The Gabriel Synthesis

by James

in Amines

We’ve seen previously that it’s hard to *usefully* build amines through the SN2 reaction, because once amines start reacting with alkyl halides, the products tend to be more nucleophilic than the reactants. In some cases, alkylation doesn’t stop until (relatively useless) ammonium salts are formed.

There is a clever workaround to this – at least for the synthesis of primary amines. It’s called the “Gabriel Synthesis”.

In the Gabriel synthesis we start with a molecule called “phthalimide”. In phthalimide, a nitrogen is flanked by two carbonyl groups. This means that the N-H is a lot more acidic than it normally would be, because the resulting anion will be resonance stabilized.

Once phthalimide is deprotonated with a strong base like NaH, NaNH2, KH (or many others) the next step is to add an alkyl halide. The nitrogen nucleophile will then attack the alkyl halide in an SN2 reaction, and form an N-C bond.

[It’s also possible to just start with conjugate base; potassium phthalimide is commercially available, and cheap]

Here’s the cool thing: because the nitrogen is attached to the two electron withdrawing groups, it’s not nearly as nucleophilic as normal amines. So the reaction stops there! 

The third step is to liberate the amine! This is done through addition of NH2NH2 (hydrazine), which ends up adding to the carbonyl carbon, and through a sequence of steps, the amine ends up as the leaving group.


Bottom line: the Gabriel synthesis is a way to make all kinds of different amines. As long as they’re primary.

So is this actually a decent way to make amines?

It’s OK. Not quite as useful as reductive amination though.

Thanks for reading!  James

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{ 1 comment… read it below or add one }

Victor

Yeah, maybe not the most useful, but represents a noticeable historical significance. Just like making a 2,4-DNPH-ide of a carbonyl. Obsolete, yet, historically important.

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