C
H3C
H2SO4
OH
H3C
100
secandry
H3C
H2
C
H2SO4
OH
primary
60
Elimination reaction
Elimination, Unimolecular - E1
When The E1 Mechanism Occurs?
E1 occurs only
1) At zero or low base concentration
2) with solvolysis (the solvent is the base)
3) with tertiary and resonance capable substrates (alkyl halides)
If a strong base is present in moderate to high concentration, or the
substrate is a primary halide, the E2 reaction dominates.
Elimination reaction
Elimination, Bimolecular – E2
Elimination reaction
Elimination, Bimolecular – E2
Alkyl Halide + Strong Base + High Heat
For a Dehydrohalogenation Reaction
This mechanism is a One Step
Elimination reaction
Elimination reactions involving R-X
2-bromopropane
2-propene
KOH and NaOH as strong bases
The mechanism
Elimination reaction
Elimination, Bimolecular – E2
The Reaction is a b-elimination
Since the b-hydrogen is lost this reaction is called a b-elimination.
The b-hydrogen
is attached to the
b-carbon.
b-carbon
H
a-carbon
C C
Cl
Reagent = a strong base
The functional
group is attached
to the a-carbon.
Elimination reaction
Elimination, Bimolecular – E2
Mechanism
The Base Takes The b-hydrogen
B:
B
H
C C
:Cl
.. :
H
C C
..
: Cl:
..
Elimination reaction
Elimination, Bimolecular – E2
What Happens If There Is More Than One b-hydrogen ?
b’
b
H
H
C C C
Cl
Which one do we lose ?
Elimination reaction
Elimination, Bimolecular – E2
b’
b
CH3CH2
CH CH3
Br
CH3
b-H
CH CH CH3
major product
81 %
2-bromobutane
2-butene
CH3CH2 CH CH2
The major product is the
one which has the lowest
energy.
b’-H
minor product
19 %
1-butene
Elimination reaction
Elimination, Bimolecular – E2
strong
base
B:
Mechanism
H
CH CH
Br
alkyl
halide
Concerted = only one step all bonds are broken and formed
without the formation of any intermediates.
Elimination reaction
Elimination, Bimolecular – E2
B:
B
H
H
CH CH
Mechanism
d-
Br
CH
Activated complex
Everything happens at once without any intermediates.
CH
Br
d-
Elimination reaction
The most basic stuff
alkyl halide + strong base + heat =
E2
alkyl halide + solvent + heat (solvolysis)
alcohol + strong acid + heat =
E1
=
E1
(acid assisted)
Only E1 reactions have rearrangements (carbocations)
Elimination Vs Substitution R-X
Both reactions involve heating the R-X under reflux with KOH or NaOH
1)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.
2)Elimination
R-X also undergo elimination reactions in the presence of sodium or potassium hydroxide.
2-bromopropane has reacted to give an alkene - propene
Elimination Vs
Substitution R-X
The very first pair of mechanisms and reactions which are
commonly taught are the substitution and elimination reactions.
All these can go by either a two-step mechanism (SN1 or
E1) or one-step (SN2 or E2). So overall, you can find four possible
mechanisms (SN2, SN1, E2 or E1,) along with combinations of
mechanisms
Elimination Vs Substitution R-X
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 favors
elimination.
Elimination reaction
E1
E2
Substrate
Strong effect; reaction favored by
tertiary halide
Strong effect; reaction favored
by tertiary halide
Reactivity – primary
Does not occur
Occurs with strong base!
Reactivity – tertiary
Occurs under solvolysis conditions or
with strong acids
Highly favored when strong
bases (OH-, OR-) are used
Reactivity –
secondary
Can occur in polar, protic solvents
Favored when strong bases are
used
Solvent
Very strong effect; reaction favored
by polar, protic solvents
Strong effect; reaction favored
by polar, aprotic solvent
Nucleophile/Base
Weak effect; reaction favored by
weak base
Strong effect; reaction favored
by strong base
Leaving Group
Strong effect; reaction favored by
good leaving group
Strong effect; reaction favored
by good leaving group
H.W
Q: Show the mechanism of this reaction?
OH
+
cyclohexanol
H2SO4
cyclohexene
The reactions in which the carbon skeleton of the molecule is rearranged to
give a structural isomer of the original molecule.
*These rearrangements can also be considered as a sequence of steps
belonging to substitution, additions or elimination reactions.
*involves a nucleophilic attack at electron deficient atoms e.g. C, O, N
Usually in such reaction atoms or groups shift from one position to another
within the molecule resulting in a new molecular structure.
Rearrangement Reactions
1. Rearrangement of Electron-Deficient Carbon
e.g. Alkyl groups and hydrogen can migrate in rearrangement
reactions to give more stable intermediate carbocations.
•
•
•
•
1° and 2° carbocations rearrange rapidly.
Methyl shift
Alkyl shift
Hydride shift
+
CH3 CH2 CH CH2
H
+
CH3 CH2 CH CH3
Rearrangement Reactions
CH3
CH3 C
CH3
CH CH3
CH3 OH
CH3 C
CH3
CH CH3
CH3 C
+
CH3 OH2
+
H
Nu
+
CH3
SN1
CH3
CH3
+ nucleophile
CH3 C
CH
Methyl
shift
CH CH3
CH3
+
CH3 C
CH3
CH CH3
CH3
Elimination
CH3
CH2 C
CH3
H
+
CH3
CH CH3 + CH3 C
CH3
C
CH3
Rearrangement Reactions
Alkene Rearrangement
• Alkenes may rearrange to produce more highly
substituted alkenes.
H
+
+
CH2 C
C
CH3 H
CH3
CH3
CH3
CH3
CH3 C
C
CH3
CH3 C
CH3
CH3 H
Base
C
CH3
Rearrangement Reactions
1)
CH3
CH3 C
CH3
slow
CH CH3
CH3 C
CH3 Br
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
transition state
Rearrangement Reactions
CH3
CH3 C
CH3
CH
CH3
Rearrangement Reactions
Carbocation Rearrangement
CH3
CH3 C
CH3
CH
CH3
Rearrangement Reactions
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
Rearrangement Reactions
Carbocation Rearrangement
CH3
CH3 C
CH
CH3
CH3
Rearrangement Reactions
CH3
CH3 C
CH
CH3
CH3
Rearrangement Reactions
CH3
CH3 C
CH
CH3
CH3




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.
Hydrogen adds to carbon with fewer hydrogens. Halogen adds to
carbon with most hydrogens.
Anti-Markovnikov
Reaction is initiated by peroxides or photochemically Free radical
mechanism
Free radical reaction
MECHANISM OF THE REACTION
 Free radical addition is an addition reaction
 The addition may occur between a radical and a non-radical,
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.
Free Radical Addition of HBr: Peroxide
Initiation
.. ..
R O O R
.. ..
..
..
.
R O + H Br :
..
..
Gives an antiMarkovnikoff
product
..
R O.
..
..
..
R O H + :Br.
..
..
2
Propagation
Br.
Br
H2C CH R
+
CH2
.
CH R
+
Br
.
CH2
CH R
H Br
H
Br
Termination
Br
CH2
2 Br
.
CH R
CH2
.
+
CH R
CH2
CH R
Br.
+
critical step
Br
Br.
Br
Br
CH2
CH2
CH R
CH CH CH2
R
R
Br
WHY ANTI -MARKOVNIKOFF ?
Br
FREE RADICAL
CH2 CH
R
2
.
+H
Br adds first
..
.
:Br
..
Br
+
H2C CH R
CH2
.
CH2
+
IONIC
CH2
H adds first
H+
FAVORED
CH R
secondary
primary
CH R
primary
H
H2C CH R
.
CH R
Br
AntiMarkovnikov
+
secondary
H CH2 CH R
FAVORED
+ BrCH3
CH R
Br
Markovnikov
Free radical reaction
Stability Of Carbon Radical Intermediates
Radicals are electron-deficient, just like carbocations, and have the same
stability order.
lowest
energy
R
R
R C R <
tertiary
R C H
<
secondary
R CH2 < CH3
primary
highest
energy
methyl
and they are stabilized by resonance and / or hyperconjugation.
()
()
CH2
()
()
CH2
()
()
etc.
Free radical reaction
Solvents
Radical reactions favor non-polar solvents when
possible.
Ionic reactions favor polar solvents.
In the HBr reactions just mentioned in these slides, water is the
solvent in both cases . However, in some of the other radical
reactions, non-polar solvents are used.
Free radical reaction
CH2Cl2
CH4 + Cl2 hv
It is a very complicated free radical
reaction
CH3Cl +
+ CHCl3 +
CCl4 + HCl
Free radical reaction
Free radical reaction
Free radical reaction
Free radical reaction
Free radical reaction
Information Enrichment
Linkage with the life
sciences


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.




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.
H.W
Find 3 different diseases caused by
free radical reactions inside the
body