"Cracking the Woodward-Hoffmann Rules for Sigmatropic Rearrangements"

 

"Cracking the Woodward-Hoffmann Rules for Sigmatropic Rearrangements"

Woodward-Hoffmann rules are a set of theoretical principles that describe the stereoselectivity and regioselectivity of pericyclic reactions, including sigmatropic rearrangements. Sigmatropic rearrangements are a type of pericyclic reaction where a σ bond is rearranged between two atoms in a molecule, resulting in a new σ bond and a rearranged molecular structure.

Understanding the Woodward-Hoffmann rules is crucial for predicting and rationalizing the outcomes of sigmatropic rearrangements, which have numerous applications in organic synthesis and natural product chemistry. In this article, we will discuss the Woodward-Hoffmann rules and their relevance to sigmatropic rearrangements.

The Woodward-Hoffmann rules were developed independently by Robert Burns Woodward and Roald Hoffmann in the 1960s. These rules are based on the principles of orbital symmetry and conservation of orbital symmetry during chemical reactions. According to the Woodward-Hoffmann rules, the stereochemistry and regiochemistry of pericyclic reactions are determined by the overlap of the orbitals involved in the reaction.

The Woodward-Hoffmann rules consist of four basic principles, which are as follows:

The Conservation of Orbital Symmetry:

This principle states that the symmetry of the orbitals involved in a pericyclic reaction must be conserved. This means that orbitals with the same symmetry will overlap and interact, while orbitals with different symmetry will not interact.

The Frontier Orbital Principle:

This principle states that the reaction will proceed through the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) involved in the reaction. The HOMO of the reactant becomes the LUMO of the product, and vice versa.

The Even-Electron Rule:

This principle states that pericyclic reactions involving an even number of electrons are allowed, while reactions involving an odd number of electrons are not forbidden.

The Correlation Diagram:

This principle is used to determine the stereochemistry and regiochemistry of the reaction by plotting the relative energies of the HOMO and LUMO orbitals involved in the reaction.

Keep in mind

• A thermal (ground state) sigmatropic rearrangement is symmetry allowed when total number of (4q + 2)s component and (4r)a component is odd.
• A sigmatropic change in the first excited state is symmetry allowed when total number of (4q + 2)s and (4r)a component is even.

Case # 1. Woodword-Hoffmann rules for (m, n) Sigmatropic rearrangements where migrating group is not hydrogen

1. Draw the mechanism for the reaction.
2. Choose the components. Only the bonds taking part in the reaction mechanism must be included.
3. Make a three-dimensional drawing of the way the components come together for the reaction, putting orbitals at the ends of the components.
4. Join up the components where new bonds are to be formed. Make sure you join orbitals that are going to form new bonds.
5. Label each component s or a. See below for the π and σ bond symmetries.

Whether π component is s or a

If both upper lobes and both lower lobes of the π component are involved in the reaction then the component will be s and it is label as π²s. If one upper lobe and other lower lobe of the π component are involved in the reaction then the component will be a and it is label as π²a.

Whether σ component is s or a

When sp³-hybrid orbital uses its large lobe for reaction then there will be retention or the small lobe then there will be inversion. 

When there is retention at both ends or inversion at both ends then σ component is σ²s. If there is retention at one end and inversion at other end then σ component is σ²a.

When applied to sigmatropic rearrangements, the Woodward-Hoffmann rules can be used to predict the stereochemistry and regiochemistry of the reaction. For example, in a [3,3] sigmatropic rearrangement, the Woodward-Hoffmann rules predict that the reaction will proceed through a concerted mechanism, with the HOMO of the reactant interacting with the LUMO of the product. The correlation diagram can be used to determine whether the reaction will result in a syn or anti stereoisomer, and whether the reaction will proceed through a suprafacial or antarafacial pathway.

Here are the clear examples of Suprafacial and Antarafacial rearrangements along with the hydrogen migratory group and carbon migratory group.

Conclusion:

 In conclusion, the Woodward-Hoffmann rules are a powerful tool for predicting and rationalizing the stereochemistry and regiochemistry of pericyclic reactions, including sigmatropic rearrangements. By understanding these principles, chemists can design more efficient and selective synthetic routes, and gain a deeper understanding of the fundamental principles that govern chemical reactivity.

“Understanding the concept of Claisen rearrangement, Ene reaction and Fluxional tautomerization”

 “Understanding the concept of Claisen rearrangement, Ene reaction and Fluxional tautomerization”

Claisen Rearrangement: 

The Claisen rearrangement is a (3,3) sigmatropic rearrangement reaction that involves the conversion of an allyl vinyl ether into a γ,δ-unsaturated carbonyl compound. The reaction was first described by Ludwig Claisen in 1887 and has since become a widely used synthetic tool in organic chemistry.

Mechanism:

The Claisen rearrangement proceeds through a concerted, pericyclic mechanism in which the vinyl ether undergoes a 1,3-alkyl migration, resulting in the formation of a new carbon-carbon bond. Because [3,3] sigmatropic rearrangements involve three pairs of electrons, So, they occur by a suprafacial pathway under thermal conditions. The stereochemistry of the products is highly dependent on the stereochemistry of the starting material.

Examples: 

Applications:

The Claisen rearrangement is often used in the synthesis of natural products, such as terpenoids and steroids. The reaction can also be used to generate a variety of γ,δ-unsaturated carbonyl compounds, which can be further functionalized to produce a range of useful compounds.

Variations:

Several variations of the Claisen rearrangement have been developed, including the Ireland-Claisen rearrangement, the Johnson-Claisen rearrangement, and the Oshima-Utiyama rearrangement. These variations involve the use of different starting materials and conditions to achieve specific reaction outcomes.

Ene Reaction:

The Ene reaction is the process by which allylic hydrogen reacts with a dieneophile (such as C=C, C=O, etc.) thermally to generate a new σ-bond to the terminal carbon of the allylic double bond.

Examples: 

Fluxional Tautomerism:

Fluxional tautomerism refers to the process in which two or more isomers of a compound rapidly interconvert through a process of bond breaking and bond forming. The phenomenon is common in organic chemistry and has important implications for the behavior of molecules in solution.

Fluxional molecules:

Fluxional molecules are those whose dynamics or fluctuations cause some or all of its atoms to switch between locations with the same symmetry.

Mechanism:

Fluxional tautomerism occurs when a molecule can exist in multiple isomeric forms that are energetically similar. The interconversion between these isomers occurs through the breaking and forming of chemical bonds. This process can be facilitated by the presence of a catalyst, such as a metal ion, or by changes in temperature, pressure, or solvent.

Examples: 

Fluxional tautomerism is observed in a variety of organic compounds, such as keto-enol tautomerism in carbonyl compounds and imine-enamine tautomerism in nitrogen-containing compounds. In many cases, the interconversion between isomers is reversible, and the ratio of isomers can be influenced by external factors.

Applications:

Fluxional tautomerism has important implications for the behavior of molecules in solution. For example, the equilibrium between keto and enol forms of a compound can affect its reactivity and selectivity in chemical reactions. Fluxional tautomerism can also be used to design new catalysts and to understand the mechanisms of enzyme-catalyzed reactions.

Conclusion:

In conclusion, the Claisen rearrangement is a powerful tool in organic synthesis. Its ability to form γ,δ-unsaturated carbonyl compounds has made it an important reaction in the synthesis of natural products and other useful compounds. Fluxional tautomerism is an important phenomenon in organic chemistry that involves the rapid interconversion of isomeric forms of a molecule. Its implications for the behavior of molecules in solution make it an important area of study in chemical research, with applications in catalysis, drug design, and enzyme mechanism studies.

"Chemistry of Cope rearrangement and Oxy-Cope rearrangement"

 

Topic: "Chemistry of Cope rearrangement and Oxy-Cope rearrangement"

Cope Rearrangement:

The Cope rearrangement is a (3,3) sigmatropic reaction that involves the thermal rearrangement of a 1,5-diene to form a substituted cyclohexadiene. The reaction was first discovered by Arthur C. Cope in 1940 and has since become a widely used synthetic tool in organic chemistry.

Mechanism: The Cope rearrangement proceeds through a concerted, electrocyclic process in which the π-bonds of the diene system undergo a 180-degree rotation. The stereochemistry of the products is highly dependent on the stereochemistry of the starting material. Cope rearrangement causes fluxional state of molecule in bullvalene family.

Variations:

Several variations of the Cope rearrangement have been developed, including the Johnson-Claisen rearrangement, the Ireland-Claisen rearrangement, and the Myers-Saito rearrangement. These variations involve the use of different starting materials and conditions to achieve specific reaction outcomes.

Here are some keypoints to remember;

• Sigmatropic rearrangement involving the migration of a carbon-carbon double bond in a six-membered ring.
• Proceeds through a concerted mechanism in which the π bond and the sigma bond break and form simultaneously.
• Reaction is promoted by heat and is typically carried out in the gas phase or in non-polar solvents.
• Can be used to form a variety of cyclic and acyclic compounds with important biological and synthetic applications.
• Because [3,3] sigmatropic rearrangements involve three pairs of electrons, they occur by a suprafacial pathway under thermal conditions.
• Widely studied and many variations have been developed to improve its selectivity and efficiency.
• Named after Arthur C. Cope, who first described the reaction in 1940.
• Can be used to synthesize a variety of compounds, including natural products, pharmaceuticals, and materials.
• Important applications in the fields of organic synthesis, drug discovery, and materials science.
• Can be used in combination with other synthetic methods to access complex molecules with high efficiency and selectivity.
• Important tool for chemists and is widely used in both academic and industrial research.

Oxy-Cope rearrangement:

The oxy-Cope rearrangement is a powerful synthetic tool used to synthesize a variety of oxygenated organic compounds. that involves the migration of a carbon-carbon double bond in the presence of an oxygen atom. In this reaction, a hydroxyl or other oxygen-containing group is introduced into the final product.

Key points about the oxy-Cope rearrangement are:

• The oxy-Cope rearrangement is a sigmatropic rearrangement that involves the migration of a carbon-carbon double bond in the presence of an oxygen atom. It is a variation of the classic Cope rearrangement.
• The reaction is often promoted by heat and can be carried out in the gas phase or in solution.
• The oxy-Cope rearrangement can be used to form a variety of oxygenated compounds, including alcohols, ketones, and ethers.
• The reaction proceeds through a concerted mechanism in which the π bond and the sigma bond break and form simultaneously.

Conclusion:

In conclusion, the Cope and oxy-Cope rearrangement both are versatile and powerful tools in organic synthesis. Both are an important reactions in the synthesis of natural products and other useful compounds.

"Going Green with Sigmatropic Rearrangement: Sustainable Approaches to Organic Synthesis"

 

"Going Green with Sigmatropic Rearrangement: Sustainable Approaches to Organic Synthesis"

In recent years, the importance of sustainable practices in organic synthesis has become increasingly apparent. With growing concerns about the impact of chemical synthesis on the environment, researchers have been exploring new methods to reduce waste and promote eco-friendly approaches. One promising technique that has emerged in this context is the use of sigmatropic rearrangement reactions, which offer a range of benefits in terms of both efficiency and sustainability.

Sigmatropic rearrangements are a class of organic reactions that involve the movement of a sigma bond from one position to another within a molecule. These reactions are highly efficient, typically occurring with excellent stereo- and regioselectivity, and often proceed under mild conditions with little or no need for toxic reagents or solvents. As a result, sigmatropic rearrangements have been identified as a powerful tool for sustainable organic synthesis, offering a range of advantages over traditional methods.

Advantages:

One key advantage of sigmatropic rearrangements is their ability to generate complex structures from simple starting materials. For example, in a [3,3]-sigmatropic rearrangement, a six-membered ring is formed from two three-membered rings. This reaction can be used to create a range of complex structures, including natural products and pharmaceuticals, from relatively simple precursors. Because the reaction occurs with high selectivity and minimal waste, it can be a highly sustainable approach to organic synthesis.

Another advantage of sigmatropic rearrangements is their compatibility with a wide range of functional groups. Unlike some traditional organic reactions, sigmatropic rearrangements often occur without the need for protecting groups or harsh reaction conditions. This means that the approach can be used to create a range of complex structures in a highly efficient and sustainable way, even in the presence of sensitive functional groups.

One example of the potential of sigmatropic rearrangements for sustainable organic synthesis is the synthesis of the natural product cortistatin A mentioned below in figure. In a recent study, researchers used a [3,3]-sigmatropic rearrangement as a key step in the synthesis of this complex natural product. The reaction proceeded with excellent stereo- and regioselectivity, and resulted in the formation of the desired product in a highly efficient manner.

The synthesis of cortistatin A involves a [3,3]-sigmatropic rearrangement as a key step. The starting material for the reaction is a highly functionalized cyclohexenone, which is converted into a diene through a series of steps. The diene is then subjected to a thermal [3,3]-sigmatropic rearrangement to form a highly substituted cyclohexene. The highly substituted cyclohexene is then subjected to a number of additional reactions to introduce the remaining functional groups needed to form cortistatin A. These reactions include a diastereoselective aldol reaction and a tandem oxidation/reduction to introduce a carbonyl group and reduce it to an alcohol. The final steps of the synthesis involve a series of functional group transformations and protection/deprotection reactions to generate the desired product, cortistatin A.

Additional keypoints:

Sure, here are some additional key points to consider when discussing the use of sigmatropic rearrangements for sustainable organic synthesis:

1.      Selectivity: Sigmatropic rearrangements typically occur with high selectivity, meaning that the desired product is formed with minimal or no formation of unwanted byproducts. This selectivity can reduce the amount of waste generated during a reaction and make it more sustainable.

2.      Mild reaction conditions: Sigmatropic rearrangements often occur under mild reaction conditions, with little or no need for toxic reagents or solvents. This can reduce the environmental impact of a reaction and make it more sustainable.

3.      Synthetic versatility: Sigmatropic rearrangements can be used to create a wide range of complex structures, including natural products and pharmaceuticals. This versatility makes the approach useful in a variety of contexts and can help to reduce the environmental impact of chemical synthesis in many different fields.

4.      Compatibility with functional groups: Sigmatropic rearrangements are often compatible with a wide range of functional groups, meaning that they can be used to create complex structures even in the presence of sensitive functional groups. This compatibility can make the approach more sustainable than traditional methods that require protecting groups or harsh reaction conditions.

5.      Potential for scalability: Because sigmatropic rearrangements are efficient and occur under mild conditions, they have the potential to be scaled up for industrial applications. This scalability can make the approach useful for large-scale production of sustainable products.

Conclusion:

Overall, sigmatropic rearrangements offer a promising avenue for sustainable organic synthesis. With their high efficiency, compatibility with a wide range of functional groups, and ability to generate complex structures from simple starting materials, these reactions have the potential to play a key role in the development of eco-friendly synthetic methods. As researchers continue to explore new ways to reduce the environmental impact of chemical synthesis, sigmatropic rearrangements are likely to become an increasingly important tool in the chemist's toolbox.

"Exploring Suprafacial vs Antarafacial Sigmatropic Rearrangements: Differences, Mechanisms, and Applications in Total Synthesis of Natural Products, with a Focus on Computational Methods and Key Reactions"

 

"Exploring Suprafacial vs Antarafacial Sigmatropic Rearrangements: Differences, Mechanisms, and Applications in Total Synthesis of Natural Products, with a Focus on Computational Methods and Key Reactions"

Introduction:

Sigmatropic rearrangements are organic reactions in which a sigma bond is rearranged in a concerted manner. Suprafacial and antarafacial sigmatropic rearrangements are two important types of these reactions. In this article, we will explore the differences between suprafacial and antarafacial sigmatropic rearrangements, their mechanisms, and their applications in organic synthesis.

Differences between Suprafacial and Antarafacial Sigmatropic Rearrangements:

Suprafacial and antarafacial sigmatropic rearrangements differ in the way the sigma bond is broken and re-formed during the reaction. In suprafacial sigmatropic rearrangements, the breaking and forming of the sigma bond occurs on the same face of the molecule. In contrast, in antarafacial sigmatropic rearrangements, the breaking and forming of the sigma bond occurs on opposite faces of the molecule.

Mechanisms of Suprafacial and Antarafacial Sigmatropic Rearrangements:

Understanding the mechanisms of suprafacial and antarafacial sigmatropic rearrangements is crucial for their successful application in organic synthesis. There mechanisms are diverse. In suprafacial sigmatropic rearrangements, the reaction occurs through a cyclic transition state in which the sigma bond is broken and re-formed on the same face of the molecule. In antarafacial sigmatropic rearrangements, the reaction occurs through a linear transition state in which the sigma bond is broken and re-formed on opposite faces of the molecule.

Computational Methods Used in Studying Suprafacial and Antarafacial Sigmatropic Rearrangement:

Theoretical studies on suprafacial and antarafacial sigmatropic rearrangement mechanisms are typically carried out using computational methods such as density functional theory (DFT) and ab initio calculations. These theoretical studies have allowed for the prediction of reaction pathways, intermediates, and transition states, and have provided insights into the factors that influence the selectivity and stereoselectivity of these reactions. These insights have allowed for the design of new and more efficient reactions, and have enabled chemists to predict the outcome of reactions with greater accuracy. Furthermore, the computational methods used to study these reactions have the potential to accelerate the discovery of new chemical reactions and to reduce the need for trial and error in the laboratory.

Suprafacial and Antarafacial Sigmatropic Rearrangement in Total Natural Synthesis: Suprafacial and antarafacial sigmatropic rearrangements are key reactions in the total synthesis of natural products due to their ability to create multiple bonds and stereocenters in a single step. For example, suprafacial sigmatropic rearrangement was employed in the total synthesis of strychnine, a complex alkaloid found in plants. In this reaction, the vinyl group migrates from the right-hand side of the conjugated diene to the left-hand side, forming a new double bond and a triple bond. This reaction creates a key intermediate that can be further transformed into strychnine.

 In another example, antarafacial sigmatropic rearrangement was used in the synthesis of jatropholone A, a natural product with anticancer activity. In this reaction, the carbon group migrates from the right-hand side of the conjugated diene to the left-hand side, forming a new carbon-carbon bond. This reaction creates a bicyclic lactam ring system that is found in the structure of jatropholone A.

Applications of Suprafacial and Antarafacial Sigmatropic Rearrangements:

Suprafacial and antarafacial sigmatropic rearrangements have important applications in organic synthesis. Suprafacial sigmatropic rearrangements are commonly used in the synthesis of natural products, such as steroids, terpenes, and alkaloids. Antarafacial sigmatropic rearrangements are important in the synthesis of cyclic compounds, such as cyclooctatetraene and benzocyclobutene.

Conclusion:

Suprafacial and antarafacial sigmatropic rearrangements are two important types of organic reactions that differ in the way the sigma bond is broken and re-formed during the reaction. Understanding the mechanisms of these reactions is crucial for their successful application in organic synthesis. Suprafacial and antarafacial sigmatropic rearrangements have a wide range of applications in the synthesis of natural products and cyclic compounds, and their importance in organic chemistry continues to grow.

"Unlocking the Sigma-Tropic Reactions: A Comprehensive Guide to Understanding the Origin, Types, Naming System, and Mechanisms"

 

"Unlocking the Sigma-Tropic Reactions: A Comprehensive Guide to Understanding the Origin, Types, Naming System, and Mechanisms"

Sigmatropic reactions are a fascinating area of organic chemistry that involves the migration of a sigma bond along a conjugated system. This type of reaction is important in organic synthesis and has been studied extensively for its usefulness in forming new carbon-carbon bonds. In this article, we will explore the background of sigma-tropic reactions, their naming system, and the different types of sigma-tropic reactions.

Introduction:

“Molecular rearrangements in which a σ-bonded atom or group, flanked by one or more π-electron systems, shifts to a new location with a corresponding reorganization of the π-bonds” are called Sigmatropic reactions. The total number of σ-bonds and π-bonds remain unchanged.

Or

In a sigmatropic rearrangement, a bond in the reactant is broken, a new bond is formed, and the electrons rearrange. The bond that breaks is a bond to an allylic carbon. It can be a bond between a carbon and a hydrogen, between a carbon and another carbon, or between a carbon and an oxygen, nitrogen, or sulfur.

Background of Sigma-tropic Reactions

The term "sigma-tropic" refers to the movement of a sigma bond. This type of reaction was first described in the early 1960s by the chemist R. B. Woodward. Woodward was awarded the Nobel Prize in Chemistry in 1965 for his pioneering work in the field of organic synthesis, which included the discovery of sigma-tropic reactions.

Sigma-tropic reactions are important in organic chemistry because they allow chemists to form new carbon-carbon bonds in a selective and efficient manner. They are also useful in the synthesis of complex natural products and pharmaceuticals.

Naming System for Sigma-tropic Reactions:

Sigma-tropic reactions are named according to the type of migration that occurs. The naming system is based on the Greek letters alpha, beta, and gamma, which refer to the position of the migrating sigma bond relative to the conjugated system Or Double numbering system (m,n or i, j) is used.

You have not encountered any numbering systems like the one used to define a sigmatropic rearrangement before.

1. Break the reactant's bond first in your mind.
2. Then label the atoms to which it was linked with the number 1.
3. After then, have a look at the product's new bond.
4. The number of atoms in each of the pieces connecting the broken connection and the new bond should be recorded.
5. The smaller number is stated first and the two numbers are enclosed in brackets.

Types of Sigma-tropic Reactions:

There are several different types of sigma-tropic reactions, each with its own unique mechanism and set of conditions. The most common types of sigma-tropic reactions include:

• 1,3 Sigmatropic shifts
• 1,5 Sigmatropic shifts of H
• 1,7 Sigmatropic shifts of C
• 2,3 Sigmatropic shifts of C
• 3,3 Sigmatropic shifts of C

[1,3]-Sigmatropic Rearrangement

In a [1,3]-sigmatropic rearrangement, the migrating sigma bond moves between one carbon and three carbon. This type of reaction is important in the synthesis of natural products and pharmaceuticals and has been extensively studied for its usefulness in the formation of carbon-carbon bonds.

[1,5]-Sigmatropic Rearrangement

In a [1,5]-sigmatropic rearrangement, the migrating sigma bond moves between one carbon and five carbon. This type of reaction is commonly used in the synthesis of natural products and pharmaceuticals.

[1,7]-Sigmatropic Rearrangement

A [1,7]-sigmatropic rearrangement involves the migration of a sigma bond from one end of a conjugated system to the other, with the simultaneous formation of a new carbon-carbon bond. This type of reaction is commonly used in the synthesis of natural products and pharmaceuticals.

[2,3]-Sigmatropic Rearrangement

The [2,3]-sigmatropic rearrangement involves the migration of a sigma bond from a carbon atom to a neighboring carbon atom, with the simultaneous formation of a new carbon-carbon bond. This type of reaction is commonly used in the synthesis of complex organic molecules.

[2,3] sigmatropic rearrangement of amine oxide is Meisenheimer rearrangement mentioned below.

[2,3] sigmatropic rearrangement of allyl-sulfoxide is Mislow Evan rearrangement given below. It bears the names of David A. Evans, who published further advances, and Kurt Mislow, who published the prototype reaction in 1966. In a 2,3-sigmatropic rearrangement, the reaction enables the synthesis of allylic alcohols from allylic sulfoxides.

[3,3]-Sigmatropic Rearrangement

This type of sigma-tropic rearrangement involves the migration of a sigma bond from one end of a conjugated system to the other. The reaction is named [3,3] because the migrating bond moves from three carbon to another three carbon.

Conclusion

Sigma-tropic reactions are an important area of organic chemistry that have been extensively studied for their usefulness in the formation of carbon-carbon bonds. They are useful in the synthesis of complex natural products and pharmaceuticals, and the naming system for sigma-tropic reactions is based on the position of the migrating sigma bond relative to the conjugated system. There are several different types of sigma-tropic reactions, each with its own unique mechanism and set of conditions. The most common types of sigma-tropic reactions include the [3,3], [1,5], and [2,3] sigmatropic rearrangements, but there are also several other types that are worth exploring. Overall, sigma-tropic reactions are an important tool in the arsenal of organic chemists, and they continue to be a fascinating area of research in the field of organic synthesis.