Imine vs Enamine

Imines and Enamines are the products formed by the nucleophilic addition of a primary (1˚) amine, secondary (2˚) amine, or ammonia (NH₃) to carbonyls such as ketones or aldehydes.

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Imine vs. Enamine: What’s the difference? 

Imines look like carbonyls and are formed from a primary amine (or ammonia) reacting with some type of acid (H⁺, H₃O⁺) with a carbonyl. In simplest terms, it looks like a carbonyl with a double bond to nitrogen instead of oxygen.

Imine Structure

Notice that after the reaction is over, you will be left with a structure that looks like this (above in green). The 3 carbon chain coming off is simply the R group that was attached to the original primary amine before it reacted. 

On the other hand, enamines form from carbonyls reacting with a secondary amine and does not have a double bond to nitrogen, but instead to carbon.

You can remember this because the nitrogen already has 2 R groups in the beginning and therefore would be positively charged if it contained a double bond. For example:

Enamine Structure

Notice that the double bond here is between 2 carbons: 1 from the carbonyl carbon that formed it, and the other is the alpha carbon.

Enamines are formed from the same mechanism that imines are formed except for the final step which is deprotonation of the iminium cation (more on this to come later).

The Reaction:

     A. Reagents 

Imine reaction

The reagents needed to form an imine are simple and really come down to 3 things:

1. A carbonyl
2. A primary (1˚) amine or NH₃, a type of 0˚ amine
3. And finally an acid such as H⁺

It is commonly seen to combine parts 2 and 3, the NH₃ and the H⁺, so that we don’t have an extra step involved. If we did this the reaction simply looks like this:

Ammonium Preparation

For enamines, the amine being used will be 2˚ and therefore commonly seen is a cyclic amine such as azetidine:

Secondary Cyclic Amine

Assuming protonation like we did before, we would get the reaction seen below and be ready to start our mechanism.  

Protonated Amine

Now, as we go into the mechanism we will focus on forming the imine through 0˚ or 1˚ amines. However, if we use the cyclic protonated amine above, the mechanism is the same until we get to the end 

     B. Mechanism Overview

Protonation is the first step where the oxygen from the carbonyl reacts with the protonated amine that we formed above. As you can see below we have already taken a proton and formed our ⁺OH.

From here we can draw a resonance structure so that we have a positive charge not on the oxygen anymore like before, but now on the carbon of the original carbonyl.

Resonance Structures

The green resonance structure is not absolutely necessary to draw because the arrows will be exactly the same once we perform the next step, however it is a more complete picture and sometimes easier to visualize.

Next, a nucleophilic attack [1,2-addition] occurs with the lone pair from the original neutral amine to the positive charge on the carbon. From this, we get a tetrahedral intermediate with a new C-N bond and nitrogen now has a positive charge again.

Tetrahedral Intermediate 

*Note: Does this look familiar? This is a very common intermediate for nucleophilic addition reactions such as the acetal/hemiacetal mechanism.

Now, you may want to draw the NH₃⁺ with one of its H’s hanging off to the side because we are trying to eliminate water and therefore do a proton exchange, which is our next step. This means the oxygen from the OH will grab one of the H’s from the H-NH₂⁺ (this is simply NH₃⁺ arranged differently) and form –H₂O⁺.

Proton Transfer Step

Once we form water we can kick out our leaving group or eliminate water. The way we do this is to use the electrons from the nitrogen, form a double bond between carbon and nitrogen and in the process form an iminium ion. Is the product looking familiar now?

Elimination Step

At this point we have our iminium cation which will be your checkpoint for these types of reactions. If you don’t get this structure you most likely did something wrong and should go back to your mechanism and the different steps to figure out where you want off track.

For the enamine mechanism, this will be the tetrahedral intermediate formed before we do a proton transfer and form water. From here, water will be our leaving group again that will be kicked out in our next step.

Enamine Tetrahedral Intermediate 

     C. Intermediates 

This is the general formula for the iminium cation (R2C=NR₂⁺), which is the key intermediate for imine and enamine reactions.

Iminium Cation General Structure

The iminium cation formation will be our last intermediate before we get to our final product which can either be an imine or an enamine. From here we can use water or the conjugate base of our original NH₄⁺  which is NH₃ (ammonia), to deprotonate the final H on the nitrogen to give us our final product, an imine.

Iminium Cation

The iminium cation for enamines looks very similar. Below is an example of one when the amine used was secondary (2˚) and cyclic.

Iminium Cation of an Enamine

     D. Products

Imine Product

Imine general formula: R₂C=NR

The product of the imine mechanism will look like a carbonyl except there is a N (nitrogen), instead of an O (oxygen) and an extra H (hydrogen) is attached. The rest will simply be our byproducts.

Also, notice that NH₄⁺ was reproduced, but if we used water to deprotonate our iminium cation we would instead have H₃O⁺ and NH₃ as byproducts instead. Both would be correct!

Enamine Product

For enamines our product would not have the double bond to nitrogen, but instead a double bond from the original carbonyl carbon position to one of the alpha carbons (more on this below).

Specific for Enamines: 

All the steps above were described for when a 0˚ or 1˚ amine is used, however when a 2˚ degree amine is used we get a different last step. That is because if we look at our iminium cation (in green above) we have no hydrogen to deprotonate on nitrogen.

The question we ask ourselves then would be: Where do we have a hydrogen (H) to remove from? The answer to that is at our alpha position from our original carbonyl.

Just as before, remember we can deprotonate with the conjugate base, which in this case would be the cyclic amine (seen below), or water.

Deprotonation Step for Enamines

Related Topics: 

     1. The alpha (α) position 

We mentioned the alpha position briefly when talking about enamines, but why is this important? Well, it turns out that enamines can do reactions at their alpha position just like many other compounds in Organic Chemistry, like enols & enolates.

The alpha position, due to its unique acidity (pka ~ 20), allows for compounds like enolates and enamines to undergo different reactions (alkylation an acylation) at the alpha carbon.

Enamines specifically are able to use their nucleophilic alpha position to add different R groups and form alpha substituted carbonyls. This happens via an iminium salt intermediate that is able to be hydrolyzed back to a carbonyl.

Enamine Alkylation & Hydrolysis    

2. Hydrolysis 

Hydrolysis in this case is referring to the ability to go from our iminium salt back to our carbonyl using water and a little bit of acid. The mechanism involves 5 steps: protonation, addition of H2O, proton transfer, elimination, deprotonation. Seem familiar? 

Here is a video of that mechanism being used to convert an ester back to a carboxylic acid.

The hydrolysis can be done for both imines and enamines to turn them back into carbonyls, as see below with the hydrolysis of an enamine.

Enamine Hydrolysis

This hydrolysis mechanism will be important when doing enamine alkylation and acylation problems because hydrolysis back to the carbonyl is usually the last step.

     3. Tautomerization 

Another important topic arises when discussing enols, the alpha carbon, and ketones in particular, which is tautomers and tautomerization. The reason this is applicable is because imines and enamines can tautomerize with each other.

First, we have keto-enol tautomerization which can be acid or base catalyzed. Remember, these 2 compounds are simply constitutional isomers.

Keto-Enol Tautomerization

The same rule applies with imines and enamines. Notice the only difference between the 2 is the double bond and 1 H (hydrogen) switched places.

Imine Enamine Tautomerization

This concept of tautomerization with imines and enamines will become increasingly important when dealing with synthesis reactions where you need to add R groups to the alpha position.

     4. Schiff bases & other nitrogen compounds 

Now, when we say imines we should recognize that they can also be referred to as Schiff bases when the group attached to the N is not hydrogen, but an alkyl group.

Take for example the structure below, which is the general structure for an imine.

Imine General Structure

We can actually call this compound different names based on what R1, R2 and R3 is. Let’s go through some of the most common names:

• If R3 ≠ H it is termed Schiff base
• If R3 = H and R1 or R2 = H it is termed primary aldimine meaning the imine was derived from an aldehyde
• If R3 ≠ H and R1 or R2 = H it is termed secondary aldimine
• If R3 = H and R1 and R2 ≠ H it is termed primary ketimine meaning the imine was derived from a ketone
• If R3 ≠ H and R1 and R2 ≠ H it is termed secondary ketimine
• 
  

Some other names you may come across are aziridine, hemiaminals, azides, and a nitroso compound.

• Hemiaminals are simply the first intermediate we see in the imine mechanism where a central carbon is attached to a hydroxyl (OH) an amine (NR2), and 2 R groups.
• Nitroso compounds are those that contain a “­–N=O” group where the N (nitrogen) is attached to an R group such as carbon, nitrogen and even sometimes oxygen.
• Aziridine refers to a structure with the chemical formula C2H5N. It is basically a 3 membered ring with a NH group attached to 2 CH2’s. It can also be seen named as ethylene imine.
• Finally, azides are simply N3- or sometimes referred to as the azide ion. You may have seen this structure back when you learned about formal charges. Structure wise it can be represented 3 different ways if we include resonance structures.

     5. Aldol condensation

Lastly, just be aware that enolates, which react very similar to enamines, can undergo a condensation reaction known as aldol condensation. It is when 1 enolate acts as a nucleophile (Nu-) and attacks an electrophile (E+) such as another carbonyl.

This forms what is known as a ß-hydroxycarbonyl which can dehydrate via 2 mechanisms to form a conjugated unsaturated carbonyl.

Here is an example: (more details on this later)

Aldol Condensation Mechanism

Q and A: 

Why is it necessary to draw equilibrium or reversible arrows?

• That is because this is a reversible reaction as seen by the hydrolysis mechanism. We can interconvert between carbonyl and imine/enamine via acid catalysis and water. 

What do we get if we use a tertiary amine?

• Tertiary amines have no N-H bond and therefore cannot form the first intermediate in imine and enamine reactions which is the hemiaminal. While good nucleophiles, NR3 groups will not react efficiently with aldehydes and ketones.  

Can we go from an imine to an enamine?

• Yes, through a tautomerization. This can be acid or base catalyzed and the result is two constitutional isomers that can interconvert.  

What is the mechanism for the reverse reaction going from an imine or enamine back to the original carbonyl?

• This is termed hydrolysis and the mechanism can be found above in the related topics section for enamines. The only difference for imines is that the first step involves protonation of the nitrogen to form the iminium cation.  

What were the 5 steps again for the mechanism?

• The 5 steps for the imine and enamine mechanism are protonation, nucleophilic attack, proton transfer, elimination and deprotonation. 

Summary of Imine & Enamine Mechanism:

     I. Imine:

Imine Mechanism

Here is a summary of the imine mechanism. Notice the 5 steps involved: Protonation, Nucleophilic Attack, Proton Transfer, Elimination and Deprotonation.

     II. Enamine: 

Enamine Mechanism

Here is a summary of the enamine mechanism. The same 5 steps for the imine mechanism can be seen here, with the exception of the deprotonation step of the iminium cation where our conjugate base grabs a hydrogen from the alpha carbon.