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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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