Amines
The Gabriel Synthesis
Last updated: September 21st, 2022 |
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”.
1. 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. (Its pKa 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 SN2 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 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.
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
- 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. - 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. - 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. - 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. - 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.
Phthalimide ion have bulky group ,So how can it act as a nucleophile?
The nitrogen atom is not actually that bulky. The entire phthalimide molecule is flat and lies behind the nitrogen. It won’t result in steric hindrance between the nitrogen lone pair and the sigma-star orbital of the alkyl halide.
Why is a strong base needed when that proton is already very acidic?
Good question! The advantage of using NaH is that it is a poor nucleophile and has no chance of reacting with our alkyl halide. (If we used NaOH, for instance, I might worry about performing an SN2 on that alkyl halide).
Another advantage is that it deprotonates the phthalimide irreversibly – there’s no equilibrium – and that the conjugate acid of H(-) is just H2, which bubbles away.
I saw in the litterature that KI or NaI can be used as catalyst for this reaction but I don’t understand how are they reacting. Can someone help me ?
What happens is that the iodide ion (a good nucleophile!) acts as a nucleophile on the alkyl halide, creating an alkyl iodide, (which has a great leaving group), and then this is displaced by the nucleophile in the Gabriel.
My book uses KOH instead of N2H4 for the last step, resulting in the sideproduct of deprotonated phthalic acid. Is one way better?
For introductory organic chemistry purposes, it doesn’t really matter. The mechanism is a little easier to draw out with KOH.
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.