Gabriel synthesis

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

The Gabriel reaction has been generalized to include the alkylation of sulfonamides and imides, followed by deprotection, to obtain amines (see #Alternative Gabriel reagents).[5][6]

The utility of the method is based on the fact that the alkylation of ammonia is an unselective and inefficient route to amines in the laboratory (on an industrial scale, the alkylation of ammonia is, however, widely employed). The conjugate base of ammonia, sodium amide (NaNH2), is more basic than it is nucleophilic. In fact, sodium amide is used to deliberately obtain the dehydrohalogenation product.[7]

Traditional Gabriel synthesis[edit]

In this method, the sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide to give the corresponding N-alkylphthalimide. The reaction fails with most secondary alkyl halides:

The Gabriel synthesis

Upon workup by acidic hydrolysis the primary amine is liberated as the amine salt.[8] 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 phthalhydrazide can be unpleasant. For these reasons, other methods for liberating the amine from the phthalimide exist.[9] Even with the use of the hydrazinolysis method, the Gabriel method suffers from relatively harsh conditions.


Mechanism of the Gabriel synthesis

Alternative Gabriel reagents[edit]

Many alternative reagents have been developed to complement the use of phthalimides. Most such reagents, e.g. the sodium salt of saccharin, are electronically similar to the phthalimide salts. In terms of their advantages, some such alternative reagents hydrolyze more readily, extend the reactivity to secondary alkyl halides, and allow the production of secondary amines.[6]

References[edit]

  1. ^ Sheehan, J. C.; Bolhofer, V. A. (1950). "An Improved Procedure for the Condensation of Potassium Phthalimide with Organic Halides". J. Am. Chem. Soc. 72 (6): 2786. doi:10.1021/ja01162a527. 
  2. ^ Gibson, M.S.; Bradshaw, R.W. (1968). "The Gabriel Synthesis of Primary Amines". Angew. Chem. Int. Ed. Engl. 7 (12): 919. doi:10.1002/anie.196809191. 
  3. ^ Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79–85. (Review)
  4. ^ Gabriel, S. (1887). "Ueber eine Darstellung primärer Amine aus den entsprechenden Halogenverbindungen". Ber. 20: 2224. doi:10.1002/cber.18870200227. 
  5. ^ Hendrickson, J (1975). "New "Gabriel" syntheses of amines". Tetrahedron 31 (20): 2517. doi:10.1016/0040-4020(75)80263-8. 
  6. ^ a b Ulf Ragnarsson, Leif Grehn (1991). "Novel Gabriel Reagents". Acc. Chem. Res. 24 (10): 285–289. doi:10.1021/ar00010a001. 
  7. ^ P. J. Ashworth, G. H. Mansfield, and M. C. Whiting, "2-Butyn-1-ol", Org. Synth. ; Coll. Vol. 4: 128 
  8. ^ Khan, M. N. (1995). "Kinetic Evidence for the Occurrence of a Stepwise Mechanism in the Hydrazinolysis of Phthalimide". J. Org. Chem. 60 (14): 4536. doi:10.1021/jo00119a035. 
  9. ^ 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. 

External links[edit]