Ch. 23 - AminesSee all chapters
All Chapters
Ch. 1 - A Review of General Chemistry
Ch. 2 - Molecular Representations
Ch. 3 - Acids and Bases
Ch. 4 - Alkanes and Cycloalkanes
Ch. 5 - Chirality
Ch. 6 - Thermodynamics and Kinetics
Ch. 7 - Substitution Reactions
Ch. 8 - Elimination Reactions
Ch. 9 - Alkenes and Alkynes
Ch. 10 - Addition Reactions
Ch. 11 - Radical Reactions
Ch. 12 - Alcohols, Ethers, Epoxides and Thiols
Ch. 13 - Alcohols and Carbonyl Compounds
Ch. 14 - Synthetic Techniques
Ch. 15 - Analytical Techniques: IR, NMR, Mass Spect
Ch. 16 - Conjugated Systems
Ch. 17 - Aromaticity
Ch. 18 - Reactions of Aromatics: EAS and Beyond
Ch. 19 - Aldehydes and Ketones: Nucleophilic Addition
Ch. 20 - Carboxylic Acid Derivatives: NAS
Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon
Ch. 22 - Condensation Chemistry
Ch. 23 - Amines
Ch. 24 - Carbohydrates
Ch. 25 - Phenols
Ch. 26 - Amino Acids, Peptides, and Proteins
Johnny Betancourt

The Gabriel synthesis is a great way to make primary amines. This alkylation procedure doesn’t produce ammonium salts like the SN2 reaction would. Potassium phthalimide is treated with base, then a primary alkyl halide, and then either hydrazine, acid, or base. 

Overview

The goal of Gabriel synthesis is to create a primary amine (RNH2). Doing a direct SN2 reaction would result in a quaternary amine salt, which can be pretty useless (unless you use Hofmann elimination). Before we get into the mechanism, let’s look at the reaction pathway. 

 Gabriel synthesis summaryGabriel Synthesis Summary

Mechanism

We start off with phthalimide, treat it with base like KOH or NaOH, add an alkyl halide, and then liberate the resulting amine. Let’s break down each step of the mechanism: Nitrogen deprotonationNitrogen deprotonation

In the very first step, the nitrogen of the phthalimide is deprotonated to create potassium phthalimide. Heads up: some professors might just start off with potassium phthalimide and skip the deprotonation step entirely.

Nitrogen alkylationNitrogen Alkylation

Now that the nitrogen has a negative charge, it can act as a nucleophile and perform an SN2 reaction on an alkyl halide. Once that happens, we’re got a primary amine just waiting to be liberated.

Hydrazine nucleophilic acyl substitutionHydrazine Nucleophilic Acyl Substitution

At this point, there are a couple of variations. Usually, hydrazine (NH2NH2) is used, but sometimes acidic hydrolysis or basic hydrolysis is used. We’ll take a look at those mechanisms later. In any case, the nucleophile kicks off the nitrogen through a nucleophilic acyl substitution mechanism.

Intramolecular N-N proton transferIntramolecular N-N Proton Transfer

The protonated hydrazine is then deprotonated by the nitrogen that was just kicked off of one carbonyl. We still need to get the amine off of the second carbonyl, and the NH2 of the hydrazine repeats the process to kick it off.  

Second NASSecond NAS

The unreacted NH2 of the hydrazine then attacks the other carbonyl through another NAS mechanism to finally kick off the amine. Now there is a negative charge and a positive charge, and those need to be taken care of. 

Primary amine formationPrimary Amine Formation

The negative nitrogen deprotonates the positive nitrogen, and drumroll please… we’ve got our primary amine (as well as the cyclic product phthalhydrazide)! In case you want to see the whole mechanism at once, here it is: 

Hydrazine full mechanismHydrazine Full Mechanism


Alternative mechanisms with acid or base

Hydrazine is a very dangerous, reactive molecule. If you’ve seen or read The Martian, you might have an idea of how much care needs to be taken when working with it. Chemists try to minimize the risk of lab accidents, so sometimes they’ll find ways to work without dangerous chemicals like hydrazine. Luckily, the amine liberation portion of this reaction can be done in acidic or basic conditions. 

Acidic hydrolysis

The acidic hydrolysis version of the amine liberation works just like ester or amide hydrolysis, and the phthalimide becomes phthalic acid (o-dicarboxybenzene). Let’s take a look at the mechanism in acidic conditions. The mechanism shows H3O+, which can be made by adding any acid (like HCl) in aqueous solution.  Acidic hydrolysis mechanismAcid Hydrolysis Mechanism

Basic hydrolysis

The mechanism in base is pretty similar to saponification (aka base-catalyzed ester hydrolysis), but with nitrogen instead of an oxygen attached to the R-group.

Basic hydrolysis mechanismBasic Hydrolysis Mechanism

For the record, look at how few steps the hydrazine and basic hydrolysis mechanisms have compared to the acidic version. If you have the choice on an exam, I’d recommend mechanisms with the fewest steps.

This reaction can be used to make tons of different primary amines, including benzylamine, n-butylamine, and many more! 


Johnny Betancourt

Johnny got his start tutoring Organic in 2006 when he was a Teaching Assistant. He graduated in Chemistry from FIU and finished up his UF Doctor of Pharmacy last year. He now enjoys helping thousands of students crush mechanisms, while moonlighting as a clinical pharmacist on weekends.


Additional Problems
Show how you would use Gabriel method to synthesize the amino acid glycine. 
In the Gabriel synthesis, the nitrogen atom comes from phthalimide, which serves as the starting material. The process requires three steps: (1) deprotonation to form potassium phthalimide, (2) nucleophilic attack with an alkyl halide, and (3) hydrolysis. Draw the reagents for all three steps of the Gabriel synthesis. 
Using a Gabriel synthesis, propose an efficient synthesis for the following transformations. Note: You will need to convert the starting material into a suitable alkyl halide that can be used in a Gabriel synthesis.
Using a Gabriel synthesis, propose an efficient synthesis for the following transformations. Note: You will need to convert the starting material into a suitable alkyl halide that can be used in a Gabriel synthesis.
Provide the principal organic product from the following chemical synthesis.
Predict the product(s) for the following reaction.
Complete the following reaction supplying the missing reactant, product or reagent.
Complete the following reaction supplying the missing reactant, product or reagent.
Draw the organic products of the following reaction. Indicate stereochemistry where appropriate. A reasonable answer may be “ No Reaction.”
Provide reagent to complete the following chemical transformation.
Provide the major product for the following transformation.
Predict the product of the following reaction. 
Provide the principal organic product from the following chemical synthesis.