Organic Chemistry, 5th Edition

L. G. Wade, Jr.

Chapter 19
Amines

Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
2003, Prentice Hall
 Introduction
• Organic derivatives of ammonia
• Many are biologically active.

=>
Chapter 19 2
 Biological Activity
• Neurotransmitters: dopamine
• Bioregulators: epinephrine
• Vitamins: niacin, B6
• Alkaloids: nicotine, morphine, cocaine
• Amino acids

=>
Chapter 19 3
 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 4
 Classify:
CH3
N
CH3

N
H

CH3 _
Br
CH3 C NH2 +
CH3CH2 N CH2CH3
CH3 CH3 =>

Chapter 19 5
 Common Names
Name the alkyl or aryl groups bonded to
nitrogen, then add suffix -amine.
(CH3CH2)2NCH3
diethylmethylamine NHCH3

NH cyclopentylmethylamine

Diphenylamine =>
Chapter 19 6
 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 7
 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 8
 Aromatic Amines
Amino group is bonded to a benzene ring.
Parent compound is called aniline.
CH3 NH2
NH2 N
CH3
H3C

aniline N,N-dimethylaniline 4-methylaniline

or p-toluidine

=>
Chapter 19 9
 Heterocyclic Amines
The nitrogen is assigned the number 1.

H
N N N N N CH3
H H Pyridine
aziridine Pyrrolidine
Pyrrole 2-methylpyridine

=>
Chapter 19 10
 Structure of Amines
Nitrogen is sp3 hybridized with a lone pair
of electrons in an sp3 orbital.

=>
Chapter 19 11
 Chirality of Amines
Nitrogen may have 3 different groups and
a lone pair, but enantiomers cannot be
isolated due to inversion around N.

Chapter 19 12 =>
 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 13
=>
 Boiling Points
• N-H less polar than O-H.
• Weaker hydrogen bonding.
• Tertiary amines cannot hydrogen bond.

=>
Chapter 19 14
 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 15
 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 19 16
 Energy Diagram
Alkyl groups are electron-donating and
stabilize the cation.

Chapter 19 17
=>
 Resonance Effects
Any delocalization of the electron pair
weakens the base.

=>
Chapter 19 18
 Hybridization Effects
Electrons are held more tightly in orbitals
with more s character, so those
compounds are weaker bases.

=>
Chapter 19 19
 Amine Salts
• Ionic solids with high melting points
• Soluble in water
• No fishy odor

=>
Chapter 19 20
Purifying an Amine

=>
Chapter 19 21
Phase Transfer Catalysts

=>
Chapter 19 22
 IR Spectroscopy
• N-H stretch between 3200-3500 cm-1.
• Two peaks for 1 amine, one for 2.

Chapter 19 23 =>
NMR Spectrum

=>
Chapter 19 24
Mass Spectrum

Chapter 19 25 =>
 Reactions with C=O
• Ammonia and primary amines react with
carbonyls to give an imine (Schiff base).
Y Y
O + HO N H + N
H H
C + Y NH2 C C
R R' R R' R R'

Y = H or alkyl gives an imine

Y = OH gives an oxime
Y = NHR gives a hydrazone
=>
Chapter 19 26
 Electrophilic Substitution
of Aniline
• -NH2 is strong activator, o-,p-directing.
• May trisubstitute with excess reagent.
• H+ changes -NH2 to -NH3+, a meta-
directing deactivator.
• Attempt to nitrate aniline may explode.

=>
Chapter 19 27
Aniline Substitution

=>
Chapter 19 28
 Electrophilic Substitution
of Pyridine
• Strongly deactivated by electronegative N.
• Substitutes in the 3-position.
• Electrons on N react with electrophile.
SO3H
fuming H2SO4
o
HgSO4, 230 C
N N

=>
Chapter 19 29
 Mechanism for
Electrophilic Substitution
Attack at the 3-position (observed)
+ + H H H
NO2 NO2
NO2 NO2 NO2 +
+ H
+ N + N
N N N

Attack at the 2-position (not observed)

+ +
+
+
NO2
X +
NO2 NO2 NO2
X + H
NO2
N N H N H N H N

No octet! =>
Chapter 19 30
 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.
_ _
OCH3 + Cl
N Cl N OCH3
=>
Chapter 19 31
 Mechanism for
Nucleophilic Substitution
Attack at the 2-position (observed)
_ _ _
OCH3
OCH3 OCH3 OCH3 OCH3
N Cl N_ Cl N Cl N Cl N

=>
Chapter 19 32
 Alkylation of Amines
• Amines react with 1 alkyl halides via the
SN2 mechanism.
• Mixtures of the mono-, di-, and tri-
alkylated products are obtained.

=>
Chapter 19 33
 Useful Alkylations
• Exhaustive alkylation to form the
tetraalkylammonium salt.
+ _
NH2 N(CH3)3 I
3 CH3I
CH3CH2CHCH2CH2CH3 CH3CH2CHCH2CH2CH3
NaHCO3

• Reaction with large excess of NH3 to

form the primary amine.
NH3 (xs)
CH3CH2CH2Br CH3CH2CH2NH2 + NH4Br

Chapter 19 34
=>
 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

NH2 O N C CH3
CH3 C Cl H

=>
to remove HCl Chapter 19 35
 Formation of Sulfonamides
• Primary or secondary amines react with
sulfonyl chloride.
O O O
+ _
R NH2 R' S Cl R' S NH R Cl base R' S NH R
O O H O

NH2

• Sulfa drugs are sulfonamides

that are antibacterial agents.
O S O
=>
NH2
Chapter 19 36
 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 I N(CH3)3 OH
Ag2O heat
CH3CHCH2CH2CH3 CH3CHCH2CH2CH3 CH2 CHCH2CH2CH3
H2O

=>
Chapter 19 37
E2 Mechanism

=>
Chapter 19 38
 Oxidation of Amines
• Amines are easily oxidized, even in air.
• Common oxidizing agents: H2O2 , MCPBA.
• 2 Amines oxidize to hydroxylamine (-NOH)
• 3 Amines oxidize to amine oxide (-N+-O-)

Chapter 19
=> 39
 Cope Elimination
Amine oxides undergo elimination to form
the least substituted alkene under
milder conditions than the Hofmann
reaction.
_
O + O HO
H N(CH3)2 H N(CH3)2 N(CH3)2
CH2 CHCH2CH2CH3 CH2 CHCH2CH2CH3 CH2 CHCH2CH2CH3

=>
Chapter 19 40
 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.

H
H
+ + +
H O N O H O N O H2O + N O N O
+

=>
Chapter 19 41
 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.

=>
Chapter 19 42
 Arenediazonium Salts
• Stable in solution at 0°–10°C.
• The -+NN group is easily replaced by
many different groups.
• Nitrogen gas, N2, is a by-product.
+
H3O Ar OH phenols
CuCl (Br) Ar Cl (Br) aryl halides
+ CuCN Ar C N benzonitriles
Ar N N HBF4 (KI) aryl halides
Ar F (I)
H3PO2 Ar H benzene
H Ar' Ar N N Ar' azo dyes =>
Chapter 19 43
 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 44
 Examples
O N OH NH2
NH2 OH H2
CH3CH2CH2 C CH3 CH3CH2CH2 C CH3 CH3CH2CH2 CH CH3
H+ Ni
primary amine

O NCH3 NHCH3
CH3NH2 1) LiAlH4
CH3 C CH3 + CH3 C CH3 CH3 CH CH3
H 2) H2O
secondary amine
H3C CH3 H3C CH3
N+ N
O
HN(CH3)2 C H C H
C H Na(CH3COO)3BH
+ H
H CH3COOH

tertiary amine =>

Chapter 19 45
 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 46
 Examples
O O
NH3 1) LiAlH4
CH3 C Cl CH3 C NH2 CH3 CH2 NH2
2) H2O
primary amine

O
O
HN(CH3)2 C N(CH ) 1) LiAlH CH2 N(CH3)2
C Cl 3 2 4
2) H2O

tertiary amine
=>
Chapter 19 47
 Direct Alkylation (1)
• Use a large excess (10:1) of ammonia
with a primary alkyl halide or tosylate.
• Reaction mechanism is SN2.

NH3
CH3CH2CH2 Br CH3CH2CH2 NH2 + NH4Br

=>
Chapter 19 48
 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.
O O
O
_
R X H2N NH2 NH
N N R + R NH2
heat NH
O O
O

=>
Chapter 19 49
 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.

Br N3 NH2
NaN3 1) LiAlH4
2) H2O

=>
Chapter 19 50
 Nitrile Reduction (1)
• Nitrile, -CN, is a good SN2 nucleophile.
• Reduction with H2 or LiAlH4 adds -CH2NH2.
Br CN CH2NH2
NaCN 1) LiAlH4
2) H2O

=>
Chapter 19 51
 Reduction of Nitro
Compounds (1)
• -NO2 is reduced to -NH2 by catalytic
hydrogenation, or active metal with acid.
• Commonly used to synthesize anilines.
CH3 Zn, HCl CH3

NO2 CH3CH2OH NH2

=>
Chapter 19 52
 Hofmann Rearrangement
of Amides (1)
In the presence of a strong base, primary
amides react with chlorine or bromine to
form amines with one less C.
O _
Br2, OH
C NH2 NH2
H2O

=>
Chapter 19 53
 Hofmann Mechanism (1)
• N-H protons of amide are abstracted.
• Rearrangement forms an isocyanate.
_
OH Br Br O
O O
_ Br
R C N H R C N
R C N
H H H
_ _
O OH O O
R C N H R C N_ R C N R N C O
Br Br
Br

Chapter 19 54
=>
 Hofmann Mechanism (2)
• Isocyanate reacts with water to form
carbamic acid, which loses CO2.
_
OH OH _ OH
_ OH
R N C O R N C O R N C O R N C O
HOH H

_
O
_ HOH
R N C O O C O + R N R NH2
H H
=>
Chapter 19 55
End of Chapter 19

Chapter 19 56