Gabriel Synthesis - Online Tutor, Practice Problems & Exam Prep

The Gabriel synthesis is an efficient method for producing primary amines using potassium thalamide, KOH, a primary alkyl halide, and hydrazine (N2H4). The process involves deprotonation of thalamide to form a strong nucleophile, followed by an SN2 reaction with the alkyl halide. The final step involves hydrazine, which facilitates the release of the primary amine through nucleophilic acyl substitution, ensuring high yields without polyalkylation issues. This method is advantageous for synthesizing specific primary amines with minimal side products.

General Reaction

Let's talk about a really efficient way to make primary amines and that's through the Gabriel synthesis. So guys, the Gabriel synthesis is going to use a really weird looking molecule called potassium thalamide. Now I know that's like a lot of consonants at the beginning. You could kind of get jumbled up there. But just consider the pH almost to be silent. It's thalamide but it's like I don't know. You got to move your lips a little bit weird on that one. Anyway, the point here being that you need to be able to recognize this molecule, not necessarily draw it from scratch. The potassium thalidomide is a secondary diamide that can yield primary amines in much better yield. Obviously, I'm talking about something that we haven't mentioned yet. In much better yield in respect to what? What is it better at making primary amines at than what's the other reaction that we're comparing it to? What I'm talking about here is amine alkylation. If you haven't watched this video yet, it's fine. But basically, amine alkylation and Gabriel synthesis kind of very inefficient, amine alkylation whereas Gabriel synthesis is much more efficient. If you haven't watched amine alkylation yet, then you can go ahead and review it. But just letting you know, that's what I'm referring to. This is going to be really our ideal way to make specific primary amines of our choosing. What you do is you take your potassium thalidomide or just thalidomide in general and you're going to use 3 reagents. You're going to use KOH. We're going to use an alkyl halide. I'm going to put here a primary alkyl halide. That's going to become important in a second. I'm going to put here R X , a primary alkyl halide. Then finally, we're going to use hydrazine. It's NH₂NH₂. It's called hydrazine. Effectively, what winds up happening is that these all serve like their own purpose. The KOH is going to deprotonate the nitrogen and it's going to turn the thalidomide into what we call potassium thalidomide. Potassium thalidomide would actually be what it's called after the first step. It'd have an N - K+ . This happens to be an excellent nucleophile because if you think about it, N - , that's one of the strongest bases that there is. It's going to be pretty good at deprotonating stuff, attacking stuff, etc. I'm going to put here strong nucleophile. What's great about that is that now I can react this with an alkyl halide. Let's say a primary alkyl halide like here we go. A 3 carbon alkyl halide. What we can do guys is just an SN2. This is just another SN2 mechanism that you need to know. You can never forget the backside attack. Vi

Here’s what students ask on this topic:

What is the Gabriel synthesis and why is it used?

The Gabriel synthesis is a method used to produce primary amines efficiently. It involves the use of potassium phthalimide, KOH, a primary alkyl halide, and hydrazine (N₂H₄). The process includes three main steps: deprotonation of phthalimide to form a strong nucleophile, an SN2 reaction with the alkyl halide, and the release of the primary amine through nucleophilic acyl substitution facilitated by hydrazine. This method is preferred because it avoids polyalkylation and ensures high yields of specific primary amines with minimal side products.

What reagents are required for the Gabriel synthesis?

The Gabriel synthesis requires three main reagents: potassium phthalimide, KOH (potassium hydroxide), and a primary alkyl halide (denoted as R-X). Additionally, hydrazine (N₂H₄) is used in the final step to release the primary amine from the phthalimide structure. Each reagent plays a crucial role in the reaction mechanism, ensuring the efficient production of primary amines.

How does the Gabriel synthesis compare to amine alkylation?

The Gabriel synthesis is more efficient than amine alkylation for producing primary amines. Amine alkylation often leads to polyalkylation, resulting in a mixture of products and lower yields. In contrast, the Gabriel synthesis uses potassium phthalimide to form a strong nucleophile, which reacts with a primary alkyl halide in an SN2 mechanism. The final step with hydrazine ensures the release of a pure primary amine, avoiding the issues of polyalkylation and providing higher yields.

What is the role of hydrazine in the Gabriel synthesis?

Hydrazine (N₂H₄) plays a crucial role in the final step of the Gabriel synthesis. It facilitates the release of the primary amine from the phthalimide structure through a nucleophilic acyl substitution mechanism. Hydrazine's nucleophilicity, due to its two nitrogen atoms with lone pairs, allows it to attack the carbonyl carbon of the phthalimide, forming a tetrahedral intermediate. This intermediate undergoes proton transfer and subsequent elimination steps, ultimately releasing the primary amine and ensuring high yields without polyalkylation.

What is the mechanism of the Gabriel synthesis?

The Gabriel synthesis mechanism involves three main steps: (1) Deprotonation of phthalimide by KOH to form potassium phthalimide, a strong nucleophile. (2) An SN2 reaction where potassium phthalimide attacks a primary alkyl halide, forming an N-alkylphthalimide intermediate. (3) Introduction of hydrazine (N₂H₄), which undergoes nucleophilic acyl substitution to release the primary amine. The hydrazine attacks the carbonyl carbon, forming a tetrahedral intermediate, followed by proton transfer and elimination steps, ultimately yielding the primary amine.