SUMMATIVE 1 A pericyclic reaction is a type of organic reaction in which the molecule produced has a cyclic geometric structure. There are no negative or positive charges on the intermediate formed as...

With examples describe how the Diels Alder reaction can be used to producestereoselective drugs.


SUMMATIVE 1 A pericyclic reaction is a type of organic reaction in which the molecule produced has a cyclic geometric structure. There are no negative or positive charges on the intermediate formed as electrons move round and are not permanently fixed in a certain place during the reaction. The reaction is concerted, meaning the bonds are formed and broken simultaneously. This simultaneous formation and breaking of bonds lead to a transition state which also has a cyclic geometrical structure. An example of this is a Diels alder reaction. It is a type of cycloaddition reaction. A cycloaddition rection is one of the three types of pericyclic reactions. The Diels alder reaction is a reaction in which a diene and dienophile react together to form a cyclohexane derivative as a product. It is a single step reaction which is accelerated using some catalysts or heating. But some types of Diels alders reactions can take place at room temperature. A diene is a compound that contains two double bonds which are usually carbon carbon double bonds. The diene may have substituted groups on them, they are most reactive when they have electron donating groups present. The diene can be open chained or cyclic but it must be able to adopt s-cis conformation. This is because s-trans conformation isomerism would prevent the double bonds of the dienes from getting close enough to react with the dienophile making them unreactive. ‘s’ isomerism is to do with stereochemistry about the single bond between the double bonds and not about the stereochemistry between either double bond. An example of such a compound would be 2,4 Hexadiene in both trans and cis isomerism. See below: A dienophile is usually an alkene. But usually, it is an alkene with some sort of functional group attached to it. The dienophile is most reactive when it has electron withdrawing groups substituted onto the dienophile. A dienophile may also have more than one carbon double bond present in the molecule, but it should not be conjugated as this will means it behaves as a diene. An example would be Norbornadiene which has two carbon double bonds but they are separated by 2 sigma bonds which prevents them behaving as a diene. A simple example of an alkene that could react with the hexadiene molecule shown above is propenal. Shown below: In a Diels alders reaction between a diene and dienophile, the diene has 2 carbon-carbon double bonds conjugated. And the dienophile will have one of its carbon-carbon double bonds also take part in this reaction. We have 3 pi bonds on the reactant side in total due to the 3 double bonds being present but after the reaction we end up with 1 new pi bond and 2 new sigma bonds formed, creating a six membered ring containing a single carbon carbon double bond. This type is called a [4+2] cycloaddition reaction because it involves two pi bonds form the diene providing 4 electrons and 2 electrons from the pi bond of the dienophile. Below is a diagram detailing the movement of electrons and bonds in this reaction to form the product. It involves a transition state where we can see the concerted nature of this reaction. In this transition state 6 delocalised Pi electrons are present. This state can be said to be aromatic. Once the double bond has joined to form the cyclic structure with the diene the remainder of the molecule becomes an attached group to the cyclic structure. Below is a visual example of the reaction between the diene s-cis-2,4 hexadiene and Propenal: The Diels alder reaction is said to be both regioselective abd stereoselective. This assignment will focus on the stereochemistry of the reaction. Any stereochemistry present in the dienophile is reproduced in the product. Below is an example taken from the textbook ‘Organic chemistry by Jonathan Clayden’ which clearly indicates the affect stereoisomerism can have on the product. The diene in this example is s-cis butadiene and the dienophile is a dimethyl maleate in the top row and a dimethyl fumarate in the bottom row. They are both stereoisomers of each other. The dimethyl maleate being a cis isomer and the dimethyl fumarate being a trans isomer. The products formed are both products exhibiting the same type of stereoisomerism as the dienophile in their respective reaction. The product formed by the s-cis isomer is called the syn product. And the product formed by the s-trans isomer is called the anti-product. The Diels alder reaction proceeds when there are favourable interactions between the HUMO and LUMO orbitals of the diene and dienophile. Whether the HUMO or LUMO of the diene or dienophile is used depends on the energy difference between the HUMOs and LUMOs. The closer in energy the HUMO and LUMO are the more stabilising and lower in energy the interaction is. The Diels alder reaction has the capability to further split the syn product into endo and exo products. When a diene reacts with the dienophile a bridge ring is formed between the interacting orbitals. If the substituent groups/or ring structure on the dienophile double bond are pointing towards the diene molecule then the resulting product will have the substituents pointing towards the double bond of the final product. This means it will be an endo product. If the dienophile double bond substituents/or ring structure are pointing away from the diene then the resulting product will have the substituents pointing away from the products double bond. This means this product will be called an exo product. An example of this is below and has been sourced from CHEGG study: The exo product is more thermodynamically stable than the endo product. This is because the endo product experiences steric hindrance because it is closer to the double bond of the final product. However, the endo product is kinetically favoured/forms faster because the orbitals of the substituents on the dienophile can interact with the dienes orbitals which lowers the energy of the transition state for the endo product. The exo product transition states have these same groups pointing away from the diene, so it does not experience these same stabilising interactions. This means the endo product is formed faster. Stereochemistry is especially important in drug synthesis and pharmacology. Drugs which have the same chemical connectivity of atoms, but they have differences in their stereochemistry although having the same chemical formula may display completely different pharmacology. Therefore, the responses they induce in a subject could be drastically different. Due to this during the drug preparation process careful consideration is given to the Stereochemistry of the drugs. In the pharmaceutical industry many chiral drugs are used. Chiral drugs are drugs with 2 enantiomers. These exists because if the way the atoms arrange themselves in space. These enantiomers will, because of there different stereochemistry, behave differently in biological systems due to these differences. For example, a drug might be targeting a specific receptor on a cell in the body. In order to bind with the active site, it needs a specific 3D structure. One of the enantiomers might be the correct fit but the other might not be.