The Diels–Alder reaction builds a six-membered ring in one step, from two pieces, with no intermediate, no catalyst and complete control of the stereochemistry. It is the most useful single reaction in this course and one of the most useful in organic chemistry generally, and almost everything about it follows from one picture: six electrons moving round a circle.
What it is
A conjugated diene (four π electrons) reacts with an alkene or alkyne called the dienophile — literally "diene-loving" — (two π electrons) to give a cyclohexene. Because it joins a four-π-electron component to a two-π-electron one, it is classified as a [4+2] cycloaddition.
The arithmetic of the bonds explains why it is so favorable. Three π bonds go in; out come two new σ bonds and one π bond. σ bonds are stronger than π bonds, so trading two of the latter for two of the former releases energy, and the reaction is downhill without anything having to drive it.
The diene must be able to reach s-cis
For the two ends of the diene to reach the two ends of the dienophile at the same time, they have to be on the same side — the diene must react from its s-cis conformation. This is the commonest reason a Diels–Alder simply does not happen, and it is a geometric requirement rather than an electronic one.
- Cyclopentadiene is locked s-cis inside its ring and is so reactive that it dimerizes on standing at room temperature, one molecule acting as the diene and another as the dienophile. It is stored cold as the dimer and cracked by distillation when needed.
- A diene locked s-trans in a ring cannot react at all, however electron-rich it is.
- An open-chain diene can rotate into s-cis, but bulky groups at the inner positions that clash in that conformation slow it down badly.
Electronics: electron-rich diene, electron-poor dienophile
The reaction is fastest when the two partners are electronically mismatched in the right direction. Electron-donating groups on the diene raise its HOMO; electron-withdrawing groups on the dienophile lower its LUMO. Bringing those two orbitals closer in energy makes the interaction between them stronger and the reaction faster.
In practice this means a good dienophile carries a carbonyl, a nitrile, a nitro group or an ester next to its double bond. Maleic anhydride, with two carbonyls flanking the alkene, is the classic fast dienophile; ethene itself reacts only under forcing conditions because it has nothing pulling its LUMO down.
Stereochemistry, and why it is completely predictable
Because the reaction is concerted, the geometry of the starting materials is carried straight into the product. Three separate statements follow, and they are the reason the reaction is so heavily used in synthesis.
It is stereospecific with respect to the dienophile. Both new bonds form on the same face of the dienophile, so substituents that were cis across its double bond come out cis on the ring, and trans comes out trans. There is no step at which anything can rotate.
The diene's geometry is carried through too. Groups at the diene's outer positions that pointed "outward" in the s-cis conformation end up on one face of the new ring, and those that pointed "inward" end up on the other.
The endo product is favored. When the dienophile carries a substituent, the two partners can stack in two orientations: endo, with the dienophile's substituent tucked under the diene, or exo, with it pointing away. The endo arrangement is more crowded and is nevertheless the faster one, because the substituent's π system interacts favorably with the developing π system of the diene in the transition state — a secondary orbital interaction. Endo is therefore the kinetic product, which is worth noticing: it is a case where the kinetic product is the more hindered one, and the general rule from the last section still holds because nothing here is reversing at ordinary temperatures.
React buta-1,3-diene with dimethyl maleate, in which the two ester groups are cis across the double bond.
Skeleton. [4+2] gives a cyclohexene. The new double bond sits between what were C2 and C3 of the diene, and the two new σ bonds join the diene's C1 and C4 to the two dienophile carbons.
Stereochemistry. The two esters were cis on the dienophile, and the addition is suprafacial on it, so they are cis on the ring — on adjacent carbons, on the same face.
Check by switching. Run the same reaction with dimethyl fumarate, the trans isomer, and the two esters come out trans on the ring. One change in the starting material, one predictable change in the product, and no mixture in either case.
Running it backwards
The reaction is reversible, and heating a cyclohexene of the right kind drives the retro-Diels–Alder, splitting it back into a diene and a dienophile. Cracking cyclopentadiene dimer before use is exactly this. It also matters in synthesis planning: seeing a cyclohexene ring and mentally cutting it apart at the retro-Diels–Alder disconnection is one of the most productive moves available when you are working a synthesis backwards.
What carries forward
Three things. The Diels–Alder is the first concerted reaction in this course that forms two bonds at once, and the reasoning — frontier orbitals, suprafacial addition, stereospecificity — is the template for pericyclic chemistry generally. It is the standard way to make a six-membered ring, which makes it a fixture of retrosynthesis. And the endo rule is a clean reminder that "more stable" and "forms faster" are separate questions, which is the lesson of the section before this one.