Chapter 1

Amines

Biologically Active Amines

The alkaloids are an important group of biologically

active amines, mostly synthesized by plants to
protect them from
and other
animals.
Many drugs of addiction are classified as
Chapter 1

Biological Activity of Amines

Dopamine is a neurotransmitter.
Epinephrine is a bioregulator.
Niacin, Vitamin B6, is an amine.
Alkaloids: nicotine, morphine, cocaine

Chapter 1

Classes of Amines
Primary (1 ): Has alkyl group bonded
to the nitrogen (RNH2).
Secondary (2 ): Has alkyl groups
bonded to the nitrogen (R2NH).
Tertiary (3 ): Has
alkyl groups
bonded to the nitrogen (R3N).
Quaternary (4 ): Has
alkyl groups
bonded to the nitrogen and the nitrogen
bears a positive charge(R4N+).
Chapter 1

Examples of Amines
NH2

CH3

Chapter 1

Common Names

Chapter 1

Amine as Substituent

On a molecule with a higher priority functional

group, the amine is named as a substituent.
Chapter 1

IUPAC Names
Name is based on longest carbon chain.
-e of alkane is replaced with -amine.
Substituents on nitrogen have N- prefix.
Br
NH2CH2CH2CHCH2CH3

N(CH3)2
CH3CH2CHCH2CH2CH3

Chapter 1

Aromatic Amines

In aromatic amines, the amino group is

bonded to a benzene ring.
Parent compound is called
.
Chapter 1

Heterocyclic Amines
When naming a cyclic amine the nitrogen is
assigned

Chapter 1

10

Structure of Amines

Nitrogen is hybridized with a lone pair of

electrons.
The angle is less than 109.5.
Chapter 1

11

Interconversion of Chiral Amines

Nitrogen may have three different groups and

a lone pair, but enantiomers cannot be
isolated due to inversion around N.
Chapter 1

12

Chiral Amines

Amines whose chirality stems from the

presence of chiral carbon atoms.
Inversion of the nitrogen is not relevant
because it will not affect the chiral carbon.
Chapter 1

13

Chiral Amines (Continued)

Quaternary ammonium salts may have a chiral

nitrogen atom if the four substituents are different.
Inversion of configuration is not possible because
there is no lone pair to undergo nitrogen inversion.
Chapter 1

14

Chiral Cyclic Amines

If the nitrogen atom is contained in a small ring, for

example, it is prevented from attaining the 120 bond
angle that facilitates inversion.
Such a compound has a higher activation energy for
inversion, the inversion is slow, and the enantiomers
may be resolved.
Chapter 1

15

Boiling Points

NH
polar than OH.
Weaker
bonds, so amines will have a
boiling point than the corresponding alcohol.
Tertiary amines
, so they have lower
boiling points than primary and secondary amines.
Chapter 1

16

Solubility and Odor

Small amines (< 6 Cs) are soluble in water.
All amines accept hydrogen bonds from water
and alcohol.
Branching increases
.
Most amines smell like rotting .

Chapter 1

17

Basicity of Amines
Lone pair of electrons on nitrogen can
accept a
from an acid.
Aqueous solutions are
to litmus.
Ammonia pKb =
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.
Chapter 1

18

Reactivity of Amines

Chapter 1

19

Base-Dissociation Constant of
Amines

An amine can abstract a proton from water, giving an

ammonium ion and a hydroxide ion.
The equilibrium constant for this reaction is called the
base-dissociation constant for the amine,
symbolized by Kb.
Chapter 1

20

Base Dissociation of an Amine

Alkyl groups stabilize the ammonium ion,

making the amine a stronger base.
Chapter 1

21

Alkyl Group Stabilization of

Amines

Alkyl groups make the nitrogen a stronger

base than ammonia.
Chapter 1

22

Resonance Effects

Any delocalization of the electron pair weakens the base.

Chapter 1

23

Protonation of Pyrrole

When the pyrrole nitrogen is protonated,

pyrrole loses its aromatic stabilization.
Therefore, protonation on nitrogen is
and pyrrole is a very weak base.
Chapter 1

24

Hybridization Effects

Pyridine is less basic than aliphatic amines,

but it is more basic than pyrrole because it
does not lose its
on protonation.
Chapter 1

25

Ammonium Salts

Ionic solids with high melting points.

Soluble in water.
No fishy odor.
Chapter 1

26

Purifying an Amine

Chapter 1

27

Phase Transfer Catalysts

Chapter 1

28

Cocaine

Cocaine is usually smuggled and snorted as the

hydrochloride salt.
Treating cocaine hydrochloride with sodium
hydroxide and extracting it into ether converts it back
to the volatile free base for smoking.
Chapter 1

29

IR Spectroscopy

NH stretch between 32003500 cm-1.

Two peaks for 1 amine, one for 2.
Chapter 1

30

NMR Spectroscopy of Amines

Nitrogen is not as electronegative as oxygen,

so the protons on the -carbon atoms of
amines are not as strongly deshielded.
Chapter 1

31

NMR Spectrum

Chapter 1

32

Alpha Cleavage of Amines

The most common fragmentation of amines is

-cleavage to give a resonance-stabilized
cationan iminium ion.
Chapter 1

33

Fragmentation of Butyl Propyl

Amine

Chapter 1

34

MS of Butyl Propyl Amine

Chapter 1

35

Reaction of Amines with Carbonyl

Compounds

Chapter 1

36

Electrophilic Substitution
of Aniline
NH2 is strong activator, ortho- and
para-directing.
Multiple alkylation is a problem.
Protonation of the amine converts the
group into a deactivator (NH3+).
Attempt to nitrate aniline may burn or
explode.
Chapter 1

37

Protonation of Aniline in
Substitution Reactions

Strongly acidic reagents protonate the amino group,

giving an ammonium salt.
The NH3+ group is strongly deactivating (and metaallowing).
Therefore, strongly acidic reagents are unsuitable for
substitution of anilines.
Chapter 1

38

Electrophilic Substitution
of Pyridine

Strongly deactivated by electronegative N.

Substitutes in the 3-position.
Electrons on N react with electrophile.
Chapter 1

39

Electrophilic Aromatic Substitution

of Pyridine

Chapter 1

40

Electrophilic Aromatic Substitution

of Pyridine (Continued)

Attack at the 2-position would have an

unfavorable resonance structure in which the
positive charge is localized on the nitrogen.
Substitution at the 2-position is not observed.
Chapter 1

41

Nucleophilic Substitution
of Pyridine

Deactivated toward electrophilic attack.

Activated toward nucleophilic attack.
Nucleophile will replace a good leaving group in the 2or 4-position.
Chapter 1

42

Mechanism for
Nucleophilic Substitution

Attack at the 3-position does not have the

negative charge on the nitrogen, so
substitution at the 3-position is not observed.
Chapter 1

43

Alkylation of Amines by Alkyl

Halides

Even if just one equivalent of the halide is added,

some amine molecules will react once, some will
react twice, and some will react three times (to give
the tetraalkylammonium salt).
Chapter 1

44

Examples of 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 1

45

Acylation of Amines

Primary and secondary amines react with

acid halides to form amides.
This reaction is a nucleophilic acyl
substitution.
Chapter 1

46

Acylation of Aromatic Amines

When the amino group of aniline is acetylated, the

resulting amide is still activating and ortho, para-directing.
Acetanilide may be treated with acidic (and mild
oxidizing) reagents to further substitute the ring.
The acyl group can be removed later by acidic or basic
hydrolysis.
Chapter 1

47

Solved Problem 1
Showhowyouwouldaccomplishthefollowingsyntheticconversioningoodyield.

Solution

Chapter 1

48

Solved Problem 1 (Continued)

Chapter 1

49

Formation of Sulfonamides

Primary or secondary amines react with

sulfonyl chloride.

Chapter 1

50

Synthesis of Sulfanilamide

Chapter 1

51

Biological Activity of Sulfanilamide

Sulfanilamide is an analogue of p-aminobenzoic acid.

Streptococci use p-aminobenzoic acid to synthesize
folic acid, an essential compound for growth and
reproduction. Sulfanilamide cannot be used to make
folic acid.
Bacteria cannot distinguish between sulfanilamide
and p-aminobenzoic acid, so it will inhibit their growth
Chapter 1
52
and reproduction.

Hofmann Elimination

A quaternary ammonium salt has a good

leaving groupa neutral amine.
Heating the hydroxide salt produces the least
substituted alkene.
Chapter 1

53

Exhaustive Methylation of Amines

An amino group can be converted into a good leaving

group by exhaustive elimination: Conversion to a
quaternary ammonium salt that can leave as a
neutral amine.
Methyl iodide is usually used.
Chapter 1

54

Conversion to the Hydroxide Salt

The quaternary ammonium iodide is

converted to the hydroxide salt by treatment
with silver oxide and water.
The hydroxide will be the base in the
elimination step.
Chapter 1

55

Mechanism of the Hofmann

Elimination

The Hofmann elimination is a one-step,

concerted E2 reaction using an amine as the
leaving group.
Chapter 1

56

Regioselectivity of the Hofmann

Elimination

The least substituted product is the major

product of the reactionHofmann product.
Chapter 1

57

E2 Mechanism

Chapter 1

58

Solved Problem 2
Predictthemajorproduct(s)formedwhenthefollowingamineistreatedwithexcessiodomethane,
followedbyheatingwithsilveroxide.

Solution

Chapter 1

59

Solved Problem 2 (Continued)

Chapter 1

60

Oxidation of Amines

Amines are easily oxidized, even in air.

Common oxidizing agents: H 2O2 , MCPBA.
2 Amines oxidize to hydroxylamine (NOH)
3 Amines oxidize to amine oxide (R3N+O-)

Chapter 1

61

Preparation of Amine Oxides

Tertiary amines are oxidized to amine oxides,

often in good yields.
Either H2O2 or peroxyacid may be used for
this oxidation.
Chapter 1

62

Cope Rearrangement

E2 mechanism.
The amine oxide acts as its own base through a
cyclic transition state, so a strong base is not needed.
Chapter 1

63

Solved Problem 3
PredicttheproductsexpectedwhenthefollowingcompoundistreatedwithH2O2andheated.

Solution

Chapter 1

64

Formation of Diazonium Salts

R NH2 + NaNO2 + 2 HCl
R N N

R N N Cl- + 2 H2O + NaCl

R

+ N N

Primary amines react with nitrous acid

(HNO2) to form dialkyldiazonium salts.
The diazonium salts are unstable and
decompose into carbocations and nitrogen.
Chapter 1

65

Diazotization of an Amine
Step 1: The amine attacks the nitrosonium ion and forms Nnitrosoamine.

Step 2: A proton transfer (a tautomerism) from nitrogen to

oxygen forms a hydroxyl group and a second N-N bond.

Chapter 1

66

Diazotization of an Amine
(Continued)
Step 3: Protonation of the hydroxyl group, followed by the
loss of water, gives the diazonium ion.

Chapter 1

67

Arenediazonium Salts

By forming and diazotizing an amine, an

activated aromatic position can be converted
into a wide variety of functional groups.
Chapter 1

68

Reactions of Arenediazonium
Salts

Chapter 1

69

The Sandmeyer Reaction

Chapter 1

70

Formation of N-Nitrosoamines

Secondary amines react with nitrous acid (HNO2) to

form N-nitrosoamines.
Secondary N-nitrosoamines are stable and have
been shown to be carcinogenic in lab animals.
Chapter 1

71

Reductive Amination: 1 Amines

Primary amines result from the condensation of

hydroxylamine (zero alkyl groups) with a ketone or an
aldehyde, followed by reduction of the oxime.
LiAlH4 or NaBH3CN can be used to reduce the oxime.
Chapter 1

72

Reductive Amination: 2 Amines

Condensation of a ketone or an aldehyde with a

primary amine forms an N-substituted imine (a Schiff
base).
Reduction of the N-substituted imine gives a
secondary amine.
Chapter 1

73

Reductive Amination: 3 Amines

Condensation of a ketone or an aldehyde with a

secondary amine gives an iminium salt.
Iminium salts are frequently unstable, so they are
rarely isolated.
A reducing agent in the solution reduces the iminium
salt to a tertiary amine.
Chapter 1

74

Solved Problem 3
Showhowtosynthesizethefollowingaminesfromtheindicatedstartingmaterials.
(a)Ncyclopentylanilinefromaniline
(b)Nethylpyrrolidinefrompyrrolidine

Solution

Chapter 1

75

Synthesis of 1 Amines by
AcylationReduction

Acylation of the starting amine by an acid chloride

gives an amide with no tendency toward
overacylation.
Reduction of the amide by LiAlH4 gives the
corresponding amine.
Chapter 1

76

Synthesis of 2 Amines by
AcylationReduction

Acylationreduction converts a primary amine

to a secondary amine.
LiAlH4, followed by hydrolysis, can easily
reduce the intermediate amide to the amine.
Chapter 1

77

Synthesis of 3 Amines by
AcylationReduction

Acylationreduction converts a secondary

amine to a tertiary amine.
Reduction of the intermediate amide is
accomplished with LiAlH4.
Chapter 1

78

Solved Problem 4
ShowhowtosynthesizeNethylpyrrolidinefrompyrrolidineusingacylationreduction.

Solution

Chapter 1

79

The Gabriel Synthesis

The phthalimide ion is a strong nucleophile, displacing

the halide or tosylate ion from a good S N2 substrate.
Heating the N-alkyl phthalimide with hydrazine
displaces the primary amine, giving the very stable
hydrazide of phthalimide.
Chapter 1

80

Reduction of Azides

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 1

81

Reduction of Nitriles

Nitrile (CN) is a good SN2 nucleophile.

Reduction with H2 or LiAlH4 converts the nitrile
into a primary amine.
Chapter 1

82

Reduction of Nitro Compounds

The nitro group can be reduced to the amine

by catalytic hydrogenation or by an active
metal and H+.
Commonly used to synthesize anilines.
Chapter 1

83

The Hofmann Rearrangement of

Amides

In the presence of a strong base, primary amides

react with chlorine or bromine to form shortened
amines, with the loss of the carbonyl carbon atom.
This reaction, called the Hofmann rearrangement, is
used to synthesize primary and aryl amines.
Chapter 1

84

Mechanism of the Hofmann

Rearrangement: Steps 1 and 2

Chapter 1

85

Mechanism of the Hofmann

Rearrangement: Steps 3 and 4

Chapter 1

86