L20 - Aromatics and Alkenes

• What is meant by alpha-beta unsaturation?

  
  

  Eg alkenes, ketones, aldehydes etc...)

  Conjugated system (double, single, double bond) including C=O group

  
  

  (aka enones)

  
• How can nucleophiles react with enones?

  - e-s move from high to low density

  - enones are electrophilic at both alpha and beta carbons

  1,2 addition OR 1,4 addition (conjugate addition)

  
• 1,2 Addition (direct addition)

  term-3

  - mechanism?

  - which func groups are likely to undergo 1,2 addition?

  Rank order of reactivity - most reactive func groups are more likely to react 1,2, eg acyl chlorides/acid anhydrides

  
• 1,4 Addition (conjugate addition)

  
  

  - mechanism?

  - which func groups are likely to undergo conjugate addition (1,4)?


  - groups with lower reactivities eg amides - less reactive to 1,2 but can undergo 1,4

  
• Which factors influence whether it's 1,4 or 1,2 addition?

  - type of nucleophile

  - type of electrophile (eg rank order of reactivity!)

  - type of solvent

  
• Glutathione


  - what is it? what three amino acids?- what does it do and how?- where is it commonly found?- Tripeptide: glutamate, cysteine, glycine

  - Detoxifies alpha-beta unsaturated toxic compounds

  - acts as Nu in body to remove harmful oxidants

  = sacrificial strong Nu to react with toxic electrophiles before they can react with key nucleophiles. Eg, DNA bases are all nucleophilic

  - commonly found in liver where there are many metabolites which need detoxifying

  
• Why are alpha-beta unsaturated carbonyls toxic?

  Bc they're electrophilic at two positions - very potent electrophiles

  
  

  Potent electrophiles are toxic bc we are mostly made of basic residues (nucleophiles! - eg DNA/proteins are all nucleophilic)

  
  

  - can undergo 1,4 addition easily

  
• EG: Paracetamol overdose

  
  

  - Why so toxic?

  - Bc paracetamol is metabolised into a compound with lots of alpha beta unsaturation, so is a very potent electrophile. Lots of places to undergo electrophilic addition.

  
  

  - metabolite is detoxified by GSH in liver (glutathione)

  - GSH gets used up quickly, leading to necrosis (tissue death)