Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis - Online Tutor, Practice Problems & Exam Prep

The N-benzyl malonic ester synthesis is a four-step process combining Gabriel and malonic ester syntheses to create amino acids. It begins with an SN2 reaction where potassium ethylamide reacts with an alpha-bromomalonic ester, forming N-methylamidomelonic ester. This is followed by enolate formation and alkylation of the enolate ion with an alkyl halide. Finally, hydrolysis and decarboxylation yield the amino acid, featuring an alpha carbon, a methyl group, an amino group, and a carboxylic acid. The amino group originates from the ethylamide, while the carbon skeleton derives from the malonic ester.

Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis Concept 1

Hey, everyone. So in this video, we're going to talk about amino acid synthesis and in particular, the N-Beta-methylamino malonic ester synthesis. Now, you're going to say that N-Beta-methylamino malonic ester synthesis combines the Gabriel synthesis and malonic ester synthesis. Now, here, it's going to take place in 4 steps. So we have steps 1, 2, 3, and then we have steps 4a and 4b.

These are steps 4 which are just segmented into 2 parts. Now, if we take a look here, we're going to say step 1 deals with an SN2 reaction. Here, we're going to say potassium ethylamide reacts with an alpha bromomolonic ester. Alright. So here we have our potassium ethylamide, which remember is a key ion key molecule in terms of the Gabriel synthesis.

We're going to say here, it's going to hit this alpha carbon and kick out the bromine. And we're going to say here, when we do that, that's going to create this, which is our N-methylamidomelonic ester. Next step 2, we have enolization. We're going to say a strong base deprotonates the alpha carbon of N. So here's our strong base here.

We're going to say, here's our alpha carbon still. This is going to come and deprotonate. We're going to say here the alpha carbon holds on to the electrons. So next, we're going to say for step 3, so again this negative carbon here. Step 3 is alkylation of the enolate.

So the enolate anion attacks an alkyl halide in an SN2 mechanism or SN2 reaction. So this is going to come in with its lone pairs. It's going to hit this carbon, kicking out the halogen by SN2. So what we've just done is we've alkylated the alpha carbon. So we've created an alkylated and N-methylamidomelonic ester.

Then we go to steps 4a and 4b. We're coming back up here. 4a, we have the imide and the esters are hydrolyzed for hydrolysis. And in decarboxylation, we're going to say one of the carboxylic acid groups is lost to CO₂. So if we come back down here, we have our H₃O⁺ which is acid hydrolysis and heat.

That'll change my esters into carboxylic acids. And then we're going to introduce this heat later here in step 4b, which causes decarboxylation, so we lose CO₂, this one here. And that's how we wind up with this amino acid at the end. Here's our alpha carbon, the methyl group that we've attached, our amino group, and our carboxylic acid. Right?

So this is yet another process that we can employ in order to make amino acid.

Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis Example 1

Hey, everyone. In this example question, it says, draw the structure of the product of hydrolysis of a non-alkylated N-methylmalonic ester. Right. So it's non-alkylated. What we're going to do here is we're going to draw our structure.

We have our benzene ring here. We're going to say that we have connected to a 5-membered ring. Here's the nitrogen here. Now, it's going to be connected to the alpha carbon. And so we have here our ester and here our ester.

That R could be ethyl or it could be another R group. Alright. So what we're going to do next is we're going to do H3O+ and some heat. So remember, what effect is that going to have? That's going to basically change these esters into carboxylic acids.

And then we're cutting this out here, excising it out, and that's going to be my coordinated amine. And then we use additional heat which is going to cause decarboxylation. So we lose one of these carboxylic acids as CO2. So we have at the end is our protonated amine. It's going to be connected to the same carbon, which is still connected to this carboxylic acid.

Right. So we've made our amino acid, our glycine, our most simplest of amino acids as our final product. Right. So this is the process we would do in order to get the product from the hydrolysis of our non-alkylated N-methylmalonic ester.

Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis Concept 2

Ampithalamidomelonic ester synthesis uses simpler starting materials than the acetomito malonic or malic ester synthesis. Now, we're going to say the amino group comes from the nitrogen atom of the pethylamide molecule. And we're going to say here that the base skeleton or the base carbon skeleton of the amino acid comes from the alpha-bromomelanic ester. And then finally, the side chain comes from an alkyl halide. So if we take a look here, here is our alkylated amino acid or amino acid in general.

So let's break this down retrosynthetically. We're going backwards here. We first cleave off this from the alpha carbon. And what we have here is our regular glycine here. We have our amino group.

We have a carboxylic acid, they're connected to this alpha carbon. If we go further and cut it here, the nitrogen that got cut off was part of the pethalamide molecule. So here it is right here. And then this alpha carbon and this carboxylic acid group was originally part of this, our malonic ester. And we're going to say here we see that the alpha carbon has a bromine on it.

And then this group here in pink or magenta that we cut off in the beginning, this was originally our alkyl halide. So, again, the way you can look at this is we have our alkyl halide, we have our methylamide molecule, and then we have our halogenated malonic ester. These components together are what we used to create this amino acid by way of our pathalmetomelonic ester synthesis.

Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis Example 2

In this example question, it suggests using an alkyl halide to synthesize histidine using the N-bethylamidomelanic ester synthesis. Alright. So let's draw out what histidine resembles. Here we're going to have our cyclic structure which has our nitrogen embedded within it. So we have NH here and then we have another pi bond here.

Oops. That goes right there. Actually, so there goes my 5-membered ring. And then it's going to be connected to this carbon here, which is then connected to an alpha carbon connected to an NH₂ group. And we have our carboxylic acid here.

Alright. So we have our carboxylic acid portion right here, which is part of the alpha carbon. This part came from our malonic ester. We have our amino group, which was part of the Bbethelimide molecule. And then we have the rest of this which was part of our alkyl halide.

Now we want to see what the alkyl halide was. All you have to do is cleave this portion right here. And looking back retrosynthetically, all we do now is redraw this again. Okay. Five-membered ring connected to this. And when we cut, we're just going to add a halogen there.

So this was our alkyl halide that we used in the beginning. So again, for this particular synthesis, look at your histidine, mark the portion that is the amino group that came from the Bbethylimide molecule, mark the portion that's the alpha carbon and the carboxylic acid group, that came from your malonic ester. The rest of it, the side chain came from an alkyl halide. So all you have to do is add a halogen to where you cut it. We cut it right here.

So you just have to add a halogen to that carbon, and you'll have your alkyl halide that you started with. Right? So that's the process you need to employ in order to get to your final answer.

Here’s what students ask on this topic:

What is the N-phthalimidomalonic ester synthesis?

The N-phthalimidomalonic ester synthesis is a method for synthesizing amino acids. It combines elements of the Gabriel synthesis and the malonic ester synthesis. The process involves four main steps: an SN2 reaction, enolate formation, alkylation of the enolate ion, and finally, hydrolysis and decarboxylation. The amino group in the final amino acid comes from the ethylamide, while the carbon skeleton is derived from the malonic ester. This method is useful for creating amino acids with specific side chains by using different alkyl halides.

What are the steps involved in the N-phthalimidomalonic ester synthesis?

The N-phthalimidomalonic ester synthesis involves four main steps:

1. SN2 Reaction: Potassium ethylamide reacts with an alpha-bromomalonic ester to form N-methylamidomelonic ester.
2. Enolate Formation: A strong base deprotonates the alpha carbon, forming an enolate ion.
3. Alkylation: The enolate ion attacks an alkyl halide in an SN2 mechanism, alkylating the alpha carbon.
4. Hydrolysis and Decarboxylation: The imide and esters are hydrolyzed, and one carboxylic acid group is lost as CO₂, yielding the final amino acid.

How does the N-phthalimidomalonic ester synthesis compare to the Gabriel synthesis?

The N-phthalimidomalonic ester synthesis is similar to the Gabriel synthesis but includes additional steps to form amino acids. While the Gabriel synthesis primarily focuses on forming primary amines, the N-phthalimidomalonic ester synthesis combines this with the malonic ester synthesis to create amino acids. The key difference is that the N-phthalimidomalonic ester synthesis involves alkylation and decarboxylation steps, allowing for the introduction of specific side chains to the amino acid.

What is the role of potassium ethylamide in the N-phthalimidomalonic ester synthesis?

In the N-phthalimidomalonic ester synthesis, potassium ethylamide plays a crucial role in the initial SN2 reaction. It reacts with the alpha-bromomalonic ester, displacing the bromine atom and forming the N-methylamidomelonic ester. This step is essential for introducing the nitrogen atom that will eventually become the amino group in the final amino acid product.

What is the significance of the enolate formation step in the N-phthalimidomalonic ester synthesis?

The enolate formation step is significant because it prepares the molecule for alkylation. A strong base deprotonates the alpha carbon, creating an enolate ion. This enolate ion is highly nucleophilic and can readily attack an alkyl halide in an SN2 reaction. This step is crucial for introducing the desired side chain to the amino acid, making it a key part of the synthesis process.