1. Chapter 21: Amines and
Their Derivatives
Medicines, amino acids, peptides,
proteins, alkaloids, industrial materials
Fluoxetin
(Prozac)
O
F
F
F
Polypeptide

2. Amphetamine MescalineEpinephrine
(Adrenaline)
Alkaloids (natural amines)
HO
OH
HO
H
NHCH3
H2C
H2N
H
CH3
H3CO
OCH3
OCH3
NH2

3. Amines in Industry: Nylon
Nylon 6,6
Hosiery, gears, textile fiber,.......

4. Primary amines
Secondary amines
Tertiary amines
Naming: Alkanamines
N-alkyl, as
in amides

5. Substituent name: Amino-
Common names: Alkylamine
4-(2-Aminoethyl)benzoic acid
HOOC
NH2

6. Physical Properties
1. Tetrahedral structure
Basic
Ea = 5-7 kcal mol-1
Inversion

7. 3. Basicity-Nucleophilicity
RNH2
:
HCl
RNH3 + Cl
-+
Primary ammonium chloride
::
: :
RNH2
:
CH3I
RNH2CH3 + I
+
::
: :
-
Secondary ammonium chloride
2. Chiral amines racemize

8. Ammonium salts are configurationally stable
N
H3C
C6H5
CH2CH3
N
H3C
C6H5
CH2CH3
CH2Cl
N
H3C
C6H5
CH2CH3
H2C
N
H3C C6H5
CH2CH3
H2C
+
Cl: :
::
-
Cl: :
::
-
+
+
+
+
Can be resolved, e.g, by
fractional crystallization of a
salt with optically active anion

9. 4. Weaker hydrogen bonds than OH
NR
H
H
NH
H
R
:
:
Only primary and secondary amines can function
as proton donors
Less electronegative
than oxygen

11. Spectroscopy
Infrared spectrum of cyclohexanamine
N-H IR stretch: 3300–3500 cm-1

12. 1H NMR spectrum of azacyclohexane
NH usually broad,
variable, like OH

13. 13C Chemical Shifts (ppm)
N is less deshielding than O

14. Mass spectrum of N,N -diethylethanamine
Odd molecular
weight

15. •C : Mass 12 and tetravalent,
e.g. CH4, results in even M+
• N: Mass 14 and trivalent,
e.g. NH3, results in odd M+ for N = 1,3,5...
• Preferred fragmentation α–β bond
cleavage (even fragments)

16. Acidity and Basicity
Acidity:

17. • Preparation of Sodium Amide:
• Preparation of LDA:
Needs strong base
2Na + 2NH3 2NaNH2 + H2
Catalytic Fe3+

18. Basicity:
Kb =
[RNH3] [HO ]
[RNH2]
+ -
~ 10-4
Ammonium ion
 pKb ~ 4
Recall:
pKa + pKb = 14
Thus, pKa of protonated amine ~ 10

19. Better (to compare with other pKa values):
O
H
H
R
+
pKa = -3

20. Synthesis
1. Alkylation of NH3, primary, and
secondary amines
Problem:
• Overalkylation: Even though amine gets more
hindered, it also gets more nucleophilic
 One solution is to have excess of RNH2 and
use RX as limiting reagent

21. 2. Via nitriles
3. Arenamine via nitroarene
1,3-Benzenediamine
HNO3,H2SO4
NO2
HNO3,H2SO4
NO2
NO2
H2,Ni
CF3CO3H
NH2
NH2

22. 4. Gabriel Synthesis ( RX RNH2)
Solves problem of overalkylation

23. 5. Reductive Amination Primary amine
Secondary amine
Tertiary amine
Goes through
iminium ion
Goes through
iminium ion

24. Formaldehyde and a secondary amine:
Use of formaldehyde
effects monomethylation
of an amine.
RedAmin

25. 6. Reduction of amides
RCNHR’
LiAlH4
O
RCH2NHR’
Recall:
7. Hofmann Rearrangement
RCCl
O
Amide and RCNHR’
O
RCNR’’R’
O
August Wilhelm
von Hofmann
1818-1892

26. Reactions of Amines
1. Hofmann Elimination
Recall:
::
Oxonium ion
Analogous (but attenuated) behavior in
quaternary ammonium ions. Works for E2
ROH
H+
R OH2
+

27. Hofmann eliminations are often used to break
down larger amines, e.g., alkaloids, into smaller
fragments.
Procedure: First, methylate exhaustively to the
quaternary ammonium salt; second, treat with
base.

28. Degradation of a simple alkaloid
H H

29. 2. Mannich Reaction
Alkylation of Enols by Iminium Ions
The enol is derived from an enolizable ketone/aldehyde and the
iminium ion is formed in situ by condensation of a second, more
reactive carbonyl component with an amine. The outcome is a β-
aminocarbonyl product.
Form iminium ion
Form iminium ion
Carl Ulrich
Franz Mannich
1877-1947

30. Net: α–Amino-
methylation of
enolizable alde-
hyde
Mannich

31. 3. Reaction with nitrous acid
• Nitrosyl cation: like C O , but more electrophilic
(charged) and gets attacked by amines
::
Tertiary
amine (stable)
Secondary
amine
N –Nitrosamines are
implicated in the
carcinogenicity of
cured meats

32. Primary N -nitrosamines decompose
R = Alkyl  mess, R = Arene  stable (Chapter 22)

33. 4. Diazomethane CH2 N N
Amides are also subject to N -Nitrosation
N-Methyl-N-nitrosourea is a precursor to diazomethane
――――

34. Step 1: Hydroxide Addition
C
O
NH2H3CN
N
O
OH C
O
NH2H3CN
N
O
OH
:
::
::
:
::
:
:
:
:
:
-
: :
:
-
Mechanism:
Step 2: Elimination
C
O
NH2H3CN
N
O
OH
CH3N N O C
HO NH2
O
HOH
CH3N NOH OH CO2 HNH2
-
: :
::
: :
:
:
:
:
:
:
:
:
:
:
:
:
:
::
:
::
:
::
-
+
+ +

35. CH2N NOH OH
-H2O
H2C N N OH
H2C N N
H2C N NH
Step 3: Dehydration
:
:
:
:
:
:
::
::
:
:
:
:
::
:
:
- OH
-
-
-
+
-
:
Diazomethane has two applications as a
reagent: In esterifications and as a source of
carbene CH2.

36. H2C N NC
O
OR H
C
O
OR
H3C N N
N N
C
O
OCH3R
• Formation of Esters
• Generation of Carbene
• Cyclopropanation
H2C N N
+ -
:
H2C N N C
H
H
::
+ - hν or Cu or
:
+
:
:
- +:
: :
+
::
:
:
-