Robinson Annulation is a process used in organic chemistry that is required for ring formation. Sir Robert Robison discovered the process in 1935, and the process was consequently named after him. In the method of Robinson annulation, three new carbon-carbon bonds are made by creating a six-membered ring. Methyl Vinyl and Ketone are used in this process, forming an aldol condensation following the formation of an αβ-unsaturated ketone using Michael addition. It is used for creating polycyclic compounds having six-membered rings, as in the case of steroids. The word 'Annulations' stands for 'building ring' and is a very complex system.
Processes Involved In Robinson Annulation
Michael addition- The alpha beta-unsaturated compounds that go through Michael's addition are the Michael acceptor, product Michael adduct, and the nucleophile-Michael donor. Michael addition involves 1,4-addition reactions of αβ-unsaturated nitriles and carbon nucleophiles, which happen to be resonance-stabilized.
Aldol condensation- This process takes place in aldehydes with an α-Hydrogen, which reacts with a diluted base, leading to the formation of β-Hydrogen aldehydes are referred to as aldols. Crossed aldol condensation occurs when this process takes place in the form of condensation occurring between two carbonyl compounds, which are not similar to one another.
Robinson Annulation Mechanism
The Robinson annulation reaction has Michael's addition and aldol condensation as essential parts.
First, in the Robinson annulation mechanism, the Michael reaction occurs after the aldol condensation occurs.
The next step in the Robinson annulation reaction mechanism is where the αβ unsaturated ketone undergoes Michael's addition.
Enolate formation takes place, and the process of Tautomerization gives way to further reactions.
This step is followed by cyclization. The six-membered cyclic product is formed from aldol condensation.
The αβ unsaturated cyclic ketones are finally formed after hydrolysis is done.
Applications Of Robinson Annulation Reaction
Spirocyclic compounds are created using the Robinson annulation reaction mechanism. Robinson annulation’s advantage is that it finds high applicability while synthesizing molecules that are complex and is readily used while making steroids, terpenoids, and alkaloids. It is a formal [4+2] reaction, and six-membered rings are always formed in this reaction followed by the condensation process. The concept of the process has also expanded to include [3+3] annulations. Generally, all ring forming cascades include intramolecular aldol reaction and the Michael addition, like in the Robinson annulation mechanism. A large number of synthesis relies on Robinson annulation. Those which use the process to create an internal ring are especially significant. The Robinson annulation is very important in the process of synthesis of the six-membered ring. A more complex application of the process is in the Enantioselective way to platensimycin.
Robinson Annulation In Stereochemistry
Hydroxyl ketones are formed using the Robinson annulation reaction. It has also been discovered that cyclization often pursues the path of synclinal orientation. Solvent interactions account for the difference in the formation of transition states and their products.
Reaction Conditions Required
Generally, primary conditions are needed for the Robinson annulation reaction to take place. However, different conditions have been used for conducting the reaction. Heathcock and Ellis used sulfuric acid and similar products, and the result was reported. With the help of an enamine, Michael's reaction can be conducted even in neutral conditions. The Michael adduct is created by heating Mannich base with a ketone present. Several variations of the process, like the Wichterle reaction, Hauser annulation, and asymmetric Robinson annulation, have been used. Methods like Dieckmann condensation and catalysts like proline catalysts have been often used to create the variations, as mentioned earlier.
Example Of a Synthesis With Robinson Annulation
This is mainly a significant example because pKa of the diketone is close to 11; thus, it will be selectively deprotonated over all the pKa-16 or alpha carbon atoms. This would, in turn, ensure that there is a high yield from the Michael reaction. The methyl group, on the other hand, makes sure that the deprotonation does not retake place during the step of an intramolecular aldol condensation. This example is frequently found in Robinson annulation practice problems.
Another example is amine promoted aldol condensation, which takes place with enamine.
The key step in this process is to use a Dean-Stark trap, which sequesters water, which is formed as a product of the reaction leading the reaction towards its completion.
Did You Know?
In 1971, Zoltan Hajos and David Parrish used L-proline without using pyrrolidine, which led to the formation of a product which is optically active. This discovery did not receive adequate attention for about three decades. The result was finally published in 2000 by Babas, List, and Lerner and consequently opened the floodgates to developing organocatalysis.
Solved Examples
1. With the help of proper equations and writing the correct organic compounds give an example of a Robinson annulation reaction.
Answer: An example of the Robinson annulation reaction is as follows:
FAQs on Robinson Annulation
1. What is the Robinson Annulation reaction?
The Robinson Annulation is a powerful ring-forming reaction in organic chemistry used to create a six-membered ring. It sequentially combines two key reactions: a Michael addition followed by an intramolecular aldol condensation. The final product is a new α,β-unsaturated cyclic ketone, which is a common structural feature in many complex natural molecules.
2. What are the two essential starting materials for a Robinson Annulation?
To perform a Robinson Annulation, you need two specific types of reactants: a Michael donor, which is typically a ketone or aldehyde that can be deprotonated to form an enolate, and a Michael acceptor, which is an α,β-unsaturated carbonyl compound. A classic example is the reaction between cyclohexanone (the donor) and methyl vinyl ketone (the acceptor).
3. What are the two distinct reaction stages in a Robinson Annulation?
The Robinson Annulation proceeds in two main stages:
- Michael Addition: In this first step, a nucleophilic enolate (formed from a ketone or aldehyde) attacks the β-carbon of an α,β-unsaturated carbonyl compound. This creates a new carbon-carbon bond and forms a larger dicarbonyl intermediate.
- Intramolecular Aldol Condensation: The intermediate formed in the first step then undergoes a ring-closing reaction where an enolate from one part of the molecule attacks the other carbonyl group within the same molecule. This forms a six-membered ring, which then dehydrates to yield the final α,β-unsaturated ketone product.
4. What is the main difference between a Michael addition and a Robinson Annulation?
The key difference is that a Michael addition is only a single reaction step, whereas the Robinson Annulation is a sequence of two reactions. A Michael addition specifically refers to the 1,4-conjugate addition of a nucleophile to an α,β-unsaturated carbonyl compound. The Robinson Annulation, on the other hand, is a more complex process that *begins* with a Michael addition and is immediately followed by an intramolecular aldol condensation to form a complete ring system. Therefore, the Michael addition is just the first part of the overall Robinson Annulation.
5. What is the specific role of the base in the Robinson Annulation mechanism?
A base plays a crucial catalytic role in both stages of the Robinson Annulation. First, it is required to deprotonate the Michael donor (the ketone) at its α-carbon to generate the nucleophilic enolate, which is necessary to initiate the Michael addition. Second, after the Michael adduct is formed, the base facilitates the subsequent intramolecular aldol condensation by creating another enolate within the intermediate, allowing it to cyclize (attack itself) and form the final ring structure.
6. How can you identify if a reaction is a Robinson Annulation from its reactants and products?
You can identify a Robinson Annulation by looking for specific structural transformations. The key indicators are:
- Product: The formation of a new six-membered ring that contains an α,β-unsaturated ketone system.
- Reactants: The starting materials will be an enolizable ketone (or a similar Michael donor) and an α,β-unsaturated ketone or aldehyde (like methyl vinyl ketone).
- Bond Formation: The reaction forms three new carbon-carbon bonds and one new carbon-carbon double bond to create the final annulated (fused ring) product.
7. What are some important real-world applications of the Robinson Annulation?
The Robinson Annulation is extremely important in the synthesis of complex polycyclic organic molecules. Its most significant application is in the construction of steroid and terpenoid skeletons, which are vital in medicine and biology. For example, it was a key step in the landmark total synthesis of cortisone, a vital anti-inflammatory steroid. It is also widely used to synthesise other natural products and pharmaceuticals containing six-membered rings.
8. What are the typical reagents used to carry out a Robinson Annulation?
The typical set of reagents for a standard Robinson Annulation includes:
- A Michael donor, such as cyclohexanone or 2-methylcyclohexanone.
- A Michael acceptor, most commonly methyl vinyl ketone (MVK).
- A base to catalyze the reaction, such as sodium ethoxide (NaOEt), sodium hydroxide (NaOH), or potassium tert-butoxide.
- A suitable protic solvent, such as ethanol, which can facilitate proton transfers.
