Chapter one

Amines

Nomenclature & Structure

 Nitrogen-containing compounds are essential to life.
 They are a major component of proteins and enzymes, nucleic acids, alkaloid
drugs, etc.
 (Alkaloids are N containing, weakly basic organic compounds; thousands of
these substances are known.)
 Their ultimate source is atmospheric nitrogen which, by a process known as
nitrogen fixation.
 Amines are organic derivatives of ammonia, NH3, in which one or more of the
three H’s is replaced by a carbon group

1
 …cont
i Simple 1°, 2°, and 3° amines: common (trivial) names are obtained
by alphabetically arranging the names of the alkyl substituents on the
nitrogen and adding the suffix -amine (e.g., ethylmethylamine).
ii Amines in the IUPAC system: the “e” ending of the alkane name
for the longest chain is replaced with –amine.

2
 ..cont
 Secondary and tertiary amines are however named as N-
Substituted derivatives of primary amines.
 The largest alkyl group is taken to be the parent molecule.
 whereas the smaller alkyl group is taken to be a substituent.
 The prefix N-is added as a locant to identify that the substituent
is bonded to the nitrogen atom and not to the carbon atom.
 If there are two, three or four identical groups then the prefix di,
tri or tetra may be used.

3
 Properties of Amines: Physical and
chemical properties

 Physical properties
• 1° and 2° amines can hydrogen bond to each other

 3° amines cannot hydrogen bond to each other

4
 …cont
 N—H bond is not quite as polar as the O—H bond.
 Nitrogen is less electronegative than oxygen.
– Hydrogen bonds from N—H’s are not as strong as those resulting
from O—H’s.
• Hydrogen bonding between 1° and 2° amines is not as strong as
those found in alcohols or carboxylic acids.
• 1° and 2° amines have lower boiling points than alcohols of similar
molecular weight.
• 3° amines, since they do not hydrogen bond to each other, have
boiling points similar to hydrocarbons of the same molecular
weight.

5
 …cont
Boiling Point:
Carboxylic acid
Alcohols
1°/2° Amines
3° Amines/Alkanes
• 1°, 2°, and 3° amines can all form hydrogen bonds with
water.
 Low-molecular weight amines are generally water-soluble.

6
 …cont
• Low molecular-weight amines tend to have sharp penetrating odors
similar to ammonia.
• Higher molecular-weight amines often smell like rotting fish, and
are often found in decaying animal tissues.
• Q Arrange the following compounds in order of increasing boiling
point. (All of the compounds have about the same molecular
weight.)
a. propanoic acid,
b. diethylamine,
c. 1-butanol,
d. ethyldimethylamine

7
 Chemical properties

• Amines are weak organic bases.

• They react with water to produce alkylammonium ions and
hydroxide anions.

 and with acids to produce alkylammonium salts:

8
 ..cont

 Salts of amines are generally white crystalline solids with high

melting points.
 The ionic charges makes these salts more soluble in water than
the neutral amines.
 Many amine containing drugs are administered in the form of
alkyl ammonium salts to increase their solubility in bodily fluids.

9
 Basicity of Nitrogen Compounds
• Amines are weak bases.
• Relative basicity of amines can be compared in terms of pKa values
for their respective conjugate acids.
• The more basic the amine, the higher the pKa of its conjugate acid.

 Primary alkyl amines are more basic than ammonia.

 An alkyl group helps to stabilize the alkylaminium ion.

10
 …cont

 gas phase : basicity increases with increasing methyl

substitution

 aqueous solution: tri methylamine is less basic than dimethyl-

or methylamine.
 An alkylaminium ion in water is solvated and stabilized by
hydrogen bonding of its hydrogens with water.

11
 …cont
• The tri methylaminium ion has only one hydrogen with which to
hydrogen bond to water.
• The tri methylaminium ion is solvated less well (and therefore
stabilized less) than the dimethylaminium ion, which has two
hydrogen atoms for hydrogen bonding.

Arylamines are weaker bases than non aromaticyclohexylamines

 The unshared electron pair is delocalized to the ring

– The lone pair is less available for protonation, i.e., it is less basic

12
 …cont

 Protonation of aniline is also disfavored because a protonated

arylamine has only two resonance forms.
 Anilinium ion is not as well stabilized by resonance as aniline
itself.

13
 Acidity of Nitrogen Compounds
• Although amines are normally considered to be bases, primary
and secondary amines are also very weakly acidic.
• In other words, amines are amphoteric compounds
• Amines react with acids to accept a hydrogen ion, making them an
acid according to the Bronsted-Lowry definition.
• This gives the amine a positive charge.
• Amines are also a base in the Lewis definition.
• An amine group has a lone pair of electrons when it forms three
bonds.

14
 Reactions of Amines
• The lone pair of the nitrogen atom accounts for most chemistry of
amines.
• The unshared electron pair can act as a base or as a nucleophile.

15
 …cont
 The nitrogen lone pair can also make a carbon nucleophilic by
resonance.

 Reactions of Amines with Sulfonyl Chlorides

 Primary and secondary amines react with sulfonyl chlorides to
produce sulfonamides.
 – A sulfonamide can be hydrolyzed to an amine by heating with
aqueous acid

16
…cont

17
 Electrophilic Substitution at Nitrogen
• Ammonia and many amines are not only bases in the Brønsted sense, they
are also nucleophiles that bond to and form products with a variety of
electrophiles.
• Some examples are:
• RCH2–X (alkalylmhalaide)
• RCH2–OSO2R (alkalyl salfonate)
• RSO2–Cl (salfonayl chloride)
• HO–N=O (nitrouse acid)
The Hinsberg Test
• This test can distinguish between primary, secondary and teretiary amines •
• An amine and benzenesulfonyl chloride are mixed with aqueous potassium
hydroxide; the reaction is acidified in a second step
• The results are different depending on the class of amine.
• A benzenesulfonamide from a primary amine is soluble in basic solution,
but precipitates upon acidification.
18
…cont

19
 …cont
• A secondary amine forms a precipitate directly because an N,N-
disubstituted sulfonamide remains insoluble in basic solution.
• There is no acidic hydrogen in an N,N-disubstituted sulfonamid

 A tertiary amine will not react to form a sulfonamide, but

will dissolve upon acidification
– Acidification converts the amine to a water soluble iminium
salt.

20
 Preparation of primary,secondary & teritari Amines
• By Nucleophilic Substitution Reactions
• Alkylation of Ammonia
• – Reaction of ammonia with an alkyl halide

21
 …cont
• Preparation of Primary, Secondary and Tertiary Amines through
Reductive Amination.

22
 Reactions with Nitrous Acid
• Nitrous acid is a Brønsted acid of moderate strength (pKa = 3.3).
Because it is unstable, it is prepared immediately before use in the
following manner.

 The reactions of nitrous acid with 1°- and 2°- aliphatic amines
may be explained by considering their behavior with the
nitrosonium cation, NO(+), an electrophilic species present in
acidic nitrous acid solutions.

23
 …cont
Primary Amines

Secondary Amines

The N-nitrosamines formed from 2º-amines are carcinogenic,

and are not generally useful as intermediates for subsequent
reactions.

24
 Reactions of Aryl Diazonium Intermediates (see Diazotization
Reactions)
• Reaction of primary arylamines with nitrous acid results in the
formation of relatively stable arenediazonium salts.
• This reaction occurs through the intermediacy of an N-
nitrosoamine.
• The N-nitrosoamine is converted to a diazonium ion.

25
…cont

26
Elimination Reactions of Amines (See Hofmann Eliminations)

• Hofmann elimination and other elimination reactions of charged

substrates proceed to give the least substituted double bond.
• This is called the Hofmann rule, and the least substituted alkene
product is called the Hofmann product.

27
 Chapter Two
Reactions of Carbonyl Compounds
Addition Reactions
 Addition is the opposite of elimination and C=C p bond is
converted to two new sigma bonds.

28
 …cont
• The pi bond is an electron-pair donor.

Hydrohalogenation: addition of H-X to an alkene can use

HCl, HBr, or HI

29
 …cont
• If the alkene is not symmetrical, then two regioisomers are
possible, depending on which carbon gets the “H” and the “X.”
• Hydrohalogenation is regioselective for Markovnikov addition.
• In 1869, Markovnikov observed the H atoms tend to add to the
carbon already bearing more H atoms.

 The halogen is generally installed at the more substituted

Carbon.

30
 …cont
• When peroxides are used with HBr, the opposite regioselectivity
is observed.

31
 Hydrohalogenation - Rearrangements
• Recall carbocations can rearrange (hydride or methyl shift) if
they can become more stable.

 When this alkene undergoes hydrohalogenation, the 2˚

carbocation could rearrange to a more stable, 3˚ carbocation.

32
 Acid-catalyzed Hydration

• The components of water (H and OH) are added across the pi

bond Acid-catalyzed hydration follows Markovnikov
regeioselectivity.

Sulfuric acid is typically the acid catalyst used

33
 …cont
• The mechanism for acid-catalyzed hydration is essentially the
same as hydrohalogenation:

34
Halogenation

• Halogenation – addition of two halogen atoms across a C=C

double bond.
• Halogenation is a key step in the production of PVC.

 Halogenation only practical with Cl2 and Br2 halogenation

with I2 is poor; halogenation with F2 is too violent why?

35
 …cont
• Br2 is nonpolar, but polarizable.
• Approach of a nucleophile will induce a dipole
• Think of Br2 as a bromine atom bonded to a good leaving group.

36
 …cont
• The formation of a bromomium ion intermediate is consistent with
anti addition.

Br- attacks backside (anti) to the bromonium ion

37
 …cont

Halohydrin Formation
Halohydrins – formed when halogenation is conducted in water
• Water acts as the nucleophile that attacks the bromonium ion.

38
 …cont

Here, the product is called

chlorohydrin

39
 Halohydrin Formation-Regioselectivity
• Halohydrin Formation is regioselective.
• The halide adds to the less substituted carbon and the OH adds to
the more substituted carbon

Regioselectivity results from H2O attacking the more substituted

carbon (faster than it attacks the less substituted one).

40
 …cont

 Regioselectivity results from H2O attacking the more

substituted carbon (faster than it attacks the less substituted
one).
 The more substituted carbon has more cationic character

41
…cont

42
 Hydration
• A hydration reaction involves the addition of water (H2O) to an
unsaturated compound.
• This is one way of preparing an alcohol from the corresponding
alkene.

43
 Hemiacetals and acetal Reaction
• Alcohols (R-OH) add to carbonyl groups(aldehydes and ketones to
form hemiacetals (hemi, Greek, half).
• This reaction can continue by adding another alcohol to form an
acetal.
• Hemiacetals and acetals are important functional groups because
they appear in sugars.

44
 mechanism for Hemiacetal and Acetal Formation
• 1) Protonation of the carbonyl

2) Nucleophilic attack by the alcohol

3) Deprotonation to form a hemiacetal

45
 …cont
• 4) Protonation of the alcohol

5) Removal of water

46
 …cont
• 6) Nucleophilic attack by the alcohol
 molecules which have an
alcohol and a carbonyl
can undergo an
intramolecular reaction to
form a cyclic hemiacetal

7) Deprotonation by water

47
 Cyanohydrins reaction
• The addition of cyanide ion to the carbonyl group is another
common reaction of aldehydes and ketones.
• The product of these reactions is a cyanohydrin.
• It works in a slightly basic conditions since the HNC itself does not
dissociate much to produce the –CN nucleophile in enough
concentration:

Hydrocyanic acid will react with the carbonyl establishing an

equilibrium over the time, however, best yields are obtained
when a salt of a cyanide ion such as KCN or NaCN is used
instead of the HCN:

48
…cont

49
 Carbinolamines
• Carbinolamines are compunds with an amine group and a
hydroxy
group attached to the same carbon.

50
 Addition of Grignard Reagents
.These reactions use organometallic reagents to add alkyl groups to
the carbonyl carbon atom.
• These reactions are nucleophilic additions; this means that the
organic group added is acting as a nucleophile in the reaction.

 The actual structure of Grignard reagents in solution is

complex.

51
 …cont
• Mechanism of addition of a Grignard reagent to a carbonyl
compound.

52
 …cont
• Formation of alcohols via addition of Grignard reagents to
aldehydes and ketones is carried out in two separate steps.
• Step 1: Addition of the nucleophilic alkyl group to the carbonyl
carbon, aided by Lewis acid interaction between MgX+ and the
carbonyl oxygen.
• Theproduct of this step is a halomagnesium alkoxide (see previous
slide).
• Step 2. Protonation of the alkoxide oxygen.
• The product of this step is an alcohol.
 Primary, secondary and tertiary alcohols may be formed in the
reactions of aldehydes or ketones with Grignard reagents.

53
…cont

54
 Addition of Hydrogen
• Hydrogenation involves adding hydrogen (H2) to an alkene.
• During hydrogenation the double bond is broken (as with
hydrohalogenation and halogenation) and more hydrogen atoms
are added to the molecule.

55
 7
Hydride Additions (lithium-aluminum
hydride and sodium-borohydride)

• The most common sources of the hydride nucleophile are lithium

aluminium hydride (LiAlH4) and sodium borohydride (NaBH4).
• Note! The hydride anion is not present during this reaction; rather,
these reagents serve as a source of hydride due to the presence of
a polar metal-hydrogen bond.
• Because aluminium is less electronegative than boron, the Al-H
bond in LiAlH4 is more polar, thereby, making LiAlH4 a
stronger reducing agent.

56
…cont

57
 Mechanism
1)Nucleophilic attack by the hydride anion
This mechanism is for a LiAlH4 reduction. The mechanism for a
NaBH4 reduction is the same except methanol is the proton source
used in the second step

2) The alkoxide is protonated

58
…cont

59
 Addition-Elimination Reactions

 Dehydrohalogenation (-HX) and Dehydration

(H2O) are the main types of elimination reactions.

60
 Imines and related compounds
• Aldehydes and ketones react with primary amines to form imines,
or Schiff bases.

 The mechanism of imine formation involves the nucleophilic

addition of the amine to the carbonyl carbon, forming a stable
intermediate species called a carbinolamine.

61
 Wittig reaction
• Phosphonium yields is reacts with aldehyde or ketone alkene is formed and
this reaction is wittig reaction.

62
…cont

63
 Reactions of acid chlorides
• Acid chlorides are prepared from carboxylic acids using either
thionyl chloride (SOCl2) or phosphorus pentachloride (PCl5).

64
 …cont

 Acid chlorides react with NH3, primary and secondary amines to

give amides.

65
 Ester hydrolysis and formation
• Carboxylic acid derivatives undergo a cleavage reaction with
water (hydrolysis) to yield carboxylic acids.
• When the reaction occurs under basic conditions, the base is not a
catalyst but is consumed in the reaction.
• Under basic conditions, the reaction is effectively irreversible

66
…cont

67
 Enolization-Ketonization reactions
• The conversion of a carbonyl compound into its enol is an
isomerization reaction called enolization.

68
Mechanisms of Enolization

69
Aldol and Related Condensation rxns

70
Mechanisms of the Aldol Reaction

71
…cont

72
…cont

73
…cont

74
 Reactions of acid anhydrides
• Acid chlorides react with carboxylic acids to form anhydrides as
shown in the reaction below.

 Acid anhydrides undergo hydrolysis and nucleophilic acyl

substitution reactions.

75
 …cont
• Acid anhydrides react with alcohols to produce esters pyridien as
solvent shown in the reaction below.

76
 mechanism
• 1) Nucleophilic Alcohol reacts with Electrophilic Carbony

2) Deprotonation by pyridine

77
 …cont
• 3) Leaving group removal

4) Protonation of the carboxylate

78
 …cont
• Acid Anhydrides react with amines to form amides.

1) Nucleophilic Amine reacts with Electrophilic Carbonyl

79
 …cont
• 2) Deprotonation by the amine

3) Leaving group removal

80
 Reductions of acid derivatives
• Acid chlorides can be converted to aldehydes using lithium tri-tert-
butoxyaluminum hydride (LiAlH(Ot-Bu)3).
• The hydride source (LiAlH(Ot-Bu)3) is a weaker reducing agent
than lithium aluminum hydride.
• Because acid chlorides are highly activated they still react with the
hydride source; however, the formed aldehyde will react slowly,
which allows for its isolation.

81
 …cont
• Esters can be converted to primary alcohols using LiAlH4, while
sodium borohydride ( NaBH4 ) is not a strong enough reducing
agent to perform this reaction.

1) Nucleophilic attack by the hydride

82
 …cont
• 2) Leaving group removal

3) Nucleopilic attack by the hydride anion

83
 …cont
• 4) The alkoxide is protonated

84
 …cont

• Carboxylic acids can be converted to primary alcohols using

Lithium aluminum hydride (LiAlH4).
• Note that NaBH4 is not strong enough to convert carboxylic acids
or esters to alcohols.
• An aldehyde is produced as an intermediate during this reaction,
but it cannot be isolated because it is more reactive than the
original carboxylic acid.

1) Deprotonation

85
 …cont
• 2) Nucleopilic attack by the hydride anion

3) Leaving group removal

86
 …cont
• 4) Nucleopilic attack by the hydride anion

5) The alkoxide is protonated

87
 …cont
• Amides can be converted to 1°, 2° or 3° amines using LiAlH4.
• General Reaction.

88
 …cont
• 1) Nucleophilic attach by the hydride

2) Leaving group removal

89
 …cont
• 3) Nucleophilic attach by the hydride

90
 Haloform Reaction of Methyl Ketones
 This reaction has been used in qualitative analysis to indicate the
presence of a methyl ketone.
 The product of iodoform is yellow and has a characteristic odour.
 The reaction has some synthetic utility in the oxidative de
methylation of methyl ketones if the other substituent on the carbonyl
groups bears no enolizable α-protons.

 The reaction readily proceeds to completion because of the

acidifying effect of the halogen substituents.

91
…cont

92
 Alkylations at the α-Carbon
• In alkylation it is important to use a strong base, such as LDA
(lithium diisopropyl amide) or sodium amide, for this reaction.
• Using a weaker base such as hydroxide or an alkoxide leaves the
possibility of multiple alkylation’s occurring.

93
 …cont

1) Enolate formation

2) Sn2 attack

94