DA INV 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. Conversely, DA INV does not have a clear date of inception, and lacks the comparative prominence of the standard Diels-Alder reaction. Since that time, use of the Diels–Alder reaction has become widespread. 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. Recently, the DA INV reaction has been used to synthesize a drug transport system which targets prostate cancer. This makes the DA INV reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles. A prototypical DA INV reaction is shown on the right.ĭA INV reactions often involve heteroatoms, and can be used to form heterocyclic compounds. During a DA INV reaction, three pi-bonds are broken, and two sigma bonds and one new pi-bond are formed. It is related to the Diels–Alder reaction, but unlike the Diels–Alder (or DA) reaction, the DA INV is a cycloaddition between an electron-rich dienophile and an electron-poor diene. The inverse electron demand Diels–Alder reaction, or DA INV or IEDDA is an organic chemical reaction, in which two new chemical bonds and a six-membered ring are formed. Bonds made and broken are labelled blue and red, respectively. Since it is part of a ring, the double bond of maleic anhydride is in a cis configuration so the cyclohexene ring will also have a cis configuration. Lastly, the product will prefer the endo position.Prototypical DA INV reaction between an electron-poor diene ( acrolein) and an electron-rich dienophile ( methyl vinyl ether). The dienophile has two nitriles attached to it both of which are electron withdrawing. Since the two nitriles in the dieneophile are cis to each other the the two nitriles will be cis to each other in the product.Ī particularly rapid Diels-Alder reaction takes place between cyclopentadiene and maleic anhydride. Cyclopentadiene is held in the required s-cis configuration so it will make a good diene for a Diels-Alder reaction. Maleic anhydride is also a very good dienophile, because the electron-withdrawing effect of the carbonyl groups causes the two alkene carbons to be electron-poor, and thus a good target for attack by the pi electrons in the diene. Because the diene already contained a ring the product will be bicyclic. The diene is locked into an s-cis configuration which will promote the reaction. The ring portion of the diene will act as electron donating groups which will also promote the reaction. Predict the product of the following reaction: Start by rotating the diene until it is in the s-cis conformation then point it towards the double bond of the dienophile. Remove the double bonds present in the diene and dieneophile. Connect carbons 1 and 4 of the the diene to a carbon in the dienophile double bond using a sigma bond to create a six-membered ring. Create a double bond between carbons 2 and 3 of diene.ĭetermine if any substituents attached to either the double bond of the dieneophile or carbons 1 and 4 of the diene have a cis/ trans conformation. If so make sure the substituents have the same configuration in the cycloalkene product. Predicting the Product of a Diels-Alder Reaction
Diels-Alder reactions with cyclic dienes favor the formation of bicyclic structures in which substituents are in the endo position. Preference of the endo position is also a facet of the suprafacial nature of the Diels-Alder reaction. The orbital overlap required for the reaction is greater when the dienophile lies directly underneath the diene.Īlkynes can also serve as dienophiles in Diels-Alder reactions: The endo position on a bicyclic structure refers to the position that is inside the concave shape of the larger (six-membered) ring. As you might predict, the exo position refers to the outside position.
The words endo and exo are used to indicate relative stereochemistry when referring to bicyclic structures like substituted norbornanes. The trans relationship of the cyano groups in the dienophile is preserved in the six-membered ring of the adduct.Īnother facet of the stereochemical retention of the dienophile is that only the endo product, rather than the alternative exo product, is formed. This stereospecificity also confirms the concerted nature of the Diels-Alder mechanism. The drawing below illustrates this fact for the reaction of 1,3-butadiene with (E)-dicyanoethene. The retention of stereochemistry is due to the planar nature of both reactants and that the forming process is suprafacial (i.e.
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