Pericyclic Reactions Part 2: Hetero-DA Reactions and 1,3-Dipolar Cycloadditions
TLDRThis tutorial explores modifications of the Diels-Alder reaction, highlighting the use of heteroatoms in dienophiles to create diverse heterocycles. It discusses kinetics, the impact of electron-withdrawing and donating groups, and the extension of the reaction through 1,3-dipolar cycloadditions involving 1,3-dipoles and standard dienophiles. The video emphasizes the technique's utility in stereoselective synthesis, showcasing examples with diazomethane and nitrile oxides, and its importance in natural product and drug synthesis.
Takeaways
- 🔬 The Diels-Alder reaction involves a diene and a dienophile to generate cyclohexene.
- 🌱 Modifications to the Diels-Alder reaction can include using dienophiles with oxygen or nitrogen, producing heterocycles.
- 🧪 Examples of products: aldehydes or ketones yield dihydropyrans, imines yield tetrahydropyridines, and thiones yield dihydrothiapyrans.
- ⚡ Electron-withdrawing groups on the dienophile accelerate the reaction.
- 🌀 Heteroatoms can be included on the diene, producing various derivatives like tetrahydropyridine.
- 🔄 1,3-dipolar cycloaddition is an extension of the Diels-Alder reaction, involving a 1,3-dipole.
- 🧬 1,3-dipolar cycloaddition produces five-membered rings and follows stereospecific and regiochemical rules.
- ⚗️ Diazomethane reacts with methyl acrylate to produce substituted pyrazoline with specific regiochemistry.
- 🌐 Nitrile oxides react with olefins to produce iso-oxazolines with strong regio and stereoselectivity.
- 💊 1,3-dipolar cycloaddition is valuable in synthesizing natural products and drugs due to its selectivity and efficiency.
Q & A
What is the Diels-Alder reaction?
-The Diels-Alder reaction is a [4+2] cycloaddition between a diene and a dienophile to form a cyclohexene ring. It is an important reaction in organic chemistry for the synthesis of six-membered rings.
Can the atoms participating in the Diels-Alder cycloaddition be other than carbon?
-Yes, the atoms participating in the cycloaddition can be other than carbon. They can be oxygen or nitrogen, which allows for the formation of various heterocycles.
What are some examples of heterocycles that can be produced using modified Diels-Alder reactions with different dienophiles?
-Examples include dihydropyrans from aldehydes or ketones, tetrahydropyridines from imines, and dihydrothiapyrans from thiones.
How do electron-withdrawing groups on the dienophile affect the Diels-Alder reaction?
-Electron-withdrawing groups on the dienophile accelerate the Diels-Alder reaction by withdrawing electron density, making the reaction more favorable.
What is the impact of electron-donating groups on the diene in a Diels-Alder reaction?
-When a diene has electron-donating groups, such as methoxy, these groups can end up either ortho or para to the tosyl group in the product, but not meta.
Can heteroatoms be incorporated into the diene as well as the dienophile in a Diels-Alder reaction?
-Yes, heteroatoms can be incorporated into both the diene and the dienophile. For example, replacing a terminal carbon of butadiene with nitrogen gives an alpha-beta unsaturated imine that can react with maleic anhydride.
What is a 1,3-dipolar cycloaddition and how is it related to the Diels-Alder reaction?
-A 1,3-dipolar cycloaddition is an extension of the Diels-Alder reaction where the diene is replaced by a 1,3-dipole, a three-atom fragment with a zwitterionic structure. It also follows a [4+2] cycloaddition pattern.
How does the 1,3-dipolar cycloaddition differ from the Diels-Alder reaction in terms of the reactants involved?
-In a 1,3-dipolar cycloaddition, instead of a diene with two pi bonds, a 1,3-dipole with one pi bond and one lone pair is used. The lone pair is considered as two pi electrons, allowing the reaction to proceed as a [4+2] cycloaddition.
What is the significance of stereospecificity in 1,3-dipolar cycloaddition reactions?
-Stereospecificity in 1,3-dipolar cycloaddition reactions ensures that the stereochemistry of the reactants is preserved in the products, allowing for precise control over the spatial arrangement of atoms in the final product.
Why is the 1,3-dipolar cycloaddition technique valuable in the synthesis of natural products and drugs?
-The 1,3-dipolar cycloaddition technique is valuable because it allows for the formation of complex molecules with high regio- and stereoselectivity, which can be difficult to achieve using standard enolate chemistry.
How can a nitrile oxide be generated and used in a 1,3-dipolar cycloaddition?
-A nitrile oxide can be generated via dehydration of nitroalkanes, typically in situ, and then immediately reacted with olefins to produce an iso-oxazoline with strong regio and stereoselectivity.
Outlines
🔬 Modifications in Diels-Alder Reactions
This paragraph delves into the variations of the Diels-Alder reaction, a fundamental organic chemistry process involving a diene and a dienophile to form cyclohexene. The traditional reaction is expanded to include heteroatoms such as oxygen or nitrogen in the dienophile, leading to the formation of heterocycles. Examples provided include the synthesis of dihydropyrans from aldehydes or ketones, tetrahydropyridines from imines, and dihydrothiapyrans from thiones. The paragraph also touches on the kinetic trends, where electron-withdrawing groups on the dienophile accelerate the reaction, and the possibility of substituting carbon atoms with heteroatoms in the diene, exemplified by the formation of a tetrahydropyridine derivative from an alpha-beta unsaturated imine and maleic anhydride. The section concludes with an introduction to 1,3-dipolar cycloadddition, an extension of the Diels-Alder reaction where a 1,3-dipole replaces the diene, resulting in a [4+2] cycloaddition to form a five-membered ring.
🧪 1,3-Dipolar Cycloaddition: A Powerful Synthetic Tool
The second paragraph focuses on the 1,3-dipolar cycloadddition, a significant extension of the Diels-Alder reaction. It explains the concept of a 1,3-dipole, characterized as a three-atom fragment with a zwitterionic structure, capable of undergoing cycloaddition with a standard dienophile to form a five-membered ring. The paragraph illustrates this with the example of diazomethane as a 1,3-dipole reacting with methyl acrylate to yield a substituted pyrazoline, emphasizing the regiochemical outcome dictated by frontier orbital theory. Another example is the nitrile oxide, which is produced in situ and reacts with olefins to form iso-oxazolines, showcasing the strong regio and stereoselectivity of the reaction. The paragraph highlights the utility of 1,3-dipolar cycloadddition in natural product and drug synthesis due to its ability to achieve complex molecular architectures with high selectivity, a challenge often encountered in traditional enolate chemistry.
Mindmap
Keywords
💡Diels-Alder reaction
💡diene
💡dienophile
💡heterocycle
💡1,3-dipolar cycloaddition
💡1,3-dipole
💡regiochemistry
💡stereochemistry
💡electron-withdrawing groups
💡electron-donating groups
💡nitrile oxide
Highlights
The Diels-Alder reaction can be modified to include heteroatoms like oxygen or nitrogen in the dienophile, leading to the formation of various heterocycles.
Examples of heterocycles formed include dihydropyrans from aldehydes or ketones, tetrahydropyridines from imines, and dihydrothiapyrans from thiones.
The utility of Diels-Alder chemistry extends beyond cyclohexene generation to the creation of diverse heterocycles.
Kinetic trends from the standard Diels-Alder reaction apply to these modifications, with electron-withdrawing groups on the dienophile accelerating the reaction.
An N-tosylimine, which withdraws electron density, can react with cyclopentadiene at room temperature due to its electron-withdrawing tosyl group.
Dienes with electron-donating groups like methoxy can lead to ortho or para positioning of methoxy and tosyl groups, but not meta.
Heteroatoms can also replace carbon atoms in the diene, as demonstrated by replacing terminal carbon with nitrogen to form an alpha-beta unsaturated imine.
The alpha-beta unsaturated imine can react with maleic anhydride to produce a tetrahydropyridine derivative.
A 1,3-dipolar cycloaddition is an extension of the Diels-Alder reaction where a 1,3-dipole replaces the diene.
A 1,3-dipole is a three-atom fragment that can be represented as a zwitterion with one pi bond and formal charges on the terminal atoms.
The [4 + 2] cycloaddition in 1,3-dipolar reactions involves the 1,3-dipole's pi bond and lone pair, along with the dienophile's two pi electrons.
These reactions are stereospecific and follow clear regiochemical laws, as demonstrated by specific examples.
Diazomethane acts as a 1,3-dipole and reacts with methyl acrylate to form a substituted pyrazoline with defined regiochemistry.
The ester group in the product ends up adjacent to the terminal nitrogen due to frontier orbital considerations.
Nitrile oxides, produced in situ from nitroalkanes, can also act as 1,3-dipoles and react with olefins to form iso-oxazolines with strong regio and stereoselectivity.
The N-O bond in iso-oxazolines can be cleaved using Raney nickel and protonated to generate Aldol-type products.
1,3-Dipolar cycloaddition offers a synthetic technique with high regio and stereoselectivity, difficult to achieve with standard enolate chemistry.
This approach is commonly used in natural product and drug synthesis due to its versatility with various heteroatoms and dipoles.
Transcripts
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