CONTENT: TOPIC NAME : ALKYL HALIDES METHODS OF

TOPIC NAME : ALKYL HALIDES

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GPAT NIPER

PHARMACEUTICAL ORGANIC CHEMISTRY – 1 SUBJECT CODE (BP202T)

CONTENT:

METHODS OF PREPARATIONS

NUCLEOPHILIC REACTIONS

DESTINATION PHARMAGENS

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METHODS OF PREPARATION OPF ALKANES

From Alcohol & HX

• It is nucleophilic substitution reaction, where alcohol and hydrogen halide are

reacted together to form haloalkanes

• It is important synthetic method used for synthesis on commercial scale

• SN1 mechanism which is followed mostly by primary alcohols

SN2 mechanism which is followed mostly by tertiary and secondary alcohols



2. HALOGENATION OF CERTAIN HYDROCARBONS

Under the influence of UV light or at 200 – 400 °C, chlorine or bromine

converts alkanes into chloroalkanes (alkyl chloride) or bromoalkanes (alkyl

bromides)

Along with this equivalent amount of HX halogen acid is also generated (eg:

HCl and HBr)

The General Reaction for the mentioned process is as follow :



Depending upon the which H-atom is replaced, any of isomeric product is

obtained. (Except in case of Methane and Ethane)

So here we have reacted Ethane with chorine, we will have only one

product here; i.e. 1-chloroethane. Here you can replace any H-ATOM but

product will be same & no isomer will be obtained.






Now let us consider case of Propane.






In case of Propane we have mixture of 2 isomers.

Similarly for Butane there will be formation of 2 isomers.

This proves that all H-ATOMS of alkanes are equally susceptible for

substitution by Halogen Atom




Mechanism

This halogenation of alkanes is Free radical substitution reactions. This

proceeds via series of Chain reactions.

Where the sequence of events are classified into three phases such as

Chain initiation

Chain Propagation

Chain Termination




Chain initiation

In this chain initiation step, high amount of energy is absorbed so as to

generate reactive radicals known as free radicals. These radicals are

generated by the process of Homolysis, where each halogen atom keeps one

electron along with it.




Chain Propagation

Each radical generated now reacts with the other molecules and generates

new radicals

Here one chlorine radical abstract H-atom from CH4 to form HCl and CH3 free

radical. Now this generated CH3 radical will react with chlorine to form

substituted product and Chlorine radical




Reaction Summary till now:




Reaction Summary till now: what possibilities we have till the end of step 2

Apart from HCl and CH3Cl

Chain Termination




3. Electrophilic Addition of HX on alkenes

Considering the structure of Alkenes, Out of two bond one is sigma bond and other one is pi bond. Pi Bond is comparatively weak bond and electrons participating in this bond are loosely held by Carbon Nuclei Now b’coz of loosely held pi-electron pair or pi-electrons , Alkenes serve as source of electrons (Thus acting as Lewis Base) Electron seeking agents/ Deficinet agents such as Electrophile attacks over this double bond



Step-1 (Proton addition and Formation of carbocation)

Step-2 (Conjugate Base addition)

H-Br bond undergoes Heterolytic clevage so as to generate proton / electron

deficient Hydrogen atom / species, which on reaction with alkene generate

Carbocation as intermediate

3. Electrophilic Addition of HX on alkenes



4. Free Radical Allylic Bromination of Alkenes

Initially Hydrogen atom at allylic position is abstracted from alkene, leading to

formation of allyl radical.

In the second step, Bromine radical is added over allyl radical forming C-Br bond

leading to formation of Bromoalkane



Reactions of Alkyl Halides

NUCLEOPHILIC SUBSTITUTION REACTION

What are Nucleophiles

• Nucleophiles are electron rich compounds (thus lewis bases) , which reacts with

the electron deficient atom / Neutral molecule



What is Nucleophilic Substitution

• Where the nucleophile get substituted over atom or functional group of substrate is

called as Nucleophilic Substitution Reaction.

• In this reaction atom or functional group that departs along with its bonding electrons

is called as Leaving Group

• Alkyl Halide reacts with number of Nucleophilic reagents such as : Hydroxide,

Cyanide, Alkoxide

• When Neutral solvent provide assistance for Nucleophilic reactions then such SN

reaction known as Solvolysis, used in case of Tertiary alkyl halides (SN1)

• Why: Solvolysis, operates in case of SN1



Why alkyl Halide Shows Nucleophilic Substitution?

• Consider C-X bond, here C-atom electropositive is attached to X-atom which is

electronegative atom.

• Now b’coz of electronegativity difference, X-atom pulls electron pair toward itself,

leading to development of partial positive and partial negative charge.

• Now our nucleus, C-atom possessing partial positive charge starts attracting

negatively charged nucleophile

• In case of SN1 reaction, Carbocation is generated where C-atom possess complete

positive charge, needs weaker nucleophile (but to stabilize strongly poalr solvent is

required)

• Whereas In case of SN2 reaction, Polarity of C-X bond is responsible for attraction

of stronger nucleophile (since here only partial charge is present not the complete

one hence we cant use weaker nucleophile)



SOME BASICS ABOUT SN1 REACTION

It stands for unimolecular substitution reaction where only one molecule is

involved in Rate determining step (RDS).

It is two step reaction which proceeds via the formation of carbocation.

Because of formation of carbocation as intermediate this reaction

necessitates the use of Polar solvent as reaction medium.

Since the carbocation is being formed stable the generating carbocation

higher will be the priority to it formation and more rapidly it is formed.

This factor decides the reactivity; according to it 3° > 2 ° > 1°



SN1 REACTION

STEP 1: FORMATION OF CARBOCATION

STEP 2: SUBSTITUTION BY NUCLEOPHILE



SN1 REACTION


Because of electronegativity differences polarization of charges occurs, this is

favored by use of polar solvent. This polar solvent assist in formation of

carbocation. Here more stable (3°) carbocation is formed.

In this step Hybridization state of C-atom changes from SP3 (Tetrahedral) to SP2

trigonal planar geometry.

Since it is RDS and dependent only on carbocation it is FIRST ORDER REACTION



SN1 REACTION


In this step Hybridization state of C-atom changes from SP3 (Tetrahedral) to

SP2 trigonal planar geometry.



SN1 REACTION


Now, C-nuclei gained complete positive charge. It possess strong tendency

to attract negative charges. Here Negatively charged Nucleophiles are

available. These electron reach species utilizes its electron to form bond

with C-atom.



SN1 REACTION STEREOCHEMISTRY


With the loss of bonding electrons, C-atom in SP3 hybridization state changes

from SP3 to SP2 state.

In this trigonal pyramidal planar geometry, One set of p-orbital is empty now,

which doesn’t possess any electron (p-orbitals lying In opposite directions of C-

nuclei)

These p-orbitals are susceptible for attack by Nucleophile.



SN1 REACTION STEREOCHEMISTRY




Factors affecting SN1 REACTION

There are four factors affecting SN1 reaction

Polarity of Solvent (Polar Protic)

Effect of Structure of Alkyl group ( 3° > 2° > 1°)

Effect of Leaving Group (I > Br > Cl > F )

Strength Of Nucleophile (weak)




Polarity of Solvent

Use of Polar Solvents favors SN1 reaction, since it helps in stabilization of

carbcation.

How ?

In the ionization of Alkyl Halide (Heterolysis), most amount of energy is

transferred by formation of dipole-dipole interaction with solvent and

transition state. Thus more polar the solvent more will be the interaction

and greater stabilization of charge will be there.

OH- --------- (C+---X-)------H+



SN2 REACTION - Features

• It stands for Bimolecular substitution reaction where Both molecules

are involved in Rate determining step (RDS).

• Thus it follows Second Order Kinetics

• It is single step reaction which proceeds via the Pentavalent Transition.

• Reactivity increases with increasing the nucleophilicity

• Inversion of Configuration occurs at α-C-atom



SN2 REACTION Mechanism

CHLORINE OXYGEN CHLORINE OXYGEN



SN2 REACTION - Mechanism

• The electropositive halogen atom attracts electron toward itself leading to

development of partial charges on both Halogen atom and Carbon atom.

• Now partialy positively charged carbon atom attracts negative nucleophile toward

itself.

• Becoz of higher basic strength of carbon forms partial bond with nucleophile and

here simultaneously halide functional group starts departing from C-atom, In

transition state.




There are four factors affecting SN1 reaction

Polarity of Solvent (Polar Aprotic)

Effect of Structure of Alkyl group ( 1° > 2° > 3°)

Effect of Leaving Group (I > Br > Cl > F )

Strength Of Nucleophile (strong)







On the basis of Location of loss of atoms or functional group there are two types of elimination reaction α-elimination (1,1-elimination) β-elimination (1,2-elimination)

Elim

inat

ion

Rea

ctio

n

β-elimination (1,2-elimination) On the basis of molecularity / kinetics it is classified into three types - E2 elimination - E1 elimination - E1cb eliminaiton



Comparing Nucleophilic AND Elimination reaction



Comparing Nucleophilic AND Elimination reaction

At higher temperature Elimination reaction favored, why ?

In Polar But Protic Elimination reaction favored, why ?



Carbocation Stability

There are four governing stability factors

Hyperconjugation

Inductive Effect

Rearrangement

Resonance Effect





Hyperconjugation

It is the stabilizing interaction that results from the interaction of

the electrons in a σ-bond (usually C-H or C-C) with an adjacent

empty or partially filled p-orbital or a π-orbital to give an extended

molecular orbital that increases the stability of the system.





Inductive Effect

It is an electronic effect due to the polarisation of σ bonds within a

molecule or ion. This is typically due to an electronegatvity

difference between the atoms at either end of the bond.





Rearrangement

1,2-Hydride Shift

1,2-Methyl Shift



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CONTENT: TOPIC NAME : ALKYL HALIDES METHODS OF