Chemistry of Amines & Amides

1. Amines

2. Amine Nomenclature

3. Alkylamine
N attached to alkyl group
Arylamine
N attached to aryl group
Primary, secondary, or tertiary
determined by number of carbon atoms
directly attached to nitrogen
Classification of Amines

4. Two IUPAC styles
1) analogous to alcohols: replace -e
ending by -amine
2) name alkyl group and attach -amine
as a suffix
Nomenclature of Primary Alkylamines (RNH2)

5. Examples: some primary alkylamines
CH3CHCH2CH2CH3
NH2
(RNH2: one carbon directly attached to N)
CH3CH2NH2
NH2
ethylamine or ethanamine
cyclohexylamine or
cyclohexanamine
1-methylbutylamine or
2-pentanamine

6. Name as derivatives of aniline.
Nomenclature of Primary Arylamines (ArNH2)
p-fluoroaniline 5-bromo-2-ethylaniline
NH2
F
NH2
Br CH2CH3

7. Amino groups as substituents
p-aminobenzaldehyde
amino groups rank below OH groups and higher
oxidation states of carbon
in such cases name the amino group as a
substituent
NH2
HC
O
HOCH2CH2NH2
2-aminoethanol

8. Name as N-substituted derivatives of parent
primary amine.
(N is a locant-it is not alphabetized, but
is treated the same way as a numerical
locant)
Parent amine is one with longest carbon
chain.
Secondary and Tertiary Amines

9. Examples
CH3NHCH2CH3 N-methylethylamine
NHCH2CH3
NO2
Cl
4-chloro-N-ethyl-3-nitroaniline
CH3
N
CH3
N,N-dimethylcycloheptylamine

10. A nitrogen with four substituents is positively
charged and is named as a derivative of
ammonium ion (NH4
+).
Ammonium Salts
CH3NH3
+
Cl
–
methylammonium
chloride
N
CH3
H
CH2CH3
+
CF3CO2
–
N-ethyl-N-methylcyclopentylammonium
trifluoroacetate

11. When all four atoms attached to N are carbon,
the ion is called a quaternary ammonium ion and
salts that contain it are called quaternary
ammonium salts.
Ammonium Salts
+
CH2 N
CH3
CH3
CH3 I
–
benzyltrimethylammonium iodide

12. Physical Properties

13. Amines are more polar and have higher boiling
points than alkanes; but are less polar and
have lower boiling points than alcohols.
Physical Properties
CH3CH2CH3 CH3CH2NH2 CH3CH2OH
dipole
moment ():
boiling point:
0 D 1.2 D 1.7 D
-42°C 17°C 78°C

14. Boiling points of isomeric amines decrease in
going from primary to secondary to tertiary amines.
Primary amines have two hydrogens on N capable
of being involved in intermolecular hydrogen
bonding. Secondary amines have one. Tertiary
amines cannot be involved in intermolecular
hydrogen bonds.
Physical Properties
CH3CH2NHCH3
CH3CH2CH2NH2 (CH3)3N
boiling
point:
50°C 34°C 3°C

15. Basicity of Amines

16. Effect of Structure on Basicity
1. Alkylamines are slightly stronger bases than
ammonia.

17. Amine Conj. Acid pKa
NH3 NH4
+ 9.3
CH3CH2NH2 CH3CH2NH3
+ 10.8
Basicity of Amines in Aqueous Solution
CH3CH2NH3
+ is a weaker acid than NH4
+;
therefore, CH3CH2NH2 is a stronger base
than NH3.

18. Effect of Structure on Basicity
1. Alkylamines are slightly stronger bases than
ammonia.
2. Alkylamines differ very little in basicity.

19. Amine Conj. Acid pKa
NH3 NH4
+ 9.3
CH3CH2NH2 CH3CH2NH3
+ 10.8
(CH3CH2)2NH (CH3CH2)2NH2
+ 11.1
(CH3CH2)3N (CH3CH2)3NH+ 10.8
Basicity of Amines in Aqueous Solution
Notice that the difference separating a primary,
secondary, and tertiary amine is only 0.3 pK units.

20. Effect of Structure on Basicity
1. Alkylamines are slightly stronger bases than
ammonia.
2. Alkylamines differ very little in basicity.
3. Arylamines are much weaker bases than
ammonia.

21. Amine Conj. Acid pKa
NH3 NH4
+ 9.3
CH3CH2NH2 CH3CH2NH3
+ 10.8
(CH3CH2)2NH (CH3CH2)2NH2
+ 11.1
(CH3CH2)3N (CH3CH2)3NH+ 10.8
C6H5NH2 C6H5NH3
+ 4.6
Basicity of Amines in Aqueous Solution

22. H2N
••
Decreased basicity of arylamines
+
H
N
H
H
+
NH2
+
•• +
H3N
pKa = 4.6
pKa =10.6
Stronger
acid
Weaker
acid
Stronger
base
Weaker
base

23. H2N
••
Decreased basicity of arylamines
+
H
N
H
H
+
NH2
+
•• +
H3N
Stronger
acid
Weaker
acid
When anilinium ion loses a proton, the
resulting lone pair is delocalized into the ring.

24. H2N
••
Decreased basicity of arylamines
+
H
N
H
H
+
NH2
+
•• +
H3N
Aniline is a weaker base because its
lone pair is more strongly held.
Stronger
base
Weaker
base

25. Decreased basicity of arylamines
C6H5NH2 (C6H5)2NH (C6H5)3N
pKa of conjugate acid:
4.6 0.8 ~-5
Increasing delocalization makes diphenylamine a
weaker base than aniline, and triphenylamine a
weaker base than diphenylamine.

26. Effect of Substituents on Basicity of Arylamines
1. Alkyl groups on the ring increase basicity, but
only slightly (less than 1 pK unit).
X NH2
X pKa of conjugate acid
H 4.6
CH3 5.3

27. Effect of Substituents on Basicity of Arylamines
2. Electron withdrawing groups, especially ortho
and/or para to amine group, decrease basicity
and can have a large effect.
X NH2
X pKa of conjugate acid
H 4.6
CF3 3.5
O2N 1.0

28. p-Nitroaniline
NH2
O
N
O
– ••
•
•
•
•
••
+
•
•
••
O
N
O
– ••
•
•
•
•
••
•
•
•
•
–
NH2
+
+
Lone pair on amine nitrogen is conjugated with
p-nitro group—more delocalized than in aniline
itself. Delocalization lost on protonation.

29. Effect is Cumulative
Aniline is 3800 times more basic than
p-nitroaniline.
Aniline is ~1,000,000,000 times more basic than
2,4-dinitroaniline.

30. Heterocyclic Amines
N
H
••
N
••
is more basic than
piperidine pyridine
pKa of conjugate acid:
11.2
pKa of conjugate acid:
5.2
(an alkylamine)
(resembles an
arylamine in
basicity)

31. Heterocyclic Amines
N
••
is more basic than
imidazole pyridine
pKa of conjugate acid:
7.0
pKa of conjugate acid:
5.2
N H
N
•
•
•
•

32. Imidazole
N H
N
•
•
•
•
Which nitrogen is protonated in imidazole?
H+ H+
N H
N •
•
H
+
N H
N
•
•
H
+

33. Imidazole
N H
N
•
•
•
•
Protonation in the direction shown gives a
stabilized ion.
H+
N H
N
H
+
•
• N H
N
H
•
•
+

34. Preparation of Amines
by Alkylation of Ammonia

35. Alkylation of Ammonia
Desired reaction is:
2 NH3 + R—X R—NH2
+ NH4X
via:
H3N•
•
••
•
•
R X
••
H3N R
+ ••
•
•
X
••
•
•
–
+ +
then:
H3N•
• + H N
H
H
R
+
H3N H
+
+ N
H
H
R
•
•

36. Alkylation of Ammonia
But the method doesn't work well in practice.
Usually gives a mixture of primary, secondary,
and tertiary amines, plus the quaternary salt.
NH3
RX
RNH2
RX
R2NH
RX
R3N
RX
R4N
+
X
–

37. Example
CH3(CH2)6CH2Br
NH3
CH3(CH2)6CH2NH2
(45%)
+
CH3(CH2)6CH2NHCH2(CH2)6CH3
(43%)
As octylamine is formed, it competes with
ammonia for the remaining 1-bromooctane.
Reaction of octylamine with 1-bromooctane
gives N,N-dioctylamine.

38. The Gabriel Synthesis of Primary Alkylamines

39. gives primary amines without formation of
secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the C—N bond
the nitrogen-containing nucleophile
is N-potassiophthalimide
Gabriel Synthesis

40. gives primary amines without formation of
secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the C—N bond
the nitrogen-containing nucleophile
is N-potassiophthalimide
Gabriel Synthesis
O
O
N
•
• •
•
–
K
+

41. the pKa of phthalimide is 8.3
N-potassiophthalimide is easily prepared by
the reaction of phthalimide with KOH
N-Potassiophthalimide
O
O
N
•
• •
•
–
K
+
O
O
NH
•
•
KOH

42. N-Potassiophthalimide as a nucleophile
O
O
N
•
• •
•
– ••
•
•
R X
••
+
O
O
N R
•
•
+
••
•
•
X
••
•
•
–
SN2

43. Cleavage of Alkylated Phthalimide
O
O
N R
•
• + H2O
H2N R
+
CO2H
CO2H
acid or base
imide hydrolysis is
nucleophilic acyl
substitution

44. Cleavage of Alkylated Phthalimide
hydrazinolysis is an alternative method of releasing
the amine from its phthalimide derivative
O
O
N R
•
•
H2N R
+
O
O
NH
NH
H2NNH2

45. Example
O
O
N
•
• •
•
–
K
+
+ C6H5CH2Cl
DMF
O
O
N CH2C6H5
•
• (74%)

46. Example
+ C6H5CH2NH2
O
O
N CH2C6H5
•
•
H2NNH2
(97%)
O
O
NH
NH

47. Preparation of Amines by Reduction

48. almost any nitrogen-containing compound can
be reduced to an amine, including:
azides
nitriles
nitro-substituted benzene derivatives
amides
Preparation of Amines by Reduction

49. SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Azides
CH2CH2Br CH2CH2N3
NaN3
(74%)
CH2CH2NH2
(89%)
1. LiAlH4
2. H2O
azides may also be
reduced by catalytic
hydrogenation

50. SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Nitriles
CH3CH2CH2CH2Br
NaCN
(69%)
CH3CH2CH2CH2CN
CH3CH2CH2CH2CH2NH2
(56%)
H2 (100 atm), Ni
nitriles may also be
reduced by lithium
aluminum hydride

51. SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Nitriles
CH3CH2CH2CH2Br
NaCN
(69%)
CH3CH2CH2CH2CN
CH3CH2CH2CH2CH2NH2
(56%)
H2 (100 atm), Ni
the reduction also
works with cyanohydrins

52. Synthesis of Amines via Nitroarenes
HNO3
(88-95%)
Cl Cl NO2
H2SO4
(95%)
1. Fe, HCl
2. NaOH
Cl NH2
nitro groups may also
be reduced with tin (Sn)
+ HCl or by catalytic
hydrogenation

53. Synthesis of Amines via Amides
(86-89%)
COH
O
1. SOCl2
2. (CH3)2NH
CN(CH3)2
O
(88%)
1. LiAlH4
2. H2O
CH2N(CH3)2
only LiAlH4 is an
appropriate reducing
agent for this reaction

54. Reductive Amination

55. The aldehyde or ketone equilibrates with the
imine faster than hydrogenation occurs.
Synthesis of Amines via Reductive Amination
O
C
R
R'
+ NH3
fast
NH
C
R
R'
+ H2O
In reductive amination, an aldehyde or ketone
is subjected to catalytic hydrogenation in the
presence of ammonia or an amine.

56. Synthesis of Amines via Reductive Amination
O
C
R
R'
+ NH3
fast
NH
C
R
R'
+ H2O
H2, Ni
NH2
R
R' C
H
The imine undergoes hydrogenation faster
than the aldehyde or ketone. An amine is
the product.

57. Example: Ammonia gives a primary amine.
O + NH3
H
NH2
H2, Ni
ethanol
(80%)
via: NH

58. Example: Primary amines give secondary amines
H2, Ni ethanol
(65%)
CH3(CH2)5CH2NH
+ H2N
CH3(CH2)5CH
O
via: N
CH3(CH2)5CH

59. Example: Secondary amines give tertiary amines
H2, Ni, ethanol
(93%)
+
CH3CH2CH2CH
O
N
H
N
CH2CH2CH2CH3

60. Example: Secondary amines give tertiary amines
CHCH2CH2CH3
N
+
possible intermediates include:
N
CH CHCH2CH3
CHCH2CH2CH3
N
HO

61. Reactions of Amines:
A Review and a Preview

62. Reactions of Amines
Reactions of amines almost always involve the
nitrogen lone pair.
•
•
N H X
as a base:
•
•
N C O
as a nucleophile:

63. Reactions of Amines with Alkyl Halides

64. Reaction with Alkyl Halides
Amines act as nucleophiles toward alkyl halides.
•
• X
+ •
•
••
••
•
•
N R
H
+ X•
•
••
••
N R
H
+ –
+
N R
••
H
+

65. Example: excess amine
NH2
+ ClCH2
NHCH2
(85-87%)
NaHCO3 90°C
(4 mol) (1 mol)

66. Example: excess alkyl halide
+ 3CH3I
(99%)
methanol heat
CH2N (CH3)3
CH2NH2
+
I
–

67. The Hofmann Elimination

68. The Hofmann Elimination
a quaternary ammonium hydroxide is the reactant
and an alkene is the product
is an anti elimination
the leaving group is a trialkylamine
the regioselectivity is opposite to the Zaitsev rule.

69. Quaternary Ammonium Hydroxides
Ag2O H2O, CH3OH
CH2N (CH3)3
+
HO
–
are prepared by treating quaternary ammmonium
halides with moist silver oxide
CH2N (CH3)3 I
–

70. The Hofmann Elimination
160°C
CH2N (CH3)3
+
HO
–
on being heated, quaternary ammonium
hydroxides undergo elimination
CH2
(69%)
+ N(CH3)3
+ H2O

71. Regioselectivity
heat
Elimination occurs in the direction that gives
the less-substituted double bond. This is called
the Hofmann rule.
N(CH3)3
+
HO
–
CH3CHCH2CH3
H2C CHCH2CH3
CH3CH CHCH3
+
(95%)
(5%)

72. Regioselectivity
Steric factors seem to control the regioselectivity.
The transition state that leads to 1-butene is
less crowded than the one leading to cis
or trans-2-butene.

73. Electrophilic Aromatic Substitution
in Arylamines

74. Nitration of Anililne
NH2 is a very strongly activating group
NH2 not only activates the ring toward
electrophilic aromatic substitution, it also
makes it more easily oxidized
attempted nitration of aniline fails because
nitric acid oxidizes aniline to a black tar

75. Nitration of Anililne
Strategy: decrease the reactivity of aniline by
converting the NH2 group to an amide
CH(CH3)2
NH2
CH(CH3)2
NHCCH3
O
O
CH3COCCH3
O
(98%)
(acetyl chloride may be used instead of acetic anhydride)

76. Nitration of Anililne
Strategy: nitrate the amide formed in the first
step
CH(CH3)2
NHCCH3
O
HNO3
CH(CH3)2
NHCCH3
O
NO2
(94%)

77. Nitration of Anililne
Strategy: remove the acyl group from the amide
by hydrolysis
CH(CH3)2
NHCCH3
O
NO2
KOH
ethanol,
heat
CH(CH3)2
NH2
NO2
(100%)

78. occurs readily without necessity of protecting
amino group, but difficult to limit it to
monohalogenation
Halogenation of Arylamines
CO2H
NH2
Br2
acetic acid
(82%)
CO2H
NH2
Br Br

79. Monohalogenation of Arylamines
Cl
NHCCH3
O
CH3
(74%)
Cl2
acetic acid
NHCCH3
O
CH3
Decreasing the reactivity of the arylamine by
converting the NH2 group to an amide allows
halogenation to be limited to monosubstitution

80. Friedel-Crafts Reactions
The amino group of an arylamine must be
protected as an amide when carrying out a
Friedel-Crafts reaction.
NHCCH3
O
CH3 CH3CCl
O
AlCl3
(57%)
NHCCH3
O
CH3
CCH3
O

81. Nitrosation of Alkylamines

82. Example
(CH3)2NH
•• NaNO2, HCl
H2O
(88-90%)
••
(CH3)2N
••
N O
••
•
•

83. Some N-Nitroso Amines
N-nitrosopyrrolidine
(nitrite-cured bacon)
N
N
O
N-nitrosonornicotine
(tobacco smoke)
N
N
O
N
(CH3)2N N O
N-nitrosodimethylamine
(leather tanning)

84. Nitrosation of Primary Alkylamines
+ analogous to
nitrosation of
secondary amines
to this point
+
••
N O
••
•
•
•
•
N
H
H
R
N
••
N O
••
•
•
+
H
H
R
+
H
+
N
••
N O
••
•
•
•
•
R
H

85. Nitrosation of Primary Alkylamines
N
••
N O
••
•
•
•
•
R
H
H
+
N
••
N O
••
•
•
R
H H
+
this species reacts further
•
•
N
••
N O
••
•
•
R
H
H
+
+
H
H
+
•
•
N
••
N O
•
•
R
H

86. Nitrosation of Primary Alkylamines
+
H
•
•
N
••
N O
•
•
R
H
+
N N•
•
R
H
•
•
O
H
•
•
+
nitrosation of a
primary alkylamine
gives an alkyl
diazonium ion
process is called
diazotization

87. Alkyl Diazonium Ions
+
N N•
•
R
alkyl diazonium ions
readily lose N2 to
give carbocations
R
+ + N N•
•
•
•

88. Example: Nitrosation of 1,1-Dimethylpropylamine
NH2 N N
+
HONO
H2O
OH
(80%)
+
(2%)
(3%)
+
– N2

89. There is no useful chemistry associated with the
nitrosation of tertiary alkylamines.
Nitrosation of Tertiary Alkylamines
•
•
N
R
R
R
N
••
N O
••
•
•
+
R
R
R

90. Nitrosation of Arylamines

91. reaction that occurs is
electrophilic aromatic substitution
Nitrosation of Tertiary Arylamines
N(CH2CH3)2
(95%)
1. NaNO2, HCl,
H2O, 8°C
2. HO–
N(CH2CH3)2
N
O

92. similar to secondary alkylamines;
gives N-nitroso amines
Nitrosation of N-Alkylarylamines
NaNO2, HCl,
H2O, 10°C
NHCH3
(87-93%)
NCH3
N O

93. Nitrosation of Primary Arylamines
gives aryl diazonium ions
aryl diazonium ions are much more stable than
alkyl diazonium ions
most aryl diazonium ions are stable under the
conditions of their formation (0-10°C)
ArN N
+
RN N
+ fast
slow
R
+ + N2
Ar
+ + N2

94. Example:
(CH3)2CH NH2
NaNO2, H2SO4
H2O, 0-5°C
(CH3)2CH N N
+
HSO4
–

95. Synthetic Origin of Aryl Diazonium Salts
Ar H
Ar NO2
Ar NH2
Ar N N
+

96. Synthetic Transformations
of Aryl Diazonium Salts

97. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

98. Preparation of Phenols
Ar N N
+
Ar OH
H2O, heat

99. Example
2. H2O, heat
(CH3)2CH NH2
1. NaNO2, H2SO4
H2O, 0-5°C
(CH3)2CH OH
(73%)

100. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

101. Preparation of Aryl Iodides
Ar N N
+
Ar I
reaction of an aryl diazonium salt with
potassium iodide
KI

102. Example
2. KI, room temp.
1. NaNO2, HCl
H2O, 0-5°C
(72-83%)
NH2
Br
I
Br

103. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

104. Preparation of Aryl Fluorides
Ar N N
+
Ar F
heat the tetrafluoroborate salt of a diazonium ion;
process is called the Schiemann reaction

105. Example
(68%)
NH2
CCH2CH3
O
2. HBF4
1. NaNO2, HCl,
H2O, 0-5°C
3. heat
F
CCH2CH3
O

106. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

107. Preparation of Aryl Chlorides and Bromides
Ar N N
+
Ar Br
Ar Cl
aryl chlorides and aryl bromides are prepared by
heating a diazonium salt with copper(I) chloride or
bromide
substitutions of diazonium salts that use copper(I)
halides are called Sandmeyer reactions

108. Example
(68-71%)
NH2
NO2
2. CuCl, heat
1. NaNO2, HCl,
H2O, 0-5°C
Cl
NO2

109. Example
(89-95%)
2. CuBr, heat
1. NaNO2, HBr,
H2O, 0-10°C
NH2
Cl
Br
Cl

110. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

111. Preparation of Aryl Nitriles
Ar N N
+
Ar CN
aryl nitriles are prepared by heating a diazonium
salt with copper(I) cyanide
this is another type of Sandmeyer reaction

112. Example
(64-70%)
2. CuCN, heat
1. NaNO2, HCl,
H2O, 0°C
NH2
CH3
CN
CH3

113. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
Ar OH
Ar I
Ar F
Ar Br
Ar Cl
Ar CN

114. Transformations of Aryl Diazonium Salts
Ar N N
+
Ar H
hypophosphorous acid (H3PO2) reduces diazonium
salts; ethanol does the same thing
this is called reductive deamination

115. Example
(70-75%)
NaNO2, H2SO4,
H3PO2
NH2
CH3 CH3

116. Value of Diazonium Salts
1) allows introduction of substituents such as
OH, F, I, and CN on the ring
2) allows preparation of otherwise difficultly
accessible substitution patterns

117. Example
Br
Br
Br
NH2
Br
Br
Br
(74-77%)
NaNO2, H2SO4,
H2O, CH3CH2OH
NH2
Br2
H2O
(100%)

118. Azo Coupling

119. Azo Coupling
Diazonium salts are weak electrophiles.
React with strongly activated aromatic
compounds by electrophilic aromatic
substitution.
Ar N N
+
Ar' H
+ Ar N N Ar'
an azo compound
Ar' must bear a strongly electron-releasing group
such as OH, OR, or NR2.

120. Example
OH
+ C6H5N N
+
OH
N NC6H5
Cl–