Pharmaceutical OrganicPharmaceutical Organic

ChemistryChemistry

211 PHC –lec. 3211 PHC –lec. 3

Dr. Ebtehal S AlAbdullah Dr. Ebtehal S AlAbdullah

ebtehalksu@yahoo.comebtehalksu@yahoo.com

LECTURE CONTENTS:LECTURE CONTENTS:

Classes and Mechanisims of Organic Reactions

o Types of organic reaction ** Elimination ** Addition ** Rearrangement ** Free radical

Elimination reactionElimination 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

There are three fundamental events in these

elimination reactions:

1. removal of a proton

2. formation of the CC p bond

3. breaking of the bond to the leaving group

ELIMINATION REACTIONELIMINATION REACTION

Elimination reactions involving R-XElimination reactions involving R-X

2-bromopropane 2-bromopropane 2-bromopropane 2-bromopropane

The mechanismThe mechanism

KOH and NaOH as strong bases KOH and NaOH as strong bases

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

R-X also undergo elimination reactions in the presence of sodium

or potassium hydroxide.

ELIMINATIONELIMINATION VERSUS VERSUS SUBSTITUTION SUBSTITUTION IN R-XIN R-X

Both reactions involve heating the R-X under reflux with KOH or NaOH

2-bromopropane has reacted to give an alkene - propene2-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 solventWater 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 ROHElimination reactions involving ROH

Alcohols, like RX undergo elimination reactions to yield alkenes

because H2O is lost in the elimination, this reaction is called dehydration

C OHH3C

H3C

H3C

C CH2H3C

H3C

+ H2OH2SO4

60

HC OHH3C

H3C

CH

CH2H3C + H2OH2SO4

100

H2C OHH3C H2C CH2

+ H2OH2SO4

60primary

secandry

tertiary

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+

OH

cyclohexanol cyclohexene

Q: Show the mechanism of this reaction?

+ H2SO4

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 reactionsRearrangement 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)

slow

++ Br

_

2)

+ +

3)

++ ROH + H

+

CH3 C CH CH3

CH3

CH3 Br

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3OR

a carbocation

WWU -- Chemistry

A Closer Look...

+ +

+

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

transition state

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3

Information Enrichment

Gene rearrangement is a mechanism of genetic recombination in the early stages of immunoglobulin (Ig) and T cell receptors (TCR) production of the immune system. V(D)J recombination takes place in the

primary lymphoid tissue (the bone marrow for B cells, and Thymus for T cells) Types Kappa chain: V-J rearrangements

Lambda chain: V-J rearrangements

Hodgkin's disease which is a cancer originating from white blood cells called lymphocytes.

Hodgkin's lymphoma is characterized by the orderly spread of disease from one lymph node group to another and by the development of systemic symptoms with advanced disease.

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.

Free radical reactionFree radical 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

MECHANISM OF THE REACTION

Chlorination of Chlorination of MethaneMethane

CH4 + Cl2 CH3Cl + CH2Cl2 + CHCl3

+ CCl4 + HCl

It is a very complicated free radical reaction.

hv

Home Work

Find 3 different disease caused by free radical

reactions inside the body

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.

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.