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Chapter 21: Amines and
Their Derivatives
Medicines, amino acids, peptides,
proteins, alkaloids, industrial materials
Fluox...
Amphetamine MescalineEpinephrine
(Adrenaline)
Alkaloids (natural amines)
HO
OH
HO
H
NHCH3
H2C
H2N
H
CH3
H3CO
OCH3
OCH3
NH2
Amines in Industry: Nylon
Nylon 6,6
Hosiery, gears, textile fiber,.......
Primary amines
Secondary amines
Tertiary amines
Naming: Alkanamines
N-alkyl, as
in amides
Substituent name: Amino-
Common names: Alkylamine
4-(2-Aminoethyl)benzoic acid
HOOC
NH2
Physical Properties
1. Tetrahedral structure
Basic
Ea = 5-7 kcal mol-1
Inversion
3. Basicity-Nucleophilicity
RNH2
:
HCl
RNH3 + Cl
-+
Primary ammonium chloride
::
: :
RNH2
:
CH3I
RNH2CH3 + I
+
::
: :
-
Se...
Ammonium salts are configurationally stable
N
H3C
C6H5
CH2CH3
N
H3C
C6H5
CH2CH3
CH2Cl
N
H3C
C6H5
CH2CH3
H2C
N
H3C C6H5
CH2...
4. Weaker hydrogen bonds than OH
NR
H
H
NH
H
R
:
:
Only primary and secondary amines can function
as proton donors
Less el...
Spectroscopy
Infrared spectrum of cyclohexanamine
N-H IR stretch: 3300–3500 cm-1
1H NMR spectrum of azacyclohexane
NH usually broad,
variable, like OH
13C Chemical Shifts (ppm)
N is less deshielding than O
Mass spectrum of N,N -diethylethanamine
Odd molecular
weight
•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 =...
Acidity and Basicity
Acidity:
• Preparation of Sodium Amide:
• Preparation of LDA:
Needs strong base
2Na + 2NH3 2NaNH2 + H2
Catalytic Fe3+
Basicity:
Kb =
[RNH3] [HO ]
[RNH2]
+ -
~ 10-4
Ammonium ion
 pKb ~ 4
Recall:
pKa + pKb = 14
Thus, pKa of protonated amine ...
Better (to compare with other pKa values):
O
H
H
R
+
pKa = -3
Synthesis
1. Alkylation of NH3, primary, and
secondary amines
Problem:
• Overalkylation: Even though amine gets more
hinde...
2. Via nitriles
3. Arenamine via nitroarene
1,3-Benzenediamine
HNO3,H2SO4
NO2
HNO3,H2SO4
NO2
NO2
H2,Ni
CF3CO3H
NH2
NH2
4. Gabriel Synthesis ( RX RNH2)
Solves problem of overalkylation
5. Reductive Amination Primary amine
Secondary amine
Tertiary amine
Goes through
iminium ion
Goes through
iminium ion
Formaldehyde and a secondary amine:
Use of formaldehyde
effects monomethylation
of an amine.
RedAmin
6. Reduction of amides
RCNHR’
LiAlH4
O
RCH2NHR’
Recall:
7. Hofmann Rearrangement
RCCl
O
Amide and RCNHR’
O
RCNR’’R’
O
Augu...
Reactions of Amines
1. Hofmann Elimination
Recall:
::
Oxonium ion
Analogous (but attenuated) behavior in
quaternary ammoni...
Hofmann eliminations are often used to break
down larger amines, e.g., alkaloids, into smaller
fragments.
Procedure: First...
Degradation of a simple alkaloid
H H
2. Mannich Reaction
Alkylation of Enols by Iminium Ions
The enol is derived from an enolizable ketone/aldehyde and the
imi...
Net: α–Amino-
methylation of
enolizable alde-
hyde
Mannich
3. Reaction with nitrous acid
• Nitrosyl cation: like C O , but more electrophilic
(charged) and gets attacked by amines
:...
Primary N -nitrosamines decompose
R = Alkyl  mess, R = Arene  stable (Chapter 22)
4. Diazomethane CH2 N N
Amides are also subject to N -Nitrosation
N-Methyl-N-nitrosourea is a precursor to diazomethane
――...
Step 1: Hydroxide Addition
C
O
NH2H3CN
N
O
OH C
O
NH2H3CN
N
O
OH
:
::
::
:
::
:
:
:
:
:
-
: :
:
-
Mechanism:
Step 2: Elimi...
CH2N NOH OH
-H2O
H2C N N OH
H2C N N
H2C N NH
Step 3: Dehydration
:
:
:
:
:
:
::
::
:
:
:
:
::
:
:
- OH
-
-
-
+
-
:
Diazome...
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
+ -
...
Chapter21胺及其衍生物
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Chapter21胺及其衍生物

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Chapter21胺及其衍生物

  1. 1. Chapter 21: Amines and Their Derivatives Medicines, amino acids, peptides, proteins, alkaloids, industrial materials Fluoxetin (Prozac) O F F F Polypeptide
  2. 2. Amphetamine MescalineEpinephrine (Adrenaline) Alkaloids (natural amines) HO OH HO H NHCH3 H2C H2N H CH3 H3CO OCH3 OCH3 NH2
  3. 3. Amines in Industry: Nylon Nylon 6,6 Hosiery, gears, textile fiber,.......
  4. 4. Primary amines Secondary amines Tertiary amines Naming: Alkanamines N-alkyl, as in amides
  5. 5. Substituent name: Amino- Common names: Alkylamine 4-(2-Aminoethyl)benzoic acid HOOC NH2
  6. 6. Physical Properties 1. Tetrahedral structure Basic Ea = 5-7 kcal mol-1 Inversion
  7. 7. 3. Basicity-Nucleophilicity RNH2 : HCl RNH3 + Cl -+ Primary ammonium chloride :: : : RNH2 : CH3I RNH2CH3 + I + :: : : - Secondary ammonium chloride 2. Chiral amines racemize
  8. 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. 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
  10. 10. Spectroscopy Infrared spectrum of cyclohexanamine N-H IR stretch: 3300–3500 cm-1
  11. 11. 1H NMR spectrum of azacyclohexane NH usually broad, variable, like OH
  12. 12. 13C Chemical Shifts (ppm) N is less deshielding than O
  13. 13. Mass spectrum of N,N -diethylethanamine Odd molecular weight
  14. 14. •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)
  15. 15. Acidity and Basicity Acidity:
  16. 16. • Preparation of Sodium Amide: • Preparation of LDA: Needs strong base 2Na + 2NH3 2NaNH2 + H2 Catalytic Fe3+
  17. 17. Basicity: Kb = [RNH3] [HO ] [RNH2] + - ~ 10-4 Ammonium ion  pKb ~ 4 Recall: pKa + pKb = 14 Thus, pKa of protonated amine ~ 10
  18. 18. Better (to compare with other pKa values): O H H R + pKa = -3
  19. 19. 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
  20. 20. 2. Via nitriles 3. Arenamine via nitroarene 1,3-Benzenediamine HNO3,H2SO4 NO2 HNO3,H2SO4 NO2 NO2 H2,Ni CF3CO3H NH2 NH2
  21. 21. 4. Gabriel Synthesis ( RX RNH2) Solves problem of overalkylation
  22. 22. 5. Reductive Amination Primary amine Secondary amine Tertiary amine Goes through iminium ion Goes through iminium ion
  23. 23. Formaldehyde and a secondary amine: Use of formaldehyde effects monomethylation of an amine. RedAmin
  24. 24. 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
  25. 25. Reactions of Amines 1. Hofmann Elimination Recall: :: Oxonium ion Analogous (but attenuated) behavior in quaternary ammonium ions. Works for E2 ROH H+ R OH2 +
  26. 26. 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.
  27. 27. Degradation of a simple alkaloid H H
  28. 28. 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
  29. 29. Net: α–Amino- methylation of enolizable alde- hyde Mannich
  30. 30. 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
  31. 31. Primary N -nitrosamines decompose R = Alkyl  mess, R = Arene  stable (Chapter 22)
  32. 32. 4. Diazomethane CH2 N N Amides are also subject to N -Nitrosation N-Methyl-N-nitrosourea is a precursor to diazomethane ――――
  33. 33. 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 - : : :: : : : : : : : : : : : : : : : :: : :: : :: - + + +
  34. 34. 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.
  35. 35. 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 : + : : - +: : : + :: : : -

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