Chapter 19

Amines

Introduction
Organic derivatives of ammonia.
Many are biologically active.

=>
Chapter 19

Biological Activity

Neurotransmitters: dopamine
Bioregulators: epinephrine
Vitamins: niacin, B6
Alkaloids: nicotine, morphine, cocaine
Amino acids
=>

Chapter 19

Classes of Amines
Primary (1): one C-N bond, 2 N-H bonds.
Secondary (2): two C-N bonds, 1 N-H
bond.
Tertiary (3): three C-N bonds, no N-H
bond.
Quaternary (4): four C-N bonds, nitrogen
has a + formal charge.
=>
Chapter 19

Classify:
N

CH3
CH3

N
H

CH3
CH3

C NH2

_
Br
+
CH3CH2 N CH2CH3

CH3

CH3
Chapter 19

=>
5

Common Names
Name the alkyl or aryl groups bonded to
nitrogen, then add suffix -amine.
diethylmethylamine
cyclohexyldimethylamine

diphenylamine

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Chapter 19

Amine as Substituent
On a molecule with a higher priority
functional group, the amine is named as
a substituent.
NH2CH2CH2CH2COOH

OH
NHCH3

-aminobutyric acid or
4-aminobutanoic acid

2-methylaminophenol
=>
Chapter 19

Aromatic Amines
Amino group is bonded to a benzene ring.
Parent compound is called aniline.

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Chapter 19

Heterocyclic Amines
The nitrogen is assigned the number 1.

Chapter 19

IUPAC Names
Name is based on longest carbon chain.
-e of alkane is replaced with -amine.
Substituents on nitrogen have N- prefix.
Br

N(CH3)2

NH2CH2CH2CHCH2CH3

CH3CH2CHCH2CH2CH3

3-bromo-1-pentanamine

N,N-dimethyl-3-hexanamine
=>
Chapter 19

10

Chapter 19

11

Structure of Amines
Nitrogen is sp3 hybridized with a lone pair
of electrons in an sp3 orbital.

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Chapter 19

12

Chirality of Amines
Nitrogen may have 3 different groups and
a lone pair, but enantiomers cannot be
isolated due to inversion around N.

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Chapter 19

13

Chiral Amines

Amines with chiral

carbon: 2-butanamine.
Quaternary ammonium
salts with four different
groups bonded to
nitrogen.
Amines in which the
nitrogen is restricted in
rotation so it cannot
interconvert.

Chapter 19

14

=>

Boiling Points
N-H less polar than O-H.
Weaker hydrogen bonding.
Tertiary amines cannot hydrogen bond.

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Chapter 19

15

Solubility and Odor

Small amines (<6 C) soluble in water.
All amines accept hydrogen bonds from
water and alcohol.
Branching increases solubility.
Most amines smell like rotting fish.
NH2CH2CH2CH2CH2CH2NH2
1,5-pentanediamine or cadaverine
=>
Chapter 19

16

Chapter 19

17

Basicity of Amines
Lone pair of electrons on nitrogen can
accept a proton from an acid
Aqueous solutions are basic to litmus.
Ammonia pKb = 4.74
Alkyl amines are usually stronger bases
than ammonia. Increasing the number of
alkyl groups decreases solvation of ion, so
2 and 3 amines are similar to 1 amines
in basicity.
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Chapter 19

18

Chapter 19

19

Chapter 19

20

Energy Diagram
Alkyl groups are electron-donating and
stabilize the cation.

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Chapter 19

21

Resonance Effects
Any delocalization of the electron pair
weakens the base.

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Chapter 19

22

Chapter 19

23

Hybridization Effects
Electrons are held more tightly in orbitals
with more s character, so those
compounds are weaker bases.

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Chapter 19

24

Amine Salts
Ionic solids with high melting points
Soluble in water
No fishy odor

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Chapter 19

25

Purifying an Amine

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Chapter 19

26

Phase Transfer Catalysts

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Chapter 19

27

IR Spectroscopy
N-H stretch between 3200-3500 cm -1.
Two peaks for 1 amine, one for 2.

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Chapter 19

28

NMR Spectrum

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Chapter 19

29

Mass Spectrum

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Chapter 19

30

Reactions with C=O

Ammonia and primary amines react with
carbonyls to give an imine (Schiff base).

=>
Chapter 19

31

Electrophilic Substitution
of Aniline
-NH2 is strong activator, o-,p-directing.
May trisubstitute with excess reagent.
H+ changes -NH2 to -NH3+, a metaallowing deactivator.
Attempt to nitrate aniline may explode.

=>
Chapter 19

32

Aniline Substitution

=>
Chapter 19

33

Chapter 19

34

Chapter 19

35

Electrophilic Substitution
of Pyridine
Strongly deactivated by electronegative N.
Substitutes in the 3-position.
Electrons on N can react with electrophile.

Chapter 19

36

Mechanism for
Electrophilic Substitution
Attack at the 3-position (observed)

Attack at the 2-position (not observed)

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Chapter 19

37

Nucleophilic Substitution
of Pyridine
Deactivated toward electrophilic attack.
Activated toward nucleophilic attack.
Nucleophile will replace a good leaving
group in the 2- or 4-position.

=>
Chapter 19

38

Mechanism for
Nucleophilic Substitution
Attack at the 2-position (observed)

Nucleophilic Attack at the 3-position (not observed)

Chapter 19

=>
39

Alkylation of Amines
Amines react with 1 alkyl halides via
the SN2 mechanism.
Mixtures of the mono-, di-, and trialkylated products are obtained.

Chapter 19

=>
40

Useful Alkylations
Exhaustive alkylation to form the
tetraalkylammonium salt.
NH2
CH3CH2CHCH2CH2CH3

3 CH3I
NaHCO3

_
+
N(CH3)3 I

CH3CH2CHCH2CH2CH3

Reaction with large excess of NH3 to

form the primary amine.
CH3CH2CH2Br

NH3 (xs)

CH3CH2CH2NH2 +

NH4Br

=>
Chapter 19

41

Acylation of Amines
by Acid Chlorides
Amine attacks C=O, chloride ion leaves.
Product is amide, neutral, not basic.
Useful for decreasing activity of aniline
toward electrophilic aromatic substitution.
O
O

NH2
CH3

C Cl

N C CH3
H

=>
to remove HCl

Chapter 19

42

Chapter 19

43

SOLVED PROBLEM 19-1

Showhowyouwouldaccomplishthefollowingsyntheticconversioningoodyield.

Solution
AnattemptedFriedelCraftsacylationonanilinewouldlikelymeetwithdisaster.Thefreeamino
groupwouldattackboththeacidchlorideandtheLewisacidcatalyst.

Chapter 19

44

SOLVED PROBLEM 19-1 (continued)

Solution (continued)
Wecancontrolthenucleophilicityofanilinesaminogroupbyconvertingittoanamide,whichisstill
activatingandortho,paradirectingfortheFriedelCraftsreaction.Acylation,followedbyhydrolysis
oftheamide,givesthedesiredproduct.

Chapter 19

45

Formation of Sulfonamides
Primary or secondary amines react with
sulfonyl chloride.
O
R NH2

R'

S
O

O
Cl

R'

+
NH R Cl

O
base

O H

R'

NH R

Sulfa drugs are sulfonamides

that are antibacterial agents.
=>
Chapter 19

46

Chapter 19

47

Hofmann Elimination
A quaternary ammonium salt has a
good leaving group - a neutral amine.
Heating the hydroxide salt produces the
least substituted alkene.

+
N(CH3)3

CH3CHCH2CH2CH3

Ag2O
H2O

+
N(CH3)3

_
OH

CH3CHCH2CH2CH3
Chapter 19

heat

CH2 CHCH2CH2CH3
48

Chapter 19

49

E2 Mechanism

Chapter 19

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50

Chapter 19

51

SOLVED PROBLEM 19-2

Predictthemajorproduct(s)formedwhenthefollowingamineistreatedwithexcessiodomethane,
followedbyheatingwithsilveroxide.

Solution
Solvingthistypeofproblemrequiresfindingeverypossibleeliminationofthemethylatedsalt.Inthis
case,thesalthasthefollowingstructure:

Chapter 19

52

SOLVED PROBLEM 19-2 (continued)

Solution (continued)
Thegreen,blue,andredarrowsshowthethreepossibleeliminationroutes.Thecorresponding
productsare

Thefirst(green)alkenehasadisubstituteddoublebond.Thesecond(blue)alkeneismonosubstituted,
andtheredalkene(ethylene)hasanunsubstituteddoublebond.Wepredictthattheredproductswill
befavored.

Chapter 19

53

Oxidation of Amines

Amines are easily oxidized, even in air.

Common oxidizing agents: H2O2 , MCPBA.
1 Amines oxidize to nitro compounds via hydroxylamine
and nitroso groups
2 Amines oxidize to hydroxylamine (-NOH).
3 Amines oxidize to amine oxide (-N+-O-).

Chapter 19

=>
54

Cope Elimination
Amine oxides undergo elimination to form
the least substituted alkene under milder
conditions than the Hofmann reaction.

HO

O +
H
N(CH3)2

CH2 CHCH2CH2CH3

CH2 CHCH2CH2CH3

O
N(CH3)2

Chapter 19

N(CH3)2
CH2 CHCH2CH2CH3

=>
55

Chapter 19

56

SOLVED PROBLEM 19-3

PredicttheproductsexpectedwhenthefollowingcompoundistreatedwithH2O2andheated.

Solution
Oxidationconvertsthetertiaryaminetoanamineoxide.Copeeliminationcangiveeitheroftwo
alkenes.Weexpectthelesshinderedeliminationtobefavored,givingtheHofmannproduct.

Chapter 19

57

Nitrous Acid Reagent

Nitrous acid is produced in situ by
mixing sodium nitrite with HCl.
The nitrous acid is protonated, loses
water to form the nitrosonium ion.

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Chapter 19

58

Reaction with Nitrous Acid

1 Amines form diazonium salts, R-N+N.
Alkyldiazonium salts are unstable, but
arenediazonium salts are widely used for
synthesis.
2 Amines form N-nitrosoamines, R2N-N=O,
found to cause cancer in laboratory animals.
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Chapter 19

59

Chapter 19

60

Arenediazonium Salts
Stable in solution at 010C.
The -+NN group is easily replaced by
many different groups.
Nitrogen gas, N2, is a by-product.

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Chapter 19

61

Chapter 19

62

Chapter 19

63

Chapter 19

64

Chapter 19

65

Chapter 19

66

Synthesis by
Reductive Amination
To produce a 1 amine, react an
aldehyde or ketone with hydroxylamine,
then reduce the oxime.
To produce a 2 amine, react an
aldehyde or ketone with a 1 amine,
then reduce the imine.
To produce a 3 amine, react an
aldehyde or ketone with a 2 amine,
then reduce the imine salt.
=>
Chapter 19

67

Examples
primary amine

secondary amine
H3C
O
C H

HN(CH3)2

N+

H3C

CH3

C H

H+

Na(CH3COO)3BH
CH3COOH

Chapter 19

CH3

C H
H
68

tertiary amine =>

SOLVED PROBLEM 19-5

Showhowtosynthesizethefollowingaminesfromtheindicatedstartingmaterials.
(a)Ncyclopentylanilinefromaniline
(b)Nethylpyrrolidinefrompyrrolidine

Solution
(a) Thissynthesisrequiresaddingacyclopentylgrouptoaniline(primary)tomakeasecondaryamine.
Cyclopentanoneisthecarbonylcompound.

(b) Thissynthesisrequiresaddinganethylgrouptoasecondaryaminetomakeatertiaryamine.The
carbonylcompoundisacetaldehyde.FormationofatertiaryaminebyNa(AcO)3BHreductive
aminationinvolvesaniminiumintermediate,whichisreducedby(sodiumtriacetoxyborohydride).

Chapter 19

69

Acylation-Reduction
An acid chloride reacts with ammonia or a
1 amine or a 2 amine to form an amide.
The C=O of the amide is reduced to CH2
with lithium aluminum hydride.
Ammonia yields a 1 amine.
A 1 amine yields a 2 amine.
A 2 amine yields a 3 amine.
=>
Chapter 19

70

SOLVED PROBLEM 19-6

ShowhowtosynthesizeNethylpyrrolidinefrompyrrolidineusingacylationreduction.

Solution
Thissynthesisrequiresaddinganethylgrouptopyrrolidinetomakeatertiaryamine.Theacidchloride
neededwillbeacetylchloride(ethanoylchloride).ReductionoftheamidegivesNethylpyrrolidine.

ComparethissynthesiswithSolvedProblem195(b)toshowhowreductiveaminationandacylation
reductioncanaccomplishthesameresult.

Chapter 19

71

Chapter 19

72

Examples

primary amine

Chapter 19

tertiary amine
=>
73

Direct Alkylation (1)

Use a large excess (10:1) of ammonia
with a primary alkyl halide or tosylate.
Reaction mechanism is SN2.
CH3CH2CH2

Br

NH3

CH3CH2CH2

NH2 + NH4Br

=>
Chapter 19

74

Gabriel Synthesis (1)

Use the phthalimide anion as a form of
ammonia that can only alkylate once.
React the anion with a good SN2
substrate, then heat with hydrazine.

=>
Chapter 19

75

Azide Reduction (1)

Azide ion, N3-, is a good nucleophile.
React azide with unhindered 1 or 2
halide or tosylate (SN2).
Alkyl azides are explosive! Do not isolate.

=>
Chapter 19

76

Chapter 19

77

Chapter 19

78

Nitrile Reduction (1)

Nitrile, -CN, is a good SN2 nucleophile.
Reduction with H2 or LiAlH4 adds -CH2NH2.
Br

CN
NaCN

1) LiAlH4

CH2NH2

2) H2O

=>
Chapter 19

79

Reduction of Nitro
Compounds (1)
-NO2 is reduced to -NH2 by catalytic
hydrogenation, or active metal with acid.
Commonly used to synthesize anilines.

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Chapter 19

80

SOLVED PROBLEM 19-4

Showhowyouwouldconverttolueneto3,5dibromotolueneingoodyield.

Solution
Directbrominationoftoluenecannotgive3,5dibromotoluenebecausethemethylgroupactivatesthe
orthoandparapositions.

Startingwithptoluidine(pmethylaniline),however,thestronglyactivatingaminogroupdirects
brominationtoitsorthopositions.Removaloftheaminogroup(deamination)givesthedesired
product.

Chapter 19

81

CH3

19.1 Name
CH3CH2

CH2CH3

N-Methyl-1-butanamine
Ethyl dimethyl amine
N-Ethyl-1-propanamine
Diethyl methyl amine

Level 3
Challenging

Chapter 19

82

19.1 answer

N-Methyl-1-butanamine
Ethyl dimethyl amine
N-Ethyl-1-propanamine
Diethyl methyl amine

Name each group attached to the

nitrogen.
Level 3
Challenging

Chapter 19

83

19.2 Name
N
H

Level 2
Easy

Pyrrolidine
Pyrrole
Piperidine
Imidazole

Chapter 19

Pyridine
Purine
Pyrimidine
Indole

84

19.2 answer

Pyrrolidine
Pyrrole
Piperidine
Imidazole

Pyridine
Purine
Pyrimidine
Indole

Pyrrolidine contains a five-membered ring

with no double bonds.
Level 2
Easy

Chapter 19

85

19.3 Give the hybridization for

a nitrogen in an amine.
sp
sp2

Level 2
Easy

sp3
sp4

Chapter 19

86

19.3 answer
sp
sp2

sp3
sp4

The nitrogen is sp3 hybridized in an amine.

Level 2
Easy

Chapter 19

87

19.4

CH3NH2

Ethyl methyl
ammonium
bromide
Diethyl methyl
ammonium
bromide
Level 3
Challenging

1. CH3CH2Br
2. -HBr

Dimethyl amine
Diethyl amine
Ethyl methyl
amine

Chapter 19

88

19.4 answer
Ethyl methyl
ammonium bromide
Diethyl methyl
ammonium bromide

Dimethyl amine
Diethyl amine
Ethyl methyl amine

An ethyl group adds to the nitrogen.

Level 3
Challenging

Chapter 19

89

19.5

CH3NH2

C
CH3CH2

Level 3
Challenging

Cl

N-Ethylpropanamide
N-Methylpropanamide
N-Ethylethanamide
N-Methylethanamide

Chapter 19

90

19.5 answer

N-Ethylpropanamide
N-Methylpropanamide
N-Ethylethanamide
N-Methylethanamide

The methylamino group replaces the

chlorine group.
Level 3
Challenging

Chapter 19

91

19.6

HNO2
(CH3)2NH

N,N-Dimethyl-N-nitrosoamine
N,N-Dimethyl diazonium salt
N-Methyl-N-nitrosoamine
No reaction

Level 3
Challenging

Chapter 19

92

19.6 answer

N,N-Dimethyl-N-nitrosoamine
N,N-Dimethyl diazonium salt
N-Methyl-N-nitrosoamine
No reaction

The nitroso group replaces the hydrogen.

Level 3
Challenging

Chapter 19

93

19.7

C6H5NH2

1. NaNO2
2. H3PO2

Aniline
Nitrosobenzene
Benzene
Phenol

Level 3
Challenging

Chapter 19

94

19.7 answer

Aniline
Nitrosobenzene
Benzene
Phenol

The reaction of aniline with sodium nitrite

produces the diazonium salt. The diazonium
salt is deaminated with hypophosphorus acid.
Level 3
Challenging

Chapter 19

95

19.8

1. CH3NH2

C
CH3CH2

Level 3
Challenging

CH2CH3

2. H+

3-Pentanone-N-ethylimine
2-Pentanone-N-methylimine
Dimethyl ethyl amine
Diethyl methyl amine

Chapter 19

96

19.8 answer

3-Pentanone-N-ethylimine
2-Pentanone-N-methylimine
Dimethyl ethyl amine
Diethyl methyl amine

The methyl amino group replaces the oxygen.

(for this to happen I think the second step
should be reduction and not protonation!!!)
Level 3
Challenging

Chapter 19

97

19.9

1. NaN3
CH3CH2CH2Cl

2. H2, Ni

1-Propanamine
2-Propanamine
2-Butanamine
1-Butanamine

Level 3
Challenging

Chapter 19

98

19.9 answer

1-Propanamine
2-Propanamine
2-Butanamine
1-Butanamine

The azide replaces the chlorine and is

then reduced to an amine group.
Level 3
Challenging

Chapter 19

99

19.10

1. NaCN
CH3CH2CH2Cl

2. H2, Ni

1-Propanamine
2-Propanamine
2-Butanamine
1-Butanamine

Level 3
Challenging

Chapter 19

100

19.10 answer

1-Propanamine
2-Propanamine
2-Butanamine
1-Butanamine

The nitrile replaces the chlorine and is

then reduced to an amine group.
Level 3
Challenging

Chapter 19

101