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Dienes and MO Theory

By James Ashenhurst

The Intramolecular Diels Alder Reaction

Last updated: December 6th, 2019 |

The Intramolecular Diels-Alder Reaction Is Awesome

Exam preparation tip: Instructors often include questions on intramolecular versions of familiar reactions on exams, since they involve no new concepts but might “look weird” if you haven’t practiced them before.  Familiarize yourself with the intramolecular versions of important reactions [e.g. SN2, ether cleavageWittig, Friedel-Crafts, and more], including (below!) the Diels-Alder.

You might think we were done with the Diels-Alder, having gone through the general mechanism, the stereochemistryexo– and endo- products, the molecular orbitals involved, and regiochemistry. Well, there’s always more to discover about this powerful reaction, so here we are again.

Today let’s investigate the intramolecular Diels-Alder reaction. It involves no new concepts. Everything you’ve already learned about the Diels-Alder still applies. The trick will be not to get “weirded out” by the starting materials and the products. Let’s go!

Table of Contents

  1. The Intramolecular Version Of The Diels-Alder Reaction
  2. Intramolecular Diels Alder Reactions Work Best When Forming Five And Six Membered Rings
  3. The Key Patterns Of The Intramolecular Diels-Alder Reaction Are No Different From The “Regular” Diels-Alder Reaction
  4. The Stereochemistry Of The Dienophile Is Preserved
  5. How To Draw The Product Of An Intramolecular Diels Alder Reaction
  6. More Practice In Drawing Intramolecular Diels-Alder Reactions
  7. What About “Endo” and “Exo” In Intramolecular Diels-Alder Reactions?
  8. Summary: The Intramolecular Diels-Alder Reaction
  9. Notes
  10. Appendix: Type 1 and Type 2 Intramolecular Diels-Alder Reactions, Transannular Diels-Alder Reactions
  11. Quiz Yourself!
  12. (Advanced) References and Further Reading

1. The Intramolecular Version Of The Diels-Alder Reaction

As we’ve seen, the Diels-Alder reaction is an awesome process where a “diene” combines with a “dienophile” to give a new six-membered ring.

We form two new C–C sigma bonds and a C–C pi bond, and break three C–C pi bonds.

Diels-Alder-Reaction-pattern-of-bonds-that-form-and-break

You can think of the (electron-rich) diene as the “nucleophile” and the (electron-poor) dienophile as the “electrophile” here.

As we’ve seen, when a nucleophile and an electrophile are present on the same molecule, rings can form.  We’ve seen it most recently with the Williamson ether synthesis, which gives cyclic ethers.

The Diels-Alder reaction is no different. If the diene and dienophile are connected together by a chain of carbon atoms, it’s possible for them to come in close enough proximity for a reaction to occur.

simple-example-of-an-intramolecular-diels-alder-reaction

Intramolecular reactions take some getting used to. Note that the pattern of bonds that form and break is exactly the same! The only thing that’s changed here is that since the diene and dienophile are on the same molecule, a ring will form.

The analogy I like to use is that of a belt or loop, where the nucleophile (the buckle) joins together with the electrophile (the notch).

Any time a new ring is formed, some restrictions apply. The nucleophile and electrophile have to be able to “find” each other in the first place. If the carbon chain isn’t long enough, no reaction will occur.

This is true of belts, too. Imagine cutting a notch in a belt about an inch away from the buckle. You can’t bring the buckle close enough to the notch for it to close! There just isn’t enough slack.

The same is true for intramolecular Diels-Alder reactions in the case where the diene and the dienophile are separated by just one or two carbons. The diene and dienophile are just too close together. The reaction doesn’t work.

(For what it’s worth, the product would also contain a new cyclopropane or cyclobutane ring so this would introduce significant ring strain! ) [Note]

via GIPHY

However, when the chain length is three or more, the intramolecular Diels-Alder reaction is possible!

2. Intramolecular Diels Alder Reactions Work Best When Forming Five And Six Membered Rings

When the diene and dienophile are separated by three carbons, a new five-membered ring will form in addition to the six-membered ring. Here’s a real-life example.2

example-of-intramolecular-diels-alder-forming-new-five-membered-ring

Again, note – the bonds that form and the bonds that break are exactly the same as above.

The intramolecular Diels-Alder reaction also works well when the diene and dienophile are separated by four carbons. In this case a new six-membered ring will form, in addition to the six-membered ring obtained in every Diels-Alder reaction. Buy one, get one free!

example-of-diels-alder-reaction-forming-new-six-membered-ring

[It’s actually possible to design a Diels-Alder reaction that results in three new rings! Note]

Of course, the tether can be extended even further to give even larger rings, but five- and six- membered rings tend to be the “sweet spot”. Forming 8-11 membered rings can be tricky for (advanced – transannular strain) reasons we won’t go into today. Additionally, as the chain gets longer, the diene and the dienophile aren’t held together as closely (something we call, “effective concentration”) so the reaction rates are lower.

For an example of a large ring synthesis (from the laboratory of Nobel Laureate Prof E.J. Corey) see this footnote7 .

3. The Key Patterns Of The Intramolecular Diels-Alder Reaction Are No Different From The “Regular” Diels-Alder Reaction

Now let’s start making things a bit more exotic. But keep your eye on the ball! The bonds formed and bonds broken will not change!

For example here is an example of a Diels-Alder containing a nitrogen:

example-of-diels-alder-reaction-incorporating-nitrogen-in-the-tether

Notice how the nitrogen isn’t the least bit involved in the bonds that form and break here. Try not to get distracted!  [Note]  

4. The Stereochemistry Of The Dienophile Is Preserved

Recall that in the intermolecular (i.e. “regular”) Diels-Alder if we have a dienophile with a trans– orientation about the double bond, that trans– relationship is transferred to the new six-membered ring.

in-the-diels-alder-reaction-the-stereochemistry-of-the-dienophile-is-preserved

Things are no different with the intramolecular Diels-Alder!

The stereochemistry of the dienophile is preserved. Here we’ve got a dienophile with a cis geometry, and note that this relationship is preserved in the Diels-Alder product.

in-the-intramolecular-diels-alder-reaction-the-stereochemistry-of-the-dienophile-is-preserved

Likewise, although we won’t present an example, the “outside” groups on the diene will end up on the same face of the new six-membered ring. We saw that previously where we covered stereochemistry in the Diels-Alder.

5. How To Draw The Product Of An Intramolecular Diels Alder Reaction

So far, we’ve been “cheating” a bit. You might have noticed that each of these examples was set up very nicely and the Diels-Alder reaction is pretty obvious.

That won’t always be the case. Sometimes you might be given a long chain polyene that you have to draw the Diels-Alder product for, such as in the example below.

draw-the-product-of-this-intramolecular-diels-alder-reaction

So what do you do?

The first rule of intramolecular reactions is to number all the carbons. (Trust me on this.)

OK. Now what?

Every Diels-Alder reaction follows the the same bond forming/bond breaking pattern. So I suggest you start with the “template” of the Diels-Alder first and then connect the two with a vague-looking “loop”. (It’s OK, we’ll fill in the missing details in the next step.)

how-to-draw-the-product-of-an-intramolecular-diels-alder-reactio

Then, since you have so nicely numbered all the carbons, it shouldn’t be too hard to go back and fill in all the parts you missed. In this case we note that we have 3 linking carbons so we will get a new 5-membered ring. Also, we need to attach the CO2CH3 to what we’re calling, C-9.

At this point go ahead and draw in the product of the Diels-Alder reaction.  It’s OK to draw the ugly version first, then clean it up.

how-to-draw-the-product-of-an-intramolecular-diels-alder-reaction

The last step is to draw in the stereochemistry. The dienophile is trans, so that means that this relationship needs to be preserved in the product. It’s OK to draw the ester as a wedge and the C-7 as a dash (or vice versa – that will imply the enantiomer). Alternatively placing an H as a wedge will imply that the other substituent is a dash (or vice versa).

That’s it.  Not so bad if you follow the steps!

6. More Practice In Drawing Intramolecular Diels-Alder Reactions

Let’s do another one. Try to draw the product of this Diels-Alder reaction. I’ve already numbered it for you.

what-is-the-productr-of-this-intramolecular-diels-alder-reaction

A helpful hint: it mght help to set up your Diels-Alder in the normal way with just a “loop” for the linker at first. Remember, if there are 3 carbons linking the diene with the dienophile, a new five-membered ring will be formed. If there are 4 linking carbons, a new six-membered ring will be formed.

The answer to this quiz along with other quiz questions can be found in the “Quiz Yourself” section below.

7. What About “Endo” and “Exo” In Intramolecular Diels-Alder Reactions?

Since everything that applies to an intermolecular Diels-Alder reaction also applies to an intramolecular Diels-Alder, you might be wondering: does “endo” and “exo” apply to the intramolecular Diels-Alder reaction too?

Well, yes.

[If you look closely, you might notice that several examples above have chiral centers where the stereochemistry is undefined. That’s on purpose just to keep things simple. ]

The factors that affect the geometry of the new ring are subtle, and I don’t think it’s appropriate to go into them today.  The Alder “Endo” rule doesn’t apply as cleanly to intramolecular Diels-Alder reactions as it does to intermolecular reactions.

If you are curious about this subject, I highly recommend starting with the work of Prof. Ken Houk in the references below2 , as well as this (open access) review by Prof. Alex Fallis of University of Ottawa.

8. Summary: The Intramolecular Diels-Alder Reaction

Here’s what we’ve covered about the intramolecular Diels-Alder reaction:

  • The pattern of bonds broken and bonds formed is the same as in any other Diels-Alder, as is the stereochemistry patterns in the diene and the dienophile.
  • We developed a system for drawing the product of an intramolecular Diels-Alder reaction when the starting material is drawn as an open chain: 1) Number the carbons 2) Draw a Diels-Alder template  3) Fill in the rest of the molecule 4) Draw out the Diels-Alder reaction (draw the ugly version first) 5) Clean up the product 6) Adjust stereochemistry of the dienophile (if necessary)

Don’t get psyched out. Take your time, methodically number your carbons, follow the key patterns, and breathe.


Notes

1. Look at the products that would result from the intramolecular Diels-Alder reaction of these molecules. Even if the diene and the dienophile could reach, the products would be very strained!

for-an-intramolecular-diels-alder-reaction-to-occur-the-tether-length-must-be-longer-than-1-or-2-carbons

These types of dienes (o-quinodimethanes) are unstable and highly reactive. Notice how the Diels-Ader product is an aromatic ring? That gives this reaction a tremendous driving force.

“Type 1” and “Type 2” Intramolecular Diels Alder Reactions

The intramolecular Diels-Alder reaction has seen tremendous use in complex target molecule synthesis.

All the examples in the article above show the diene and dienophile attached where the tether is on one of the termini of the diene.

These are sometimes called, “Type 1” intramolecular Diels-Alder reactions – the most common kind, in other words.

However, there is another way to do it: link the diene and dienophile together through carbon #2 of the diene.

These are referred to as “Type 2” intramolecular Diels-Alder reactions.

Type-1-and-Type-2-Diels-Alder-Reactions

The result will be a bridged bicyclic product, which can sometimes be helpful in synthesis. Here’s a (simplified) example from Prof. Tohru Fukuyama’s synthesis of the fungal metabolite CP-263,114.Ref 

Fukuyama-type-2-intramolecular-diels-alder-reaction-cp-molecules

Note also that the product has a bridgehead double bond – but that’s OK since the parent ring is 9-membered, and bridehead alkene stability roughly correlates to the stability of the parent trans-cycloalkene (trans-cyclononene is stable and isolable)

“Transannular” Intramolecular Diels-Alder Reactions

All of the examples above had the diene and the dienophile attached via a linker on one end of the diene. This results in two rings – the 6 membered ring of the Diels Alder, plus the new ring. It’s also possible to have the diene and dienophile attached through both ends of the diene. In this case three new rings will form. This is referred to as a transannular Diels-Alder reaction5 .

Here is an example of a transannular Diels-Alder reaction resulting in a synthesis the steroid nucleus.

Example-of-a-transannular-diels-alder-reaction-to-form-the-steroid-nucleus

An incredible example of a transannular Diels-Alder came up in Prof. Erik Sorensen’s (Princeton) synthesis of the hexacyclic beast below which was a double transannular intramolecular Diels-Alder reaction! This actually happens in nature!

double-intramolecular-diels-alder-reaction-forming-FR182877-Sorensen
Image source: https://chemistry.princeton.edu/faculty/erik-j-sorensen

This process was discovered concurrently (and independently)  by the laboratory of Prof. David A. Evans of Harvard University.


Quiz Yourself!

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(Advanced) References and Further Reading

After the initial report of the Diels-Alder reaction in 1928, it took several decades for an intramolecular version to appear. Alder reported an intramolecular Diels-Alder reaction in 1956, but it wasn’t until the early 1960’s that significant progress began to be made.

  1. Synthetic Transformation of Natural Products. I. 1-Methylene-2,10-methano-5,5,9-trimethyldecahydronaphthalene
    Brieger, G.
    Journal of the American Chemical Society 1963 85 (23), 3783-3784
    DOI: 10.1021/ja00906a015
    One of the earliest published examples of an intramolecular Diels-Alder reaction, toward the construction of the longifolene skeleton. f
  2. Intramolecular diels-alder reactions of 1,3,8-nonatriene and 1,3,9-decatriene
    Yi-Tsong Lin, K. N. Houk
    Tetrahedron Letters
    1985, 26 (19) 2269-2272
    DOI: 10.1016/S0040-4039(00)95071-8 
  3. Intramolecular Diels-Alder reactions of ethyl 2,4,9-decatrienoate and 2,4,10-undecatrienoate
    Yi-Tsong Lin, K. N. Houk
    Tetrahedron Letters1985, 26 (21) 2517-2520
    DOI
    : 10.1016/S0040-4039(00)98825-7
    These two classic studies are aimed at investigating some of the simplest possible intramolecular Diels-Alder reactions and examining the subtle factors that affect the stereochemistry of the new ring junction.
    study-by-houk-1984-stereochemistry-of-ring-junctions-intramolecular-diels-alder
  4. The Type 2 Intramolecular Diels-Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes
    Bear, B. R.; Sparks, S. M.; Shea, K. J.
    Angew. Chem. Int. Ed. Engl. 200140, 820-49
    DOI: 10.1002/1521-3773(20010302)40:5%3C820::AID-ANIE820%3E3.0.CO;2-F
    A review on “Type 2” intramolecular Diels-Alder reactions by Prof. Kenneth J. Shea (University of California, Irvine).
  5. The Transannular Diels-Alder Strategy: Applications to Total Synthesis
    Marsault, E.; Toro, A.; Nowak, P.; Deslongchamps, P.
    Tetrahedron 200157, 4243-60
    DOI: 10.1016/S0040-4020(01)00121-1
    Prof. Pierre Deslongchamps (U. de Sherbrooke) has been a pioneer in developing the transannular Diels-Alder reaction.
  6. An Enantioselective Synthesis of FR182877 Provides a Chemical Rationalization of Its Structure and Affords Multigram Quantities of Its Direct Precursor
    Christopher D. Vanderwal,David A. Vosburg,Sven Weiler, and, and Erik J. Sorensen
    Journal of the American Chemical Society 2003 125 (18), 5393-5407
    DOI: 10.1021/ja021472b
    Epic double intramolecular Diels-Alder cascade reaction resulting in the complex hexacyclic molecule (+)-FR182877.
  7. Formation of Macrocyclic Structures By Use Of The Diels-Alder Reaction
    Corey, E. J. ; Petrzilka, M.
    Tetrahedron Letters, 1975, 2537.
    DOI: 10.1016/S0040-4039(00)75172-0
    Formation of a new 12-membered ring using an intramolecular Diels-Alder reaction from the laboratory of Prof. E.J. Corey (Harvard)

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