Download Amines, Syntheses

Amines
(organic ammonia)
:NH3
:NH2R or RNH2
1o amine
:NHR2 or R2NH
2o amine
:NR3
3o amine
NR4+
or R3N
(R may be Ar)
4o ammonium salt
Amines are classified by the class of the nitrogen, primary
amines have one carbon bonded to N, secondary amines have
two carbons attached directly to the N, etc.
Nomenclature.
Common aliphatic amines are named as “alkylamines”
CH3NH2
methylamine
1o
CH3CH2NHCH3
ethylmethylamine
2o
(CH3)2NH
dimethylamine
2o
CH3CH2CHCH3
NH2
sec-butylamine
1o
(CH3)3N
trimethylamine
3o
CH3
CH3CCH3
NH2
tert-butylamine
1o
NH2
CH2NH2
cyclohexylamine
1o
benzylamine
Complex amines are named by prefixing
"amino"-" ( or N-methylamino, N,N-dimethyl
amino-, etc.) to the parent chain:
CH3CH2CHCH2CH2CH3
NH2
3-aminohexane
CH3NHCH2CH2OH
2-(N-methylamino)ethanol
NH2
NH2
NH2
NH2
CH3
CH3
o-toluidine
aniline
H3C
N
CH3
m-toluidine
p-toluidine
CH3
H
N
N,N-dimethylaniline
diphenylamine
Salts of amines: change amine  ammonium + anion
change aniline  anilinium + anion
CH3CH2CH2NH3+Cl-
n-propylammonium chloride
(C6H5NH3)2SO4
anilinium sulfate
N
Amines, physical properties:
Nitrogen is sp3 hybridized, amines are polar
and can hydrogen bond.
mp/bp are relatively high for covalent substances
amines are basic and will turn litmus blue
insoluble in water (except for four-carbons or less)
soluble in 5% HCl
“fishy” smell 
RNH2 + HCl  RNH3+ + Clwater
water
insoluble
soluble
RNH3+ + OH-  RNH2 + H2O
water
water
soluble
insoluble
1. test for amines
2. can be used to separate amines from neutral
or acidic organic compounds
O
C O
O
C OCH3
N
CH3
cocaine
3o amine
m 98o C
water insoluble
volatile
"free base"
"crack"
smoked
shorter "high"
lower dose, cheaper
5 g = 5 years
HCl
NaHCO3
O
C O
O
C OCH3
N
H
Cl
CH3
cocaine.HCl
HCl salt of 3o amine
m 195o C
water soluble
non-volatile
"powder", "blow"
"snow"
snorted
longer "high"
higher dose, expensive
500 g = 5 years
Amines, syntheses:
1. Reduction of nitro compounds
Ar-NO2 + H2,Ni  Ar-NH2
2. Ammonolysis of 1o or methyl halides
R-X + NH3  R-NH2
3. Reductive amination
R2C=O + NH3, H2, Ni  R2CHNH2
4. Reduction of nitriles
R-CN + 2 H2, Ni  RCH2NH2
5. Hofmann degradation of amides
RCONH2 + KOBr  RNH2
1. Reduction of nitro compounds:
NH2
NO2
metal + acid; then OHor H2 + Ni, Pt, or Pd
R NO2
$$$
Chiefly for primary aromatic amines.
R NH2
CH3
HNO3,H2SO4
CH3
+ orthoNO2
H2,Ni
CH3
NH2
p-toluidine
2. Ammonolysis of 1o or methyl halides.
NH3
R-X
RNH2
R-X
R2NH
2o
1o
R-X
R3N
3o
R-X
R-X must be 1o or CH3
R4N+X4o salt
CH3CH2CH2CH2Br
NH3
CH3CH2CH2CH2NH2
n-butylamine
CH3CH2CH2NH2
n-propylamine
NH2
CH3Cl
CH3CH2CH2NHCH3
methyl-n-propylamine
2 CH3CH2Br
aniline
Et
N
Et
N,N-diethylaniline
(xs) CH3I
H2
C NH2
benzylamine
H2 CH3
C N CH3
CH3
I
benzyltrimethylammonium iodide
Ammonolysis of alkyl halides is an SN2 reaction. The
alkyl halide must be primary or methyl. If the alkyl halide
is secondary or tertiary, then an E2 reaction will take place
and the product will be an alkene!
Br
NH2
+ NH3
2o RX
3. Reductive amination:
O + NH3
O + RNH2
O + R2NH
Avoids E2
H2, Ni
or NaBH3CN
H2, Ni
CH NH2
1o amine
CH NHR
2o amine
CH NR2
3o amine
or NaBH3CN
H2, Ni
or NaBH3CN
Reductive amination via the imine.
O
C
NH3
H2,Ni
H
C
NH2
H2, Ni
OH
C
NH2
- H2O
C
NH
imine
H3C
O
C
NH3, H2/Ni
CH3
NH2
CH3CHCH3
isopropylamine
acetone
O
CCH2CH3 + CH3CH2NH2
propiophenone
O
cyclohexanone
NaBH3CN
CH2CH3
NH
CHCH2CH3
1-(N-ethylamino)-1-phenylpropane
NH3, H2/Ni
NH2
cyclohexylamine
4. Reduction of nitriles
R-CN + 2 H2, catalyst  R-CH2NH2
1o amine
R-X + NaCN  R-CN  RCH2NH2
primary amine with one additional carbon
(R must be 1o or methyl)
CH2Br
benzyl bromide
NaCN
CH2C N
2 H2, Ni
CH2CH2NH2
1-amino-2-phenylethane
5. Hofmann degradation of amides
O
R C
NH2
KOBr
R-NH2
Removes one carbon!
CH3 O
CH3C C
CH3 NH2
OBr
2,2-dimethylpropanamide
CH3
CH3C NH2
CH3
tert-butylamine
Amines, syntheses:
1. Reduction of nitro compounds
1o Ar
Ar-NO2 + H2,Ni  Ar-NH2
2. Ammonolysis of 1o or methyl halides
R-X = 1o,CH3
R-X + NH3  R-NH2
3. Reductive amination
avoids E2
R2C=O + NH3, H2, Ni  R2CHNH2
4. Reduction of nitriles
+ 1 carbon
R-CN + 2 H2, Ni  RCH2NH2
5. Hofmann degradation of amides
RCONH2 + KOBr  RNH2
- 1 carbon
Outline possible laboratory syntheses for each of the following
amines, starting with toluene. Use a different method for each
compound.
NH2
H3C
aniline
NH2
p-toluidine
CH2CH2NH2
1-amino-2-phenylethane
CH2NH2
benzylamine
H3C
NH2
CHCH3
1-amino-1-(p-tolyl)ethane
First decide which method you
are going to use for which
compound…
NH2
H3C
1. nitration
5. Hofmann degradation
CH2CH2NH2
4. Reduction of nitrile
CH2NH2
2. ammonolysis
NH2
H3C
NH2
CHCH3
3. Reductive amination
CH3
H2, Ni
HNO3
H2SO4
H3C
Br2,hv
KMnO4,heat
O
CCH3
H3C
PCl3
H2,Ni
H3C
2 H2
CH2CH2NH2
Pt
OBr-
NH3
COCl
NH2
CHCH3
NH3
CH2CN
CH2Br
NH2
CH2NH2
NaCN
Br2,hv
COOH
NH3
CH2Br
(CH3CO)2O
AlCl3
H3C
NO2
CONH2
NH2