Gabriel Phthalimide Synthesis Mechanism

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. Click here to learn about more named reactions relevant to CBSE class 12 chemistry.

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