2. A triple Diels-Alder reaction followed by a triple retro Diels Alder reaction give this interesting product:

Transcription

1 Lecture 8 October 6, 2011 Last time we talked a lot about highly reactive dienes, especially those developed by the group of Sam Danishefsky. One more example of an interesting diene is isobenzofuran: Isobenzofuran by itself is not stable enough to be isolated, but various analogues of it are isolable. Isobenzofuran acts as a diene with the two bonds of the furan (five-membered ring) with typical dienophiles: Always remember that you form one more six membered ring in your product than what you started with. What is interesting about isobenzofuran is that it undergoes a retro-diels Alder reaction very easily to lose the oxygen and generate two aromatic rings. Retro-Diels Alder reaction just means a reaction in which a ring falls apart through the movement of six electrons simultaneously. So the net result of this type of reaction is that you have replaced a furan ring with an additional aromatic ring. Other dienes (especially those that contain heteroatoms) also undergo retro-diels Alder reactions to release stable molecules/ gases. A few examples are shown below: 1. The initial product of the hetero-diels-alder reaction decomposes to lose HCN gas and generate a highly substituted pyridine product: 2. A triple Diels-Alder reaction followed by a triple retro Diels Alder reaction give this interesting product: Researchers have used this reaction to synthesize polycyclic aromatic hydrocarbons (PAHs) in general, as you add benzene rings in a linear fashion, the resulting compounds become less and less stable:

2 Pentacene cannot be synthesized by itself, but you can add enough functional groups to stabilize it and synthesize it. Why do these molecules become less stable with more fused aromatic rings? The best way to think about this is to look at benzene vs. naphthalene. Benzene has six pi electrons for its single aromatic ring. Naphthalene has two aromatic rings, but only 10 pi electrons (rather than the twelve electrons that it would prefer). This means that naphthalene has less aromatic stability than two isolated benzene rings would have. The same argument applies as you keep increasing the number of aromatic rings the number of pi electrons does not increase in proportion to the number of aromatic rings, which results in decreased stability. Additionally, when you react these fused aromatic rings, they always react to generate the most benzene rings possible. For example anthracene will react at its center ring, which generates two isolated benzene rings in the product, rather than at the terminal ring (which generates a naphthalene ring system in the product). One example of how people can synthesize pentacene is from the Diels-Alder reaction of an isobenzofuran (diene) and anthraquinone (dienophile). The retrosynthesis is shown below: The way this actually worked in the forward direction is shown below: OK that will end our discussion of specific dienes, and we will move on to a discussion of dienophiles. First I will go through several common dienophiles and their nomenclature:

3 Most of these (except for acrylonitrile) have two electron withdrawing groups attached to the double bond, which enables these compounds to be highly reactive dienophiles. DMAD has a triple bond, which reacts exactly the same way as the double bonds do in the Diels-Alder reaction, however you end up with an additional double bond in your six-membered ring product: Cycloalkenones are in general not good dienophiles, because they only have one electron withdrawing group and no other driving force for reactivity: (1) Cyclobutenone - One new dienophile (developed just in 2010) was cyclobutenone: This cyclobutenone reacts very quickly with a variety of dienes, especially compared to the larger-ring analogues. The enhanced reactivity is probably due to ring strain making the double bond more reactive. Here is an example of a few Diels-Alder reactions with cyclobutenone: The real advantage to these products is that they can easily undergo a variety of ring-expansion reactions:

4 And the reason that nobody thought about using cyclobutenone as a dienophile before 2010 is that it is not so easy to synthesize. The synthetic route to cyclobutenone is shown below: (2) Other reactive dienophiles: Several other highly reactive dienophiles are part of hetero-diels alder reactions. So far we have mostly talked about diels-alder reactions involving six carbon atoms. However, you can replace one or more of those atoms with a heteroatom (nitrogen, oxygen, etc) to generate heterocycle compounds. These are called hetero-diels Alder reactions. The oxo-diels Alder reaction involves a carbonyl compound (where the oxygen itself is one of the six reacting atoms): The aza-diels Alder reaction involves a nitrogen atom in one or both of the reaction partners: The imine that is needed for the aza-diels Alder reaction is often generated in situ (during the reaction) from the reaction of an amine with formaldehyde: via the in situ generated imine:

5 Several common dienophiles used in hetero-diels alder reactions are shown below: Imines Diazo compounds: Your first test is a week from today. START STUDYING NOW.