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UNIT 07: Organic reaction and Synthesis of a drug molecules

All chemical reactions involve the breaking of existing bond in the reactant molecule and
formation of new bonds in the product molecules. Covalent bonds are broken in two ways.
1. Homolytic fission
2. Heterolytic fission
1. Homolytic fission: When a bond between two atoms breaks in such a way that one electron
of the shared pairs remains with each of the two departing atoms it is called hemolytic fission.
 It results into the formation of two free radicals.

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

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2. Carbonium ion or Carbocation

Carbon species carrying positive charge on a carbon atom is called carbonium or carbocation.
 There are six electrons in it.
 The carbon atom containing positive charge is sp2 hybridized.
 Carbocations are planer.
Relative stability of Carbocations: 3o > 2o > 1o > methyl free radical

3. Carbanion:

Chemical species carrying negative charge on negative carbon atom are called carbanion.

 They possess one unshared pair of electrons.

 The carbon containing the negative charge is sp3 hybridised.
 The shape of a carbanion is pyramidal.

Relative stability of Carbanions: Methyl free radical > 1o > 2o > 3o

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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:

 All Lewis base which contain lone pairs:

The star (*) indicates the atom which donates electrons to the substrate.
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CLASSIFICATION OF ORGANIC REACTION

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

1. NUCLEOPHILIC SUBSTITUTION REACTION

In organic chemistry, nucleophilic substitution is a class of reactions in which a leaving group

(LG) is replaced by an electron rich species (nucleophile). The whole molecular entity of which
the electrophile and the leaving group are part is usually called the substrate.
The most general form of substitution reaction may be given as the following:

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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.

There are two fundamental events in a nucleophilic substitution reaction:

1. breaking of the σ bond to the leaving group
2. formation of the new σ bond to the nucleophile
Nucleophilic substitution at an sp3 hybridized carbon, therefore, involves two σ bonds: the bond
to the leaving group, which is broken, and the bond to the nucleophile, which is formed.
Depending on that nucleophilic reaction is of two types.
a. Nucleophilic substitution bimolecular (SN2) reaction
b. Nucleophilic substitution unimolecular (SN1) reaction

a. Nucleophilic substitution bimolecular (SN2) reaction:

Mechanism of SN2 reaction:

 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.

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Stereochemistry of the SN2 Reaction:

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.

b. Nucleophilic substitution unimolecular (SN1) reaction

Mechanism of SN1 reaction:

 In SN1 reaction bond breaking takes place before bond making.
 It is a twostep reaction.
 In the initial step, the leaving group departs from the substrate generating a
stable carbocation intermediates. This is the slowest step and thus this step is
considered to be rate determining.
 In second step, the nucleophile adds to the carbocation intermediates to give
substituted product.
 It is a first order reaction and the molecularity of it is one.

Stereochemistry of the SN1 Reaction:

The carbocation intermediate formed in step 1 of the SN1 reaction mechanism is an sp2 hybridized
carbon. Its molecular geometry is trigonal planar, therefore allowing for two different points of
nucleophilic attack, left and right.

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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.

Important things to note:

If a carbon containing leaving group is 1o then it preferentially goes substitution through SN2
pathway. The reactivity order for SN2 reaction: Methyl > 1o > 2o > 3o
If a carbon containing leaving group is 3o then it preferentially goes substitution through SN1
pathway. The reactivity order for SN1 reaction: 3o > 2o > 1o > methyl

SN1 reaction
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Difference between SN2 and SN1 reaction:

SN1 reaction SN2 reaction
The rate of reaction is unimolecular. The rate of reaction is bimolecular
It is a two-step mechanism It is only a one-step mechanism
Carbocation is formed as an intermediate part No carbocation is formed during the reaction.
of the reaction.
There is no partial bond formed with the Carbon forms a partial bond with the
carbon during this reaction. nucleophile and the leaving group.
There are many steps in this reaction which The process takes place in only one cycle,
start with the removal of the group while with a single intermediate stage.
attacking the nucleophile.

2. ELECTROPHILIC SUBSTITUTION REACTION

An electrophilic substitution reaction is a chemical reaction in which the functional group
attached to a compound is replaced by an electrophile. The displaced functional group is typically
a hydrogen atom.
Types of Electrophilic Substitution Reactions
The two primary types of electrophilic substitution reactions undergone by organic compounds
are
1. Electrophilic aromatic substitution reactions
2. Electrophilic aliphatic substitution reactions

 Electrophilic aromatic substitution reactions

In electrophilic aromatic substitution reactions, an atom attached to an aromatic ring is replaced
with an electrophile. Examples of such reactions include aromatic nitrations, aromatic
sulphonation, and Friedel-Crafts reactions.
It is important to note that the aromaticity of the aromatic compound is preserved in electrophilic
aromatic substitutions.

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.

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 Electrophilic aliphatic substitution reactions

In electrophilic aliphatic substitution reactions, an electrophile replaces the functional group
(generally hydrogen) in an aliphatic compound. These reactions can be classified into the
following five types.
 Halogenation of ketones
 Nitrration
 Keto-Enol tautomerism
 Insertion of a carbene into a carbon-hydrogen bond
 Diazonium coupling (aliphatic)
These electrophilic substitution reactions can result in an inversion of configuration if the
electrophilic attack occurs at an angle of 180o to the leaving group (attack from the rear).
Mechanism of Electrophilic Substitution Reaction
Electrophilic substitution reactions generally proceed via a three-step mechanism that involves
the following steps.
1. The generation of an electrophile.
2. The formation of a carbocation (which is an intermediate).
3. The removal of a proton from the intermediate.
Step 1: Generation of Electrophile:
Anhydrous aluminium chloride is a very useful Lewis acid in the generation of electrophile from
the chlorination, alkylation, and acylation of an aromatic ring. The resulting electrophiles (from
the combination of anhydrous aluminium chloride and the attacking reagent) are Cl +, R+, and
RC+O respectively as shown below:

Step 2: Formation of Carbocation

The electrophile attacks the aromatic ring, forming a sigma complex or an arenium ion. One of
the carbons in this arenium ion is sp3 hybridized.

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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.

Step 3: Removal of Proton

In order to restore the aromatic character, the sigma complex releases a proton from the sp3
hybridized carbon when it is attacked by the [AlCl4]–. The reaction describing the removal of a
proton from the sigma complex is given below:

Thus, the electrophile replaces the hydrogen atom in the benzene ring.
Different Electrophilic Substitution Reactions:
1. Chlorination:

2. Sulfonation:

3. Nitration:

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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:

(A) Friedel-Crafts Acylation:

The Friedel-Crafts acylation reaction involves the addition of an acyl group to an aromatic ring.
Typically, this is done by employing an acid chloride (R-(C=O)-Cl) and a Lewis acid catalyst
such as AlCl3. In a Friedel-Crafts acylation reaction, the aromatic ring is transformed into a
ketone. The reaction between benzene and an acyl chloride under these conditions is illustrated
below.

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Mechanism:
Step-1:

Step-2:

Step-3:

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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.

Fig: Examples of β-elimination

According to the kinetics elimination reaction can be classified as follows.
1. Elimination Unimolecular (E1 reaction)
2. Elimination Bimolecular (E2 reaction)
1. Elimination Unimolecular (E1 reaction)
E1 describes an elimination reaction (E) in which the ratedetermining step is unimolecular (1)
and does not involve the base.
Mechanism:
It is a two-step process of elimination: ionization and deprotonation.
• Ionization: The carbon-halogen bond breaks to give a carbocation intermediate.

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• Deprotonation: Deprotonation of the carbocation gives the alkene.

E1 reaction typically takes place with tertiary alkyl halides (R3CX), but is possible with some
secondary alkyl halides.

Fig: Mechanism for E1 reaction

 The reaction rate is influenced only by the concentration of the alkyl halide because
carbocation formation is the slowest step, known as the rate-determining step. Therefore,
first-order kinetics apply (unimolecular).
 The reaction usually occurs in the complete absence of a base or the presence of only a
weak base (acidic conditions and high temperature).
 E1 reactions are in competition with SN1 reactions because they share a common
carbocation intermediate.
 There is no antiperiplanar requirement.

Elimination Bimolecular (E2 reaction)

E2 describes an elimination reaction (E) in which the ratedetermining step is bimolecular (2) and
the base is involved in the rate equation. The eliminating groups, proton and the leaving groups
leave in this step.
It is typically undergone by primary substituted alkyl halides, but is possible with some
secondary alkyl halides and other compounds.
Mechanism:
The E2 mechanism (E2 stands for bimolecular elimination) involves a one-step mechanism in
which carbon-hydrogen and carbon-halogen bonds break to form a double bond (C=C π-bond).
Thus, E2 is a single step elimination, with a single transition state.

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Fig: E2 Elimination Reaction

 The reaction rate is second order, because it's influenced by both the alkyl halide and
the base (bimolecular).
 Because the E2 mechanism results in the formation of a π-bond, the two leaving groups
(often a hydrogen and a halogen) need to be antiperiplanar. An antiperiplanar transition
state has staggered conformation with lower energy than a synperiplanar transition state
which is in eclipsed conformation with higher energy. The reaction mechanism involving
staggered conformation is more favorable for E2 reactions (unlike E1 reactions).
 E2 competes with the SN2 reaction mechanism if the base can also act as a nucleophile
(true for many common bases).
Orientation in E2: Saytzeff vs Hofmann
In substrates which have alternative β-hydrogen atoms available, it is possible to obtain more
than one alkene on elimination. Thus, there will be two possibilities:

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.’

Fig: Saytzeff rule.

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.’

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Nucleophilic Addition Reaction

A nucleophilic addition reaction is a chemical addition reaction in which a nucleophile forms a
sigma bond with an electron-deficient species.
These reactions are considered very important in organic chemistry since they enable the
conversion of carbonyl groups into a variety of functional groups. Generally, nucleophilic
addition reactions of carbonyl compounds can be broken down into the following three steps.
1. The electrophilic carbonyl carbon forms a sigma bond with the nucleophile.
2. The carbon-oxygen pi bond is now broken, forming an alkoxide intermediate (the bond
pair of electrons are transferred to the oxygen atom).
The subsequent protonation of the alkoxide yields the alcohol derivative.
The carbon-oxygen double bond is directly attacked by strong nucleophiles to give rise to the
alkoxide. However, when weak nucleophiles are used, the carbonyl group must be activated with
the help of an acid catalyst for the nucleophilic addition reaction to proceed.

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.

Free Radical Addition Reaction

A free Radical addition is a polymerizing approach by which successive addition of free radicals
takes place to form a polymer unit. It is a type of chain-growth polymerization.
In presence of peroxide, this addition reaction takes place (Anti-Markovnikov rule)
Mechanism:
Free Radical addition occurs in three steps, i.e.
1. Initiation of Free Radical
2. Propagation of Free Radical
3. Termination of Free Radical
1. Initiation of Free Radical:

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2. Propagation of Free Radical:

3. Termination of Free Radical:

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.

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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).

4. Oxidation with hot alkaline KMnO4:

If alkene is heated with concentrated solution of alkaline solution of KMnO4 at 373-383 K,
cleavage of C=C bond takes place which leads to the formation of CO2 and carboxylic acid or
ketone depending on the nature of alkene.
 Terminal =CH2 is oxidized to CO2
 If any H present with the double bonded other carbon, then carboxylic acid will be the
product.
 While, if there is no H attached to the other doubly bonded carbon then ketone will be
the end product.

In case of aromatic compounds, the alkene chain outside the benzene ring is/are oxidized to –
COOH group, keeping the aromatic ring unaltered.

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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.

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REDUCTION REACTION

1. Reduction or hydrogenation of Alkenes:

2. Reduction or hydrogenation of Alkynes:

3. Reduction of aromatic compounds:

4. Reduction of Carboxylic acid:

(i) Reduction to alkane: Carboxylic acid can be reduced to alkane with HI and Red Phosphorous
at about 430K.
(ii) Reduction to alcohol: Carboxylic acid can be converted to alcohol by the treatment with
LiAlH4.

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5. Reduction of Acid chloride:

(i) Reduction to Aldehyde (Rosenmund Reduction):
The Rosenmund reaction is a hydrogenation process where molecular hydrogen reacts with the
acyl chloride in the presence of catalyst – palladium on barium sulfate. Barium sulfate reduces
the activity of the palladium due to its low surface area, thereby preventing over reduction.

(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).

6. Reduction of Acid amide:

Acid amides on reduction with LiAlH4 give primary amines with the same number of carbon
atomes.

CYCLISATION REACTION

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2. Freund's method (Cyclisation of α,ω-dihalogen compounds):

When α,ω-dihalogen compounds are heated with Zn or Na metal in presence of EtOH,
cycloalkane is formed.

3. From Barium or Calcium salts of dibasic acids (Wislicenus method):

4. Condensation of α,ω-dihalide with malonic ester (Perkin’s method):

5. Diels-Alder Reaction ([4+2]-cyclo addition reaction)

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The [4+2]-cycloaddition of a conjugated diene and a dienophile (an alkene or alkyne), an

electrocyclic reaction that involves the 4 π-electrons of the diene and 2 π-electrons of the
dienophile. The driving force of the reaction is the formation of new σ-bonds, which are
energetically more stable than the π-bonds.

RING OPENING REACTION

(A) Cyclopropanes are very reactive due to its high angle stain (60o) and undergoes addition
reactions like alkenes.

(B) Cyclobutane (bond angle 90o) is generally less reactive because of less ring strain and
therefore, does not undergo additional reaction under normal conditions.

(C) Cycloalkanes are oxidized by alkaline KMnO4 to produce dicarboxylic acid.

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SYNTHESIS OF COMONLY USED DRUG MOLECULE

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: It is used as anti-pyretic and pain killer medicine.

1. PARACITAMOL:
 Common chemical name: para-hydroxyacetanilide.
 Synthesis: Paracetamol is obtained by acetylation of p-aminophenol with acetic
anhydride or acetyl chloride.

 Use: Paracetamol is a medicine used to treat mild to moderate pain. Paracetamol can
also be used to treat fever (high temperature).

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