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
NH
2
+ HCl
NH
3
+
Cl
-
(CH
3
CH
2
)
2
NH
+ CH
3
COOH (CH
3
CH
2
)
2
NH
2
+
,
-
OOCCH
3
anilinium chloride
diethylammonium acetate
relative base strength
RNH
2
> NH
3
> ArNH
2

b
ionization oI the base in water
:Base H
2
O H:Base

OH
-

b
| H:Base

| | OH
-
| / | :Base |

b
aliphatic amines 10
-3
10
-4
ammonia 1.8 x 10
-5
anilines 10
-9
or less
hy are aliphatic amines more basic than ammonia?
NH
3
H
2
O NH
4

OH
-
R-NH
2
H
2
O R-NH
3

OH
-
The alkyl group, -R, is an electron donating group.
The donation oI electrons helps to stabilize the ammonium
ion by decreasing the positive charge, lowering the AH,
shiIting the ionization Iarther to the right and increasing the
basicity.
hy are aromatic amines less basic than aliphatic amines?
R-NH
2
H
2
O R-NH
3

OH
-
NH
2
+ H
2
O
NH
3
+ OH
NH
2
NH
2
NH
3
NH
3
NH
2
NH
2
NH
2
resonance stabilization oI the
Iree base, increases the AH,
shiIts the ionization to the leIt,
decreasing base strength.
Effect of substituent groups on base strength:
NH
2
+ H
2
O
NH
3
+ OH
G
G
lectron donating groups will stabilize the anilinium ion,
decreasing the AH, shiIting the ionization Iarther to the right and
making the compound a stronger base.
lectron withdrawing groups destabilize the anilinium ion,
increasing the AH, shiIting the ionization towards the reactants,
making the compound a weaker base.
ommon substituent groups:
-NH
2
, -NHR, -NR
2
-OH
-OR
-NHOH
3
electron donating
-

H
5
groups
-R
-H
-X
-HO, -OR
-SO
3
H electron withdrawing
-OOH, -OOR groups
-N
-NR
3

-NO
2
Number the Iollowing in decreasing order oI base strength (let
#1 most basic, etc.
NH
3
NH
2
NH
2
NH
2
NH
2
NO
2
OCH
3
4 1 5 3 2
2. Alkylation (ammonolysis of alkyl halides)
#NH
2
#-X
#
2
NH
#-X
#
3
N
#-X
#

N
+
X
-
1
o
2
o
3
o

o
salt
S
N
2: #-X must be 1
o
or CH
3
CH
3
CH
2
CH
2
CH
2
Br
NH
3
CH
3
CH
2
CH
2
CH
2
NH
2
3-butylamine
CH
3
CH
2
CH
2
NH
2
CH
3
Cl
CH
3
CH
2
CH
2
NHCH
3
3-propylamine
methyl-3-propylamine
NH
2
2 CH
3
CH
2
Br
N
Et
Et
aniline
-diethylaniline
H
2
C NH
2
benzylamine
(xs) CH
3
H
2
C N
CH
3
CH
3
CH
3

benzyltrimethylammonium iodide
3. Reductive amination
C O
H
2
, Ni
or NaBH
3
CN
CH NH# + #NH
2
C O
H
2
, Ni
or NaBH
3
CN
CH N#
2
+ #
2
NH 3
o
amine
2
o
amine
CCH
2
CH
3
O
propiophenone
+ CH
3
CH
2
NH
2
NaBH
3
CN
CHCH
2
CH
3
NH
CH
2
CH
3
1-(-ethylamino)-1-phenylpropane
O
cyclohexanone
CH
3
NH
2
, H
2
/Ni
NHCH
3
cyclohexylmethylamine
4. Conversion into amides
R-NH
2
ROl RONHR Hl
1
o
-subst. amide
R
2
NH ROl RONR
2
Hl
2
o
-disubst. amide
R
3
N ROl NR
3
o
NH
2 + (CH
3
CO)
2
O
H
N C CH
3
O
-phenylacetamide
C
O
Cl
(CH
3
CH
2
)
2
NH +
C
O
N CH
2
CH
3
CH
2
CH
3
-diethyl-2-toluamide
N CH
3
CH
3
+ CH
3
C
O
Cl
N#
H
3
C
H
3
C
DEET
onversion into sulIonamides
R-NH
2
ArSO
2
l ArSO2NHR Hl
1
o
-subst.sulIonamide
R
2
NH ArSO
2
l ArSO
2
NR
2
Hl
2
o
-disubst.suIonamide
R
3
N ArSO
2
l NR
Schotten-Baumann technique: reactions oI aromatic acid
chlorides are sped up by the addition oI base.
R-NH
2
ArSO
2
l OH ArSO2NHR
1
o
acidic
ArSO
2
NR
water soluble salt
R
2
NH ArSO
2
l OH ArSO
2
NR
2
Hl
2
o
-disubst.suIonamide
water insoluble
Hinsberg Test:
unknown amine benzenesulIonyl chloride, OH (aq)
Reacts to produce a clear solution and then gives a
ppt upon acidiIication primary amine.
Reacts to produce a ppt secondary amine.
Doesn`t react tertiary amine.
NH
2 N
N CH
3
CH
3
+ SO
2
Cl S
O
O
KOH
(CH
3
CH
2
)
2
NH
SO
2
Cl
KOH
+ SO
2
Cl
KOH
+
S
O
O
N
CH
2
CH
3
CH
2
CH
3
N#
ater sol.
ppt
sulIanilamide 'magic bullet antibiotic
NH
2
SO
2
NH
2
N
N N
N
OH
H
2
N
H
2
C
H
N C
O
H
N CH
COOH
CH
2
CH
2
COOH
folic acid
H
2
N COOH
5-aminobenzoic acd
H
2
N SO
2
NH
2
sulfanilamide
5. EAS
-NH
2
, -NHR, -NR
2
are powerful activating groups and
47945,7, directors
a) nitration
b) sulfonation
c) halogenation
d) Friedel-Crafts alkylation
e) Friedel-Crafts acylation
f) coupling with diazonium salts
g) nitrosation
a) nitration
NH
2
HNO
3
H
2
SO

TA#
(CH
3
CO)
2
O
NHCOCH
3
HNO
3
H
2
SO

NHCOCH
3
NO
2
+ 4794
H
2
O,OH
-

NH
2
NO
2
b) sulfonation
NH
2
+ H
2
SO

NH
3
SO
3
cold H
2
SO

NH
3
HSO

c) halogenation
NH
2
+ Br
2
, aq.
NH
2
Br Br
Br
no catalyst needed
use polar solvent
Br
2
,Fe
Br
HNO
3
H
2
SO

Br
NO
2
+ 4794
H
2
/Ni
Br
NH
2
polyhalogenation
NH
2
Cl
2
(aq.)
NH
2
CH
3
Cl
Cl
CH
3
4-toluidine
bright yello
Swimming pool test kit Ior chlorine:
e) Friedel-Crafts alkylation
NR with NH
2
, -NHR, -NR
2
NH
2
CH
3
+ CH
3
CH
2
Br, AlCl
3
N#
Do not confuse the above ith the alkylation reaction:
NH
2
CH
3
+ CH
3
CH
2
Br
NHCH
2
CH
3
CH
3
f) Friedel-Crafts acylation
NR with NH
2
, -NHR, -NR
2
NH
2
CH
3
+
N#
Do not confuse the above ith the formation of amides:
NH
2
CH
3
NHCCH
3
CH
3
H
3
C C
O
Cl
AlCl
3
+
H
3
C C
O
Cl
O
g) nitrosation
N
H
3
C CH
3
NaNO
2
, HCl
N
H
3
C CH
3
N
O
The ring is sufficiently activated toards EAS to react
ith the eak electrophile NO+
h) coupling with diazonium salts azo dyes
NH
2
CH
3
+
N
2
Cl
benzenediazonium
chloride
CH
3
NH
2
N
N
an azo dye
6. Hofmann elimination from quarternary hydroxides
step 1, exhaustive methylation 4
o
salt
step 2, reaction with Ag
2
O 4
o
hydroxide AgX
step 3, heat to eliminate alkene(s) R
3
N
H
3
H
2
H
2
H
2
(xs) H
3
I
H
3
H
2
H
2
H
2
NH
2
N
CH
3
CH
3
CH
3

-
H
3
H
2
H
2
H
2
N
CH
3
CH
3
CH
3

-
Ag
2
O
H
3
H
2
H
2
H
2
N
CH
3
CH
3
CH
3
OH
-
+ Ag
H
3
H
2
H
2
H
2
N
CH
3
CH
3
CH
3
OH

CH
3
CH
2
CH=CH
2
+ (CH
3
)
3
N
CH
3
CH
2
CHCH
3
NH
2
+ (xs) CH
3

CH
3
CH
2
CHCH
3
N
CH
3
CH
3
H
3
C

-
CH
3
CH
2
CHCH
3
N
CH
3
CH
3
H
3
C

-
Ag
2
O
CH
3
CH
2
CHCH
3
N
CH
3
CH
3
H
3
C
OH
+ Ag
CH
3
CH
2
CHCH
3
N
CH
3
CH
3
H
3
C
OH

CH
3
CH
2
CH=CH
2
+ CH
3
CH=CHCH
3
+ (CH
3
)
3
N
chief product
Hofmann orientation
7. Reactions with nitrous acid
NH
2
+ HONO N N
diazonium salt
#-NH
2
+ HONO
N
2
+ mixture of alchols & alkenes
primary amines
secondary amines
H
N #
+ HONO
N #
N
O
-nitrosamine
tertiary amines
N #
#
+ HONO
N #
#
N
O
5-nitrosocompound
note: 90 oI all tested nitrosamines are carcinogenic in man.
Many nitrosamine cancers are organ speciIic. 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 Ior botulism poisoning. In the stomach, the nitrous
acid produced Irom sodium nitrite can react with secondary
and tertiary amines to Iorm nitrosamines. To reduce the
Iormation oI nitrosamines, ascorbic acid (Vitamin ) is now
added to Ioods cured with sodium nitrite.
Nitrosamines are also Iound 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