The Gabriel Synthesis of Primary Alkylamines

Even the tertiary amine competes with ammonia for the alkylating agent. The prodnct is a qnatemary ammonium salt. 

Because alkylation of ammonia can lead to a complex mixture of products, it is used to prepare primary amines only when the starting alkyl halide is not particularly expensive and the desired amine can be easily separated from the other components of the reaction mixture. 

PROBLEM 22.9 Alkylation of ammonia Is sometimes employed in industrial processes the resulting mixture of amines is separated by distillation. The ultimate starting materials for the industrial preparation of allylamine are propene, chlorine, and ammonia. Write a series of equations showing the industrial preparation of allylamine from these starting materials. (Allylamine has a number of uses, including the preparation of the diuretic drugs meralluride and mercaptomerin.) 

Aryl halides do not normally react with ammonia under these conditions. The few exceptions are special cases and will be described in Section 23.5. 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis. Alkyl halides are converted to primary alkylamines without contamination by secondary or tertiary amines. The key reagent is the potassium salt of phthal-imide, prepared by the reaction 

Aryl halides that are substituted with electron-withdrawing groups react with amines by nucleophilic aromatic substitution (see Section 12.19). 

Phthalimide, with a pisTa of 8.3, can be quantitatively converted to its potassium salt with potassium hydroxide. Tlie potassium salt of phthalimide has a negatively charged nitrogen atom, which acts as a nucleophile toward primary alkyl haUdes in a bimolecular nucleophilic substitution (Sn2) process. 

The product of this reaction is an imide, a diacyl derivative of an amine. Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine. A more effective method of cleaving the two amide bonds is by reaction with hydrazine  

Aryl halides cannot be converted to arylamines by the Gabriel synthesis because they do not undergo nucleophilic substitution with A-potassiophthalimide in the first step of the procedure. 

Among compounds other than simple alkyl halides, a-halo ketones, a-halo esters, and alkyl /7-toluenesulfonates have also been used. Because phthalimide can undergo only a single alkylation, the formation of secondary and tertiary amines does not occur, and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines. 

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Gabriel synthesis (Section 22 8) Method for the synthesis of primary alkylamines in which a key step is the formation of a carbon-nitrogen bond by alkylation of the potassium salt of phthalimide... 

Alkylation of phthalimide The Gabriel synthesis (Section 22 8) The potassium salt of phthalimide reacts with alkyl hal ides to give N alkylphthalimide deriva fives Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine... 

SAMPLE SOLUTION (a) The Gabriel synthesis is limited to preparation of amines of the type RCH2NH2, that is, primary alkylamines in which the amino group is bonded to a primary carbon. Butylamine may be prepared from butyl bromide by this method. 

Recently Mukaiyama and Ta chi [244] have reported a new method for the preparation of primary alkylamines which may offer advants es over the Gabriel synthesis (Section 2.1.2.1) for certain applications. Di(phenylsulphenyl)imide (39) readily yields an iV-lithio derivative which may be alkylated with halides orp-toluenesulphonates and subsequently hydrolyzed to give good yields of primary amines. 

Primary alkylamines are also available from alkenes in a simple two-step phosphoramidomercuration-demercuration sequence, and from halides via iV-carbalkoxyphosphoromonoamidates in an alternative to the Gabriel synthesis. The synthesis of N-labelled primary alkylamines has also been described. ... 

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