Julia Reaction
TLDRThe script delves into the Julia olefination, a method for synthesizing olefins, first reported by Marc Julia in 1973. It involves the addition of a sulfone carbanion to an aldehyde, forming a beta-sulfonyl alcohol, which is then reduced to an olefin. The tutorial explains the original and modified Julia reactions, highlighting the latter's elimination of a separate reduction step through an internal oxidative process. It also touches on the Julia-Kocienski reaction and discusses the complexities of controlling E and Z stereochemistry in olefin formation, exemplified by the synthesis of Ambruticin, an antifungal agent.
Takeaways
- 🔬 The Julia olefination is a method for synthesizing olefins, involving the addition of a sulfone carbanion to an aldehyde, first reported by Marc Julia in 1973.
- 🧪 The reaction produces a beta-sulfonyl alcohol, which can be reduced to yield an olefin, typically in the E form.
- 📚 The primary adduct is formed by the reaction of a nucleophilic sulfone carbanion with an electrophilic carbonyl compound.
- ⚗️ In the original Julia reaction, the hydroxyl group is acylated, and the beta-sulfonyl acetate is reduced to form the olefin.
- 🌐 The reduction mechanism can vary depending on the reducing agent, with sodium amalgam and mercury being a common reagent combination.
- 🔄 The modified Julia reaction, reported by Sylvestre Julia in 1991, eliminates the need for a separate reduction step.
- 🌿 The modified reaction uses a sulfone with a benzothiazole group, allowing for an intramolecular attack and Smiles rearrangement, leading to olefin formation without external oxidative steps.
- 🔑 The Julia-Kocienski reaction is a mild variant using an N-phenyl tetrazolyl system, where the leaving group is the conjugate base of 5-hydroxy-1-phenyltetrazole.
- 📉 The stereochemistry of the Julia reaction is influenced by the first step, with the syn or anti addition determining the E or Z olefin outcome.
- 🧬 Stereoselectivity can be influenced by the metal used and solvent effects, which can promote or hinder coordination with the sulfone and aldehyde groups.
- 💊 The script includes an example of the Julia reaction in the synthesis of Ambruticin, an antifungal agent, highlighting the empirical nature of organic synthesis.
Q & A
What is the Julia olefination reaction?
-The Julia olefination reaction, also known as the Julia reaction, is a method for olefination that involves the addition of a sulfone carbanion to an aldehyde, resulting in the formation of a beta-sulfonyl alcohol, which can be reduced to yield an olefin, typically in the E form.
Who first reported the Julia reaction?
-The Julia reaction was first reported by French chemist Marc Julia in 1973.
What is the initial product of the Julia reaction?
-The initial product of the Julia reaction is a beta-sulfonyl alcohol, which is formed by the addition of a sulfone carbanion to an aldehyde.
What is the typical reagent used in the reduction step of the original Julia reaction?
-In the original Julia reaction, the most typical reagent used for the reduction step is a sodium amalgam with mercury, which is used under basic conditions.
How does the reduction step in the original Julia reaction lead to the formation of an olefin?
-The reduction step involves the elimination of the acetate group via an E2 or more likely an E1CB mechanism, leading to the formation of a vinyl sulfone, which is then reduced to yield a mixture of E and Z olefins.
What is the modified Julia reaction and who reported it?
-The modified Julia reaction is an important extension of the original Julia reaction, reported by Marc Julia's younger brother Sylvestre Julia in 1991. It eliminates the need for a separate reduction step by incorporating an internal oxidative process.
What is the role of the benzothiazole group in the modified Julia reaction?
-In the modified Julia reaction, the sulfone bears a benzothiazole group, which allows for an intramolecular attack by a nucleophilic alkoxy group on the C=N functionality, leading to the formation of an alkyl sulfinate and ultimately to the olefin.
What is the Julia-Kocienski reaction and how does it differ from the modified Julia reaction?
-The Julia-Kocienski reaction is a mild and smooth variant of the Julia reaction, where the leaving group is the conjugate base of 5-hydroxy-1-phenyltetrazole. It operates on the same principle as the modified Julia reaction but with a different leaving group.
How does the stereochemistry of the Julia reaction influence the formation of E or Z olefins?
-The stereochemistry of the Julia reaction is set in the first step with the formation of syn A or anti A. The stereochemical outcome is determined by the transition states leading to these forms, where anti C gives E olefins and syn C gives Z olefins, assuming all other steps are stereospecific and irreversible.
What is the significance of the Ambruticin synthesis example in the script?
-The synthesis of Ambruticin, a natural antifungal agent, serves as an example to illustrate how changing the base and solvent can alter the selectivity of the Julia olefination from Z to the desired E olefin, highlighting the empirical nature of organic synthesis.
How does the Julia reaction handle reversible first steps and its impact on stereochemistry?
-When the first step of the Julia reaction is reversible, such as with benzylic sulfones and aromatic aldehydes, the stereochemistry is determined by which syn A or anti A undergoes the Smiles rearrangement more quickly. Despite the presence of an eclipsing interaction in anti A, both syn and anti forms typically lead to preferential E olefin formation.
What happens when the Julia reaction is applied to ketones?
-When the Julia reaction is applied to ketones, it leads to the formation of trisubstituted olefins. The stereochemical factors in this case are very complex, but some measure of stereocontrol has been achieved.
Why is it important for chemists to keep up with the evolving field of Julia chemistry?
-It is important for chemists to keep up with the evolving field of Julia chemistry because new mechanistic insights and synthetic applications appear frequently in the literature, offering opportunities for discovery and innovation in organic synthesis.
Outlines
🧪 Julia Olefination: A Historical Overview and Mechanism
The Julia olefination, introduced by French chemist Marc Julia in 1973, is a method for synthesizing olefins. It involves the addition of a sulfone carbanion to an aldehyde, resulting in a beta-sulfonyl alcohol, which can be reduced to form an olefin, typically in the E configuration. The process begins with the formation of an alpha-carbanion from the sulfone, which then reacts with the carbonyl compound. The original Julia reaction includes an acylation step to form a beta-sulfonyl acetate, followed by a reduction that can proceed via different mechanisms depending on the reducing agent used. The reaction can yield a vinyl sulfone through an E2 or E1CB mechanism, leading to a mixture of E and Z isomers, predominantly the E isomer. The rationale for E selectivity is not discussed as the original method is rarely used today. A significant advancement was made in 1991 by Marc Julia's brother, Sylvestre, introducing a modified Julia reaction that eliminates the need for a separate reduction step.
🔍 Modified Julia Reaction and Stereochemistry Insights
The modified Julia reaction, introduced by Sylvestre Julia, involves a sulfone with a benzothiazole group, leading to a primary adduct with a nucleophilic alkoxy group. This group can intramolecularly attack the C=N functionality, resulting in a Smiles rearrangement that forms an alkyl sulfinate. This intermediate tends to lose SO2 gas, and the breakage of the second C-S bond leads to the formation of a double bond and the elimination of a conjugate base of 2-hydroxy benzothiazole. The stereochemistry of the reaction is set in the first step, with syn A or anti A formation determining the E or Z olefin outcome. The stereochemical outcome is influenced by the metal used, solvent effects, and the nature of the groups involved. An example of the modified Julia olefination is showcased in the synthesis of Ambruticin, an antifungal agent, where changing the base and solvent can alter the selectivity from Z to E olefins. The reaction's stereochemistry can be complex, especially with reversible first steps, but understanding the Smiles rearrangement and the anti-periplanar or syn-coplanar elimination can provide insights into the preferential formation of E olefins. The field of Julia chemistry continues to evolve, with new applications and mechanistic insights emerging regularly.
Mindmap
Keywords
💡Olefination
💡Julia Reaction
💡Sulfone Carbanion
💡Beta-Sulfonyl Alcohol
💡Reduction
💡E2 Mechanism
💡E1CB Mechanism
💡Modified Julia Reaction
💡Smiles Rearrangement
💡Stereochemistry
💡Ambruticin
Highlights
Introduction of the Julia olefination, a widely used method for olefin synthesis.
Historical background of the reaction, first reported by Marc Julia in 1973.
The Julia reaction involves the addition of a sulfone carbanion to an aldehyde.
Generation of a beta-sulfonyl alcohol which can be reduced to yield an olefin, typically in the E form.
Explanation of the primary adduct formation through nucleophilic attack of the carbanion on the carbonyl compound.
Different ways to transform beta-sulfonyl alcohol into an olefin.
Original Julia reaction involves acylation of the hydroxyl group and reduction to the olefin.
Use of sodium amalgam with mercury for reduction and the mechanism involving E2 or E1CB elimination.
Formation of vinyl sulfone as a mixture of E and Z isomers.
Introduction of the modified Julia reaction by Sylvestre Julia in 1991.
Elimination of the need for a separate reduction step in the modified Julia reaction.
Use of a sulfone with a benzothiazole group in the modified Julia reaction.
Smiles rearrangement in the modified Julia reaction leading to the alkyl sulfinate.
Julia-Kocienski reaction as a mild variant of the Julia reaction using N-phenyl tetrazolyl system.
Stereochemistry of the Julia reaction and its dependence on the first step.
Control of E and Z stereochemistry through transition states of syn A and anti A.
Role of metal coordination and solvent polarity in stereoselectivity.
Empirical nature of predicting stereoisomer outcomes in organic synthesis.
Synthesis of Ambruticin using a modified Julia olefination as a key step.
Alteration of selectivity from Z to E olefin through base and solvent optimization.
Complexity of stereochemical factors in Julia reaction applied to ketones.
Ongoing evolution and discovery in the field of Julia chemistry.
Transcripts
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