SNAr Reactions of Pyridine - Online Tutor, Practice Problems & Exam Prep

Nucleophilic aromatic substitution (SNAr) reactions of pyridine are more favorable than those of benzene due to the electron deficiency of pyridine. Key reactions include the Chichi Babin reaction, which produces 2-aminopyridine by substituting an NH₂ group using sodium amide, and organometallic reactions that introduce alkyl groups via Grignard or organolithium reagents, resulting in ortho-alkylated pyridine. Both reactions follow an addition-elimination mechanism, highlighting the versatility of pyridine in organic synthesis.

SNAr Reactions of Pyridine Concept 1

Hey, everyone. So in this video, we're going to talk about SNAr reactions of our pyridine. Now when we say SNAr, that stands for nucleophilic aromatic substitution. Here, we're going to say that the electron deficiency of pyridine makes it more susceptible to nucleophilic aromatic substitution than benzene. And we're going to say two major NAS or nucleophilic aromatic substitution reactions of pyridine involve substitution on the ortho position.

Here we have reaction 1, which is called the Chichibabin reaction. Now this is typical of our SNAr reaction of NH₂ onto the pyridine ring. And then we have an organometallic reaction, where this is an SNAr of an alkyl anion onto the pyridine ring. Right now, let's look at the first reaction, our Chichibabin reaction. We're going to say that this is a method to create 2-aminopyridine by reacting pyridine with sodium amide.

Remember, sodium amide represents a strong base. So here we have our pyridine, and we're looking at this hydrogen here. Through the use of sodium amide over our ammonia solvent, followed by H⁺ and water, which we could think of as acidic hydrolysis, we would have our hydrogen being replaced with an NH₂. This would make our 2-aminopyridine product, and then we'd have our hydrogens.

So this blue hydrogen here with another hydrogen to give us an H₂. This H₂ would just be a byproduct. What's more important is that we made a 2-aminopyridine through the Chichibabin reaction. Now recall when we talk about nucleophilic aromatic substitution, it occurs by an addition-elimination mechanism. So when we look at the mechanism for this reaction, we're going to remember some of the NAS reactions we've seen before in the past.

Alright. So it's going to be stuff that's not exactly new, but we're just applying it now to make a 2-aminopyridine product.

SNAr Reactions of Pyridine Example 1

Hey, everyone. So in this example, it says, provide the mechanism for the Chichibabin reaction of 4-methylpyridine. And so we're gonna say the mechanism itself follows these important steps. Step 1 is nucleophilic attack; Step 2 is loss of leaving group; and steps 3a and 3b can be seen as basically subdivisions of proton transfer.

3a is proton transfer, and 3b is protonation. Now for step 1, we have the amide ion attacks the ortho position of Pyridine forming a tetrahedral intermediate. So here we're gonna have our 4-methylpyridine. So we have this structure here, and it says the ,amide ion is gonna do a nucleophilic attack of this structure. So it's gonna come in, hit here, causing this bond to come to the nitrogen here.

So what we're gonna get initially is this: Nitrogen now is negatively charged. Here goes the NH₂^- that we added. Next, we're gonna say step 2, the nitrogen atom forms the double bond, kicking out the hydrogen as a hydride ion to restore aromaticity. So here, nitrogen decides it wants to remake its double bond, so it does.

Now, normally, we don't want strong bases to be leaving groups. We've learned that weak bases are good leaving groups, but this is overwritten because we're making an aromatic ring. We're willing to let go of a strong base as a leaving group because it helps to reestablish our very stable aromatic ring. So what we're gonna have here now, there goes a double bond. There goes our structure.

Next, we're gonna have deprotonation of the amino group by the hydride ion. So I'm gonna bring this down here so we can see this part better. Alright. So again, this is what we made initially. K.

There goes my NH₂. We're gonna say the hydride ion that left can come and deprotonate. It's gonna remove one of these hydrogens, and nitrogen will hold on to the electrons. So we have this. So there goes my negative nitrogen now.

In step 3b, we're gonna say protonation of the conjugate base anion by water forms an amino pyridine. So now we're gonna bring in the water molecule. This water molecule will protonate this negative NH portion to give us our final product. So now, here goes our NH. Now that's gonna be coming NH₂.

And that's how we get our final answer here. And remember, we had a methyl group here on position 4 the whole time. So this gives us our final product of 4-methylpyridine at the end. We just worked it out mechanistically to see how this occurs. But remember, in simple terms, all that happens is where we replace the hydrogen that was there with an amino group, an NH₂ group.

Select the best set of reagents for the following synthesis. 

• A. 1) NaNH₂, NH₃    2) H⁺, H₂O    3) NaNO₂/HCl;    4) NaCN/DMSO;      5) CH₃I;       6) Br₂/hν
• B. 1) NaNH₂, NH₃    2) H⁺, H₂O    3) NaNO₂/HCl;    4) H₃O⁺;      5) NaOH;      6) CH₃CH₂CH₂Br
• C. 1) NaNH₂, NH₃    2) H⁺, H₂O    3) NaNO₂/HCl;    4) HBF₄;     5) CH₃I;       6) Br₂/hν
• D. 1) NaNH₂, NH₃    2) H⁺, H₂O    3) NaNO₂/HCl;    4) H₃O⁺;     5) H₃PO₃;      6) CH₃CH₂CH₂Br

Starting from pyridine, use your knowledge of diazonium salts and the Chichibabin Reaction to synthesize the following product. 

• A.
• B.
• C.
• D.

SNAr Reactions of Pyridine Concept 2

Now the second type of reaction we can look at are our organometallic reactions. These deal with the treatment of pyridine with either a Grignard or organolithium reagent to produce an ortho alkylated pyridine ring. So if we take a look here, we have our pyridine and we have R-M. R here just stands for carbon. It could be a methyl, an ethyl, a longer chain.

It could be a ring. It could be benzene. M here stands in for MGBR, if we were talking about Grignard, or lithium, if we're talking about an organolithium reagent. All that happens here is just think of the hydrogen here getting replaced with the carbon group here. At the end, that gives us an orthoalkylated pyridine ring.

As simple as that. So you have your pyridine ring. You can introduce Grignard or an organolithium reagent to bring in an alkyl group or a carbon group to that position on the pyridine ring.

SNAr Reactions of Pyridine Example 2

In this example, it says predict the final product based on the list of reagents given. So here we have a cyclopentane ring. When we do bromine over ultraviolet light, this is radical catalyzed halogenation. That's going to add a Br to the ring. Next, we do magnesium over ether.

Remember, that's going to change this into a Grignard reagent. And then finally, I'm introducing pyridine. And we know with this reaction, all that happens is we're going to substitute out this hydrogen for the carbon group of the Grignard reagent. At the end, we get an orthoalkylated pyridine ring. So what we get here at the end is this answer.

This would be my final answer. We have our pyridine ring with this cyclopentane attached to carbon 2 of the pyridine ring.

Determine the final product for the following reaction. 

• A.
• B.
• C.
• D.

Propose a synthetic route for the following transformation.

• A.
• B.
• C.
• D.

Here’s what students ask on this topic:

What is the Chichibabin reaction in pyridine chemistry?

The Chichibabin reaction is a nucleophilic aromatic substitution (SNAr) reaction that involves the substitution of a hydrogen atom on the pyridine ring with an amino group (NH₂). This reaction is typically carried out by reacting pyridine with sodium amide (NaNH₂) in an ammonia solvent, followed by acidic hydrolysis. The product of this reaction is 2-aminopyridine. The mechanism follows an addition-elimination pathway, where the nucleophile (NH₂^-) adds to the electron-deficient pyridine ring, followed by the elimination of a hydrogen atom.

Why is pyridine more susceptible to SNAr reactions than benzene?

Pyridine is more susceptible to nucleophilic aromatic substitution (SNAr) reactions than benzene due to its electron-deficient nature. The nitrogen atom in the pyridine ring is more electronegative than carbon, which withdraws electron density from the ring, making it more electrophilic. This increased electron deficiency makes the pyridine ring more reactive towards nucleophiles, facilitating SNAr reactions. In contrast, benzene is more electron-rich and less reactive towards nucleophiles.

What are organometallic reactions involving pyridine?

Organometallic reactions involving pyridine typically refer to the substitution of a hydrogen atom on the pyridine ring with an alkyl group using organometallic reagents such as Grignard reagents (RMgBr) or organolithium reagents (RLi). These reactions result in the formation of ortho-alkylated pyridine. The general mechanism involves the nucleophilic attack of the organometallic reagent on the electron-deficient pyridine ring, followed by the elimination of a hydrogen atom, leading to the substitution of the hydrogen with the alkyl group.

What is the mechanism of nucleophilic aromatic substitution (SNAr) in pyridine?

The mechanism of nucleophilic aromatic substitution (SNAr) in pyridine follows an addition-elimination pathway. First, the nucleophile adds to the electron-deficient carbon atom of the pyridine ring, forming a negatively charged intermediate known as a Meisenheimer complex. This intermediate is stabilized by the electron-withdrawing nature of the nitrogen atom in the pyridine ring. In the second step, the intermediate undergoes elimination, where a leaving group (usually a hydrogen atom) is expelled, resulting in the substitution of the nucleophile on the pyridine ring.

How does the Chichibabin reaction produce 2-aminopyridine?

The Chichibabin reaction produces 2-aminopyridine by reacting pyridine with sodium amide (NaNH₂) in an ammonia solvent. The reaction proceeds through an addition-elimination mechanism. First, the nucleophilic NH₂^- adds to the electron-deficient carbon atom at the ortho position of the pyridine ring, forming a negatively charged intermediate. This intermediate then undergoes elimination, where a hydrogen atom is expelled, resulting in the substitution of the NH₂ group at the ortho position, forming 2-aminopyridine.