Gabriel Phthalimide Reaction: Definitions, Siegmund Gabriel, Mechanism, Reagents, Applications, Limitations, Acid and Basic Hydrolysis

Gabriel Phthalimide Reaction Overview

The Gabriel Phthalimide Synthesis Mechanism consists of three stages. The Synthesis is named for the German chemist Siegmund Gabriel and is used to get primary amines from primary alkyl halides. 

Who is Siegmund Gabriel?

Siegmund Gabriel was a German chemist who lived from November 7, 1851, to March 22, 1924. In 1871, Siegmund Gabriel enrolled at the University of Berlin to study chemistry. In 1872, he resumed his studies with Professor Robert Wilhelm Bunsen at the University of Heidelberg. He obtained his degree in 1874 and returned to Berlin. He began as an assistant in the Department of Inorganic Chemistry before becoming an associate professor in 1886. Gabriel's own studies eventually led him to organic chemistry.

Gabriel Phthalimide Reaction Highlights

The following table gives details about the Gabriel Phthalimide synthesis reaction-

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What is Gabriel Phthalimide Synthesis?

Gabriel Synthesis was developed in 1887 by German scientist Siegmund Gabriel and his colleague James Dornbush. The Gabriel Phthalimide Reaction is a chemical process that converts primary alkyl halides into primary amines. Traditionally, potassium phthalimide is used in the process; Siegmund Gabriel, a German scientist, inspired the reaction's name. The Gabriel reaction has been broadened to include the alkylation of sulfonamides and imides followed by deprotection to produce amines. Ammonia alkylation is frequently an unselective and inefficient approach to amines. The Gabriel technique employs phthalimide anion as a substitute for H₂N.

Example of Gabriel Phthalimide Reaction

Chloroethane may be converted to ethylamine via the Gabriel synthesis. The following diagram shows the example of Gabriel Phthalimide Synthesis reaction-

Traditional Gabriel Phthalimide Reaction

The sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide in this process to yield the equivalent N-alkyl phthalimide. The main amine is freed as the amine salt during acidic hydrolysis. Alternatively, the Ing-Manske approach, which involves a hydrazine reaction, might be used. This procedure yields a phthalhydrazide (C₆H₄(CO)₂N₂H₂) precipitate along with the main amine-

C₆H₄(CO)₂NR + N₂H₄→ C₆H₄(CO)₂N₂H₂+ RNH₂

Gabriel synthesis is usually unsuccessful with secondary alkyl halides. The first procedure frequently results in low yields or byproducts. The separation of phthalhydrazide might be difficult. Other methods for releasing the amine from the phthalimide have been devised as a result of these factors. Even when using the hydrazinolysis process, the Gabriel method is subjected to relatively rigorous circumstances.

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Gabriel Phthalimide Reaction Mechanism

The reaction process may be broken down into three major steps-

Step 1

The first step is to add potassium hydroxide to phthalimide, which causes an acid-base reaction in which the hydroxide ion removes a hydrogen atom from the imide, resulting in the production of a more acidic proton compared to a simple amine. The presence of two contiguous carbonyl-like groups in the imide, which offer resonance stabilization, accounts for the elevated acidity. As a result, the resultant imide ion is an effective nucleophile. 

Step 2

An N-alkyl phthalimide is generated in the second phase of the Gabriel synthesis. This includes the nucleophilic imide ion attacking the electrophilic carbon in the alkyl halide, leading to the substitution of the halogen atom (fluorine, chlorine, bromine, or iodine) with the nitrogen atom. The nitrogen atom becomes bound to the carbon atom as a result of this reaction, resulting in the production of an N-alkyl phthalimide. 

Step 3

The R group connects with the nitrogen atom in the third stage, which is similar to the base-catalyzed hydrolysis of esters except that the resultant bond is between nitrogen and the R group rather than oxygen and nitrogen. The hydroxide ion in potassium hydroxide then targets the carbon atom, causing the N-alkyl phthalimide to break apart and form a primary amine. 

The stages of the Gabriel phthalimide production procedure are illustrated below-

Applications for Gabriel Phthalimide Reaction

The Gabriel phenylpiperazine synthesis is used to make primary amines. This Gabriel phthalimide synthesis reaction has been widely used for sulfonamide and imide alkylation, as well as deprotection (the removal of a protective group) to generate amines.

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Alternative Gabriel Phthalimide Reaction Reagents

Many additional reagents have been developed to augment the use of phthalimides. The sodium salts of saccharin and di-tert-butyl-iminodicarboxylate, for example, are electrically similar to phthalimide salts, which are composed of imido nucleophiles. These chemicals have the advantage of hydrolyzing more quickly, expanding reactivity to secondary alkyl halides, and permitting secondary amine production. 

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Gabriel Phthalimide Reaction involving Acid Hydrolysis

Gabriel synthesis begins with the formation of H₃O+ ions in an aqueous solution by the addition of any acid. The hydronium ion protonates one of the carbonyl groups of phthalimide, resulting in the addition of water and the cleaving of N-alkyl phthalimide. The charge on the molecules is then developed by another molecule of nucleophilic water attacking the other carbon in carbonyl carbon. This additional charge causes RNH₂ to separate from carbonyl carbons. The Gabriel synthesis concludes with the replacement of RNH₂ by OH from the N-alkyl phthalimide, resulting in the production of an amine.

Gabriel Phthalimide Reaction involving Basic Hydrolysis

The Gabriel phthalimide reaction begins with an OH- attack on one of the carbonyl carbons. By nucleophilic substitution, the OH ion attacks the carbon of the carbonyl group. This causes N-alkyl phthalimide tocleave. The oxygen atom of the carbonyl group receives a negative charge during this reaction. Another OH ion molecule attacks the second carbonyl group. RNH₂ detaches from carbonyl carbon as a result of the charge transfer between nucleophiles and electrophiles to obtain stability and neutralize molecules. O- ions replace nitrogen. This signals the conclusion of the nucleophilic substitution process and, with it, the synthesis of Gabriel phthalimide.

Limitations of Gabriel Phthalimide Reaction

The limitations of Gabriel Phthalimide Synthesis are as follows-

1. Only primary alkyl amines may be formed using the Gabriel phthalimide synthesis process. 
2. It cannot be converted into a secondary or tertiary amine. 
3. The Gabriel Phthalimide Reaction cannot be used to create aryl amine.

Points to Remember

1. Primary amines are synthesized using the Gabriel Phthalimide Synthesis Reaction.
2. Primary alkyl halides are employed in the Gabriel Phthalimide Reaction to produce primary amines. Phthalimide is also used in the production of primary amide.
3. The hydroxide ion dehydrogenates the imide when phthalimide and potassium hydroxide are combined. This results in the formation of a powerful nucleophile.
4. The nucleophilic amide ion attacks the electrophilic carbon in the alkyl halide. 
5. The nitrogen atom replaces the halogen in the alkyl halide. The nitrogen atom forms a connection with the carbon atom, resulting in the formation of N-alkyl phthalimide.
6. The nitrogen atom binds to the R group, while the carbon atom is attacked by the potassium hydroxide ion. 
7. Finally, the N-alkyl phthalimide separates.