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