Monosaccharides - Kiliani-Fischer - Online Tutor, Practice Problems & Exam Prep

The Kiliani-Fischer synthesis extends monosaccharide chains by utilizing cyanohydrins. This process involves nucleophilic addition of cyanide to aldehydes, forming a cyanohydrin. The cyano group is then reduced to an imine using a weaker reducing agent, such as palladium on barium sulfate, before hydrolysis converts it back to an aldehyde. This method allows for the creation of longer sugar chains, though it results in a mixture of diastereomers due to the achiral nature of certain carbons. Understanding these reactions is crucial for manipulating carbohydrate structures in organic synthesis.

Monosaccharides - Kiliani-Fischer

Hey guys, in this video, I'm going to show you how to make monosaccharide chains longer through a process called the Kiliani Fischer Synthesis. Alright guys, so you have to love saccharides because saccharides have alcohols, they have carbonyls, there's so many different things we can do with them, so they're so versatile. And one thing that you should always keep in mind is that the reactions that we learned about aldehydes and ketones back in your carbonyl section of Organic Chemistry apply; many of those reactions apply to saccharides because we have an aldehyde present, okay. So just keep in mind that many of the same nucleophilic addition reactions that we learned in your carbonyl and hydrogen cyanide, aldoses can reversibly transform into cyanohydrins. Okay.

Now guys, this shouldn't be a shock to you because this is exactly what we learned back when we did carbonyl chemistry, okay? What we learned is that if you react an aldehyde or a ketone with hydrogen cyanide, what's going to end up happening is that you get a CN^- that comes in and attacks and kicks electrons up to the oxygen, right? So we're just drawing out the cyanohydrin mechanism right now. And then what would happen, this is called a nucleophilic addition. The CN would attack the positive of the carbonyl, kick the electrons up to the O. What you would get now is a carbon triple bond nitrogen attached to that carbonyl carbon and then you would get a carbon and an O^-, and that O^- would later on get protonated by this hydrogen that dissociated. So eventually, this becomes an OH and guys, this is what we call a cyanohydrin functional group, okay. So everything that I just showed you is 100% based on other videos. If you want to type in cyanohydrin into your search bar right now, you will find the same exact mechanism just instead of working with sugars, we were just working with a regular aldehyde, okay. So there's zero new information here.

Now, what's interesting is that we can take advantage of the fact that cyano groups have an extra carbon. We can take advantage of that fact to lengthen the chain. And if we can keep adding cyano groups, we can keep lengthening this chain. So ideally, we could turn a pentose into a hexose by just adding more and more cyanohydrins, okay. Now the way that we do this is that we're going to have to hydrolyze that CN and turn it into a carbonyl in some way, okay. So let's go ahead and figure out how to do that. Okay, so the cyano group can then be reduced and hydrolyzed to form a new chain-lengthened aldehyde.

Okay, so guys it turns out that we have learned in the past how to reduce nitriles or cyano groups, okay. But when we have studied the reduction of cyano groups in the past, it's usually been with catalytic hydrogenation. And what catalytic hydrogenation does is it adds hydrogens to every pi bond. So if we just use for example H₂ and palladium, let's say. If we just use that as catalytic hydrogenation, what we would expect to get is CH₂, don't draw this by the way because this is the wrong answer, NH₂. Okay? It would completely reduce, we would add a ton of H's. Now it turns out that we don't want this because we only want to reduce it to a double bond, not to a single bond because we want to keep a carbonyl, okay? So what we're going to do is we are going to develop some kind of reduction, not this one, but we're going to develop some kind of reduction, some weaker form of reduction to leave it as an CN double bond. So we're going to do this, carbon double bond NH. Okay? And then obviously this hydrogen is still present.

Now you don't know what this reducing agent is, but I'm just letting you know that that's going to be part of the synthesis is to find a reducing agent that only reduces it one stage and not two stages. Cool? Then once you have this functional group, this is called an imine. And guys, we learned back in the carbonyl in the carbonyl chapter that imines can be reversibly hydrolyzed into carbonyls using just water and acid. Through hydrolysis, it's possible to turn that nitrogen into an oxygen. Okay?

Now if you're wondering, this is just going over my head. I don't know any of these reactions. I have all these on video. So if you type in imine, you'll see all the imine reactions and you'll see mechanisms of how we can turn a double bond nitrogen into a double bond oxygen. If you search cyanohydrins, you can look at the first step. So really the steps that you should already know from what we've already learned in organic chemistry are this step and this step. Both of these steps come from carbonyl chemistry. The only step that should still be a big question mark for you is this step, and that's fine because I'm going to explain that step more in a little bit, okay? Cool.

So just before I go into the specific reagents and the specific mechanisms, I'm trying to give you the big picture. One thing I want to show you—oh by the way, I'm sorry this would still be an H—but one thing I want to show you is that this synthesis can be repeated. Before I started with ribose, which is a pentose, right? Now I have 1, 2, 3, 4, 5, 6 carbons, and I still have an aldehyde present. What can aldehydes do when you expose them to CN negative? They can react again and they can do another cyanohydrin. So the whole idea here is that you can repeat this cycle as many times as you want and get your carbon chain to be longer and longer. And you could theoretically just keep on going forever, okay?

Now, one thing to keep in mind though is that the chirality at carbon two is always going to be a mixture. It's never going to be a solid, like diastereomer or a solid configuration. And the reason, guys, is because this carbon here is the same as this carbon here. It never had chirality; it started off as achiral because it was trigonal planar. And now after we've added the alcohol, we don't know which side the alcohol added to. It could have added from the right, it could have added from the left. So the one limitation of Kiliani Fischer is even though it's a great way to lengthen the chain, you're going to continue to get mixtures of configurations at every carbon as you go up. The more times you do it, the more uncertain carbons you're going to have where you don't know if the O faces toward the right or if the O faces toward the left. What you're actually going to get is a mixture of both. And actually, guys, it's not even 50/50 because these are diastereomers, so they tend to have different properties. So it could be a mess. It could be like 60% of the right and 40% of the left, like you don't really know. So that's just one of the limitations of Kiliani Fischer. Does that make sense so far? Cool. So in the next video, I want to talk about some specific reagents and I want to talk about why in my title it's modern Kiliani Fischer, and I'll explain that in the next video.

Monosaccharides - Kiliani-Fischer

So why did I call this reaction the modern Kiliani Fischer synthesis? Well, guys, that's because when doctors Kiliani and Fischer first made this reaction, they were using slightly different reagents. So the first step was the same; it was still done through a cyanohydrin. What they would do, just as I explained in the first step in the previous video, is add a CN group here, and this would become an OH, and they would form a cyanohydrin. So that part was identical, but the reagents that they used afterwards to hydrolyze the cyanohydrin were actually very different. It required more steps, so it required 2 additional steps and it resulted in poor yields, okay. So, it was a very important reaction at the time back in the 1800s, but we've had 150 years to improve it, and now, the new set of reagents is what would be referred to as the Modern Kiliani Fischer. Okay, cool.

So what are these newer reagents? So guys, it turns out that we were able to design a better reducing agent that would work on the CN and turn it into an imine, okay. And this reducing agent, you've never really seen this exact reducing agent before, but it's similar to others we've seen because what it is, is it's H₂, palladium. This looks like catalytic hydrogenation, but it's not exactly palladium; it's palladium on barium sulfate. So Pd, over BaSO₄. This combination, you're just going to have to memorize it; probably put it on a flashcard. This is what we call a poison, reducing agent, and why what poison means, guys, if you ever hear the term poison, it means weaker. Weaker. Okay, so whenever you hear poison, that means it's weaker than normal. So another example of a poison hydrogenation is Lindlar's catalyst. Remember how Lindlar's instead of going from a triple bond to a single bond, it goes to a cis double bond? This goes all the way back to Organic Chemistry 1. Well, in a similar way, this is a poison catalyst

Predict the product(s) for the following reaction. Provide the mechanism of the imine hydrolysis step if required.

Predict the products for the following reaction and provide the mechanism of the amine hydrolysis step if required. So let's go ahead and look at what we're given and figure out what we're dealing with. It looks like I have a cyclic sugar and I'm reacting that with HCN and then a hydrogenation that includes H2, palladium, but then barium sulfate as well. This is indicative of a poison catalyst that would happen in a Kiliani Fischer synthesis. So just go ahead and write that down. I am going to go ahead and just call it Kiliani Fischer chain lengthening to remind us that this is a reaction that is going to try to add a new carbon to my sugar. So however many carbons I have in this sugar right now, it looks like 5. 1, 2, 3, 4, 5. By the end of this whole process, I should have a 6 carbon sugar. First, I need to convert my cyclic sugar into a straight chain, because cyclic sugars cannot react with HCN at all; you need an aldehyde present. We will convert this to the Fischer projection as this happens readily in any kind of acid or base in an aqueous solution. HCN has acid in it, so this conversion would easily happen. Now, the mechanism for the cyanohydrin formation would look like this:CN−+H+, where the cyanide ion (CN−) adds to the carbonyl carbon, and the oxygen gets protonated. The product then would be a cyanohydrin. The second step is a reduction using hydrogen (H2), palladium, and barium sulfate, forming an imine. For the imine hydrolysis, we can outline the mechanism as follows: First, the nitrogen is protonated. Water then attacks the imine carbon, pushing up electrons to nitrogen and forming an intermediate with an -OH group bound to the carbon. A proton transfer occurs from the water to the nitrogen, leading to the release of an NH3 molecule and formation of the carbonyl. This gives us our final product, a 6-carbon sugar with a new aldehyde group. This hydrolysis converts the -NH2 group into an -OH, completing the transformation into a fully functionalized sugar. The resulting sugar has its carbon chain extended by one carbon, directly due to the processes detailed in Kiliani Fischer synthesis. Finally, interpreting the stereochemistry involves understanding that we could end up with a mixture of diastereomers due to the new chiral center at the carbon attached to the cyanide, indicated with a squiggly line. This means the product could be any combination of diastereomers. The reaction pathway is indicated with reversible arrows since cyanohydrin formation is reversible under certain conditions. Moving forward to the next video tutorial, it is important to understand the chemical logic and maneuvers executed here.

Here’s what students ask on this topic:

What is the Kiliani-Fischer synthesis in organic chemistry?

The Kiliani-Fischer synthesis is a method used in organic chemistry to extend the carbon chain of monosaccharides. It involves the nucleophilic addition of cyanide (CN^-) to an aldehyde group in a sugar, forming a cyanohydrin. This cyanohydrin is then reduced to an imine using a weaker reducing agent, such as palladium on barium sulfate (Pd/BaSO₄). Finally, the imine is hydrolyzed back to an aldehyde, resulting in a longer sugar chain. This process can be repeated to further extend the chain, although it produces a mixture of diastereomers due to the achiral nature of certain carbons.

How does the Kiliani-Fischer synthesis lengthen monosaccharide chains?

The Kiliani-Fischer synthesis lengthens monosaccharide chains by adding an extra carbon atom through the formation of a cyanohydrin. Initially, cyanide (CN^-) is added to the aldehyde group of a sugar, forming a cyanohydrin. This cyanohydrin is then reduced to an imine using a weaker reducing agent like palladium on barium sulfate (Pd/BaSO₄). The imine is subsequently hydrolyzed to form a new aldehyde, effectively adding one carbon to the original sugar chain. This process can be repeated to further extend the chain, although it results in a mixture of diastereomers.

What are the reagents used in the modern Kiliani-Fischer synthesis?

In the modern Kiliani-Fischer synthesis, the key reagents include hydrogen cyanide (HCN) for the initial formation of the cyanohydrin, and a weaker reducing agent such as palladium on barium sulfate (Pd/BaSO₄) for the reduction of the cyanohydrin to an imine. The imine is then hydrolyzed using water and acid to convert it back to an aldehyde. This modern approach improves the efficiency and yield of the reaction compared to the original method developed by Kiliani and Fischer.

What are the limitations of the Kiliani-Fischer synthesis?

One major limitation of the Kiliani-Fischer synthesis is that it produces a mixture of diastereomers. This occurs because the carbon atom added during the formation of the cyanohydrin is achiral, leading to uncertainty in the configuration of the resulting alcohol group. As a result, each extension of the sugar chain introduces more stereoisomers, complicating the purification and characterization of the final product. Additionally, the yields can be lower due to the multiple steps involved in the synthesis.

How does the reduction of cyanohydrins to imines occur in the Kiliani-Fischer synthesis?

In the Kiliani-Fischer synthesis, the reduction of cyanohydrins to imines is achieved using a weaker reducing agent, such as palladium on barium sulfate (Pd/BaSO₄). This combination is known as a poisoned catalyst, which means it selectively reduces the cyanohydrin to an imine without fully hydrogenating it to an amine. The reaction proceeds as follows: the cyanohydrin (R-CH(OH)-C≡N) is reduced to an imine (R-CH(OH)-C=NH), which can then be hydrolyzed to form the corresponding aldehyde (R-CH(OH)-CHO).