The Gabriel Synthesis

The Gabriel Synthesis For Making Primary Amines

We’ve seen previously that it’s hard to *usefully* build amines through the S_N2 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”.

1. The Gabriel Synthesis Uses A “Protected” Amine (Phthalimide) In An S_N2 Reaction That Does Not Undergo Over-Alkylation

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. (Its pK_a is 8.3 )

A common choice of base is a hydride base such as KH, which results in potassium phthalimide and a molecule of hydrogen (H₂).

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

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 S_N2 reaction, and form an N-C bond.

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! 

2. After The S_N2 Reaction, The Amine Is Liberated Through Addition Of NH₂NH₂ (Hydrazine)

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.

Here are some specific examples.

So is this actually a decent way to make amines?

It’s OK. Not nearly as useful as reductive amination though. Now that’s generally the best way to go.

Notes

Quiz Yourself!

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Further Reading

1. Entsprechenden Halogenverbindungen
   S. Gabriel Chem. Ber. 1887, 20 (2), 2224-2236
   DOI: 10.1002/cber.18870200227
   The original paper by Siegmund Gabriel on the synthesis of primary amines using phthalimide.
2. γ-AMINOBUTYRIC ACID
   C. DeWitt
   Org. Synth. 1937, 17, 4
   DOI: 10.15227/orgsyn.017.0004
   This procedure in Organic Syntheses, a source of reliable and independently tested synthetic organic reactions, is a slight variation of the Gabriel amine synthesis, using acid to hydrolyze the phthalimide and liberate the primary amine.
3. An Improved Procedure for the Condensation of Potassium Phthalimide with Organic Halides
   John C. Sheehan, William A. Bolhofer
   J. Am. Chem. Soc. 1950, 72 (6), 2786-2788
   DOI: 10.1021/ja01162a527
   This paper shows that DMF (N,N-dimethylformamide) is a suitable solvent for the first step of the Gabriel amine synthesis.
4. Novel Gabriel reagents
   Ulf Ragnarsson, Leif Greh
   Acc. Chem. Res. 1991, 24 (10), 285-289
   DOI: 10.1021/ar00010a001
   This account covers alternatives to phthalimide that can be used in the Gabriel amine synthesis.
5. The Gabriel Synthesis of Primary Amines
   Gibson, M. S.; Bradshaw R. W. Chem. Int. Ed. 1968, 7 (12), 919-930
   DOI: 10.1002/anie.196809191
   An older, but still useful review, on the scope and limitations of the Gabriel amine synthesis.