Gabriel synthesis

The Gabriel synthesis, named for the German chemist Siegmund Gabriel, is a chemical reaction that transforms primary alkyl halides into primary amines using potassium phthalimide.^[1][2][3][4]

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The sodium or potassium salt of the product reacts with a primary alkyl halide to form an alkyl phthalic imide. The reaction fails with secondary alkyl halides.

Upon workup by acidic hydrolysis the primary amine is liberated as the amine salt.^[5] Alternatively the workup may be via the Ing-Manske procedure, involving reaction with aqueous or ethanolic hydrazine at reflux. This produces a precipitate of phthalhydrazide along with the primary amine. The first technique often produces bad yields or side products; separation of phtalhydrazide can be unpleasant. For these reasons, other methods for liberating the amine from the phthalimide exist.^[6]

References

1. ^ Gabriel, S. (1887). "Ueber eine Darstellung primärer Amine aus den entsprechenden Halogenverbindungen". Ber. 20: 2224.
2. ^ Sheehan, J. C.; Bolhofer, V. A. (1950). "An Improved Procedure for the Condensation of Potassium Phthalimide with Organic Halides". J. Am. Chem. Soc. 72: 2786. doi:10.1021/ja01162a527.
3. ^ Gibson, M.S.; Bradshaw, R.W. (1968). "The Gabriel Synthesis of Primary Amines". Angew. Chem. Int. Ed. Engl. 7: 919. doi:10.1002/anie.196809191.
4. ^ Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85. (Review)
5. ^ Khan, M. N. (1995). "Kinetic Evidence for the Occurrence of a Stepwise Mechanism in the Hydrazinolysis of Phthalimide". J. Org. Chem. 60: 4536. doi:10.1021/jo00119a035.
6. ^ Osby, J. O.; Martin, M. G.; Ganem, B. (1984). "An Exceptionally Mild Deprotection of Phthalimides". Tetrahedron Lett. 25 (20): 2093. doi:10.1016/S0040-4039(01)81169-2.