Pyridines, Quinolines and Isopuinolines

  • Created by: E.H13
  • Created on: 28-05-20 13:53
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  • Pyridines, Quinolines and Isoquinolines
    • General
      • Pyridine is very electron poor
        • Due to very electronegative N in ring
        • Dominates it's chemistry
      • Reactions with electrophiles very slow
      • Nucleophilic attack rapid
      • Protonates on N
    • Electrophilic Substitution
      • Essentially inert to this
      • Extremely harsh conditions
      • Preferentially in 3 position
        • Rationalised through resonance forms
          • Both C2/4 and C3 have 3 resonance forms
          • When protonated on C2 deocalisation of +ve charge on N with only  e
      • Most electrophiles like to react with N anyway, so it's even worse
      • Nitration
        • Very poor
        • c/HNO3 and c/H2SO4, 300oC for 24h
          • 6% yield
        • Particularly slow, as almost all N are protonated
      • Bromination
        • One of the few to work
        • Not simple EArS
        • Br2, oleum, 130 degrees
    • Nucleophilic Attack on Pyridine
      • 3 position relativity unreactive
        • -ve charge can't be delocalised onto N
    • Lithiation
      • Direct lithiation
        • Can be directed to position 2 using Hexafluoroacetone
        • Hexafluoroacetone, then LDA, then electrophile, then aq work up
      • Metal-halogen exchange
        • Take a bromopyridine, then exchange for Li
        • BuLi, Et2O, -78 degrees
          • Kept cold to avoid rearrangement
      • Ortho-lithiation
        • If a ring contains an ortho-lithiation directing group, you can just use that
          • e.g. amides, SEM, Boc
          • Will just direct Li ortho to group
        • Very unfavourable to add ortho to N
          • Electron repulsion between lp on N and Li
    • Palladium Catalysed Couplings
      • Bromopyridines are useful
      • Suzuki and Stille reactions
        • Suzuki is more useful as the by-products are non-toxic and easily removed
    • Alkyl Pyridines
      • 2-Methylpyridine is relatively acidic, ad can be deprotonated using BuLi
    • Quinolines and Isoquinolines
      • Positions 5 and 8 susceptible to electrophilic attack
        • Has 2 major resonance forms without distrupting the aromaticity of both rings, vs the 1
      • Positions 2 and 4 susceptible to nucleophilic attack
      • Nitration and sulphonation both occur readily
      • Readily attacked, but 3-Cl relatively unreactive, as -ve charge can't be delocalised onto N
    • Oxy Quinolines
      • Keto-enol tautomerism
        • 2 and 4 oxyquinoline and 1 oxyisoquinoline favour carbonyl
        • All others favour hydroxyl form


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