Alkyl Halide Reactions: Amine Formation (Gabriel Synthesis)

The Gabriel Synthesis is a widely used method for preparing primary amines from alkyl halides. The reaction occurs when an alkyl halide is reacted with phthalimide, a strong base (such as NaOH or KOH), followed by a reaction with hydrazine (NH2NH2) in a basic or acidic environment. This reaction is known for its ability to selectively produce primary amines without forming secondary or tertiary amines.

Alkyl bromides and chlorides work best as those two haldies are among the best leaving groups.

Mechanism

The mechanism for this reaction is presented below:

In the first step, the OH group from whichever strong base is used reacts with phthalimide to prime it for the next step by removing the hydrogen from the nitrogen atom. This allows the pi electrons to form a double bond with the nearby carbonyl carbon, sending the pi electrons from the carbonyl bond to the oxygen atom.

In the second step, the pi electrons from the N=C bond react with the alkyl halide, displacing the halide atom and forming a new bond with the alkyl group and nitrogen. The negatively charged oxygen atom then sends its pi electrons down to the carbon, thereby reforming the carbonyl bond.

In the third step, the hydrazine attacks the carbonyl carbon, which breaks the bond between the nitrogen atom and carbonyl carbon, breaking the ring. The carbonyl carbon accomodates this by quickly sending the pi electrons to the oxygen atom, which then reform the double bond shortly after the ring breaks.

In the fourth step, an intermolecular reaction occurs between the newly negatively charged nitrogen atom and one of the hydrogen atoms on the hydrazine moiety.

In the fifth step, the second nitrogen on the hydrazine moiety attacks the other carbonyl carbon in a similar fashion as before, but this time cleaving off the former alkyl-halide alkyl group that now has a nitrogen. A new ring structure is formed with both hydrazine nitrogens as part of the newly formed ring.

In the sixth and final step, the recently cleaved alkyl-amine molecule has its negatively charged nitrogen pull off one of the hydrazine hydrogen atoms, which forms an amine and completes the Gabriel Synthesis.

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