CHEM3038

• Conjugate (1,4) addition:

  • Thermodynamic control
  • Sterically unhindered system
  • Soft nucleophile (S, P, N)

  
• Direct (1,2) addition:

  • Kinetic control
  • Sterically hindered beta carbon
  • Hard nucleophile (O)

  
• Michael addition occurs in nucleotides, where the beta carbon/nitrogen (Michael acceptor) is under attack by nucleophiles or enolates Michael donor).

  
• Epoxides can be formed with mCPBA, or hydrogen peroxide in base.

  
• Amines give reversible addition to carbonyl groups - stable under equilibrium conditions.

  
• Nucleophilic addition by alcohols can be done under acid or base catalysis.

  
• The Robinson Annulation can be used to synthesise molecules such as hormones.

  • Base catalysis
  • Combination of aldol and Michael addition
  • Trans compounds disfavoured due to final aldol condensation

  
• SNAr is a second order reaction that is faster if there are multiple -M groups ortho or para to the leaving group.

  
• Enol formation is either acid or base catalysed.

  • Bases include MeOH, LDA and NEt3

  
• Enols can form in nitrogenous compounds, forming either iminium ions or enamines.

  
• Alkyl nitriles can be reacted with MeOH and a primary amine in acid to make a peptide bond.

  
• Alkylation of beta dicarbonyls is done via the enolate and alkyl iodide compounds.

  
• Removal of water from an aldol reaction product will give an alpha-beta unsaturated carbonyl via an E1 elimination.

  
• Cyclisation of polyketide chains can be simplified as the Dieckmann condensation.

  
• The Mannich reaction is a reaction between a carbonyl, formaldehyde and primary or secondary amine to from a beta amino carbonyl.

  • Nucleophilic addition of amine to carbonyl
  • Dehydration to the Schiff base
  • Electrophilic addition to the enol formed at the acidic alpha proton

  
• Decarboxylation can be conducted in acid with heat applied.

  
• The stability of carbenium ions is increased by:

  • Delocalisation (pi bonds in conjugation with vacant p-orbital)
  • Tertiary > secondary > primary
  • Substituents with electron donating groups
  • Adjacent heteroatoms with a lone pair
• SN2 is more likely to occur with less steric hindrance.

  
• SN1:

  • Loss of stereochemistry
  • Poor nucleophile
  • Requires a polar solvent

  
• SN2:

  • Inversion of configuration
  • Requires good nucleophile
  • Little solvent effect, except accelerated by polar aprotic solvents

  
• Neighbouring group participation is able to stabilise carbocations.

  
• Rearrangements such as alkyl shifts are used to synthesise terpenes.

  1. Identify the group that leaves
  2. Identify the group that migrates

  
• The neighbouring group that migrates in rearrangements is the one that will form the most stable carbenium ion.

  
• C-C or C-H bonds will tend to migrate antiperiplanar to the C-LG bond. This is affected by axial and equatorial substituents (axial will migrate to axial and vice versa).

  
• The Baeyer-Villiger rearrangement:

  • Reagent is peracid e.g., mCPBA
  • Migration gives insertion of O into acyl-carbon bond
  • Retention of migrating group geometry

  
• The Bayer-Villiger rearrangement is often used for indirectly hydroxylating aromatic rings. This can form cyclic esters or lactones, where the secondary carbon migrates in preference to primary.

  
• E1 elimination:

  • Carbenium stability important - formed in the RDS (tertiary orbitals overlap to stabilise)
  • Not stereospecific but stereoselective
  • C-H sigma bond must be lined-up with p orbital

  
• E2 elimination:

  • Rate depends on leaving group and base strength
  • Steric hindrance relatively unimportant as hydrogens are usually accessible (removes least hindered proton)
  • Stereospecific due to requirement for orbital alignment

  
• Formation of C-C bonds with radicals:

  • Requires Bu3SnH and an initiator (AIBN)
  • Termination by H atom abstraction or radical recombination