Hofmann Rearrangement - Online Tutor, Practice Problems & Exam Prep

The Hofmann rearrangement, also known as Hofmann degradation, transforms amides into primary amines through a two-step mechanism involving a base and bromine (Br₂). Initially, the base deprotonates the amide, creating a nucleophile that attacks Br₂, forming an N-bromoamide. This intermediate undergoes a rearrangement to yield isocyanate, which reacts with the base to form a primary amine and liberate CO₂ gas as a byproduct. The reaction highlights the importance of understanding nucleophilic attack and rearrangements in organic synthesis.

General Reaction

Hey guys. In this video, we're going to break down the mechanism for a reaction called the Hofmann rearrangement. The Hofmann rearrangement is also known as the Hofmann degradation. If you hear that term, just consider it synonymous with Hofmann rearrangement. It's a method to turn amides into primary amines. Now guys, I do want to let you know that this is similar to another mechanism that you may or may not know at this point called the Curtius rearrangement. I'm just going to put here it's similar to Curtius rearrangement. Just letting you know, if you have seen my video on that reaction or if you've learned about it already, this mechanism is going to remind you a whole lot of that one. They're kind of similar. Now if you don't know that reaction yet, it's fine because I'm going to teach you the mechanism anyway. You don't need to know the Curtius to understand this reaction. But similar to Curtius, there's going to be 2 really similar things here which is that this is a reaction intermediate. Okay. Now, I use the term intermediate here very precautiously because I don't like to say intermediate. It actually sounds like it's got a charge or that it's a highly energized species. Isocyanate is pretty stable. I'm just saying it's like an intermediary structure where we make the isocyanate first and then we add something to it. Let's just make sure that we're clear on that. Then also similar to Curtius, it's going to liberate CO2 gas as a byproduct. But other than that, it's a mechanism all on its own. So guys, here's the general reaction. We've got an amide and you react it with 2 different steps. One is you have a base. So you have some kind of base that's going to deprotonate the nitrogen, turn it into a nucleophile and we've got an electrophilic Br2. The Br2 is going to be what the nitrogen then attacks. After you're able to add one equivalent of the bromine, what we're going to see is a rearrangement take place and a decarboxylation that's going to produce our gas or CO2 gas and the part we really care about, the amine. Now notice that one thing that happens here, just talking in general terms, is that the R group that was originally on one side of the carbonyl eventually gets attached directly to the N. Notice that before I had them separated by a carbon and now I have them directly attached to each other. That's because I'm able to get rid of the carbonyl in the middle through my decarboxylation that you're going to see later. Now in the next video, I'm going to go through the whole mechanism of Hofmann rearrangement so you guys know exactly what to expect.

Mechanism

All right, guys. So we're going to start off with our amide, NH₂ and our R group on one side. Well, that's part of the amide. And in our first step, we're going to react it with our base. So usually we use sodium hydroxide, OH^-. So in my first step, what I'm going to do is I'm going to deprotonate the amide to make it nucleophilic. So I'm going to take out an H, make a double bond, kick my electrons up to the O. This is now going to give me a nucleophilic structure that looks like this. Now when this structure interacts with my Br₂, remember that, guys, Br₂ is a pretty good electrophile. Remember that we have a lot of instances of negative charges attacking Br₂. We're going to do that. We're going to kick our electrons back down, use this nucleophilic double bond to attack one of the Brs and kick out one. What this is going to give us is a new structure that looks like this. It's a nitrogen with now one hydrogen. Actually, let me flip that around a little bit. Let me put the bromine here. That's the new bromine and the hydrogen there. This is what we would call an N-bromoamide because we have a bromine coming straight off of the nitrogen. The thing about the N-bromoamide is that it can react with my OH^- again because it has an H still. We're going to do that whole step again. Again, we're going to take another equivalent of our OH^- and you can predict what's going to happen. We're going to form the same type of structure. We get a nucleophilic molecule. Let's go ahead and bring this structure down. We've got O^-. We've got a double bond to N, to bromine. And that's pretty much it. And then we're always getting water here. You would have water here and you'd have water here that was created because your OH grabbed an H. Awesome guys.

Well, this is the part that gets a little bit weird. This is the rearrangement step. This is the hard part. This is why this is a tricky reaction. So I'm going to put here this is the rearrangement. Because instead of doing what we did before, we're going to grab a bromine, we're going to get a strange rearrangement where eventually this R group on this side is going to attach to the N and make our isocyanate. How does that happen? Well because these electrons are going to make a double bond. Now notice that this carbon is in a tricky situation right here, this carbon. Let me just write that really big. Why? Because if you make a double bond, now you've got your 4 carbons. You would assume that if you make that bond, you have to break a bond and you'd have to break a bond in order to preserve the octet of the carbon. If it were me predicting this mechanism and I was just drawing from my past experience, I would think that the next bond that breaks is this one. Don't draw it. But that's what I would think. I would think make a bond, break a bond, make a negative charge on that end. Great. Awesome. But that's not what happens. This is where the rearrangement part comes Instead of breaking that double bond, it's actually going to be more energetically favorable to break this single bond and attach that carbon to the nitrogen. Notice that by doing that, I still preserve my octet but now I'm going to get that the nitrogen is attached to an R group. Once I do that, what's going to happen? I get my isocyanate. By the way, we still got a problem if you make of new bonds in the N, now the N is going to have a formal charge if you don't kick something out. We're going to kick up the Br. Now we get our isocyanate which is oxygen double bond carbon. That's from the electrons coming down, making a double bond. Now double bond nitrogen and then the nitrogen is attached to an R group. This is our isocyanate.

Now guys, isocyanate is an important molecule on its own and there's a ton of different things that isocyanate can react with. It can react with amines. It can react with alcohol. It can react with water to make all kinds of structures. But in this case, we're only going to react with one thing which is the base that we used for deprotonation. We're going to react with base. When we react with base, where do you think a nucleophilic attack would add to my isocyanate? What do you think is the most electrophilic atom or the most positively charged atom on the isocyanate? Good job. You guys got this one. It's the carbon, right? We've got that positively charged carbon because of our strong dipoles pulling away from it. We're going to make a bond and break a bond. What that's going to give us is now a double bond O C with an OH on one side. And then on this side, we're going to have a nitrogen with an R group. Now I'm going to skip a step if you guys don't mind because notice that I would have

Here’s what students ask on this topic:

What is the Hofmann rearrangement mechanism?

The Hofmann rearrangement mechanism involves converting an amide into a primary amine using a base and bromine (Br₂). First, the base deprotonates the amide, creating a nucleophilic species. This nucleophile attacks Br₂, forming an N-bromoamide. The N-bromoamide then undergoes a rearrangement, where the R group migrates to the nitrogen, forming an isocyanate intermediate. The isocyanate reacts with the base, leading to the formation of a primary amine and the release of CO₂ gas as a byproduct.

What are the similarities between Hofmann rearrangement and Curtius rearrangement?

Both the Hofmann and Curtius rearrangements involve the formation of an isocyanate intermediate and the release of CO₂ gas. In the Hofmann rearrangement, an amide is converted into a primary amine using a base and Br₂, while in the Curtius rearrangement, an acyl azide is converted into an isocyanate, which can then be hydrolyzed to form a primary amine. Both reactions involve nucleophilic attack and rearrangement steps, making their mechanisms quite similar.

What are the reagents used in the Hofmann rearrangement?

The Hofmann rearrangement requires two main reagents: a base and bromine (Br₂). Commonly, sodium hydroxide (NaOH) is used as the base. The base deprotonates the amide, making it nucleophilic, which then attacks the electrophilic Br₂. This sequence of reactions leads to the formation of an N-bromoamide intermediate, which undergoes rearrangement to produce an isocyanate, eventually yielding a primary amine and CO₂ gas.

What is the role of the base in the Hofmann rearrangement?

The base in the Hofmann rearrangement serves multiple roles. Initially, it deprotonates the amide, creating a nucleophilic species that can attack Br₂. Later, the base facilitates the rearrangement of the N-bromoamide to form the isocyanate intermediate. Finally, the base reacts with the isocyanate, leading to the formation of the primary amine and the release of CO₂ gas. Sodium hydroxide (NaOH) is commonly used as the base in this reaction.

What are the byproducts of the Hofmann rearrangement?

The primary byproducts of the Hofmann rearrangement are carbon dioxide (CO₂) gas and water (H₂O). The CO₂ gas is released during the decarboxylation step, where the isocyanate intermediate is converted into the primary amine. Water is formed during the deprotonation steps when the base (usually NaOH) removes protons from the amide and other intermediates.