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SolutionsNucleophilic Substitution

1. Gabriel synthesis

Write the steps of the Gabriel synthesis of 2-phenylethylamine from (2-bromoethyl)benzene.

  1. Phthalimide (pKa 9) is deprotonated with KOH to give potassium phthalimide.
  2. The anion attacks the C–Br by SN2 to form N-(2-phenylethyl)phthalimide.
  3. Hydrazine (or hydrolysis) releases 2-phenylethylamine, C6H5CH2CH2NH2, and phthalhydrazide.

The nitrogen of the alkylated phthalimide is no longer nucleophilic (its lone pair is delocalized over two carbonyls), so there is no polyalkylation.

2. Does it work?

State whether these reactions are useful to prepare the amine and why:

  1. Potassium phthalimide + 2-bromo-2-methylpropane
  2. NaN3 + cyclohexyl bromide, then LiAlH4
  3. Potassium phthalimide + bromobenzene
  1. No: the halide is tertiary and elimination (isobutene) takes place instead of SN2.
  2. Yes: azide is a good, weakly basic nucleophile and the product is reduced to cyclohexylamine; with a secondary substrate some elimination may compete.
  3. No: an aryl halide does not undergo SN2.

3. Cyclization

What product is formed when 4-chloro-1-butanamine, Cl(CH2)4NH2, is treated with triethylamine? Why is it favourable?

Pyrrolidine (a five-membered cyclic amine). The reaction is an intramolecular SN2: five- and six-membered rings form quickly because the chain ends meet easily and the ring is not strained. Et3N neutralizes the HCl formed.

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