Diels–Alder Reaction

Section Overview

• What is the Diels Alder Reaction?
• Precautions
• Applications for Diels Alder Reaction
• Recent Research and Trends
• Related Materials

What is the Diels Alder Reaction?

The Diels–Alder reaction is the reaction between a conjugated diene and an alkene (dienophile) to form unsaturated six-membered rings. Since the reaction involves the formation of a cyclic product via a cyclic transition state, it is also referred to as a "cycloaddition". The Diels–Alder reaction is an electrocyclic reaction, which involves [4+2]‑cycloaddition of 4 π-electrons of the conjugated diene and 2 π-electrons of the dienophile (an alkene or alkyne). The reaction involves the formation of new σ-bonds, which are energetically more stable than the π-bonds. This reaction has great synthetic importance and was discovered by two German chemists, Otto Diels and Kurt Alder in 1928. They were awarded the Nobel Prize in 1950.¹

The hetero-Diels–Alder reaction is a variant of this reaction and is useful for the synthesis of six-membered heterocyclic rings. In this reaction, either the diene or the dienophile contains a heteroatom, usually nitrogen or oxygen.¹

Precautions

Please consult the Safety Data Sheet for information regarding hazards and safe handling practices.

Applications for Diels Alder Reaction

The Diels–Alder reaction is useful for the synthesis of:

• Novel Diels−Alder reactions of arynes with functionalized acyclic dienes have been reported for the synthesis of useful cis-substituted dihydronaphthalene building blocks.²

• Natural and unnatural polycarbocycles and polyheterocycles.³
• Substituted (tetrahydro)quinolines and diverse N-polyheterocycles, including some alkaloids, which contain pyrroloquinoline or cyclopentaquinoline ring systems.⁴
• Pyrano[3,2-c]quinolines and indeno[2,1-c]quinolones.⁵
• Symmetrically substituted 1,8-diaza-9,10-anthraquinone derivatives.⁶
• Oxazaborolidine derived from N-tosyl (αS,βR)-β-methyltryptophan has been employed as the catalyst for the enantioselective Diels-Alder reaction of 2‑bromoacrolein and furan. This reaction leads to the synthesis of chiral 7‑oxabicyclo[2.2.1]heptene derivatives.⁷

• Functionalized 4-(R)-1,2-bis(trimethylsilyl)benzenes.⁸
• Functionalized oxabicyclic alkenes.⁹

Recent Research and Trends

• Intra- and intermolecular imino Diels–Alder reactions (Povarov reactions) of N-aryl imines and diverse electron-rich alkenes have been studied.⁴
• Ultrasonic irradiation promoted the Diels–Alder reaction of substituted furans with reactive dienophiles such as dimethyl acetylenedicarboxylate (DMAD) and dimethyl maleate afforded functionalized oxabicyclic alkenes in good yields.⁹

• The Diels–Alder reaction of graphite and tetracyanoethylene has been used for the mechanical exfoliation of graphite into graphene adducts.¹⁰
• Cross-linked hydrogels have been prepared using Diels-Alder “click” reaction without employing a catalyst.¹¹
• The asymmetric Diels–Alder reaction between N-acryloyloxazolidinone and cyclopentadiene has been catalyzed by heterogeneous copper(II)-bis(oxazoline)-based polymer immobilized ionic liquid phase (PIILP) systems.¹²
• Chiral oxazaborolidine−aluminum bromide complexes are potential catalysts for enantioselective Diels–Alder reactions.¹³
• Halocycloalkenones have been investigated as potent dienophiles in inter- and intramolecular Diels–Alder cycloadditions.¹⁴
• The chemical thermodynamics of Diels–Alder addition reactions of a series of acenes (anthracene, 9,10-dimenthylanthracene, tetracene and pentacene) to C₆₀ fullerene has been analyzed.¹⁵

Factors Enhancing the Efficiency and Selectivity of Diels–Alder Reaction:

• Diene and Dienophile Selection: Conjugated Dienes-Dienes should be in a s-cis conformation to facilitate overlap with the dienophile. Electron-Deficient Dienophiles-Dienophiles that are electron-poor (e.g., containing carbonyl groups or nitro groups) tend to react more readily with electron-rich dienes.
• Regioselectivity: The ability to predict and control the regioselectivity of the reaction is crucial. Substituents on the diene and dienophile can influence the outcome.
• Stereoselectivity: The formation of specific stereoisomers can be optimized by choosing appropriate substituents or using chiral catalysts to direct the reaction.
• Reaction Conditions: Temperature - Elevated temperatures can increase reaction rates, while lower temperatures may favor selectivity.
• Solvent: The choice of solvent can impact the reaction mechanism and product distribution.
• Kinetics: A good Diels-Alder reaction should proceed at a reasonable rate, allowing for practical application in synthetic processes.
• Functional Group Compatibility: The presence of other functional groups should not interfere with the reaction, and the products should be easily separable and purifiable.
• Yield and Purity: High yields and purity of the desired product are essential for the reaction to be considered successful.

References

1. Fringuelli F, Taticchi A. 2001. The Diels?Alder Reaction. https://doi.org/10.1002/0470845813

2. Dockendorff C, Sahli S, Olsen M, Milhau L, Lautens M. 2005. Synthesis of Dihydronaphthalenes via Aryne Diels?Alder Reactions:  Scope and Diastereoselectivity. J. Am. Chem. Soc.. 127(43):15028-15029. https://doi.org/10.1021/ja055498p

3. Smith MB. 2011. Organic Synthesis.

4. Kouznetsov VV. 2009. Recent synthetic developments in a powerful imino Diels?Alder reaction (Povarov reaction): application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron. 65(14):2721-2750. https://doi.org/10.1016/j.tet.2008.12.059

5. Babu G, Perumal PT. 1998. Convenient synthesis of pyrano[3,2-c]quinolines and indeno[2,1-c] quinolines by imino Diels-Alder reactions. Tetrahedron Letters. 39(20):3225-3228. https://doi.org/10.1016/s0040-4039(98)00397-9

6. Pérez JM, López-Alvarado P, Avendaño C, Menéndez J. 2000. Hetero Diels?Alder Reactions of 1-Acetylamino- and 1-Dimethylamino-1-azadienes with Benzoquinones. Tetrahedron. 56(11):1561-1567. https://doi.org/10.1016/s0040-4020(00)00058-2

7. Corey E, Loh T. 1993. Catalytic enantioselective diels-alder addition to furan provides a direct synthetic route to many chiral natural products. Tetrahedron Letters. 34(25):3979-3982. https://doi.org/10.1016/s0040-4039(00)60594-4

8. Reus C, Liu N, Bolte M, Lerner H, Wagner M. 2012. Synthesis of Bromo-, Boryl-, and Stannyl-Functionalized 1,2-Bis(trimethylsilyl)benzenes via Diels?Alder or C?H Activation Reactions. J. Org. Chem.. 77(7):3518-3523. https://doi.org/10.1021/jo3002936

9. Wei K, Gao H, Li WZ. 2004. Facile Synthesis of Oxabicyclic Alkenes by Ultrasonication-Promoted Diels?Alder Cycloaddition of Furano Dienes. J. Org. Chem.. 69(17):5763-5765. https://doi.org/10.1021/jo049210a

10. Ji Z, Chen J, Huang L, Shi G. High-yield production of highly conductive graphene via reversible covalent chemistry. Chem. Commun.. 51(14):2806-2809. https://doi.org/10.1039/c4cc09144b

11. García-Astrain C, Algar I, Gandini A, Eceiza A, Corcuera MÁ, Gabilondo N. 2015. Hydrogel synthesis by aqueous Diels-Alder reaction between furan modified methacrylate and polyetheramine-based bismaleimides. J. Polym. Sci. Part A: Polym. Chem.. 53(5):699-708. https://doi.org/10.1002/pola.27495

12. Doherty S, Knight JG, Ellison JR, Goodrich P, Hall L, Hardacre C, Muldoon MJ, Park S, Ribeiro A, de Castro CAN, et al. An efficient Cu(ii)-bis(oxazoline)-based polymer immobilised ionic liquid phase catalyst for asymmetric carbon?carbon bond formation. Green Chem.. 16(3):1470-1479. https://doi.org/10.1039/c3gc41378k

13. Liu D, Canales E, Corey EJ. 2007. Chiral Oxazaborolidine?Aluminum Bromide Complexes Are Unusually Powerful and Effective Catalysts for Enantioselective Diels?Alder Reactions. J. Am. Chem. Soc.. 129(6):1498-1499. https://doi.org/10.1021/ja068637r

14. Ross AG, Townsend SD, Danishefsky SJ. 2013. Halocycloalkenones as Diels?Alder Dienophiles. Applications to Generating Useful Structural Patterns. J. Org. Chem.. 78(1):204-210. https://doi.org/10.1021/jo302230m

15. Cataldo F, García-Hernández DA, Manchado A. 2015. Chemical Thermodynamics Applied to the Diels?Alder Reaction of C60Fullerene with Polyacenes. Fullerenes, Nanotubes and Carbon Nanostructures. 23(9):760-768. https://doi.org/10.1080/1536383x.2014.997354