Gabriel synthesis
Summary
The Gabriel synthesis makes a primary amine from a primary alkyl halide: the phthalimide anion attacks by SN2, then hydrolysis or hydrazine releases R–NH₂. Its testable advantage is that it avoids the overalkylation seen when NH₃ is alkylated directly.
Detail
Meaning: The Gabriel synthesis converts a primary alkyl halide (R–X) into a primary amine (R–NH₂) without overalkylation. Step 1: a base such as KOH removes the N–H proton of phthalimide, which is acidic because the nitrogen sits between two carbonyls and the anion is resonance-stabilized. Step 2: this anion attacks R–X by SN2, giving N-alkylphthalimide. Step 3: hydrolysis with aqueous acid or base, or treatment with hydrazine (N₂H₄), releases R–NH₂. Two acyl groups occupy the nitrogen, so it cannot be alkylated again.
On the MCAT: Expect a question asking for the reagents or product of a route to a primary amine, often contrasted with NH₃ plus R–X, which gives a mixture of primary, secondary, and tertiary amines and quaternary ammonium salts. Because step 2 is SN2, methyl and primary halides work best; secondary halides react poorly, and tertiary and aryl halides do not give product this way.
Common confusion: Students sometimes expect an extra carbon (that is the cyanide route: R–X + CN⁻, then reduction gives R–CH₂NH₂) or expect a secondary amine. The Gabriel synthesis gives R–NH₂ with the same R group as the halide.
Sources
- Organic Chemistry (Wade)
- Organic Chemistry (McMurry)
- Organic Chemistry (Clayden, Greeves, Warren)
Written for the MCAT and checked before it was published. For study reference only. Spotted an error? Let us know.