1. 22.7 Reactions of Amines: A Review and a Preview3

2. Two questions to answer: 1) How is the C—N bond to be formed?
Preparation of Amines
Two questions to answer:
1) How is the C—N bond to be formed?
2) How do we obtain the correct oxidation state of nitrogen (and carbon)? 6

3. Methods for C—N Bond Formation
Nucleophilic substitution by azide ion (N3–) (Section 8.1, 8.13)
Nitration of arenes (Section 12.3)
Nucleophilic ring opening of epoxides by ammonia (Section 16.12)
Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11)
Nucleophilic substitution by ammonia on a-halo acids (Section 19.16)
Nucleophilic acyl substitution (Sections 20.3, 20.5, and 20.11)
Hofmann rearrangement (Section 20.17) 6

4. 22.8 Preparation of Amines by Alkylation of Ammonia3

5. Alkylation of Ammonia
Desired reaction is:
2 NH3 +
R—X
R—NH2 +
NH4X 3

6. Alkylation of Ammonia Desired reaction is: 2 NH3 + R—X R—NH2 + NH4X
via: ••
• • R X
H3N R + ••
• • X –
H3N
• • + + H N R + N H R
• •
then:
H3N H + +
H3N
• • + 3

7. Alkylation of Ammonia
But the method doesn't work well in practice. Usually gives a mixture of primary, secondary, and tertiary amines, plus the quaternary salt. RX RX
NH3
RNH2
R2NH RX RX
R4N + X –
R3N 3

8. Example NH3 CH3(CH2)6CH2Br CH3(CH2)6CH2NH2
As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine. 4

9. Example NH3 CH3(CH2)6CH2Br CH3(CH2)6CH2NH2 (45%) +
CH3(CH2)6CH2NHCH2(CH2)6CH3
(43%)
As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine. 4

10. 22.9 The Gabriel Synthesis of Primary Alkylamines3

11. uses an SN2 reaction on an alkyl halide to form the C—N bond
Gabriel Synthesis
gives primary amines without formation of secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form the C—N bond
the nitrogen-containing nucleophile is N-potassiophthalimide 6

12. uses an SN2 reaction on an alkyl halide to form the C—N bond
Gabriel Synthesis
gives primary amines without formation of secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form the C—N bond
the nitrogen-containing nucleophile is N-potassiophthalimide O N
• • – K + 6

13. N-Potassiophthalimide
the pKa of phthalimide is 8.3
N-potassiophthalimide is easily prepared by the reaction of phthalimide with KOH O O N
• • – K + NH
KOH
• • O 7

14. N-Potassiophthalimide as a nucleophileR
• •
SN2 – ••
• • R X N +
• •
• • O + ••
• • X – 7

15. Cleavage of Alkylated PhthalimideN R
• • +
H2O
imide hydrolysis is nucleophilic acyl substitution
acid or base
CO2H +
H2N R 7

16. Cleavage of Alkylated Phthalimide
hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative O N R
• • O NH
H2NNH2 +
H2N R 7

17. Example O N
• • – K + +
C6H5CH2Cl
DMF 4

18. Example O N
• • – K + +
C6H5CH2Cl
DMF O N
CH2C6H5
• •
(74%) 4

19. Example O NH +
C6H5CH2NH2
(97%)
H2NNH2 O N
CH2C6H5
• • 4

20. 22.10 Preparation of Amines by Reduction3

21. Preparation of Amines by Reduction
almost any nitrogen-containing compound can be reduced to an amine, including:
azides nitriles nitro-substituted benzene derivatives amides 6

22. Synthesis of Amines via Azides
SN2 reaction, followed by reduction, gives a primary alkylamine.
CH2CH2Br
NaN3
CH2CH2N3
(74%)
1. LiAlH4
2. H2O
CH2CH2NH2
(89%) 12

23. Synthesis of Amines via Azides
SN2 reaction, followed by reduction, gives a primary alkylamine.
CH2CH2Br
NaN3
CH2CH2N3
(74%)
azides may also be reduced by catalytic hydrogenation
1. LiAlH4
2. H2O
CH2CH2NH2
(89%) 12

24. Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a primary alkylamine.
NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%) 12

25. Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a primary alkylamine.
NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69%)
nitriles may also be reduced by lithium aluminum hydride
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%) 12

26. Synthesis of Amines via Nitriles
SN2 reaction, followed by reduction, gives a primary alkylamine.
NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69%)
the reduction also works with cyanohydrins
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%) 12

27. Synthesis of Amines via NitroarenesCl
NO2
HNO3 Cl
H2SO4
(88-95%)
1. Fe, HCl
2. NaOH Cl
NH2
(95%) 12

28. Synthesis of Amines via NitroarenesCl
NO2
HNO3 Cl
H2SO4
nitro groups may also be reduced with tin (Sn) + HCl or by catalytic hydrogenation
(88-95%)
1. Fe, HCl
2. NaOH Cl
NH2
(95%) 12

29. Synthesis of Amines via Amides
COH O
CN(CH3)2 O
1. SOCl2
2. (CH3)2NH
(86-89%)
1. LiAlH4
2. H2O
CH2N(CH3)2
(88%) 12

30. Synthesis of Amines via Amides
COH O
CN(CH3)2 O
1. SOCl2
2. (CH3)2NH
(86-89%)
only LiAlH4 is an appropriate reducing agent for this reaction
1. LiAlH4
2. H2O
CH2N(CH3)2
(88%) 12

31. 22.11 Reductive Amination 3

32. Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. O C R R'
fast NH C R R' +
NH3 +
H2O
The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. 12

33. Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product. O C R R'
fast NH C R R' +
NH3 +
H2O
NH2 R R' C H
H2, Ni 12

34. Example: Ammonia gives a primary amine.
H2, Ni O H
NH2 +
NH3
ethanol
(80%) NH
via: 18

35. Example: Primary amines give secondary amines
CH3(CH2)5CH O +
H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%) 18

36. Example: Primary amines give secondary amines
CH3(CH2)5CH O +
H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%) N
CH3(CH2)5CH
via: 18

37. Example: Secondary amines give tertiary aminesH
CH3CH2CH2CH O +
H2, Ni, ethanol N
CH2CH2CH2CH3
(93%) 18

38. Example: Secondary amines give tertiary amines
possible intermediates include:
CHCH2CH2CH3 N HO
CHCH2CH2CH3 N + N CH
CHCH2CH3 18