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Sep 26

Blog Carnival: The Diels-Alder Reaction!

by azmanam | Categories: synthetic chemistry | (51187 Views)

This post was excerpted and featured in a recent edition of C&ENews

No reaction is more elegant, more heartwarmingly satisfying than the Diels-Alder reaction.  No reaction is also more nuanced.  It appears deceptively simple and yet has the ability to create immense structural complexity often without additional reagents and sometimes solvent-free.  Straightforward enough for an undergraduate organic chemistry class, yet intricate enough to spend several days in a graduate organic chemistry class reading into the engrossing story that is the Diels-Alder reaction.  It is by far my favorite reaction and the subject of my Blog Carnival Post.  And I am grateful to BRSM for deciding not to blog about the Diels-Alder Reaction. :)

First reported in 1928 by Otto Diels (1876-1952) and his graduate student Kurt Alder (1902-1958), the chemists at once saw the importance of their work and wanted the exclusive rights to utilize their reaction.  They write in their 1928 paper: “[T]he possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect … We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.”  Fortunately for us, this exclusivity no longer applies.  Oh, by the way, the pair won the 1950 Nobel Prize in Chemistry for the reaction.

Striped away from all its layers of complexity, at its core, the Diels-Alder reaction (here’s a 3-D animation of the Diels-Alder Reaction) is a reaction of a conjugated diene (4π electrons, in the s-cis conformation) and an alkene (2π electrons, called the dienophile) to form a cyclohexene ring – the reaction is classified as a [4π + 2π] cycloaddition.  This is the bare-bones Diels-Alder reaction we all remember from undergraduate organic chemistry classes.  Straightforward, right?  The Diels-Alder is usually the only cycloaddition reaction to make it into undergraduate organic textbooks.  And that may be as deep as most undergraduate texts delve into the Diels-Alder reaction. (Click images for larger throughout.  And, like CJ, I also went with the hand-drawn structures.)

The Diels-Alder Reaction

The Diels-Alder Reaction

But the story is so much more interesting and rich.  Note that the electrons don’t really start and end anywhere in particular.  Like Kekulé’s apocryphal tail-eating snake, the electrons travel around in a ring in this mechanism; the Diels-Alder reaction joins other privileged mechanisms – electrocyclizations (Nazarov) and sigmatropic rearrangements (Cope, Claisen) – in the tribe known as pericyclic reactions.  Pericyclic reactions are an immensely rewarding cadre of reactions to study.  This is one of the few times where thoroughly wading through the theory behind the reactions pays great dividends in clarifying the reactions and predicting their products.

Pericyclic Examples

Examples of Other Pericyclic Reactions

Let’s look at application.  Your prototypical, run-of-the-mill Diels-Alder reaction yields a cyclohexene.  For most undergraduate courses, the regiochemical implications of this are enough.  An ambitious professor will make the diene a cyclic diene, which yields a bridged bicyclic system.  Those are always fun to draw.  A tethered diene and dienophile will form a fused bicycle (and tether a dienophile to a cyclic diene to make a sweet looking tricycle).  And for bonus fun, positioning a diene and a dienophile at opposite ends of a macrocycle leads to a transannular Diels-Alder, which has the awesome acronym TADA!

Diels-Alder Reaction Examples

Examples of the Diels-Alder Reaction

One of my favorite applications of the Diels-Alder exploits the fact that this reaction can run in reverse if the conditions are right (we call this a retro Diels-Alder) to turn a cyclohexene into a diene and a dienophile.  Reacting an unsaturated lactone as the diene with an alkyne as the dienophile produces an intermediate bridged bicyclic lactone.  A retro-Diels-Alder follows to liberate gaseous carbon dioxide, which bubbles out of solution, to yield a substituted benzene ring.  Very slick reaction.

Diels-Alder/Retro Diels-Alder Sequence

Diels-Alder/Retro Diels-Alder Sequence

Vollhardt’s 1980 synthesis of estrone showcases a beautiful example of an intramolecular Diels-Alder reaction.  Under thermal conditions, the benzocyclobutene (prepared in remarkably short order through alkyne trimerization methodology) undergoes a 4π-electrocyclic ring opening (another pericyclic reaction) to give an intermediate ortho-quinodimethane – a perfectly situated and highly reactive diene.  The pendant dienophile readily reacts with this diene to close the last two rings of the cholesterol framework.

Diels-Alder Example in Estrone Synthesis

Estrone Synthesis: Diels-Alder Example

Similarly, Corey’s 1969 prostaglandin F synthesis is a retrosynthetic masterpiece which every aspiring organic chemist needs to study.  Only a five-membered ring exists in the product, yet Corey had the vision to see that carbon atoms 6-11 (prostaglandin numbering) could form the 6 carbon atoms of the cyclohexene Diels-Alder product.  Diels-Alder reaction of the cyclopentadiene derivative and a ketene equivalent yielded a bridged bicyclic product.  Conversion to the ketone, followed by Baeyer-Villiger oxidation, gave the bridged bicyclic lactone.  A few steps later, the bridged lactone had been converted into the fused lactone which we now call the Corey lactone in homage to the organic chemistry giant.

Diels-Alder Example in Prostaglandin Synthesis

Prostaglandin Synthesis: Diels-Alder Example

The Diels-Alder reaction is not merely restricted to the synthetic lab; nature also enjoys a good Diels-Alder reaction from time to time.  And who can forget the endiandric acids from the pericyclic chemistry unit in their graduate organic chemistry class?  The unsaturated acid with seven double bonds is a naturally occurring polyene.  Once formed, the molecule spontaneously undertakes three separate pericyclic reactions to form an incredible amount of molecular complexity as a single pair of enantiomers.  Initial 8π conrotatory electrocyclization yields a cyclooctatriene.  A 6π disrotatory electrocyclization forms a fused bicycle.  Depending on which diastereomer is formed in this electrocyclization, the bicycle is in perfect orientation to perform one of two Diels-Alder reactions to form either endiandric acid B or endiandric acid C.    All this occurs non-enzymatically in nature.

Endiendric Acid: Diels-Alder Example

Endiendric Acid Synthesis: Diels-Alder Example

Where would we be without the Diels-Alder reaction?  Two σ-bonds, a ring, and up to four new contiguous stereocenters prepared in one elegant reaction.  Through judicious choice of starting materials, an enormous amount of molecular complexity can be formed.  My students always laugh at me for having a favorite reaction.  I don’t care.  The Diels-Alder reaction will always be my very favorite reaction.

 

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I almost cut this last part out of the final draft.  It’s a lot of the theory behind the Diels-Alder reaction.  But it’s just so cool to see it all come together I had to include it:

Like all pericyclic reactions, the Diels-Alder reaction is governed by what we now call the Woodward-Hoffman(-Corey???) rules.  For a pericyclic reaction to proceed, the p-orbitals of the reactants must overlap.  And the sign of the overlapping p-orbitals must be the same: the sign of the terminal orbitals in the HOMO of the diene and the LUMO of the dienophile must match.  This happens naturally with the HOMO/LUMO overlap in the [4π + 2π] Diels-Alder cycloaddition, though this analysis fails with the HOMO/LUMO overlap in the analogous [2π + 2π] cycloaddition (but if you photochemically excite one electron up one orbital level, this changes which orbital is the HOMO and the corresponding orbital signs.  Thus [2π + 2π] cycloadditions are said to be thermally disallowed, but photochemically allowed).

Molecular Orbital Picture for the Diels-Alder Reaction

Molecular Orbital Analysis for the Diels-Alder Reaction

The reaction works best when the HOMO and LUMO are close in energy.  Since the antibonding LUMO is always higher in energy than the bonding HOMO, anything to raise the energy of the HOMO and/or lower the energy of the LUMO makes Diels-Alder reactions more facile.  Chemists have long known that adding Electron Donating Groups (EDGs) to the diene and Electron Withdrawing Groups (EWGs) to the dienophile make for a smoother Diels-Alder reaction (although Inverse-Demand Diels-Alder reactions are known).  Adding a Lewis acid to further stabilize the LUMO helps, too.  But once you start tinkering with the electronic distribution of the π-system, you have to deal with the unintended consequence of altering the regioselectivity of the reaction.  If this is accounted for when planning the Diels-Alder reaction, however, this regioselectivity can be strategically used to the chemist’s advantage by plotting the partial charges and reacting the partial positive charges with the partial negative charges.

Regiochemical Analysis of the Diels-Alder Reaction

Regiochemical Analysis of the Diels-Alder Reaction

While regiochemistry is relatively easy to predict and control for simple systems, the stereochemical outcome of the reaction can be harder to grasp.  A Diels-Alder reaction has the ability to produce as many as four new contiguous stereocenters in a single reaction.  That’s a possibility of as many as 2^4 = 16 different stereoisomeric products that could form.  Since the reaction is concerted (and suprafacial), however, eight of these stereochemical outcomes are impossible to access.

We can rationalize the following eight possibilities with the following analysis.  When the dienophile approaches the diene in a Diels-Alder reaction, the diene can be oriented any one of eight ways with respect to the dienophile.  Four of these orientations will be disfavored due to regiochemical arguments outlined above.  Two of the remaining orientations will have the dienophile substituent tucked under the diene (endo transition state), and the other two will have the dienophile substituent pointing away from the diene (exo transition state).  While pointing the large substituent away from the diene might seem like the best orientation for steric reasons, the Diels-Alder reaction prefers the endo transition state, eliminating two other orientations.  The remaining two orientations will react without preference to give a racemic mixture of enantiomers… unless some external stereocontrol is imparted on the system (chiral Lewis acid, chiral auxiliary, etc).  From 16 possible outcomes to two (and maybe even one!) by reasoning through the theoretical underpinnings.  That’s so cool.

Stereochemical Analysis of the Diels-Alder Reaction

Stereochemical Analysis of the Diels-Alder Reaction

But enough theory.  If I want theory, I can go back to grad school (and I don’t see anyone running back to take a graduate level organic chemistry course at their local university…)

Thanks for listening.

15 comments

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  1. azmanam

    Ok, first person to tell me why my images aren’t centered wins!

  2. Chris

    If you’re using html, try the tag. http://www.htmlcodetutorial.com/linepar/_CENTER.html

    Also, in your final image you draw two diastereomers (both an endo and exo) as the major products. Did you mean to draw the two endo enantiomers (with the two exo enantiomers as the minor products)?

  3. Chris

    BTW. Sorry if I sound like a know-it-all up there^

    I should say that the DA reaction is one of my favorites and I love this post. It’s one of those reactions where the more you uncover, the crazier it gets, but still follows a set of rules quite well. Very powerful stuff.

  4. azmanam

    Yeah… the {center} tag is deprecated, though, isn’t it? I can write the post in a visual editor with Microsoft Word-like tools at the top, or in html by hand. I thought the way to center images was to change to style to {margin: 0 auto;}, but that didn’t seem to work.

    Yes, in looking over the diastereomers, I’ve got wedge/dash issues to deal with. I need to go teach lab right now, so it won’t get fixed til later this afternoon. Thanks for pointing it out!!! :)

  5. Chris

    {DIV ALIGN=CENTER}text{/DIV} Looks to be the new flavor of {center}. Web development is not my strong point, but still happy to be of any service.

  6. azmanam

    Seems like the {div align} tag is also deprecated. Even though, I plugged it into the html… still not centering images. This has been a problem with me on this blog for as long as I’ve been adding images. WHHHHYYYYYY!!!!

  7. James

    Nice drawings! Re: the diels alder of cyclopentadienes, one thing I notice that “spooks” students is when the D.A. is drawn from the “top” for the starting material, but from the “side” for the product. I’ve had students ask me “how do you know when to switch?”. Mapping out the Diels Alder of cyclopentadiene with a dienophile bond-by-bond seems to help, but have you noticed this too?

  8. Pcb1

    The margins: auto; thing should be the way to go – though it doesn’t always work with Internet explorer. Think you need a display: block in there too:

    display:block;
    margin-left:auto;
    margin-right:auto;

    …and possibly a:

    text-align: center;

    in the parent paragraph, for ie.

  9. azmanam

    @James: Hand drawing all my images is HARD. Kudos to Carmen at The Haystack for hand drawing all her structures. I can’t promise I’ll be doing it for all my posts!

    I always struggle when we start depicting 3-dimensions on a 2-dimensional paper. We’re doing Newman projections now in class (at 8am, mind you), and I’m getting lots of furrowed brows and stares that communicate: ‘huh?’

    One thing I’m doing new this fall that I think is working really really really well (although we’ll see when we get to exams…) is bringing Avogadro to class. I can show the molecules (large enough to be seen by all) and rotate them and manipulate them and change dihedral angles and switch between line-angle and Newman projections… I think I’m seeing light bulbs now, but again, we’ll have to wait for the exam.

    I also used Avogadro to show MOs for resonance structures to show that the pi cloud is delocalized over several atoms and the electrons are located in this large orbital. I’ll be using it again tomorrow to try to bring chair conformations to life. I’ll be using electrostatic potential maps to show strong vs weak nucleophiles. I can definitely see myself using it to show the different perspective drawings of bridged bicycles. I also don’t care if they draw them flat with the pentagon inside the hexagon. (as long as they get the stereochemistry right).

    @pcb1: I’ll give it a try. It’s a wordpress blog, so I can’t dig in to the underlying html/css. I can get to the html of the actual post. Your suggestion would go into the inline {style=} tag, right?

  10. BRSM

    A great post, and many thanks for chucking a link my way! I was pretty certain at least one other person would pick the DA, but I’m glad you did. Great hand drawn images!

  11. Pcb1

    @Azmanam Your suggestion would go into the inline {style=} tag, right?

    that’s the theory (I’m assuming you can’t easily tweak/add your own stylesheets). The text centering thing apples to the paragraph, so you’d wind up with the image in its own paragraph…something like:

    ..in html, anyway. Unfortunately, I’m not a wordpress user, so I can’t really help with how you might get it to produce that html.

  12. Pcb1

    heh. looks like it won’t let me post the actual html. I’ll paraphrase, then.

    The “text-align: center;” goes in the inline style of a paragraph (“P” tags) that contains an “IMG” tag for the picture you want to center.

    The other stuff – “display:block; margin-left:auto; margin-right:auto;” goes in the inline style tag for the image tag itself.

  13. azmanam

    Oh joyous day!

    The insert image script in WordPress gives all new images the following inline notation

    {img class=”size-medium wp-image-#### ” …} (where the #### is a 4 digit id number for each image)

    I don’t know what that class is supposed to do, but I think this is where the unbreakable left-formatting occurs. We tried wrapping the image in all sorts of tags, adding all sorts of hackneyed code – nothing worked. I stripped away all absolutely non-essential elements and reformatted to just what you said

    {p class=”text-align: center;”}{img class=”margin-left: auto; margin-right: auto;” src=… /}{/p}
    {p class=”test-align: center;”}CAPTION{/p}

    As you can see for image one: IT WORKS!!!! WOOOOOHOOOOO!!!

    I’ll go back and recode the rest of the images later this morning :)

    Thank you Pcb1. If I could upvote you or something, I would.

  14. azmanam

    All images centered and fixed! Thanks Pcb1.

  15. Simon

    Great blog. Another application of DA chemistry, in organic materials chemistry, was the so-called ‘Durham route’ to polyacetylene by Jim Feast.

  1. Chemistry Blog Carnival! « chembites

    [...] the only blogger to talk about a cycloaddition – ChemistryBlog has an awesome post about the Diels-Alder reaction.  I strongly suggest you take a look at that post and all of the other submissions. [...]

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