Chapter 1

Amines

Biologically Active Amines

The alkaloids are an important group of biologically

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

Biological Activity of Amines

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

Chapter 1

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

Examples
Classes of Amines
NH2

Primary
(1)

CH3

Secondary
(2)

Tertiary
(3)

Chapter 1

Common Names
= names of the alkyl/aryl groups bonded + amine
= prefixes di-, tri-, and tetra used to describe
two, three or four identical subs.

Chapter 1

Amine as Substituent

On a molecule with a higher priority functional

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

Main groups in order of decreasing priority

RCOOH
ESTERS
AMIDES
NITRILES
ALDEHYDES
KETONES
ALCOHOLS
AMINES
ALKENES
ALKYNES
ALKANES
ETHERS
HALIDES

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

3-bromo-1-pentanamine

N,N-dimethyl-3-hexanamine
Chapter 1

Aromatic Amines

In aromatic amines, the amino group is

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

10

Heterocyclic Amines
When naming a cyclic amine the nitrogen is
assigned position number 1.

Chapter 1

11

Pair Discussion
Give correct names for the following amines:
NH2

a.

d.
NH

COOH

NH2

e.

b.

c.

NH2
CHO

f.

NH2

N
H

NH2

Chapter 1

12

Structure of Amines

Nitrogen is sp3 hybridized with a lone pair of

electrons.
The angle is less than 109.5.
Chapter 1

13

Boiling Points

NH less polar than OH ( because O more

electronegative than N).
Weaker hydrogen bonds, so amines will have a lower
boiling point than the corresponding alcohol.
Tertiary amines cannot form hydrogen-bond, so they have
lower boiling points than primary and secondary amines.
Chapter 1

14

Chapter 1

15

Solubility and Odor

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

Chapter 1

16

Hydrogen bond

Chapter 1

17

Pair Discussion
Rank each set of compounds in order
of increasing boiling points and explain your answer.
(a) Trimethylamine, ethylmethylanime, n-propylamine
(b) Ethanol, dimethylamine, dimethyl ether
(c) Triphenylamine, N-methylanaline, ethylamine
ANSWERS
a. Trimethylamine(3.5oC)< ethylmethylamine(37oC) < n-propylamine (59oC)
b. Dimethyl ether (- 25oC) < dimethylamine (7 oC) < ethanol (78 oC)
c.

Ethylamine (17oC) < N-methylanaline (196oC) < triphenylamine ( 225oC)

Chapter 1

18

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.
Chapter 1

19

Reactivity of Amines

Chapter 1

20

Base-Dissociation Constant of
Amines

Stronger bases have

smaller value of pKb
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

21

Base Dissociation of an Amine

Alkyl groups stabilize the ammonium ion,

making the amine a stronger base.
Chapter 1

22

Alkyl Group Stabilization of

Amines

Alkyl groups make the nitrogen a stronger

base than ammonia.
Chapter 1

23

What we can conclude??

1. Simple alkylamines are stronger bases than ammonia?

2. Secondary amines are stronger bases than

primary amines?
3. Tertiery amines to be the strongest bases of all?

Why??
Chapter 1

24

solvation effects of water

Solvation is the process of attraction and association of
molecules of a solvent with molecules or ions of a solute.
As ions dissolve in a solvent they spread out and become
surrounded by solvent molecules.

Smaller the R groups,

better solvation effect,
better stabilize the ion

Chapter 1

25

Strength of bases is combination of stabilization

of alkyl groups + solvation effects

Secondary amines slightly stronger bases than

primary or tertiary alkylamines

Chapter 1

26

Basicity of arylamines

Arylamines are much weaker than simple aliphatic amines

Any delocalization of the electron pair weakens the base.
Chapter 1

27

Protonation of Pyrrole

When the pyrrole nitrogen is protonated,

pyrrole loses its aromatic stabilization.
Therefore, protonation on nitrogen is
unfavorable and pyrrole is a very weak base.
Pyridine is less basic than aliphatic amines,
but it is more basic than pyrrole because it
does not lose its aromaticity on protonation.

Hybridization Effects
Electrons held more tightly by orbitals with
more s character
Unsaturated amines tend to be weaker bases

pyridines lone pair electrons are less available for

bonding to a proton.
Chapter 1

29

What do you expect the basicity for acetonitrile?

sp orbital -----> more s character ----> much more weaker base

pKb = 24
Chapter 1

30

ACTIVITY
Rank each set of compounds in order of increasing
basicity and explain
(a) NaOH, NH3, CH3NH2, Ph-NH2
(b) Aniline, p-methylaniline, p-nitroaniline
(c) Aniline, pyrrole, pyridine, piperidine
(d) Pyrrole, imidazole, 3-nitropyrrole
Answers (pKb):
(a) Ph-NH2(9.4), NH3(4.74), CH3NH2(3.36), NaOH (1)
(b)p-nitroaniline(13), Aniline(9.4), p-methylaniline
(c) pyrrole(15), aniline(9.4), pyridine(8.75), piperidine(2.85)
(d) 3-nitropyrrole, pyrrole(15), imidazole

31

Synthesis of amines
1.
2.
3.
4.
5.

Reduction of nitro, Azides, Nitriles and Amides

Alkylation of ammonia
Gabriel Synthesis
Hofmann Rearrangement of Amides
Reductive Amination of Aldehydes and Ketones

Chapter 1

32

1a. 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

33

1b. 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

34

1c. Reduction of Nitriles

Nitrile (CN) is a good SN2 nucleophile.

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

35

1d. 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

36

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

37

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

38

Solved Problem 4
ShowhowtosynthesizeNethylpyrrolidinefrompyrrolidineusingacylationreduction.

Solution
Thissynthesisrequiresaddinganethylgrouptopyrrolidinetomakeatertiaryamine.Theacidchloride
neededwillbeacetylchloride(ethanoylchloride).ReductionoftheamidegivesNethylpyrrolidine.

Chapter 1

39

2. Alkylation of Ammonia
step 1:

NH3 +

R X

R NH3 X

ammonia
step 2:

R NH3 X

alkylammonium halide
+

RNH2 +

NaOH

H2 O +

NaX

primary amine

How to synthesize secondary, tertiery, quartenary

and aromatic amines?

Chapter 1

40

3. 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

41

4. 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

42

5. 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

43

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

44

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

45

REACTIONS OF
AMINES

Chapter 1

46

1. Salt Formation
Amines are bases and react with acid to form
alkylammonium salts
The salt formed is water soluble but insoluble in organic solvents
Can use to separate amines with other class of
functional groups

Chapter 1

47

Ammonium Salts

Ionic solids with high melting points.

Soluble in water.
No fishy odor.
Chapter 1

48

Purifying an Amine

Chapter 1

49

2. Reaction With Acyl

Chloride and Sulfonyl
Chloride

Chapter 1

50

Acylation of Amines

Primary and secondary amines react with

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

51

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

52

Solved Problem
Showhowyouwouldaccomplishthefollowingsyntheticconversioningoodyield.

Solution
AnattemptedFriedelCraftsacylationonanilinewouldlikelymeetwithdisaster.Thefreeamino
groupwouldattackboththeacidchlorideandtheLewisacidcatalyst.

Chapter 1

53

Solved Problem 1 (Continued)

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

Chapter 1

54

Formation of Sulfonamides

Primary or secondary amines react with

sulfonyl chloride.

Chapter 1

55

3. Hofmann Elimination

A quaternary ammonium salt has a good

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

56

Step 1: 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

57

Step 2: 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

58

Step 3: Hofmann Elimination

The Hofmann elimination is a one-step,

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

59

Regioselectivity of the Hofmann

Elimination

The least substituted product is the major

product of the reactionHofmann product.
Chapter 1

60

Solved Problem 2
Predictthemajorproduct(s)formedwhenthefollowingamineistreatedwithexcessiodomethane,
followedbyheatingwithsilveroxide.

Solution
Solvingthistypeofproblemrequiresfindingeverypossibleeliminationofthemethylatedsalt.Inthis
case,thesalthasthefollowingstructure:

Chapter 1

61

Solved Problem 2 (Continued)

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

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

Chapter 1

62

4. Alkylation of Amines by Alkyl

Halides
R- NH2

primary amine

R'-CH2-Br

primary halide

R-NH2-CH2-R'

Br

salt of secondary amine

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).

5a. Reactions of Primary

amines with nitrous
acid
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

64

Mechanism:
Step 1: The amine attacks the nitrosonium ion and forms Nnitrosoamine.
R

N
H

primary
amine

N O

H
R N N O
H

H2O

nitrosonium
ion

R N N O + H3O
H

N-nitrosoamine

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

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

Chapter 1

65

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

Chapter 1

66

5b. Reactions of secondary

Amines with nitrous acid
Secondary amines: both aryl amines and alkyl amines
react with nitrous acid to yield N-nitrosoamines

NHCH3 + NaNO2 + 2 HCl

N-nitrosoamines are usually separated from
the reaction mixture as oily yellow liquids

N O
CH3

5c. Reactions of Tertiary

amines with nitrous acid
R3 N

NaNO2 / HCl
0-5 oC

R3NHCl
alkylammonium salt

Tertiary amines react with cold nitrous acid to

form ammonium salt
Soluble in water and form a colourless solution
Chapter 1

68

5d. Reactions of
Primary aromatic
amines with nitrous
acid

By forming and diazotizing an amine, an

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

69

Reactions of Arenediazonium
Salts

Chapter 1

70

Coupling Reactions of
Arenediazonium Salts

Chapter 1

71

Mechanism

Chapter 1

72