Mr. V. T.

Pawar,
Asst.Prof.,
Pharmaceutical Chemistry Department
Bharati Vidyapeeth College of Pharmacy,
Kolhapur.
 Organic compounds with an
electronegative atom or an
electron-withdrawing group
bonded to a sp3 carbon
undergo substitution or
-
elimination reactions

Halide ions are good leaving

groups. Substitution reaction
on these compounds are easy alkyl fluoride alkyl chloride alkyl bromide alkyl iodide
and are used to get a wide
variety of compounds
Substitution

Nucleophilic

Bimolecular
 The SN2 Reaction
Substitution: This reaction involves a substitution of players – two reactants
produce two products, in which some things have been switched around:

AB + C AC + B
Nucleophilic:
These reactions involve a nucleophile (Nuc:-) replacing a leaving group.

Nucleophiles attack the substrate, donating an electron pair to the new

bond, and replacing the leaving group (a substitution).

Bimolecular:
 A bimolecular reaction is one whose rate depends on the concentrations of two
of its reactants.

SN2 reactions happen in one step – the nucleophile attacks the substrate as the
leaving group leaves the substrate.
SN2 summary:

(1)Nucleophile back-side attacks the δ+ carbon center.

(2) Transition state forms in which nucleophile is forming bond

(3) The leaving group leaves, forming the final product.

Substitution Reaction with Halides

(1) (2)

bromomethane methanol

If concentration of (1) is
doubled, the rate of the
reaction is doubled. If concentration of (1) and
(2) is doubled, the rate of
the reaction quadruples.
If concentration of (2) is
doubled, the rate of the
reaction is doubled.
 Mechanism of SN2 Reactions
Alkyl halide Relative rate

The rate of reaction depends on the 1200

concentrations of both reactants.

When the hydrogens of bromomethane

40
are replaced with methyl groups the
reaction rate slow down.

The reaction of an alkyl halide in which 1

the halogen is bonded to an asymetric
center leads to the formation of only
one stereoisomer
≈0
 Mechanism of SN2 Reactions

Hughes and Ingold proposed the following mechanism:

Transition state

Increasing the concentration of either of the

reactant makes their collision more probable.
 Mechanism of SN2 Reactions
Steric effect

activation
energy: DG2
Energy

activation
energy: DG1

reaction coordinate reaction coordinate

Inversion of configuration

(R)-2-bromobutane (S)-2-butanol
 Factor Affecting SN2 Reactions
The leaving group
relative rates of reaction pKa HX
HO
- + RCH I RCH2OH + I
- 30 000 -10
2
HO
- + RCH2Br RCH2OH + Br
- 10 000 -9
HO
- + RCH2Cl RCH2OH + Cl
- 200 -7
HO
- + RCH2F RCH2OH + F
- 1 3.2

The nucleophile

In general, for halogen substitution the

strongest the base the better the
nucleophile.

pKa Nuclephilicity
Notes:

In the SN2 reaction, the nucleophile attacks from the most δ+ region:

This back-side attack causes an inversion (study the previous slide):

The nucleophile must be able to reach the δ+ carbon center that it is

Substitution

Nucleophilic

Unimolecular
SN1 reactions are nucleophilic substitutions, involving a nucleophile replacing a
leaving group (just like SN2).

However: SN1 reactions are unimolecular: the rate of this reaction depends
only on the concentration of one reactant.

SN1 reactions happen in two steps:

1. The leaving group leaves, and the substrate forms a carbocation intermediate.

2. The nucleophile attacks the carbocation, forming the product.

Substrate Carbocation Intermediate Products
1. The Slow Step:

First step of the SN1 reaction:

The leaving group leaves, and the substrate carbon now only has three
Carbocations are most stable when there are more atoms to distribute
Carbocation stability:
3º > 2º >> 1º

2. The Fast Step:

Second step of the SN1 reaction:

The nucleophile attacks the carbocation intermediate, bringing its electron
The substrate loses any stereospecificity during the carbocation intermediate
Substitution Reactions With Halides

1-bromo-1,1-dimethylethane 1,1-dimethylethanol

Rate law:
If concentration of (1) is
doubled, the rate of the rate = k [1-bromo-1,1-dimethylethane]
reaction is doubled.
this reaction is an example of a SN1
reaction.
If concentration of (2) is S stands for substitution
doubled, the rate of the N stands for nucleophilic
reaction is not doubled. 1 stands for unimolecular
 Mechanism of SN1 Reactions
Alkyl halide Relative rate

The rate of reaction depends on the ≈0*

concentrations of the alkyl halide only.

When the methyl groups of 1-bromo- ≈0*

1,1-dimethylethane are replaced with
hydrogens the reaction rate slow down.

The reaction of an alkyl halide in which 12

the halogen is bonded to an asymetric
center leads to the formation of two
stereoisomers
1 200 000

* a small rate is actually observed as a result of a SN2

Mechanism of SN1 Reactions
nucleophile attacks the
carbocation

slow

C-Br bond breaks

fast

Proton dissociation
Mechanism of SN1 Reactions

Rate determining step

Carbocation
intermediate

DG R++ X-
+
R-OH2

R-OH
 Mechanism of SN1 Reactions

Inverted
configuration relative Same configuration
the alkyl halide as the alkyl halide
Factor Affecting SN1 reaction

Two factors affect the rate of a SN1 reaction:

• The ease with which the leaving group dissociate from the carbon
• The stability of the carbocation

As in the case of SN2, the

The more the substituted the
weaker base is the leaving
carbocation is, the more
group, the less tightly it is
stable it is and therefore the
bonded to the carbon and the
easier it is to form.
easier it is to break the bond

The reactivity of the

nucleophile has no effect on
the rate of a SN1 reaction
 Comparison SN1 – SN2

SN1 SN2
A two-step mechanism A one-step mechanism
A unimolecular rate-determining step A bimolecular rate-determining step
Products have both retained and inverted Product has inverted configuration
configuration relative to the reactant relative to the reactant
Reactivity order: Reactivity order:
3o > 2o > 1o > methyl methyl > 1o > 2o > 3o
 Molecular Formula:
C2H5Cl or CH3CH2C

Uses of Ethyl Chloride:

• This medication is used to prevent pain caused by injections and minor
surgical procedures.
• It is also used for the temporary relief of minor sports injuries.
• Ethyl chloride also helps to relieve deep muscle pain when used with
muscle stretching techniques.
• Ethyl chloride is a cooling substance that is applied to the skin to numb it.
• It acts as a mild topical anesthetic by its chilling effect when sprayed on
skin
How to use Ethyl Chloride Spray, Non-Aerosol
This medication is for use on the skin only. It is applied by healthcare professional.
Do not apply to broken skin or mucous membranes (e.g., inside the nose or mouth).
Do not spray into the eyes. Do not inhale the spray.
• Solvent: The hydrogen attached to carbon in chloroform Molecular Formula:
participates in hydrogen bonding. Worldwide, chloroform CHCl3
is also used in pesticide formulations, as a solvent
or fats, oils, rubber, alkaloids, waxes, gutta-percha,
and resins, as a cleansing agent, grain fumigant, in fire
extinguishers, and in the rubber industry.
• Chloroform is majorly used for the manufacturing of
Freon refrigerant R-22. The application of R-22 as
refrigerants has been phased out in developed countries
due to global warming, but it continues to be in high
demand in developing countries owing to its easy
availability and manufacturing
 It has been used as a prominent anaesthetic during medical surgeries ever since its
effects were discovered.
Even criminals use this compound to knock out their victims due to is anaesthetic
effects.
The oxidation of chloroform in the presence of light produces a highly poisonous
gas, called phosgene. This is the reason for storing chloroform in air-tight dark
coloured bottles filled completely so that it has no contact with air.
Molecular Formula:
C2HCl3 or ClCH=CCl2

Uses of Trichloroethylene:
 The main use of trichloroethylene is in the vapor degreasing of metal parts.

 Trichloroethylene is also used as an extraction solvent for greases, oils,

fats, waxes, and tars, a chemical intermediate in the production of other
chemicals, and as a refrigerant.

 Trichloroethylene is used in consumer products such as typewriter

correction fluids, paint removers/strippers, adhesives, spot removers, and
rug-cleaning fluids.
 Trichloroethylene was used in the past as a general anesthetic.
 Molecular Formula:
C2Cl4 or Cl2C=CCl2

Uses
 Tetrachloroethylene is used for dry cleaning and textile processing, as a
chemical intermediate, and for vapor degreasing in metal-cleaning operations
 Adhesives and sealant chemicals
 Functional fluids (closed systems)
 Intermediates
 Laboratory chemicals
 Processing aids, not otherwise listed
 Processing aids, specific to petroleum production
 Solvents (for cleaning or degreasing)
 Solvents (which become part of product formulation or mixture)
Molecular Formula: CH2Cl2

Uses
 The greatest use of DCM is as a paint remover.
 Solvent and cleaning agent in chemical manufacture, textiles, electronics.
metals and plastics, pesticides industries.
 Blowing and cleaning agent in the urethane foam industry.
 Fumigant for strawberries and grains.
 Degreener for citrus fruits.
 In pharmaceuticals as an anesthetic; in extraction of caffeine, cocoa, fats,
spices and beer hops.
 As a heat transfer agent in refrigeration products.
Molecular Formula: CCl4

Uses
 Most carbon tetrachloride is used to make chlorofluorocarbon propellants
and refrigerants.

 Though this has been declining steadily. It has also been used as a dry
cleaning agent and fire extinguisher.

 In making nylons; as a solvent for rubber cement, soaps, insecticides, etc.

 Molecular Formula: ‎CHI3

Uses of Iodoform:
 The compound finds small-scale use as a disinfectant.

 Around the beginning of the 20th century, it was used in medicine

as a healing and antiseptic dressing for wounds and sores.

 Although this use is now superseded by superior antiseptics.