Amines Chapter 23

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

Required background:
Acidity and basicity Aromatic electrophilic substitution E2 elimination, Zaitsevs rule SN2 substitution Aldehydes, ketones Carboxylic acid derivatives

Essential for:
1. Heterocyclic compounds 2. Aminoacids, peptides

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

R N H 3 R N H 2 R Ammonia N H

R N R

R A primary amineA secondary amineA tertuary amine

Examples:
R R R A primary amine NH2 R R A tertuary alkcohol NH2 NH
pentan-2-amine

R OH NH2

N-methylcyclohexanamine

cyclohexanamine

Amines are much more polar, than hydrocarbons, especially in acidic conditions

Priority of citation: -COOH > -CHO > -OH > -NH2 > C=C

H N 2 O H
2 a m in o e t h a n o l

H N 2
p r o p 2 e n 1 a m in e

Common names of some am N H 2 N N H 2 Aniline Trimethylamine Ethylamine

Some cyclic amines are named as heterocyclic comp

N Piperidine H

The atom of N has the trigonal pyramid or trigonal planar geometry (favored by conjugation)
H H H C 3 N .. H N H trigonal planar N
+

C H H H

tetrahedral

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

Amines are typical bases due to the lone electron pair at nitrogen

H3C

NH2

Cl

H3C

NH3

Cl

Conjugation of the lone electron pair stabilizes the amine, but not its conjugate acid (w hich decreases the amine's basicity) H H
+ N H

H +

pKa = 11 Fe3+ (catalyst) Na

pKa = 5

NH3

NaNH2

H 2 R-NHLi + CH 3CH2CH2CH3

R-NH2

CH 3CH2CH2CH2-Li

a stronger base
Conjugation of the lone electron pair stabilizes the amine's conjugate base more, than the amine (w hich increases the amine's acidity)

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

3. Alkylation of amines
N H 3+H 3C SN2 I H 3C N H 3
+ N H 2 -

N H 3 I

H 3C H 3C I CH 3I

It is hard to stop the reaction H 3C N H 2

4I + NH

CH 3 H 3C H N
+

H 3C N
+

CH 3 I
-

H 3C CH 3

CH 3

Tetramethylammonium iodide (a quaternary ammoni

More examples of alkylation:

H C 3 H C 3 H C 3 N H 2+ O H C 3 H C 3 O CN N H 3
-

H C 3 N H 2
+

H C 3 H C 3 H C 3 O H H N 2 32 % CN N H

H N 3

CN C H
-

4. Reductive amination
R2 O R2-NH 2 R R1 R R1 N Reduction R HN

R2

R1

Options for reduction: 1. H2 / Ni, pressure 2. NaBH4

This reaction provides an efficient approach to primary and secondary amines

Borch reduction (one-step reductive amination)

O 1. R2-NH2, H+, NaBH3CN R R1 R2-NH2, H H R2 NaBH3CN

+

R2 HN

2. OH-

R1 HO
-

H H

R2

R R R1 iminium (more reactive with reducing agents)

R1

Borch reduction is also efficient to synthesize tertiary amines

+

1. R2R3NH, H , NaBH3CN R1 R2R3NH, H

+

R3 N

R2

2. OH-

R1 HO
-

R3

R2 NaBH3CN

R3 H

R2

R R R1 iminium (more reactive with reducing agents)

R1

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

O NH R R1 R Options for acylation: 1. Acid chloride, Py 2. Anhydride 3. Ester, heat Acylation N

R2

an amide R1

For details see chemistry of carboxylic acid derivatives

As opposed to alkylation, acylation efficiently produces all types of amides, because amides are weaker nucleophiles, than the starting amines, and do not react further

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

Br (CH 3)3N (alkylation) Heat (E2 reaction)

HO Br
-

H HO
-

Because of the steric hindrance, created by the bulky trimethylammonium group, the reaction proceeds against the Zaitsevs rule

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

H2N Br2, H2O Br

H2N Br

Br Strong activator H2N HNO3 H2SO4, 20 oC NO2 H

+

H2N

H2N

+
NO2 51% 47%

H3N

nitration

A standard sequence of protection-deprotection allows to synthesize p-nitroaniline in a high yield

H2N ? H2N

NO 2 Acylation Hydrolysis O HN HN O

Nitration

a very weak base

NO 2

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

+ H

NaNO 2 a .P r i m a r ya m i n e s O R N H 2 N

H O 2 HNO 2 O 3

O R N

N H 2

R O

N H N

O Nitrosamine

Enoliz S 1 N R E 1
+

N 2

N N
+ O H 2

a diazonium cation

N N O H

relatively stable if R = aryl fast, if R = alkyl

Examples:
+ N aN O 2, H

N H 2

H 2O

+
O H 60%(result of SN1)
+

31%(result of E 1)

H 2N
+ N aN O 2, H

N C l
-

H 2O

b. Secondary amines N2O3 R R1 NH R

R1 N

Enolization

O Nitrosamine A carcinogene, destroyed by Vitamin C

a. Tertiary amines N2O3 R R1 N R2 R

R1 N N
+

R2 O

The reaction does not yield a product for alkylamines, however, nitrosation can occur at an aryl substituent

N NaNO2, H+

N O

Reactions of diazonium salts with loss of nitrogen

I I
-

C l

C l N
+

CuCl O H H 2O N
B F eat 4, h

CuCN CN

H 3PO 2, H 2O

Reactions of diazonium salts without loss of nitrogen

CH 3 N N O S 3
+

CH 3 N O S 3 N H N

CH 3
+

CH 3

CH 3 H N O S 3 N N CH 3
+

H
-

N CH 3

H O CH 3 O S 3 methyl orange (red)

methyl orange (yel

Diazonium salts also act as weak electrophiles with phenols, and produce a vast variety of azo-dyes. Many of these dyes are acid-base indicators.

Outline

1. Structure, nomenclature and physical properties of amines 2. Acidity and basicity of amines 3. Alkylation of amines 4. Reductive amination 5. Acylation of amines 6. Hoffmann elimination 7. Electrophilic reactions of aniline 8. Reaction of amines with nitrous acid. Diazonium salts 9. Synthesis of amines

Gabriel synthesis of primary amines

O N H O K O H C H 2H 5O O
+ H ,H ,h eat 2O

O N K
+

O R OTs N O R

N H 2

COOH COOH

H O

+
R N H 3
+

NO 2 L iA lH 4 N N R e d u c tio n

N H 2

O p tio n sf o r re d u c tio n : a .H d 2/P b . (N H )2S ,H O 4 2 c .1 .S n/ H C l. 2 .O H

azobenzene

N a B H 4

N H 2 H t 2/P CH OH 2 O H d 2/P O N 2

NO 2 N a B H 4 CHO

NO 2

CH OH 2 O

H N 2

Curtius rearrangement
O N a N 3 R C l R N
-

O h e a t N
+

N N N2 R

an alkyl isocyanate an acyl azide O N R C O H O 2 R N

+ ~ H

O C O 2 N H C R O H N H 2 R

C O H 2
+

Example:
1. heat 2. H+, H2O 3. OHH NH2

N3 H H3C O

H3C The stereocenter is not affected

Hoffmann rearrangement (an alternative way to produce an isocyanate)

O B r2, N aO H R N H 2 H O
-

N R

H 2O R N H 2

O O B r R R N H
-

Br 2

H O

N B r