Organic With Drug Molecule

UNIVERSITY OF ENGINEERING & MANAGEMENT, KOLKATA
Course Name : Chemistry (Module 3 lecture1) By Dr. Suvadra Das
Click to edit Master subtitle style

Types of Reactions
Addition reactions – two molecules combine
Elimination reactions – one molecule splits into two
2
Substitution – parts from two molecules exchange
Rearrangement reactions – a molecule undergoes changes in the

way its atoms are connected
3
How Organic Reactions Occur: Mechanisms
• A reaction mechanism is a detailed description of how bonds are

broken and formed as starting material is converted into product.
Reactions occur in defined steps that lead from reactant to product
4
5
• To illustrate the movement of a single electron, use a half-headed curved

arrow, sometimes called a fishhook.
• A full headed curved arrow shows the movement of an electron pair.
6
• Homolysis generates two uncharged species with unpaired electrons.

• A reactive intermediate with a single unpaired electron is called a radical.
• Radicals are highly unstable because they contain an atom that does not
have an octet of electrons.
• Heterolysis generates a carbocation or a carbanion.
• Both carbocations and carbanions are unstable intermediates. A carbocation
contains a carbon surrounded by only six electrons, and a carbanion has a
negative charge on carbon, which is not a very electronegative atom.
7
• Radicals and carbocations are electrophiles because they contain an electron

deficient carbon.
• Carbanions are nucleophiles because they contain a carbon with a lone pair.
8
• Bond formation occurs in two different ways.

• Two radicals can each donate one electron to form a two-electron bond.
• Alternatively, two ions with unlike charges can come together, with the
negatively charged ion donating both electrons to form the resulting two-
electron bond.
• Bond formation always releases energy.
9
A number of types of arrows are used in describing organic reactions.
10
Nucleophile:
A reagent which can donate an electron pair in a reaction
is called a nucleophile.
 The name nucleophile means nucleus loving and
indicates that it attacks regions of low electron density
(positive centers) in the substrate molecule.
 Nucleophiles are electron rich.
They may be negative ions including carbanions or neutral
molecules with free electron pair
A nucleophile can be represented by a by general symbol
Nu:-
Examples
Cl-, Br-, I-, CN -, OH-, RCH2-, NH3, RNH2, H2O, ROH
11
Electrophiles
A reagent which can accept an electron pair in a reaction
called an electrophile.
The name electrophile means electron-loving and
indicates that it attacks regions of high electron density
(negative centers) in the substrates molecule.
Electrophiles are electron deficient. They may be
positive ions including carbonium ions or neutral
molecules with electron deficient centres.
 An electrophile can represented by E+.
Examples: H+, NO2+, R3C+, +SO3H, AlCl3, BF3 12

Electron Displacement Effects

Inductive effect
•The inductive effect is related to the ability of substituent(s) to either
withdraw or donate electron density to the attached carbon atom. Based on
this ability, the substitutents can be classified as electron withdrawing (-I
efect) or electron donating groups relative to hydrogen (+I efect) .
+ I effect - I effect
13
14
15
16
Inductive Effects and Carbocation Stability

LEAST MOST
STABLE STABLE
H CH3 CH3 CH3

C C C C
H H H H H3C H H3C CH3
Methyl Primary Secondary Tertiary

Carbocation Carbocation Carbocation Carbocation
17
Resonance effect
When a compound can be represented by more than one Lewis
structure and actual structure is hybrid of all these structure, the
compound is said to posses resonance.
The resonance structures are hypothetical and individually

do not represent any real molecule.
• The resonance structures have (i) the same positions of nuclei
(ii) the same number of unpaired electrons. 18
19
• i) Positive Resonance Effect (+R effect)

• In this effect, the transfer of electrons is away from an atom or substituent
group attached to the conjugated system.
(ii) Negative Resonance Effect (- R effect)

• This effect is observed when the transfer of electrons is towards the atom
or substituent group attached to the conjugated system.
The atoms or substituent groups, which represent +R or –R electron

displacement effects are as follows :
• +R effect :- –OH, –OR, –OCOR, –NH2, –NHR, –NR2, –NHCOR,
• – R effect :- – COOH, –CHO, >C=O, – CN, –NO2
20
+ R effect - R effect
Course Name : Chemistry (Module 3 lecture 2) by Dr. Suvadra Das

Hyperconjugation
Hyperconjugation is the overlapping of a sigma bond with an adjacent empty or
partially filled p orbital, which results in an increased stability of the molecule
•The electrons of the sigma bond between C and H are involved in delocalization.
• In structure to the right: No bond between C and H due to migration of the
sigma bond.Hence Hyperconjugation is also called as ‘NO BOND RESONANCE’.
2
2
23
24
Electromeric effect
It is a temporary effect. The organic compounds having a multiple bond (a
double or triple bond) show this effect in the presence of an attacking
reagent only. It is defined as the complete transfer of a shared pair of π-electrons
to one of the atoms joined by a multiple bond on the demand of an attacking
reagent.
+E effect : When displacement of electrons is away from the atom or group.

e.g : addition of H+ to alkene.
-E effect : When displacement of electrons is towards the atom or group.
e.g : addition of cyanide ion(CN-) to the carbonyl group.
2
+E effect - E effect 5
Addition reactions
Specific example of addition reaction:
Reaction of an alkene with a
CH2=CH2 + HBr = CH3CH2Br
hydrogen halide to yield halo-alkanes
(alkyl halides)
1. Electrophilic addition
An electrophilic addition reaction is an addition reaction where, in a

chemical compound, a π bond is broken and two new σ bonds are formed.
The substrate of an electrophilic addition reaction must have a double bond
or triple bond.
26
Bonding in Alkenes
Electrons in pi bond are loosely held.

• The double bond acts as a nucleophile
attacking electrophilic species.
• Carbocations are intermediates in the
reactions.
• These reactions are called electrophilic
additions.
2
7
Electrophilic Addition
Step 1 is the protonation of the double bond. The protonation step forms the most
stable carbocation possible.
In step 2, the nucleophile attacks the carbocation, forming an alkyl halide. HBr,
HCl, and HI can be added through this reaction.
28
29
•Reaction is called an electrophilic addition
reaction, because in 1st step of reaction, an
electrophile (H+) is added to the alkene
30
Kinetics
Second order
Rate = [alkene] [Electrophile]
Addition reactions are exothermic (two stronger sigma bonds formed in expanse of one π
bond)
31
CH3-CH=CH-CH3 + HCl CH3-CH-CH2-CH3

Symmetrical UnSymmetrical Cl
CH3-CH=CH2 + Br2 CH3-CH-CH2-Br

UnSymmetrical Symmetrical Br
CH3-CH=CH2 + HCl CH3-CH2-CH2-Cl + CH3-CH-CH3

UnSymmetrical UnSymmetrical Cl
Two possible product Markownikoff Product
Markownikoff’S Rule:
In the ionic additions of an unsymmetrical reagent to a double bond, the positive
portion of the adding reagent attaches itself to a carbon atom of the double bond so
as to yield the MORE STABLE CARBOCATION as an INTERMEDIATE.
32
33
Markownikoff’s Rule
34
Free-Radical Addition of HBr
• In the presence of peroxides, HBr adds to to form the “anti-Markovnikov”

product.
• Peroxides produce free radicals.
• Only HBr has the right bond energy.
• The HCl bond is too strong, so it will add according to Markovnikov’s rule,
even in the presence of peroxide.
• The HI bond tends to break heterolytically to form ions, it too will add
according to Markovnikov’s rule.
35
Free-Radical Initiation
The peroxide bond breaks homolytically to form the first radical:
Hydrogen is abstracted from HBr.

Propagation Steps
Bromine adds to the double bond forming the most stable radical possible:
Hydrogen is abstracted from HBr:
36
Termination
Br. + Br. Br2
Anti-Markovnikov Stereochemistry
• The intermediate tertiary

radical forms faster because it is
more stable.
37
2. Nucleophilic addition Reaction

A nucleophilic addition reaction is an addition reaction where in a chemical
compound a π bond is removed by the creation of two new covalent bonds by the
addition of a nucleophile.
An example of a nucleophilic addition reaction that occurs at the carbonyl group of a
ketone by substitution with hydroxide based compounds.In this example, an
unstable hemiketal is formed
Addition reactions of a nucleophile to carbon – hetero double
bonds such as C=O or CN triple bond.
These bonds are polar thus carbon carries a partial positive
charge.
This makes this atom the primary target for the nucleophile.
This type of reaction is also called a 1,2

nucleophilic addition.
38
Course Name : Chemistry (Module3 Lecture 3) By Dr. Suvadra Das

Substitution reactions
Specific example of substitution reaction: Reaction of 2-bromo-2- methylpropane with

water to yield 2-methylpropan-2-ol & hydrogen bromide
Nucleophilic substitution is a fundamental class of substitution reaction in which

an "electron rich” nucleophile selectively bonds with or attacks the positive or partially
positive charge of an atom attached to a group or atom called the leaving group; the
positive or partially positive atom is referred to as an electrophile.
SN1 : substitution nucleophilic unimolecular

SN2 : substitution nucleophilic bimolecular
SNi : substitution nucleophilic intramolecular
4
0
SN1 : Unimolecular nucleophilic substitution
Solvolysis of tert-butyl bromide to give tertiary butyl alcohol.
Mechanism
Step 1: the leaving A carbocation
group dissociates intermediate;
to form a carbon is
carbocation trigonal planar
Step 2: reaction of the
carbocation (an
electrophile) with water
(a nucleophile) gives an
oxonium ion
Step 3: proton transfer

41
completes the reaction
Kinetics
• First order
• Rate-determining step is formation of carbocation
• Rate = k [RX]
• Depends only on the concentration of the substrate
Stereochemistry : Proceed with partial recemisation and some inversion
Recemisation : the nucleophile can attack from either face of the planar carbocation
intermediate
42
SN2 : Bimolecular nucleophilic substitution
Mechanism: The nucleophile and the alkyl halide combine to form a

pentacoordinate transition state. This is the slow rate determining step (r.d.s); it
entails two species, R-X and Nu - . The dotted lines indicate partially formed or
partially broken covalent bonds.
Kinetics: The study of rates of reactions is called kinetics The reaction involves a
transition state in which both reactants R-X and OH- are together
Rate = k [RX] [OH]
The rate is dependent of the concentration of two species, i.e. the alkyl halide 43
and
NaOH
Stereochemistry of SN2 Reaction

Stereochemistry :
•The transition state of an SN2 reaction has a planar arrangement of the
carbon atom and the remaining three groups
•Occurs with inversion of chiral center called Walden Inversion.
44
Factors influencing the rate of the reaction

•Effect of Substituent
•Nature of the nucleophile
•Nature of the leaving group
•Solvent effect
Effect of substituents on SN reaction
SN1 reactions
• Governed by electronic factors namely the relative stabilities of carbocation
intermediates
• Relative rates: 3° > 2° > 1° > methyl
4
5
SN2 reactions
•Governed by steric factors namely the relative ease of approach of the
nucleophile to the site of reaction
•Relative rates: methyl > 1° > 2° > 3°
The SN2 reaction is fastest with unhindered halides.
46
Effect of the nucleophile on SN reaction
•Nucleophile is a neutral or negatively charged Lewis base.

• Anions are usually more reactive than neutrals
• More basic nucleophiles react faster
• Better nucleophiles are lower in a column of the periodic table
Order of nucleophilicity
CN- > I- >RS- >OH- ≈ C2H5O- >Br - > Cl- > NO3-
I- >Br- > Cl- > F- (in polar protic solvents)
F- > Cl- > Br- > I- ( aprotic solvents)
47
Effect of Leaving groups in SN reaction

Stable anions that are weak bases are usually excellent leaving groups and
can delocalize charge.
Leaving group breaks away with the shared pair of electron So weak bases
are easier to be displaced and are considered as good leaving group in
comparison to strong bases.
Less basic is the substituent, more easily it can be displaced by an attacking
nucleophile in SN2 reaction and by the solvents in SN1 reactions.
Stronger the base less easily it can be displaced. So it is tough to displace OH-
and NH2-
Displacement can be made in such case by modifying the leaving group often
through protonation.
R OH + Br- No Reaction
H+
+ Br-
R OH + H+ R OH2 R Br + H2O
48
Solvent effect on SN reaction
Protic solvent: a solvent that can form hydrogen bond (-OH, -NH)
• these solvents favor SN1 reactions; the greater the polarity of the solvent, the
easier it is to form carbocations in it. Examples of polar protic solvents are: acetic
acid, isopropanol, ethanol, methanol, formic acid, water, etc.
Aprotic solvent: does not contain an -OH group

•It is more difficult to form carbocations in aprotic solvents
•Aprotic solvents favor SN2 reactions
49
Since the hydrogen atom in a polar protic solvent is highly positively charged, it can
interact with the anionic nucleophile which would negatively affect an SN2, but it does not
affect an SN1 reaction because the nucleophile is not a part of the rate-determining step.
Polar protic solvents actually speed up the rate of the unimolecular substitution reaction
because the large dipole moment of the solvent helps to stabilize the transition state. The
highly positive and highly negative parts interact with the substrate to lower the energy of
the transition state. Since the carbocation is unstable, anything that can stabilize this even
a little will speed up the reaction.
Solvent effect
•Solvents that can donate hydrogen bonds (-OH or –NH) slow SN2 reactions by
associating with reactants
•Energy is required to break interactions between reactant and solvent
•Polar aprotic solvents which have large dielectric constant and large dipole
moment but they do not participate in hydrogen bonding (acetone, DMF,
acetonitrile, Dimethyl sulfoxide)form weaker interactions with substrate and
permit faster reaction
Summary
Optimize SN2 rate: Optimize SN1 rate:

• Factor 1: CH3>1o>2o; never 3o • Factor 1: 3o >2o; never 1o, CH3
• Factor 2: Strong, small Nu: • Factor 2: Any Nu:
• Factor 3: Good LG • Factor 3: Good LG
• Factor 4: Polar aprotic solvent • Factor 4: Polar protic solvent
• Factor 5: Stereospecific • Factor 5: Non-stereospecific
51
Course Name : Chemistry (Module 3 Lecture 4) by Dr. Suvadra Das

ELIMINATION REACTION
Elimination reactions involve the loss of fragments or groups from a molecule to
generate multiple bonds. A generalized equation is shown below for 1,2-elimination
wherein the X and Y from two adjacent carbon atoms are removed,
α-elimination: two atoms or groups are removed from the same atom. It is also known as
1,1-elimination
β-elimination: loss of atoms or groups on adjacent atoms. It is also known as 1,2-

elimination
53
β-eliminations can be further subdivided into three categories depending upon the
mechanistic pathway. The important aspect is to establish the number of molecules
taking part in the elimination step (molecularity of the reaction) The types of β-
eliminations are 1) E2 2) E1 3) E1cB
E1 Eliminations (Elimination unimolecular)
Step 1 :
departure of chlorine with stable carbocation

bonding electron pair (tertiary)
5
4
Step 2 :
Formation of carbocation is a slower process, as compared to the reaction

between a ‘reactive-carbocation’ and a base/solvent. Hence, carbocation
formation is the rate determining step.
 Ideal conditions are for E1 mechanism are (a) highly substituted carbon
atom for the carbocation center, such as a tert-carbon atom, (b) use of polar
solvents (which can stabilize the resulting carbocation in addition to
stabilizing a polar transition state involved in the heterolytic bond cleavage.
55
E2 Eliminations (Elimination bimolecular)

Key mechanistic features are
•Two groups depart simultaneously
•Involves one step (in other words, no intermediates are involved)
•bimolecular reaction i.e., both substrate and nucleophile participate in a
single step
•The base abstracts the β hydrogen and leaving group simultaneously leaves
such that it forms a multiple bond between α and β carbon atoms.
56
The sequence of events involved are,

(i)The attack of ethoxide on β hydrogen and its abstraction as a proton is the
first event. This will leave two electrons of the C-H bond available for the
formation of a new double bond between the carbon atoms.
(ii)As the new double bond is created, the C-Br bond begins to break away
(leaving group). This will result in the departure of the bromide ion.
57
Molecular rearrangement /Carbocation Rearrangements

When carbocations are intermediates, a less stable carbocation can rearrange to a
more stable carbocation by a shift of a hydrogen or an alkyl group. This is called a
carbocation rearrangements.
Hydride Shift
5
8
Alkyl Shift
59
Cannizzaro Reaction
Aldehydes which do not have an α-hydrogen atom, undergo self oxidation and
reduction (disproportionation) reaction on heating with concentrated alkali.
In this reaction, one molecule of the aldehyde is reduced to alcohol while another is
oxidised to carboxylic acid salt.
60
Step I: Nucleophilic addition of an OH - ion to the 1st aldehyde molecule gives a

tetrahedral intermediate I .
Step II
Hydride shift: The tetrahedral intermediate I , expels a hydride ion as a leaving
group and is thereby oxidized. A second aldehyde molecule accepts the hydride
ion in another nucleophilic addition step and is thereby reduced.
61
Course Name : Chemistry (Module 3 Lecture 5)

Aldol condensation
Aldol condensation: Aldehydes and ketones having at least one α-hydrogen undergo a
reaction in the presence of dilute alkali as catalyst to form β-hydroxy aldehydes (aldol)
or β-hydroxy ketones (ketol), respectively. This is known as Aldol reaction.
The name aldol is derived from the names of the two functional groups, aldehyde and
alcohol, present in the products.
63
Step 1 Aldol condensation mechanism

α hydrogen atom is removed from
aldehyde or ketone and enolate ion is
formed
Step 2
The enolate ion attacks the carbonyl
carbon of another aldehyde or ketone
to form alkoxide ion
Alkoxide ion
Step 3
Alkoxide ion is
protonated by water
Aldol 64
Beckmann rearrangement
Oximes (Oximes are condensation product between hydroxylamine and an

aldehydes/ketones) on treatment with Lewis acid or protic acid rearrange to
give substituted amides. This reaction is called as Beckmann rearrangement.
Generally group anti to hydroxyl migrates. However, there are several
exception reported. R and R’can be alkyl, aryl or hydrogen. (Hydrogen does not
migrate under normal reaction conditions, but it migrates when the reaction is
carried out with nickel acetate under neutral conditions.)
Like Schmidt rearrangement, oximes of cyclic ketones give ring-expansion.
Hofmann rearrangement
The Hofmann rearrangement is an organic reaction used to convert a primary amide
to a primary amine using a halogen, base, water, and heat. The reaction begins with
deprotonation of the amide by the base to form an anion which then attacks the
halogen to form a N-haloamide. A second deprotonation by the base
provides an anion that rearranges to an isocyanate intermediate and releases a halide
anion. The isocyanate is then attacked by water which after a series of proton transfer
step results in a zwitterionic intermediate, containing an ammonium cation and a
carboxylate anion. Thermal conditions result in the explosion of carbon dioxide gas
and quenching of the ammonium cation to the amine product.
The Diels-Alder Reaction

The Diels-Alder reaction is a method of producing cyclical organic
compounds(cycloaddition reaction).
A conjugated diene reacts with a double-bonded dienophile
Reaction between a conjugated diene and an alkene (dienophile) to give a

cyclohexene
69
Diene : diene are electron rich compound. In the presence of electron

releasing groups such as alkyl,phenyl,or alkoxy groups may further enhance
the reactivity of diene
Dienophile: the most common dienophiles are the electron poor alkenes and
alkyne. A good dienophile generally has one or more electron-withdrawing
groups(CHO,COOH,CN) pulling electron density away from the π bond
70
The Diels-Alder reaction is a six-electron cyclic reaction

• The dienophile can be considered as simultaneously a nucleophile and electrophile
• The driving force is the conversion of two π bonds into two σ bonds
• The reaction will not happen without a Hückel number of electrons.
Normally, dienes are electron-rich; dienophiles are electron-poor
71
Synthesis of paracetamol from phenol (acetaminophen)
In a small-scale laboratory, paracetamol is prepared by a three-reaction

sequence. First, nitration of phenol with sodium nitrate gives a mixture of two
isomers, from which the wanted 4-nitrophenol (bp 279 °C) can easily be
separated by steam distillation. In this electrophilic aromatic substitution
reaction, phenol's oxygen is strongly activating, thus the reaction requires only
mild conditions as compared to nitration of benzene itself. The nitro group is
then reduced to an amine, giving 4-aminophenol. This
reaction can be accomplished using sodium borohydride. Finally, the amine is
acetylated with acetic anhydride.The industrial process is analogous, but
hydrogenation is used instead of the sodium borohydride reduction.
Oil of Wintergreen
It is the commom name of a plant and one of its major constituent is methyl salicylate
Wintergreen (methyl salicylate) Gaultheria procumbens This tiny, North American

plant of the heath family grows in pine forests and on humid ground with sphagnum.
The Indians knew its effects, which is due to methyl salicylate. Like salicylic acid,
it is analgesic and antipyretic.
O OCH3
HO
Preparation of Methyl Salicyclate
O
O
OH
+ CH3OH OCH3 + H2O
OH
OH

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UNIVERSITY OF ENGINEERING & MANAGEMENT, KOLKATA

Course Name : Chemistry (Module 3 lecture1) By Dr. Suvadra Das

Click to edit Master subtitle style

Elimination reactions – one molecule splits into two

Substitution – parts from two molecules exchange

Rearrangement reactions – a molecule undergoes changes in the

How Organic Reactions Occur: Mechanisms

• A reaction mechanism is a detailed description of how bonds are

• To illustrate the movement of a single electron, use a half-headed curved

• Homolysis generates two uncharged species with unpaired electrons.

• Radicals and carbocations are electrophiles because they contain an electron

• Bond formation occurs in two different ways.

A number of types of arrows are used in describing organic reactions.

Examples: H+, NO2+, R3C+, +SO3H, AlCl3, BF3 12

Electron Displacement Effects

Inductive Effects and Carbocation Stability

H CH3 CH3 CH3

Methyl Primary Secondary Tertiary

The resonance structures are hypothetical and individually

• i) Positive Resonance Effect (+R effect)

(ii) Negative Resonance Effect (- R effect)

The atoms or substituent groups, which represent +R or –R electron

Click to edit Master subtitle style

+E effect : When displacement of electrons is away from the atom or group.

An electrophilic addition reaction is an addition reaction where, in a

Electrons in pi bond are loosely held.

CH3-CH=CH-CH3 + HCl CH3-CH-CH2-CH3

CH3-CH=CH2 + Br2 CH3-CH-CH2-Br

CH3-CH=CH2 + HCl CH3-CH2-CH2-Cl + CH3-CH-CH3

Free-Radical Addition of HBr

• In the presence of peroxides, HBr adds to to form the “anti-Markovnikov”

• Peroxides produce free radicals.

• Only HBr has the right bond energy.

Hydrogen is abstracted from HBr.

Hydrogen is abstracted from HBr:

• The intermediate tertiary

2. Nucleophilic addition Reaction

This type of reaction is also called a 1,2

Click to edit Master subtitle style

Specific example of substitution reaction: Reaction of 2-bromo-2- methylpropane with

Nucleophilic substitution is a fundamental class of substitution reaction in which

SN1 : substitution nucleophilic unimolecular

SN1 : Unimolecular nucleophilic substitution

Solvolysis of tert-butyl bromide to give tertiary butyl alcohol.

Step 3: proton transfer

SN2 : Bimolecular nucleophilic substitution

Mechanism: The nucleophile and the alkyl halide combine to form a

Stereochemistry of SN2 Reaction

Factors influencing the rate of the reaction

The SN2 reaction is fastest with unhindered halides.

Effect of the nucleophile on SN reaction

•Nucleophile is a neutral or negatively charged Lewis base.

Effect of Leaving groups in SN reaction

Solvent effect on SN reaction

Aprotic solvent: does not contain an -OH group

Optimize SN2 rate: Optimize SN1 rate:

Click to edit Master subtitle style

β-elimination: loss of atoms or groups on adjacent atoms. It is also known as 1,2-

departure of chlorine with stable carbocation

Formation of carbocation is a slower process, as compared to the reaction

E2 Eliminations (Elimination bimolecular)

The sequence of events involved are,

Molecular rearrangement /Carbocation Rearrangements