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SolutionsAlkylation

1. A synthetic scheme with enamines

Fill the blanks in the following synthetic scheme:

Scheme with blanks: acetone with pyrrolidine (Dean-Stark), 1,3-dibromopropane and H₃O⁺, pyrrolidine again, an intermediate in brackets, H₃O⁺, pyrrolidine and finally benzyl iodide and H₃O⁺
  1. Acetone and pyrrolidine, with removal of water (Dean-Stark apparatus): enamine, 1-(prop-1-en-2-yl)pyrrolidine.
  2. The enamine is alkylated by one end of 1,3-dibromopropane and, after acid hydrolysis, gives 6-bromo-2-hexanone.
  3. With pyrrolidine an enamine forms again. The one with the double bond towards the terminal CH3 attacks the carbon bearing bromine in its own chain: an intramolecular alkylation that closes a six-membered ring. The product in brackets is the iminium salt of cyclohexanone (1-cyclohexylidenepyrrolidinium bromide).
  4. Acid hydrolysis gives cyclohexanone.
  5. With pyrrolidine the enamine of cyclohexanone, 1-(cyclohex-1-en-1-yl)pyrrolidine, forms.
  6. Alkylation with benzyl iodide and hydrolysis give 2-benzylcyclohexanone.

Enamines are neutral equivalents of enolates: they are alkylated at the α carbon by reactive alkyl halides and the final hydrolysis recovers the carbonyl (Stork alkylation).

2. Kinetic and thermodynamic enolate

Which main product is obtained when 2-methylcyclohexanone is alkylated with methyl iodide under these conditions: a) LDA at −78 °C and then CH3I; b) NaOEt in refluxing ethanol and then CH3I?

  1. 2,6-Dimethylcyclohexanone: bulky LDA at low temperature removes the most accessible proton and forms the less substituted enolate (kinetic control).
  2. 2,2-Dimethylcyclohexanone: under equilibrium conditions the more substituted, more stable enolate predominates (thermodynamic control).

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