of Synthesis Amines
Nucleophilic Substitution Reactions: Direct Alkylation Method
The nucleophilic substitution of alkyl halides with ammonia is a
general synthesis of primary amines.
+ R-X
aminium salt
base
(-HX)
:
:
NH3
+
RNH3 X-
RNH2
primary
amine
The reaction may be carried out in aqueous or alcoholic (to improve
the solubility of RX) solutions of ammonia. All the usual structural
limitations of an SN2 reaction apply.
CH3CH2CH2CH2Br
CH3
while CH CBr
3
CH3
NH3
+
CH3CH2CH2CH2NH3 Brbutyl ammonium bromide
NH3
+
CH3C=CH2 + NH4 BrCH3
isobutene
Side Products in the Direct Alkylation Synthesis
of Primary Amines
A serious problem in synthesizing primary amines by the direct
alkylation reaction is the formation of secondary and tertiary
amines, as shown in the scheme below.
NH3
R3N
tertiary
amine
NH3
(-HX)
:
RX
+
NH3
RNH3 X(-HX)
1o-aminium salt
RNH2
RX
primary
amine
+
R3NH X3o-aminium salt
+
R2NH2 X2o-aminium salt
(-HX) NH3
RX
R2NH
secondary
amine
While the direct alkylation synthesis of primary amines is simple, it
provides products contaminated by small amounts of secondary
and tertiary amines. When primary amines are needed that are free
of such contaminants, the Gabriel synthesis is used.
The Gabriel Synthesis of Primary Amines (S. Gabriel, 1887)
This synthesis utilizes the anion of phthalimide as a nucleophile in
the reaction with alkyl halides. Alkaline hydrolysis of the
N-alkylated phthalimide yields the primary amine free of secondary
and tertiary amines.
O
=
=
O
=
=
+
alkaline
hydrolysis
CO2-
HO- , H2O
N-R
=
CO2-
O
=
primary
amine
(-KX)
O
O
phthalimide, pKa = 9
RNH2
:
N-H
N: K+ R-X
KOH
O
N-alkyl phthalimide
The Synthesis of Amines by Reduction Methodologies
The Reduction of Nitro Compounds
Anilines may be prepared by the reduction of nitrobenzenes. The
overall synthetic sequence begins with nitration.
reduction
nitration
Ar-H
HNO3
H2SO4
Ar-NO2
[H]
Ar-NH2
The Dissolving Metal Reduction of Nitrobenzenes to Anilines
One standard way to reduce nitrobenzenes to anilines is by
dissolving metal reductions. These reactions with metals such as
iron, zinc and tin typically are carried out at reflux in hydrochloric
acid solution, sometimes with acetic acid to help dissolve the
aromatic compound. The chemical driving force for these
reductions is derived from the favorable potentials for the metal
half-cell couples:
Zn2+ + 2e-
Zn
Fe2+
Fe
+
2e-
Sn2+ + 2e-
Sn
o = -0.76 V
o = -0.44 V
o = -0.13 V
reduction
strength
Examples
NH3+ Cl-
NO2
Fe
NH2
HOH2O
30% HCl, heat
anilinium chloride
nitrobenzene
NO2
Sn
NH2
NH3+ ClHO-
HCl, heat
CH3
p-nitrotoluene
aniline
H2O
CH3
p-toluidine
CH3
Catalytic Hydrogenation of Nitroaromatics
Anilines may also be
prepared by catalytic
hydrogenation of
nitroaromatics:
NO2
NH2
H2, Pt
ethanol
CO2Et
ethyl p-nitrobenzoate
CO2Et
ethyl p-aminobenzoate
Reductive Amination
Aldehydes and ketones may be converted into amines by reaction
with ammonia or a primary or secondary amine under reduction
conditions. The overall synthetic schemes are shown below.
[H]
NH3
=
O
RCR'
[H]
R''NH2
[H]
R''NH
R'''
NH2
RCHR'
primary amine
NH-R''
RCHR'
secondary amine
R''- N-R'''
RCHR'
tertiary amine
A General Scheme for Reductive Amination
Reductive involves amination formation of an imine, and its
reduction as it is produced to the amine product.
imine formation
O
RCR' + :NH3
=
OH
(-H2O)
R-C-NH2
R'
(or amine)
addition product
reduction
R-C=NH
R'
imine
[H]
R-CH-NH2
R'
R-C=NH
R'
imine
The reduction is carried out
with H2/Ni or with NaBH3CN,
sodium cyanohydridoborate
Examples
O
CH
CH2NH2
NH3
H2, Ni pressure, heat
benzylamine
benzaldehyde
O
CH3CH2CH2CCH3
NH3
NaBH3CN
2-pentanone
NH2
CH3CH2CH2CHCH3
2-aminopentane
O
(CH3)2NH
CH3
CH3 N H
NaBH3CN
cyclohexanone
N,N-dimethylcyclohexanamine
Reduction of Amides, Oximes and Nitriles
Reduction of any of these functional groups by catalytic
hydrogenation or lithium aluminum hydride (LiAlH 4)
yields an amine.
=
O
RC-N-R'
R''
amide
RC N
nitrile
R-C=NOH
R'
oxime
[H]
[H]
[H]
RCH2N-R'
R''
1o, 2o, or 3o amine
RCH2NH2
RCHNH2
R'
(Oximes are often reduced with sodium metal in alcohol.)
Examples
=
NOH
Na
H2NOH, H+
ethanol
(-H2O)
NH2
=
O
cyclohexanamine
NH3
H2, Ni
CH2C N
CH2CH2NH2
H2, Ni
140o C
2-phenylethanamine
2-phenylethanenitrile
CH3CH2NH2
O
CNHC2H5
CH2NHC2H5
=
=
O
CCl
(i) LiAlH4/ether
(ii) H2O
benzoyl chloride
benzylethylamine
The Hofmann Rearrangement: Amines from Primary Amides
Primary amides are converted into amines with loss of the carbonyl
carbon atom in aqueous basic solutions of Br 2 or Cl2.
=
O
RCNH2 + X2 + 4 NaOH
amide
RNH2 + 2NaBr + Na2CO3 + 2 H2O
amine
The Hofmann rearrangement of primary amides provides
primary amines exclusively with no contamination from
secondary or tertiary amines.
A Mechanism for the Hofmann Rearrangement in Br2/KOH Solution
The proposed mechanism begins with base-promoted N-bromination,
analogous to -bromination of enolizable ketones.
pKa ~ 22
O
RCNH + H2O
low conc.
=
=
acid-base reaction
O
RCNH2 + HO-
=
=
nucleophilic attack: N-bromination step
O
O
RCNHBr
RCNH + Br-Br
+ Br
The N-bromoamide is more acidic than the unsubstituted
amide and deprotonation readily occurs:
+ HO-
O_
RC-N-Br
::
=
:
=
O
RC-N-Br
+ H2O
H
pKa << 22
anion is unstable
The Rearrangement Step
molecular rearrangement of unstable anion to isocyanate
:
R
_
N Br
:
=
O
C
:
(-Br-)
R-N=C=O
isocyanate
The R group (alkyl or aryl) shifts from the carbonyl
to the nitrogen with departure of the bromide ion.
Formation of a bond produces the isocyanate.
Hydrolysis of the Isocyanate to the Amines
Isocyanates undergo nucleophilic addition reactions at the
electropositive carbon center.
:
:O:
R-N-C=O
H
~H+
::
fast
:
::
::
::
:
R-N=C=O + HO-
- OH
R-N-C=O
carbamate ion
unstable
decarboxylation of carbamate anion
:
:O:
R-N-C=O
H
:
::
:
+ H-O-H
RNH2 + CO2 + HOamine
HCO3-
Some Features of the Hofmann Rearrangement
the migrating group may be alkyl or aryl
=
O
CH3CH2CH2CH2CH2CNH 2
hexanamide
=
O
CNH2
benzamide
Br2, NaOH
H2O
Br2, NaOH
H2O
CH3CH2CH2CH2CH2NH2
pentanamine
NH2
aniline
stereocenters migrate with retention
=
CH3
O
H C CNH2
C6H5
CH3
H C NH2
C6H5
Br2, NaOH
H2O
(S)-(+)-2-phenylpropanamide
(S)-(-)-1-phenylethanamine
It is suggested that the migrating group never becomes detached.
H
H
C*
:
* (S) center
C6H5
C
CH3
C N:
O
Br
:
CH3_
C6H5 C N:
Br
O
C6H5
H
C*
+ BrCH3
O=C=N
* (S) center