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Gabriel synthesis

Method for the synthesis of primary amines

Method for the synthesis of primary amines

The Gabriel synthesis is a chemical reaction that transforms primary alkyl halides into primary amines. Traditionally, the reaction uses potassium phthalimide.{{cite journal

:[[File:Gabriel Synthese 1 Überblick4.svg]]

The Gabriel reaction has been generalized to include the alkylation of sulfonamides and imides, followed by deprotection, to obtain amines (see Alternative Gabriel reagents).

The alkylation of ammonia is often an unselective and inefficient route to amines. In the Gabriel method, phthalimide anion is employed as a surrogate of H2N−.

Traditional Gabriel synthesis

In this method, the sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide to give the corresponding N-alkylphthalimide. This step is an SN2 reaction; the Gabriel synthesis generally fails with secondary alkyl halides unless they are especially reactive. Upon workup by acidic hydrolysis the primary amine is liberated as the amine salt. Alternatively the workup may be via the Ing–Manske procedure, involving reaction with hydrazine. This method produces a precipitate of phthalhydrazide along with the primary amine:

:[[File:Gabriel, Hydrazinolyse.svg|450px]]

The acid-hydrolysis technique often produces low yields or side products. Separation of phthalhydrazide byproduct of the hydrazine technique can be challenging. For these reasons, other methods for liberating the amine from the phthalimide have been developed.{{cite journal| title = An Exceptionally Mild Deprotection of Phthalimides

Alternative Gabriel reagents

Many alternative reagents have been developed to complement the use of phthalimides. Most such reagents (e.g. the sodium salt of saccharin and di-tert-butyl-iminodicarboxylate) are electronically similar to the phthalimide salts, consisting of imido nucleophiles. In terms of their advantages, these reagents hydrolyze more readily, extend the reactivity to secondary alkyl halides, and allow the production of secondary amines.

References

References

  1. (1968). "The Gabriel Synthesis of Primary Amines". [[Angew. Chem. Int. Ed. Engl.]].
  2. Mitsunobu, O. ''Compr. Org. Synth.'' '''1991''', ''6'', 79–85. (Review)
  3. S. Gabriel. (1887). "Ueber eine Darstellung primärer Amine aus den entsprechenden Halogenverbindungen". [[Chemische Berichte]].
  4. (2007). "Advanced Organic Chemistry: Part B: Reactions and Synthesis". Springer.
  5. (1975). "New "Gabriel" syntheses of amines". Tetrahedron.
  6. (1991). "Novel Gabriel Reagents". [[Acc. Chem. Res.]].
  7. T. O. Soine and M. R. Buchdahl "β-Bromoethylphthalimide" Org. Synth. 1952, volume 32, 18. {{doi. 10.15227/orgsyn.032.0018
  8. C. C. DeWitt "γ-Aminobutyric Acid" Org. Synth. 1937, volume 17, 4. {{doi. 10.15227/orgsyn.017.0004
  9. Richard H. F. Manske "Benzyl Phthalimide" Org. Synth. 1932, volume 12, 10. {{doi. 10.15227/orgsyn.012.0010
  10. M. N. Khan. (1995). "Kinetic Evidence for the Occurrence of a Stepwise Mechanism in the Hydrazinolysis of Phthalimide". [[J. Org. Chem.]].
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