Amines, reactionsAmines 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-
(CH3CH2)2NH + CH3COOH (CH3CH2)2NH2+, -OOCCH3
anilinium chloride
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
+ H2O
NH3
+ 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
+ H2O
NH3
+ 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.
NH3
NH2 NH2 NH2 NH2
NO2 OCH3
4 1 5 3 2
2. Alkylation (ammonolysis of alkyl halides)
RNH2R-X
R2NHR-X
R3NR-X
R4N+X-
1o 2o 3o 4o salt
SN2: R-X must be 1o or CH3
CH3CH2CH2CH2BrNH3
CH3CH2CH2CH2NH2
n-butylamine
CH3CH2CH2NH2CH3Cl
CH3CH2CH2NHCH3
n-propylamine methyl-n-propylamine
NH2
2 CH3CH2BrN
Et
Et
aniline N,N-diethylaniline
H2C NH2
benzylamine
(xs) CH3I H2C N
CH3
CH3
CH3 Ibenzyltrimethylammonium iodide
3. Reductive amination
C OH2, Ni
or NaBH3CNCH NHR+ RNH2
C OH2, Ni
or NaBH3CNCH NR2+ R2NH 3o amine
2o amine
CCH2CH3
O
propiophenone
+ CH3CH2NH2NaBH3CN
CHCH2CH3
NH
CH2CH3
1-(N-ethylamino)-1-phenylpropane
O
cyclohexanone
CH3NH2, H2/Ni NHCH3
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
NH2 + (CH3CO)2OHN C CH3
O
N-phenylacetamide
CO
Cl(CH3CH2)2NH + C
O
N CH2CH3
CH2CH3
N.N-diethyl-m-toluamide
N CH3
CH3
+ CH3CO
ClNR
H3C H3C
DEET
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.
NH2 N
N CH3
CH3
+ SO2Cl S
O
O
KOH
(CH3CH2)2NH SO2ClKOH
+ SO2ClKOH
+ S
O
O
NCH2CH3
CH2CH3
NR
water sol.
ppt
sulfanilamide “magic bullet” antibiotic
NH2
SO2
NH2
N
N N
N
OH
H2N
H2C
HN C
OHN CH
COOH
CH2CH2COOH
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
H2SO4
TAR!
(CH3CO)2O
NHCOCH3
HNO3
H2SO4
NHCOCH3
NO2
+ ortho-
H2O,OH-
NH2
NO2
b) sulfonation
NH2
+ H2SO4
NH3
SO3
cold H2SO4
NH3 HSO4
c) halogenation
NH2
+ Br2, aq.
NH2
Br Br
Brno catalyst neededuse polar solvent
Br2,Fe
Br
HNO3
H2SO4
Br
NO2
+ ortho-
H2/Ni
Br
NH2
polyhalogenation!
NH2
Cl2 (aq.)NH2
CH3
Cl
ClCH3
o-toluidine
bright yellow!
Swimming pool test kit for chlorine:
e) Friedel-Crafts alkylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+ CH3CH2Br, AlCl3 NR
Do not confuse the above with the alkylation reaction:
NH2
CH3
+ CH3CH2Br
NHCH2CH3
CH3
f) Friedel-Crafts acylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+ NR
Do not confuse the above with the formation of amides:
NH2
CH3
NHCCH3
CH3
H3C CO
Cl
AlCl3
+ H3C CO
Cl
O
g) nitrosation
NH3C CH3
NaNO2, HCl
NH3C CH3
NO
The ring is sufficiently activated towards EAS to reactwith the weak electrophile NO+
h) coupling with diazonium salts azo dyes
NH2
CH3+
N2 Cl
benzenediazoniumchloride
CH3
NH2
N
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
CH3CH2CH2CH2
(xs) CH3ICH3CH2CH2CH2NH2 N
CH3
CH3
CH3 I-
CH3CH2CH2CH2 N
CH3
CH3
CH3 I-Ag2O
CH3CH2CH2CH2 N
CH3
CH3
CH3 OH- + AgI
CH3CH2CH2CH2 N
CH3
CH3
CH3 OH
CH3CH2CH=CH2 + (CH3)3N
CH3CH2CHCH3
NH2
+ (xs) CH3I CH3CH2CHCH3
N
CH3
CH3H3C I-
CH3CH2CHCH3
N
CH3
CH3H3C I-Ag2O CH3CH2CHCH3
N
CH3
CH3H3C OH + AgI
CH3CH2CHCH3
N
CH3
CH3H3C OH CH3CH2CH=CH2 + CH3CH=CHCH3
+ (CH3)3Nchief product
Hofmann orientation
7. Reactions with nitrous acid
NH2 + HONO N N diazonium salt
R-NH2 + HONO N2 + mixture of alchols & alkenes
primary amines
secondary amines
HN R + HONO N R
NO
N-nitrosamine
tertiary amines
N R
R
+ HONO N R
R
N
Op-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, reactionsAmines 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