Amines, reactions
Amines are similar to ammonia in their reactions.
Like ammonia, amines are basic.
Like ammonia, amines are nucleophilic and react with
alkyl halides, acid chlorides, and carbonyl compounds.
The aromatic amines are highly reactive in electrophilic
aromatic substitution.
Amine, reactions:
1. As bases
2. Alkylation
3. Reductive amination
4. Conversion into amides
5. EAS
6. Hofmann elimination from quarternary
ammonium salts
7. Reactions with nitrous acid
1. As bases
a) with acids
b) relative base strength
c) Kb
d) effect of groups on base strength
with acids
NH2
+ HCl
NH3+Clanilinium chloride
(CH3CH2)2NH + CH3COOH
(CH3CH2)2NH2+, -OOCCH3
diethylammonium acetate
relative base strength
RNH2 > NH3 > ArNH2
Kb
ionization of the base in water
:Base + H2O
H:Base+ + OH-
Kb = [ H:Base+ ] [ OH- ] / [ :Base ]
Kb
aliphatic amines
10-3 – 10-4
ammonia
1.8 x 10-5
anilines
10-9 or less
Why are aliphatic amines more basic than ammonia?
NH3 + H2O  NH4+ + OHR-NH2 + H2O  R-NH3+ + OH-
The alkyl group, -R, is an electron donating group.
The donation of electrons helps to stabilize the ammonium
ion by decreasing the positive charge, lowering the ΔH,
shifting the ionization farther to the right and increasing the
basicity.
Why are aromatic amines less basic than aliphatic amines?
R-NH2 + H2O  R-NH3+ + OHNH3
NH2
+ H2O
NH2
NH2
+ OH
NH2
NH2
NH3
NH2
NH3
resonance stabilization of the
free base, increases the ΔH,
shifts the ionization to the left,
decreasing base strength.
Effect of substituent groups on base strength:
NH2
NH3
+ H2O
G
+ OH
G
Electron donating groups will stabilize the anilinium ion,
decreasing the ΔH, shifting the ionization farther to the right and
making the compound a stronger base.
Electron withdrawing groups destabilize the anilinium ion,
increasing the ΔH, shifting the ionization towards the reactants,
making the compound a weaker base.
Common substituent groups:
-NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3+
-NO2
electron donating
groups
electron withdrawing
groups
Number the following in decreasing order of base strength (let
#1 = most basic, etc.
NH2
NH2
NH2
NH2
NH3
OCH3
NO2
4
1
5
3
2
2. Alkylation (ammonolysis of alkyl halides)
RNH2
1o
R-X
R2NH
R-X
R3N
3o
2o
R-X
R4N+X4o salt
SN2: R-X must be 1o or CH3
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
3. Reductive amination
C O + RNH2
C O + R2NH
H2, Ni
CH NHR
2o amine
CH NR2
3o amine
or NaBH3CN
H2, Ni
or NaBH3CN
O
CCH2CH3 + CH3CH2NH2
propiophenone
O
cyclohexanone
NaBH3CN
CH2CH3
NH
CHCH2CH3
1-(N-ethylamino)-1-phenylpropane
CH3NH2, H2/Ni
NHCH3
cyclohexylmethylamine
4. Conversion into amides
R-NH2 + RCOCl  RCONHR + HCl
1o
N-subst. amide
R2NH + RCOCl  RCONR2 + HCl
2o
R3N
3o
N,N-disubst. amide
+ RCOCl  NR
NH2
O
H
N C CH3
+ (CH3CO)2O
N-phenylacetamide
O
C
Cl
(CH3CH2)2NH +
H3C
H3C
O
C
N CH2CH3
CH2CH3
N.N-diethyl-m-toluamide
DEET
O
N CH3
CH3
+
CH3C
Cl
NR
Conversion into sulfonamides
R-NH2 + ArSO2Cl  ArSO2NHR + HCl
1o
N-subst.sulfonamide
R2NH + ArSO2Cl  ArSO2NR2 + HCl
2o
R3N
N,N-disubst.sufonamide
+ ArSO2Cl  NR
Schotten-Baumann technique: reactions of aromatic acid
chlorides are sped up by the addition of base.
R-NH2 + ArSO2Cl + KOH  ArSO2NHR
1o
acidic
ArSO2NR
water soluble salt
R2NH + ArSO2Cl + KOH  ArSO2NR2 + HCl
2o
N,N-disubst.sufonamide
water insoluble
Hinsberg Test:
unknown amine + benzenesulfonyl chloride, KOH (aq)
Reacts to produce a clear solution and then gives a
ppt upon acidification  primary amine.
Reacts to produce a ppt  secondary amine.
Doesn’t react  tertiary amine.
O
S
O
KOH
NH2
+
SO2Cl
N
water sol.
O
CH2CH3
S N
CH2CH3
O
KOH
(CH3CH2)2NH +
SO2Cl
ppt
KOH
N CH3
CH3
+
SO2Cl
NR
sulfanilamide
“magic bullet”
NH2
SO2
NH2
antibiotic
OH
N
N
H2N
N
H2 H
C N
O
H COOH
C N CH
CH2CH2COOH
N
folic acid
H2N
COOH
p-aminobenzoic acd
H2N
SO2NH2
sulfanilamide
5. EAS
-NH2, -NHR, -NR2 are powerful activating groups and
ortho/para directors
a) nitration
b) sulfonation
c) halogenation
d) Friedel-Crafts alkylation
e) Friedel-Crafts acylation
f) coupling with diazonium salts
g) nitrosation
a) nitration
NH2
HNO3
TAR!
H2SO4
(CH3CO)2O
NHCOCH3
NH2
NHCOCH3
HNO3
H2O,OH-
H2SO4

NO2
+ ortho-
NO2
b) sulfonation
NH3
NH2
+ H2SO4
SO3
cold H2SO4
NH3 HSO4
c) halogenation
NH2
NH2
Br
Br
polyhalogenation!
+ Br2, aq.
Br
no catalyst needed
use polar solvent
Br
Br2,Fe
Br
HNO3
Br
H2/Ni
H2SO4
NO2
+ ortho-
NH2
Swimming pool test kit for chlorine:
NH2
CH3
o-toluidine
NH2
Cl2 (aq.)
Cl
CH3
Cl
bright yellow!
e) Friedel-Crafts alkylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+ CH3CH2Br, AlCl3
NR
Do not confuse the above with the alkylation reaction:
NH2
NHCH2CH3
CH3
CH3
+ CH3CH2Br
f) Friedel-Crafts acylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+
O
H3C C
Cl
AlCl3
NR
Do not confuse the above with the formation of amides:
O
NH2
NHCCH3
CH3
CH3
O
+ H3C C
Cl
g) nitrosation
H3C
N
H3C
CH3
N
CH3
NaNO2, HCl
O
N
The ring is sufficiently activated towards EAS to react
with the weak electrophile NO+
h) coupling with diazonium salts  azo dyes
N2 Cl
NH2
NH2
CH3
CH3
+
benzenediazonium
chloride
an azo dye
N
N
6. Hofmann elimination from quarternary hydroxides
step 1, exhaustive methylation  4o salt
step 2, reaction with Ag2O  4o hydroxide + AgX
step 3, heat to eliminate  alkene(s) + R3N
(xs) CH3I
CH3
CH3CH2CH2CH2 N CH3
CH3
CH3CH2CH2CH2 NH2
CH3
CH3CH2CH2CH2 N CH3
CH3
I-
CH3
CH3CH2CH2CH2 N CH3 OH
CH3
Ag2O

I-
CH3
CH3CH2CH2CH2 N CH3 OH- + AgI
CH3
CH3CH2CH=CH2 + (CH3)3N
CH3CH2CHCH3 + (xs) CH3I
NH2
CH3CH2CHCH3
H3C N CH3
CH3
CH3CH2CHCH3
H3C N CH3
CH3
I-
OH
Ag2O

CH3CH2CHCH3
H3C N CH3
CH3
CH3CH2CHCH3
H3C N CH3
CH3
I-
OH
+ AgI
CH3CH2CH=CH2 + CH3CH=CHCH3
chief product
+ (CH3)3N
Hofmann orientation
7. Reactions with nitrous acid
primary amines
R-NH2
N N
+ HONO
NH2
+ HONO
diazonium salt
N2 + mixture of alchols & alkenes
secondary amines
H
N R
O
N
N R
+ HONO
N-nitrosamine
tertiary amines
N R + HONO
R
O
N
N R
R
p-nitrosocompound
note: 90% of all tested nitrosamines are carcinogenic in man.
Many nitrosamine cancers are organ specific. For example,
dimethylnitrosamine causes liver cancer while the nitrosamines
in tobacco smoke cause lung cancer.
Sodium nitrite (“cure”) is used as a preservative in meats such
as bacon, bologna, hot dogs, etc. to kill the organism
responsible for botulism poisoning. In the stomach, the nitrous
acid produced from sodium nitrite can react with secondary
and tertiary amines to form nitrosamines. To reduce the
formation of nitrosamines, ascorbic acid (Vitamin C) is now
added to foods cured with sodium nitrite.
Nitrosamines are also found in beer!
Amines, reactions
Amines are similar to ammonia in their reactions.
Like ammonia, amines are basic.
Like ammonia, amines are nucleophilic and react with
alkyl halides, acid chlorides, and carbonyl compounds.
The aromatic amines are highly reactive in electrophilic
aromatic substitution.
Amine, reactions:
1. As bases
2. Alkylation
3. Reductive amination
4. Conversion into amides
5. EAS
6. Hofmann elimination from quarternary
ammonium salts
7. Reactions with nitrous acid