The Diels Alder reaction is a [4+2] cycloaddition reaction between a conjugated diene and a dienophile. Here we explain its mechanism, orbital theory, stereoselectivity and endo rule using 3D models and examples.

3D model: Diene (top – ignore the tilt, it’s drunk) and dienophile (bottom) approaching for a Diels Alder reaction. Can you see the HOMO and LUMO orbital overlap?

Summary

• 1. Mechanism: The Diels Alder reaction is a concerted [4+2] cycloaddition of a diene in its s-cis conformation with a dienophile.
• 2. Selectivity: Diels Alder reactions can be regioselective and stereoselective. As there are no intermediates, they are also stereospecific.
• 3. Substituent effects: Normal electron demand DA reactions feature a nucleophilic, electron-rich diene reacting with an electrophilic, electron-poor dienophile. Resonance structures explain regioselectivity, while secondary orbital overlap explains the endo rule.
• 4. Orbitals: In the normal electron demand DA reaction, the diene’s HOMO reacts with the dienophile’s LUMO. Higher reactivity (substituents, Lewis acids) arises from smaller energy gap between those interacting orbitals.
• 5. Hetero Diels Alder reactions: Involve reactants with non-carbon heteroatoms
• 6. Inverse electron demand Diels Alder: Feature electron-poor dienes and electron-rich dienophiles.
• In case you are working on retrosynthesis problems, the DA is often the easiest way to synthesize six-membered rings!

1. reaction mechanism

As the Diels Alder is a pericyclic reaction, it proceeds in one step / concerted.
The diene, containing two conjugated alkenes, reacts with a dienophile which is usually an alkene or alkyne (the name means something that likes dienes; sorry, chemistry is strange). Both reactants are flat (double bonds and diene is conjugated) and approach each other in a face-to-face manner.

The driving force of the Diels-Alder reaction is the formation of two σ-bonds (σ-bonds are stronger than π-bonds) in the cyclohexene product. The four atoms linked to these sigma bonds all change from sp² to a sp³ hybridization in the product.

Note that the cycloaddition initially gives the cyclohexene in its boat conformation. Try to really visualize how the transition state. If the dienophile approaches from the bottom (as drawn here; the alternative approach from the top is equally likely for achiral molecules), we form the boat conformation where the hydrogen that was previously pointing away from the diene, the H_exo, “looks up” (wedge in the product). As we see below, the reaction is stereospecific so both H_exo and H_endo in the diene retain their relative orientation (i.e., they look the same way in the product).

The diene has to be in the s-cis conformation to react (bonds form simultaneously).

Unlike π-bonds in alkenes, the single bond can rotate and thus change its conformation. However, given the steric interactions that the CH2 groups experience when they are on the same same of the bond, the s-cis conformation is higher energy than s-trans. The energy difference is ~2.9 kcal/mol [ref 1], so only ~1-2% of butadiene molecules are actually in the s-cis form at a given time.

Note that some dienes like cyclopentadiene are extremely reactive because they are locked in the s-cis conformation.

By the way, we do not say [4+2] because 4 electrons from the diene react with 2 electrons from the dienophile. This is indeed the case – the transition state can actually be considered to be aromatic – but [4+2] refers to the number of atoms involved. For instance, there are so-called [3+2] dipolar cycloadditions which also operate with 6 electrons in total, but only 5 atoms are involved.

Chemistry would be so easy without substituents! By adding substituents on the diene and dienophile, we start to observe reaction selectivity and increased or decreased reactivity. Let’s first understand this in theory, and then check out the specific substituent effects.

2. Selectivity in Diels Alder reactions

Diels Alder reactions are usually regioselective, stereospecific and stereoselective.

Depending on which atoms of the diene and dienophile make contact, we can get two regioisomers (A is either next to E, or A is next to F). The actual regioselectivity is driven by the nature of the substituents (see below).

Because 1) there are no intermediates in the Diels Alder, and 2) both σ-bonds are created from the same side/face, the relative orientation of substituents is fully retained in the product. This is why the reaction is stereospecific.

Beyond the different orientation leading to regioselectivity, the dienophile can also be oriented outside or inside of the diene. This again gives two different products, exo and endo. Note that the example here shows just one regioisomer (it does not show products where A is next to F).

3. Substituent effects in diels alder reactions

Substituents critically influence selectivity and reactivity of Diels Alder reactions.

Normal electron demand DA reactions are cases where the diene is electron-rich, while the dienophile is electron-poor. Typically, the diene has electron-donating groups (EDG; e.g., -OMe) while the dienophile has electron-withdrawing groups ( EWG; e.g., -CO₂Me). The majority of reactions follow this polarity, so let’s focus on such examples first. The opposite happens in inverse electron demand DA reactions (explained further below).

The regioselectivity of Diels-Alder reactions can be predicted by considering potential resonance structures of the two reactants.
➡️ The most nucleophilic position of the diene will prefer to add to the most electrophilic position of the dienophile.

Diels Alder reactions can give endo (kinetically preferred) or exo products (thermodynamically more stable).
➡️ If the dienophile carries substituents with π-electrons, the endo product is usually preferred. (explanation requires orbital theory, see below)
➡️ If you are struggling with drawing endo versus exo, draw the transition state in 3D (e.g., as here, diene adding from the top) and draw the resulting boat conformation to compare which groups point which way.

4. Frontier Molecular Orbital (FMO) Analysis

The Diels Alder reaction, just like many other reactions, can be explained by purely looking at the so-called frontier molecular orbitals (FMO). These are the HOMO (highest occupied molecular orbital; filled) and LUMO (lowest unoccupied molecular orbital; empty) of the π-system.

The Diels Alder reaction is exergonic (ΔG<0) – the Hammond postulate tells us that such a reaction has a relatively “early” transition state that looks similar to the starting materials. Thus, the orbitals of the starting materials are a good “proxy” for what will happen in the transition state.

In case you cannot construct the MO diagram for butadiene or ethylene, I refer you to other web sources that explain this.

In the normal electron demand scenario, the HOMO of the diene reacts with the LUMO of the dienophile. Notice how the orbital lobes (positive and negative, grey and black) that overlap have the same phase.

The closer the orbitals in energy (small HOMO-LUMO energy gap), the easier the reaction! This is because when orbitals of similar energies overlap, they experience a higher stabilization of the newly formed orbitals. We want as high of a stabilization as possible, as this decreases the energy of the electrons that we use to populate the new molecular orbital.

Electron-donating groups raise the energy of all molecular orbitals; electron-withdrawing groups decrease the energy of all molecular orbitals.

By having an electron-rich diene and an electron-deficient dienophile, we lower the HOMO-LUMO energy gap (new green line). This means the stabilization experienced by orbital interaction for the purple electrons will increase (they will go down in energy, which is good). This effect is additive – the more substituents we add, the easier and faster the reaction.

The stereoselectivity and endo rule can also be explained through orbital considerations. If the dienophile is oriented endo, the π-orbitals of the carbonyl group (or any other group that has π-system) can interact with the “central” diene orbitals. This lowers the transition state (TS) of the endo approach compared to the exo approach – and thus, the two substituents in our example above point in the same direction.

This might be a bit clearer from the 3D model here. Ignore the non-planarity of the butadiene (my orbital computation was trolling me).

Substituents do not only influence the energy of molecular orbitals, they also change the orbital coefficients at the different atoms. A larger coefficient means that an orbital is relatively more localized on a given atom – e.g., for the HOMO, the atom with the largest coefficient is most nucleophilic. This explains the regioselectivity of Diels Alder reactions more truthfully than the resonance structures which we have mentioned above. However, because this article is not intended to be fully exhaustive, we will not explain coefficients in detail here.

For dienophiles with basic sites on electron-withdrawing groups, Lewis acids can function as catalysts and increase the regio- and stereoselectivity. Coordination of the Lewis acid makes the dienophile even more electron-deficient, and increases the relative polarization (and orbital coefficient).

5. Hetero Diels Alder reaction

DA reactions are not limited to only carbon atoms. Both the diene or the dienophile can feature non-carbon heteroatoms.
An example for such hetero Diels Alder reactions is the cycloaddition above with an aldehyde as the dienophile. This works well with the normal electron demand scenario as the carbonyl π-system has a low-energy LUMO.

6. Inverse electron demand Diels Alder

Inverse electron demand Diels Alder reactions are cases where the diene is electron-poor, while the dienophile is electron-rich. Now, the HOMO and LUMO are mapped the other way around: the electron-rich dienophile is nucleophilic and has a high-energy HOMO – while the electron-poor diene is electrophilic and has a low-energy LUMO.

Typically, inverse electron demand reactions as part of multi-step cascade reactions.

Draw the correct product for the given Diels Alder reaction!

So the heteroaromatic ring clearly has a diene, but where is our dienophile [ref 2]? The first step of the reaction is a condensation-enamine formation of the amine with our ketone. The enamine is an electron-rich olefin, so a perfect dienophile in the inverse electron demand scenario. To figure out which regioisomer will be preferred, we need to consider which resonance structures are stabilized by the EDG and EWG, respectively.

After the first Diels Alder reaction, we have a twist: The N=N group can be kicked out in a reverse or retro Diels Alder reaction. It works the exact other way around, with the very stable N2 driving the reaction forward (irreversible step). The last step is aromatization to the much more stable product after elimination of pyrrolidine. I will work on a separate article on the retro Diels Alder reaction in future.

If you learned something, feel free to check out my other articles!

Diels Alder Reaction: Exemplary procedure [ref 3]

To a Schlenk tube charged with 3,5-dibromo-2-pyrone [diene] (20, 561 mg, 2.21 mmol) in 7 mL of toluene was added alkenyl boronate [dienophile] (600 mg, 1.70 mmol) at rt. The resulting mixture was heated in an oil bath at 110 °C for 3 days. The reaction mixture was cooled to rt, concentrated in vacuo, and chromatographed (20:1 hexane/EtOAc → 5:1 hexane/EtOAc) to give cycloadduct as a white solid (720 mg, 70%).

Diels Alder reaction references

• [1] Thermodynamics of conformational change in 1,3-butadiene studied by high-temperature ultraviolet absorption spectroscopy | Philip W. Mui, Ernest Grunwald | J. Am. Chem. Soc. 1982, 104, 24, 6562–6566
• [2] Inverse electron demand Diels-Alder reactions of heterocyclic azadienes: formal total synthesis of streptonigrin | Dale L. Boger, James S. Panek | J. Am. Chem. Soc. 1985, 107, 20, 5745–5754
• [3] Total Synthesis of (±)-Clivonine via Diels–Alder Reactions of 3,5-Dibromo-2-pyrone | Cheng-dong Wang, Qinyang Chen, Seunghoon Shin, Cheon-Gyu Cho | J. Org. Chem. 2020, 85, 15, 10035–10049