1. Chapter 20
Amines

2. Nomenclature
1o Amines
2o Amines

3. 3o Amines

4. 1A. Arylamines

5. 1B. Heterocyclic Amines

6. Physical Properties and Structure of Amines
2A. Physical Properties

7. 2B. Structure of Amines
N: sp3 hybridized
Trigonal pyramidal
Bond angles close to 109.5o

8. 3o Amines with three different groups
The two enantiomeric forms interconvert rapidly:
Impossible to resolve enantiomers.
Pyramidal or nitrogen inversion:
Barrier ~ 25 kJ/mol.
Enough to occur rapidly at room temperature.

9. Ammonium salts with four different groups.
enantiomers
can be resolved

10. Basicity of Amines: Amine Salts

11. The aminium ion of a more basic amine will have a larger pKa than the aminium ion of a less basic amine

12. >
>
By releasing electrons, R— stabilizes the alkylaminium ion through dispersal of charge
>

13. Basicity of amines:

14. 3A. Basicity of Arylamines
Compare cyclohexylamine with arylamines.

15. Five resonance structures
Aniline
Five resonance structures

16. Only two resonance structures

18. 3B. Basicity of Heterocyclic Amines

20. 3C. Amines versus Amides
Amides are far less basic than amines (even less basic than arylamines). The pKa of the conjugate acid of a typical amide is about zero
Larger resonance stabilization
Smaller resonance stabilization

21. <
>

22. 3D. Aminium Salts and Quaternary Ammonium Salts
Cannot act
as bases
However, R4N⊕ ⊖OH are strong bases (as strong as NaOH)

23. 3E. Solubility of Amines in Aqueous Acids

24. 3F. Amines as Resolving Agents
Enantiomerically pure amines are often used to resolve racemic forms of acidic compounds by the formation of diastereomeric salts.

26. Preparation of Amines 4A. Through Nucleophilic Substitution Reactions
Alkylation of ammonia

28. Alkylation of azide ion and reduction

29. The Gabriel synthesis

30. Alkylation of 3o amines

31. 4B. Preparation of Aromatic Amines through Reduction of Nitro Compounds

32. 4C. Preparation of Primary, Secondary,
and Tertiary Amines through Reductive
Amination

33. Mechanism Sodium cyanoborohydride, NABH3CN,
is often used to reduce the imine.

34. Examples

35. 4D. Preparation of Primary, Secondary,
or Tertiary Amines through
Reduction of Nitriles, Oximes,
and Amides

36. Examples

37. Examples

38. 4D. Preparation of Primary Amines
through the Hofmann and Curtius Rearrangements
Hofmann rearrangement:

39. Examples

40. Mechanism

41. Curtius rearrangement:

42. Reactions of Amines
Acid-base reactions
Alkylation

43. Acylation

44. Electrophilic aromatic substitution
NH2: powerful activating group, ortho-para director

45. 5A. Oxidation of 3o Amines

46. Reactions of Amines with Nitrous Acid
Nitrous acid (HONO) is a weak, unstable acid

47. (aliphatic diazonium salt)
6A. Reactions of Primary Aliphatic
Amines with Nitrous Acid
1o aliphatic amine
(aliphatic diazonium salt)
(highly unstable)

48. (arenediazonium salt)
6B. Reactions of Primary Arylamines
with Nitrous Acid
(arenediazonium salt)
(stable at <5oC)

49. Mechanism

50. Mechanism (Cont'd)
diazonium ion

51. 6C. Reactions of Secondary Amines with Nitrous Acid
N-Nitroso-
amines

52. 6D. Reactions of Tertiary Amines with Nitrous Acid

53. Replacement Reactions of Arenediazonium Salts

54. 7A. Syntheses Using Diazonium Salts

55. 7B. The Sandmeyer Reaction: Replacement of the Diazonium Group by -Cl, -Br, or -CN
The Sandmeyer reactions use a copper containing reagent.

56. A Sandmeyer reaction.

57. A Sandmeyer reaction.

58. 7C. Replacement by —I

59. 7D. Replacement by —F

60. 7E. Replacement by —OH

61. 7F. Replacement by Hydrogen: Deamination by Diazotization

62. Coupling Reactions of Arenediazonium Salts

63. Examples

64. Examples

65. Examples

66. Reactions of Amines with Sulfonyl Chlorides
A sulfonamide

67. 9A. The Hinsberg Test
Sulfonamide formation is the basis for a chemical test, called the Hinsberg test, that can be used to demonstrate whether an amine is primary, secondary, or tertiary.

68. Hinsberg with a 1o Amine

69. Hinsberg with a 2o Amine

70. Hinsberg with a 3o Amine

71. Synthesis of Sulfa Drugs

72. Analysis saltsof Amines
11A. Chemical Analysis
They dissolve in dilute aqueous acid
Moist pH paper is
 basic
Hinsberg test for 1o, 2o and 3o.
1o aromatic amines form diazo salts.
 azo dye formation with 2-naphthol

73. 11B. Spectroscopic AnalysisIR
1o amines
3300 – 3555 cm-1 (N–H)
 two bands.
2o amines
 one band only.
3o amines
No bands at 3300 – 3555 cm-1 region.

74. Aliphatic amines
1020 – 1220 cm-1 (C–N)
Aromatic amines
1250 – 1360 cm-1 (C–N)

75. 1H NMR spectra 1o and 2o amines
N–H d (0.5 – 5 ppm), usually broad, exact position depends on the solvent, concentration, purity and temperature.
N–H protons are not usually coupled to protons on adjacent carbons.
Protons on the a carbon of an aliphatic amine are deshielded by the electron-withdrawing effect of the nitrogen and absorb typically in the d 2.2–2.9 region.

76. Protons on the b carbon are not deshielded as much and absorb in the range d 1.0–1.7

77. 13C NMR chemical shifts (d)
13C NMR spectra
23.0
34.0
14.3
29.7
42.5
13C NMR chemical shifts (d)

78. Mass spectra
The molecular ion in the mass spectrum of an amine has an odd number mass (unless there is an even number of nitrogen atoms in the molecule).
The peak for the molecular ion is usually strong for aromatic and cyclic aliphatic amines but weak for acyclic aliphatic amines.
Cleavage between the a and b carbons of aliphatic amines is a common mode of fragmentation.

79. Eliminations Involving Ammonium Compounds
12A. The Hofmann Elimination

80. Preparation of the 4o ammonium hydroxide

81. Although most eliminations involving neutral substrates tend to follow the Zaitsev rule, eliminations with charged substrates tend to follow what is called the Hofmann rule and yield mainly the least substituted alkene

82. An anti mechanism

83. 12B. The Cope Elimination Prep of amine oxide, see slide 45.
A syn mechanism

84. Summary of Preparations and Reactions of Amines
Preparation of amines

86. Reactions of amines

89.  END OF CHAPTER 20 