Diels-Alder Reaction: Kinetic and Thermodynamic Control

Kinetic and Thermodynamic Control In The Diels-Alder Reaction: The Diels Alder Reaction Is Reversible At High Temperatures

• We’ve seen that the products of addition to dienes can be controlled using temperature (See article – Kinetic and Thermodynamic Control).
• The Diels-Alder reaction is also subject to kinetic and thermodynamic control!
• At low temperatures the endo product dominates (the kinetic product, formed faster due to a lower-energy transition state – See article – Why Do Diels-Alder Reactions Favor Endo Products?).
• At higher temperatures, the Diels-Alder product is in equilibrium with its starting materials, and the product distribution is governed by the thermodynamic stability of the products.
• Since the exo products tend to be less sterically hindered, they also tend to be the major products under conditions of thermodynamic control

Table of Contents

1. The Commonly Used “Cyclopentadiene” Can’t Be Bought From Chemical Suppliers.  Why?
2. Upon Standing For 1-2 Days At Room Temperature, Cyclopentadiene Slowly Undergoes Reaction To Give “Dicyclopentadiene”
3. Get Your Cyclopentadiene Back…  With This “One Weird Trick”
4. Cyclopentadiene Slowly Undergoes A Diels-Alder Reaction With Itself To Give “Dicyclopentadiene”, Which Reverts Back To Cyclopentadiene Upon Heating To 180°C.
5. The Reverse (“Retro”) Diels-Alder Reaction: At High Temperatures, The Diels-Alder Reaction Is Reversible
6. Reaction Coordinate Diagram For The Diels-Alder Reaction
7. Kinetic And Thermodynamic Control In The Diels-Alder
8. A Reaction Coordinate Diagram For Kinetic vs. Thermodynamic Control In The Diels-Alder Reaction
9. An Exo-Selective Diels-Alder Reaction
10. More On The Retro Diels-Alder
11. Notes
12. (Advanced) References and Further Reading

1. The Commonly Used “Cyclopentadiene” Can’t Be Bought From Chemical Suppliers.  Why?

Let’s talk about cyclopentadiene, a commonly used diene for Diels-Alder reactions that, by the way, comes up all the time on tests and exams. Like here:

Gather around closely folks, because I’m going to tell you a little secret about this molecule. Something lots of people don’t know about. Something you’ll never believe.

Despite the fact that you might see this being used in reactions all the time…

… you can’t actually buy cyclopentadiene! 

You heard that right.It’s not commercially available. Nobody on Earth sells the stuff. Call up Aldrich and ask for some. They’ll tell you that they don’t have any.

In fact, even if you do manage to get your hands on some, if you leave it out on the bench for a day or so, it goes away! [Note 1]

2. Upon Standing For 1-2 Days At Room Temperature, Cyclopentadiene Slowly Undergoes Reaction To Give “Dicyclopentadiene”

And by “goes away” I don’t mean that it evaporates… I mean that it changes into a different molecule altogether. 

The new molecule has a molecular formula of C₁₀H₁₂ and has a completely different structure from cyclopentadiene.

True fact!

But check this out, folks. I’m about to tell you another little secret. A mind-blowing secret THEY don’t want you to know about.

Introducing…

3. Get Your Cyclopentadiene Back…  With This “One Weird Trick™”

Now only $19.95! FREE! limited time offer! 

If you heat dicyclopentadiene to 180°C, and then distill it, you get your cyclopentadiene back!

“AMAZING! I was skeptical, but this one weird trick totally worked! I’m so glad I got my cyclopentadiene back! Woohoo! ”

– Homeau L’Oumeau, chemistry graduate student

4. Cyclopentadiene Slowly Undergoes A Diels-Alder Reaction With Itself To Give “Dicyclopentadiene”, Which Reverts Back To Cyclopentadiene Upon Heating To 180°C.

So what the heck is this “dicyclopentadiene” stuff, anyway? How does it form? And what happens when you heat it? How do you get cyclopentadiene back?

As you may recall,  cyclopentadiene is a particularly reactive diene, due to the fact that its double bond is locked in the “s-cis” conformation. [See article: s-cis and s-trans ]

Cyclopentadiene that is left “neat” (i.e. undiluted) at room temperature [Note 1]  can undergo a Diels-Alder reaction with itself, giving “dicyclopentadiene”. This is what our mysterious “dicyclopentadiene” looks like:

What about this “Diels-Alder reaction with itself” ?

That means that one molecule of cyclopentadiene acts as a diene, and another molecule of cyclopentadiene acts as a dienophile.

Here it is below, drawn in a way so that it looks just like all the previous Diels-Alder reactions we’ve shown in this series of posts.

As usual, three pi bonds break, and two sigma bonds + one pi bond form:

As we’ve seen, the Diels-Alder can form both endo and exo diastereomers [See article: Exo and Endo Products In The Diels-Alder – How To Tell them Apart ].  (only the endo is shown here).

Nothing new to see here, so far.

Here’s the cool thing (and – shhhh! –  the secret behind that “One Weird Trick” ). At high enough temperatures, the Diels-Alder reaction is reversible.

5. The Reverse (“Retro”) Diels-Alder Reaction: At High Temperatures, The Diels-Alder Reaction Is Reversible

That’s right. If you heat the product of a Diels-Alder reaction to a high enough temperature, the reaction can progress in reverse, regenerating the starting diene and dienophile (which both happen to be cyclopentadiene in this case).

This is called the reverse (or “retro”) Diels-Alder reaction. In the “retro-Diels-Alder”:

• a six membered ring is broken,
• three C-C pi bonds are formed, and
• two single bonds + one pi bond are broken.

One consequence of this fact:

Since the Diels-Alder is reversible at high temperature, this means that we should actually draw it as an equilibrium!

Quiz. Why might high temperature favor the reverse reaction? Answer below [Note 2] [Hint: It has to do with ΔG = ΔH – TΔS]

6. Reaction Coordinate Diagram For The Diels-Alder Reaction

A sketch of the reaction energy diagram for the Diels-Alder would look something like the the sketch below:

Here we show  ΔE (blue) as the activation energy for the Diels Alder reaction in the forward direction, and a second ΔE (in red) depicting the activation energy for the reverse reaction (with the endo depicted).

At low temperatures, only the forward reaction is energetically accessible, but at higher temperatures,  the reverse reaction can occur.

Why Should I Care?

You may very well ask why you need to care about this.

Well, with a little more detail added, it will help us to solve at least one important lingering mystery. Helpfully, this also ties back to a concept we’ve already learned! 

7. Kinetic And Thermodynamic Control In The Diels-Alder

You may recall that the Diels-Alder tends to favor the endo product even though it would appear that the exo is in fact less sterically hindered (and, in addition, is more thermodynamically stable). This was puzzling at the time, and we had no good answer for it. [See: Why Are Endo Products Favored In The Diels-Alder?]

In fact, it turns out to be another example of a concept covered earlier in this section on dienes, called Thermodynamic and Kinetic Control [See: Thermodynamic and Kinetic Control].

We saw examples of 1,2- versus 1,4 addition of HBr to dienes and wondered why it was that low temperatures favored the formation of the less stable product, whereas higher temperatures favored formation of the more stable product.

We saw that at low temperatures (where the reaction is irreversible) products with the lowest-energy transition state  were obtained [kinetic control]  whereas in situations where the reaction was reversible (higher temperatures) the product mixture reflected the difference in heat of formation (i.e. energy) between the two products [thermodynamic control].

The Diels-Alder presents us with another example of this very same phenomenon.

8. A Reaction Coordinate Diagram For Kinetic vs. Thermodynamic Control In The Diels-Alder Reaction

Let’s draw in the reaction coordinate for the exo product (blue) to make it more clear.

• The transition state for the endo product (C) is lower in energy than the transition state for the exo product (B), meaning that it is formed faster (i.e. has a lower activation energy)
• At low temperatures, the forward reaction to make the endo is accessible (A→C→D) but not the reverse reaction (D→C→A). Therefore the reaction mixture will reflect the difference in energy between B and C. This is kinetic control.
• At higher temperatures, the reverse reaction (D→C→A) is energetically accessible, and the reaction becomes an equilibrium between starting materials (A) and the products (D and E). The reaction mixture will reflect the difference in energy of D and E. This is thermodynamic control. 

The Diels-Alder is normally run under conditions where the reaction is irreversible, and for reasons we discussed previously [in Why Are Endo Products Favored In The Diels-Alder?] the endo transition state tends to be lower in energy than the exo transition state. Hence, endo products tend to dominate at low temperatures.

But at higher temperatures, where the reaction is reversible, more of the exo product will form due to its greater thermodynamic stability. For example, while the Diels-Alder of cyclopentadiene with itself at 23°C gives only the endo product, heating a solution of cyclopentadiene at 200 °C  over about 2 days gives an endo:exo ratio of 4:1. [source]  .

One can even heat a pure endo product and obtain a mixture of exo and endo products!

9. An Exo-Selective Diels-Alder Reaction

Here’s one prominent example of an exo-selective Diels-Alder reaction.

Furan (below) appears similar to cyclopentadiene. But as you may already have seen (or will soon see, here: Rules For Aromaticity] furan has a peculiar property called aromaticity: for this reason, it is about 20 kcal/mol more stable than one would expect based on bond energies alone. Furan can act as a diene in Diels-Alder reactions, but this disrupts the aromaticity of furan. For this reason, Diels-Alder products of furan undergo retro Diels-Alder reactions at much lower temperatures than those of most other dienes.

For example, the Diels-Alder reaction of furan with maleic anhydride in acetonitrile at 40 °C gives the exo product exclusively after 48 h.

[Interestingly, in this reaction the endo is intially the dominant product (formed at a rate about 500 times faster than the exo, [Note 3], but quickly reverts to the starting materials. Owing to the difference of 1.9 kcal/mol between the exo and endo products, the exo is the dominant product isolated. ]

10. More On The Retro Diels-Alder

This is probably enough for one post, but in the next one we’ll briefly go through a few prominent examples of retro Diels-Alder reactions and see how they can be applied in synthesis.

Next post: The Retro Diels-Alder Reaction

Notes

Note 1. Although, it should be noted, cyclopentadiene can be kept in the freezer indefinitely.

Note 2. Why might higher temperatures favor the reverse Diels-Alder?

Recall that for any reaction to be “spontaneous” , the Gibbs free energy ΔG must be negative:

ΔG = ΔH – TΔS

where  ΔS is the entropy.

Even a reaction that is endothermic (positive ΔH) can be made to be spontaneous through heating if the reaction itself has a large entropy (ΔS).

[The heat of formation for the reaction between cyclopentadiene and maleic anhydride is about –25 kcal/mol at room temperature, which would make the ΔH +25 kcal/mol for the reverse reaction]. [Source]

In the retro Diels-Alder, a single molecule (the Diels-Alder product) reverts to two starting molecules (the diene and dienophile), which represents a large net increase in entropy. Therefore, heating the reaction (increasing T) will make the –TΔS term increasingly negative, until it dominates the positive ΔH term.

Note 3. The difference in rate of 500 gives a difference in activation energy of 3.8 kcal/mol favoring the endo.

(Advanced) References and Further Reading

1. FERROCENE
   G. Wilkinson
   Org. Synth. 1956, 36, 31
   DOI: 10.15227/orgsyn.036.0031
   The synthesis of ferrocene is commonly carried out in undergraduate labs today, and this requires cyclopentadiene, prepared by ‘cracking’ of dicyclopentadiene. This procedure is particularly famous, as the discovery of ferrocene kicked off the field of modern organometallic chemistry in the 20^th century. Prof. Wilkinson went on to receive the Nobel Prize for his work in this regard.
2. Study of the Diels–Alder and retro-Diels–Alder reaction between furan derivatives and maleimide for the creation of new materials
   V. Froidevaux, M. Borne, E. Laborbe, R. Auvergne, A. Gandinib, and B. Boutevin
   RSC Adv., 2015, 5, 37742-37754
   DOI: 10.1039/C5RA01185J
3. Synthetic applications of furan Diels-Alder chemistry
   Oliver Kappe, S. Shaun Murphree, and Albert Padwa
   Tetrahedron 1997, 53 (42), 14179-14233
   DOI: 10.1016/S0040-4020(97)00747-3
   These two reviews cover the mechanistic aspects and synthetic applications of the Diels-Alder reaction with furan.
4. endo- and exo-Stereochemistry in the Diels-Alder Reaction: Kinetic versus Thermodynamic Control
   James H. Cooley and Richard Vaughan Williams
   Journal of Chemical Education 1997, 74 (5), 582
   DOI: 10.1021/ed074p582
   An experiment suitable for undergraduates that illustrates thermodynamic and kinetic control in Diels-Alder reactions.
5. Thermodynamic vs. kinetic control in the Diels-Alder cycloaddition of cyclopentadiene to 2,3-dicyano-p-benzoquinone
   Bott, S.G., Marchand, A.P. & Kumar, K.A.
   Chem. Crystallogr. 1996, 26, 281–286
   DOI: 10.1007/BF01677782
   Scheme 2 in this paper illustrates a representative Diels-Alder reaction that gives endo or exo products under thermodynamic or kinetic conditions, respectively, and that the kinetic (exo) product can be converted to the thermodynamic (endo) product upon heating.
6. https://organicchemistrydata.org/hansreich/resources/pericyclic/#pericyclic04
   The late Prof. Hans Reich (U. Wisconsin-Madison) had a website full of useful information on organic chemistry, including this page on the Diels-Alder reaction. His website is now being maintained by the ACS Division of Organic Chemistry.