Transcript 22.7 Reactions of Amines: A Review and a Preview

22.7
Reactions of Amines:
A Review and a Preview
Preparation of Amines
Two questions to answer:
1) How is the C—N bond to be formed?
2) How do we obtain the correct oxidation
state of nitrogen (and carbon)?
Methods for C—N 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)
Nucleophilic acyl substitution (Sections 20.3, 20.5, and 20.11)
Hofmann rearrangement (Section 20.17)
22.8
Preparation of Amines
by Alkylation of Ammonia
Alkylation of Ammonia
Desired reaction is:
2 NH3
+
R—X
R—NH2 +
NH4X
Alkylation of Ammonia
Desired reaction is:
2 NH3
+
R—X
R—NH2 +
NH4X
+
H3N
•• –
•• X ••
••
via:
H3N •• + R
then:
H3N •• + H
••
X ••
••
H
+
N R
H
R +
H
+
H3N
H + •• N
H
R
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.
NH3
RX
RNH2
RX
R2NH
RX
+
R4N
X
–
RX
R3 N
Example
CH3(CH2)6CH2Br
NH3
CH3(CH2)6CH2NH2
As octylamine is formed, it competes with
ammonia for the remaining 1-bromooctane.
Reaction of octylamine with 1-bromooctane
gives N,N-dioctylamine.
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.
22.9
The Gabriel Synthesis of Primary Alkylamines
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
is N-potassiophthalimide
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
is N-potassiophthalimide
O
–
•• N •
•
O
K
+
N-Potassiophthalimide
the pKa of phthalimide is 8.3
N-potassiophthalimide is easily prepared by
the reaction of phthalimide with KOH
O
O
•• NH
O
KOH
–
•• N •
•
O
K
+
N-Potassiophthalimide as a nucleophile
O
O
–
•• N • + R
•
••
X ••
SN2
•• N
••
O
O
+
•• –
•• X ••
••
R
Cleavage of Alkylated Phthalimide
O
•• N
R + H2O
O
imide hydrolysis is
nucleophilic acyl
substitution
acid or base
CO2H
+
CO2H
H2N
R
Cleavage of Alkylated Phthalimide
hydrazinolysis is an alternative method of releasing
the amine from its phthalimide derivative
O
O
•• N
R
H2NNH2
NH
NH
O
O
+
H2N
R
Example
O
–
•N •
• •
O
K
+
+
C6H5CH2Cl
DMF
Example
O
–
•N •
• •
K
+
+
C6H5CH2Cl
DMF
O
O
•• N
O
CH2C6H5
(74%)
Example
O
NH
+
C6H5CH2NH2 (97%)
NH
H2NNH2
O
O
•• N
O
CH2C6H5
22.10
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.
CH2CH2Br
NaN3
CH2CH2N3
(74%)
1. LiAlH4
2. H2O
CH2CH2NH2
(89%)
Synthesis of Amines via Azides
SN2 reaction, followed by reduction, gives a
primary alkylamine.
CH2CH2Br
NaN3
CH2CH2N3
(74%)
1. LiAlH4
2. H2O
azides may also be
reduced by catalytic
hydrogenation
CH2CH2NH2
(89%)
Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a
primary alkylamine.
NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%)
Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a
primary alkylamine.
NaCN
CH3CH2CH2CH2Br
nitriles may also be
reduced by lithium
aluminum hydride
CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%)
Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a
primary alkylamine.
NaCN
CH3CH2CH2CH2Br
the reduction also
works with cyanohydrins
CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%)
Synthesis of Amines via Nitroarenes
HNO3
Cl
NO2
Cl
H2SO4
(88-95%)
1. Fe, HCl
2. NaOH
Cl
NH2
(95%)
Synthesis of Amines via Nitroarenes
HNO3
Cl
H2SO4
nitro groups may also
be reduced with tin (Sn)
+ HCl or by catalytic
hydrogenation
Cl
NO2
Cl
(88-95%)
1. Fe, HCl
2. NaOH
NH2
(95%)
Synthesis of Amines via Amides
O
COH
O
1. SOCl2
CN(CH3)2
2. (CH3)2NH
(86-89%)
1. LiAlH4
2. H2O
CH2N(CH3)2
(88%)
Synthesis of Amines via Amides
O
COH
O
1. SOCl2
CN(CH3)2
2. (CH3)2NH
(86-89%)
only LiAlH4 is an
appropriate reducing
agent for this reaction
1. LiAlH4
2. H2O
CH2N(CH3)2
(88%)
22.11
Reductive Amination
Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketone
is subjected to catalytic hydrogenation in the
presence of ammonia or an amine.
R
fast
C
R'
R
O + NH3
C
NH +
R'
The aldehyde or ketone equilibrates with the
imine faster than hydrogenation occurs.
H2O
Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation faster
than the aldehyde or ketone. An amine is
the product.
R
fast
C
R
O + NH3
R'
C
H
NH +
R'
R
R'
C
H2, Ni
NH2
H2O
Example: Ammonia gives a primary amine.
O + NH3
H2, Ni
H
ethanol
NH2
(80%)
via:
NH
Example: Primary amines give secondary amines
O
CH3(CH2)5CH
+ H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%)
Example: Primary amines give secondary amines
O
CH3(CH2)5CH
+ H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
via:
CH3(CH2)5CH
N
(65%)
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:
HO
N
+
N
CHCH2CH2CH3
CHCH2CH2CH3
N
CH
CHCH2CH3