Dienes and MO Theory
The Retro Diels-Alder Reaction
Last updated: February 17th, 2023 |
Mechanism and Examples of the Retro Diels-Alder Reaction
In the last post in this series on the Diels-Alder [See: Diels-Alder Reaction: Kinetic and Thermodynamic Control] we saw that if you apply enough heat, the Diels-Alder can operate in both the forward and reverse directions!
Table of Contents
- What Is The “Retro” Diels-Alder Reaction
- Diels-Alder / Retro Diels-Alder Reactions With Pyrone
- The Retro Diels-Alder Of This Molecule Does Not Give Back The Original Reactants!
- The Pyrone Retro Diels-Alder Is Particularly Favorable Because It Generates An Aromatic Ring And Liberates CO2
- Summary: The Retro Diels-Alder Reaction
- (Advanced) References and Further Reading
1. What Is The “Retro” Diels-Alder Reaction?
The “retro-Diels Alder” reaction is the exact reverse of the Diels-Alder and passes through the same transition state. (We sometimes say it’s the “microscopic” reverse – if you were to play a film of the Diels-Alder reaction occurring, and then reverse the film, it would be indistinguishable from the retro-Diels Alder reaction).
In the most common case, where the reverse Diels-Alder is exactly the same as the forward Diels-Alder, all that really happens is that an equilibrium is established between the diene/dienophile and the Diels-Alder product.
However, there are cases where the Diels-Alder product can undergo more than one possible retro-Diels Alder reaction, and this can result in the formation of products that differ from the “original” diene and dienophile.
This situation doesn’t come up very often in introductory organic chemistry courses, but when it does, it’s usually when you’re sitting in an exam hall. What makes the retro-Diels Alder reaction exam-question catnip for instructors is that it asks you to apply concepts you already know, but in the reverse direction.
Here, we’ll go through a classic example of a retro-Diels Alder reaction that shows how the reaction can be used to make useful new products, instead of just reverting to the starting diene and dienophile. (And if that isn’t enough, there’s a bonus, second example of a retro-Diels Alder in the supplemental section ).
2. Diels-Alder / Retro-Diels-Alder Reactions With Pyrone
Pyrone (specifically 2-Pyrone) is a cyclic molecule that resembles benzene but is not actually aromatic. Locked in the s-cis conformation, pyrone will participate in the Diels-Alder reaction with dienophiles. For reasons that will soon be clear, a useful category of dienophile is electron-poor alkynes such as dimethylacetylene dicarboxylate (DMAD), which results in the following Diels-Alder reaction:
The “top view” (above) shows the new six-membered ring as outlined from the (arbitrary) numbering scheme. It’s also possible to draw the same molecule from the side, which shows this bridged bicyclic molecule in perspective [See: Putting Diels-Alder Products in Perspective ]
3. The Retro Diels-Alder Of This Molecule Does Not Give Back The Original Reactants!
Now comes the fun part.
When this Diels-Alder product is heated, a retro-Diels Alder reaction occurs, but the final product isn’t 2-pyrone and the alkyne dienophile!
Instead, the products are a new aromatic ring and carbon dioxide (CO2)!
Why doesn’t it fragment to give back the pyrone and alkyne?
Well, it’s possible that it does, to some extent (more on that in a second). But the main point is that more than one retro-Diels-Alder pathway is possible here!
The second six-membered ring that can undergo retro-Diels Alder fragmentation is highlighted in red below:
4. The Pyrone Retro Diels-Alder Reaction Is Favorable Because It Generates An Aromatic Ring And Liberates CO2
Note that this retro-Diels Alder involves the same pattern of bond formation and bond breaking as in the retro-Diels Alder reaction at the top of the article:
- three pi bonds are formed
- two sigma bonds and one pi bond is broken
(One difference is that one of the pi bonds that forms is a C–O pi bond instead of a C–C pi bond, which technically makes it a retro-“hetero”-Diels Alder. A hetero Diels-Alder is a Diels Alder reaction that incorporates a heteroatom (i.e. non-carbon atom) such as oxygen or nitrogen into the new six-membered ring. )
What makes this particular retro-Diels Alder favorable, relative to the retro-Diels Alder that regenerates the pyrone and alkyne?
- First, the products are particularly stable. In addition to liberating CO2, the reaction also produces a new six membered ring with a property known as aromaticity that makes it particularly stable (about 36 kcal/mol more stable than would be expected based on bond energies alone).
- Secondly, this particular retro-Diels Alder reaction is irreversible, since the CO2 that is released is a notoriously poor dienophile for Diels-Alder reactions. Even if the retro-Diels Alder to generate the alkyne and pyrone does occur, equilibrium will eventually drive the reaction mixture towards formation of the aromatic ring and CO2.
See the supplementary section for a clever example of a pyrone / alkyne Diels-Alder reaction.
5. Summary: The Retro Diels-Alder Reaction
The retro-Diels Alder reaction is the microscopic reverse of the Diels-Alder reaction. It has the same transition state as the Diels-Alder, but as we saw in the previous post, requires more heating (i.e. has a higher energy barrier) than the forward Diels-Alder process.
When a retro-Diels Alder reaction just causes the Diels-Alder product to revert to the starting diene and dienophile, that’s essentially just setting up an equilibrium between the reactants and product.
However, by using certain cleverly designed reaction partners, some Diels-Alder products can undergo a retro-Diels Alder that irreversibly leads to new products, usually liberating a gas and an aromatic ring. The most common example is in the use of pyrone as diene with an acetylene as a dienophile, but there are others (see bonus section, below).
Diels-Alder / Retro Diels Alder Reactions of Tetrazines (Loss of N2)
This could be a bad analogy, but the retro-Diels Alder reminds me a little bit of the famous “adrenaline shot” scene in Pulp Fiction.
Why? Rather than have John Travolta stab Uma Thurman in the chest with a syringe, Tarantino filmed Travolta pulling the needle out of Thurman’s chest, and then reversed the footage.
The reverse process had a lower activation barrier for all concerned, particularly Uma Thurman.
Another example of a retro-Diels Alder that generates a new product begins with a class of very electron-poor diene called tetrazines.
When tetrazine is combined with a electron-rich acetylene like diphenylacetylene, a new Diels-Alder product results. (This puts the shoe on the other foot, energetically – the diene is electron poor, and the dienophile is electron rich! These reactions are called “inverse-electron demand Diels Alder reactions“, and although less frequently observed than their “normal electron demand” cousins, still see a lot of use. )
When this Diels-Alder product is heated, it undergoes a retro-Diels Alder reaction, losing N2 and forming a new aromatic ring:
With a few exceptions (mostly involving reactions with metals) nitrogen gas is completely inert.
The product can even be induced to undergo a second Diels-Alder / retro-Diels-Alder reaction (with loss of a second molecule of nitrogen).
Dale Boger’s group at Scripps has been extremely active in coming up with inventive applications of the retro-Diels Alder reaction, which you can read about in more detail here (Aldrich).
Sometimes the retro-Diels Alder is like that beautiful, rarely-used tool in a mechanic’s shop that is perfect for a very specific job.
A few years ago the Baran research group (also at Scripps) faced a problem where they were trying to form a medium-sized, highly strained ring in the molecule Haouamine A, which featured a “bent” aromatic ring. After banging their heads against the wall trying all of the conventional approaches to ring formation, they eventually solved the problem through bringing together an alkyne and a pyrone in an intramolecular Diels-Alder reaction, followed by a retro Diels-Alder to generate the aromatic ring. This required heating in a sealed tube at 250°C for 10h, which gave them the product in 21% yield along with 30% recovered starting material. (they later came up with higher-yielding approaches toward synthesizing the ring).
The reaction scheme is drawn up here on Hans J. Reich’s organic chemistry site (free) ; full paper here.
(Advanced) References and Further Reading
- Derivatives of Hemimellitic Acid. A Synthesis of Erythrocentaurin
Ernest Wenkert, David B. R. Johnston, and K. G. Dave
The Journal of Organic Chemistry 1964, 29 (9), 2534-2542
This paper uses the Diels-Alder-retro-Diels-Alder domino reaction to generate Hemimellitic acid and its derivatives, which are used in total synthesis.
- Diels-Alder reactions of 2-pyrones. Direction of the addition reaction with acetylenes
Joe A. Reed, Curtis L. Schilling Jr., R. F. Tarvin, Thomas A. Rettig, and John K. Stille
The Journal of Organic Chemistry 1969, 34 (7), 2188-2192
This paper is more concerned with the first step – addition of the alkyne (e.g. DMAD) to 2-pyrone. Note the author – this is the same John Stille of Stille reaction fame.
- Recent developments in the retro-Diels–Alder reaction
Sambasivarao Kotha and Shaibal Banerjee
RSC Advances 2013, 3, 7642-7666
- Retro-Diels-Alder Reaction. Part I. C-C Dienophiles
Organic Reactions 1998, 52, 1-393
- The Retro–Diels–Alder Reaction Part II. Dienophiles with One or More Heteroatom
Organic Reactions 1998, 53, 223-629
- Photo Retro-Diels–Alder Reactions
Valentine K. Johns, Zheng Shi, Wei Dang, Matthew D. McInnis, Yuxiang Weng, and Yi Liao
The Journal of Physical Chemistry A 2011, 115 (28), 8093-8099
Retro-Diels-Alder reactions can also be initiated by light, as this paper demonstrates.
- Total Synthesis of (±)-Haouamine A
Phil S. Baran and and Noah Z. Burns
Journal of the American Chemical Society 2006, 128 (12), 3908-3909
The final step in the total synthesis of (±)-Haouamine A is a tandem Diels-Alder-Retro-Diels Alder reaction. The paper states, “After extensive experimentation, 15 was converted into 1 [(±)-Haouamine A] upon microwave irradiation of 15 in dichlorobenzene at 250 °C for 10 h followed by basic (K2CO3, MeOH) acetate hydrolysis.”
On another note, Noah Burns is now a professor at Stanford University, and I remember reading his first paper as an assistant professor back in 2013, which was an elegant method for asymmetric dibromination of alkenes, ala K. B. Sharpless.
- Retro Diels-Alder Reactions
Hans J. Reich (U. Wisconsin-Madison) has a website chock full of useful information on organic chemistry, including this section on Retro-Diels-Alder reactions. Another one can be found here:
- Diels-alder reactions with inverse electron demand. II. The reaction of benzamidine with π-deficient heteroaromatic compounds
P. Figeys, A. Mathy
Tet. Lett. 1981, 22 (15), 1393-1396
The normal Diels-Alder reaction proceeds best when the diene is electron-rich and the dienophile electron-poor. However, in certain cases, the opposite polarity is possible, and these reactions are known as inverse electron-demand Diels-Alder reactions.
- Inverse Electron-Demand Diels Alder Reactions
This technical article by Sigma-Aldrich has a lot of useful information on inverse-electron-demand Diels-Alder reactions.
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