Inverse electron-demand Diels–Alder reaction

This makes the DAINV reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles.

Recently, the DAINV reaction has been used to synthesize a drug transport system which targets prostate cancer.

[3] The Diels–Alder reaction was first reported in 1928 by Otto Diels and Kurt Alder; they were awarded the Nobel Prize in chemistry for their work in 1950.

Conversely, DAINV does not have a clear date of inception, and lacks the comparative prominence of the standard Diels-Alder reaction.

DAINV does not have a clear date of discovery, because of the difficulty that chemists had in differentiating normal from inverse electron-demand Diels-Alder reactions before the advent of modern computational methods.

The reaction proceeds via a single transition state, but not all bonds are formed or broken at the same time, as would be the case in a concerted mechanism.

[2] The formal DAINV mechanism for the reaction of acrolein and methyl vinyl ether is shown in the figure to the right.

Like the standard DA, DAINV reactions proceed via a single boat transition state, despite not being concerted.

The single boat transition state is a simplification, but DFT calculations suggest that the time difference in bond scission and formation is minimal, and that despite potential asynchronicity, the reaction is concerted, with relevant bonds being either partially broken or partially formed at some point during the reaction.

[2] The reaction can be modeled using a closed, boat-like transition state, with all bonds being in the process of forming or breaking at some given point, and therefore must obey the Woodward–Hoffman general selection rules.

Thus, the LUMOdiene and HOMOdienophile are the frontier orbitals that interact the most strongly, and result in the most energetically favourable bond formation.

The exact cause of this selectivity is still debated, but the most accepted view is that endo approach maximizes secondary orbital overlap.

The exo pathway would be favored by sterics, so a different explanation is needed to justify the general predominance of endo products.

[15] In addition, DAINV reactions can produce an array of different products from a single starting material, such as tetrazine.

[2][13] DAINV reactions have been utilized for the synthesis of several natural products, including (-)-CC-1065, a parent compound in the Duocarmycin series, which found use as an anticancer treatment.

After several more steps, an intramolecular DAINV reaction occurs, followed again by a retro Diels-Alder in situ, to afford an indoline product.

DAINV reaction between 2,3,4,5-tetrachlorothiophene-1,1-dioxide (diene) and 4,7-dihydroisoindole derivative (dienophile) afforded a new precursor for tetranaphthoporphyrins (TNP) bearing perchlorinated aromatic rings.

This precursor can be transformed into corresponding porphyrins by Lewis acid-catalyzed condensation with aromatic aldehydes and further oxidation by DDQ.

Heavy aggregation and poor solubility of the parent tetranaphthoporphyrins severely degrade the usefulness of this potentially very valuable porphyrin family.

Besides the effect on the solubility, polychlorination also turned out to improve substantially the stability of these compounds towards photooxidation, which has been known to be another serious drawback of tetranaphthoporphyrins.

Prototypical DA INV reaction between an electron-poor diene ( acrolein ) and an electron-rich dienophile ( methyl vinyl ether ). Bonds made and broken are labelled blue and red, respectively.
Arrow pushing mechanism of DA INV . Bonds broken are labelled in red; bonds made are labelled in blue.
The DA INV reaction proceeds through a boat transition state, with the diene and dienophile approaching on parallel planes.
Generic molecular orbital diagram for the standard DA reaction. The HOMO diene and LUMO dienophile are the closest pair of frontier molecular orbitals , and that those two interact to form the new orbital in the transition state.
FMO diagram for the DA dimerization of acrolein . The FMO overlap is relatively poor, due to the large difference in orbital energies.
In DA INV , the LUMO diene and HOMO dienophile are very close in energy, which results in a strong bonding interaction between the two.
Using the DA INV reaction of acrolein and methyl vinyl ether as an example, the regiochemical outcome of the DA INV reaction can often be predicted. Resonance contributors of each molecule can be used to assign partial positive charges. The preferred reaction pathway connects the partially negative atoms to the partially positive ones.
The orbitals with the largest coefficients in the reactive FMO's will overlap most strongly, and bond. Qualitatively, the largest FMO coefficients of the diene and dienophile are on gamma-carbon of acrolein and the terminal CH 2 of the methyl vinyl ether, respectively.
Because there is a single transition state, and all modes of attack are suprafacial, stereochemistry in this reaction is retained. R 4 and R 5 are cis in the dienophile, and syn in the product. Conversely, R 3 and R 5 are trans in the dienophile, and anti in the product. In addition, R 1 and R 2 share the same starting chemistry both in the diene, and the product.
In the endo transition state, the methoxy group is "inside" the boat; where in the exo transition state, it is "outside".
The synthesis of PDE-I and PDE-II contained two distinct uses of the DA INV reaction. The first DA INV reaction noccurs between a substituted tetrazine and a vinyl acetal. After several more steps, ad second DA INV reaction is used to close one of the ring systems. The two PDE pieces were then coupled to form (-)-CC-1065 .
Use of inverse electron-demand reaction between 2,3,4,5-tetrachlorothiophene-1,1-dioxide and 4,7-dihydroisoindole derivation in the synthesis of polychlorinated tetranaphthoporphyrin.