General

Organic Chemistry
Two credits
Second Semester 2009

King Saud bin Abdulaziz University for Health Science

Reference Book: Organic Chemistry: A Brief Course,

by Robert C. Atkins and Francis A. Carey
Third Edition

Instructor: Rabih O. Al-Kaysi, PhD.

 Lecture 23

Chapter 14

Amines
Preparation of Amines by
Reduction
 Preparation of Amines by Reduction

almost any nitrogen-containing compound can

be reduced to an amine, including:

azides
nitriles
nitro-substituted benzene derivatives
amides
 Synthesis of Amines via Azides

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaN3
CH2CH2Br CH2CH2N3

azides may also be (74%)

1. LiAlH4
reduced by catalytic
hydrogenation 2. H2O

CH2CH2NH2

(89%)
 Synthesis of Amines via Nitriles

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaCN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN

nitriles may also be (69%)

reduced by lithium H2 (100 atm), Ni
aluminum hydride
CH3CH2CH2CH2CH2NH2

(56%)
 Synthesis of Amines via Nitroarenes

HNO3
Cl Cl NO2
H2SO4
nitro groups may also (88-95%)
be reduced with tin (Sn)
+ HCl or by catalytic 1. Fe, HCl
hydrogenation
2. NaOH

Cl NH2

(95%)
 Synthesis of Amines via Amides

O O
1. SOCl2
COH CN(CH3)2
2. (CH3)2NH
(86-89%)
only LiAlH4 is an
appropriate reducing
1. LiAlH4
agent for this reaction
2. H2O

CH2N(CH3)2

(88%)
Reductive Amination
Synthesis of Amines via Reductive Amination

The imine undergoes hydrogenation faster

than the aldehyde or ketone. An amine is
the product.

R fast R
C O + NH3 C NH + H2O
R' R'
R
H2, Ni
R' C NH2

H
Example: Ammonia gives a primary amine.

H2, Ni H
O + NH3
ethanol NH2

(80%)

via: NH
 Reactions of Amines:
A Review and a Preview
 Reactions of Amines

Reactions of amines almost always involve the

nitrogen lone pair.

as a base: N •• H X

as a nucleophile: N •• C O
 Reactions of Amines

Reactions already discussed

basicity
reaction with aldehydes and ketones

reaction with acyl chlorides

Reactions of Amines with Alkyl
Halides
 Reaction with Alkyl Halides

Amines act as nucleophiles toward alkyl halides.

•• • + •• •–
N •• + R X• •
N R + • X•
•• ••

H H

+
N R + H
••
Example: excess amine

NH2 + ClCH2

(4 mol) (1 mol)
NaHCO3 90°C

NHCH2

(85-87%)
Nitrosation of Alkylamines
 Nitrite Ion, Nitrous Acid, and Nitrosyl Cation

+
–• •• •• •• • H •• •• •• •
•O N O• H O N O•
•• ••
+
H

H H
•• •• • + •• •• •
•• O •• + N O• •• O N O•
+
H H
Nitrosyl Cation and Nitrosation

•• •• •
N O•
+
 Nitrosyl Cation and Nitrosation

+ •• •• •
N N O•

•• •• •
N •• + N O•
+
 Nitrosation of Secondary Alkylamines

+ •• •• • •• •• •
N N O• •• N N O•

H +
+
H

•• •• • nitrosation of secondary
N •• + N O•
+ amines gives an N-nitroso
amine
H
 Example

•• NaNO2, HCl •• •• •• •
(CH3)2NH (CH3)2N N O•
H2O
(88-90%)
 Some N-Nitroso Amines

N-nitrosodimethylamine
(CH3)2N N O
(leather tanning)

N N

N N
N
O O

N-nitrosopyrrolidine N-nitrosonornicotine
(nitrite-cured bacon) (tobacco smoke)
 Nitrosation of Primary Alkylamines

R R
H + •• •• • •• •• •
N N O• •• N N O•

H H +
+
R H
H
•• •• • analogous to
N •• + N O•
+ nitrosation of
secondary amines to
H
this point
 Nitrosation of Primary Alkylamines

R R
+
•• •• + H •• •• •
•• N N O •• N N O•

H H H
this species reacts further
R R H
+
•• •• • H ••
•• N N O• •• N N O ••
+
+ H H
H
 Nitrosation of Primary Alkylamines

H
nitrosation of a primary
+
alkylamine gives an N N •• + •• O ••
R
alkyl diazonium ion
process is called H
diazotization
R H
••
•• N N O ••
+
H
 Alkyl Diazonium Ions

+
+ + •
R •N N •• R N N ••

alkyl diazonium ions

readily lose N2 to
give carbocations
 Nitrosation of Tertiary Alkylamines

There is no useful chemistry associated with the

nitrosation of tertiary alkylamines.

R R
R R + •• •• •
N •• N N O•

R R
Nitrosation of Arylamines
 Nitrosation of Tertiary Arylamines

reaction that occurs is

electrophilic aromatic substitution

N(CH2CH3)2 N(CH2CH3)2
1. NaNO2, HCl,
H2O, 8°C
2. HO–

N
O
(95%)
Nitrosation of N-Alkylarylamines

similar to secondary alkylamines;

gives N-nitroso amines

NaNO2, HCl, N O
H2O, 10°C
NHCH3 NCH3

(87-93%)
 Nitrosation of Primary
Arylamines
gives aryl diazonium ions
aryl diazonium ions are much more stable than
alkyl diazonium ions
most aryl diazonium ions are stable under the
conditions of their formation (0-10°C)
+ fast +
RN N R + N2

+ slow +
ArN N Ar + N2
Example:

(CH3)2CH NH2

NaNO2, H2SO4
H2O, 0-5°C

+
(CH3)2CH N NHSO4–
Synthetic Origin of Aryl Diazonium Salts

Ar H

Ar NO2

Ar NH2

+
Ar N N
Synthetic Transformations
of Aryl Diazonium Salts
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
Preparation of Phenols

+
Ar N N

H2O, heat

Ar OH
Example

(CH3)2CH NH2

1. NaNO2, H2SO4
H2O, 0-5°C
2. H2O, heat

(CH3)2CH OH

(73%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Iodides

reaction of an aryl diazonium salt with

potassium iodide

+
Ar N N
KI
Ar I
Example

NH2 I
1. NaNO2, HCl
Br H2O, 0-5°C Br

2. KI, room temp.

(72-83%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Fluorides

Ar F
+
Ar N N

heat the tetrafluoroborate salt of a diazonium ion;

process is called the Schiemann reaction
 Example

NH2 1. NaNO2, HCl, F

H2O, 0-5°C

2. HBF4
CCH2CH3 CCH2CH3
3. heat
O O
(68%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Chlorides and
Bromides
Ar Cl Ar Br

+
Ar N N
aryl chlorides and aryl bromides are prepared by heating
a diazonium salt with copper(I) chloride or bromide
substitutions of diazonium salts that use copper(I) halides
are called Sandmeyer reactions
 Example

NH2 1. NaNO2, HBr, Br

H2O, 0-10°C
Cl Cl

2. CuBr, heat

(89-95%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Nitriles

Ar CN
+
Ar N N

aryl nitriles are prepared by heating a diazonium

salt with copper(I) cyanide
this is another type of Sandmeyer reaction
 Example

NH2 1. NaNO2, HCl, CN

H2O, 0°C
CH3 CH3

2. CuCN, heat

(64-70%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Transformations of Aryl Diazonium Salts

hypophosphorous acid (H3PO2) reduces diazonium

salts; ethanol does the same thing
this is called reductive deamination
+
Ar N N

Ar H
 Example

NH2 NaNO2, H2SO4,

H3PO2
CH3 CH3

(70-75%)
 Value of Diazonium Salts

1) allows introduction of substituents such as OH, F, I,

and CN on the ring
2) allows preparation of otherwise difficultly
accessible substitution patterns
 Example

NH2 NH2
NaNO2, H2SO4,
Br Br
Br2 H2O, CH3CH2OH
H2O

Br Br
Br
(100%)

Br
(74-77%)
Azo Coupling
 Azo Coupling

Diazonium salts are weak electrophiles.

React with strongly activated aromatic compounds by
electrophilic aromatic substitution.

+
Ar N N +Ar' H Ar N N Ar'

an azo compound

Ar' must bear a strongly electron-releasing group

such as OH, OR, or NR2.
Example
OH

+
+ C6H5N N Cl–

OH

N NC6H5