The Gabriel synthesis of amines

by James

Description: The Gabriel synthesis is a method for making primary amines through an SN2 reaction of a phthalimide with an alkyl halide followed by cleavage with hydrazine (NH2NH2).
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Notes: A number of bases can be used for this reaction; it’s common to use sodium hydride (NaH) or potassium hydride (KH), although sometimes other bases are used.

Examples: 

Notes: Note that it’s possible to use the potassium or sodium salt of phthalimide with the alkyl halide, instead of adding the base first (examples 1 and 2). It doesn’t matter whether phthalimide is written above or below the arrow.

Mechanism: If a base is used with phthalimide, deprotonation occurs first (Step 1, arrows A and B). This forms the anion, which then performs an SN2 reaction on the primary alkyl halide (Step 2, arrows C and D) to give the alkylated phthalimide.

The second step is hydrolysis of the phthalimide. It’s not common to be asked to draw out the whole mechanism for cleavage, but here is a suggestion. Addition of nucleophilic hydrazine (NH2NH2) to the carbonyl carbon (Step 1, arrows A and B) results in a tetrahedral intermediate, which undergoes proton transfer (Step 2, arrows C and D). Elimination of the amide (Step 3, arrows E and F) results in a resonance-stabilized amide anion (only one resonance form shown) which then undergoes proton transfer (Step 4, arrows G and H). Addition of the hydrazine NH2 to the carbonyl (Step 5, arrows I and J) results in another tetrahedral intermediate which undergoes proton transfer (Step 6, arrows K and L) resulting in a protonated nitrogen, which is eliminated by oxygen to give the free amine (Step 7, arrows M and N).

Notes: Note in Step 6 of the cleavage that the proton is transferred to the nitrogen; it’s important that the amine leaves as the neutral amine and not RNH(–), which would be a very strong base (and a poor leaving group)!
It’s possible to show other mechanisms for proton transfer; the “intramolecular” version has been shown to save space.

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{ 2 comments… read them below or add one }

Shirin Pillai November 21, 2014 at 10:50 pm

Hi,
When would you use Gabriel vs Azide to make a primary amine in synthesis?

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James December 2, 2014 at 7:29 am

Great question! For uncomplicated molecules without a lot of different functional groups, they both work.

From a practical standpoint, N3- tends to get more use.

N3- tends to be a better nucleophile (faster rxn) than potassium phthalimide. Also, reduction of N3 to NH2 can be done many different ways (Pd-C/H2, LiAlH4, etc) and only blows off N2, whereas cleavage of the phthalimide necessitates getting rid of the byproduct.

For your purposes though – either one is probably fine!

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