Methods for C—N Bond Formation

Nucleophilic substitution by azide ion (N3–)

Nitration of arenes
Nucleophilic ring opening of epoxides by ammonia
Nucleophilic addition of amines to aldehydes and
ketones
Nucleophilic substitution by ammonia on -halo
acids
Nucleophilic acyl substitution
 Alkylation of Ammonia to Make
Amines
Desired reaction is:

2 NH3 + R—X R—NH2 + NH4X

via:
•• • + •• –
H3N •• + R X• H3N R + •• ••
X
•• ••
then: H H
+ +
H3N •• + H N R H3N H + •• N R

H H
 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.

RX RX
NH3 RNH2 R2NH

RX
+ – RX
R4N X R3N
 Example

NH3
CH3(CH2)6CH2Br 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.
 Gabriel Synthesis

gives primary amines without formation of

secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the C—N bond
the nitrogen-containing nucleophile
O
is N-potassiophthalimide
–
•• N–• +
• K

O
N-Potassiophthalimide as a nucleophile

O O
SN2
–
•• N–• •• •
• + R X• •• N R
••

O O

•• •
–
+ •• X •
••
 Cleavage of Alkylated Phthalimide

•N
• R + H2O

O imide hydrolysis is
acid or base nucleophilic acyl
substitution
CO2H
+ H2N R
CO2H
 Cleavage of Alkylated Phthalimide

hydrazinolysis is an alternative method of releasing

the amine from its phthalimide derivative

O O
H2NNH2 NH
•• N R
NH
O
O
+ H2N R
Example

O
–
•• N–• +
• K + C6H5CH2Cl

O DMF

•N CH2C6H5 (74%)
•

O
Example (cont)

NH
+ C6H5CH2NH2 (97%)
NH
H2NNH2
O
O

•N CH2C6H5
•

O
 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 Nitriles

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaCN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN

the reduction also (69%)

works with cyanohydrins H2 (100 atm), Ni

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%)
 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
Example: Primary amines give secondary amines

O
CH3(CH2)5CH + H2N

H2, Ni ethanol

CH3(CH2)5CH2NH (65%)

via: CH3(CH2)5CH N
Example: Secondary amines give tertiary amines

O
CH3CH2CH2CH +
N

H
H2, Ni, ethanol

N
CH2CH2CH2CH3 (93%)
 Example: Secondary amines give tertiary amines

possible intermediates include:

+
N N

HO CHCH2CH2CH3 CHCH2CH2CH3

CH CHCH2CH3