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Amines

By James Ashenhurst

The Gabriel Synthesis

Last updated: June 25th, 2019 |

The Gabriel Synthesis For Making Primary 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”.

The Gabriel Synthesis Uses A “Protected” Amine (Phthalimide) In An SN2 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.

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! 

After The SN2 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.

So is this actually a decent way to make amines?

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


Further Reading

  1. entsprechenden Halogenverbindungen
    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.

Comments

Comment section

1 thought on “The Gabriel Synthesis

  1. 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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