Unit VII - Org. Reac. Syn. Drug - Total Notes - SM
Unit VII - Org. Reac. Syn. Drug - Total Notes - SM
Unit VII - Org. Reac. Syn. Drug - Total Notes - SM
Tech
2. Heterolytic fission: When two shared electrons remain associated with only one of the two
atoms, the type of fission is heterolytic fission. It results in the formation of cations and anions.
REACTIVE INTERMEDIATES
1. Free Radicals
Free radicals are chemical species having odd or unpaired electrons.
They have no charge.
They are paramagnetic in nature.
These species are highly reactive due to the presence of unpaired electrons.
Free radicals are either planar or pyramidal.
In planar free radicals, carbon atom bearing odd electron is sp2 hybridized and the odd
electron remains in p-orbital.
In pyramidal free radicals, carbon atom bearing odd electron is sp3 hybridized and the
odd electron remains in sp3 orbital.
Relative stability of free radicals: 3o > 2o > 1o > methyl free radical
1
B.Tech
3. Carbanion:
Chemical species carrying negative charge on negative carbon atom are called carbanion.
2
B.Tech
ATTACKING REAGENT
The species that attacks a substrate molecule or intermediate and forms a product is called an
attacking reagent. It is of two types:
1. Electrophilic reagents or electrophiles
2. Nucleophilic reagents or nucleophiles
1. Electrophilic reagents or electrophiles
The word electrophile is made from “electro”, derived from electron and “phile”, which means
loving.
Any molecule, ion or atom that is deficient in electrons in some manner can act as an electrophile.
In other words, the reagent which attacks the negative of the molecule or loves electrons is called
electrophile. They are generally positively charged or neutral species (electron-deficient
molecules) with empty orbitals.
The different types of electrophiles can be classified as follows:
Positively Charged Electrophiles: H+, SO3H+, NO+, NO2+, X+, R+, C6H5N2+
Neutral Electrophiles: They showcase electron deficiency.
(a) All Lewis acids: BF3, AlCl3, SO3, ZnCl2, BeCl2, FeCl3, SnCl2, CO2, SnCl4.
(b) The neutral atom that accepts electrons from the substrates:
> *C = O, R*COCl, R–*Mg–X, *I–Cl, CH3–*CN, R*–Cl, R*–O
The star (*) indicates the atom that accepts electrons.
3. Nucleophilic reagents or nucleophiles
The word nucleophile is made from two words “Nucleo”, derived from the nucleus and “phile”,
which means loving. Species that attack the positive side of the substrate or love the nucleus are
called nucleophiles.
They consist of electrons and are attracted towards the nucleus. They are either negatively or
neutrally charged. They are donors of electrons. Electrons move from low-density areas to high-
density areas. They support nucleophilic addition and nucleophilic substitution reactions. They
are also called Lewis bases.
The different types of nucleophiles can be classified as follows:
Negatively Charged Nucleophiles:
The star (*) indicates the atom which donates electrons to the substrate.
3
B.Tech
The entire organic reactions have been classified under the following hands.
1. Substitution reaction
2. Elimination reaction
3. Addition reaction
Further reactions are classified as:
1. Oxidation reaction 3. Cyclization
2. Reduction reaction 4. Ring opening
SUBSTITUTION REACTION
The substitution reaction is defined as a reaction in which the functional group of one chemical
compound is substituted by another group or it is a reaction which involves the replacement of
one atom or a molecule of a compound with another atom or molecule.
In order to substitution reaction to occur there are certain conditions that have to be used. They
are-
Maintaining low temperatures such as room temperature.
The strong base such as NaOH has to be in dilute form. Suppose if the base is of a higher
concentration, there are chances of dehydrohalogenation taking place.
The solution needs to be in an aqueous state such as water.
Depending upon the nature of the reagents which bring about substitution reactions are of there
types-
1. Nucleophilic substitution reaction 2. Electrophilic substitution reaction
3. Free radical substitution reaction
4
B.Tech
The electron pair from the nucleophile (Nu:) attacks the substrate (R-LG) forming a new bond,
while the leaving group (LG:) departs with an electron pair. The principal product in this case is
R-Nu.
The nucleophile may be electrically neutral or negatively charged, whereas the substrate is
typically neutral or positively charged.
Three components are necessary in any nucleophilic substitution reactions as abbreviated in its
general form:
1. R- in R-X: An alkyl group R containing an sp3 hybridized carbon atom bonded to X (leaving
group) in the substrate, R-X.
2. X- in R-X: An atom (or group of atoms) called a leaving group, which is capable of accepting
the electron density in the C-X bond.
3. Nu: or Nu-: A nucleophile is an electron rich (a neutral or an anion) species that tends to
attack the substrate at a position of low electron density.
In case of SN2 reaction bond breaking and bond formation occur at the same time.
This is a single step reaction where the attack by a nucleophile and the departure of the
leaving group occur simultaneously.
It follows a second order reaction kinetics and the molecularity of the reaction is 2.
It depends both on the nucleophile as well as on the substrate.
5
B.Tech
In SN2 reaction nucleophile attacks the substrate from the back side of the leaving group. In
backside attack, the nucleophile approaches from the opposite side to the leaving group of the
substrate (A), forming B. In this example, the leaving group was drawn on the right, so the
nucleophile attacks from the left. Because the nucleophile and leaving group are in the opposite
position relative to the other three groups on carbon, backside attack results in inversion of
configuration around the stereogenic centre.
6
B.Tech
If the reaction takes place at a stereocenter and if neither avenue for the nucleophilic attack is
preferred, the carbocation is then attacked equally from both sides, yielding an equal ratio of left
and right-handed enantiomers as shown below.
SN1 reaction
7
B.Tech
Here, the chlorine cation acts as an electrophile and replaces a hydrogen atom in the benzene
ring. The products formed in this electrophilic substitution reaction include a proton and a
chlorobenzene molecule.
8
B.Tech
9
B.Tech
This arenium ion finds stability in a resonance structure. Since the delocalization of electrons
stops at the sp3 hybridized carbon, the sigma complex or the arenium ion loses its aromatic
character.
Thus, the electrophile replaces the hydrogen atom in the benzene ring.
Different Electrophilic Substitution Reactions:
1. Chlorination:
2. Sulfonation:
3. Nitration:
10
B.Tech
4. Friedel-Crafts Reaction
These reactions were developed in the year 1877 by the French chemist Charles Friedel and the
American chemist James Crafts.
A Friedel-Crafts reaction is an organic coupling reaction involving an electrophilic aromatic
substitution that is used for the attachment of substituents to aromatic rings. The two primary
types of Friedel-Crafts reactions are the (A) alkylation and (B) acylation reactions.
(A) Friedel-Crafts Alkylation:
Friedel-Crafts Alkylation refers to the replacement of an aromatic proton with an alkyl group.
This is basically the reaction between Aromatic system with alkyl halide in presence of a lewis
acid. A Lewis acid catalyst such as FeCl3 or AlCl3 is employed in this reaction in order to form
a carbocation by facilitating the removal of the halide. The resulting carbocation undergoes a
rearrangement before proceeding with the alkylation reaction.
Mechanism:
11
B.Tech
Mechanism:
Step-1:
Step-2:
Step-3:
12
B.Tech
ELIMINATION REACTION
An elimination reaction is a type of organic reaction in which two atoms or groups are
removed from a molecule resulting in the formation of a multiple bond.
In the great majority of such reactions the atoms or groups are lost from adjacent carbon atoms,
one of them very often being a proton and the other a good leaving group. A general scheme of
elimination reactions is presented below.
Classification:
β-elimination: The type of elimination reactions in which the carbon atom from which the
leaving group is removed is generally designated as the α carbon and the adjacent carbon from
which the hydrogen atom is removed is called the β carbon. So, these type of eliminations are
known as the 1,2- (or α,β-) elimination or simple the β-elimination.
13
B.Tech
14
B.Tech
Saytzeff rule
Saytzeff (working on RBr compounds) states that hydrogen will be eliminated preferentially
from that β-carbon atom which is attached with least number of hydrogen atom/s. Therefore,
according Saytzeff rule
‘that alkene will predominate which has most alkyl substituents on the double bond carbons.’
Hofmann rule
Hofmann (working on RNMe3+ compounds) states that hydrogen will be eliminated
preferentially from that β-carbon atom which is attached with most number of hydrogen atoms.
Therefore, according to Hofmann rule.
‘that alkene will predominate which has least alkyl substituents on the double bond carbons.’
15
B.Tech
The carbonyl group has a coplanar structure and its carbon is sp2 hybridized. However, the attack
of the nucleophile on the C=O group results in the breakage of the pi bond. The carbonyl carbon
is now sp3 hybridized and forms a sigma bond with the nucleophile. The resulting alkoxide
intermediate has a tetrahedral geometry, as illustrated above.
22
B.Tech
OXIDATION REACTION
1. Complete Combustion:
When burnt with excess oxygen, alkanes undergo complete combustion to produce carbon
dioxide (CO2), water (H2O) and large quantities of heat.
2. Incomplete Combustion:
When burnt with insufficient air or oxygen, alkanes undergo incomplete combustion to produce
carbon monoxide (CO), water (H2O) and heat.
Sometimes alkanes after incomplete combustion, leads to the formation of soot or carbon black.
3. Catalytic Oxidation:
In presence of different catalyst, alkanes give different oxidized products.
23
B.Tech
In case of methane, it gives methanol (CH3OH) when it is passed through Cu tube at 475/100
atm. On the other hand, methane when oxidized in presence of Molybdenum, it produces
formaldehyde (HCHO).
In case of aromatic compounds, the alkene chain outside the benzene ring is/are oxidized to –
COOH group, keeping the aromatic ring unaltered.
24
B.Tech
5. Oxidation of Aldehydes:
Aldehydes can be easily oxidized to carboxylic acids having same number of carbon
atoms.
Ketones cannot be easily oxidized, as their oxidation involves the cleavage of C-C bond.
Ketones are oxidized by strong oxidizing agents like acidified KMnO4 conc. HNO3, or
conc. H₂SO₄ + K2Cr₂O7, under strong conditions to carboxylic acids with less number of
carbon atoms.
Aldehydes can be oxidized by mild oxidizing agent like Br, water, Tollen's reagent, Fehling's
and Benedict's solution.
(i) Tollen's reagent: It is ammonical AgNO3. When aldehydes are warmed with Tollen's reagent,
a silver mirror is formed on the walls of container, i. e. Tollen's reagent is reduced to metallic
silver and aldehydes are oxidized to carboxylic acids. This test is also known as silver mirror
test.
(ii) Fehling's solution: Fehling's solution is prepared by mixing equal volume of Fehling's
solution 'A', which is copper sulphate solution containing few drops of conc. H2SO4, and
Fehling's solution 'B', which is alkaline solution of Rochelle salt. Rochelle salt is sodium
potassium tartarate.
Aldehydes form Complex with Cu2+ (from Fehling's solution) and are oxidized to carboxylic
acid while Cuprous oxide (CuO) is reduced to red coloured Cuppric oxide (Cu2O).
Note: Aromatic aldehyde does not give positive response to Fehling’s solution. While Aliphatic
and aromatic both types of aldehydes give positive response to Tollen’s reagent.
25
B.Tech
REDUCTION REACTION
26
B.Tech
(ii) Reduction to Alcohol: Acid chloride is being reduced to alcohols when it is treated with
LiAlH4 or Na in an alcohol (ethanol or isopropanol).
CYCLISATION REACTION
27
B.Tech
28
B.Tech
(B) Cyclobutane (bond angle 90o) is generally less reactive because of less ring strain and
therefore, does not undergo additional reaction under normal conditions.
29
B.Tech
1. ASPIRIN:
Common chemical name: Acetylsalicylic acid
Synthesis: Aspirin is obtained by the acetylation of Salicylic acid (o-hydroxy benzoic
acid) with acetic anhydride or acetyl chloride in the presence of little concentrated
suphuric acid or phosphoric acid.
Use: Paracetamol is a medicine used to treat mild to moderate pain. Paracetamol can
also be used to treat fever (high temperature).
30