Robinson Annulation

Core Concepts

The Robinson Annulation is a reaction that combines two other mechanisms in organic chemistry, the Michael Addition and an intramolecular aldol condensation, to create a new six membered ring containing an alpha,beta-unsaturated ketone. 

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Overview of the Robinson Annulation

The Robinson Annulation is a method of synthesizing a six membered ring with an alpha,beta-unsaturated ketone that combines two already known reactions, the Michael addition and the intramolecular aldol condensation. Those each will be covered in detail later on, but it might be helpful to start by looking at the big picture.

robinson annulation start and end materials

The starting materials are a ketone, and an alpha,beta-unsaturated ketone, which is a ketone with an alkene only one carbon away. In the image above, it’s reactant above the arrow. After the two reactions have taken place, the final product is a 6-membered ring that contains one alpha,beta-unsaturated ketone, as shown above. 

Now, the in-between steps will combine the two separate molecules into one via a Michael Addition, and then react two ends of the resulting single molecule with itself in order to close the ring via intramolecular aldol condensation. 

Review of intramolecular reactions

Before getting into the mechanisms, it’s important to briefly review intramolecular reactions. Because these reactions involve a nucleophile and electrophile on the same molecule, these can be confusing.

Though it seems complicated, intramolecular reactions actually work exactly the same way as intermolecular reactions, where the reactants are separated. When a nucleophile attacks an electrophile, it creates a bond between the two, and kicks out the leaving group. For the intramolecular reaction, the nucleophile, electrophile, and leaving group are all in the same molecule.

normal nucleophilic attack

Reaction in two parts

As previously stated, the two reactions that make up the Robinson Annulation are first a Michael addition and second an intramolecular aldol condensation.

Michael Addition

First, the Michael addition combines two separate molecules via enolate chemistry. Here is what the reaction looks like. 

michael reaction overview

The first reactant is an alpha,beta-unsaturated ketone, which is a molecule containing one carbonyl, as well as an alkene only one carbon away. This molecule is conjugated and therefore a good electrophile. This reactant is the Michael Acceptor.

The second reactant contains two electronegative functional groups separated by one carbon as well. This makes that carbon a great nucleophile due to two groups pulling on the center carbon’s electrons. This is the Michael Donor. 

A base must also be present to catalyze this reaction. 

The mechanism starts with the base removing a hydrogen from the central carbon of the Michael Donor. The resulting carbanion donates its electrons to the nucleophilic carbon on the Michael Acceptor, the third carbon from the ketone oxygen. This creates an enolate on the acceptor. 

mechanism of michael addition 1

The oxygen now donates its electron pair back to the carbonyl carbon atom, and the pi bond next to it attacks the proton on the base.

In the case of the Robinson Annulation, the Michael Donor must have a ketone on it in order to form the diketone that reacts in the aldol condensation step. 

Intramolecular Aldol Condensation

The second part of the Robinson Annulation is the intramolecular aldol condensation. This is the same as a regular aldol condensation, just with two ketones on the same molecule.

First, a base must be added to form an enolate from one of the ketones. Luckily, the base is already present because of the first step in this reaction. Since both sides are symmetrical, either enolate may form. However, one ring may be more favored over another, due to ring strain or sterics. Below is a diol that could form enolates by deprotonating the terminal carbon (C1), or the interior carbon (C3). The condensation following deprotonation of C3 gives a strained four membered ring, while deprotonation of C1 gives a six membered ring. Thus, deprotonation at C1 will be more likely, since the final reaction product is more favored.

4 vs 6 membered ring

The carbanion at C1 attacks the carbon of the other carbonyl, five carbons away at C6. This interaction forms the 6-membered ring. Finally, the now negatively charged C6 oxygen is protonated from the conjugated acid, and base removes an H from the next C to form another enolate. This enolate then pushes off the adjacent OH to reform a double bond between those two carbons, completing the reaction.

The final result is a 6-membered ring containing an alpha,beta-unsaturated ketone.

Applications of the Robinson Annulation

The goal of the Robinson Annulation is to create the alpha,beta-unsaturated ketone on the 6-membered ring. This reaction is very commonly used for its ability to easily form the 6-membered ring. Therefore, it is a good choice for synthesizing molecules like steroids and other natural products.