Side-Chain Reactions of Substituted Pyridines - Online Tutor, Practice Problems & Exam Prep

Substituted pyridines exhibit unique side chain reactions due to the acidity of benzylic hydrogens, particularly influenced by the electronegative nitrogen atom. The pKa values for alkylated pyridines vary, with C2 and C4 positions being more acidic (pKa ~34) compared to C3 (pKa ~36). Deprotonation leads to resonance stabilization, allowing for nucleophilic addition reactions similar to enolate anions in carbonyl chemistry, ultimately forming stable alpha-beta unsaturated products. Understanding these mechanisms is crucial for mastering organic synthesis and reaction pathways involving pyridine derivatives.

Side-Chain Reactions of Substituted Pyridines Concept 1

Hey, everyone. So in this video, we're going to talk about side chain reactions of our substituted pyridines. Now remember that benzylic hydrogens are acidic due to stable intermediate anions. And remember, the benzylic position is the carbon that's connected to an aromatic ring. In this case, we're not just dealing with benzene; we're dealing with pyridine because pyridine is also an aromatic ring.

Now we have our ordinary benzylic carbanion, so those are the ones that are attached to benzene. Well, they're stabilized by resonance, which is great, But pyridine carbanions are even more acidic because not only are they stabilized by resonance, but they're also stabilized by induction of the electronegative nitrogen atom. The creation of this negative charge when we remove an H⁺ can be stabilized by the more electronegative nitrogen. This is displayed in the pKa values of our ordinary benzylic carbanion versus our pyridine carbanions. So if we take a look here, in both of these, we have a base, and they will deprotonate the benzylic carbon in both of these structures.

So the base comes in, deprotonates, the Carbon holds on to the electrons. What we get here is our ordinary benzylic carbanion, and its relative pKa is around 41. For pyridine though, we deprotonate as well. We're going to form our own carbanion. It has a pKa of around 34 to 36 or so, and we'll see why later.

But we see, nevertheless, that it has a lower pKa than our typical benzylic carbanions. Remember, lower pKa means more acidic. We're going to say here that the benzylic position can be deprotonated by strong bases, and we can see that in the form of organolithiums and also the strong sodium amide base. Alright.

So just remember, we can make our different types of carbon ions from these benzylic positions. When it comes to pyridine, they're even more acidic because of resonance and the inductive effect of the electronegative nitrogen atom.

Side-Chain Reactions of Substituted Pyridines Example 1

Hey, everyone. So in this example, it says, arrange the following compounds in order of increasing acidity, from weakest acid to highest acid. If we take a look here, we would say that we have a pyridine here, and here is its benzylic carbon. We know, because of resonance and induction, that this benzylic carbon is even more acidic than a typical benzylic carbanion.

So, we know that this is going to be the most acidic. So we're going to say b is most acidic, and let's figure out what the other ones would be. c should be the least acidic because, in c, we don't even have a benzylic position to deal with. So that's going to be even less. Right.

Next, remember, we're trying to deprotonate the benzylic position to make a carbanion. Here, it's harder to make that carbanion if you're already double bonded. It'd be kind of a weird situation. So a would be next. d would be the next acidic because, yes, we have a benzylic position here.

We could make a negative charge here that could resonate. But again, it's not as great acid-wise as b because the presence of the nitrogen means that we can resonate towards that more electronegative nitrogen. Through induction, it's better able to hold on to that negative charge. So in order of weakest to strongest acid, it would be c, a, then d, and then b being the strongest.

Side-Chain Reactions of Substituted Pyridines Concept 2

So in this video, we're going to talk about the resonance structures that form when we're dealing with the deprotonation of our benzylic position. Certain side chain positions of alkylated pyridines are more acidic than others. In fact, we're going to say that C₂ and C₄ alkylated pyridines are more acidic because of the negative charge on the electronegative nitrogen atom. So if we take a look at C₂ here, we're going to first talk about the pKa values that we see. And when it's in the ortho position, it's going to be approximately 34 or so, as well as in position C₄.

But when we talk about C₃, we're going to see it's closer to being 36. Remember that the pKas of these alkylated pyridines range between around 34 to 36. 34 is lower, so those are more acidic positions. 36 is higher, so it's less acidic. Let's see why.

Here, in this first one, we deprotonate the benzylic carbon, so that becomes negatively charged. It can then resonate throughout this, so it can resonate here to make a double bond, kicking this pi bond to the nitrogen. Nitrogen now has 2 lone pairs and 2 bonds, so it's negatively charged. It could then resonate here to make a pi bond, kicking this bond to this carbon. So now the negative charge is here.

It could then move here to make a pi bond, moving the bond here. So now this is negative. And then finally, this could resonate here, moving this pi bond back to the benzylic carbon. We can see that we formed a negative nitrogen here. Remember that more electronegative nitrogen atom is better able to hold on to that negative charge.

For C₃, let's do this one now. This base deprotonates. So now this is negative. It can resonate here to make a double bond, kicking this bond here. This moves here, moving this bond here.

Then we could say that this moves here, moving this bond here. And then finally, this moves here, moving this bond here. Cycling through all the resonance structures, we see that we didn't make a negatively charged nitrogen at any instance. So that negative charge was never put on the more ideal electronegative nitrogen atom. For C₄, we're going to deprotonate.

So we have this negative initially. It resonates down to make a double bond, moving this bond here. Then this resonates here, moving this pi bond to the nitrogen. So, again, we have a negatively charged nitrogen atom. This can then move here, causing this bond to move here.

And finally, this moves here to give us this structure. Alright. So we can see that in C₂ and C₄, they're more preferred because we make a negatively charged nitrogen atom. Since it's more electronegative than carbon, it's better that if there's going to be a negative charge around, it'd be good if it landed on that nitrogen in an instance. Alright?

So that's why C₂ and C₄ are better than C₃ for these alkylated pyridine molecules.

Side-Chain Reactions of Substituted Pyridines Example 2

In this example, it says, provide all the resonance structures formed when 4-ethylpyridine reacts with Sodium Amide. Alright. So here we're going to draw this out. We have our 4-ethylpyridine, and we're going to have Sodium amide. Remember, we're going to deprotonate this benzylic position here.

So this base comes in and removes this hydrogen. Carbon holds on to the electrons initially. So what we're going to make initially is this structure. Now here we show all the resonance structures that can be created from it. This can move here to make a double bond.

Keeping this bond here. All we're going to do is move it around. Alright. So now this is double bonded. Here's our negative charge here.

This decides it wants to fully make a double bond, so it does, kicking this pi bond to the nitrogen. Now nitrogen itself already had one lone pair. Now it's going to have 2. And now it's going to be negatively charged. This nitrogen then decides to use this lone pair to make a pi bond, kicking this bond up here.

Okay. So then we're going to have now this structure. And then finally, we decide to move this here to make a pi bond, kicking this pi bond back to the benzylic carbon. So now the benzylic carbon is negatively charged. And these will represent all the resonance structures when 4-ethylpyridine reacts with sodium amide.

Side-Chain Reactions of Substituted Pyridines Concept 3

We now take a look at addition reactions for these alkylated pyridines. We're going to say the conjugate base of pyridine reacts in a similar way to the enolate anion of carbonyl chemistry. Now recall that aldehydes and ketones can react with an enolate anion via an aldol reaction. If we take a look, let's see our carbonyl chemistry first and see how it relates to our purine chemistry next. So remember that we have our carbonyl, and the carbon next to it is the alpha carbon.

If we use a base, we can deprotonate that alpha carbon, which holds on to the electrons. That alpha carbon now is negatively charged. And what it could do is it can then do a nucleophilic attack on another aldehyde or ketone, kicking this bond up. And in that way, we're connecting this to this water on the bottom, protonating the negative oxygen that would have formed. So we have an OH here.

We have this structure. We just created a beta hydroxy carbonyl compound. And remember, this is alpha and this is beta. These types of reactions tend to go a step further to create an alpha beta unsaturated product. So what would happen is we would create a pi bond.

So here goes our pi bond here, with our 2 R groups still attached. We've lost the OH. So we've created an alpha beta unsaturated. Now remember, benzylic carbon compounds tend to readily form these alpha beta unsaturated products. The same can be seen with pyridine.

So again, if we're looking, you're going to see how similar they are. We're going to deprotonate here, the benzylic carbon. It can then react with an aldehyde or ketone. We're going to create this. So there goes this portion.

The water again protonates the oxygen to make it OH. And then alpha beta, we can do dehydration and we lose water. So at the end, we again make an alpha beta unsaturated structure. Here, this is even better because it's even more conjugated, which makes it even more stable. Right?

This is seen even more so with the pyridine structures. Again, this is a mix of things we've seen in the past with all the reactions, and now we're just applying it to our pyridine molecule.

Side-Chain Reactions of Substituted Pyridines Example 3

In this example, it says, using 2-methylpyridine as a starting material, predict the final product based on the list of reagents given. So what we're going to do here is we are going to deprotonate this carbon because of the presence of this strong base in the form of butyllithium. So that's going to give us a negatively charged carbon or negatively charged benzylic carbon, which would then react with this aldehyde. So this is going to come in, hit here, and kick this bond up. Water here would then protonate that oxygen.

Now normally, we'd give this thing time to undergo condensation to make an alpha-beta unsaturated structure, but we quickly followed up with PCC over methylene chloride. Remember, PCC is a weak oxidizing agent that would change my alcohol here into a carbonyl group. So instead of creating an alcohol group here, we're going to make a carbonyl group. And then finally, we follow up with the Wolff-Kishner reaction. So remember, under Wolff-Kishner, this is a way of completely removing the carbonyl group.

So it gets rid of the double bond O. We'll have, here now, a kel chain at the end. So this will be our final answer. Alright. So based on the reagents given, this is what we get at the end.

We get an ortho-alkylated pyridine's ring.

Starting from pyridine, show the reagents necessary to make the following compound. 

• A.
• B.
• C.
• D.

Here’s what students ask on this topic:

Why are the benzylic hydrogens in substituted pyridines more acidic than those in benzene?

The benzylic hydrogens in substituted pyridines are more acidic than those in benzene due to the presence of the electronegative nitrogen atom in the pyridine ring. When a benzylic hydrogen is removed, the resulting carbanion is stabilized by resonance and the inductive effect of the nitrogen atom. The nitrogen atom, being more electronegative, can better stabilize the negative charge, leading to a lower pKa value (around 34-36) compared to the benzylic carbanion in benzene (pKa ~41). This increased acidity is crucial for various side-chain reactions in pyridine derivatives.

What are the pKa values for the C2, C3, and C4 positions in alkylated pyridines?

The pKa values for the C2, C3, and C4 positions in alkylated pyridines vary due to the different resonance stabilization effects. The C2 and C4 positions have pKa values of approximately 34, making them more acidic. This is because the negative charge can be delocalized onto the electronegative nitrogen atom. In contrast, the C3 position has a higher pKa value of around 36, indicating it is less acidic. This is because the negative charge cannot be delocalized onto the nitrogen atom, making it less stable.

How do resonance structures affect the acidity of alkylated pyridines?

Resonance structures significantly affect the acidity of alkylated pyridines. When a benzylic hydrogen is removed, the resulting carbanion can resonate through the pyridine ring. For C2 and C4 positions, the negative charge can be delocalized onto the electronegative nitrogen atom, stabilizing the carbanion and lowering the pKa value (around 34). For the C3 position, the negative charge cannot be delocalized onto the nitrogen, resulting in less stabilization and a higher pKa value (around 36). This difference in resonance stabilization explains the varying acidity of different positions in alkylated pyridines.

What is the mechanism of nucleophilic addition reactions in alkylated pyridines?

Nucleophilic addition reactions in alkylated pyridines are similar to enolate anion reactions in carbonyl chemistry. When a strong base deprotonates the benzylic carbon, a carbanion is formed. This carbanion can then perform a nucleophilic attack on an aldehyde or ketone, forming a new carbon-carbon bond. The intermediate product is a beta-hydroxy carbonyl compound, which can undergo dehydration to form an alpha-beta unsaturated product. This process is facilitated by the resonance stabilization of the carbanion and the inductive effect of the nitrogen atom in the pyridine ring, making the reaction more favorable.

Why are C2 and C4 positions in alkylated pyridines more acidic than the C3 position?

The C2 and C4 positions in alkylated pyridines are more acidic than the C3 position due to the resonance stabilization of the carbanion. When a hydrogen is removed from the C2 or C4 position, the negative charge can be delocalized onto the electronegative nitrogen atom, stabilizing the carbanion and lowering the pKa value to around 34. In contrast, the C3 position does not allow the negative charge to be delocalized onto the nitrogen, resulting in less stabilization and a higher pKa value of around 36. This difference in resonance stabilization explains the varying acidity of these positions.