Robinson Annulation - Kemicalinfo

Introduction: Robinson Annulation

Robinson Annulation is a reaction in organic chemistry that allows the synthesis of cyclic compounds. The reaction involves the condensation of a carbonyl compound, usually a ketone or an aldehyde, with a cyclic α,β-unsaturated ketone, also known as a Michael acceptor. It proceeds via a six-membered transition state, in which the carbonyl group and the Michael acceptor are brought together to form a new carbon-carbon bond. The reaction is catalyzed by a base, usually an amine or an alkoxide, and can be carried out under mild conditions. The Robinson Annulation is a useful tool for the synthesis of complex natural products and pharmaceuticals.

Robinson Annulation General Reaction

The general reaction equation for Robinson Annulation is:

Carbonyl compound + α,β-unsaturated ketone (Michael acceptor) + Base → Cyclic compound

For example, a possible reaction could be the condensation of cyclohexanone (a carbonyl compound) with methyl vinyl ketone (a Michael acceptor) in the presence of a base such as potassium tert-butoxide:

Cyclohexanone + Methyl vinyl ketone + Base → 3-Cyclohexenone

In this reaction, the carbonyl group of cyclohexanone reacts with the α,β-unsaturated system of methyl vinyl ketone to form a six-membered ring, resulting in the formation of 3-cyclohexenone.

Mechanism of the Robinson Annulation

The mechanism of the Robinson Annulation involves a series of steps that lead to the formation of a cyclic compound. The reaction proceeds through a six-membered transition state, in which the carbonyl group and the α,β-unsaturated ketone are brought together to form a new carbon-carbon bond. Here’s a step-wise explanation of the mechanism:

Deprotonation: The base deprotonates the α-carbon of the Michael acceptor, generating a carbanion. The carbanion is stabilized by the conjugated system of the α,β-unsaturated ketone.
Addition: The carbanion attacks the carbonyl group of the ketone or aldehyde, resulting in the formation of an intermediate compound called an enolate.
Protonation: The enolate is protonated by the solvent or the conjugate acid of the base, leading to the formation of a new carbon-carbon bond and the formation of a six-membered ring.
Tautomerization: The six-membered ring undergoes tautomerization to give the final product, a cyclic compound.

Factors Affecting Robinson Annulation

Several factors can affect the outcome of Robinson Annulation, which is an important reaction in organic synthesis. Here are some of the factors that can influence the reaction:

Reactivity of carbonyl compound: The reactivity of the carbonyl compound can affect the yield of the reaction. Ketones are generally more reactive than aldehydes in Robinson Annulation.
Choice of base: The choice of the base can impact the reaction. Strong bases like potassium tert-butoxide can promote faster and more efficient reactions, but can also lead to side reactions. Weaker bases like sodium ethoxide can result in slower reaction rates but with greater selectivity.
Reactivity of Michael acceptor: The reactivity of the α,β-unsaturated ketone, or Michael acceptor, is also important. Highly electron-rich acceptors can result in low yields of the desired product.
Solvent: The solvent can affect the reaction by influencing the rate and selectivity of the reaction. Polar aprotic solvents like dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) are commonly used in Robinson Annulation.
Temperature: The reaction temperature can also impact the yield and selectivity of the reaction. Low temperatures may lead to slower reaction rates but better selectivity, while high temperatures can result in faster reaction rates but lower selectivity.

Applications of Robinson Annulation

Robinson Annulation is a versatile and widely used reaction in organic chemistry. Here are some of the applications of Robinson Annulation:

Synthesis of natural products: Robinson Annulation is frequently used in the synthesis of complex natural products, such as terpenoids and alkaloids.
Drug discovery: This reaction is a useful tool for the synthesis of pharmaceuticals. Several drugs, including cholesterol-lowering agents and anti-tumor agents, have been synthesized using Robinson Annulation.
Synthesis of heterocycles: The reaction enables the synthesis of heterocycles, including pyridines and quinolines.
Polymer chemistry: In polymer chemistry, researchers can utilize this reaction to prepare cyclic polymers like cyclodextrins.
Total synthesis: Total synthesis employs this reaction extensively to synthesize intricate natural products or compounds using basic starting materials.
Diversity-oriented synthesis: In diversity-oriented synthesis, researchers use this reaction to synthesize diverse libraries of compounds that can be screened for biological activity.

History of Robinson Annulation

Sir Robert Robinson, a British organic chemist, discovered the Robinson Annulation reaction in the early 20th century. He received the Nobel Prize in Chemistry in 1947 for his work in the field of organic chemistry.

Robinson’s research focused on the synthesis of complex organic compounds from simpler starting materials. In 1917, he discovered that the reaction between a ketone and an α,β-unsaturated ketone in the presence of a base could lead to the formation of cyclic compounds. He initially referred to the reaction as the “intramolecular Michael reaction.”

However, it was not until the 1930s that the reaction was fully understood and widely used in organic synthesis. Robinson’s work laid the foundation for the development of numerous synthetic routes for the production of complex organic molecules.

Since then, Robinson Annulation has become an important tool in the synthesis of natural products, pharmaceuticals, and other complex organic compounds. It has also been studied extensively by chemists seeking to understand the mechanisms and factors that influence the reaction.

Organic chemists continue to recognize and celebrate the fundamental contribution of this reaction to the field, as it remains a crucial reaction in their research.

Limitations of Robinson Annulation

While Robinson Annulation is a versatile and powerful reaction in organic chemistry, it also has some limitations. Here are some of the limitations of this reaction:

Stereoselectivity: The reaction is not always stereoselective, which can lead to the formation of undesired products. This is particularly true when using α,β-unsaturated ketones that have multiple chiral centers.
Limitations of starting materials: The reaction requires a ketone and an α,β-unsaturated ketone, which can limit the scope of the reaction. Not all ketones or α,β-unsaturated ketones are suitable for this reaction.
Side reactions: The reaction can be prone to side reactions, such as Michael’s addition. This can compete with the desired Robinson Annulation product.
Low yields: The reaction can sometimes result in low yields, which can be due to a variety of factors. These include the reactivity of the starting materials, the choice of base, and the reaction conditions.
Complex reaction mechanism: The mechanism of this reaction is complex and not well understood in some cases. This can make it difficult to predict the outcome of the reaction.

Despite these limitations, Robinson Annulation remains a valuable and widely used reaction in organic synthesis. By carefully selecting the starting materials, and reaction conditions, and optimizing the reaction, researchers can often overcome these limitations.

Questions:

Q: What are the names of the two parts of the mechanism in a Robinson Annulation?

A: The two parts of the mechanism are the Michael addition and the intramolecular aldol condensation.

Q: What forces stereochemistry in Robinson Annulation?

A: During the Michael addition in Robinson Annulation, the conformation of the α,β-unsaturated ketone actively determines the orientation of the incoming nucleophile, thus forcing the stereochemistry.

Q: How to find a theoretical yield of Robinson Annulation?

A: One can use stoichiometry to calculate the maximum amount of product that can be obtained from a given amount of starting material in order to find the theoretical yield of this reaction. To calculate the theoretical yield, one should divide the amount of product that the balanced chemical equation predicts by the amount of limiting reagent used. Then, multiply the result by 100 to express the yield as a percentage.

Q: What materials would you use to prepare the following compound using a Robinson Annulation?

A: The choice of materials for preparing a specific compound using this reaction would depend on the structure of the compound. In general, the reaction requires a ketone and an α,β-unsaturated ketone, along with a base. The specific choice of starting materials and reaction conditions would depend on the desired product.

Q: How to tell Robinson Annulation vs. Michael?

A: Robinson Annulation is a specific type of intramolecular Michael reaction that involves a cyclic product formation through an intramolecular aldol condensation step. Michael reaction, on the other hand, can involve both intermolecular and intramolecular nucleophilic addition to an α,β-unsaturated carbonyl compound. In other words, this reaction is a type of Michael reaction that involves a specific sequence of steps leading to a cyclic product.