Horner-Wadsworth-Emmons Reaction
TLDRThe Horner-Wadsworth-Emmons (HWE) reaction is a widely used method for olefin synthesis, involving the addition of stabilized carbanions from phosphonates to aldehydes and ketones. The reaction typically produces E olefins and is more nucleophilic than the Wittig reaction. The Still-Gennari modification of the HWE reaction allows for the synthesis of Z olefins with high stereoselectivity using trifluoroethyl phosphonates and specific bases. Both methods are crucial for the synthesis of complex molecules, such as natural macrolide antibiotics, exemplified by the total synthesis of Archazolide A, which utilizes the HWE reaction for assembling its multiple olefinic bonds.
Takeaways
- 📚 The Horner-Emmons (HWE), also known as Horner-Wadsworth-Emmons (HWE), is a widely used olefination reaction for the synthesis of alkenes.
- 👨🔬 Developed by Leopold Horner in 1958 and later perfected by William Wadsworth and William Emmons, the HWE reaction involves the addition of stabilized carbanions from phosphonates to aldehydes and ketones.
- 🔬 The reaction requires carbanions to be stabilized by both a phosphonate group and an electron-withdrawing group such as an ester, ketone, amide, or nitrile.
- 📉 The olefin produced from the HWE reaction is predominantly E, indicating a preference for the E isomer in the product.
- 🔄 Similar to the Wittig reaction, the HWE reaction uses a phosphorus-based group to stabilize the negative charge on the carbanion, but the mechanisms differ significantly.
- 🧬 The HWE reaction proceeds in two steps: formation of the anion followed by its attack on the carbonyl group, leading to a beta-phosphonyl alkoxide.
- 🔄 The stereochemistry of the olefin is usually determined by the syn elimination of the phosphate anion in a cyclic intermediate, favoring the E olefin.
- 🔑 The Still-Gennari modification of the HWE reaction allows for the synthesis of Z olefins with high stereoselectivity, using trifluoroethyl phosphonates and specific bases.
- 🌡 The Still-Gennari olefination is typically performed in THF at low temperatures, enhancing the kinetic control and selectivity of the reaction.
- 🔬 The reasons for the high Z selectivity in the Still-Gennari modification are not fully understood but are thought to involve the rapid fragmentation of the intermediate due to the electron-withdrawing ability of the fluorine-substituted phosphonate.
- 💊 The HWE reaction, including its Still-Gennari modification, is crucial in the synthesis of complex natural products, such as macrolide antibiotics, which often contain multiple olefinic bonds.
Q & A
What is the Horner-Emmons reaction, also known as?
-The Horner-Emmons reaction is also known as the Horner-Wadsworth-Emmons reaction. It is an olefination reaction that involves the addition of stabilized carbanions from phosphonates to aldehydes and ketones.
Who invented the Horner-Emmons reaction and when?
-The Horner-Emmons reaction was invented by German chemist Leopold Horner in 1958.
What are the necessary conditions for the Horner-Emmons reaction to work?
-The reaction works when the carbanions are stabilized not only by a phosphonate group but also by an ester or another electron-withdrawing functionality such as ketone, amide, or nitrile.
What is the predominant configuration of the olefin produced in the Horner-Emmons reaction?
-The olefin produced in the Horner-Emmons reaction is predominantly in the E configuration.
How does the Horner-Emmons reaction differ from the Wittig reaction?
-While both reactions use phosphorus-based groups to stabilize the negative charge on the carbanion, the Horner-Emmons reaction uses phosphonate anions which are more basic and nucleophilic compared to the phosphorus ylides in the Wittig reaction.
What is the significance of the first step in the Horner-Emmons reaction?
-The first step in the Horner-Emmons reaction is the formation of the anion, which then attacks the electrophilic carbonyl group to yield a beta-phosphonyl alkoxide. This step is usually reversible and determines the stereochemistry of the reaction.
What is the Still-Gennari modification of the Horner-Wadsworth-Emmons reaction?
-The Still-Gennari modification is an important variation of the HWE reaction that achieves the synthesis of Z olefins with excellent stereoselectivity, using trifluoroethyl phosphonates and typically potassium hexamethyldisilazide as the base.
Why is the Still-Gennari modification effective in producing Z olefins?
-The selectivity is assumed to be due to the electron-withdrawing ability of the fluorine-substituted phosphonate, which makes the second step of fragmentation quite fast, preventing the first step from reversing and favoring the erythro intermediate over the threo.
At what temperature is the Still-Gennari olefination usually performed?
-The Still-Gennari olefination is usually performed in THF at low temperatures, typically around -78 °C, to enhance kinetic control of the reaction.
How can the Horner-Wadsworth-Emmons reaction be applied in the synthesis of complex molecules?
-The Horner-Wadsworth-Emmons reaction can be iteratively used to stitch together complex molecules, such as in the total synthesis of Archazolide A, where it is used to prepare fragments within the macrocycle with high E or Z selectivity.
What is the role of the Horner-Wadsworth-Emmons reaction in modern organic synthesis?
-The Horner-Wadsworth-Emmons reaction is one of the most popular tools in the synthesis of complex chemical substances, and the Still-Gennari modification, which yields Z olefins, complements this reaction, making it an essential tool in modern organic synthesis.
Outlines
🧪 Horner-Wadsworth-Emmons Olefination: A Key Reaction in Organic Synthesis
The first paragraph introduces the Horner-Wadsworth-Emmons (HWE) olefination reaction, a widely used method for the synthesis of alkenes. Developed by Leopold Horner and later refined by William Wadsworth and William Emmons, the reaction involves the addition of stabilized carbanions from phosphonates to aldehydes and ketones. It is noted for its preference for E-olefin formation and its reliance on electron-withdrawing groups for carbanion stabilization. The paragraph also contrasts the HWE reaction with the Wittig reaction, highlighting the differences in acidity and nucleophilicity between phosphonium salts and phosphonate anions. The Still-Gennari modification of the HWE reaction, which enables the synthesis of Z-olefins with high stereoselectivity, is also discussed, with emphasis on the use of trifluoroethyl phosphonates and potassium hexamethyldisilazide as the base.
📚 Application of HWE Reaction in Complex Molecule Synthesis: Archazolide A Example
The second paragraph delves into the application of the Horner-Wadsworth-Emmons reaction in the synthesis of complex organic compounds, specifically using Archazolide A as an example. This macrolide antibiotic features a 24-membered ring with multiple stereogenic centers and olefinic bonds. The paragraph outlines Professor Dirk Menche's total synthesis approach at the University of Bonn, which heavily utilizes olefination reactions. It describes the iterative use of the Still-Gennari reaction to form Z olefins and the classical HWE conditions for E olefins, emphasizing the method's utility in constructing complex molecules. The paragraph concludes by highlighting the Horner-Wadsworth-Emmons reaction as an indispensable tool in modern organic synthesis, particularly with the Still-Gennari modification for Z olefin synthesis.
Mindmap
Keywords
💡Olefination reactions
💡Horner-Emmons reaction
💡Stabilized carbanions
💡Electron-withdrawing functionality
💡E olefin
💡Wittig reaction
💡Still-Gennari modification
💡Trifluoroethyl phosphonates
💡Potassium hexamethyldisilazide
💡Macrolide antibiotics
💡Archazolide A
Highlights
Introduction to the Horner-Emmons (HWE) olefination reaction, also known as Horner-Wadsworth-Emmons reaction.
HWE reaction was invented by Leopold Horner in 1958 and perfected by William Wadsworth and William Emmons.
HWE involves the addition of stabilized carbanions from phosphonates to aldehydes and ketones.
Carbanions must be stabilized by both a phosphonate group and an electron-withdrawing group like ester, ketone, amide, or nitrile.
The olefin produced by HWE is predominantly E, differing from the Wittig reaction.
Phosphonium salts are more acidic than phosphonates, leading to different reactivity.
HWE reaction proceeds in two steps: anion formation followed by nucleophilic attack on the carbonyl group.
Stereochemistry of HWE is determined by the syn elimination of the phosphate anion via a cyclic intermediate.
Still-Gennari modification of HWE reaction allows for the synthesis of Z olefins with excellent stereoselectivity.
Still-Gennari modification uses trifluoroethyl phosphonates and potassium hexamethyldisilazide as the base.
The selectivity in Still-Gennari modification is assumed to be due to the fast fragmentation step.
HWE and Still-Gennari olefinations can be applied to simple ketones and retain high E or Z selectivity.
Alpha-alkyl phosphonyl esters lead to high selectivity, especially when the alkyl group is a methyl group.
Stereoselective olefin synthesis is key in the synthesis of natural macrolide antibiotics.
Archazolide A serves as an example of a complex structure synthesized using HWE and Still-Gennari reactions.
Professor Dirk Menche's total synthesis of Archazolide A demonstrates the iterative use of olefination reactions.
HWE reaction is a popular tool in the synthesis of complex chemical substances.
Still-Gennari modification complements the HWE reaction, making it a crucial tool in modern organic synthesis.
Transcripts
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