chapter 22by

8/2/2019 Chapter 22by

1/54

Dr. Wolf's CHM 201 & 202 22-1

22.6

Reactions of Amines:

A Review and a Preview


2/54

Dr. Wolf's CHM 201 & 202 22-2

Preparation of Amines

Two questions to answer:

1) How is the CN bond to be formed?

2) How do we obtain the correct oxidation

state of nitrogen (and carbon)?


3/54

Dr. Wolf's CHM 201 & 202 22-3

Methods for CN Bond Formation

Nucleophilic substitution by azide ion (N3

) (Section 8.1, 8.13)

Nitration of arenes (Section 12.3)

Nucleophilic ring opening of epoxides by ammonia (Section

16.12)

Nucleophilic addition of amines to aldehydes and ketones

(Sections 17.10, 17.11)

Nucleophilic substitution by ammonia on a-halo acids

(Section 19.16)

Nucleoph

ilic acyl substitution (Sections 20.4, 20.6, and

20.12)


4/54

Dr. Wolf's CHM 201 & 202 22-4

22.7

Preparation of Aminesby Alkylation of Ammonia


5/54

Dr. Wolf's CHM 201 & 202 22-5

Alkylation of Ammonia

Desired reaction is:

2 NH3 + RX RNH2 + NH4X

via:

H3N

R

X

H3N R

+

X

+ +

then:

H3N

+ H N

H

H

R

+H3N H

++ N

H

H

R


6/54

Dr. Wolf's CHM 201 & 202 22-6

Alkylation of Ammonia

But the method doesn't work well in practice.Usually gives a mixture of primary, secondary,

and tertiary amines, plus the quaternary salt.

NH3RX

RNH2RX

R2NH

RX

R3NRX

R4N

+X


7/54Dr. Wolf's CHM 201 & 202 22-7

Example

CH3(CH2)6CH2Br NH3 CH3(CH2)6CH2NH2

(45%)

+

CH3(CH2)6CH2NHCH2(CH2)6CH3

(43%)

As octylamine is formed, it competes with

ammonia for the remaining 1-bromooctane.

Reaction of octylamine with 1-bromooctane

gives N,N-dioctylamine.


8/54Dr. Wolf's CHM 201 & 202 22-8

22.8

The Gabriel Synthesis of Primary Alkylamines


9/54Dr. Wolf's CHM 201 & 202 22-9

gives primary amines without formation of

secondary, etc. amines as byproducts

uses an SN2 reaction on an alkyl halide to form

the CN bond

the nitrogen-containing nucleophile

is N-potassiophthalimide

Gabriel Synthesis


10/54Dr. Wolf's CHM 201 & 202 22-10

gives primary amines without formation of

secondary, etc. amines as byproducts

uses an SN2 reaction on an alkyl halide to form

the CN bond

the nitrogen-containing nucleophile

is N-potassiophthalimide

Gabriel Synthesis

O

O

N

K

+


11/54Dr. Wolf's CHM 201 & 202 22-11

the pKa of phthalimide is 8.3

N-potassiophthalimide is easily prepared by

the reaction of phthalimide with KOH

N-Potassiophthalimide

O

O

N

K+

O

O

NHKOH


12/54Dr. Wolf's CHM 201 & 202 22-12

N-Potassiophthalimide as a nucleophile

O

O

N

R X

+

O

O

N R

+X

SN

2


13/54Dr. Wolf's CHM 201 & 202 22-13

Cleavage of Alkylated Phthalimide

O

O

N R + H2O

H2N R+

CO2H

CO2H

acid or baseimide hydrolysis is

nucleophilic acyl

substitution


14/54Dr. Wolf's CHM 201 & 202 22-14

Cleavage of Alkylated Phthalimide

hydrazinolysis is an alternative method of releasing

the amine from its phthalimide derivative

O

O

N R

H2

N R+

O

O

NH

NH

H2NNH2


15/54Dr. Wolf's CHM 201 & 202 22-15

Example

O

O

N

K

++ C6H5CH2Cl

DMF

O

O

N CH2C6H5 (74%)


16/54Dr. Wolf's CHM 201 & 202 22-16

Example

+ C6H5CH2NH2

O

O

N CH2C6H5

H2NNH2

(97%)

O

O

NH

NH


17/54Dr. Wolf's CHM 201 & 202 22-17

22.9

Preparation of Amines by Reduction


18/54Dr. Wolf's CHM 201 & 202 22-18

almost any nitrogen-containing compound can

be reduced to an amine, including:

azides

nitriles

nitro-substituted benzene derivatives

amides

Preparation of Amines by Reduction


19/54Dr. Wolf's CHM 201 & 202 22-19

SN2 reaction, followed by reduction, gives aprimary alkylamine.

Synthesis of Amines via Azides

CH2

CH2

Br CH2

CH2

N3

NaN3

(74%)

CH2CH2NH2

(89%)

1. LiAlH4

2. H2O

azides may also be

reduced by catalytic

hydrogenation


20/54Dr. Wolf's CHM 201 & 202 22-20


Synthesis of Amines via Nitriles

CH3

CH2

CH2

CH2

BrNaCN

(69%)

CH3

CH2

CH2

CH2

CN

CH3CH2CH2CH2CH2NH2

(56%)

H2 (100 atm), Ni

nitriles may also be

reduced by lithium

aluminum hydride


21/54Dr. Wolf's CHM 201 & 202 22-21


Synthesis of Amines via Nitriles

CH3CH2CH2CH2BrNaCN

(69%)

CH3CH2CH2CH2CN

CH3CH2CH2CH2CH2NH2

(56%)

H2 (100 atm), Ni

the reduction also

works with cyanohydrins


22/54Dr. Wolf's CHM 201 & 202 22-22

Synthesis of Amines via Nitroarenes

HNO3

(88-95%)

Cl Cl NO2H2SO4

(95%)

1. Fe, HCl

2. NaOH

Cl NH2

nitro groups may alsobe reduced with tin (Sn)

+ HCl or by catalytic

hydrogenation


23/54Dr. Wolf's CHM 201 & 202 22-23

Synthesis of Amines via Amides

(86-89%)

COH

O 1. SOCl2

2. (CH3)2NHCN(CH3)2

O

(88%)

1. LiAlH4

2. H2O

CH2N(CH3)2

only LiAlH4 is an

appropriate reducing

agent for this reaction


24/54

Dr. Wolf's CHM 201 & 202 22-24

22.10

Reductive Amination


25/54

Dr. Wolf's CHM 201 & 202 22-25

The aldehyde or ketone equilibrates with the

imine faster than hydrogenation occurs.

Synthesis of Amines via Reductive Amination

OC

R

R'

+ NH3

fast

NHC

R

R'

+ H2O

In reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in the

presence of ammonia or an amine.


26/54

Dr. Wolf's CHM 201 & 202 22-26

Synthesis of Amines via Reductive Amination

OC

R

R'

+ NH3

fast

NHC

R

R'

+ H2O

H2, Ni

NH2

R

R' C

H

The imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is

the product.


27/54

Dr. Wolf's CHM 201 & 202 22-27

Example: Ammonia gives a primary amine.

O + NH3H

NH2

H2, Ni

ethanol

(80%)

via: NH


28/54

Dr. Wolf's CHM 201 & 202 22-28

Example: Primary amines give secondary amines

H2, Ni ethanol

(65%)CH3(CH2)5CH2NH

+ H2NCH3(CH2)5CH

O

via: NCH3(CH2)5CH


29/54

Dr. Wolf's CHM 201 & 202 22-29

Example: Secondary amines give tertiary amines

H2, Ni, ethanol

(93%)

+CH3CH2CH2CH

O

N

H

N

CH2CH2CH2CH3


30/54

Dr. Wolf's CHM 201 & 202 22-30

Example: Secondary amines give tertiary amines

CHCH2CH2CH3

N+

possible intermediates include:

N

CH CHCH2CH3

CHCH2CH2CH3

N

HO


31/54

Dr. Wolf's CHM 201 & 202 22-31

22.11

Reactions of Amines:

A Review and a Preview


32/54

Dr. Wolf's CHM 201 & 202 22-32

Reactions of Amines

Reactions of amines almost always involve the

nitrogen lone pair.

N H Xas a base:

N C Oas a nucleophile:


33/54

Dr. Wolf's CHM 201 & 202 22-33

Reactions of Amines

basicity (Section 22.4)

reaction with aldehydes and ketones (Sections

17.10, 17.11)

reaction with acyl chlorides (Section 20.4),anhydrides (Section 20.6), and esters (Section 20.12)

Reactions already discussed


34/54

Dr. Wolf's CHM 201 & 202 22-34

22.12

Reactions of Amines with Alkyl Halides


35/54

Dr. Wolf's CHM 201 & 202 22-35

Reaction with Alkyl Halides

Amines act as nucleophiles toward alkyl halides.

X+

N R

H

+ X

N R

H

+

+N R

H+


36/54

Dr. Wolf's CHM 201 & 202 22-36

Example: excess amine

NH2 + ClCH2

NHCH2

(85-87%)

NaHCO3 90C

(4 mol) (1 mol)


37/54

Dr. Wolf's CHM 201 & 202 22-37

Example: excess alkyl halide

+ 3CH3I

(99%)

methanol heat

CH2N (CH3)3

CH2NH2

+I


38/54

Dr. Wolf's CHM 201 & 202 22-38

22.13

The Hofmann Elimination


39/54

Dr. Wolf's CHM 201 & 202 22-39


a quaternary ammonium hydroxide is the reactant

and an alkene is the product

is an anti elimination

the leaving group is a trialkylamine

the regioselectivity is opposite to the Zaitsev rule.


40/54

Dr. Wolf's CHM 201 & 202 22-40

Quaternary Ammonium Hydroxides

Ag2O H2O, CH3OH

CH2N (CH3)3

+HO

are prepared by treating quaternary ammmoniumhalides with moist silver oxide

CH2N (CH3)3 I


41/54

Dr. Wolf's CHM 201 & 202 22-41


160C

CH2N (CH3)3

+HO

on being heated, quaternary ammoniumhydroxides undergo elimination

CH2

(69%)

+ N(CH3)3 + H2O


42/54

Dr. Wolf's CHM 201 & 202 22-42

Mechanism

H

CH2

+N(CH3)3

O

H O

HH

N(CH3)3

CH2


43/54

Dr. Wolf's CHM 201 & 202 22-43

Regioselectivity

heat

Elimination occurs in the direction that givesthe less-substituted double bond. This is called

the Hofmann rule.

N(CH3)3+

HO

CH3CHCH2CH3 H2C CHCH2CH3

CH3CH CHCH3

+

(95%)

(5%)


44/54

Dr. Wolf's CHM 201 & 202 22-44

Regioselectivity

Steric factors seem to control the regioselectivity.The transition state that leads to 1-butene is

less crowded than the one leading to cis

or trans-2-butene.


45/54

Dr. Wolf's CHM 201 & 202 22-45

Regioselectivity

N(CH3)3+

H

H

H H

CH3CH2

largest group is between two H atoms

C

HC

HH

CH3CH2

major product


46/54

Dr. Wolf's CHM 201 & 202 22-46

Regioselectivity

N(CH3)3+

H

H

H

CH3

largest group is between an

H atom and a methyl group

C

HC

CH3 H

CH3

minor product

CH3


47/54

Dr. Wolf's CHM 201 & 202 22-47

22.14

Electrophilic Aromatic Substitutionin Arylamines


48/54

Dr. Wolf's CHM 201 & 202 22-48

Nitration of Anililne

NH2 is a very strongly activating group

NH2 not only activates the ring toward

electrophilic aromatic substitution, it alsomakes it more easily oxidized

attemped nitration of aniline fails because

nitric acid oxidizes aniline to a black tar

Ni i f A ilil


49/54

Dr. Wolf's CHM 201 & 202 22-49


Strategy: decrease the reactivity of aniline by

converting the NH2 group to an amide

CH(CH3)2

NH2

CH(CH3)2

NHCCH3

O

O

CH3COCCH3

O

(98%)

(acetyl chloride may be used instead of acetic anhydride)

Ni i f A ilil


50/54

Dr. Wolf's CHM 201 & 202 22-50


Strategy: nitrate the amide formed in the first

step

CH(CH3)2

NHCCH3

O

HNO3

CH(CH3)2

NHCCH3

O

NO2

(94%)

Nit ti f A ilil


51/54

Dr. Wolf's CHM 201 & 202 22-51


Strategy: remove the acyl group from the amide

by hydrolysis

CH(CH3)2

NHCCH3

O

NO2 KOH

ethanol,

heat

CH(CH3)2

NH2

NO2

(100%)


52/54

Dr. Wolf's CHM 201 & 202 22-52

occurs readily without necessity of protectingamino group, but difficult to limit it to

monohalogenation

Halogenation of Arylamines

CO2H

NH2

Br2

acetic acid

(82%)

CO2H

NH2

Br Br

Monohalogenation of Arylamines


53/54

Dr. Wolf's CHM 201 & 202 22-53

Monohalogenation of Arylamines

Cl

NHCCH3

O

CH3

(74%)

Cl2

acetic acid

NHCCH3

O

CH3

Decreasing the reactivity of the arylamine by

converting the NH2 group to an amide allows

halogenation to be limited to monosubstitution

Friedel Crafts Reactions


54/54

Friedel-Crafts Reactions

The amino group of an arylamine must be

protected as an amide when carrying out a

Friedel-Crafts reaction.

NHCCH3

O

CH3 CH3CCl

O

AlCl3

(57%)

NHCCH3

O

CH3

CCH3O

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