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
- Pyridine is very electron poor
- 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
- Rationalised through resonance forms
- 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
- 3 position relativity unreactive
- 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
- If a ring contains an ortho-lithiation directing group, you can just use that
- Direct lithiation
- 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
- Positions 5 and 8 susceptible to electrophilic attack
- Oxy Quinolines
- Keto-enol tautomerism
- 2 and 4 oxyquinoline and 1 oxyisoquinoline favour carbonyl
- All others favour hydroxyl form
- Keto-enol tautomerism
- General
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