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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+Cl-

anilinium 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+ + OH-

R-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+ + OH-

NH2 NH3

+ H2O + OH

NH2 NH2 NH3 NH3

NH2 NH2 NH2


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 + OH

G 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 electron donating
-C6H5 groups
-R
-H
-X
-CHO, -COR
-SO3H electron withdrawing
-COOH, -COOR groups
-CN
-NR3+
-NO2
Number the following in decreasing order of base strength (let
#1 = most basic, etc.

NH2 NH2 NH2 NH2

NH3

NO2 OCH3

4 1 5 3 2
2. Alkylation (ammonolysis of alkyl halides)

R-X R-X R-X


RNH2 R2NH R3N R4N+X-

1o 2o 3o 4o salt

SN2: R-X must be 1o or CH3

NH3
CH3CH2CH2CH2Br CH3CH2CH2CH2NH2
n-butylamine
CH3Cl
CH3CH2CH2NH2 CH3CH2CH2NHCH3
n-propylamine methyl-n-propylamine

2 CH3CH2Br Et
NH2 N
Et
aniline N,N-diethylaniline

H2 (xs) CH3I H2 CH3


C NH2 C N CH3
CH3 I
benzylamine benzyltrimethylammonium iodide
3. Reductive amination

H2, Ni
C O + RNH2 CH NHR 2o amine
or NaBH3CN

H2, Ni
C O + R2NH CH NR2 3o amine
or NaBH3CN
CH2CH3
O NH
NaBH3CN
CCH2CH3 + CH3CH2NH2 CHCH2CH3

propiophenone
1-(N-ethylamino)-1-phenylpropane

O CH3NH2, H2/Ni NHCH3

cyclohexanone cyclohexylmethylamine
4. Conversion into amides

R-NH2 + RCOCl  RCONHR + HCl


1o N-subst. amide

R2NH + RCOCl  RCONR2 + HCl


2o N,N-disubst. amide

R3N + RCOCl  NR
3o
O
H
NH2 + (CH3CO)2O N C CH3

N-phenylacetamide

O O
(CH3CH2)2NH + C C
Cl N CH2CH3
H3C H3C CH2CH3
N.N-diethyl-m-toluamide
DEET

O
N CH3 + CH3C NR
Cl
CH3
Conversion into sulfonamides

R-NH2 + ArSO2Cl  ArSO2NHR + HCl


1o N-subst.sulfonamide

R2NH + ArSO2Cl  ArSO2NR2 + HCl


2o N,N-disubst.sufonamide

R3N + 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.


KOH O
NH2 + SO2Cl S N
O
water sol.

KOH O CH2CH3
(CH3CH2)2NH + SO2Cl S N
O CH2CH3

ppt

KOH
N CH3 + SO2Cl NR
CH3
sulfanilamide “magic bullet” antibiotic

NH2

SO 2
NH2
OH O
H2 H H COOH
N C N C N CH
N
CH2CH2COOH
H2N N N
folic acid

H2N COOH H2N SO2NH2

p-aminobenzoic acd 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 NHCOCH3 NH2

HNO3 H2O,OH-
H2SO4 
NO2 NO2

+ ortho-
b) sulfonation

NH2 NH3

+ H2SO4

SO3

cold H2SO4

NH3 HSO4
c) halogenation

NH2 NH2
Br Br
+ Br2, aq. polyhalogenation!
Br
no catalyst needed
use polar solvent

Br Br Br
Br2,Fe HNO3 H2/Ni

H2SO4
NO2 NH2

+ ortho-
Swimming pool test kit for chlorine:

NH2 NH2
CH3 Cl2 (aq.) Cl CH3

o-toluidine 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 AlCl3
+ H3C C NR
Cl

Do not confuse the above with the formation of amides:


O
NH2 NHCCH3
CH3 O CH3
+ H3C C
Cl
g) nitrosation

H3C CH3 H3C CH3


N N
NaNO2, HCl

N
O

The ring is sufficiently activated towards EAS to react


with the weak electrophile NO+
h) coupling with diazonium salts  azo dyes

NH2 N2 Cl NH2
CH3 CH3
+

benzenediazonium N
chloride N

an azo dye
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 NH2 CH3CH2CH2CH2 N CH3 I-
CH3

CH3 Ag2O CH3


CH3CH2CH2CH2 N CH3 I- CH3CH2CH2CH2 N CH3 OH- + AgI
CH3 CH3

CH3
 CH3CH2CH=CH2 + (CH3)3N
CH3CH2CH2CH2 N CH3 OH
CH3
CH3CH2CHCH3 + (xs) CH3I CH3CH2CHCH3
NH2 H3C N CH3 I-
CH3

CH3CH2CHCH3 Ag2O CH3CH2CHCH3


H3C N CH3 I- H3C N CH3 OH + AgI
CH3 CH3

CH3CH2CHCH3
 CH3CH2CH=CH2 + CH3CH=CHCH3
H3C N CH3 OH
CH3 chief product
+ (CH3)3N

Hofmann orientation
7. Reactions with nitrous acid

primary amines

NH2 + HONO N N diazonium salt

R-NH2 + HONO N2 + mixture of alchols & alkenes

secondary amines
O
N
H N-nitrosamine
N R + HONO N R

tertiary amines
O
N N R p-nitrosocompound
N R + HONO
R R
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