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Going out in the sun can work wonders for your mood, but unfortunately too much UV exposure can do serious damage to your DNA. This damage occurs through a type of organic reaction called a pericyclic reaction. In this episode of Crash Course Organic Chemistry, we’ll explore pericyclic reactions to see how the sun can both give us life, and hurt us, and also look at other important pericyclic reactions, such as the Diels-Alder reaction.

Episode Sources:
Ohashi, M., Jamieson, C.S., Cai, Y. et al. An enzymatic Alder-ene reaction. Nature 586, 64–69 (2020).

Further Reading on Pericyclic Reactions and the Woodward-Hoffman Rules:
Fleming, I. (1977). Frontier orbitals and organic chemical reactions. Wiley.

Series Sources:
Brown, W. H., Iverson, B. L., Ansyln, E. V., Foote, C., Organic Chemistry; 8th ed.; Cengage Learning, Boston, 2018.
Bruice, P. Y., Organic Chemistry, 7th ed.; Pearson Education, Inc., United States, 2014.
Clayden, J., Greeves, N., Warren., S., Organic Chemistry, 2nd ed.; Oxford University Press, New York, 2012.
Jones Jr., M.; Fleming, S. A., Organic Chemistry, 5th ed.; W. W. Norton & Company, New York, 2014.
Klein., D., Organic Chemistry; 1st ed.; John Wiley & Sons, United States, 2012.
Louden M., Organic Chemistry; 5th ed.; Roberts and Company Publishers, Colorado, 2009.
McMurry, J., Organic Chemistry, 9th ed.; Cengage Learning, Boston, 2016.
Smith, J. G., Organic chemistry; 6th ed.; McGraw-Hill Education, New York, 2020.
Wade., L. G., Organic Chemistry; 8th ed.; Pearson Education, Inc., United States,

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 Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

 Going out on a sunny day can be a real mood booster. But those lovely rays of ultraviolet light can cause some potentially harmful reactions with our DNA. Of the four DNA bases, thymine and cytosine are classified as pyrimidines. When they're hit by UV light, the double bonds in two adjacent pyrimidines can react to form a ring structure. This is one type of pericyclic reaction! These now-covalently-bound bases – called pyrimidine dimers – can interfere with copying DNA and reading the encoded genetic messages, which can make things go pretty haywire. Sometimes even causing cancer. Because pyrimidine dimers are quite dangerous, but also very common, our bodies have developed ways to remove and replace the damaged section of DNA. (And we also use sunscreens to protect us from UV light!) So, in this episode we’ll explore pericyclic reactions – and how they relate to the Sun's dangers and life-giving properties.

 [Theme Music]

 There are quite a few pericyclic reactions across organic chemistry, where overlap of molecular orbitals causes single and double bonds to break and form simultaneously in a concerted reaction. There’s a cyclic transition state, but no distinct intermediates—it’s all one step! A super important one is the Diels-Alder reaction, where a conjugated compound with two adjacent double bonds reacts with an alkene. This transformation makes two carbon-carbon bonds at the same time and shows incredible stereoselectivity and regioselectivity. This reaction bears the names of its discoverers and is a tale of a joint Nobel Prize awarded in 1950.

 Otto Diels was a professor that cared deeply about research and teaching. You’d find him demonstrating experiments at the front of lecture halls packed with hundreds of students at Kiel University in Germany. Kurt Alder was a student of Diels and became a professor himself, after a stint in the rubber industry. He’s also got a moon crater named in his honor, and the insecticide aldrin, which is formed by a Diels-Alder reaction. In this reaction, our key players aren't just called "a conjugated compound with two adjacent double bonds" and "an alkene." They have special names. The first reactant is a diene, and the other is called the dienophile: the “lover of the diene.”

Like we just mentioned, this mechanism is concerted, and the bonds break and form at the same time. To show an arrow pushing mechanism for the Diels-Alder reaction, I like to draw dotted lines that connect each end of the conjugated system of our diene to each side of the pi bond in the dienophile.

 Now, we can add three arrows to show the pi electrons forming new sigma bonds and a rearranged pi bond. This helps me keep track of where to make the new bonds, even in more complex molecules like the insecticide aldrin. Again, we’re sacrificing two pi bonds to make two new sigma bonds. Now, even though we’ve been using arrow pushing to help visualize how electrons move and form bonds, really molecular orbitals are what combine during a chemical reaction. Last episode, we constructed the molecular orbitals of butadiene. And these orbitals can be used to represent the pi system of any conjugated diene! We can also construct the molecular orbitals of ethylene, which can be used to represent the pi system of any dienophile. Ethylene has two electrons in the pi system. Those electrons pair up in the lower energy molecular orbital, where we combine two p orbitals in phase. So, this is the highest occupied molecular orbital or HOMO. We can only construct one other molecular orbital by combining the two p orbitals out of phase. And this is the lowest unoccupied molecular orbital, or LUMO. That’s it!

 Now that we have the puzzle pieces, we can see how the molecular orbitals of a diene and dienophile interact during a chemical reaction. In any chemical reaction, the HOMO of one reactant combines with the empty molecular orbital of the other reactant that is closest in energy. So, usually, the HOMO of the diene reacts with the LUMO of the dienophile. To be able to form new bonds, these orbitals need to be in phase. Look here: one shaded lobe of the HOMO lines up with a shaded lobe of the LUMO, and on the other end, the unshaded orbitals align. And when orbitals approach from the same face, like in the Diels-Alder, we call this suprafacial. To be totally honest, the reaction of butadiene and ethylene to make cyclohexene is kind of terrible – it happens under extreme conditions and in low yield. The HOMO of butadiene and the LUMO of ethylene are a bit too far away in energy. So, to help most Diels-Alder reactions along, we’ll put electron donating groups on our diene, and electron withdrawing groups on our dienophile.

 (And for a refresher on how to recognize these groups, check out Episode 38.)

 Electron donating groups push electrons into the HOMO, raising its energy. So, putting these groups on the diene gets its HOMO closer to the energy of the dienophile’s LUMO. Electron withdrawing groups on the dienophile lower the energy of its LUMO, which brings it even closer to the energy of the diene’s HOMO. Let’s look at a specific example, with weakly electron donating methyl groups on our diene and electron withdrawing esters on our dienophile. With these groups, the HOMO of the diene is raised in energy, the LUMO of the dienophile is lowered, and the reaction occurs with gentle warming. No extreme conditions here!

 But we can't just stick electron donating groups anywhere and expect chemistry magic! For example, this placement of methyl groups on this diene creates steric hindrance, so it can’t adopt the reactive conformation, and the Diels-Alder reaction won’t happen. The reactive conformation with the double bonds ready to react is called s-cis, and the unreactive conformation is called s-trans. The "s" at the beginning of these terms is really important, so we don't confuse them with cis and trans bonding arrangements – which, for double bonds, we've also been calling Z and E respectively. Compounds like cyclopentadiene that lock the double bonds in the s-cis configuration react well. And because it’s a ring already, the product of this example reaction is this cool double-ring bicyclic structure!

Now that we know the basics of the Diels-Alder reaction, we can learn about its incredible stereoselectivity. First, we’ll focus on alkene dienophiles. If the groups are on “Z zame zide” in a Z-alkene, they end up cis on the cyclohexene ring. And if the groups are "E-cross" in an E-alkene, they end up trans on the ring. Alkynes can be dienophiles too! In these Diels-Alder reactions, the alkyne dienophile groups end up on a double bond and so they aren’t cis or trans.

 Let’s react an alkyne dienophile so we can look really carefully at where the groups on just our diene go. With our diene in the s-cis conformation, we can label its groups “out” and “in”, depending on where they're pointing. In the products, the “out” groups end up on the same side of the molecular plane, and the “in” groups on the same side – remember, look carefully at the solid or dashed triangles that represent these bonds. But sometimes, we’re not only focusing on dienes or dienophiles to figure out stereoselectivity. We may see situations where both the diene and dienophile have groups that wind up on chiral carbons in the product. With this Z-alkene dienophile, for example, we know our carboxylic acids will end up on the same side. And we know this diene has two “out” groups that will end up on the same side. But... what will the stereochemistry of the final molecule look like? The groups on the dienophile can have favorable interactions with the pi molecular orbitals on the diene. So, the dienophile approaches in this orientation, lining up the pi bonds in these carboxylic acid groups with the pi bonds of the diene. The bonds rearrange in our concerted Diels-Alder reaction.

And when we flatten out the molecule, we can see it’s this crowded product, with all groups on the same side of the molecular plane. This elbow-bumping molecule is called the endo product, and the other potential diastereomer, called the exo product, is disfavored. Bicyclic examples let us see the endo product pretty well. In this example, the ester points toward the more crowded side of the bicyclic ring in 3D space. And in our bicyclic insecticide aldrin, we see the carbon-chlorine bridge faces the more crowded side too!

That’s all we’ll cover for stereochemistry, even though there’s so much more to learn. If you’re curious, the stereochemistry of all pericyclic reactions can be described with the Woodward-Hoffman rules. A chain smoker with a propensity for blue neckties, Robert Burns Woodward won the Nobel Prize in 1965 for the synthesis of complex natural products. He collaborated with Roald Hoffmann, chemistry professor at Cornell University, to describe molecular orbital symmetry and predict the stereochemistry and regiochemistry of pericyclic reactions. And in 1981, Hoffman shared the Nobel Prize with Kenichi Fukui, the first Asian person to win the award in chemistry. Their understanding of the influence of molecular orbitals on chemical reactions was a huge contribution to the field!

 Now, we still have to talk about Diels-Alder reaction regiochemistry. If we have one group on each reactant, we need to know how to predict where they end up relative to each other in the products. The groups in the products are actually kind of similar to the ortho and para positions on a benzene ring. This is a cyclohexene – not a benzene – so this isn't official terminology, but it's a little trick that can help us remember where these groups end up. The position of these groups is actually dictated by the sizes of molecular orbitals, also called the orbital coefficients. We don’t have time for that deep of a dive in this episode, but we’ve put extra references in the video description.

 We've been talking about the Diels-Alder reaction this whole time, but it's just one example of a cycloaddition, a type of ring-forming reaction where two new bonds form simultaneously. Cycloadditions are classified by counting the number of carbons in the pi system in each reactant, so the Diels Alder is a [4+2] cycloaddition. The pyrimidine dimers we saw at the beginning of the episode are a [2+2] cycloaddition, and we can draw arrows for the mechanism like this.

But looking at the molecular orbitals… wait a second, the HOMO of one ethylene molecule doesn’t line up with the LUMO of the other! This isn't suprafacial like the Diels-Alder reaction, because one of the two pairs of orbitals don’t line up. In fact, the antarafacial, or opposite face, approach that would be required because of the not-in-phaseness won't let us form new bonds. The rigid double bonds don’t let our ethylene molecule reach the opposite face. So, what do we do? Don’t forget, we have another key ingredient: sunlight! Just like with UV/vis spectroscopy, the UV light excites an electron in one reactant to the next energy level, so it has a new HOMO! You can review this in episode 41.

 Let’s try lining up our orbitals for the [2+2] cycloaddition again. They're in phase and suprafacial now! So, with UV light, [2+2] cycloaddition can occur – so we say that the photo-chemical reaction is allowed. However, if we add a different special ingredient: heat, the reaction doesn’t happen. So, we say the thermal reaction is forbidden in the cycloaddition world.

 There are four major types of pericyclic reactions. And, besides the cycloaddition we just learned, two more happen thanks to the Sun interacting with our bodies. One of the many reasons we need sunlight to survive is because a pericyclic reaction occurs in our skin during the synthesis of Vitamin D3. In the first step, a pericyclic reaction called an electro-cyclic ring opening causes the bond in a cholesterol derivative to break. Then, without the help of sunlight (so no new HOMO is needed), we get another pericyclic reaction called a sigma-tropic rearrangement, where pi and sigma bonds both rearrange. In this reaction, a hydrogen atom also gets moved to another part of the chain. Just looking at these reactions, we can see that they're… complicated. And that's ok!

These two and the Alder-ene pericyclic reactions are taught in advanced organic chemistry courses. Even though this series is trying to cover the basics, there's always more chemistry (involving sunlight or not) to learn! In this episode, we saw: The Diels-Alder reaction is a [4+2] cycloaddition that gives very specific stereochemistry and regiochemistry because of molecular orbital interactions, Molecular orbitals need to be in phase to react, and Sunlight can cause damage to our DNA, but is also essential for other human biological processes – all because of pericyclic reactions.

 Next episode, we'll learn about the chemistry of carbon nucleophiles made from carbonyl compounds, as we begin to explore enols and enolates. Until then, thanks for watching this episode of Crash Course Organic Chemistry.

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