Stereochemistry of the Diels-Alder Reaction

Stereochemistry of the Diels-Alder Reaction

• The Diels-Alder reaction always has the same pattern of bonds that form and break. Three pi bonds are broken, and two sigma bonds (and a pi bond) are formed. The result is a new six-membered ring.
• But how does the stereochemistry of the starting diene and dienophile translate into the stereochemistry around the new six-membered ring?
• The Diels-Alder reaction is stereospecific. 
• Substituents that are cis (trans) on the dienophile will be cis (trans) on the new six-membered ring.
• The two substituents on the “outside” of the diene (in the s-cis conformation) will end up cis on the new six-membered ring, as will the two substituents on the “inside” of the diene.

Table of Contents

1. Stereochemistry In  The Diels-Alder: A Tale of Two Dienophiles (cis– and trans-)
2. The Relationship Of The Substitutents About The Double Bond In The Dienophile Is Preserved In The Diels-Alder Product
3. Stereochemistry of The Diene Substituents In The Diels-Alder Product: “Outside” And “Inside” Substituents
4. Applying The “Outside / Inside” Rule For Dienes
5. What Happens When Both the Diene and Dienophile Are Substituted?
6. When Substituted Dienes React With Substituted Dienophiles, Diastereomers May Also Be Formed (Note: We  Call These “Exo” and “Endo”)
7. Endo And Exo Diels-Alder Products Are Diastereomers
8. Summary: Stereochemistry of the  Diels-Alder Reaction
9. Notes
10. Quiz Yourself!

1. Stereochemistry In  The Diels-Alder: A Tale of Two Dienophiles (cis– and trans-)

Here’s what we’ve learned about the Diels Alder reaction so far: [previous post in this series]

• 3 pi bonds are always broken
• 2 sigma bonds and a pi bond are always formed, resulting in a new six-membered ring
• electron withdrawing groups on the dienophile increase the reaction rate

One factor we haven’t addressed yet?  Stereochemistry.

Let’s get started!

A pi bond is broken on the dienophile during the course of the Diels-Alder reaction, and the hybridization goes from sp² to sp³. So what happens to the stereochemistry of the groups attached the pi bond?

Take the two dienophiles maleic acid and fumaric acid for example. These two molecules are diastereomers, differing only in the orientation of the two carboxylic acid groups about the double bond.

This pair of diastereomers makes an excellent probe for determining how the stereochemistry of the dienophile pi bond is affected in the Diels-Alder reaction.

Will the cis carboxylic acids of maleic acid remain cis in the product? Will the trans carboxylic acids of fumaric acid remain trans in the product? Or does something else happen?

Here’s what experiments show us:

2. The Relationship Of The Substitutents About The Double Bond In The Dienophile Is Preserved In The Diels-Alder Product

Let’s call this Diels-Alder Stereochemistry Rule #1:

cis– dienophiles give us cis- products, and trans– dienophiles give us trans- products.

This is an example of a stereospecific reaction.

A stereospecific reaction is one where two compounds differing only in their configuration are converted into stereoisomeric products. (see IUPAC for the full reference).

The cis– and trans– dienophiles shown here (maleic and fumaric acid, respectively) are converted into two compounds that are stereoisomers of each other.

What about the diene?

3. Stereochemistry of The Diene Substituents In The Diels-Alder Product: “Outside” And “Inside” Substituents

Substituents on C-2 and C-3 of the diene aren’t an issue: they start the reaction on a (flat) sp² hybridized carbon and end the reaction on a (flat) sp² hybridized carbon. No chiral centers are created here, so there’s no stereochemistry issues to concern ourselves with.

But what about the substituents on C-1 and C-4? They are on an sp² hybridized carbon in the starting material and end up on an sp³ hybridized carbon in the product.

Here’s what we observe from experiment:

It turns out that the two “outside groups” on the diene (labelled “A“, below) when drawn in the s-cis conformation end up on one face of the new six-membered ring, and the two “inside” groups (labelled “B“)  both end up on the other face of the ring. Let’s call this Diels-Alder Stereochemistry Rule #2.

For example, let’s examine two isomers of 2,4 hexadiene: (E, E) [example 1] and (E, Z) [example 2].

4. Applying The “Outside / Inside” Rule For Dienes

Drawing each diene in the s–cis conformation, which is necessary for the Diels-Alder to proceed, we see that the two “outside” groups end up on the same face of the six-membered ring, and the two “inside” groups also end up on the same face of the six-membered ring.

Actually, if we look back to one of the earliest examples of the Diels-Alder that we’ve seen, this is also true for cyclopentadiene:

So far, I hope that this seems straightforward enough.

So let’s combine these two effects, and see what happens!

5. What Happens When Both the Diene and Dienophile Are Substituted?

If we have substitution on both the diene and dienophile, what happens?  What do we do then?

The same thing! Rule #1 and Rule #2 still hold. They hold for every single Diels-Alder reaction, actually.

For example, here’s the case of the reaction of fumaric acid with (E, E) 2,4 hexadiene:

This results in a single product formed as a racemic mixture of enantiomers.

Simple?

Not always. 

6. When Substituted Dienes React With Substituted Dienophiles, Diastereomers May Also Be Formed (Note: We  Call These “Exo” and “Endo”)

Fumaric acid has the property of being symmetrical with respect to rotation (you might sometimes hear this described as C2 symmetry), which has the consequence that only one product (as a pair of enantiomers) is  formed in the reaction with 2,4-hexadiene.

However, fumaric acid’s cousin, maleic acid, lacks this property.

When we combine a substituted diene such as (E, E) 2,4-hexadiene with maleic acid, and follow both Rule #1 and Rule #2, there are actually two possible products!

In the first product, the “outside” CH₃ groups are on the same side of the new six-membered ring as the carboxylic acids in maleic acid. We call this the “endo” product.

In the second product, the “outside” CH₃ groups are on the opposite side of the new six-membered ring as the carboxylic acids in maleic acid. We call this the “exo” product.

7. Endo And Exo Diels-Alder Products Are Diastereomers

The “endo” and “exo” products in this case are diastereomers. They are stereoisomers of each other, but are not enantiomers. (In fact, neither the “endo” or “exo” products in the example above possess an enantiomer. Can you see why?).

In practice, for reasons that will not be immediately obvioius, the “endo” product tends to be favored over the “exo” product.

This subject of exo and endo turns out to be such an important topic that it deserves its own article. So we’ll explore exactly how to tell the difference between “exo” and “endo” products, as well as how they form, in the next article.

8. Summary: Stereochemistry of the  Diels-Alder Reaction

• The stereochemistry of the dienophile is preserved  in the Diels-Alder product
• The “outside” groups on  the diene end up on the same face of  the new  six-membered ring, as  do   the “inside” groups.
• When both the diene and  dienophile are substituted, diastereomers may form, which we call “exo” and “endo”.

Thanks to Tom Struble for assistance with this post. 

Notes

Note 1. The Diels-Alder reaction of (E,E) 2,4 hexadiene with fumaric acid produced a pair of enantiomers, but neither of the products of the Diels-Alder of (E,E)-2,4-hexadiene with maleic acid has an enantiomer. Can you see why?

Quiz Yourself!

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.