Gabriel Phthalimide Synthesis Mechanism

What is Gabriel Phthalimide Synthesis Reaction?

Gabriel Phthalimide Synthesis Mechanism has 3 steps. The Synthesis is used to get primary amines from primary alkyl halides and is named after the German scientist Siegmund Gabriel.

The reaction has been generalized for applications in the alkylation of sulfonamides and imides & their deprotection in order to obtain amines. Alkylation of ammonia is quite inefficient, therefore it is substituted with phthalimide anion in the Gabriel synthesis.

Synthesis Details

The biggest advantage of using the Gabriel synthesis is the avoidance of over alkylation. A good nucleophile in the form of an imide ion is also formed with the reaction of potassium hydroxide with the phthalimide. The imide ion executes a nucleophilic substitution reaction on the alkyl halide and creates an intermediate – N-alkyl phthalimide. Hydrolysis or Hydrazinolysis of this phthalimide yields a primary alkyl amine. However, aryl amines cannot be prepared via Gabriel synthesis as aryl halides don’t undergo simple nucleophilic substitution.

Gabriel Phthalimide Synthesis Mechanism

Gabriel Phthalimide Synthesis Mechanism

Step 1

When potassium hydroxide is introduced to the phthalimide, an acid-base reaction ensues. The hydroxide ion deprotonates the imide. The resulting proton is more acidic than any simple amine (the two adjacent carbonyl-like groups offer resonance stabilization), generating a strong nucleophile – the imide ion.

Gabriel Phthalimide Synthesis Mechanism

Step 2

The nucleophilic imide ion attacks the electrophilic carbon of the alkyl halide. The nitrogen atom subsequently replaces the halogen (Fluorine, Chlorine, Bromine or Iodine) in the alkyl halide and bonds with the carbon itself. This results in the formation of an N-Alkyl Phthalimide.

Gabriel Phthalimide Synthesis Mechanism

Step 3

The mechanism that takes place here is quite similar to base-catalyzed hydrolysis of esters, with nitrogen attached to the R group instead of oxygen. The hydroxide ion attacks the carbon atom bonded to the nitrogen atom, cleaving the N-Alkyl phthalimide. The cation in the base attaches itself to the oxygen atom as well. It is important to note that the nitrogen atom attached to the R group bonds with the hydrogens ejected from the hydroxide ion when the oxygen atom replaces it in the phthalimide. An example of the third step of the Gabriel phthalimide synthesis mechanism is shown below.

Gabriel Phthalimide Synthesis Mechanism

To conclude, the Gabriel method can be used to get primary amines from phthalimides. The mechanism can also be followed by the use of acidic hydrolysis or hydrazinolysis instead of using an aqueous base (as was shown in the mechanism above). The Gabriel method generally doesn’t work with secondary alkyl halides. Another disadvantage of this synthesis is that using acidic/basic hydrolysis gives a low yield whereas the usage of hydrazine can make the conditions of the synthesis relatively harsh.

Frequently Asked Questions

How is Phthalimide formed?

Phthalimide can be prepared by heating distilled ammonia with phthalic anhydride, which yields 95–97 per cent. Additionally, it may be treated by adding ammonium carbonate or urea to cure the anhydride. Only it can be provided by o-xylene ammoxidation.

What is Gabriel phthalimide reaction?

The Gabriel synthesis is a chemical reaction that transforms primary alkyl halides into primary amines. Traditionally, the reaction uses potassium phthalimide. The name of the reaction comes from the German chemist Siegmund Gabriel.

Can aniline be prepared by Gabriel phthalimide synthesis?

Gabriel’s synthesis can not prepare aniline. Using this process, aniline can not be prepared, because aryl halides do not undergo nucleophilic substitution with the phthalimide-formed anion.

Why are aliphatic amines more basic than ammonia?

Both aliphatic amines are more basic than ammonia but aniline is a poorer base than ammonia owing to the delocalization of the lone pair of nitrogen atom electrons on the benzene ring.

Why secondary amines are more basic?

The further stabilizing factors that are present on a form of amine conjugate acids the more basic it would be. Secondary alkyl amines have two groups of alkyl which stabilize the conjugate acid better (by their electron-donating inductive effect) than primary alkyl amines do, making secondary amines more simple.

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