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

The Strecker synthesis is a two-step process for producing alpha amino acids from aldehydes. Initially, an imine is formed from an aldehyde and ammonium chloride, followed by nucleophilic attack from cyanide, yielding an alpha aminonitrile. The second step involves acid hydrolysis, converting the nitrile to a carboxylic acid and protonating the amino group, resulting in an amino acid. This synthesis highlights the roles of functional groups, such as the carbonyl and cyano groups, in organic synthesis, emphasizing the importance of retrosynthetic analysis in understanding molecular transformations.

Synthesis of Amino Acids: Strecker Synthesis Concept 1

Everyone. So in this video, we're going to take a look at amino acid synthesis by way of the Strecker synthesis. Now, Strecker synthesis is just an extension of imine formation and cyanohydrin formation. It takes place in 2 steps, with step 1 being the formation of an alpha aminonitrile. Here's step 1:

We start out with an aldehyde, and we're going to use ammonium chloride here. This will help to make our imine. Now remember, an imine is when carbon is double bonded to a nitrogen. So our imine here would be carbon double bonded to nitrogen and then that nitrogen connected to an H. Because remember, nitrogen still ideally wants to make 3 bonds.

We then use sodium cyanide over H⁺ catalyst. This would transform my imine into an alpha aminonitrile. So we'd have here, we'd have our NH₂ and then CN. And then step 2 is the hydrolysis of our alpha aminonitrile. This would be here where we use acid hydrolysis, H₃O⁺, and heat.

Now, H₃O⁺, acid hydrolysis transforms a nitrile or CN group into a carboxylic acid. And because the environment itself is acidic, it would also protonate this amino group into its NH₃⁺ form, thus creating at the end, an alpha amino acid. Right. So these are the two steps that are involved in the Strecker synthesis.

Synthesis of Amino Acids: Strecker Synthesis Concept 2

Hey everyone. So in this video, let's take a look at the mechanism for the Strecker synthesis. Alright. So we're going to say here that it has a lot of steps. We're going to say step 1 deals with protonation.

Step 2 deals with nucleophilic attack. Step 3 is proton transfer. Step 4 is leaving group. Step 5 is nucleophilic attack. And then step 6 is hydrolysis.

Alright. So let's start out with step 1. Here we have protonation takes place at the carbonyl oxygen. We're going to say here that this oxygen will use its lone pairs to grab this H+, thus becoming protonated and positively charged. Next, we're going to say the NH3 attacks the carbonyl carbon forming a tetrahedral intermediate.

So it's going to come in here, get this carbon kicking this bond up to the oxygen. So what we're going to have here is we're going to have an OH and then we're going to have an NH3+. Step 3, we're going to have an H+ is going to be transferred from nitrogen to oxygen. So we have our proton transfer. So this is going to create water, which is a great leaving group and NH2.

Now, the nitrogen was going to make a double bond here, so the amino group kicks out the water. Amino group kicks out the water because it's a good leaving group, forming a protonated imine. So here goes our protonated imine. Next, we're going to say the cyanide ion attacks the protonated imine to form an alpha aminonitrile. So we're going to come in here, hit this carbon of the imine picking the bond up to the nitrogen.

So we're going to have here a CN and then we're going to have nitrogen now is neutral since it's only making 3 bonds again. We're then going to protonate that amino group into an NH3 positive group. Now finally, the CN or nitrile group of the alpha aminonitrile is hydrolyzed to a carboxylic acid to yield an amino acid. Alright. So all we're going to say here now is this is going to get transformed into a carboxylic acid, and again, our amino group is protonated in the process.

It's an NH3+ to give us our carboxylic acid. Now, technically, I'm not showing the mechanism of this. We're going through from the nitrile to the carboxylic acid. But again, you can look back on our older videos where we talk about what happens when we do acid hydrolysis of a nitrile group to create a carboxylic acid. Again, look back on those older videos.

Here, we're just going straight in step 6 from the nitrile to the carboxylic acid. But this is the process of the Strecker synthesis. You can see all the steps that are necessary to go from our starting material to this final amino acid.

Synthesis of Amino Acids: Strecker Synthesis Concept 3

So with the Strecker synthesis, now we're going to look at it retrosynthetically. We're going to look at our final amino acid and think back to what we had beforehand. Now, we're going to say that Strecker synthesis produces alpha amino acids from aldehydes. We're going to say here that the amino group comes from our NH3+ group. And we're going to say that the side chain and the alpha carbon come from the aldehyde.

And then finally we're going to say that the carboxylic acid group comes from the nitrile. So if we take a look here, here is our alpha carbon here. It's connected to a carboxylic acid, a protonated amino group, and here we have our R group. We're going to say, if we make the cuts here and here, we'd say here that the carboxylic acid group came about by doing acid hydrolysis of a nitrile group. So that carboxylic acid, it came from this nitrile.

We're then going to say that the amino group here came from NH3. I mean, actually just NH3 neutral. And then here this portion, this came from an aldehyde. So this alpha carbon, just make it there's the alpha carbon here, make it a carbonyl with an H on it. There goes our aldehyde.

So we have our amino acid. Thinking backwards to what we had beforehand, we had aldehyde, we had a nitrile, and we had ammonia or ammonia here. Alright? So again, this is how you have to think about it retrosynthetically when dealing with that Strecker synthesis.

Synthesis of Amino Acids: Strecker Synthesis Example 1

Everyone, in this example question, it asks us to suggest an aldehyde that can be used to synthesize methionine using the Strecker synthesis. Right. So if we're going to draw this amino acid, remember, it is a methyl group connected to sulfur, connected to two CH₂s. We have our alpha carbon here now, connected to our amino group, NH₂, connected to a carboxylic acid.

Here, we're not worried about the stereochemistry around the alpha carbon NH₂ group because we're just concerned with what the beginning aldehyde was. So remember, we're going to say here that this carboxylic acid came from our nitrile. This NH₂ came from ammonia. And all of this here was part of my aldehyde. So thinking retrosynthetically here, we have that chain there.

And this carbon here, which is the alpha carbon, it was part of the aldehyde. It was the carbonyl group. So, just add C=O and then an H off of it. So this was our beginning aldehyde that we used in the Strecker synthesis in order to make our methionine amino acid. Right.

So, this would be our final answer.

Draw a complete mechanism for the Strecker synthesis of alanine.

In this practice question, it says, "Draw a complete mechanism for the structure synthesis of alanine." Now, alanine here has its R group in the form of a methyl group. So, this is alanine and here I'm just going to have this NH2. Now remember, our starting material is an aldehyde, and the aldehyde portion comes from here. That alpha carbon was the carbonyl group. So, we're going to start off our mechanism with our carbonyl group, our aldehyde, and it has the methyl group attached there. What we're going to do now is we're going to protonate that carbonyl oxygen. Protonate that. Gives us this. What we're going to do next is we're going to use ammonia, which is going to come in and attack this carbonyl carbon, kicking the bond up to oxygen. We're then going to have a proton transfer. So our proton transfer here, remember we use double arrows here. Our proton transfer would go towards this oxygen. So, from nitrogen to oxygen, making it water. Water is a great leaving group. This is then going to come here to make a double bond kicking out the water. We now have a protonated imine. Okay. Because it's protonated now, now we have our cyanide ion come in, attack this imine carbon, kicking the bond up here. And so we have this structure here. Alright. Then what we can do next is here again, when it comes to the conversion of our nitrile group into a carboxylic acid group, go back and take a look at our earlier videos where we talk about when a nitrile is within an acidic environment, it gets transformed into a carboxylic acid. At this point, all we're going to show is H0 plus protonating, probing this NH2 to make it an NH3, and also we're going to have our nitro be converted into a carboxylic acid. Oops. And actually, this should be an H here. So we have H is all here. So this would be our final product. Right? This would create our alanine. And if I wanted to clean it up some, alpha carbon, and I have to carboxylic acid, connected it's methyl. Right? So this would be our final answer, and this would be the mechanism of how we created alanine using the Strecker synthesis.

Pipecolic acid is an unusual amino acid that accumulates in the bodies of people with pipecolic acidemia, a rare genetic disorder. Write a synthetic method to prepare pipecolic acid using Strecker synthesis.

Here, we're told that picicholic acid is an unusual amino acid that accumulates in the bodies of people with picicholic acidemia, a rare genetic disorder. It says to write a synthetic method to prepare hypocholic acid using the Strecker synthesis. Alright. So, remember, with the Strecker synthesis, we start out with an aldehyde. In order to create that, we're going to start out with our amino group connected to our string of carbons and an aldehyde here at the end. What we're going to do first is use H3O+ over NaCN. That would transform this into our imine. And because the amino group and the aldehyde are on the same chain, this would do an intramolecular reaction creating a cyclic imine. So we know that this nitrogen would attach itself to this carbonyl in order to make our imine. We have a 6-membered ring in order to make this imine. Okay. So there goes our imine. The nitrogen will be positively charged since it's making 4 bonds. Now, we're going to say here, so we're going to do CN, Na+CN− here. It would come in and attack this carbon by kicking the bond here. And we'd say here, CN is attached there. And then we do H3O+ and some heat. Doing that, we just transform our nitrile into a carboxylic acid. So this will be our final answer and the method that we use in order to make this particular amino acid.

Here’s what students ask on this topic:

What is the Strecker synthesis and how does it work?

The Strecker synthesis is a two-step process for producing alpha amino acids from aldehydes. In the first step, an imine is formed from an aldehyde and ammonium chloride. This imine then undergoes nucleophilic attack by cyanide, yielding an alpha aminonitrile. In the second step, the alpha aminonitrile undergoes acid hydrolysis, converting the nitrile group to a carboxylic acid and protonating the amino group, resulting in an amino acid. This synthesis highlights the roles of functional groups, such as the carbonyl and cyano groups, in organic synthesis.

What are the steps involved in the mechanism of the Strecker synthesis?

The mechanism of the Strecker synthesis involves several steps: (1) Protonation of the carbonyl oxygen, (2) Nucleophilic attack by NH₃ on the carbonyl carbon, forming a tetrahedral intermediate, (3) Proton transfer from nitrogen to oxygen, creating water as a leaving group, (4) Formation of a protonated imine, (5) Nucleophilic attack by the cyanide ion on the protonated imine, forming an alpha aminonitrile, and (6) Hydrolysis of the nitrile group to a carboxylic acid, yielding the final amino acid.

How does retrosynthetic analysis apply to the Strecker synthesis?

Retrosynthetic analysis in the Strecker synthesis involves thinking backwards from the final amino acid product to the starting materials. The amino group in the amino acid comes from NH₃, the carboxylic acid group comes from the nitrile group via acid hydrolysis, and the alpha carbon and side chain come from the aldehyde. By identifying these components, one can determine the necessary starting materials and the sequence of reactions required to synthesize the amino acid.

What are the key reagents used in the Strecker synthesis?

The key reagents used in the Strecker synthesis include an aldehyde, ammonium chloride (NH₄Cl), sodium cyanide (NaCN), and an acid catalyst (H₃O⁺). The aldehyde reacts with ammonium chloride to form an imine, which then reacts with sodium cyanide to form an alpha aminonitrile. Finally, the alpha aminonitrile undergoes acid hydrolysis to yield the amino acid.

What is the role of acid hydrolysis in the Strecker synthesis?

In the Strecker synthesis, acid hydrolysis plays a crucial role in the second step. It converts the nitrile group (CN) of the alpha aminonitrile into a carboxylic acid (COOH). The acidic environment also protonates the amino group, resulting in the formation of the final alpha amino acid. This step is essential for transforming the intermediate into the desired amino acid product.