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

Amino acid synthesis via acetoamido malonic ester synthesis involves three main steps: enolization, alkylation, and hydrolysis followed by decarboxylation. The process begins with a strong base deprotonating the alpha carbon of the acetoamido malonic ester, forming an enolate ion. This enolate then undergoes an SN2 reaction with an alkyl halide, introducing a new alkyl group. Hydrolysis converts the amide and ester into carboxylic acids, and decarboxylation releases CO₂, yielding the final amino acid product. Understanding retrosynthetic analysis aids in tracing the origins of the amino acid structure from starting materials.

Synthesis of Amino Acids: Acetamidomalonic Ester Synthesis Concept 1

Hey everyone. So, here we're going to talk about amino acid synthesis through the use of our acetoamido malonic ester synthesis. Now, here in the intro, we're going to say acetoamido malonic ester synthesis is a variation of malonic ester synthesis. If we take a look at our structure to the right, we're going to say it uses diethyl, which are these apples here, acetamidos which is our mind portion right here, and then we have malony, so the portion that we've seen in yellow. That portion, as well as the apple portions, we should be familiar with because, again, it's a variation of the malonic ester synthesis.

Now, here, it's going to take place in 3 steps. If we look, we have steps 1, 2, and then steps 3a and 3b are step 3. You've just broken them down into 2 portions. If we take a look at each of these steps, we're going to have step 1 which is enolization. This is where a strong base deprotonates the alpha carbon of Acetomedomalonic Ester.

So we take a look here. We're going to have our alpha carbon here in between both carbonyls. It's an acidic hydrogen. We're going to use here our ethoxide as our strong base. It's going to come in and deprotonate.

We remove this H here, the carbon holds onto the electrons. So now we have our negatively charged carbon because it has possession of that lone pair. So we're going to say here this represents the enolate of our acetometomalonic ester. Next, we're going to have alkylation of our enolate. So the enolate anion attacks an alkyl halide in an SN2 reaction.

So now I've introduced this methyl halide. This negative carbon will use its lone pair to attack this carbon, kicking out the halogen. And in that way, you've attached the methyl group to the alpha carbon. So we can see this as an alkylated acetomedomelonic ester. Now, step 3a is hydrolysis.

We're going to say here that the amide and the esters are hydrolyzed. Remember, esters and amides are carboxylic acid derivatives. So if we do hydrolysis here, it will return the esters into their carboxylic acids. And if we're breaking this amido or amide group or cleaving here, this NH becomes this protonated amino group here. And this portion which we don't see becomes a carboxylic acid.

It's left to the side because we're not really concerned with it. We want to take a look at the alkylaminomalonic acid here. So now that we have this, step 3b deals with decarboxylation where one of the carboxylic acid groups is lost as carbon dioxide. So if we take a look here, we introduce heat and that's going to cause decarboxylation. We'd lose this portion of CO2.

And at the end, what have we created? We've created an amino acid. So again, portions of this should be pretty familiar to you because they are dealing with malonic ester synthesis, a reaction we've seen before in the past. We're now incorporating additional steps to help us get to our final amino acid.

So, just remember, this particular way of creating an amino acid is comprised of 3 steps with step 3 being broken down into 3a and 3b.

Synthesis of Amino Acids: Acetamidomalonic Ester Synthesis Example 1

Hey everyone. In this example question, it says, draw the structure of the product when the enolate of diethylacetamidomalanate reacts with methyl iodide followed by treatment with warm aqueous acid. So, they're already saying that we're dealing with the enolate, which means we've already deprotonated the alpha carbon. Let's draw that structure.

We're going to need some room, so let's write it down here. We have our enolate form already. Here goes our ethyl. Here goes the rest of this. And then we have to draw the N H connected to this spot right here. This alpha carbon is already negatively charged because it's lost its hydrogen.

We're now reacting it with methyl iodide. So here, CH₃I, this will come in, bond here, and kick this bond out towards the iodine. We're going to have our structure here, which is our amide again.

And here goes the added methylamide. Then, using warm aqueous water. First, let's show the aqueous portion so that we don't miss any steps. That's going to change the esters into carboxylic acids. We have this methyl group here, and that'll change this into our protonated amine, and then the heat here. Remember, that's going to cause decarboxylation, so we're going to lose this portion here as CO₂. So, what we'll have at the end is our protonated amine connected to the alpha carbon connected to a carboxylic acid. We still have this methyl that we added earlier. This would represent the amino acid that we've created in this particular example question.

Synthesis of Amino Acids: Acetamidomalonic Ester Synthesis Concept 2

Now, when it comes to the synthesis of amino acids, we're going to say that our acetometomalonic ester synthesis produces amino acids in good yields. Now, we're going to have the base structure of the amino acid comes from the acetometo malonic ester. So here it is in green comprised of this carboxylic acid, the pronated amino group, and this alpha carbon here. If we cleave right here, we're going to say this portion here that is in this magenta or pinkish color, well, that comes from an alkyl halide. If we go retrosynthetically, we see that we have this portion with the alpha carbon that was here.

Right? And we're going to say that if we go further, we can see that it was incorporated within this acetylmetal malonic ester. And we can see that what was in magenta or pink was the alkyl halide. This is how we have to think retrosynthetically when dealing with these structures as products. We have to think about where did they come from in order to make this particular amino acid.

Alright. So again, we're just working backwards from our product to our starting materials. This will help us to figure out synthetic pathways as well as any types of question where they're asking to go from products to starting reagents.

Synthesis of Amino Acids: Acetamidomalonic Ester Synthesis Example 2

In this example question, it suggests an alkyl halide to synthesize methionine using the acetaminomelonic ester synthesis. Alright. So here, we need to draw this structure. What this structure represents is we have a methyl group connected to a sulfur, and then we have our CH₂CH₂ groups. They're connected to our alpha carbon, which is attached to our amino group, which could be protonated or non-protonated.

And then we have our carboxylic acid here. Now, remember, if we're taking a look at this amino acid, we'll say that our base structure has the amino group, alpha carbon, and the carboxylic acid. That would mean here that our side chain, which is this portion here, came from an alkyl halide. So all you need to do is to cut the connection between the side chain and the alpha part. Doing that and working backwards retrosynthetically, all we have to do now is here goes my side chain.

To make it an alkyl halide, where I cut this carbon, it needs to be connected to something. What is it connected to? It's connected to a halogen. This was the alkyl halide that we used in this process to make this amino acid. So, this would represent our starting alkyl halide.

Which amino acid is formed when 1,3-dibromopropane is used in the acetamidomalonic ester synthesis and the final product mixture is treated with a base?

• A.
• B.
• C.
• D.

How can aspartic acid be synthesized using acetamidomalonic ester synthesis?

Can Spark acid be synthesized using the acetaminomelonic ester synthesis? Alright. So what we're going to start with is the enolate form of this malonic ester derivative. We are going to have here our ethyl group connected to an oxygen, which is connected to our carbonyl, which is linked to an alpha carbon, and on the other side the same arrangement. We are going to be connected here to this amide group. Remember, we're dealing with the enolate form, so this alpha carbon has already been deprotonated, making it negative. If we want to make our aspartic acid, we will then include here our carboxylate end, and then we will have here an alpha carbon with bromine. Remember, aspartic acid is one of our acidic amino acids. What's going to happen now is this alpha carbon is going to attack this carbon, kicking out the bromine. What we are going to have now is that group attached to the alpha carbon. Okay. So we're going to be connected now to this carbon, which is the same carbon, and that carbon is still connected to this carboxylate end. Next, we're going to treat it with H3O+. So, when we treat it with H3O+, what effect is that going to have? It will do a couple of things. First, it's going to convert these ester ends into carboxylic acids, because it takes us from our derivative back to the parent carboxylic acid. It's also going to cleave this connection of the amide, leaving us with a protonated amine at the end. It is also going to protonate this carboxylate to form a carboxylic acid. Next, we're going to apply heat. Heat would cause decarboxylation, meaning that we lose CO2. Thus, we lose one of these carboxylic acids. At the end, what do we have? We have this protonated amine that is still present. It's still connected to this alpha carbon, which is still connected to this carboxylic acid, and we are still connected to this carboxylic acid group. So, this would be our synthesis of aspartic acid starting with our reagents; this is the process you need to employ in order to get to this final product.

Here’s what students ask on this topic:

What are the main steps involved in the acetoamido malonic ester synthesis of amino acids?

The acetoamido malonic ester synthesis of amino acids involves three main steps: enolization, alkylation, and hydrolysis followed by decarboxylation. In the first step, a strong base deprotonates the alpha carbon of the acetoamido malonic ester, forming an enolate ion. In the second step, this enolate undergoes an SN2 reaction with an alkyl halide, introducing a new alkyl group. The third step involves hydrolysis, which converts the amide and ester into carboxylic acids, followed by decarboxylation, which releases CO₂ and yields the final amino acid product.

How does enolization occur in the acetoamido malonic ester synthesis?

Enolization in the acetoamido malonic ester synthesis occurs when a strong base, such as ethoxide, deprotonates the alpha carbon of the acetoamido malonic ester. This alpha carbon is located between two carbonyl groups, making its hydrogen atom acidic. The base removes this hydrogen, resulting in the formation of an enolate ion, which is a negatively charged carbon with a lone pair of electrons.

What role does the alkyl halide play in the acetoamido malonic ester synthesis?

The alkyl halide plays a crucial role in the alkylation step of the acetoamido malonic ester synthesis. The enolate ion, formed during enolization, attacks the carbon of the alkyl halide in an SN2 reaction. This nucleophilic attack displaces the halogen atom and introduces a new alkyl group to the alpha carbon of the acetoamido malonic ester, forming an alkylated product.

What happens during the hydrolysis and decarboxylation steps in the acetoamido malonic ester synthesis?

During hydrolysis, the amide and ester groups of the acetoamido malonic ester are converted into carboxylic acids. This process involves breaking the ester and amide bonds, resulting in the formation of carboxylic acids and a protonated amino group. In the subsequent decarboxylation step, one of the carboxylic acid groups is lost as CO₂ when heat is applied. This results in the formation of the final amino acid product.

How does retrosynthetic analysis help in understanding the acetoamido malonic ester synthesis of amino acids?

Retrosynthetic analysis helps in understanding the acetoamido malonic ester synthesis of amino acids by allowing chemists to trace the origins of the amino acid structure back to the starting materials. By working backwards from the final amino acid product, chemists can identify the key intermediates and reagents involved in the synthesis. This approach aids in designing synthetic pathways and understanding the transformations that occur at each step of the synthesis.